Current Opinion in Rheumatology - September 2004, Volume 16, Issue 5

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Current Opinion in Rheumatology - September 2004, Volume 16, Issue 5

Issue Table of Contents

September 2004, Volume 16, Issue 5 Editorial introductions null Editorial introductions. Systemic Lupus erythematosus and Sjogren syndrome EDITORIAL OVERVIEW SLE and Sjogren syndrome in 2004. 497 Tsokos, George Systemic lupus erythematosus trials: successes and issues. 499 Ginzler, Ellen M; Moldovan, Ioana B cells in human and murine systemic lupus erythematosus. 505 Anolik, Jennifer; Sanz, Inaki Update on human systemic lupus erythematosus genetics. 513 Tsao, Betty P Apoptosis and estrogen deficiency in primary Sjogren syndrome. 522 Hayashi, Yoshio; Arakaki, Rieko; Ishimaru, Naozumi Cerebral inflammation and degeneration in systemic lupus erythematosus. 527 Trysberg, Estelle; Tarkowski, Andrej Antinuclear autoantibodies in systemic lupus erythematosus. 534 Sawalha, Amr H a; Harley, John B b,c,d Interferon-[alpha] in systemic lupus erythematosus. 541 Crow, Mary K; Kirou, Kyriakos A T lymphocytes in systemic lupus erythematosus: an update. 548 Kyttaris, Vasileios C; Tsokos, George C Pediatric and heritable disorders EDITORIAL OVERVIEW Pediatric rheumatology workforce: a status update. 553 Hirsch, Raphael Psychosocial aspects in pediatric rheumatology. 555 Kietz, Daniel Update on childhood vasculitides. 560 Ting, Tracy V; Hashkes, Philip J International research networks in pediatric rheumatology: the PRINTO perspective. 566 Ruperto, Nicolino; Martini, Alberto Current Opinion in Rheumatology - September 2004, Volume 16, Issue 5

Remittive agents in pediatric rheumatology. 571 Singer, Nora G; Scalzi, Lisabeth V Update on pediatric systemic lupus erythematosus. 577 Stichweh, Dorothee a,b; Arce, Edsel a,b; Pascual, Virginia a,b Genetics of juvenile idiopathic arthritis: an update. 588 Prahalad, Sampath Osteoarthritis EDITORIAL OVERVIEW Galectin-3 in osteoarthritis: when the fountain of youth doesn't deliver its promises. 595 Reboul, Pascal; Martel-Pelletier, Johanne; Pelletier, Jean-Pierre Mesenchymal stem cells in osteoarthritis. 599 Luyten, Frank P Neoantigens in osteoarthritic cartilage. 604 Kato, Tomohiro; Xiang, Yang; Nakamura, Hiroshi; Nishioka, Kusuki Angiogenesis in osteoarthritis and spondylosis: successful repair with undesirable outcomes. 609 Walsh, David A Signaling transduction: target in osteoarthritis. 616 Berenbaum, Francis mPGES-1 as a novel target for arthritis. 623 Fahmi, Hassan Pain and osteoarthritis: new drugs and mechanisms. 628 Hinz, Burkhard; Brune, Kay Sports and osteoarthritis. 634 Buckwalter, Joseph A; Martin, James A Current World Literature 640 Bibliography Current World Literature. List of journals scanned null List of journals scanned. Editorial introductions

Current Opinion in Rheumatology was launched in 1989. It tors of the Research Foundation of the American College is one of a successful series of review journals whose of Rheumatology. unique format is designed to provide a systematic and critical assessment of the literature as presented in the Raphael Hirsch, MD many primary journals. The field of rheumatology is divided into 15 sections that are reviewed once a year. Dr. Hirsch is the Aldo V. Lon- Each section is assigned a Section Editor,a leading dino Professor and Chief of the authority in the area,who identifies the most impor- Division of Pediatric Rheuma- tant topics at that time. Here we are pleased to intro- tology at Children’s Hospital of duce three of the Journal’s Section Editors for this Pittsburgh,University of Pitts- issue. burgh School of Medicine. Prior to July 2002,he was Professor of Pediatrics with tenure at Cincin- Section Editors nati Children’s Hospital Medical Center and the University of George Tsokos, MD Cincinnati College of Medicine and was on the faculty of the graduate program in De- Dr. Tsokos obtained his Medi- velopmental and Molecular Biology. There he held nu- cal Degree at the University of merous leadership responsibilities. He spearheaded the Athens,Greece,and finished his successful application for the Cincinnati Rheumatic Dis- training in Internal Medicine at eases Core Center (P30),funded in 2001,and served as the Veterans Administration Director of the Center until his departure. He also es- Hospital and Georgetown Uni- tablished and directed the Flow Cytometry Core at Cin- versity in Washington,D.C. Af- cinnati Children’s and established an interdisciplinary ter a fellowships in Immunology Gene Therapy Program. He was a member of the Ex- and Rheumatology at the Na- ecutive Committee of the NIH-funded Cincinnati Mul- tional Institutes of Health, tipurpose Arthritis and Musculoskeletal Diseases Center Bethesda,MD,he joined the (MAMDC) and the Cincinnati Pediatric Rheumatology staff of the Uniformed Services University in Bethesda Training Grant. He served on the Medical and Scientific where he is a Professor of Medicine and Cell/Molecular Committee of the Ohio Chapter of the Arthritis Foun- Biology,Director of the Immunology/Rheumatology Di- dation. He is board certified in Pediatrics and in Pediatric vision and Vice Chair of for Research Programs in the Rheumatology. Department of Medicine. He also serves as Chief of the Department of Cellular Injury at the Walter Reed Army Raphael Hirsch leads a federally funded research pro- Institute of Research. He studies immune cell signaling gram focused on arthritis. His areas of expertise include and gene transcription aberrations and mechanisms of gene transfer,gene expression in arthritis,modulation of tissue injury in SLE. His recent contributions indicate T cell immune responses,and therapy of autoimmune that SLE immune cells display unique biochemical and diseases. He has published over sixty articles in medical molecular aberrations that are responsible for increased journals. His research has been supported by the response to antigen/autoantigen on one hand and for fail- National Institutes of Health,the Arthritis Foundation, ure to produce sufficient amounts of interleukin-2 on the the American College of Rheumatology,and the Ohio other. He is involved in the editorial activities of several Cancer Research Associates. He holds two patents re- journals including Section Editor of the Journal of Im- lated to gene therapy and immunomodulation. He has munology and Associate Editor-in-Chief of Clinical Im- had continuous NIH funding since 1992. He has re- munology. Dr. Tsokos is President-elect of the Clinical ceived a number of awards for his research,including the Immunology Society and serves on the Board of Direc- American College of Rheumatology Senior Rheumatol- ogy Scholar Award (1990),the Arthritis Foundation, Johanne Martel-Pelletier, PhD Young Investigator Award (1992),and the American Col- lege of Rheumatology,Arthritis Investigator Award Professor Martel-Pelletier re- (1992). ceived her Ph.D. in Physiology from the University of Montreal He is a member of the American Academy of Pediatrics, (Montreal,Quebec,Canada) in the Society for Pediatric Research,the American Pedi- 1979. She completed her train- atric Society,the American Association of Im- ing in rheumatology at the Uni- munologists,the American College of Rheumatology, versity of Miami (Miami, and the American Society of Gene Therapy. He Florida,USA) in 1981 and was has served as a scientific consultant to Marion Merrell appointed Associate Professor of Dow,University of Minnesota,Schulman Associates, Medicine in 1989 and Full Pro- Schering-Plough,and Canji. Current and recent respon- fessor in 1995. She is Director of sibilities in national organizations include membership the Osteoarthritis Research Unit at the Notre-Dame on the Subboard of Rheumatology and the Credentials Hospital of the University of Montreal Hospital Center Committee of the American Board of Pediatrics,mem- (CHUM),which she co-founded in 1981. Her research bership on the American College of Rheumatology An- interests lie in understanding the mechanisms involved nual Meeting Planning Committee,Chairman of the Pe- in the pathophysiology of osteoarthritis,as well as in diatric Abstract Selection Committee of the American investigating and developing new therapeutic strategies College of Rheumatology 1996 Annual Meeting,and for the treatment of osteoarthritis. She is an active mem- member of the Arthritis Foundation Cellular Immunol- ber of several editorial boards and committees and is a ogy Study Section. He has served on numerous NIH highly respected reviewer for numerous rheumatology study sections and as a grant reviewer for the Lupus and connective tissue journals,and governmental and Foundation of America,the United States-Israel Bina- private research funding agencies. She is also member of tional Science Foundation,and the Veteran’s Adminis- several committees reviewing doctoral theses and pre- tration. He serves on the editorial board of Modern doctoral examinations. Rheumatology.

Dr. Hirsch has devoted a great deal of attention to Professor Martel-Pelletier was recipient of the Interna- the training of students and fellows in rheumatic disease tional League of Associations for Rheumatology (ILAR) research. Many of these have received national awards Prize (2001),the international Carol-Nachman Award for and grants,including the ACR Senior Scholar Award Rheumatology (1996) and the European League Against and Arthritis Foundation Physician Scientist De- Rheumatism (EULAR) Award (1991),all distinguished velopment Award (Michael Henrickson,M.D.),the scientific awards honoring her excellence in osteoarthri- ACR Medical Student Summer Research Fellow- tis research. She has authored over 210 publications in- ship (Catherine Hughes),and the Arthritis Founda- cluding journal articles and book chapters as well as over tion Post-doctoral Fellowship Award (Constance Cullen, 365 abstracts. Ph.D.). Most recently,his post-doctoral fellow, Sherry Thornton,Ph.D.,was awarded an NIH post- Jean-Pierre Pelletier, MD doctoral fellowship,and this year received an Arthritis Foundation Arthritis Investigator Award for junior Professor Pelletier obtained his faculty. Medical Degree at the Univer- sity of Montreal (Montreal,Que- Prior to his academic appointment in Cincinnati,he was bec,Canada) in 1974. Following a pediatric rheumatology fellow at the Children’s Hos- a fellowship in rheumatology,he pital National Medical Center,Washington,DC (1989- was appointed Associate Profes- 1991). From 1986 to 1991,he was a Medical Staff Fellow sor of Medicine in 1985 and Full at the National Cancer Institute,Bethesda,MD,where Professor in 1992. He heads the his research focused on modulation of T cell function in University of Montreal’s Arthri- transplantation and autoimmunity. From 1983 to 1986, tis Center and the Arthritis Di- he was a pediatric resident at the University of Min- vision at the Notre-Dame Hos- nesota and was Chief-Resident in Pediatrics. Raphael pital since 1985. He is co-founder and Director of the Hirsch earned his bachelor of arts degree at Northwest- Osteoarthritis Research Unit at the Notre-Dame Hospi- ern University and his medical degree at the University tal of the University of Montreal Hospital Center of Illinois College of Medicine. He is married with three (CHUM). In 1997,he was appointed Head of the Divi- children. sion of Rheumatology of the CHUM — an amalgamation of three major teaching hospitals. He was instrumental in Foundation of the CHUM (2001),International League the formation of the Osteoarthritis Research Society In- of Associations of Rheumatology (ILAR) Prize (2001), ternational (OARSI),served as President from 1996 to Distinguished Investigator Award from the Canadian 1998 and was later appointed Director of Society Devel- Rheumatology Association (2000),the international opment. He also served for eight years (1988-1996) as Carol-Nachman Award for Rheumatology (1996),and President of the Canadian Laurentian Conference of the European League Against Rheumatism (EULAR) Rheumatology. Award (1991). He is a world-renowned expert in the field of osteoarthritis research. The success of his work is also Professor Pelletier is the winner of the Award for Lead- illustrated by his numerous publications and guest ership and Distinction in the Medical Field from the speaker appearances. EDITORIAL OVERVIEW SLE and Sjo¨ gren syndrome in 2004 George Tsokos

Current Opinion in Rheumatology 2004, 16:497–498 either a population-based case-control study or a family- based transmission disequilibrium test. Candidate genes © 2004 Lippincott Williams & Wilkins 1040–8711 located within the most promising loci linked to SLE that have shown evidence for association with SLE are reviewed. PDCD1 has been identified as a single gene to contribute to multiple autoimmune diseases. The SLE- associated PDCD1 polymorphism disrupts a binding site Eight articles presented in this issue have attempted to of RUNX1 transcription factor, which may represent a capture recent progress in our understanding of autoim- common mechanism in susceptibility to other autoimmunity, organ damage, and treatment in two major hu- mune diseases. man autoimmune diseases: systemic lupus erythematosus (SLE) and Sjo¨gren syndrome. B cells are in the center of autoimmunity by presenting The first article discusses the nature of putative autoan- autoantigen to Tcells, producing autoantibody and cy- tigen in Sjo¨gren syndrome and mechanisms that contrib- tokines. The launching of therapeutic trials targeting B ute to its expression. A cleavage product of 120-kDa cells (anti-CD20 and anti-BLYS antibody treatments) ␣-fodrin was identified as an important organ-specific further signifies their importance and underlines the autoantigen in human Sjo¨gren syndrome. It appears that need to understand their biology in autoimmunity so that ␣-fodrin is cleaved by caspase 3, calpain, and granzyme new treatments can be better targeted. A large body of B. The generated peptide products may instigate auto- experimental and observational studies in both mice and reactive CD4+ cells and also interfere with the function humans indicates that B cells play complex and impor- of local cells. Treatment with caspase inhibitors appears tant roles in SLE. The evidence suggests that depending to correct sicca symptoms in animals. Estrogens appear to on genetic background and specific environmental in- suppress the activity of caspases and lack or inhibition of sults, the disease may be induced by a subversion of their action may promote ␣-fodrin cleavage. Through the B-cell tolerance that may be brought about by diverse action of metalloproteinases, Fas is cleaved off the sur- mechanisms operating at different censor points. Intrin- face of cells and as result increased amounts of soluble sic B-cell abnormalities and extrinsic influences medi- Fas are present. Soluble Fas inhibits activation-induced ated by other adaptive and innate immune cells (Tcells cell death of CD4+ autoreactive cells that infiltrate and and dendritic cells) possibly triggered by infectious destroy lacrimal glands. The dichotomy between in- agents are likely to be required for full clinical expression creased intracellular increased apoptotic activity that of the disease. The discovery that Toll-like receptors leads to increased autoantigen production and the de- contribute to breaking B-cell tolerance has significant creased death rate of activated Tcells needs to be re- implications in the development of novel treatments, ie, solved. decoy toll-like receptors. On the basis of great strides made recently in the phenotypic and genetic character- Multiple susceptibility genes clearly contribute to the ization of B cells, the study of B-cell populations holds development of SLE. Linkage analyses in SLE have great promise for our understanding of SLE. The iden- identified several susceptibility loci that display strong tification of B-cell subsets such as the VH4.34 that enter linkage and have been confirmed or supported in several inappropriately germinal centers in SLE patients may independent studies. Linkage analysis conditioned on lead to the development of biologics directed against pedigrees in which one family member with SLE exhib- them or limiting their presence in germinal centers. its a particular clinical manifestation has revealed associations of certain loci with distinct clinical manifesta- The production of autoantibodies against nuclear anti- tions. This approach appears to be rewarding and should gens is the hallmark of SLE. Among the large number of obviously be confirmed. autoantibodies known, only a limited number appear to Methods to reduce sufficiently the number of candidate be clinically important. Recent advances include the genes in identified loci have been developed. One of clear demonstration of autoantibody transport into living them is based on linkage disequilibrium mapping using cells, a process that clearly includes interactions with a 497 498 Systemic lupus erythematosus and Sjo¨ gren syndrome number of cellular components that may play a role in Characterization of the molecular biology of each gene cellular dysfunction and disease. Also, the anti-Sm B/BЈ will definitely enhance our understanding of T-cell bi- response originates from a single antigenic epitope that ology. This line of research aims at two things: the study appears to be the same structure in different patients, of molecular markers that may, first, help identify sub- before spreading to other epitopes and becoming the groups of patients that are clinically homogeneous and, typically mature, complex humoral autoimmune anti-Sm second, identify molecular targets for novel treatments. autoantibody response. An important contribution has been the demonstration that autoantibodies are present As many as one in eight patients with SLE develops in the sera of patients with SLE several years prior to the serious central nervous system involvement and three or clinical expression and diagnosis of the disease. The mo- four in 10 develop neuropsychiatric manifestations. Ef- lecular mimicry between Sm antigen and Epstein Barr forts have been made to classify these manifestations and virus (EBV)-defined antigens, along with the demon- proper diagnostic approaches are considered. It has been strated inability of SLE Tcells to control EBV infection, understood that organ damage in SLE may be dissoci- provides support for a role of EBV infection in the ex- ated from autoimmunity. The processes involved in cen- pression of the disease. tral nervous system organ damage are discussed. In- creased levels of interleukin-6 may affect neuronal and astroglial cell function. Metalloproteinases are present in Studies over the past few years have helped us under- the cerebrospinal fluid, as are products indicating neu- stand the functional aberrations of Tcells in patients ronal damage such as astroglial fibrillary acidic protein. with lupus. The T cell in SLE shows a phenotype of Antibodies cross-reacting with neurotransmitting recep- hyperexcitability with increased calcium and protein ty- tors may enhance neuronal cell death. rosine phosphorylation responses. The described rewiring of the T-cell receptor whereby the missing ␨ chain is Important developments have occurred in the past two replaced by the FcR␥ chain and the aggregation of lipid years in the development and testing of novel agents for rafts on the surface membrane help explain the de- the treatment of SLE as interest in this area has in- scribed overexcitable phenotype. Additional studies creased, largely because of the participation of industry. have characterized the molecular reasons for the de- Several important large-scale, multicenter, randomized creased expression of interleukin-2. A new possibility controlled trials have been completed, but none has yet for exploring the therapeutic value of COX-2 inhibitors resulted in a new approved indication for SLE. The ma- has been introduced as it was shown that upregula- jority of published reports include either small numbers tion of COX-2 may interfere with the death of acti- of patients in controlled trials, which lack statistical vated/autoreactive Tcells. Therecent report that SLE power to draw conclusions, or are uncontrolled anecdotal sera have increased levels of interferon-␣ that may en- series or individual case reports. Besides developing and hance antigen presentation is also discussed. It appears testing new biologics in treatment of SLE, important that SLE lymphocytes express an array of genes that are studies have addressed the clinical value of mycopheno- associated with the presence of interferon. This is known late mofetil either in the induction or consolidation as the “interferon signature.” phase of the treatment of lupus nephritis. Systemic lupus erythematosus trials: successes and issues Ellen M. Ginzler and Ioana Moldovan

Purpose of review IV intravenous LN lupus nephritis The purpose of this review is to discuss the most recent MMF mycophenolate mofetil published clinical trials for systemic lupus erythematosus and SLE systemic lupus erythematosus to identify important issues that have arisen in association with © 2004 Lippincott Williams & Wilkins the search for new therapies for systemic lupus 1040–8711 erythematosus, as well as new regimens or indications for the use of “standard-of-care” agents such as corticosteroids and Introduction cyclophosphamide. Clinicians interested in new developments in the chal- Recent findings lenging treatment of systemic lupus erythematosus Important developments have occurred during the past 2 years (SLE) should find this review useful. SLE is a complex as interest in this area has increased, largely because of the disease, and investigators designing clinical trials are participation of pharmaceutical and biotechnical companies in faced with an array of manifestations and difficult-to- the development and testing of novel agents for systemic measure response to treatment. Ideally, the protocols for lupus erythematosus. Several important large-scale, clinical trials and ultimate therapeutic decisions should multicenter, randomized controlled trials have been completed, be guided by evidence-based medicine, considering the but none has yet resulted in a new, approved indication for pathophysiologic mechanisms and epidemiologic prin- systemic lupus erythematosus. Many issues in the ciples that influence the clinical course. Few large-scale, identification of new therapeutic modalities remain. These prospective, randomized studies have been published, include the fact that a majority of published reports include most of them addressing lupus nephritis as the disease either small numbers of patients in controlled trials that lack manifestation, with better defined end points such as statistical power to draw conclusions, or are uncontrolled changes in serum creatinine, urine protein excretion, de- anecdotal series or individual case reports. Among the larger velopment of end-stage renal disease, and death. Our controlled trials, a pervasive issue in the failure to reach goal is to provide a comprehensive review of the clinical statistical significance may be the initial study design. Inclusion trials and relevant case series in SLE published during of patients with mild and/or stable disease activity does not the past 2 years, outlining the important developments and allow for an effect size sufficient to show differences in reinforcing some of the most significant issues that arise. treatment arms without recruitment of very large numbers of Hormonal considerations subjects. Finally, several potentially important trials have been Although the etiology and pathogenesis of SLE are not reported only in abstract form to date. Further assessment of yet completely understood, experimental data and the the results must await formal publication of these studies. high prevalence of disease in women after puberty suggest that anomalies of both estrogen and androgen me- Keywords tabolism may play a role in disease development. clinical trials, systemic lupus erythematosus, lupus nephritis, immunosuppressive drugs, biologics Data from the SELENA trial by Buyon et al. (Buyon et al., paper presented at the annual meeting of the Ameri-

Curr Opin Rheumatol 16:499–504. © 2004 Lippincott Williams & Wilkins. can College of Rheumatology, 2003) examined the question of whether hormone replacement therapy (HRT) in the form of conjugated estrogen and medroxyprogester- SUNY Downstate Medical Center, Rheumatology Division, Brooklyn, one increases the flare rate in postmenopausal women New York, USA with lupus. A total of 351 menopausal women with in- Correspondence to Ellen M. Ginzler, MD, SUNY Downstate Medical Center, active or stable/active SLE were randomized to HRT or Rheumatology Division, 450 Clarkson Ave, Brooklyn, NY 11203, USA Tel: 718 270 1662; fax: 718 270 1562; placebo and were followed for 12 months. Patients with e-mail: [email protected] a history of thrombosis or moderate/high titer of anti- Current Opinion in Rheumatology 2004, 16:499–504 phospholipid antibodies were excluded. The primary end point, severe flare, was rare and not statistically sig- Abbreviations nificant between groups. Stable/active patients were AZA azathioprine CYC cyclophosphamide more prone to develop flares compared with those with HRT hormone replacement therapy inactive disease. In contrast to severe flares, mild/mod- 499 500 Systemic lupus erythematosus and Sjögren syndrome erate flares were significantly increased in the HRT arm. and lymphoproliferative malignancies, has led to an at- Adverse events included one death (HRT arm), three tempt to minimize the exposure to this agent for both deep vein thromboses (two in the HRT arm), one stroke induction and maintenance of remission. Several studies (HRT arm), and one case of thrombosis in an arteriove- examining the efficacy and toxicity of various CYC regi- nous graft (HRT arm). The results suggest that exog- mens in SLE were published during the past 2 years. Of enous estrogen can increase disease activity, but the ef- considerable interest was the Euro-Lupus Nephritis fect is only recognized in mild/moderate flares. Trial by Houssiau et al. [4], in which 90 patients with class IV LN were assigned by the method of minimiza- In 1994, Genelabs Technologies began the first of a se- tion to receive either high-dose (six monthly pulses fol- ries of clinical trials designed and sponsored by industry lowed by two quarterly pulses) or low-dose (500 mg bi- to find new therapies for SLE. Two recent articles de- weekly × six pulses) intravenous IV) CYC induction scribe the experience with prasterone (dehydroepi- followed by azathioprine (AZA) maintenance in a dose of androsterone), a weak androgenic steroid. Petri et al. [1] 1 mg/kg/day. Renal remission was achieved in 71% of the enrolled 191 women who had received at least 12 months low-dose group and in 54% of the high-dose group, with of prednisone 10 to 30 mg/day in a randomized, blinded subsequent renal flares occurring in 27% and 29% re- trial of prasterone 100 mg or 200 mg, or placebo. The spectively. Severe infections were twice as frequent in goal was to achieve a sustained decrease in prednisone the high-dose group. None of the differences between Յ dose to 7.5 mg/day over 7 months. The proportion of groups reached statistical significance. Low-dose IV responders was highest in the 200-mg prasterone group CYC followed by maintenance AZA may be a less toxic (55%) and was lowest in the placebo group, but the re- and equally effective alternative to standard IV CYC sults did not reach statistical significance. A secondary therapy for class IV LN. analysis in the active SLE subset did show a difference in steroid sparing. Acne was the most common side ef- Despite its acceptance as the standard of care for treat- fect. ment of severe LN, a significant proportion of patients fail to achieve a remission with CYC, or experience a In another randomized, blinded trial, Chang et al. [2] relapse of active nephritis during maintenance therapy studied 120 women with SLE who received prasterone [5]. It has been suggested by some but not all investiga- 200 mg/day or placebo for 24 weeks. The primary end tors that children may have a poorer response to CYC point was change in SLAM score; no significant differ- than adults [6–8]. In a number of reports, the lack of ence was observed between treatment arms. This was efficacy of CYC appeared to be related to racial, ethnic, attributed to the short duration of the study and the or socioeconomic factors. Dooley et al. [9] observed that small sample size. Significant differences were seen in nonblack patients with class IV LN retained a stable the number of flares and patient visual analog scale renal survival rate of 95% through 5 years of follow-up, scores. whereas black patients had a progressive decline in renal Immunosuppressive therapies survival to 71% at year 5. Two recent reports suggest that Prednisone, the oldest marketed immunosuppressive the outcome of IV CYC therapy in a Jamaican SLE co- drug approved for the treatment of SLE, continues to hort of African descent and a Chilean SLE population receive attention from investigators. In a prospective, may be poorer than that seen in controlled clinical trials. multicenter study by Tseng et al. [3•] moderate-dose The high frequency and severity of renal insufficiency at corticosteroids were administered to prevent severe SLE onset of therapy, as well as socioeconomic factors, may flares. Of 180 patients with inactive or stable/active dis- explain these differences [10,11]. In a novel examination ease, 41 had a serologic flare (elevation in C3a, increased of outcome in 128 patients with proliferative LN at Co- anti-dsDNA) and were randomized to receive either lumbia Presbyterian Medical Center, Barr et al. [12•] prednisone 30 mg/day tapered over 4 weeks or placebo. found that poverty, defined as residence in a poor neigh- Patients in the placebo group had an average of six se- borhood, was associated with doubling of serum creati- vere flares during a 12- to 18-month follow-up compared nine after adjustment for age, gender, hypertension, with none in the prednisone group. The authors con- CYC therapy, and race/ethnicity (RR = 3.5, P = 0.03). cluded that elevations in C3a and anti-dsDNA predict The influence of Hispanic ethnicity was retained after flares, and short-term, moderate doses of prednisone pre- adjustment for poverty and insurance status, whereas the vent severe flares and thus exposure to high-dose ste- effect of African-American race was not. These reports roids. point out the necessity to consider the racial/ethnic and socioeconomic balance of lupus cohorts when recruiting Cyclophosphamide (CYC) has been generally accepted patients for clinical trials. as the standard of care for treatment of severe lupus nephritis (LN) and other life-threatening manifestations Both the imperfect efficacy and toxicity of CYC have led of SLE. Both short- and long-term toxicity of CYC, es- investigators to search for alternative therapies for severe pecially the risk for infection, premature gonadal failure, manifestations of SLE, particularly LN. Mycophenolate SLE trials Ginzler and Moldovan 501 mofetil (MMR; CellCept) has received considerable at- Biologics tention regarding its use in both anecdotal series and Loss of B-cell tolerance is a key feature of SLE. Re- controlled clinical trials. MMF is a reversible inhibitor of cently, rituximab(Rituxan), a chimeric monoclonal anti- inosine monophosphate dehydrogenase, the rate- body directed against the CD20 receptor present on B limiting enzyme in purine synthesis, and is approved for lymphocytes, has received considerable attention from the prevention of allograft rejection. It has a selective researchers and clinicians. A number of studies were effect on lymphocytes, thereby decreasing the potential published during the past 2 years, most of them case for hematologic toxicity. A number of case reports and reports of therapeutic success for lupus manifestations uncontrolled series have described the experience with including central nervous system, renal, vasculitic, and MMF in SLE, usually in patients unresponsive to ste- hematologic features [23–26,27•] (Yamazaki et al., Paper roids and CYC, or with unacceptable toxicity [13,14,15•– presented in abstract form at the American Society of 17•,18]. Hematology, 2002). Three other studies, none controlled or blinded, included a larger number of patients and longer follow-up. In an open-label protocol, Leandro et In 2000, Chan et al. [19] showed the potential benefits of al. [28,29] described six female patients with active SLE using MMF in a randomized, controlled, open-label who received two weekly doses of 500 mg rituximaband study comparing this agent with oral CYC in 42 patients 750 mg IV CYC plus high-dose oral prednisone. At 6 to with class IV LN. The efficacy of MMF and CYC were 18 months of follow-up, five patients remained in the found to be equivalent, with similar toxicity, in this study and experienced clinical and laboratory improve- 1-year study at a single center. In another single-center, ment. No major side effects were observed. randomized, open-label trial of 46 patients with class IV LN treated for 6 months, Hu et al. [20] found that MMF Albert et al. (Albert et al., Paper presented at the annual was more effective in controlling clinical activity than IV meeting of the American College of Rheumatology, CYC. In a multicenter, randomized, open-label study by 2003) treated nine patients with active persistent SLE Ginzler et al. [21••], 140 patients were randomized to with visceral involvement not adequately controlled by either MMF or IV CYC for induction therapy of LN. at least one immunosuppressive agent, with four weekly Complete remission was observed in 16 patients (23%) infusions of rituximab. Six of the patients demonstrated on MMF compared with four patients (6%) on IV CYC. clinical improvement in SLEDAI score; half had disease Twenty-one patients on MMF versus 17 on IV CYC had remission at 6 to 9 months. There were no serious infu- a partial remission (combined end point, 37 patients on sion-related events. Two patients developed human an- MMF vs 21 patients on IV CYC, P = 0.009). Three tichimeric antibodies. The largest rituximab series was deaths occurred, all in patients randomized to IV CYC. reported by Anolik et al. [30]. Of 19 patients enrolled, 16 There was a trend toward more serious infections in the finished the protocol. Patients received either one infu- IV CYC group. Gastrointestinal side effects, particularly sion of 100 mg/m2 rituximab, one infusion of 375 mg/m2, nausea/vomiting and diarrhea, were common with MMF, or four weekly 375-mg/m2 doses. Among the patients but the episodes were generally self-limited, whereas who finished the study, 10 achieved full lymphocyte B vomiting and dehydration from IV CYC required hospi- depletion and had significant improvement in disease talization and drug discontinuation in some patients. activity scores. One patient with class IV LN achieved The authors concluded that the superior tolerability of resolution of proteinuria over 1 year, and renal biopsy MMF with at least equivalent efficacy justifies its con- showed complete resolution of previous proliferative sideration as an alternative to IV CYC as a standard-of- changes. care induction regimen for LN. Abetimus sodium (LJP 394, Riquent) was specifically In a randomized, open-label study, Contreras et al. [22••] designed to decrease severity and number of renal flares compared the efficacy of MMF, AZA, and IV CYC as a in SLE by selectively reducing antibodies to dsDNA and maintenance regimen in 59 patients with proliferative their parent B cells via antigen-specific tolerance. A LN induced with IV CYC and followed for as long as 30 large, randomized, controlled study by Alarcon–Segovia months. The primary end points were patient and renal et al. [31••] enrolled 230 patients who received either survival. During maintenance therapy, five patients died LJP 394 or placebo. Treatment duration was 76 weeks. (four on CYC and one on MMF) and five developed The time to renal flare and the number of renal flares chronic renal failure (three on IV CYC, one on MMF, was not significantly different in the two groups, and the and one on AZA). Event-free survival at 72 months was trial was discontinued prematurely. As expected, anti- higher with MMF or AZA. Relapse-free survival was dsDNA levels decreased significantly more in treated higher with MMF compared with IV CYC. Hospitaliza- patients, and C3 levels increased. Subgroup analysis in tion, amenorrhea, infections, and gastrointestinal side ef- only those patients with high-affinity antibodies to LJP fects were significantly lower in the MMF and AZA 394 revealed a longer time to renal flare, fewer flares, and groups. fewer subsequent courses of IV CYC in the treated group 502 Systemic lupus erythematosus and Sjögren syndrome versus the placebo group. LJP 394 was well tolerated; the Another interesting approach is via inhibition of T cells. rate of adverse events and mortality were similar to pla- Cytotoxic T-lymphocyte antigen 4 (CD152), a molecule cebo. Health-related quality of life was also significantly with an inhibitory effect on T-cell activation, and CD137 improved in the LJP 394 group [32]. The authors sug- costimulatory T-cell receptor inhibition have been re- gested that the failure to reach the primary study end cently studied in animal models as potential therapeutic point might be explained by inadequate drug doses, es- targets [34,35]. Clinical trials in lupus patients are pecially in the subset with low-affinity antibodies to LJP awaited to assess the efficacy of these agents. 394. It is also possible that the inclusion criteria allowed enrollment of patients with an inadequate level of dis- Immunoablation The long-term follow-up (mean, 10.7 years) to a case ease activity to show a treatment effect. series using total lymphoid irradiation in 21 patients with refractory diffuse membranoproliferative LN was re- LymphoStat-B, a fully human monoclonal antibody, in- ported by Genovese et al. [36]. Survival was not im- hibits soluble B-lymphocyte stimulator and has been proved compared with that with immunosuppressive shown to increase survival in murine models of SLE. regimens, with 15 patients surviving, nine without Results from a phase I single- and double-dose escalation ESRD. Additional immunosuppressive therapy was study in SLE patients were reported by Furie et al. [33]. required in five of the survivors. Serious morbidity in- Fifty-seven patients with stable disease at study entry cluded infections (majority herpes zoster) and malig- were enrolled and followed for 84 to 105 days. There was nancy (two lymphoma, thyroid carcinoma, cervical carci- a significant reduction of peripheral B cells but no noma). change in SLE activity during this short exposure. No increase in incidence of adverse events was observed. A Immune ablation with high-dose immunosuppression phase II multicenter study is currently in progress. followed by rescue with autologous hematopoietic stem

Table 1. Recent controlled trials and case series

Sample Authors size Methodology Key findings

Buyon et al. (see in text 351 Double-blind, placebo- Results suggest that exogenous estrogen can increase disease activity, but the reference) controlled study effect is only recognized in mild/moderate flares. These data suggest that female hormones may play a role in pathogenesis of SLE. Tseng et al. [3] 180 Double-blind, placebo- This study suggests that elevation in C3a and dsDNA predict flares, and controlled study short-term, moderate doses of PDN prevent severe flares and exposure to high-dose steroids. Kapitsinou et al. [15•] 18 Retrospective study The conclusion of this study is that MMF appears to be a safe and efficacious alternative treatment in proliferative SLE nephritis, whereas its efficacy in lupus membranous nephropathy remains unclear. Riskalla et al. [16] 54 Retrospective study In this study the majority of patients tolerated MMF in a range of doses and showed clinical improvement, suggesting that flexible dose scheduling should be considered when using MMF in patients with SLE. Doria et al. [17•] 42 Prospective In this study MMF seems to be well tolerated and effective in patients with uncontrolled study refractory disease and no different from standard therapy in maintaining GN remission over 9 months of follow-up. Ginzler et al. [21••] 140 Prospective, The conclusion of this trial was that MMF is better tolerated than IV CYC, with multicentric, fewer pyogenic or other serious infections; GI side effects did not limit the controlled study tolerability of MMF. Contreras et al. [22••] 59 Prospective, controlled The conclusion of this study was that for patients with proliferative lupus study nephritis, short-term therapy with IV CYC followed by maintenance therapy with MMF or azathioprine appeared to be more efficacious and safer than long-term therapy with IV CYC. Alarcon-Segovia et al. 230 Randomized, placebo- LJP appeared to be well tolerated; the rate of adverse events was similar to [31••] controlled trial placebo. One patient died in each group. In patients with creatinine more than 1.5 mg/dL, the placebo group had a higher percentage of flares. Higher doses of drug had a better response. Lisukov et al. [38•] 6 Case series This case series concludes that high-dose immunosuppression with autologous stem cell transplantation achieves prolonged, corticosteroid-free remissions, and that a more judicious selection of patients with less severe disease but with a high risk of relapse or further progression will diminish tansplant-related mortality. Petri et al. [40•] 14 Prospective, The conclusion was that cyclophosphamide without stem cell transplantation uncontrolled study led to rapid hematopoietic reconstitution and has significant clinical benefit in patients with refractory disease. Karassa et al. [43] Meta-analysis The conclusion of this meta-analysis is that several aspects of the design and reporting of RCT on SLE can be improved, with larger, adequately powered and accurately reported trials needed. CYC, cyclophosphamide; GI, gastrointestinal; GN, glomerulonephritis; IV, intranvenous; MMF, mycophenolate mofetil; PDN, prednisone; RCT, randomized controlled trial; SLE, systemic lupus erythematosus. SLE trials Ginzler and Moldovan 503 cell transplantation has been proposed as a mechanism to tions, and the absence of contemporaneous controls have reverse the immune dysfunction in SLE. Traynor et al. made these reports difficult to interpret when seeking [37] reported a long-term follow-up with this regimen in prospective evidence-based data. The randomized clini- 17 patients refractory to conventional therapies. Two pa- cal trials that have been reported have frequently been tients died, one of fungal sepsis before stem cell replace- limited by small sample size, lack of allocation conceal- ment and one of central nervous system disease 4 ment, and short-duration protocols [40••]. Fortunately, months after hematopoietic stem cell transplantation. the past few years have begun a period of more rigorous The median follow-up in 15 survivors was 36 months, study of potential new therapies. This review identifies with all having a gradual but marked improvement in the recent controlled studies that have suggested effi- serologic and clinical manifestations. At the last follow- cacy and an improved toxicity profile for some commer- up only two patients required steroids. Two patients re- cially available agents such as MMF, and others which lapsed at 30 and 40 months and were treated with IV will seek an indication for treatment of some aspects of CYC. In another series, the results have been less prom- SLE, such as LJP 394. As new agents are tested, it is ising. Lisukov et al. [38•] described six patients with essential that protocols are carefully designed, consider- severe refractory disease treated with hematopoietic ing adequate sample size, randomization and blinding stem cell transplantation, three of whom died within 2 procedures, inclusion and exclusion criteria, and months of transplant-related complications. racial/ethnic and socioeconomic heterogeneity of subjects. Promising results in animal models and anecdotal Because high-dose immunosuppression with CYC is not series must be confirmed with randomized clinical trials myeloablative, it may be possible to avoid reinfusing au- of adequate duration to identify durable efficacy of pro- toreactive effector cells. Preliminary results comparing posed new agents. very high dose (50 mg/kg for 4 days) IV CYC with monthly IV CYC 750 mg/m2 in 51 patients were recently References and recommended reading reported by Bronson et al. [41], suggesting a superior Papers of particular interest, published within the annual period of review, health status at 6 months in the high-dose group as mea- are highlighted as: sured by SF-36. In an uncontrolled series of 14 patients • Of special interest treated with high-dose CYC, the same investigators re- •• Of outstanding interest ported five 5 durable, complete responses with a signifi- 1 Petri M, Lahita RG, van Vollenhoven RF, et al.: Effects of prasterone on corticosteroid requirements of women with systemic lupus erythematosus. Ar- cant improvement in steroid dose and SLEDAI score thritis Rheum 2002, 46:1820–1829.

[39•]. There were no deaths or fungal infections. 2 Chang DM, Lan JL, Lin HY, et al.: Dehydroepiandrosterone treatment of women with mild-to-moderate systemic lupus erythematosus. Arthritis Rheum Nonpharmacologic therapies 2002, 46:2924–2927. A different approach to the treatment of lupus includes 3 Tseng C, Buyon J, Belmont HM, et al.: Moderate dose steroids prevent severe • flares of serologically active, clinically stable SLE patients. Arthritis Rheum nonpharmacologic therapies, reported in two recent large 2003, 48:S260. studies. Edworthy et al. [42] proposed group psycho- In stable patients with SLE, changes in C3a and anti-dsDNA levels are predictive of clinical flares, which can be suppressed with moderate-dose steroids. therapy to reduce illness intrusiveness in SLE. A total of 124 women at nine centers were randomly assigned to 4 Houssiau FA, Vasconcelos C, D’Cruz D, et al.: Immunosuppressive therapy in lupus nephritis. The Euro-Lupus Nephritis Trial, a randomized trial of low-dose receive either standard care or 12-week brief supportive- versus high-dose intravenous cyclophosphamide. Arthritis Rheum 2002, expressive group psychotherapy followed by three 46:2121–2131. monthly booster sessions. Analysis of covariance, control- 5 Illei GG, Takada K, Parkin D, et al.: Renal flares are common in patients with severe proliferative lupus nephritis treated with immunosuppressive therapy: ling for disease activity and household income, indicated long-term followup of a cohort of 145 patients participating in randomized significant improvement in relationships and personal controlled studies. Arthritis Rheum 2002, 46:995–1002. development and intimacy at 6 and 12 months of follow- 6 Al Salloum AA: Cyclophosphamide therapy for lupus nephritis: poor renal up. Tench et al. [43] reported the results of a randomized, survival in Arab children. Pediatr Nephrol 2003, 18:357–361. controlled trial of exercise to improve fatigue in 93 SLE 7 Lehman TJ, Edelheit BS, Onel KB: Combined intravenous methotrexate and cyclophosphamide for refractory childhood lupus nephritis. Ann Rheum Dis patients without major organ involvement. Subjects were 2004, 63:321–323. assigned to one of three groups receiving either exercise 8 Barbano G, Gusmano R, Damasio B, et al.: Childhood-onset lupus nephritis: therapy, relaxation, or no intervention. At 12 weeks, fa- a single-center experience of pulse intravenous cyclophosphamide therapy. J tigue significantly improved in the exercise group; how- Nephrol 2002, 15:123–129. ever, this was not sustained 3 months later, except in 9 Dooley MA, Hogan S, Jennette C, et al.: Cyclophosphamide therapy for lupus nephritis: poor renal survival in black Americans. Kidney Int 1997, 51:1188– patients who continued to exercise. 1195.

10 Williams W, Bhagwandass A, Sargeant LA, et al.: Severity of systemic lupus Conclusion erythematosus with diffuse proliferative glomerulonephritis and the ineffec- For many years the assessment of new therapies for SLE tiveness of standard pulse intravenous cyclophosphamide therapy in Jamai- can patients. Lupus 2003, 12:640–645. has been based on case reports, anecdotal retrospective 11 Velasquez X, Verdejo U, Massardo L, et al.: Outcome of Chilean patients with series, and small, single-center clinical trials. Patient se- lupus nephritis and response to intravenous cyclophosphamide. J Clin Rheu- lection biases, lack of heterogeneity of patient popula- matol 2003, 9:7–14. 504 Systemic lupus erythematosus and Sjögren syndrome

12 Barr RG, Seliger S, Appel GB, et al.: Prognosis in proliferative lupus nephritis: 27 Eisenberg R: Rituximab in lupus. Arthritis Res Ther 2003, 5:157–159. • the role of socio-economic status and race/ethnicity. Nephrol Dial Transplant • This review outlines the pathophysiologic basis for which rituximab has been 2003, 18:2039–2046. used in the treatment of SLE. This retrospective review of a large series of patients with proliferative lupus ne- 28 Leandro MJ, Edwards JE, Cambridge G, et al.: An open study of B lymphocyte phritis points out the important association of poverty with poor outcome. depletion in systemic lupus erythematosus. Arthritis Rheum 2002, 46:2673– 13 Alba P, Karim MY, Hunt BJ: Mycophenolate mofetil as a treatment for auto- 2677. immune hemolytic anemia in patients with systemic lupus erythematosus and 29 Leandro MJ, Ehrenstein MR, Edwards JCW, et al.: Treatment of refractory antiphospholipid syndrome. Lupus 2003, 12:633–635. lupus nephritis with B lymphocyte depletion. Arthritis Rheum 2003, 48:S378. 14 Samad AS, Lindsley CB: Treatment of pulmonary hemorrhage in childhood 30 Anolik JH, Campbell D, Felgar R, et al.: B lymphocyte depletion in the treat- systemic lupus erythematosus with mycophenolate mofetil. South Med J ment of systemic lupus (SLE); phase I/II trial of rituximab (Rituxan in SLE). 2003, 96:705–707. Arthritis Rheum 2002, 46:S717. 15 Kapitsinou PP, Boletis JN, Skopouli FN, et al.: Lupus nephritis: treatment with 31 Alarcon–Segovia D, Tumlin AJ, Furie R, et al.: LJP 394 for the prevention of • mycophenolate mofetil. Rheumatology 2004, 43:377–380. •• renal flare in patients with systemic lupus erythematosus. Arthritis Rheum In this retrospective review of 18 patients with LN, MMF appeared to be safe and 2003, 48:442–454. effective in those with proliferative histology, whereas efficacy in membranous LN LJP 394, a B-cell tolerogen against anti-dsDNA antibodies, was compared with was not observed. placebo in a large trial of patients with prior LN. A difference in flare rates did not reach statistical significance. 16 Riskalla M, Somers EC, Fatica RA, et al.: Tolerability of mycophenolate mofetil • in patients with systemic lupus erythematosus. J Rheumatol 2003, 30:1508– 32 Strand V, Aranow C, Cardiel MH, et al.: Improvement in health-related quality 1512. of life in systemic lupus erythematosus patients enrolled in a randomized clini- This retrospective review of 54 consecutive patients treated with MMF describes cal trial comparing LJP 394 treatment with placebo. Lupus 2003, 12:677– the most common side effects of this agent and the reasons for drug discontinua- 686. tion. 33 Furie R, Stohl W, Ginzler E, et al.: Safety, pharmacokinetics and pharmaco- 17 Doria A, Frassi M, Della Libera S, et al.: Prospective study on tolerability and dynamic results of a phase I single and double dose-escalation study of Lym- phoStat B (human monoclonal antibody to BLyS) in SLE patients. Arthritis • efficacy of mycophenolate mofetil (MMF) in SLE. Arthritis Rheum 2003, 48:S587. Rheum 2003, 48:S377. This prospective review of 42 patients, some with refractory manifestations of ac- 34 Hirashima M, Fukasawa T, Abe K, et al.: Expression and activity analyses of tive lupus and others with newly diagnosed nephritis, found MMF therapy to be well CTLA4 in peripheral blood lymphocytes in systemic lupus erythematosus pa- tolerated and effective in reducing overall disease activity. tients. Lupus 2004, 13:24–31. 18 Ferro ML, Karim MY, Abbs IC, et al.: Mycophenolate mofetil: a potential treat- 35 Foell J, Strahontin S, O’Neil SP, et al.: CD137 costimulatory T cell receptor ment for reducing proteinuria associated with membranous lupus nephritis. engagement reverses acute disease in lupus prone NZB x NZW F1 mice. J Arthritis Rheum 2003, 48:S588. Clin Invest 2003, 111:1505–1518. 19 Chan TM, Li FK, Tang CSO, et al.: Efficacy of mycophenolate mofetil in pa- 36 Genovese MC, Uhrin Z, Bloch DA, et al.: Long-term follow-up of patients tients with diffuse proliferative lupus nephritis. N Engl J Med 2000, treated with total lymphoid irradiation for lupus nephritis. Arthritis Rheum 343:1156–1162. 2002, 46:1014–1018. 37 Traynor AE, Barr WG, Rosa RM, et al.: Hematopoietic stem cell transplanta- 20 Hu W, Liu Z, Chen H, et al.: Mycophenolate mofetil vs cyclophosphamide tion for severe and refractory lupus. Analysis after five years and fifteen pa- therapy for patients with diffuse proliferative lupus nephritis. Chin MedJ tients. Arthritis Rheum 2002, 46:2917–2923. 2002, 115:705–709. 38 Lisukov IA, Sizikova SA, Kulagin AD, et al.: High-dose immunosuppression 21 Ginzler EM, Aranow C, Merrill JT, et al.: Toxicity and tolerability of mycophe- • with autologous stem cell transplantation in severe refractory systemic lupus •• nolate mofetil (MMF) versus intravenous cyclophosphamide (IVC) in a multi- erythematosus. Lupus 2004, 13:89–94. center trial as induction therapy for lupus nephritis (LN). Arthritis Rheum This series of six SLE patients treated with stem cell transplantation suggests that 2003, 48:S586. long-term, steroid-free remissions are possible, but early mortality is not uncom- In a randomized, open-label trial of 140 patients with severe LN, MMF was found to mon. be superior to IV CYC in inducing complete remissions, with better patient tolerability. 39 Petri M, Jones RJ, Brodsky RA: High-dose cyclophosphamide without stem • cell transplant in systemic lupus erythematosus. Arthritis Rheum 2003, 22 Contreras G, Pardo V, Leclercq B, et al.: Sequential therapies for proliferative 48:166–173. •• lupus nephritis. N Engl J Med 2004, 350:971–980. In an uncontrolled series of 14 patients with refractory features of SLE, high-dose In patients with proliferative LN, induction therapy with IV CYC followed by main- CYC without stem cell transplantation resulted in rapid hematopoietic reconstitu- tenance therapy with either MMF or AZA appeared to be more efficacious and safer tion with significant clinical benefit. than long-term IV CYC. 40 Karassa FB, Tatsioni A, Ioannidis JPA: Design, quality, and bias in randomized 23 Saito K, Nawata M, Nakayamada S, et al.: Successful treatment with anti- •• controlled trials of systemic lupus erythematosus. J Rheumatol 2003, CD20 monoclonal antibody (rituximab) of life-threatening refractory systemic 30:979–984. lupus erythematosus with renal and central nervous system involvement. Lu- This excellent review of all published, randomized, clinical trials in SLE identifies the pus 2003, 12:798–800. problematic issues in the design and reporting of studies, which need to be considered in improving the quality of subsequent trials. 24 Saigal K, Valencia IC, Cohen J, et al.: Hypocomplementemic urticarial vascu- 41 Bronson K, Petri M, Brodsky R, et al.: High-dose cyclophosphamide is pref- litis with angioedema, a rare presentation of systemic lupus erythematosus: erable to monthly IV cyclophosphamide at six months. Arthritis Rheum 2003, rapid response to rituximab. J Am Acad Dermatol 2003, 49:S283–S285. 48:S588. 25 Perrotta S, Locatelli F, La Manna A, et al.: Anti-CD20 monoclonal antibody 42 Edworthy SM, Dobkin PL, Clarke AE, et al.: Group psychotherapy reduces (rituximab) for life-threatening autoimmune hemolytic anemia in a patient with illness intrusiveness in systemic lupus erythematosus. J Rheumatol 2003, systemic lupus erythematosus. Br J Haematol 2002, 116:465–467. 30:1011–1016. 26 Weide R, Heymans J, Pandorf A, et al.: Successful long-term treatment of 43 Tench CM, McCarthy J, McCurdie, et al.: Fatigue in systemic lupus erythe- systemic lupus erythematosus with rituximab maintenance therapy. Lupus matosus: a randomized controlled trial of exercise. Rheumatology 2003, 2003, 12:779–782. 42:1050–1054. B cells in human and murine systemic lupus erythematosus Jennifer Anolik and In˜aki Sanz

Purpose of review Introduction The purpose of this review is to discuss recent publications Although undoubtedly multiple immunologic abnormali- dealing with the control of autoreactive B cells, how this ties are important for the development and clinical ex- control is subverted in human systemic lupus erythematosus pression of systemic lupus erythematosus (SLE), a grow- and in murine models of systemic lupus erythematosus, and ing body of evidence, more recently including the how dysregulated autoreactive B cells may then contribute to effectiveness of therapeutic B-cell depletion, strongly disease expression through both regulatory and effector points to the B cell as a central player in the pathogenesis mechanisms. of this disease [1]. The mechanisms by which B cells Recent findings may influence SLE are diverse and include both auto- Autoreactive B cells are abundant in the mature peripheral antibody-dependent and -independent functions [2]. In B-cell repertoire and need to be censored to avoid turn, autoantibody-independent functions that may con- autoimmunity. This censoring is accomplished in diverse ways tribute to SLE include the ability of B cells to regulate T and may be broken down by multiple mechanisms both cells and dendritic cells and their frequently underrec- intrinsic and extrinsic to the B cells. ognized ability to produce cytokines such as interleukin- Summary 10, interleukin-6, and interferon (IFN)-␥ in a regulated, The work reviewed here paints a suggestive picture while polarized fashion [3–7,8•]. In this article we review in- confirming the pathogenic potential of autoreactive B cells and formation published during the last year regarding ge- pointing to specific defects that warrant further exploration and netic, signaling, and homeostatic abnormalities in lupus could represent future therapeutic targets for this autoimmune B cells. We also discuss new insights into the mecha- disease. nisms that may participate in the breakdown of B-cell tolerance that is central to this disease. The effectiveness Keywords and potential mechanisms of action of B-cell depletion in autoreactive B cells, human SLE, murine SLE SLE is briefly discussed, but have been recently reviewed in detail elsewhere [9•]. Curr Opin Rheumatol 16:505–512. © 2004 Lippincott Williams & Wilkins. B-cell tolerance and human systemic lupus erythematosus Immunologic tolerance for self-antigens is enforced at several checkpoints throughout B-cell development [10]. Department of Medicine, Clinical Immunology and Rheumatology Unit, Rochester, Although central mechanisms such as receptor editing New York, USA and clonal deletion initiate control of autoreactivity dur- Correspondence to In˜aki Sanz, Department of Medicine, Clinical Immunology and ing early bone marrow development, it is apparent that a Rheumatology Unit, 601 Elmwood Avenue, Rochester, NY 14642, USA Tel: 585 275 2891; fax: 585 442 3214; significant fraction of autoreactive B cells proceed un- e-mail: [email protected] checked into the peripheral repertoire, thereby creating

Current Opinion in Rheumatology 2004, 16:505–512 the need for additional censoring at later stages [11]. This need, which is well established in transgenic mod- Abbreviations els, has been recently emphasized in humans by several ANA antinuclear antibodies reports demonstrating that the peripheral lymphoid com- BAFF B-cell activating factor of the tumor necrosis factor family BLyS B lymphocyte stimulator partments still contain a high frequency of autoreactive B GC germinal center cells. In one study, single-cell PCR followed by cloning IFN interferon MZ marginal zone and expression of the corresponding antibodies was used pDC plasmacytoid dendritic cell to measure autoreactivity (both directly by binding as- SLE systemic lupus erythematosus TLR toll-like receptor says and indirectly through the expression of surrogate molecular markers) in the immature and mature B-cell © 2004 Lippincott Williams & Wilkins 1040–8711 compartments [12••]. The results show that although the frequency of autoreactive B-cells significantly de- clines in the transition from the immature B-cell stage into the peripheral mature compartment, as much as 20% 505 506 Systemic lupus erythematosus and Sjo¨ gren syndrome of peripheral naive B cells are still reactive with nuclear issue either by direct analysis of B-cell tolerance in au- antigens. toimmune mouse strains or by delineating mechanisms that could possibly be at work in SLE. In another study, investigators used direct flow– cytometric detection of antigen-specific B cells to dem- Indeed, the analysis of transgenic autoreactive B cells onstrate a relatively high frequency (0.5 to 1%) of has identified a number of mechanisms by which these mutated antiphospholipid B cells in the memory com- cells may escape censoring. These mechanisms include partment of healthy donors [13•]. Using patients with loss of clonal ignorance in anti-Smith B cells of mice with acute infectious mononucleosis, this study also corrobo- defective clearance of apoptotic cells containing this rated the ability of the Epstein–Barr virus to expand nuclear antigen. Such antigenic stimulation resulted in these preexisting autoreactive memory B cells. Given the expansion of B1 and marginal zone (MZ) B cells and the pathogenic potential of antiphospholipid antibodies the generation of anti-Smith antibody-producing cells and the possible role of Epstein–Barr virus infection in [23•]. In contrast, failure to sequester anti-ds DNA into SLE [14,15•], this work highlights the need for mecha- the MZ compartment was demonstrated in MRL/lpr nisms that would maintain tolerance in memory B cells mice expressing transgenic VH3H9/56R antibodies. In- that are in all likelihood frequently subjected to micro- terestingly, these mice experienced inefficient receptor bial stimulation by a number of, mechanisms including dilution by editing light chains (which usually dimin- antigen-independent polyclonal stimulation through toll- ishes autoreactivity and may promote selection into the like receptors (TLRs) and production of IFN-␣ (dis- MZ) and altered receptor editing with enhanced heavy- cussed later). chain replacement of the original anti-DNA transgene [24]. Enhanced heavy-chain replacement and increased Finally, the importance of peripheral B-cell tolerance anti-ds DNA antibodies were also triggered in nonauto- and its breakdown in human SLE has been documented immune transgenic mice on induction of chronic graft- by the analysis of autoreactive B cells expressing versus-host reactions. These studies highlight the rather VH4.34-encoded autoantibodies (VH4.34 B cells). Se- counterintuitive potential of receptor editing as a mecha- rum levels of these potentially treacherous autoantibod- nism for the generation of autoreactive B cells [25••]. ies are consistently very low in healthy subjects but are Furthermore, T cells appear quite versatile in their abil- greatly increased in patients with active SLE, in whom ity to abrogate tolerance in anti-ds DNA B cells. Thus, they likely play pathogenic roles [16,17]. It was previ- the spontaneous presence of CD4 T cell helps in lupus- ously shown that VH4.34 B cells, which in healthy sub- prone lpr/lpr mice, and the provision of such help to jects represent 5 to 10% of all naive B cells but are rare nonautoimmune Balb/c mice both disrupted one of the in the IgG memory compartment, are normally censored best established mechanisms of B-cell tolerance: namely, in the germinal centers (GC) [18]. A recent study sug- the follicular exclusion of anti-DNA B cells. Moreover, at gests that this safety mechanism may be faulty in pa- least in nonautoimmune mice, decreased regulatory ac- tients with SLE, because VH4.34 B cells were found tivity of CD4+/CD25+ T cells was also required for full highly expanded in the IgG memory population, and tolerance breakdown, because in the presence of these VH4.34 antibodies contributed a major fraction of total cells, follicular entry per se did not induce the generation serum IgG and of anti-B-cell IgG autoantibodies [19•]. of antibody-forming cells [26]. Interestingly, IgG anti- The finding that SLE VH4.34 IgG autoantibodies re- DNA antibodies were only produced in the presence of tained the antigenic binding profile of monoclonal IgM a clonally diverse CD4+ T-cell repertoire [27•]. VH4.34 antibodies rescued from healthy donors strongly suggests, albeit it does not formally prove, that their posi- Potentially, B-cell tolerance can also be disrupted by T- tive selection in SLE may be the result of their germline- independent polyclonal activation mediated by innate encoded self-reactivity against poly-N-acetyl lactos- immunity TLRs. Therefore, it might be expected that to amine epitopes expressed by the iI blood group antigens, avoid autoimmunity, autoreactive B cells should be re- multiple other glycoproteins, and apoptotic cells fractory to this type of stimulation in healthy individuals. [20,21•]. More important, a preliminary report indicates Consistent with this view, stimulation through TLR9 or that, indeed, SLE IgG VH4.34 antibodies bind apoptotic TLR4 does not overcome anergy in high-affinity anti- cells [22]. HEL transgenic B cells [28••]. Yet, costimulation of the B-cell receptor and TLR9 by IgG–chromatin complexes Breakdown of B-cell tolerance in systemic is capable of disrupting tolerance in low-affinity rheuma- lupus erythematosus toid factor transgenic B cells, thereby establishing the A wealth of knowledge regarding the mechanisms that potential of this mechanism to induce autoimmunity ensure B-cell tolerance has been gathered using trans- [29]. More recently, the same investigators have shown genic mice. Yet, an understanding of how this informa- that isolated DNA (in the absence of antichromatin an- tion applies to SLE awaits a better definition of the spe- tibodies) can also activate anti-ds DNA B cells through cific checkpoints that go awry in this disease. During the dual stimulation of the BCR and TLR9 [30••]. More last year, a number of publications have shed light on this important, this study also demonstrated that hypometh- B cells in SLE Anolik and Sanz 507

Figure 1. Schematic representation of B-cell development

Checkpoints for censoring of autoreactive B-cells (as identified in different models) are indicated by numbers as follows: (1) receptor editing [24–25••]; (2) clonal deletion; (3) censoring mechanism acting upon T2 cells possibly through antigen-dependent Fas-mediated apoptosis [Carsetti et al. J Exp Med 1995; 2129–2140]. (4) B1 cell sequestration/selection into peritoneal cavity (mouse) [23•]; (5) sequestration/selection into the marginal zone [24,63–64•] (6) Anergy and follicular exclusion/premature death (in the presence of competing B-cells) [10–11]; (7) lack of T-cell help [25–27]; (8) defective survival in response to BAFF stimulation [36•–37••,38••]; (9) Fas-mediated T-cell dependent killing [10]; (10) competitive disadvantage with higher-avidity B-cells [Dal Porto et al. J Exp Med 2002; 195:1215–1221]; (11) autoantigen-mediated apoptosis [Shakat and Goodnow. Nature 1995; 375:334–338]; (12) although not well defined yet, an additional checkpoint presumably blocks autoreactive memory cells from terminal differentiation into long-lived plasma cells. The corresponding mechanism may include resistance to polyclonal, antigen-independent activation through TLR receptors [28••,29–30••,31]. *The origin of B1 cells continues to be a matter of debate even in the mouse and therefore no specific developmental pathway is assigned here. References discussed in this review that identified defective checkpoints in SLE are included or otherwise noted. ylated CpG motifs present at low abundance in mamma- plasmacytoid dendritic cells (pDCs) synergistically en- lian DNA can mediate this activity. In combination, the hanced B-cell activation, plasma cell differentiation, and data provide tantalizing evidence for the possibility that antibody secretion [8•]. The latter report follows on the both microbial DNA and mammalian DNA could break steps of a previous study demonstrating the ability of tolerance in SLE anti-DNA B cells. This possibility is pDCs stimulated by influenza virus to induce plasma cell further substantiated by the finding that human periph- differentiation of human B cells under the sequential eral blood-naive and memory B cells can be induced to influence of IFN-␣/␤ and interleukin-6 [32••]. These differentiate into plasma cells and secrete antibody by studies delineate another mechanism by which type I costimulation of TLR9 with CpG DNA [8•,31]. Inter- interferons could contribute to the pathogenesis of SLE estingly, in one study the presence of IFN-␣-producing [33•].

Figure 2. B-cell abnormalities in the peripheral blood (PBL) of patients with SLE

The cartoon on the left depicts the distribution of PBL B-cell subsets according to their expression of CD27 and IgD. The dot plots on the right illustrate a typical distribution of these subsets in healthy individuals and two representative SLE patients. Both SLE patients display naı¨ve B-cell lymphopenia and a significant expansion of a population of CD27/IgD double negative B-cells (DN) [68,73]. The nature of DN cells remains to be elucidated. In addition, patient SLE-2 demonstrates a substantial expansion of CD27High plasmablasts [66–67]. 508 Systemic lupus erythematosus and Sjo¨ gren syndrome

Excessive stimulation of B cells by a cytokine with cen- B-cell tolerance breakdown. In either scenario, the lag tral roles in B-cell maturation and tolerance such as time observed between the appearance of ANA and BAFF (B-cell activating factor of the tumor necrosis fac- clinical expression of SLE could be explained by the tor family)/BLyS (B lymphocyte stimulator) also has the need for epitope spreading and/or a subsequent stochas- potential to dysregulate B-cell homeostasis and induce tic antigenic hit. This possibility is strengthened by the SLE-like phenotypes [34]. New functions recently de- observation that although clinical manifestations lagged scribed for this cytokine provide plausible mechanistic significantly in more than 90% of patients with an initial explanations for these observations. Thus, excessive lev- positive test for either ANA, anti-Ro, anti-La, or anti- els of BLyS/BAFF, which have been demonstrated in double-stranded DNA antibodies, the subsequent ap- patients with active SLE, may improve the survival of pearance of antiribonucleoprotein and anti-Sm antibod- anergic autoreactive B cells in the presence of competing ies was closely linked in time with a diagnosis of SLE B cells [35•,36•]. Furthermore, signaling through the [44••]. BAFF-R may play a role in the maintenance and completion of productive GC reactions, because abortive GCs Interestingly, although the cited study indicates that appear to be the consequence of defective signaling breakdown of tolerance for nuclear antigens, including through this receptor [37••,38••]. It is therefore possible native DNA, is not sufficient for the generation of sig- that excessive BAFF-R stimulation could promote sur- nificant clinical manifestations of human SLE, another vival of autoreactive B cells in the GC, thereby leading to report demonstrates that at least in some mouse strains, autoimmunity. Interestingly, lymphoproliferation and lu- this defect may not be necessary for the induction of puslike autoimmunity has been observed in mice made lupus nephritis [45•]. Thus, using strains of lupus-prone deficient for the BAFF/BLyS receptor TACI, indicating NZM2328 mice congenic for loci responsible either for that abnormal B-cell survival can also be induced by de- chronic glomerulonephritis or for the production of ANA fects in the expression, regulation or activity of this in- and anti-ds DNA antibodies (Cgnz1 and Adnz1 respec- hibitory receptor [39••]. Finally, BAFF/BLyS stimula- tively), the authors were able to confirm that chronic tion of another of its receptors (BCMA) has been shown glomerulonephritis and antinucleosome antibodies are to enhance in vitro the survival of human splenic memory under separate genetic control and demonstrate that tol- B cells and of plasmablasts generated from memory cells erance breakdown for these antigens is not required for [40••]. Similar effects of BCMA activation in the survival the induction of lupus nephritis. of long-lived plasma cells have been reported in the mouse [41••]. Intrinsic B-cell abnormalities leading to autoimmunity Is the breakdown of B-cell tolerance a Accumulating evidence from both spontaneous and in- primary event in systemic ducible models of murine lupus implicates intrinsic ab- lupus erythematosus? normalities in B cells as critical to the emergence and Although it is generally accepted that SLE is character- progression of autoimmunity. Three broad categories of ized by a breakdown of B-cell tolerance that leads to the defects that can lead to a lupuslike phenotype have been generation of pathogenic autoantibodies, it is unclear defined in murine models, affecting (1) B-cell activation whether such tolerance breakdown takes precedence thresholds (eg, CD22 knockout) [46,47], (2) B-cell lon- over other immune abnormalities or, instead, whether it gevity (eg, BLyS transgenics) [39••,48,49], or (3) apo- is secondary to abnormal regulation by T cells and/or ptotic cell/autoantigen processing (eg, mer knockout) DCs. Indeed, primary tolerance breakdown could be ex- [50]. Here we concentrate on some recently elucidated plained by microbial stimulation of intrinsically abnormal abnormalities that impact B-cell activation and signaling, lupus B cells. Acting as antigen-presenting cells, acti- with effects on B-cell longevity and apoptosis pathways vated autoreactive B cells could in turn break tolerance detailed in other reviews. Of particular interest are B-cell in the T-cell compartment and produce antiapoptotic regulatory molecules perturbed in both mouse and hu- cell antibodies capable of inducing IFN-␣ production by man disease. This is exemplified by PD-1, a protein with pDCs, a mechanism likely to contribute to SLE structural similarities to CTLA-4, that acts as a negative [3,42,43••]. regulator of B-cell activation and whose inactivation was previously shown to induce either lupuslike glomerulo- The recent demonstration that patients with SLE may nephritis or autoimmune dilated cardiomyopathy, de- express antinuclear antibodies (ANA) several years be- pending on genetic background [51,52]. Interestingly, fore the onset of clinical disease suggests that the break- the autoimmune cardiomyopathy appears to be induced down of B-cell tolerance occurs very early in this disease by antitroponin I antibodies [53••]. The potential rel- and may precede or even trigger other immune malfunc- evance of these findings for human SLE is suggested by tions [44••]. However, this study does not formally ex- the identification of PD-1 as a susceptibility gene and clude the possibility that abnormalities in other arms of the association of PD-1 polymorphisms with lupus ne- the innate or adaptive immune system might predate phritis [54,55•]. B cells in SLE Anolik and Sanz 509

The role of intrinsic B-cell abnormalities leading to al- sitional (T2) and MZ B cells [61]. A likely role for MZ B tered B-cell activation in human SLE has been more cells in SLE had also been postulated because they are challenging to define. Recently, data have emerged from expanded in young (NZB × NZW) F1 mice [62]. More- multiple groups indicating that polymorphisms in the over, activation and expansion of autoreactive anti- inhibitory Fc receptor, Fc␥RIIb, are associated with SLE dsDNA MZ B cells have been observed in a murine and have a direct functional consequence on B-cell sig- model of estrogen-induced lupus [63], and as a conse- naling [56•]. More specifically, an Fc␥RIIb membrane- quence of tolerance breakdown in anti-Smith B cells on spanning Ile232 to Thr232 substitution associated with stimulation with apoptotic cells [23•]. However, enthu- lupus in Asian populations caused decreased FcR lipid siasm in assigning a universally deleterious role to the raft association and greater, more sustained calcium mo- expansion of MZ B cells must be tempered by the pre- bilization and downstream biochemical signaling events viously discussed observation that failure to sequester on B-cell receptor engagement [57]. This is in keeping anti-dsDNA B cells in this compartment may also allow with previous data that altered Fc␥RIIb signaling con- these cells to escape tolerance in MRL/lpr mice [24]. tributes to augmented calcium responses in human SLE This caveat is further supported by the recent demon- B cells [58]. Of note, distinct FcR polymorphisms may stration that lupus-prone BXSB mice display impaired be associated with lupus in different patient populations development of MZ B cells [64•]. The same investiga- and could have differential effects on modifying BCR tors have also shown that MZ B-cell expansion is not signaling [56•]. Overall, FcR polymorphisms are likely necessary for the genetic contribution of the NZB back- one of the many genetic modifiers in human lupus that ground to a lupus phenotype. may directly impact B-cell signaling, but act in a complicated, epistatic fashion. This notion is supported by The contribution of specific B-cell subsets to human the fact that Fc␥RIIb deficiency leads to a lupuslike SLE remains uncertain. Yet, meaningful abnormalities of phenotype in Fas-deficient lpr/lpr mice, but with differ- B-cell homeostasis have been described in this disease. ent penetrance depending on the genetic background Such abnormalities include naive lymphopenia, in- [59•]. creased circulating GC founder cells, and an expansion of peripheral blood plasmablasts [65,66]. Of note, the Another interesting example of the convergence of ge- frequency and absolute number of plasmablasts and netic and B-cell signaling studies, with relevance for plasma cells (CD19+/CD27high B cells) in the peripheral both murine and human lupus, is the recent elucidation blood of patients with SLE correlated with overall dis- of a polymorphism of the leukocyte tyrosine kinase Ltk, ease activity, as measured by the SLEDAI, and with expressed in immature B cells [60•]. This study found a anti-dsDNA antibody titers [67•]. Abnormal expansion gain-of-function mutation in the Ltk kinase domain, of peripheral blood B cells with a pre-GC phenotype has common to NZB lupus-prone mice and SLE patients, also been reported and may indicate either exuberant or which associated with B1 cell expansion in mice and abnormally regulated GC reactions in SLE [65,66]. In phosphatidylinositol-3-kinase upregulation in both fact, the ability of anti-CD154 (CD40L) antibodies to mouse and human B cells. Although interesting, it is decrease some subsets of peripheral blood B cells and important to note that this Ltk allele was found in 7.3% anti-dsDNA antibody production in patients with lupus of SLE patients and 2.8% of healthy control subjects, nephritis [68,69•] has been used to suggest that blockade indicating that such a single gene defect is neither nec- of the CD40-CD154 interaction may interfere with ab- essary nor sufficient for the development of lupus in normal GC reactions in SLE [69•]. Although this hy- humans. pothesis is worth pursuing, the previous conclusion must be tempered by the realization that only IgD+ cells were In combination, the fact that abnormal B-cell signaling significantly diminished during treatment with anti- can be a feature of both murine and human lupus, and CD154. In contrast, IgD- subsets, which include GC- lupuslike phenotypes are clearly produced by the tar- derived post-switch memory and plasma cells, did not geted disruption of molecules that modulate Ig- experience significant decline with treatment. There- mediated signaling indicates that altered B-cell signaling fore, this intervention was not able to interrupt produc- is likely important in the breakdown of B-cell tolerance tive GC reactions, although it may have affected earlier and the pathogenesis of lupus. stages of GC formation or even GC-independent generation of IgD+ memory B cells and plasma cells Abnormal B-cell homeostasis in systemic [70•,71,72]. lupus erythematosus Interestingly, many of the genetic manipulations that The effects of B-cell depletion in human yield an autoimmune phenotype in mice also result in systemic lupus erythematosus the abnormal development of discreet B-cell subsets. Recently, the autoantibody-independent role of B cells For example, BAFF overexpression in mice results in in human SLE and the contribution of B cells to ongoing lupuslike disease in association with an increase in tran- disease activity has been corroborated by studies of the 510 Systemic lupus erythematosus and Sjo¨ gren syndrome effects of B-cell depletion with rituximab in this disease 5 Llorente L, Richaud–Patin Y, Wijdenes J, et al.: Spontaneous production of interleukin-10 by B lymphocytes and monocytes in systemic lupus erythema- (as reviewed in detail by Looney et al. [9•]). A phase I/II tosus. Eur Cytokine Netw 1993, 4:421–427. dose-escalation trial of rituximab demonstrated clinical 6 Harris DP, Haynes L, Sayles PC, et al.: Reciprocal regulation of polarized efficacy in the subset of SLE patients with effective cytokine production by effector B and T cells. Nat Immunol 2000, 1:475– B-cell depletion, independent of serum autoantibody re- 482. duction [73]. Clinical response in the absence of sero- 7 Moulin V, Andris F, Thielemans K, et al.: B lymphocytes regulate dendritic cell (DC) function in vivo: increased interleukin 12 production by DCs from B logic response is consistent with the previously detailed cell-deficient mice results in T helper cell type 1 deviation. J Exp Med 2000, autoantibody-independent function of B cells demon- 192:475–482. strated in murine SLE [1–4]. Interestingly, CD20- 8 Poeck H, Wagner M, Battiany J, et al.: Plasmacytoid dendritic cells, antigen, targeted B-cell depletion effectively normalized the sig- • and CpG-C license human B cells for plasma cell differentiation and immunoglobulin production in the absence of T-cell help. Blood 2004, 103:3058– nificant disturbances in peripheral B-cell homeostasis 3064. discussed earlier, including naive lymphopenia, expan- CpG DNA induces pDCs to stimulate naive and memory human B cells through IFN-␣ production. sion of a novel population of IgD/CD27 double-negative cells, the presence of plasma cell precursors, and expan- 9 Looney RJ, Anolik J, Sanz I: B lymphocytes in systemic lupus erythematosus: • lessons from therapy targeting B cells. Lupus 2004, 13:1–10. sion of autoreactive memory B-cell populations (Anolik, This paper reviews the effects of B-cell depletion in SLE. unpublished data). 10 Goodnow CC, Cyster JG, Hartley SB, et al.: Self-tolerance checkpoints in B lymphocyte development. Adv Immunol 1995, 59:279–368.

Conclusion 11 Goodnow CC: Balancing immunity and tolerance: deleting and tuning lym- A large body of experimental and observational studies phocyte repertoires. Proc Natl Acad SciUSA1996, 93:2264–2271. both in mice and humans indicate that B cells play com- 12 Wardemann H, Yurasov S, Schaefer A, et al.: Predominant autoantibody pro- plex and important roles in SLE. The evidence dis- •• duction by early human B cell precursors. Science 2003, 301:1374–1377. This is an elegant demonstration of the substantial autoreactive potential of mature cussed suggests that depending on genetic background human B cells and the need for peripheral B-cell tolerance. and specific environmental insults, the disease may be 13 Lieby P, Soley A, Knapp A-M, et al.: Memory B cells producing somatically induced by a subversion of B-cell tolerance that may be • mutated antiphospholipid antibodies are present in healthy individuals. Blood brought about by diverse mechanisms operating at dif- 2003, 102:2459–2465. This article expands the observations of Wardemann et al. [12] to human memory ferent censor points. It also suggests that both intrinsic B cells.

B-cell abnormalities and extrinsic influences mediated 14 James JA, Kaufman KM, Farris AD, et al.: An increased prevalence of Epstein– by other adaptive and innate immune cells (T cells and Barr virus infection in young patients suggests a possible etiology for sys- DCs) possibly triggered by infectious agents are likely to temic lupus erythematosus. J Clin Invest 1997, 100:3019–3026. be required for full clinical expression of the disease. 15 Mockridge CI, Rahman A, Buchan S, et al.: Common patterns of B cell per- • turbation and expanded V4-34 immunoglobulin gene usage in autoimmunity These observations, along with the known clinical het- and infection. Autoimmunity 2004, 37:9–15. erogeneity of human SLE, strongly suggest that this dis- Changes in global B-cell compartments and autoantibody production may be ease is likely to be induced by different mechanisms in shared between patients with infectious mononucleosis (transiently) and SLE. individual patients, and point to the need for better iden- 16 Stevenson FK, Smith GJ, North J, et al.: Identification of normal B-cell coun- terparts of neoplastic cells which secrete cold agglutinins of anti-I and anti-i tification of disease subsets. Achieving this goal would specificity. Br J Haematol 1989, 72:9–15. allow investigators to develop better biologic markers of 17 Bhat NM, Lee LM, Vollenhoven RV, et al.: VH4-34 Encoded antibody in sys- disease activity and outcome, and to design therapeutic temic lupus erythematosus: effect of isotype. J Rheumatol 2002, 29:2114– approaches tailored to the pathophysiologic process re- 2121. sponsible for distinct disease subsets. On the basis of the 18 Pugh–Bernard AE, Silverman GJ, Cappione AJ, et al.: Regulation of inherently autoreactive VH4-34 B cells in the maintenance of human B cell tolerance. J great strides recently made in the phenotypic and ge- Clin Invest 2001, 108:1061–1070. netic characterization of B cells, the study of B-cell popu- 19 Cappione AJ, Pugh–Bernard AE, Anolik JH, et al.: Lupus IgG VH4.34 anti- lations holds great promise for our understanding of • bodies bind to a 220-kDa glycoform of CD45/B220 on the surface of human SLE. B lymphocytes. J Immunol 2004, 172:4298–4307. This paper demonstrates dramatic expansion of VH4.34 autoantibodies in the SLE IgG repertoire and suggests that iI-related antigens may pay a selecting role in this References and recommended reading disease. Papers of particular interest, published within the annual period of review, 20 Bhat NM, Bieber MM, Spellerberg MB, et al.: Recognition of auto- and exo- have been highlighted as: antigens by V4-34 gene encoded antibodies. Scand J Immunol 2000, • Of special interest 51:134–140.

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J Clin Invest 2003, ciency may produce a lupuslike phenotype. 112:286–297. Combined with the findings of others [41••], this paper demonstrate an important 60 Li N, Nakamura K, Jiang Y, et al.: Gain-of-function polymorphism in mouse and role for BCMA in the survival of long-lived plasma cells. • human Ltk: implications for the pathogenesis of systemic lupus erythematosus. Hum Mol Genet 2004, 13:171–179. 41 O’Connor BP, Raman VS, Erickson LD, et al.: BCMA is essential for the sur- Ltk gain-of-function polymorphism may impact B-cell function and may be associ- •• vival of long-lived bone marrow plasma cells. J Exp Med 2004, 199:91–98. ated with SLE. 512 Systemic lupus erythematosus and Sjo¨ gren syndrome

61 Mackay F, Woodcock SA, Lawton P, et al.: Mice transgenic for BAFF develop An extension of earlier work [66] showing a correlation between the expansion of lymphocytic disorders along with autoimmune manifestations. J Exp Med peripheral blood plasmablasts and disease activity in SLE. 1999, 190:1697–1710. 68 Huang W, Sinha J, Newman J, et al.: The effect of anti-CD40 ligand antibody 62 Wither JE, Roy V, Brennan LA: Activated B cells express increased levels of on B cells in human systemic lupus erythematosus. Arthritis Rheum. 2002, costimulatory molecules in young autoimmune NZB and (NZB × NZW)F(1) 46:1554–1562. mice. Clin Immunol 2000, 94:51–63. 69 Grammer AC, Slota R, Fischer R, et al.: Abnormal germinal center reactions in 63 Grimaldi CM, Michael DJ, Diamond B: Cutting edge: expansion and activation • systemic lupus erythematosus demonstrated by blockade of CD154-CD40 of a population of autoreactive marginal zone B-cells in a model of estrogen- interactions. J Clin Invest 2003, 112:1506–1520. induced lupus. J Immunol 2001, 167:1886–1890. Clinical and immunologic abnormalities are improved, as detailed elsewhere [68]. IgD+ (but not IgD–) CD38+ B cells markedly decreased by treatment suggesting 64 Amano H, Amano E, Moll T, et al.: The yaa mutation promoting murine lupus block in early GC reactions and/or extrafollicular reactions. causes defective development of marginal zone B cells. J Immunol 2003, • 70 170:2293–2301. Kelsoe G: Therapeutic CD154 antibody for lupus: promise for the future? J Lupus phenotypes are observed despite abnormal development of MZ B cells. • Clin Invest 2003, 112:1480–1482. This paper is an insightful analysis and discussion of the article by Grammer et al. 65 Arce E, Jackson DG, Gill MA, et al.: Increased frequency of pre-germinal [69•]. center B cells and plasma cell precursors in the blood of children with sys- 71 Weller S, Faili A, Garcia C, et al.: CD40-CD40L independent Ig gene hyper- temic lupus erythematosus. J Immunol 2001, 167:2361–2369. mutation suggests a second B cell diversification pathway in humans. Proc 66 Odendahl M, Jacobi A, Hansen A, et al.: Disturbed peripheral B lymphocyte Natl Acad SciUSA2001, 98:1166–1170. homeostasis in systemic lupus erythematosus. J Immunol 2000, 165:5970– 72 William J, Euler C, Christensen S, et al.: Evolution of autoantibody responses 5979. via somatic hypermutation outside of germinal centers. Science 2002, 297:2066–2070. 67 Jacobi AM, Odendahl M, Reiter K, et al.: Correlation between circulating • CD27high plasma cells and disease activity in patients with systemic lupus 73 Looney RJ, Anolik JH, Campbell D, et al.: B cell depletion as a novel treatment erythematosus. Arthritis Rheum 2003, 48:1332–1342. for SLE. Arthritis Rheum 2004. In press. Update on human systemic lupus erythematosus genetics Betty P. Tsao

Purpose of review This work was supported in part by grants from the NIH AR43814, the Southern California Chapter of the Arthritis Foundation, and the Paxson Family Foundation. Susceptibility to systemic lupus erythematosus (SLE) has a genetic component. In recent years, nine complete genome Correspondence to Betty P. Tsao, PhD, Department of Medicine, Division of Rheumatology, UCLA School of Medicine, 1000 Veteran Avenue, Room 32-59, scans using family collections that differ greatly in ethnic Los Angeles, CA 90095-1670, USA compositions and geographic locations have identified several Tel: 310 825 8906; fax: 310 206 8606; e-mail: [email protected] strong, confirmed SLE susceptibility loci. Evidence implicating Current Opinion in Rheumatology 2004, 16:513–521 individual gene polymorphisms (or haplotypes) within some of Abbreviations the linked intervals has been reported. This review highlights CRP C-reactive protein recent findings that may lead to the identification of putative PBX1 pre–B-cell leukemia transcription factor genes and new insights in the pathogenesis of SLE. PDCD1 program cell death gene 1 SLE systemic lupus erythematosus Recent findings SNP single nucleotide polymorphism Eight of the best-supported SLE susceptibility loci are 1q23, TDT transmission disequilibrium test

1q25-31, 1q41-42, 2q35-37, 4p16-15.2, 6p11-21, 12p24, © 2004 Lippincott Williams & Wilkins and 16q12. These are chromosomal regions exhibiting 1040–8711 genome-wide significance for linkage in single studies and suggestive evidence for linkage in other samples. Linkage analyses conditioning on pedigrees in which one affected Introduction member manifesting a particular clinical condition have also Systemic lupus erythematosus (SLE) is a complex, het- yielded many chromosomal regions linked to SLE. The linked erogeneous autoimmune disease. Epidemiology data on interval on chromosome 6p has been narrowed to 0.5 ∼ 1.0 the sibling risk ratio, familial aggregation of SLE, and the Mb (million basepairs) of 3 MHC class II containing risk disease concordance rate in twins all support a genetic haplotypes in white subjects. Cumulative results have shown component of the occurrence of SLE (reviewed in [1•]). that hereditary deficiencies of complement component C4A (a Individual differences in risk for SLE are mainly genetic, MHC class III gene) confer risk for SLE in almost all ethnic which is further modified by environmental exposures groups studied. The Fc␥R genes (located at 1q23) have been and/or chance occurrences that the patient experiences convincingly demonstrated to play an important role in in life. A recent study has shown that a family history of susceptibility to SLE (and/or lupus nephritis). The evidence for autoimmune diseases may be a risk factor for SLE, and the intronic single nucleotide polymorphism of program cell first-degree relatives of female patients with SLE have a death gene 1 (PDCD1 at 2q37) to confer susceptibility is fourfold risk of having autoimmune diseases over first- promising but not yet compelling. Within several established degree relatives of female subjects without an autoim- susceptibility loci, evidence for association of positional mune disease [2•]. Familial clustering of autoimmune candidate genes is emerging. diseases may be explained by a common set of suscep- Summary tibility genes controlling clinically distinct autoimmune Further replications of linkage and association are the diseases [3] shared among family members. There are immediate task. The respective contribution of each examples that a single gene plays a role in the develop- susceptibility gene, relationships between genotypes and ment of more than one autoimmune disease, such as phenotypes, and potential interactions between susceptibility cytotoxic T-lymphocyte antigen 4 gene in both type 1 gene products need to be elucidated. This line of investigation diabetes and Graves disease [4••]; NOD2/CARD15 in is now well poised to provide novel insights into how genetic Crohn disease, psoriatic arthritis, and Blau syndrome variants can affect functional pathways leading to the [5,6•,7]; and PDCD1 (program cell death gene 1) in SLE, development of SLE. type 1 diabetes, and rheumatoid arthritis [8,9•,10].

Keywords Linkage analyses linkage, association, SLE, susceptibility, gene variants In linkage studies, the goal is to identify genomic segments cotransmitted with the disease in families contain- Curr Opin Rheumatol 16:513–521. © 2004 Lippincott Williams & Wilkins. ing two or more affected members [11]. This positional genetic approach has the potential to locate susceptibil- Department of Medicine, Division of Rheumatology, UCLA School of Medicine, Los Angeles, California, USA ity genes without previous knowledge of the disease eti- 513 514 Systemic lupus erythematosus and Sjögren syndrome ology by using a few hundred genetic markers evenly containing region is not the most prominent susceptibil- spaced throughout the whole genome. Although this ity locus detected in these scans, suggesting a similar strategy proves successful to locate susceptibility genes contribution between the MHC and individual non- of strong effect in genetically simple Mendelian disor- MHC loci, which is different from other autoimmune ders, it has limited power to detect genes of modest to diseases, including ankylosing spondylitis, type 1 diabe- small effect in genetically complex diseases such as SLE; tes, and rheumatoid arthritis. Because this review high- thus, a large family collection is preferable. Linkage sig- lights new findings within the last year, the three most nals detected in complex diseases may result from the recent genome scans are described: (1) linkage at 12q24 combined effect of a cluster of genes of modest effects. with SLE, a newly established and confirmed locus, is Because hundreds of genetic markers are assayed in a mainly observed in Hispanic and European American genome scan, multiple testing increases the probability families [20•]; (2) a nationwide study in Finland (a geo- of false-positive results. To address this concern, Lander graphically isolated population) has recruited 35 multi- and Kruglyak [12] proposed thresholds for significant plex SLE families (containing 73 patients and 96 healthy linkage (ie, a genome-wide significance of P < 0.05 cor- relatives) for the recent genome scan, providing support responds to a logarithm of odds score of 3.3 or 3.6, de- for linkage at 14q21-23, the HLA region, 5p13, and 6q25- pending on the linkage method used), suggestive link- 27 [22•]; (3) another recent genome scan of a cohort of 62 age (a logarithm of odds score of 1.9 or 2.2), and multiplex SLE families (containing 88 affected and 456 confirmed linkage (significant linkage from one or a com- total sibling pairs) has revealed evidence for linkage to bination of initial studies that has been confirmed with a four previously reported (1q23, 2q33, 16q12, and 17q21- P value of 0.01 in an independent sample). 23) and four novel (3p24, 10q23-24, 13q32, and 18q23) chromosomal regions [21•]. Individual genome scan of- Evidence for linkage to SLE of 1q41-42 was first shown ten lacks power to detect loci with modest gene effects. in a targeted genome screen of the human chromosome Increasing sample size by combining the data from all 1 region corresponding to the identified murine SLE nine of the genome-wide scans for SLE susceptibility susceptibility loci [13]. Subsequently, nine genome-wide loci is the most expedient approach to address this prob- linkage analyses [14–19,20•–22•] and six targeted ge- lem to improve the localization and the magnitude of nome scans [13,23–27] using separate cohorts have lo- linkage signal. cated many genomic segments that are likely to harbor SLE susceptibility genes. Cohorts studied in the nine The quite extensive clinical and laboratory heterogene- genome scans vary tremendously in their ethnic compo- ity of SLE has drawn many attempts to reduce disease sitions, sample sizes, family structures, and geographic heterogeneity, and presumably genetic heterogeneity. locations. Although not a single, common locus identi- One approach adopted by Harley et al. has been linkage fied in all these scans, eight loci (Table 1; 1q23, 1q25-31, analysis conditioned on pedigrees in which one family 1q41-42, 2q35-37, 4p16-15.2, 6p11-21, 12 q24, and member with SLE exhibiting a particular clinical mani- 16q12) have reached the threshold for significant linkage festation, which has yielded 10 recent publications re- to SLE [14–18,20•,23,27], and all eight have been con- porting strong evidence for linkage [28–33,34•,35,36•, firmed in at least one independent cohort for linkage to 37] (Table 2). A disadvantage of this approach is the SLE [15–17,19,20•,21•,24] using the Lander and Krug- reduced sample size after phenotype stratification, high- lyak [12] criteria for interpretation of linkage statistics. lighting the importance of independent verification of Replication of significant linkage of a locus offers the the findings. Recently, linkage at 5p13 to SLE stratifying strongest evidence for the existence of putative suscep- on families with one SLE member with self-reported tibility genes, which sets the stage for narrowing the rheumatoid arthritis has been confirmed [36•], whereas linked regions to localize susceptibility genes. These others await verification. Rather than conditioning on the eight chromosomal regions exhibiting strong and well- presence or absence of a single manifestation, a principal established linkage to SLE, and genes within some of component approach has used seven major SLE-related these linked regions that have been associated with phenotypes plus age at SLE onset and race to conduct SLE, are summarized in Table 1. Of note, the MHC- multivariate analysis of the genome scan data, identi-

Table 1. Chromosomal regions exhibiting confirmed significant linkage to systemic lupus erythematosus (SLE)

Chromosome 1 1 1 2 4 6 12 16

Cytogenetic location 1q23 1q25-31 1q41-42 2q35-37 4p16-15.2 6p11-21 12q24 16q12 Locus name SLEB1 SLEB2 SLEB3 SLEB4 Candidate genes* CRP, FCGR2A, PARP PDCD1 MHC haplotypes, OAZ FCGR2B, FCGR3A, C4Q0, TNFA PBX1

*Candidate genes within the linked interval that has been shown to be associated with SLE. Human systemic lupus erythematosus genetics Tsao 515

Table 2. Loci linked to systemic lupus erythematosus and the disease-predisposing gene) appear to be inher- identified using stratification of pedigrees in which one affected member exhibiting a specific clinical manifestation ited together more frequently than expected from their respective allele frequencies [11]. Because allele fre- Stratifying Locus Chromosome quencies are affected by the history of populations, false- manifestation name location Study positive associations may occur if controls are not Neuropsychiatric disorder SLEB3 4p16 [32] matched with the cases in ancestry (population stratifi- Anti-dsDNA antibodies SLED1 19p13.2 [29] SLED2 18q21.1 cation), which is not a potential problem for family-based SLED3 10q22.3 association tests. In the family-based TDT, the number Hemolytic anemia SLEH1 11q14 [28] of times a test allele is transmitted (or not transmitted) Nucleolar antinuclear SLEH1 11q14 [35] antibody from heterozygous parents to affected offspring is re- Renal disease SLEN1 10q22.3 [33] corded, and preferential transmission of the test allele SLEN2 2q34-35 (or a specific haplotype) provides evidence for associa- SLEN3 11p15.6 Self-reported rheumatoid SLER1 5p15.3 [30] and tion of the test allele (or haplotype) with disease suscep- arthritis confirmed tibility [41]. Applying this methodology in a collection in [36•] of hundreds of mainly white families containing patients Vitiligo SLEV1 17p13 [31] Thrombocytopenia 1q22-23 [34•] with SLE, the large genomic interval 6p11-21 linked to 11p13 SLE has been narrowed to a 500 kb to 1 Mb chromosomal Discoid lupus 11p13 [37] segment of 3 MHC class II-containing risk haplotypes— erythematosus DRB1*1501 (DR2)/DQB1*0602, DRB1*0801 (DR8)/DQB1*0402, and DRB1*0301 (DR3)/DQB1*0201 [42]. The systematic evaluation of the linked chromo- fying suggestive linkage of several SLE-related traits somal region and the large sample size used in the fam- [38]. The clinical implications of the stratification ily-based TDT makes it the best HLA study in SLE method seem less clear in another study [38]. The same genetics to date. Another TDT based study of white (or enlarged) genome scan data from the OMRF SLE families also confirmed the association between multiplex pedigrees have been used to conduct one prin- DRB1*1501 and SLE [43]. cipal component analysis [38], two affected relative pair linkage analyses [17,39], and 10 linkage analyses on se- Candidate susceptibility gene lected pedigrees with one affected member having one Case-control association studies have identified several particular clinical manifestation [20•,28–33,34•,35,37], genes exhibiting convincing evidence for allelic associa- which raises the possibility of false discoveries as the tion with SLE, including certain MHC alleles (haplo- result of multiple testing. Familiality of thrombocytope- types), inherited deficiency in a classical complement nia, discoid rash, neurologic disorder (defined as seizure component (C1q, C1r, C1s, C4A, and C2), and genes or psychosis), hemolytic anemia, co-occurring neurologic encoding low-affinity receptors for the Fc region of IgG disorder plus hemolytic anemia, and age at SLE diagno- (FCGR2A and FCGR3A). Hereditary deficiency of early sis has been observed in 159 sibling pairs affected with components of the classical complement pathway (C1q, SLE [40]. Linkage to familial subphenotypes of SLE C2, and C4) has been strongly associated with SLE sus- may reduce heterogeneity and facilitate the localization ceptibility [44]. This association is paradoxical because of genes predisposing to a particular clinical manifesta- complement is a mediator of inflammation. Homozygous tion. Now that many chromosomal regions of positive C1q deficiency is extremely rare (approximately 40 re- linkage to SLE have been identified, the current task is ported cases) but is a powerful disease susceptibility to narrow the chromosomal regions exhibiting convinc- gene, because >90% of these patients develop SLE. A ing evidence for linkage and to assess genes within the significant portion of C1q-deficient mice spontaneously SLE-linked genomic segments for the identification of develop glomerulonephritis with immune deposits in putative SLE susceptibility genes. certain genetic backgrounds but not in others, suggesting the importance of gene–gene interactions in developing Fine mapping lupuslike disease [45,46]. Functionally, C1q participates Chromosomal regions linked to complex diseases, such in clearance of apoptotic cells and thus plays a role in the as SLE, identified by the initial whole genome scans are maintenance of the immune tolerance. usually rather large (10–30 cM), containing 100 to 300 genes. A method to reduce sufficiently the number of The positional genetics approach from linkage to locate candidate genes is to use narrow the linked interval the putative susceptibility alleles within the chromosom- based on linkage disequilibrium mapping, either using a al region linked to the disease had proven to be ex- population based case-control study or a family-based tremely difficult until recent successful examples of the transmission disequilibrium test (TDT). Linkage dis- identification of NOD2/CARD15 in Crohn disease [47,48] equilibrium occurs when certain alleles of neighboring and ADAM33 in asthma [49]. In both cases, evidence for loci (as an example, the tested genetic polymorphism linkage has been replicated in a number of clinically 516 Systemic lupus erythematosus and Sjögren syndrome well-characterized cohorts, emphasizing the importance Asian descent, but not for SLE susceptibility per se in the of convincing evidence for linkage to justify costly efforts absence of nephritis [52•]. in fine mapping and gene identification. In SLE, some candidate genes located within the identified SLE- Because IgG2 and IgG3 are major subclasses of ICs de- linked genomic intervals (positional candidate genes) posited in renal biopsies of patients with lupus nephritis have been associated with SLE (Table 1). Results of [53•], the relative importance of Fc␥RIIa-H/R131 and these studies are reviewed here. Fc␥RIIIa-V/F158 polymorphisms might depend on the IgG subclass of pathogenic autoantibodies in each patient. Fc␥RIIa-R131 and Fc␥RIIIa-F158 may not be in- Systemic lupus erythematosus-associated dependent risk alleles and often are inherited together genes at 1q23 on the same chromosome as a single risk haplotype for FCGR2A, FCGR3A, FCGR3B, and FCGR2B, a cluster of SLE [54•], and the presence of multiple at-risk alleles of four genes at 1q23, encode low-affinity receptors for IgG genes affecting immune complex clearance may interact containing ICs. Genetic polymorphisms of these four to enhance risk for SLE [55•]. Haplotype studies suggest genes, especially alleles of FCGR2A and FCGR3A, have linkage disequilibrium between Fc␥RIIa-H/R131 and been associated with SLE. Fc␥RIIa and Fc␥RIIIa mol- Fc␥RIIIa-V/F158 in some but not in other studied popu- ecules are cell surface receptors with immunoreceptor lations (discussed in [52•]). Although both of these gene tyrosine-based activation motifs in their cytoplasmic variants have shown evidence for linkage to SLE [15,56], tails, which could trigger cellular activation processes on they may not be sufficient to account for the observed receptor cross-linking by IgG containing ICs (reviewed linkage at 1q23 to SLE, suggesting the possibility of in [50]). A single nucleotide polymorphism (SNP) in ge- additional SLE susceptibility genes in their flanking re- nomic DNA results in either the histidine [H] or the gions. Other neighboring genes have also been associ- arginine [R] residue at codon 131 of Fc␥RIIa (CD32). ated with SLE, including Fc␥RIIIb-NA1/2, Fc␥RIIb- Compared with Fc␥RIIa-H131, Fc␥RIIa-R131 binds I/T 232, C-reactive protein (CRP), and PBX1. less efficiently to IgG2 and might delay clearance of IgG2 containing ICs [50]. The relation between R/H 131 Fc␥RIIb expressed on the surface of B cells contains an and susceptibility to SLE and lupus nephritis has been immunoreceptor tyrosine-based inhibitory motif, which assessed in >20 studies of several ethnic groups, yielding negatively regulates immunoreceptor tyrosine-based ac- inconsistent results. A meta-analysis of 17 studies has tivation motif-dependent activation. The Fc␥RIIb-I/T concluded that the low-binding R131 allele confers a 232 polymorphism that may alter the inhibitory function 1.3-fold risk for developing SLE, but not lupus nephritis [57•] has been associated with SLE susceptibility in [51]. The modest relative risk for SLE (and no signifi- Japanese [58] but not in African American, US white, and cant risk for lupus nephritis) might be an underestimate Swedish populations [54•,57•]. Recently, the association influenced by genetic heterogeneity, genotyping errors, of Fc␥RIIb-T232 allele and SLE has been confirmed in and/or low penetrance of genotypic effects. Genotyping Thais and Chinese [59••,60•], suggesting that it may be errors are a serious concern because extensive sequence a common susceptibility gene in Asian populations. homology among Fc␥R genes makes it difficult to achieve highly specific PCR-based genotyping assays, Within 1q23.2, CRP gene has been considered as a lupus especially in earlier studies in which the human genome candidate gene. Recent studies have shown genetic consequence database is not available. tribution to individual variation in basal levels of CRP [61••,62]. An intronic microsatellite GT repeat has been Fc␥RIIIa (CD16) binds to both IgG1 and IgG3 contain- associated with serum CRP levels, but not with SLE ing ICs and is expressed on cell surfaces of NK cells, susceptibility [62]. The minor alleles of two novel SNPs monocytes, and macrophages. A T/G polymorphism re- within CRP locus (CRP2 corresponds to a synonymous sults in phenylalanine (F)/valine (V) at amino acid 176 substitution of codon 188, and CRP4 is located in the 3Ј (including the leader sequence or amino acid 158 exclud- flanking/untranslated region) may independently lower ing the leader sequence), and people homozygous for basal CRP levels, and the minor allele of CRP4 is asso- F/F bind IgG1 and IgG3 containing ICs less efficiently ciated with SLE and the production of antinuclear anti- than those with V/V genotypes (reviewed in [50]). Asso- bodies [61••]. CRP is a pentraxin protein that binds to ciation between the Fc␥RIIIa-V/F158 polymorphism ribonucleoproteins and polar phospholipid materials re- and susceptibility to SLE and/or to lupus nephritis has leased during apoptosis, autoantigens of SLE. Relative been reported in some but not in other similar studies. A deficiency of CRP may predispose to the production of meta-analysis of more than 1000 subjects in each of the ANA, leading to the development of SLE. three categories (lupus nephritis, SLE without renal involvement, and non-SLE controls) has concluded that Linkage disequilibrium analyses of a 10-cM interval of the F158 allele confers a 1.2-fold risk for developing 1q23-24 have recently suggested the presence of a novel lupus nephritis in patients of European, African, and SLE susceptibility gene, pre–B-cell leukemia transcrip- Human systemic lupus erythematosus genetics Tsao 517 tion factor (PBX1), using a cohort of 210 Chinese patients the 85-bp allele is not associated with SLE susceptibility with SLE and their parents [63]. PBX1 is expressed at in most studies. It might be informative to analyze lower levels in peripheral blood leukocytes of patients whether PARP promoter haplotypes containing the CA with SLE compared with normal controls. PBX1 SNP polymorphism are associated with SLE, and to fine-map haplotypes (G-C-C and G-C-C-G) were associated with further the 1q41-42 region linked to SLE [25] to localize SLE in 262 Chinese families, and the SLE-associated other positional candidate genes. haplotypes were replicated in 149 white families, implicating PBX1 as a susceptibility gene within the 1q23 locus linked to SLE susceptibility [64]. Systemic lupus erythematosus-associated genes at 2q37 In summary, the strong linkage at 1q23 to SLE observed PDCD1 located within 2q37 has recently been associated in many cohorts may reflect multiple genetic factors lo- with SLE [10]. PDCD1 is a member of the CD28/cyto- cated within this genomic interval to reach the threshold toxic T-lymphocyte antigen 4 gene/ICOS costimulatory for linkage detection. In association studies, each tested receptor family, which delivers inhibitory signals that gene allele has low to modest genetic effect in various have profound effects on T-cell and B-cell immunity studied cohorts, which makes convincing evidence of a (reviewed in [74]). Mice deficient in PDCD1 develop lupus susceptibility gene a challenging goal. glomerulonephritis and arthritis in the C57BL/6 background [75] and autoimmune dilated cardiomyopathy in Systemic lupus erythematosus-associated the BALB/c background [76]. A large study of ∼2500 genes at 1q41-42 people has shown association between an intronic SNP PARP (PARP1, ADP-ribosyltransferase, ADP-ribosyl- (PD1.3A, also known as the minor A allele of 7146 G/A) transferase 1, or poly[ADP ribose] synthetase), located in PDCD1 and SLE susceptibility in Europeans and on 1q42, encodes a nuclear enzyme that mediates ADP- Mexicans [10]. The SLE-associated SNP affects a bind- ribosylation of proteins. The PARP activity is induced ing site of a transcription factor RUNX1 in an intronic strongly by DNA strand breaks and plays a role in DNA enhancer, suggesting a potential functional mechanism repair, proliferation, stress response, apoptosis, genomic predisposing to SLE. This SLE-associated SNP is found stability, and malignancy [65]. Autoantibodies to PARP more frequently in female patients with lupus nephritis are frequently found in patients affected with autoim- from Sweden but is not confirmed in female patients mune diseases [66], some of which may prevent caspase- with SLE from the United States of European American 3–mediated PARP cleavage during apoptosis, resulting descent, suggesting genetic heterogeneity [77••]. Be- in accumulation of autoimmune cells [67]. A polymor- cause the 2q35-37 linked region has not been systemati- phic CA dinucleotide repeat located close to a transcrip- cally evaluated, it is not entirely clear whether this tion factor binding site within the PARP promoter region PDCD1 intronic SNP accounts for the observed linkage. might affect transcription [68], which has been associ- A PDCD1 SNP located in exon 5 (C+872T) has recently ated with SLE [23]. Skewed transmission of PARP al- been associated with rheumatoid arthritis, but not SLE, leles is observed from heterozygous parents of 124 fami- in a Chinese population [8]. Because this rheumatoid lies to their oldest affected offspring, but not to arthritis-associated SNP causes no change in the en- unaffected offspring, and the 85-bp PARP allele is sig- coded amino acid, it is unlikely to play a role in risk for nificantly associated with SLE, whereas the 97-bp allele the disease, but may be in linkage disequilibrium with is protective [23]. However, a similar family-based asso- the disease risk allele. The minor allele of the intronic ciation study fails to confirm the association between the 7146G/A SNP has recently been associated with type 1 PARP allele 85 and SLE [69]. Case-control studies in diabetes [9•], in addition to the previously demonstrated French and German white subjects show no significant association with SLE [10]. It appears that PDCD1 poly- association [70,71]. A significant difference in allele fre- morphisms may be a shared genetic factor for multiple quencies of PARP CA repeat is observed between Afri- autoimmune diseases in humans, similar to observations can American patients with SLE and their ethnically in knockout mice. However, the specific disease- matched controls, suggesting that PARP alleles might be associated genetic polymorphism and the resulting in linkage disequilibrium with the disease locus in this functional consequences leading to the occurrence of the African American cohort [72]. Recently, a specific PARP disease have not been well characterized as yet. Of in- promoter haplotype, containing the CA repeats and four terest, two recent publications report that individual additional SNPs, was associated with rheumatoid arthri- SNPs affecting a RUNX1 binding site are associated tis in a Spanish population [73•]. Within the rheumatoid with rheumatoid arthritis [78••] and psoriasis [79•], arthritis-associated PARP haplotype, the 97-bp CA re- highlighting the potential importance of a loss of a peat, a SLE protective allele [23], might be the rheuma- RUNX1 binding site in susceptibility to an autoimmune toid arthritis-predisposing marker [73•]. The cumulative disease [80••]. These exciting findings await validation data show that skewed allele distributions of the PARP by independent confirmation and further functional CA repeat have been observed in two studies, although studies. 518 Systemic lupus erythematosus and Sjögren syndrome

Systemic lupus erythematosus-associated other susceptibility loci to manifest multiple autoim- genes at 6p11-21 mune disorders. In SLE, evidence for genetic interaction The HLA-DR2 and DR3 class II genes are consistently of the 16q12 locus and other susceptibility loci has been associated with SLE in many studied white populations, reported by two groups [91•,92]. The identification of with a twofold relative risk conferred by each allele [81]. three SNPs of NOD2/CARD15 as independent risk factor The HLA complex contains many genes important in for Crohn disease has made this gene an excellent posi- immune responses, and the strong linkage disequilib- tional candidate gene for SLE. However, case-control rium within the MHC region makes it challenging to studies in Spanish and Chinese populations have shown delineate the relative importance of each gene compo- no association between NOD2/CARD15 and SLE nent in risk for SLE. For an example, the extended [93•,94•]. Fine mapping of 16q12 has led to the identi- MHC haplotypes −HLA-A1, B8, C4AQ0, C4B1, DR3 fication of a novel gene OLF1/EBF-associated zinc fin- (DRB1*0301), and DQ2 contain two class III gene al- ger protein, associated with SLE in a preliminary report leles (C4AQ0 and −308A TNFA) that have been impli- [95•]. Further studies are in progress to identify the cau- cated in SLE susceptibility. C4AQ0 (deficiency of C4A), sal gene variants and to delineate their roles in develop- either heterozygous or homozygous deficiency, is found ing SLE. in 40 to 60% of patients with SLE from multiple ethnic groups (recently reviewed in [82••]). Murine studies Conclusion have supported a role of C4 in immune tolerance, pre- Multiple susceptibility genes clearly contribute to the venting the development of SLE [83,84]. The minor development of SLE. Linkage analyses in SLE have allele (−308A, TNF2) has been shown in most studies to identified a few susceptibility loci exhibiting strong link- ␣ be associated with high TNF- production and with the age that have been confirmed or supported in other in- occurrence of SLE (reviewed in [85]). A strong associa- dependent studies (Table 1). Many potentially interest- tion between the −308A allele with subacute cutaneous ing loci await further evidence for harboring a disease lupus erythematosus has been reported, which may con- gene. Systematic narrowing the linked interval has been tribute to ultraviolet-induced photosensitivity of these successfully conducted within the MHC region. Within patients [86]. these most promising loci linked to SLE, candidate The human genome project provides the entire se- genes that have shown evidence for association with quence of the MHC region, permitting the construction SLE are reviewed. Recent association studies of PDCD1 of a dense map of microsatellites encompassing the com- have suggested that a single gene may contribute to mul- plete region. Using genotypes of these MHC markers tiple autoimmune diseases. The SLE-associated PDCD1 from ∼300 families, three class II-containing SLE risk polymorphism disrupts a binding site of RUNX1 tran- haplotypes (DRB1*1501 (DR2)/DQB1*0602, DRB1* scription factor, which may be a common mechanism in 0801 (DR8)/DQB1*0402, and DRB1*0301 susceptibility to other autoimmune diseases. Further (DR3)/DQB1*0201) have been identified by the TDT replications of linkage and association are the immediate method [42]. In this systematic fine mapping experi- task. The respective contribution of each susceptibility ment, both the class I and III regions (including the gene, relationships between genotypes and phenotypes, genes encoding TNF-␣, and complement C2 and C4) and potential interactions between susceptibility gene may be excluded from the critical risk region (∼500 kb) products need to be elucidated. This line of investiga- of the DRB1*1501 extended haplotype. The excessive tions is now well poised to provide novel insights into linkage disequilibrium of the DRB1*0301-containing how genetic variants can affect functional pathways lead- haplotype reduces ancestral recombinants, resulting in a ing to the development of SLE. ∼1 Mb critical genomic segment of most class II and III regions. The risk interval of DRB1* 0801 haplotypes has References and recommended reading ∼ been narrowed to 500 kb. The estimated genotype rela- Papers of particular interest, published within the annual period of review, tive risk for each of the three haplotypes is between have been highlighted as: 1.9-fold and 2.6-fold, and people with two copies of risk • Of special interest haplotypes exhibit a dose-dependent increased risk (3.5- •• Of outstanding interest fold to 6.8-fold) for SLE. This extensive study is per- 1 Tsao BP: The genetics of human systemic lupus erythematosus. Trends Im- formed mainly in white subjects; similar studies in non- • munol 2003, 24:595–602. A useful review describing earlier studies and basic concepts of the genetic basis white subjects are needed to elucidate the MHC risk of SLE. haplotypes for SLE. 2 Priori R, Medda E, Conti F, et al.: Familial autoimmunity as a risk factor for Systemic lupus erythematosus-associated • systemic lupus erythematosus and vice versa: a case-control study. Lupus 2003, 12:735–740. genes at 16q12 An interesting study supports shared risk factors among autoimmune diseases. The 16q12 region has linked not only to SLE but also to 3 Becker KG, Simon RM, Bailey-Wilson JE, et al.: Clustering of non-major his- other autoimmune diseases [87–90], suggesting the pos- tocompatibility complex susceptibility candidate loci in human autoimmune sibility of a shared susceptibility gene interacting with diseases. Proc Natl Acad SciUSA1998, 95:9979–9984. Human systemic lupus erythematosus genetics Tsao 519

4 Ueda H, Howson JM, Esposito L, et al.: Association of the T-cell regulatory sion disequilibrium of marker haplotypes at chromosome 1q41 in human sys- •• gene CTLA4 with susceptibility to autoimmune disease. Nature 2003, temic lupus erythematosus. Arthritis Res 2001, 3:299–305. 423:506–511. An important study showing a common susceptibility gene for more than one au- 26 Magnusson V, Lindqvist AK, Castillejo-Lopez C, et al.: Fine mapping of the toimmune disease. SLEB2 locus involved in susceptibility to systemic lupus erythematosus. Ge- nomics 2000, 70:307–314. 5 Lesage S, Zouali H, Cezard JP, et al.: CARD15/NOD2 mutational analysis 27 and genotype-phenotype correlation in 612 patients with inflammatory bowel Johanneson B, Lima G, Von Salome J, et al.: A major susceptibility locus for disease. Am J Hum Genet 2002, 70:845–857. systemic lupus erythematosus maps to chromosome 1q31. Am J Hum Genet 2002, 71:1060–1071. 6 Rahman P, Bartlett S, Siannis F, et al.: CARD15: a pleiotropic autoimmune 28 Kelly JA, Thompson K, Kilpatrick J, et al.: Evidence for a susceptibility gene • gene that confers susceptibility to psoriatic arthritis. Am J Hum Genet 2003, 73:677–681. (SLEH1) on chromosome 11q14 for systemic lupus erythematosus (SLE) An interesting study implicating CARD15 (an established susceptibility gene for families with hemolytic anemia. Proc Natl Acad SciUSA2002, 99:11766– Crohn disease) in risk for psoriatic arthritis. 11771. 29 Namjou B, Nath SK, Kilpatrick J, et al.: Genome scan stratified by the pres- 7 Miceli-Richard C, Lesage S, Rybojad M, et al.: CARD15 mutations in Blau ence of anti-double-stranded DNA (dsDNA) autoantibody in pedigrees mul- syndrome. Nat Genet 2001, 29:19–20. tiplex for systemic lupus erythematosus (SLE) establishes linkages at 8 Lin SC, Yen JH, Tsai JJ, et al.: Association of a programmed death 1 gene 19p13.2 (SLED1) and 18q21.1 (SLED2). Genes Immun 2002, 3(suppl 1): polymorphism with the development of rheumatoid arthritis, but not systemic S35–S41. lupus erythematosus. Arthritis Rheum 2004, 50:770–775. 30 Namjou B, Nath SK, Kilpatrick J, et al.: Stratification of pedigrees multiplex for 9 Nielsen C, Hansen D, Husby S, et al.: Association of a putative regulatory systemic lupus erythematosus and for self-reported rheumatoid arthritis de- • polymorphism in the PD-1 gene with susceptibility to type 1 diabetes. Tissue tects a systemic lupus erythematosus susceptibility gene (SLER1) at 5p15.3. Antigens 2003, 62:492–497. Arthritis Rheum 2002, 46:2937–2945. This gene variant has been associated with SLE previously. 31 Nath SK, Kelly JA, Namjou B, et al.: Evidence for a susceptibility gene, SLEV1, 10 Prokunina L, Castillejo-Lopez C, Oberg F, et al.: A regulatory polymorphism in on chromosome 17p13 in families with vitiligo-related systemic lupus erythe- PDCD1 is associated with susceptibility to systemic lupus erythematosus in matosus. Am J Hum Genet 2001, 69:1401–1406. humans. Nat Genet 2002, 32:666–669. 32 Nath SK, Kelly JA, Reid J, et al.: SLEB3 in systemic lupus erythematosus 11 Lander ES, Schork NJ: Genetic dissection of complex traits. Science 1994, (SLE) is strongly related to SLE families ascertained through neuropsychiatric 265:2037–2048. manifestations. Hum Genet 2002, 111:54–58. 12 Lander ES, Kruglyak L: Genetic dissection of complex traits: guidelines for 33 Quintero-Del-Rio AI, Kelly JA, Kilpatrick J, et al.: The genetics of systemic interpreting and reporting linkage results. Nat Genet 1995, 11:241–247. lupus erythematosus stratified by renal disease: linkage at 10q22.3 (SLEN1), 2q34-35 (SLEN2), and 11p15.6 (SLEN3). Genes Immun 2002, 3(suppl 1): 13 Tsao BP, Cantor RM, Kalunian KC, et al.: Evidence for linkage of a candidate S57–S62. chromosome 1 region to human systemic lupus erythematosus. J Clin Invest 34 1997, 99:725–731. Scofield RH, Bruner GR, Kelly JA, et al.: Thrombocytopenia identifies a severe • familial phenotype of systemic lupus erythematosus and reveals genetic link- 14 Gaffney PM, Kearns GM, Shark KB, et al.: A genome-wide search for sus- ages at 1q22 and 11p13. Blood 2003, 101:992–997. ceptibility genes in human systemic lupus erythematosus sib-pair families. This study suggests chromosomal locations of genes contributing to thrombocy- Proc Natl Acad SciUSA1998, 95:14875–14879. topenia, a manifestation associated with poor prognosis. 15 Moser KL, Neas BR, Salmon JE, et al.: Genome scan of human systemic lupus 35 Sawalha AH, Namjou B, Nath SK, et al.: Genetic linkage of systemic lupus erythematosus: evidence for linkage on chromosome 1q in African-American erythematosus with chromosome 11q14 (SLEH1) in African-American fami- pedigrees. Proc Natl Acad SciUSA1998, 95:14869–14874. lies stratified by a nucleolar antinuclear antibody pattern. Genes Immun 2002, 3(suppl 1):S31–S34. 16 Gaffney PM, Ortmann WA, Selby SA, et al.: Genome screening in human systemic lupus erythematosus: results from a second Minnesota cohort and 36 Nath SK, Namjou B, Garriott CP, et al.: Linkage analysis of SLE susceptibility: combined analyses of 187 sib-pair families. Am J Hum Genet 2000, 66:547– • confirmation of SLER1 at 5p15.3. Genes Immun 2004, 5:209–214. 556. This study presents the first confirmation of linkage analysis stratifying pedigrees in which one member has self-reported rheumatoid arthritis. 17 Gray-McGuire C, Moser KL, Gaffney PM, et al.: Genome scan of human systemic lupus erythematosus by regression modeling: evidence of linkage and 37 Nath SK, Namjou B, Kilpatrick J, et al.: A candidate region on 11p13 for epistasis at 4p16-15.2. Am J Hum Genet 2000, 67:1460–1469. systemic lupus erythematosus: a linkage identified in African-American families. J Investig Dermatol Symp Proc 2004, 9:64–67. 18 Lindqvist AK, Steinsson K, Johanneson B, et al.: A susceptibility locus for human systemic lupus erythematosus (hSLE1) on chromosome 2q. J Auto- 38 Rao S, Olson JM, Moser KL, et al.: Linkage analysis of human systemic lupus immun 2000, 14:169–178. erythematosus-related traits: a principal component approach. Arthritis Rheum 2001, 44:2807–2818. 19 Shai R, Quismorio FP Jr, Li L, et al.: Genome-wide screen for systemic lupus 39 erythematosus susceptibility genes in multiplex families. Hum Mol Genet Olson JM, Song Y, Dudek DM, et al.: A genome screen of systemic lupus 1999, 8:639–644. erythematosus using affected-relative- pair linkage analysis with covariates demonstrates genetic heterogeneity. Genes Immun 2002, 3(suppl 1): 20 Nath SK, Quintero-Del-Rio AI, Kilpatrick J, et al.: Linkage at 12q24 with sys- S5–S12. temic lupus erythematosus (SLE) is established and confirmed in Hispanic • 40 Tsao BP, Grossman JM, Riemekasten G, et al.: Familiality and co-occurrence and European American families. Am J Hum Genet 2004, 74:73–82. of clinical features of systemic lupus erythematosus. Arthritis Rheum 2002, This study presents strong evidence for linkage of 12q24 to SLE. 46:2678–2685. 21 Cantor RM, Yuan J, Napier S, et al.: Systemic lupus erythematosus genome 41 Spielman RS, McGinnis RE, Ewens WJ: Transmission test for linkage dis- scan: support at 1q23, 2q33, 16q12 and 17q21 and novel evidence at 3p24, • equilibrium: the insulin gene region and insulin-dependent diabetes mellitus 10q23, 13q32 and 18q23. 2004, submitted. (IDDM). Am J Hum Genet 1993, 52:506–516. This study shows results of a new genome scan using an independent US cohort. 42 Graham RR, Ortmann WA, Langefeld CD, et al.: Visualizing human leukocyte 22 Koskenmies S, Lahermo P, Julkunen H, et al.: Linkage mapping of systemic antigen class II risk haplotypes in human systemic lupus erythematosus. AmJ lupus erythematosus (SLE) in Finnish families multiply affected by SLE. J Med • Hum Genet 2002, 71:543–553. Genet 2004, 41:e2–e5. 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the effects of genetic background on disease expression. J Immunol 2002, antibodies in autoimmune rheumatic and bowel diseases. Arthritis Rheum 168:2538–2543. 1998, 41:918–926. 47 Hugot JP, Chamaillard M, Zouali H, et al.: Association of NOD2 leucine-rich 67 Decker P, Isenberg D, Muller S: Inhibition of caspase-3-mediated poly(ADP- repeat variants with susceptibility to Crohn’s disease. Nature 2001, ribose) polymerase (PARP) apoptotic cleavage by human PARP autoantibod- 411:599–603. ies and effect on cells undergoing apoptosis. J Biol Chem 2000, 275:9043– 9046. 48 Ogura Y, Bonen DK, Inohara N, et al.: A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature 2001, 411:603–606. 68 Oei SL, Shi Y: Poly(ADP-ribosyl)ation of transcription factor Yin Yang 1 under conditions of DNA damage. Biochem Biophys Res Commun 2001, 49 Van Eerdewegh P, Little RD, Dupuis J, et al.: Association of the ADAM33 285:27–31. gene with asthma and bronchial hyperresponsiveness. Nature 2002, 418:426–430. 69 Criswell LA, Moser KL, Gaffney PM, et al.: PARP alleles and SLE: failure to confirm association with disease susceptibility [letter]. J Clin Invest 2000, 50 Salmon JE, Pricop L: Human receptors for immunoglobulin G: key elements in 105:1501–1502. the pathogenesis of rheumatic disease. Arthritis Rheum 2001, 44:739–750. 70 Delrieu O, Michel M, Frances C, et al.: Poly(ADP-ribose) polymerase alleles in 51 Karassa FB, Trikalinos TA, Ioannidis JP: Role of the Fcgamma receptor IIa French Caucasians are associated neither with lupus nor with primary anti- polymorphism in susceptibility to systemic lupus erythematosus and lupus phospholipid syndrome. GRAID Research Group. Group for Research on nephritis: a meta-analysis. Arthritis Rheum 2002, 46:1563–1571. Auto-Immune Disorders. 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Rheum 2003, 48:460–470. 73 Pascual M, Lopez-Nevot MA, Caliz R, et al.: A poly(ADP-ribose) polymerase A well-conducted study exploits the relationship between genotypes and disease • haplotype spanning the promoter region confers susceptibility to rheumatoid phenotypes. arthritis. Arthritis Rheum 2003, 48:638–641. 54 Magnusson V, Johanneson B, Lima G, et al.: Both risk alleles for Fcgamma- This is the first study implicating this gene in the pathogenesis of rheumatoid ar- • RIIA and FcgammaRIIIA are susceptibility factors for SLE: a unifying hypoth- thritis. esis. Genes Immun 2004, 5:130–137. 74 Nishimura H, Honjo T: PD-1: an inhibitory immunoreceptor involved in periph- This study presents data supporting an interesting hypothesis. eral tolerance. Trends Immunol 2001, 22:265–268. 55 Sullivan KE, Jawad AF, Piliero LM, et al.: Analysis of polymorphisms affecting 75 Nishimura H, Nose M, Hiai H, et al.: Development of lupus-like autoimmune • immune complex handling in systemic lupus erythematosus. Rheumatology diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying 2003, 42:446–452. immunoreceptor. Immunity 1999, 11:141–151. This study addresses the pathways that genetic risk factors may play a role. 76 Nishimura H, Okazaki T, Tanaka Y, et al.: Autoimmune dilated cardiomyopathy 56 Edberg JC, Langefeld CD, Wu J, et al.: Genetic linkage and association of in PD-1 receptor-deficient mice. Science 2001, 291:319–322. Fcgamma receptor IIIA (CD16A) on chromosome 1q23 with human systemic lupus erythematosus. Arthritis Rheum 2002, 46:2132–2140. 77 Prokunina L, Gunnarsson I, Sturfelt G, et al.: The systemic lupus erythemato- •• sus-associated PDCD1 polymorphism PD1.3A in lupus nephritis. 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Arthritis Rheum 2002, A provocative finding implicating an unexpected candidate gene. 46:1242–1254. 79 Helms C, Cao L, Krueger JG, et al.: A putative RUNX1 binding site variant 59 Chu ZT, Tsuchiya N, Kyogoku C, et al.: Association of Fcgamma receptor IIb • between SLC9A3R1 and NAT9 is associated with susceptibility to psoriasis. •• polymorphism with susceptibility to systemic lupus erythematosus in Chi- Nat Genet 2003, 35:349–356. nese: a common susceptibility gene in the Asian populations. Tissue Antigens An interesting study supporting a role of regulatory SNPs in the pathogenesis of 2004, 63:21–27. autoimmune diseases. This study suggests ethnic variations in susceptibility genes. 80 Alarcon-Riquelme ME: A RUNX trio with a taste for autoimmunity. 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87 Hugot JP, Laurent-Puig P, Gower-Rousseau C, et al.: Mapping of a suscep- 92 Tsao BP, Cantor RM, Grossman JM, et al.: Linkage and interaction of loci on tibility locus for Crohn’s disease on chromosome 16. Nature 1996, 379:821– 1q23 and 16q12 may contribute to susceptibility to systemic lupus erythe- 823. matosus. Arthritis Rheum 2002, 46:2928–2936. 88 Jawaheer D, Seldin MF, Amos CI, et al.: A genomewide screen in multiplex 93 Chong WP, Ip WK, Lau CS, et al.: Common NOD2 polymorphisms in Hong rheumatoid arthritis families suggests genetic overlap with other autoimmune Kong Chinese patients with systemic lupus erythematosus. Rheumatology diseases. Am J Hum Genet 2001, 68:927–936. • 2004, 43:104–105. 89 Nair RP, Henseler T, Jenisch S, et al.: Evidence for two psoriasis susceptibility Although results are negative, this is an important study. loci (HLA and 17q) and two novel candidate regions (16q and 20p) by genome-wide scan. Hum Mol Genet 1997, 6:1349–1356. 94 Ferreiros-Vidal I, Garcia-Meijide J, Carreira P, et al.: The three most common CARD15 mutations associated with Crohn’s disease and the chromosome 90 Tromp G, Kuivaniemi H, Raphael S, et al.: Genetic linkage of familial granu- • 16 susceptibility locus for systemic lupus erythematosus. Rheumatology (Ox- lomatous inflammatory arthritis, skin rash, and uveitis to chromosome 16.Am ford) 2003, 42:570–574. J Hum Genet 1996, 59:1097–1107. An important study with negative results. 91 Gillett CD, Graham RR, Rodine PR, et al.: The human systemic lupus erythe- • matosus locus (SLE) at 16q12 is linked to renal disease and shows evidence 95 Shen N, Feng X-BCSL, Qian J, et al.: Identification of a novel candidate gene for epistatic interaction with other identified SLE loci [abstract]. Arthritis • within the putative SLE susceptibility locus at 16q12 in a Chinese cohort Rheum 2003, 48:S257. [abstract]. Arthritis Rheum 2003, 48:S257. An interesting preliminary study. An interesting preliminary study suggesting a new candidate gene. Apoptosis and estrogen deficiency in primary Sjo¨ gren syndrome Yoshio Hayashi, Rieko Arakaki and Naozumi Ishimaru

Purpose of review Current Opinion in Rheumatology 2004, 16:522–526 Primary Sjo¨ gren syndrome is an autoimmune disorder Abbreviations characterized by lymphocytic infiltrates and destruction of the AICD activation-induced cell death salivary and lacrimal glands, and systemic production of FasL Fas ligand SS Sjo¨ gren syndrome autoantibodies to the ribonucleoprotein particles SS-A/Ro and TCR T-cell antigen receptor SS-B/La. The purpose of this review is to discuss recent © 2004 Lippincott Williams & Wilkins advances in the pathogenesis of primary Sjo¨ gren syndrome. 1040–8711 Recent findings Although several candidate autoantigens including ␣-fodrin have been reported in Sjo¨ gren syndrome, the pathogenic roles of the autoantigens in initiation and progression of SS are still Introduction unclear. It is possible that individual T cells activated by an Organ-specific autoimmune diseases are characterized appropriate self antigen can proliferate and form a restricted by tissue destruction and functional decline due to au- clone. Recent evidence suggests that the apoptotic pathway toreactive T cells that escape self-tolerance [1,2]. Sjo¨gren plays a central role in tolerizing T cells to tissue-specific self syndrome (SS) is a T-cell-mediated autoimmune disorder characterized by lymphocytic infiltrates and destruc- antigen, and may drive the autoimmune phenomenon. tion of the salivary and lacrimal glands, and systemic Cleavage of certain autoantigens during apoptosis may reveal production of autoantibodies to the ribonucleoprotein immunocryptic epitopes that could potentially induce particles SS-A/Ro and SS-B/La [3,4]. Autoreactive T autoimmune response. The studies reviewed imply that cells bearing CD4 molecule may recognize unknown au- Fas-mediated cytotoxicity and caspase-mediated ␣-fodrin toantigen triggering autoimmunity in the salivary and proteolysis are involved in the progression of tissue lacrimal glands, leading to clinical symptoms of dryness destruction in Sjo¨ gren syndrome. Fas ligand (FasL), and its of the mouth and eyes (sicca syndrome) [5]. It is now receptor Fas are essential in the homeostasis of the peripheral evident that the interaction of Fas with FasL regulates a immune system. It can be considered that a defect in large number of pathophysiological processes of apopto- activation-induced cell death of effector T cells may result in sis including autoimmune diseases [6]. Recent studies the development of autoimmune exocrinopathy in Sjo¨ gren have now confirmed the observation that apoptotic cells syndrome. in various cell types are implicated as the source of au- Summary toantigen when stimulated with different proapoptotic Although the mechanisms by which estrogen deficiency stimuli [7,8]. Although cleavage of certain autoantigens influences autoimmune lesions remain unclear, it is possible during apoptosis may reveal immunocryptic epitopes that antiestrogenic actions might be a potent factor in the that could potentially induce autoimmune responses in formation of pathogenic autoantigens. systemic autoimmune diseases [9], accumulated evi- dences suggest an important role of apoptosis in disease Keywords pathogenesis of Sjo¨gren syndrome [10]. Sjo¨ gren syndrome, apoptosis, activation-induced cell death, estrogen deficiency Apoptotic cells in Sjo¨ gren syndrome Recent studies have suggested that the Fas-Fas ligand Curr Opin Rheumatol 16:522–526. © 2004 Lippincott Williams & Wilkins. (FasL) system plays a major role on the induction of apoptosis in target organs with autoimmune diseases such as autoimmune gastritis, Hashimoto thyroiditis, and Department of Pathology, Tokushima University School of Dentistry, Tokushima, Japan rheumatoid arthritis [11,12]. It has been reported that both Fas and FasL are present in thyrocytes, and their This work was supported in part by Grants-in-Aid for Scientific Research (Nos. 12307040 & 12557022) from the Ministry of Education, Science and Culture of concomitant expression on thyrocytes, independent of Japan. infiltrating T cells, is responsible for thyrocyte destruc- Correspondence to Yoshio Hayashi, Department of Pathology, Tokushima tion in Hashimoto thyroiditis [13]. In contrast, expression University School of Dentistry, 3 Kuramotocho, Tokushima 770, Japan of Fas by pancreatic ␤ cells has been shown to have a Tel: 81 88 633 7327; fax: 81 88 633 7327; e-mail: [email protected] major influence on the susceptibility of tissue destruc- 522 Apoptosis and estrogen deficiency in Sjo¨ gren syndrome Hayashi et al. 523 tion in nonobese diabetic (NOD) mice to diabetes caspases [27,28]. The development of autoimmune exo- [14,15•]. Since it was reported that Fas expression was crinopathy in Sjo¨gren syndrome appears to be dependent observed in the salivary gland cells with human Sjo¨gren on autoantigen cleavage through caspase cascade, and syndrome [16], it was likely that Fas-mediated apoptosis caspase-inhibitors might provide a new therapeutic op- may contribute to tissue destruction in the salivary tion directed at reducing tissue damage. glands with Sjo¨gren syndrome. A cleavage product of 120-kDa ␣-fodrin was identified as an important autoantigen in human Sjo¨gren syndrome besides NFS/sld mu- T cell apoptosis in Sjo¨ gren syndrome rine model for Sjo¨gren syndrome [17]. ␣-Fodrin is a Activation-induced cell death (AICD) is a well-known ubiquitous, calmodulin-binding protein [18] found to be mechanism of peripheral T-cell tolerance that depends cleaved by calcium-activated protease (calpain) in apo- upon an interaction between Fas and FasL [29]. AICD ptotic T cells, and by calpain or caspase 3 [19] in anti- plays a central role, especially in killing autoreactive T Fas-stimulated Jurkat cells or neuronal apoptosis [20]. It cells and in preventing autoimmune responses [30]. It was demonstrated that the fodrin ␣ subunit is cleaved in has been reported that activation of T-cell clones in- association with apoptosis, and the 120-kDa fragment is duces FasL expression, and AICD in autoreactive T a breakdown product of the mature form of 240-kDa cells in vivo has been proposed to limit the expansion of fodrin-␣ subunit [20,21]. Previous studies have demon- an immune response by eliminating effector cells [31••]. strated evidence that caspase 3 is required for ␣-fodrin Although it can be considered that a defect in AICD of cleavage during apoptosis [21]. In Jurkat cells, caspase effector T cells may result in the development of auto- 3-like proteases have been reported to cleave ␣-fodrin immune disease [32], an in vivo role of organ-specific and poly (ADP-ribose) polymerase [21]. The observation autoantigen for AICD is entirely unclear. Because the that ubiquitously expressed autoantigens (e.g., ␣-fodrin, administration of a soluble form of anti-FasL antibody La, and nuclear mitotic apparatus protein) in Sjo¨gren (FLIM58) results in severe destructive autoimmune exo- syndrome are specifically cleaved by granzyme B crinopathy in a murine model of Sjo¨gren syndrome [33], strongly suggests that a common biochemical event it is possible that an organ-specific autoantigen may play (novel autoantigen cleavage during granule-induced ep- an important role on down-regulation of AICD. A high ithelial cell death) is responsible for selecting the uncon- titer of serum autoantibodies against 120-kD ␣-fodrin nected group of molecules [22]. autoantigen was detected in the FLIM58-treated mice, and splenic T-cell culture supernatants contained high In vitro studies demonstrated that apoptotic mouse sali- level of interferon-␥. FasL-mediated AICD is down- vary gland (MSG) cells result in a specific ␣-fodrin cleav- regulated by autoantigen stimulation in spleen cells from age into 120 kDa, and preincubation with caspase- the murine Sjo¨gren syndrome model, but not from Fas- inhibitor peptides blocked ␣-fodrin cleavage [23]. A deficient MRL/lpr mice and FasL-deficient MRL/gld significant increase of TUNEL+-apoptotic epithelial mice. FasL undergo matrix metalloproteinase–mediated duct cells in the salivary glands was detected in NFS/sld proteolytic processing in their extracellular domains, re- Sjo¨gren syndrome mouse model. MSG cells constitu- sulting in the release of soluble trimeric ligands (soluble tively express Fas with high proportion, and tissue- FasL [sFasL]). In this case, the processing of sFasL oc- infiltrating CD4+ T cells isolated from the salivary gland curs in autoantigen-specific CD4+ T cells, and a signifi- tissues bear a large proportion of FasL. Importantly, the cant increase in expressions of metalloproteinase-9 tissue-infiltrating CD4+ T cells, but not CD8+ T cells, mRNA was observed in spleen cells from Sjo¨gren syn- are responsible for tissue destruction as judged by in vitro drome mouse model [33]. The increased generation of 51Cr release cytotoxic assay against MSG cells in vitro. sFasL inhibits the normal AICD process, leading to the Although it has been reported that Fas-induced apopto- proliferation of effector CD4+ T cells in the murine SS sis seems to be the major killing pathway of the CD4+ model. Previous studies have demonstrated that CD4+ T cytotoxic T cells [24], one mechanism by which acti- cells are susceptible to AICD induced through T-cell vated CD4+ T cells induce cytotoxicity towards salivary receptor–mediated recognition of allogeneic MHC class gland cells in Sjo¨gren syndrome is Fas based. In vivo II molecules, supporting the notion that AICD can be treatment with caspase-inhibitors, z-VAD-fmk and triggered in activated T cells through the T-cell recep- DEVD-CHO, into murine model results in dramatically tor–mediated recognition of antigen [34,35]. Mice or hu- inhibitory effects on the development of autoimmune man individuals lacking functional Fas or FasL display lesions, and in restoration of sicca syndrome [23]. There profound lymphoproliferative reactions associated with is increasing evidence that the cascade of caspases is a autoimmune disorders [36]. In proteoglycan-induced ar- critical component of the cell death pathway [25,26], and thritis, CD4+ T cells proliferate at a high rate in response a few proteins have been found to be cleaved during to proteoglycan stimulation, and exhibit a Th1-type re- apoptosis. These include poly (ADP-ribose) polymerase, sponse [37]. These observations have suggested that a a small U1 nuclear ribonucleoprotein, and ␣-fodrin, defect in AICD of autoreactive Th1 cells may contribute which were subsequently identified as substrates for to the pathogenesis of Sjo¨gren syndrome. 524 Systemic lupus erythematosus and Sjo¨ gren syndrome

Estrogen deficiency in Sjo¨ gren syndrome postmenopausal women. Recent data demonstrated sig- Sex hormones influence both humoral and cell-mediated nificant apoptosis associated with ␣-fodrin cleavage in immune response, and estrogen is one of the potential the salivary gland cells of estrogen-deficient healthy factors in this immunologic dimorphism [38,39]. Estro- C56BL/6(B6) mice [54••]. Interestingly, inflammatory genic action has been suggested to be responsible for the lesions developed exclusively in the salivary and lacrimal strong female preponderance of autoimmune diseases in- gland after the adoptive transfer with ␣-fodrin-reactive T cluding systemic lupus erythematosus and SS [40,41]. cells in both ovariectomized B6 and ovariectomized Although a number of autoimmune diseases are known SCID mice. It has been suggested that ␣-fodrin cleavage to develop in postmenopausal women, the mechanisms triggered by estrogen deficiency plays an important role by which estrogen deficiency influences autoimmune lein the development of autoimmune exocrinopathy in SS. sions remain unclear. Previous reports indicate that the In in vitro studies using primary cultured MSG and hu- increase in autoantibody production as a result of estro- man salivary gland cells (HSG), a cleavage product of gen deficiency is mediated by cytokines such as inter- 120-kD ␣-fodrin was detected in cells that had under- leukin-6, interferon-␥ (interferon-␥, and tumor necrosis gone tamoxifen (Tam)-induced apoptosis, not in other factor-␣ (TNF-␣), and that estrogen plays an important type of cells including MCF-7 [54••]. Because pretreat- role in the regulation of B lymphocyte development in ment with estrogen inhibits the Tam-induced apoptosis mouse bone marrow and activation of human monocytes of MSG and HSG cells, estrogen may play a crucial role [42–44]. Estrogen deficiency induced by ovariectomy ac- in the apoptosis-related signal pathway. A recent report celerates destructive autoimmune lesions, and these le- by Morkuniene et al. [55] has shown that 17␤-estradiol sions were recovered by estrogen administration in an SS prevents calcium-induced release of cytochrome c from mouse model [45]. It was demonstrated that the dysfunc- heart mitochondria. When we analyzed whether cysteine tion of regulatory T cells caused by estrogen deficiency proteases are involved in Tam-induced apoptosis of may play a crucial role in acceleration of organ-specific HSG cells, we observed a time-dependent increase in autoimmune lesions, and that estrogenic action influ- the active forms of caspase 1. In addition, the promoter ences target epithelial cells through Fas-mediated apo- activity of caspase 1 was significantly increased when ptosis [45]. It was also demonstrated that interferon-␥- HSG cells transfected with the promoter-caspase 1 gene induced Fas expression on these cells was reduced by were stimulated with Tam. the addition of estrogens. Previous studies have shown that physiologic concentration of estrogens augmented Conclusion the activity of the interferon-␥ promotor in mitogen- A cleavage product of 120-kDa ␣-fodrin was identified as stimulated murine spleen cells [46], and the administra- an important organ-specific autoantigen in human SS. tion of exogenous estrogens could induce Fas-mediated The data discussed in this review are strongly suggestive apoptosis not only in cultured cells but also in vivo [47]. of essential roles of caspase cascade for ␣-fodrin autoan- Several reports have demonstrated that estrogen may tigen cleavage leading to tissue destruction in autoim- play an inhibitory role on apoptosis in endothelial cells, mune exocrinopathy in SS. ␣-Fodrin cleavage by breast cancer cells, cardiac myocytes, prostate cells, and caspases can potentially lead to cytoskeletal rearrange- neuronal cells [48,49]. ment, and it is of interest to point out that ␣-fodrin binds to ankylin, which contains a cell death domain [56]. It Previous studies concerning gender differences in auto- has been shown that cleavage products of ␣-fodrin in- immunity have suggested that estrogen influences the hibit ATP-dependent glutamate and ␥-aminobutyric cytokine production of effector cells and autoantibody acid accumulation into synaptic vesicles [57], assuming production [50,51]. The distinct immune environments that a cleavage product of 120 kDa ␣-fodrin could be a in males and females underlie many of the gender- novel component of an unknown immunoregulatory net- related differences in autoimmunity. These environ- works such as cytolinker proteins [58]. In vitro T-cell ments are established by the cytokines that are released apoptosis assay indicated that FasL-mediated AICD is by immune cells, particularly T helper (Th) lympho- down-regulated by autoantigen stimulation in spleen cytes. Sex hormones, pituitary hormones including pro- cells from murine SS. The processing of sFasL occurs in lactin, and growth hormones, as well as liver-derived in- autoantigen-specific CD4+ T cells in vivo, and a signifi- sulin-like growth factor-1 affect autoimmune diseases by cant increase in expressions of metalloproteinase-9 modulating cytokine productions [52]. Estrogen with- mRNA was observed in spleen cells from mouse model. drawal after menopause leads to an increase in the pro- These data indicate that the increased generation of duction of cytokines, such as granulocyte-macrophage sFasL inhibits the normal AICD process, leading to the colony-stimulating factor (GM-CSF), interleukin-1, in- proliferation of effector CD4+ T cell (Fig. 1). Moreover, terleukin-6, and tumor necrosis factor-␣ [53]. Although antiestrogenic actions have a potent effect on the prote- many studies have described the effects of estrogen on olysis of ␣-fodrin autoantigen through up-regulation of cytokine production in effector cells, much less is known caspase 1 activity. It has been strongly suggested that about the effect of estrogen deficiency in target organs of ␣-fodrin fragments induced by estrogen deficiency may Apoptosis and estrogen deficiency in Sjo¨ gren syndrome Hayashi et al. 525

Figure 1. An organ-specific autoantigen may play an important role on down-modulation of AICD A cleavage product of 120-kD ␣-fodrin in the target cells could be induced by estrogen deficiency during apoptosis through caspase activation, in particular caspase 1. Activation-induced cell death (AICD) results from the interaction between Fas and FasL, and activated T cells expressing both Fas and FasL are usually killed either by themselves or by interacting with each other. FasL undergo matrix metalloproteinase (MMP)–mediated proteolytic processing in their extracellular domains, resulting in the release of soluble FasL (sFasL). FasL-mediated AICD is down-regulated by autoantigen stimulation, indicating that the increased generation of soluble FasL inhibits the normal AICD process, leading to the proliferation of autoreactive CD4+ T cells. A defect in AICD may result in the development of autoimmune diseases.

play an important role in the development of autoim- SSB/La autoantibodies bind the surface of apoptotic fetal cardiocytes and promote secretion of TNF-alpha by macrophages. J Immunol 2000, mune lesions in SS. Molecular mechanisms responsible 165:5345–5351. for tissue-specific apoptosis induced by estrogen defi- 9 Utz PJ, Hottelet M, Schur PH, et al.: Proteins phosphorylated during stress- ciency are being further investigated. induced apoptosis are common targets for autoantibody production in patients with systemic lupus erythematosus. J Exp Med 1997, 185:843–854.

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Purpose of review Introduction This review deals with new information related to central Central nervous system (CNS) involvement has been nervous system lupus, with special emphasis on mechanisms reported to occur in 14% to 75% of patients with sys- engaged in inflammation and neurodegeneration. temic lupus erythematosus (SLE), and it is associated Recent findings with increased mortality. Acquisition of valuable treat- We report the very recent findings related to neuropsychiatric ment remedies increases the need for early recognition lupus in areas of (1) neuroimaging, (2) immunology and of CNS manifestations in SLE and evaluation of re- genetics, (3) biochemistry, and (4) neuropsychological tests. sponses to the medication. Neuropsychiatric SLE The relation between treatment of central nervous system (NPSLE) manifestations can occur as single or multiple lupus and immunologic/biochemical parameters as an events at any time during the course of the disease, even outcome variable is also reported. during periods in which SLE seems quiescent [1]. Pro- Summary spective observations of SLE patients for periods of 2 to The recent advances in the field of neuropsychiatric lupus 5 years suggest poor clinical outcome associated with a allow better understanding of the pathogenesis of the disease history of NPSLE events. Approximately 21% to 47% of and follow-up of disease activity during immunosuppressive NPSLE patients show recurrence or onset of new treatment. NPSLE syndromes, and 10% die of SLE-related CNS involvement [2]. In fact, CNS involvement has been the Keywords major factor contributing to mortality in cohorts where systemic lupus erythematosus, central nervous system, 5% of patients die during the first 5 years after SLE cytokines, metalloproteinases, astroglial fibrillary acidic protein, diagnosis. The range and acuity of NPSLE are broad; it neurofilament, amyloid protein, Tau, MRI, cerebrospinal fluid, can display an acute onset or an indolently progressive neuropsychological examinations onset. The symptoms and signs of CNS lupus are protean. They include encephalopathies (for example, acute Curr Opin Rheumatol 16:527–533. © 2004 Lippincott Williams & Wilkins. confusional disorder, dementia), headaches (and mi- graine), mood disorders (particularly depression), psychosis, movement disorders (in particular chorea), stroke, neurovascular diseases, myelopathies, cranial neuropathies, peripheral neuropathies, and myasthenia. Both Department of Rheumatology and Inflammation Research, Go¨teborg University, neurologic and psychiatric abnormalities appear in forms Sahlgrenska University Hospital, Go¨teborg, Sweden that may not be conspicuous on clinical examination. This work has been supported by the Go¨teborg Medical Society, Swedish However, these subtle symptoms may be sufficient to Association against Rheumatism, King Gustaf V: s Foundation, Swedish Medical Research Council, Nanna Svartz’ Foundation, Bo¨rje Dahlin’s Foundation, Swedish change a person’s lifestyle and therefore, lead to disabil- National Inflammation Network, Swedish National Infection and Vaccination ity. The management of patients with NPSLE includes Network, AME Wolff Foundation, and the University of Go¨teborg. both symptomatic (for example, anticonvulsant) and im- Correspondence to Estelle Trysberg, Department of Rheumatology and munosuppressive therapies. Because of the lack of con- Inflammation Research, University of Go¨teborg, Guldhedsgatan 10, S-413 46 Go¨teborg, Sweden trolled trials, treatment is often based on clinical expe- Tel: 46 31 342 64 52; fax: 46 31 82 39 25; e-mail: [email protected] rience. Current Opinion in Rheumatology 2004, 16:527–533 Immunologic events in neuropsychiatric Abbreviations systemic lupus erythematosus APL anti-phospholipid antibodies The pathogenesis of NPSLE is likely to be multifactorial A␤42 ␤-amyloid protein CSF cerebrospinal fluid and may involve autoantibody production specific for MMP matrix metalloproteinase brain structures, immune complex depositions, microan- NPSLE neuropsychiatric systemic lupus erythematosus SLE systemic lupus erythematosus giopathy, and intrathecal production of proinflammatory cytokines. In addition, in a recently published study [3] © 2004 Lippincott Williams & Wilkins 1040–8711 it has been shown that NPSLE is associated with apolipoprotein E polymorphism. Histopathological studies reveal a wide range of brain abnormalities including mul- 527 528 Systemic lupus erythematosus and Sjo¨ gren syndrome tifocal microinfarcts, cortical atrophy, gross infarcts, Several studies have shown that the level of interleu- hemorrhages, ischemic demyelination, and patchy mul- kin-6 in cerebrospinal fluid (CSF) is elevated in patients tiple sclerosis–like demyelination [4]. The most common with NPSLE [18]. Increased production of other cyto- finding in autopsy studies is a small-vessel noninflam- kines such as interleukin-1 [19], transforming growth fac- matory proliferative vasculopathy characterized by tor-␤ [20], interleukin-10, and interferon-␥ [21] have also hyalinization, occasionally associated with occlusion, been reported in CSF of patients with NPSLE. Tsai et pericapillary microgliosis, microinfarcts, and microhem- al. [22] found elevated levels of prostaglandin E2 in CSF orrhages. Vasculitis of the brain vessels has been docu- of NPSLE patients. Increased levels of CSF interleukin- mented in only 7% to 15% of NPSLE autopsy cases [5]. 1␤, interleukin-6, interleukin-10, and tumor necrosis factor-␣ in NPSLE patients were observed by Dellaliberia- The most important autoantibodies with potential to Joviliano et al. [23•]. The same group found significantly cause abnormalities in brains of SLE patients are the increased CSF and serum concentrations of kinins (high prothrombotic anti-phospholipid antibodies. Potential molecular weight kininogen, low molecular weight ki- targets of anti-phospholipid antibodies are the endothe- ninogen, prekallikrein, tissue kallikrein, and kininase II) lial cell, prostacyclin, protein C, the protein C-S com- in CNS lupus patients. We investigated levels of pro-and plex, and platelets. Acute impact on coagulation as well anti-inflammatory cytokines in both serum and CSF of as more chronic effects on the vessel wall are possible. 31 SLE patients. CSF-interleukin-6 and CSF- The pathogenetic mechanism underlying the association interleukin-8 levels showed statistically significant in- between thromboembolic disease and anti-phospholipid crease in NPSLE patients [24]. These results were re- antibodies is still uncertain. In a recently published peated in a larger cohort of SLE patients [25••], both for study [6], cerebrovascular disease was one of the most interleukin-6 (Fig. 1) and interleukin-8 (Fig. 2). Inter- common presenting complaints, only second to deep leukin-8 is a chemokine that, after alteration of the per- vein thrombosis. Apart from ischemic stroke and tran- meability of the blood–brain barrier, attracts B and T sient ischemic attacks, brain hemorrhages, venous sinus cells to the site of inflammation. Interleukin-6 serves as thrombosis, amaurosis fugax, and acute subdural hema- an important growth factor for activated B cells. Our find- tomas have also been reported in association with anti- ings of oligoclonal bands in the CSF of patients with phospholipid antibodies. Zaccagni et al. [7] showed that NPSLE concomitantly with increased interleukin-6 lev- elevated serum levels of intercellular adhesion molecule- els suggest a direct influence of this cytokine on B- 1, vascular cell adhesion molecule-1, and E-selectin lymphocytes infiltrating the brain. correlated with anti-phospholipid antibody titers. Inter- estingly, the anti-phospholipid antibodies are able to up- Biochemical alterations in neuropsychiatric regulate adhesion molecule expression, thereby enhanc- systemic lupus erythematosus ing not only risk for thromboembolic events but also for Cytokines and other inflammatogenic molecules occur- inflammatory responses. ring in the brain are capable of inducing production of proteolytic enzymes, metalloproteinases, with ability on Seven independent studies have shown a relation be- the one hand to defend us against the intruding infec- tween anti-ribosomal P antibodies and NPSLE [8–14]. It tious agents but on the other destroying brain paren- has been suggested that fluctuations of ribosomal P- chyma. In the case of NPSLE, it has been recently dem- antibodies are associated with episodes of psychosis [8] as well as with general disease activity in SLE [10,11]. There is good evidence suggesting that P protein resides Figure 1. Increased IL-6 levels of CSF in NPSLE on neuronal cells in an immunologically accessible way [15]. Furthermore, the presence of anti-neuronal antibodies correlates with a subset of NPSLE, particularly encephalopathies and seizures. DeGiorgio et al. [16] demonstrated that a subset of anti-DNA antibodies cross-react with N-methyl-D-aspartate receptors and can signal neuronal death through an exitotoxic mechanism. Serum levels of antibodies to microtubule-associated protein 2, a cellular protein restricted to neurons, were examined in SLE patients, in patients with neurologic disorders, and in healthy controls. Seventeen percent of the overall cohort of SLE patients had autoantibodies to microtubule-associated protein 2, in contrast to 4% of the Serum and cerebrospinal fluid (CSF) levels of interleukin (IL)-6 in 31 patients with neurologic disease and 1.7% of normal con- neuropsychiatric systemic lupus erythematosus (NPSLE) patients and 54 SLE patients without any significant central nervous system engagement. Pg/mL, trols. In the NPSLE patients group, 76.5% displayed mean ± SEM. anti-microtubule-associated protein 2 positivity [17•]. Neuropsychiatric SLE Trysberg and Tarkowski 529

Figure 2. Increased IL-8 levels of CSF in NPSLE Figure 3. Increased soluble neurofilament levels of CSF in NPSLE

Serum and cerebrospinal fluid (CSF) levels of interleukin (IL)-8 in 31 neuropsychiatric systemic lupus erythematosus (NPSLE) patients and 54 SLE patients without any significant CNS engagement. Pg/mL, mean ± SEM. onstrated that a significant difference was not found between the overall group of SLE patients and controls with respect to serum matrix metalloproteinase (MMP)-9 Neurofilament in cerebrospinal fluid (CSF) of 31 neuropsychiatric systemic lupus levels. However, SLE patients with NPSLE had signifi- erythematosus (NPSLE) patients, 54 SLE patients without central nervous system involvement, and in 99 healthy controls. Ng/L, mean ± SEM. Published cantly higher serum MMP-9 concentrations than did with permission [25••]. SLE patients without CNS lupus (P = 0.009). Among NPSLE patients, those with cognitive dysfunction had significantly higher levels of serum MMP-9 than those pared with the SLE group without overt CNS involve- with normal cognitive function did (P = 0.027). Further- ment. Even in case of glial fibrillary acidic protein, the more, serum MMP-9 levels had a significant positive CSF of healthy blood donors showed the lowest levels, correlation with the volumes of T1-weighted and T2- significantly lower even in comparison with cerebrally weighted lesions in the brain MRI (P = 0.031 and P = healthy SLE patients (Fig. 4). Also, protein Tau levels in 0.015, respectively) [26•]. Our recent results demon- CSF were significantly increased in the SLE patients strate that CSF levels of free, enzymatically active subgroup, characterized by MRI-verified brain abnor- MMP-9 were significantly increased in patients with malities as compared with SLE patients without such NPSLE as compared with SLE patients without CNS engagement [20]. We showed that CSF interleukin-6 engagement (P < 0.05) as well as compared with healthy levels significantly correlated with those of neuronal deg- controls (P = 0.0012). In addition, intrathecal levels of radation product, neurofilament (r = 0.32, P Յ 0.005). interleukin-6 and interleukin-8 displayed both signifi- Fisher et al. [27] demonstrated an increased rate of neu- cant correlations with MMP-9 levels in CSF (P < 0.0001), ron survival after brain injury in interleukin-6 deficient suggesting the potential MMP-9 activation pathway. mice. These data suggest that increased levels of inter- CSF levels of MMP-2 showed no statistically significant Figure 4. Increased soluble GFAp levels in CSF of NPSLE differences between NPSLE patient and patients without CNS lupus or compared with cerebrally healthy controls (Trysberg et al., 2004, in press).

Having in mind occurrence of neurodegradative enzymes in CNS of patients with SLE, we decided to assess whether a chronic neurodegenerative process is ongoing in the brains of these patients. We found the presence of soluble molecules indicating neuronal and astrocytic damage/astrogliosis, such as neurofilament (a neuronal degradation product), Tau (axonal degeneration product), and astroglial fibrillary acidic protein in CSF of NPSLE patients shows ongoing brain damage [25••]. Indeed, in patients with NPSLE, CSF- neurofilament levels were increased on average seven times as compared with SLE patients without CNS in- Astroglial fibrillary acidic protein (GFAp) in cerebrospinal fluid (CSF)of31 volvement, and 51 times compared with healthy controls neuropsychiatric systemic lupus erythematosus (NPSLE) patients, 54 SLE (Fig. 3). Intrathecal glial fibrillary acidic protein levels patients without central nervous system involvement and in 99 healthy controls. Ng/L, mean ± SEM. Published with permission [25••]. were increased three times in the NPSLE group com- 530 Systemic lupus erythematosus and Sjo¨ gren syndrome leukin-6 would have a detrimental effect on neurons in considerable background abnormalities of uncertain sig- CNS lupus. nificance.

We assessed CSF levels of amyloid precursor protein and Combining the use of MRI with other imaging modali- ␤-amyloid (A␤42), two proteins related to dementia dis- ties has been shown to be a more powerful tool in dif- orders [20]. Amyloid precursor protein and A␤42 levels ferentiating active from residual brain disease but also in were significantly decreased in SLE patients irrespective increasing specificity [33]. Oku et al. [34•] showed that of CNS involvement, as compared with healthy controls. MRI findings correlated with CNS manifestations in Patients with NPSLE who underwent a second lumbar SLE, and the combination of MRI and SPECT was use- puncture after successful cyclophosphamide treatment ful in predicting CNS manifestations after start of steroid showed further decreases of A␤42. These data might be therapy. Sibbitt et al. [35•] showed that fluid attenuated interpreted as due to anti-inflammatory/immuno- inversion recovery is superior to PD/T2 in detecting le- suppressive treatment decreasing the production of amy- sions typical for NPSLE, but use of fluid attenuated loid precursor protein. An alternative explanation is inversion recovery resulted in only a small improvement putative occurrence of neutralizing anti-neuronal anti- of 5% in the overall diagnostic sensitivity. bodies specific for amyloid precursor protein/A␤42. Cognitive functions in NPSLE are an issue of great interest, primarily because of the high prevalence of ner- Neuroimaging and vous system involvement in lupus patients [36,37]. The neuropsychiatric evaluations documented sensitivity of neuropsychological proce- There is no single diagnostic test showing high sensitiv- dures for subclinical disturbances of CNS integrity in a ity and specificity for NPSLE diagnosis, but cranial MRI variety of clinical populations [38] suggests that neuro- is currently the anatomic imaging modality of choice for psychological studies of SLE patients have the potential patients with NPSLE. We believe that this examination to contribute substantially to the evaluation of the more displays high sensitivity but probably low specificity in subtle symptoms. case of NPSLE. Lesions are commonly observed in active NPSLE; the prevalence of detectable lesions varies Current challenges in neuropsychiatric from 62% to 100% in NPSLE patients. In addition, a systemic lupus erythematosus significant correlation has recently been shown between Classification of neuropsychiatric systemic pathologic MRI and occurrence of neuronal and as- lupus erythematosus troglial degradation products in brains of SLE patients Diagnostic criteria for NPSLE are poorly defined in with CNS involvement [25••]. Among SLE patients ARA’s 1982 revised criteria for SLE because only two without active NPSLE, chronic MRI lesions may be ob- elements are given: psychosis and seizures. The goals of served in 16% to 53% of cases, and the frequency of the American College of Rheumatology case definition, these lesions increases with disease severity, age, and a criteria, and nosology guidelines were to increase consis- history of CNS flares [2,28,29]. These lesions may be tency in the classification of patients and to standardize reversible [2,29,30]. The majority (40% to 80%) of ab- clinical descriptions and reporting requirements in normalities in NPSLE are small punctate focal lesions NPSLE research. Ainiala et al. used these criteria in a concentrating in periventricular and subcortical white cross-sectional, population-based study covering an area matter areas. Cortical atrophy, ventricular dilatation, dif- inhabited by 440,000 people. A total of 58 patients with fuse white matter changes, and gross infarctions are less a definite diagnosis of SLE were found. Ninety-one per- common [31]. In a recently published paper [32] it was cent of the SLE patients and 56% of the healthy shown that MRI findings in NPSLE were associated matched controls fulfilled at least one of the American with lupus anticoagulants (P < 0.01) and hypertension (P College of Rheumatology NPSLE criteria [39]. Similar = 0.00041). The presence of antiphospholipid antibodies results were found by the San Antonio Lupus group, who was associated with abnormal MRI even after controlling reported that NPSLE was present in 80% of unselected for the effect of age and hypertensive status (P = 0.011) patients with SLE [40]. In both studies, headache, cog- [32]. Cerebral angiography, even in the setting of cere- nitive dysfunction, and psychiatric disorders were the bral infarctions, is typically completely normal, indicat- most common manifestations. Ainiala et al. revised the ing limited sensitivity, possibly combined with the fact American College of Rheumatology case definition cri- that thrombotic events are situated on the venous side of teria by removing mild cognitive deficit, headache, mild vascular tree. Single photon emission computed tomog- depression, anxiety, and electroneuromyography- raphy (SPECT) and positron emission tomography may negative polyneuropathy. In their inclusion setting, the be sensitive for NPSLE but have poor specificity for prevalence of NPSLE dropped to 46% [41]. differentiating NPSLE versus non-NPSLE, reversible versus irreversible lesions, old versus new lesions, and In our studies [20,24,25••,42], CNS lupus was defined as NPSLE versus confounding disorders common to SLE. the presence of at least two of the following seven items Positron emission tomography and SPECT also show occurring in association with clinical evidence of disease Neuropsychiatric SLE Trysberg and Tarkowski 531

Figure 5. Normalization of CSF IL-6 levels in NPSLE patients token, a decline in neuronal and astroglial degradation following cyclophosphamide therapy products was observed in patients who were considered to have NPSLE and had a favorable response to cyclophosphamide treatment. On the second occasion, CSF levels of glial fibrillary acidic protein and neurofilament were clearly decreased, indicating reversal of an ongoing cerebral degradation [25••].

Liu et al. [43] used technetium-99m ethyl cysteinate dimer brain SPECT to detect regional cerebral blood flow in 12 NPSLE patients. All patients had normal brain MRI but abnormal technetium-99m ethyl cysteinate dimer SPECT findings. SPECT was performed before Serum and cerebrospinal fluid (CSF) interleukin (IL)-6 levels in neuropsychiatric systemic lupus erythematosus patients before and after treatment with and after methylprednisolone pulse therapy (1 g/d, given cyclophosphamide. intravenously for 3 consecutive days) and oral prednisolone (2 mg/kg per day) for 1 week. After this therapy, 10 of the 12 patients showed complete recovery of regional progression: (1) recent onset psychosis, (2) transverse cerebral blood flow in follow-up brain SPECT, and the myelitis, (3) aseptic meningitis, (4) seizures, (5) patho- remaining two demonstrated partial recovery. logic brain MRI, (6) severely abnormal neuropsychiatric test, and (7) oligoclonal immunoglobulin G bands in Denburg et al. [44••] suggest that even if major involve- CSF. With this set of criteria, the specificity of NPSLE ment of CNS is not occurring, minor symptoms may should be high, whereas the sensitivity relatively limited. nevertheless suggest compromised brain function due to cognitive disturbances. Routine use of a neuropsychiatric Judgment of disease expression/progressivity questionnaire may prove useful in testing the suspicion Within the CNS, interleukin-6 can be expressed by as- regarding neuropsychiatric involvement. trocytes, microglial cells, and folliculostellate cells. Un- der normal physiologic conditions, levels of interleukin-6 Conclusion in the CNS are low. In our study [24], CSF from NPSLE Recent studies demonstrate unequivocally that NPSLE patients treated with immunosuppressive drugs was as- is not only a common and potentially life-threatening sayed for the second time. Interestingly, after successful condition but also a state whose pathogenetic mecha- treatment with cytotoxic drugs resulting in clinical im- nisms are being progressively clarified. A flow chart provement, a second LP performed 4 months later showing hypothetical events during NPSLE is presented showed significantly decreased interleukin-6 levels (Fig. in Figure 6. Better biochemical and radiologic tech- 5). In contrast, serum levels of interleukin-6 in the same niques permit more accurate diagnosis and evaluation of patients were not significantly decreased. By the same disease activity, not of least importance when it comes to

Figure 6.

Hypothetical mechanisms of inflammation and tissue destruction in neuropsychiatric systemic lupus erythematosus. APP, amyloid precursor protein; BBB, blood–brain barrier; GFAp, astroglial fibrillary acidic protein; Ig, immunoglobulin; IL, interleukin; MMP, matrix metalloproteinase; TGF, transforming growth factor; A␤42, ␤-amyloid protein. 532 Systemic lupus erythematosus and Sjo¨ gren syndrome duration and intensity of immunosuppressive treatment. 19 Alcocer-Varela J, Aleman-Hoey D, Alarcon-Segovia D: Interleukin-1 and interleukin-6 activities are increased in the cerebrospinal fluid of patients with To further improve quality of diagnosis and follow-up, it CNS lupus erythematosus and correlate with local late T-cell activation mark- is of utmost importance to provide international criteria ers. Lupus 1992, 1:111–117. for NPSLE diagnosis. 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Purpose of review Introduction The production of autoantibodies against nuclear antigens is Systemic lupus erythematosus is a multisystem autoim- the hallmark of systemic lupus erythematosus. Among the mune disease characterized by the production of auto- large number of autoantibodies known, only a limited number antibodies against a host of nuclear constituents. The appear to be clinically important. The various autoantibodies etiology of this chronic disease is incompletely under- have different clinical significance in lupus patients. In this stood; however, both genetic and environmental factors review, we will discuss the various antinuclear autoantibodies are clearly involved. detected in lupus patients, their potential pathogenic role, and their usefulness in clinical practice. Evidence for a genetic component in lupus comes from Recent findings a higher concordance rate in monozygotic twins com- Recent advances include the clear demonstration of pared with dizygotic twins, familial aggregation, and the autoantibody transport into living cells, a process that clearly various genetic polymorphisms that come from linkage includes interactions with a number of cellular components and association studies in lupus patients and their family that may play a role in cellular dysfunction and disease. Also, members. No one gene alone is thought to cause lupus, Ј the anti-Sm B/B response originates from a single antigenic but instead, multiple genes are thought to be involved, epitope that appears to be the same structure in different with many interacting with a number of environmental patients, before spreading to other epitopes and becoming the factors to produce the disease. typically mature, complex humoral autoimmune anti-Sm autoantibody response. Because the hallmark of lupus is the production of au- Summary toantibodies, the various genetic and environmental fac- The existing data strongly support a central role of tors that interact to cause lupus should influence auto- autoantibodies in the pathogenesis of lupus. Better antibody production. Therefore, whether the particular characterization of autoantibodies, their mechanisms of autoantibodies being considered are pathogenic or epi- production, and their interactions with various cellular phenomena, a more complete understanding of the pro- constituents will clarify the pathogenesis of this disease. cesses and mechanisms that induce autoantibodies are expected to help in the search for the etiology of lupus. Keywords In addition, many autoantibodies are associated with systemic lupus erythematosus, autoantibodies, pathogenesis specific manifestations of the disease, thereby being an aid to the clinical management of lupus patients. Herein, Curr Opin Rheumatol 16:534–540. © 2004 Lippincott Williams & Wilkins. we will review the various antinuclear autoantibodies detected in lupus patients, their potential role in the patho- aDepartment of Medicine, University of Michigan, Ann Arbor, Michigan, genesis of the disease, and their clinical associations bDepartment of Medicine, University of Oklahoma, Oklahoma City, Oklahoma, (Table 1). cArthritis and Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, and dUS Department of Veterans Affairs Medical Center, Oklahoma City, Oklahoma, USA Antinuclear antibody Supported by the National Institutes of Health (RR020143, AR42460, AR12253, Antinuclear antibodies (ANA) are present in approxi- AI24717, RR15577, AI31584, AR048940, AR049084, AI053747, DE15223, AI54117) and US Department of Veterans Affairs (CC103). mately 98% of lupus patients, making the ANA test the most sensitive test for lupus. However, ANA are not Correspondence to Amr H. Sawalha, Division of Rheumatology, University of Michigan, 3918 Taubman Center, 1500 E. Medical Center Drive, Ann Arbor, MI specific, because they can be detected in a variety of 48109, USA autoimmune, rheumatic, and infectious conditions. Tel: 734 936 5561; fax: 734 763 1253; e-mail: [email protected] Moreover, ANA can be detected in normal individuals, Current Opinion in Rheumatology 2004, 16:534–540 especially in the elderly. In any case, the absence of

Abbreviations ANA makes the diagnosis of lupus much less likely, al- ANA antinuclear antibodies though still possible. ANA are most commonly detected anti-dsDNA anti-double-stranded DNA using the indirect immunofluorescent technique on a tissue culture cell substrate. Human esophageal tumor cells © 2004 Lippincott Williams & Wilkins 1040–8711 (HEp-2) are the most common cell line for this purpose 534 Antinuclear antibodies in SLE Sawalha and Harley 535

Table 1. Common antinuclear autoantibodies in lupus

Frequency in Autoantibody lupus Autoantigen (function) Clinical association

Anti-dsDNA 50–60% DNA double helix Lupus nephritis (genetic information) Anti-Sm 10–25% Spliceosomal snRnp: subunits B,BЈ, and D (splicing of pre-mRNA) Anti-Ro (SS-A) 25–40% 60-kDa or 52-kDa proteins Subacute cutaneous lupus erythematosus (unknown) Photosensitivity Neonatal lupus Interstitial lung disease Anti-La (SS-B) 10–15% 48-kDa protein Absence of lupus nephritis (transcription termination factor) Anti-Ribosomal P 15% Ribosomal phosphoproteins P0, P1, P2 Psychiatric lupus (protein synthesis) Lupus nephritis Lupus hepatitis Anti-nRNP 23–40% Spliceosomal snRNP; subunits A, C, and 70 kDa Raynaud phenomenon (splicing of pre-mRNA) Myosistis Absence of lupus nephritis Anti-Histone 50–70% H1, H2A, H2B, H3, H4, H5 Drug-induced lupus (chromatin component) Anti-Ku 20–40% p70/p80 proteins Arthritis (DNA break repair) Pericarditis Pulmonary hypertention Overlap syndromes dsDNA, double-stranded DNA; Sm, Smith; snRNP, small nuclear ribonucleoprotein; nRNP, nuclear ribonucleoprotein. because of their large nucleus and prominent nuclear patterns. The presence of rim pattern, also called periph- (especially nucleoli) constituents. HEp-2 cells are much eral pattern, may indicate antibodies to double-stranded more sensitive for ANA and, consequently, have virtually DNA, but also can be an artifact. Antibodies against ri- completely replaced mouse kidney or liver tissue section bosomal P bind in a cytoplasmic pattern, or a cytoplasmic substrates. and nucleolar pattern. Nucleolar ANA pattern is usually seen in other connective tissue diseases such as sclero- The rare anti-Ro precipitin-positive lupus patient con- derma; however, a minority of lupus patients (∼5%) have tinues to be ANA negative because the paucity of the Ro a nucleolar ANA pattern. The ANA pattern has been antigen and the loss of its antigenicity with fixation. This used to stratify lupus patients for the purpose of studying finding has fostered the commercial development of a lupus genetics. For example, African-American lupus HEp-2 derivative that overexpresses Ro in the nucleoli families stratified by the presence of nucleolar ANA pat- of a minor population of cells that have been transfected tern reveal a significant linkage at chromosome 11q14, with a Ro-expressing vector. suggesting a susceptibility locus for lupus in that region [2]. The ANA test is reported by titer and pattern. The higher titers loosely correlate with pathologic signifi- Autoantibodies present in lupus sera are also detected cance. Indeed, in a large multicenter study, it was re- using other techniques, including double immunodiffu- ported that only 5% of normal individuals have a positive sion, immunoblotting, enzyme-linked immunosorbent ANA at a dilution of 1:160, whereas 31.7% of ANA tests assay, and immunoprecipitation. Anti-double-stranded were positive at a dilution of 1:40 [1]. The ANA test is DNA (dsDNA) antibodies are also detected by indirect dependent upon immunologic reagents and laboratory immunofluorescence using Crithidia luciliae as substrate. conditions, producing substantial variation in the test be- Recent work has shown that ANA autoantibodies pre- tween laboratories. Understanding the relative perfor- cede the onset of clinical lupus by many years [3••]. This mance of normal controls is important to the interpreta- result suggests that those with the clinical illness emerge tion of any ANA test. from the large reservoir of normal ANA-positive individuals and that a positive ANA increases the risk of The different antigens bound by autoantibody produce developing lupus by as much as 20-fold. Of course, even different ANA immunofluorescent patterns, depending in ANA-positive normals, the risk of developing lupus is upon their cellular localization and the particular changes low, less than 5%. that occur with fixation (Fig. 1). Anti-histone antibodies typically give a nuclear homogeneous pattern, and anti- Anti-double-stranded DNA antibody Sm, anti-nRNP, anti-Ro and anti-La most commonly Anti-double-stranded DNA (anti-dsDNA) antibody is give a nuclear speckled pattern, although anti-Ro (SS-A) among the most specific autoantibodies in lupus, but is and anti-La (SS-B) can give a cytoplasmic or nucleolar not particularly sensitive because it may be transiently 536 Systemic lupus erythematosus and Sjögren syndrome

Figure 1. Indirect immunofluorescence using the HEp-2 cell most specific test because there are no histones or single line, showing various antinuclear antibody patterns stranded DNA in this structure.

Prophylactic treatment of patients with a rise in the anti- dsDNA titer was shown to prevent relapse [5], contributing to the suspicion that anti-dsDNA is a specificity that is closely allied with clinical disease. Experience with abetimus (or LJP 394), an immunomodulating agent that induces tolerance in Bcells directed against dsDNA, supports this position by reducing the number of renal flares in patients with high-affinity antibodies to the abetimus DNA epitope [6]. On the other hand, Ar- buckle et al. has shown that lupus patients presenting with anti-dsDNA have typically had anti-dsDNA for almost 2 asymptomatic years before clinical disease onset [3••].

Anti-dsDNA has been associated with lupus nephritis and is widely suspected to be responsible for kidney damage in many lupus patients. Even now the mechanism of lupus nephritis is not known. Two theories dominate the discussion. First, antibody antigen complexes are postulated to deposit in the glomerular basement membrane, forming the nidus for subsequent inflammatory responses. Anti-dsDNA–nucleosomal DNA complexes get trapped via interactions between the posi- tively charged cationic N-termini of the core histones and the negatively charged heparan sulphate in the glomeruli [7]. Apoptotic blebs are important in antigen presentation in apoptosis, and are believed to be the source of nucleosomal material involved in the formation of these immune complexes [8]. Indeed, the clearance of apoptotic material is decreased with disease progression (A) Speckled. (B) Homogeneous. (C) Nucleolar. (D) Cytoplasmic. (Courtesy of in lupus mice [9]. On the other hand, there is also new Dr. Morris Reichlin). support for the alternative theory, that a subset of anti- dsDNA autoantibodies cross-reacts with an antigen in the kidney by molecular mimicry, thereby leading to tissue damage [10]. present and found in only 50% to 60% of lupus patients at some point in their disease course. Anti-dsDNA auto- Some antibodies penetrate living cells, even to the antibodies can be present in some cases of autoimmune nucleus, and bind various intracellular constituents hepatitis and infections including syphilis, parasitic in- [11•,12]. These activities are thought to be a source of fections, and bacterial endocarditis. variation between autoantibodies that may determine pathogenic mechanism and to represent opportunities to The specificity of the various anti-dsDNA assays and develop a therapeutic strategy. Cellular components their derivative clinical associations have been controver- cross-reacting with DNA, as shown by their binding to sial for more than two decades. Solid phase (for example, anti-dsDNA include Fc receptors, Hp8 on human and enzyme-linked immunosorbent assay), immunofluores- murine renal tubular cells, ribosomal P proteins on rat cence (e.g., Crithidia luciliae substrate), and immunopre- and human glomerular mesangial cells, and myosin 1 in cipitation (for example, Farr assay) all have their ad- rat hepatoma cells [12]. Apparently, calreticulin on the vocates. An enzyme-linked immunosorbent assay for cell surface is another intracellular access point for some anti-dsDNA was positive for anti-dsDNA in 30% of pa- anti-dsDNA antibodies, which, of course, would suggest tients who did not have lupus, but were ANA positive that antibodies entering cells this way would have the [4]. Consequently, individual interpretations should be potential to alter calcium signaling [13]. informed by the performance characteristics and specificity of the test being used. Immunofluorescence of the Binding to some of the autoantigens during trafficking of kinetoplast of C. luciliae is generally considered to be the anti-dsDNA may render them more or less immunogenic Antinuclear antibodies in SLE Sawalha and Harley 537 and immunopathogenic. The effect on apoptosis of anti- Anti-Ro and anti-La antibodies dsDNA binding to cellular autoantigens is variable; it is Antibodies to Ro (SS-A) and La (SS-B) are present in shown to prevent apoptosis in some studies while pro- 25% to 40% and 10% to 15% of lupus patients, respec- moting it in others [14]. This variability may reflect the tively [30]. Both anti-Ro and anti-La are more common different autoantigens bound by different anti-dsDNA in Sjögren syndrome. antibody subsets. All anti-Ro positive sera bind the Ro-60 kDa protein, complexed with small RNAs known as the Y RNAs. Interestingly, anti-dsDNA antibodies have various ef- There are four Y RNAs in humans: hY1, hY3, hY4, and fects on a number of cellular cytokines, providing an- hY5. A subset of Y RNAs is found in some cells. For other aspect that can explain potential pathogenic effect example, erythrocytes contain hY1 and hY4 [31] and of anti-dsDNA in lupus patients. Cellular interactions platelets contain hY3 and hY4 [32]. Some patients with with anti-dsDNA antibodies have been shown to be as- anti-Ro 60 kDa antibodies also bind the Ro-52 kDa au- sociated with increased expression of interleukin-1, in- toantigen. Whether the Ro-60 kDa and the Ro-52 kDa terleukin-6, interleukin-8, interleukin-1␤, transforming are physically associated continues to be controversial. growth factor-␤, and Von Willebrand factor [14]. Kurien et al. have shown that antibodies binding the leucine zipper, a major linear epitope in the Ro-52 kDa Anti-ribosomal P antibody autoantigen, also bind native Ro-60 kDa, providing a Soon after the discovery of the highly specific lupus au- basis for the cross-reaction [33]. There is a parallel situ- toantibody, anti-ribosomal P in 1985 [15], a correlation ation between anti-Ro and anti-La in that a high level of between this antibody and lupus psychosis was reported anti-La is almost never present in the absence of anti-Ro. [16]. Several subsequent studies confirmed this associa- The La particle is a 48-kDa protein and is believed to tion and also reported association with depression function as a termination factor for RNA polymerase III [17,18], although not without dissenters [19]. Anti- [34]. It also is associated with small RNA molecules, ribosomal P antibody is detected in about 15% of lupus most of which terminate with poly-uridine. The associa- patients and correlates with the activity of lupus [20], tion of anti-La with anti-Ro has been attributed to the particularly with lupus nephritis [21,22]. Furthermore, physical association of the Ro and La RNA-proteins with both anti-dsDNA and anti-ribosomal P antibodies to- each other. gether are more closely associated with lupus nephritis than is the presence of either of them alone [23•]. Anti- The function of the Ro particle is not well understood. ribosomal P antibody is also associated with lupus hepa- Recent evidence suggests that the Ro particle might be titis [24]. Indeed, the association of anti-ribosomal P with involved in quality control of misfolded small RNAs [35], lupus hepatitis is not seen with autoimmune hepatitis and in protecting against ultraviolet light–induced cellu- except when lupus is present, again emphasizing the lar damage [35]. Other evidence implicates Ro in telo- high specificity of anti-ribosomal P with lupus [25]. merase function [36]. Others postulate that Ro modulates the immune response to other proteins, for example, calreticulin, thereby influencing autoimmunity [37]. The ribosomal P autoantigen consists of three distinct phosphoprotein molecules in the 60S ribosomal subunit. Curiously, murine knockout for Ro has been prepared These are known as P0, P1, and P2 and are 38 kDa, 19 and is viable [38••]. Therefore, no matter what the func- kDa, and 17 kDa, respectively [15]. It appears that tions are for this RNA–protein complex, it is not indis- the main antigenic epitope of these ribosomal autoanti- pensable for mammalian life. Biologic duplication may gens is present within the last 11 amino acids at the be operating and, thereby, protect life from what would C-terminus [26]. Further characterization of this region otherwise be a lethal dysfunction. revealed that the most shared epitope is in fact the six C-terminal amino acids, GFGLFD [27••]. This amino The recently published murine Ro knockout develops acid motif is also present in several microorganisms, an autoimmune phenotype [38••], a finding consistent which raises the possibility of a molecular mimicry with the idea that Ro might protect against autoimmu- mechanism in the development of anti-P antibody in nity. These mice lacking the Ro-60-kDa protein develop lupus. glomerulonephritis and a clinical syndrome similar to lupus. Some anti-ribosomal P antibodies cross-react with other autoantigens, particularly the Sm D and Sm B/BЈ spli- The presence of anti-Ro autoantibody is associated with ceosomal subunits [28], nucleosomal molecules, and subacute cutaneous lupus erythematosus, photosensitiv- DNA [29]. As in the case of anti-dsDNA, anti-ribosomal ity, and neonatal lupus. Neonatal lupus provides perhaps P antibodies also are capable of penetrating living cells, the strongest clinical evidence for a pathogenic role of and profoundly suppressing protein synthesis [12]. anti-Ro autoantibodies. The syndrome is related to the 538 Systemic lupus erythematosus and Sjögren syndrome presence of anti-Ro antibodies in the mother and is char- anti-PPPGMRPP antibody production, followed by an- acterized by any combination of skin rash, cytopenias, tibodies binding to other different epitopes of the B/BЈ cholestasis, or congenital heart block. A recent prospec- subunit. Epitope spreading then carries the humoral im- tive study of 100 women with anti-Ro antibodies showed mune response to the rest of the spliceosome, including that the risk of complete congenital heart block is ap- A, C, and 70 kDa. Some immunized animals also develop proximately 2%; however, no effect was observed on anti-dsDNA, thrombocytopenia, seizures, or proteinuria other pregnancy outcomes [39,40]. [51,52].

The risk of developing congenital heart block varies with PPPGMRPP closely resembles PPPGRRP from Ep- the anti-Ro antibody specificity in the anti-Ro-positive stein-Barr nuclear antigen-1 (EBNA-1), and anti-Sm an- pregnant woman. Congenital heart block is associated tibodies cross-react with both peptides. This molecular with antibodies binding the Ro-52 kDa [41], confirming mimicry may partially explain the strong association of earlier findings [42]. Further characterization revealed Epstein-Barr virus infection with lupus [53–55]. More that these antibodies specifically bind to amino acid 200- recently, Kang et al. reported that lupus patients have an 239 in the leucine zipper region of the Ro52 molecule approximately 40-fold increase in Epstein-Barr virus [43], also confirming earlier findings [44]. loads compared with controls, a finding not explained by disease activity or immunosuppressive medications [56]. Anti-Sm antibody and anti-nRNP antibodies Conclusion Both anti-Sm and anti-nRNP are specificities of compo- Systemic lupus erythematosus is an autoimmune disease nents of the spliceosome, which splices pre-messenger that is characterized by the production of autoantibodies RNA. They consist of RNA–protein complex particles, against a number of cellular antigens, mostly localized known as snRNPs (small nuclear ribonuclear proteins) within the nucleus. The various autoantibodies pro- with the U1-U6 RNAs complexing with members of a duced not only are helpful for diagnosis, but also in pre- set of different protein subunits [45]. The Sm specificity dicting the disease manifestations in individual patients. is associated with U2, U4, and U6 RNAs and the B, BЈ, In addition, certain antibodies, such as anti-dsDNA, are D1, D2, D3, E, F, and G polypeptides. The U1 snRNP helpful in monitoring disease activity and response to is associated with anti-nRNP composed of the U1 RNA treatment. Autoantibodies are such a consistent part of and A, C, or 70-kDa polypeptides. lupus that their presence in one way or another is required for diagnosis. Indeed, autoantibodies are usually The anti-Sm antibody is detected in about 10% to 25% present for years before the development of clinical ill- of European-American lupus patients and substantially ness [3••]. higher frequency in African-American patients [46]. In fact, a recent study of 114 lupus patients (68% African- Mechanisms of pathogenesis offer opportunities for new American, 19% Hispanic-American, and 13% whites) re- therapeutic strategies, whether these be a consequence ported anti-Sm antibodies in 40% of patients [47]. Anti- of autoantibody transport into the cell or of the action of Sm antibody is almost pathognomonic for lupus, genetic or environmental etiologic factors (for example, although particular clinical associations are not strong for Epstein-Barr virus). anti-Sm. Anti-nRNP, on the other hand, is present in more than 20% of European-Americans and about 40% References and recommended reading of African-American lupus sera. Lupus patients with Papers of particular interest, published within the annual period of review, anti-nRNP autoantibodies tend to have myositis and have been highlighted as: Raynaud phenomenon, but are less likely to develop • Of special interest lupus nephritis. •• Of outstanding interest 1 Tan EM, Feltkamp TE, Smolen JS, et al.: Range of antinuclear antibodies in “healthy” individuals. Arthritis Rheum 1997, 40:1601–1611. Nearly all of the patients with high levels of anti-Sm will 2 Sawalha AH, Namjou B, Nath SK, et al.: Genetic linkage of systemic lupus eventually develop anti-nRNP [48], thereby creating an erythematosus with chromosome 11q14 (SLEH1) in African-American fami- association between the two specificities. The basis for lies stratified by a nucleolar antinuclear antibody pattern. 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Purpose of review To describe the lines of evidence supporting a significant role PRKR dsRNA-dependent protein kinase ␣ ␣ SLE systemic lupus erythematosus for interferon- (IFN ) in the pathogenesis of systemic lupus TLR Toll-like receptor erythematosus (SLE) and to propose potential mechanisms by ␣ © 2004 Lippincott Williams & Wilkins which IFN contributes to the autoimmunity and immune 1040–8711 dysfunction of SLE. Recent findings Long-standing data indicating elevated levels of IFN␣ in the circulation of patients with SLE have recently been Introduction supplemented by reports from clinical practice, gene Data linking interferon-␣ (IFN␣) to systemic autoim- expression data, analysis of patient cells studied ex vivo, and mune diseases, particularly systemic lupus erythemato- studies of mechanisms of induction of IFN␣ production to sus (SLE), were presented as early as 1979, when Hooks provide complementary data strongly supporting a pathogenic et al. [1] first observed elevated levels of IFN in SLE role for IFN␣ in SLE. Recombinant IFN␣, when administered as sera. However, the pace of accumulation of support for a therapy to patients with malignancy or hepatitis infection, can an important pathogenic role for IFN in SLE has accel- induce SLE. IFN␣-regulated genes are highly expressed in erated over the past few years as clinical data, gene ex- SLE peripheral blood cells compared with cells from control pression data, and in vitro studies have supported the subjects. Functional alterations of SLE mononuclear cells have prominent role for this important cytokine in disease been attributed to effects of IFN␣. In addition, immune pathogenesis. Investigations of murine lupus models complexes bearing lupus autoantibodies and RNA or DNA have added to these human data, and also point to a role have been shown to induce IFN␣ production. Finally, progress for IFN␣, as well as IFN␥, in lupus disease. in understanding the role of Toll-like receptors (TLR) in the activation of the innate immune response has suggested Data linking IFN to SLE are in the context of an exten- potential mechanisms by which adjuvant-like factors act sive literature that describes altered phenotype and be- through TLR to induce IFN␣ as well as effective processing of havior of nearly all cells and mediators of the immune self-antigens, resulting in activation of an adaptive immune system in lupus patients [2,3]. In the setting of these response directed against self, as well as cytokine-mediated multiple documented dysfunctions, those specifically re- immune dysfunction. lated to IFN were not particularly emphasized until re- Summary cently. This review will summarize recent distinct and Substantial evidence supports a significant role for IFN␣ in the complementary observations that together comprise a pathogenesis of lupus. The IFN␣ pathway represents a compelling case for a primary role for IFN␣ in SLE promising target for therapeutic intervention in patients with pathogenesis. SLE. Expression of interferon-␣ in systemic Keywords lupus erythematosus interferon-␣; systemic lupus erythematosus; autoimmunity; The earliest observations linking IFN␣ to SLE came Toll-like receptor; cytokine from measurement of IFN␣ in SLE sera [1,4]. Subse- quent data have shown that IFN␣ increases as pa- Curr Opin Rheumatol 16:541–547. © 2004 Lippincott Williams & Wilkins. tients’ disease flares and is associated with multiple organ involvement [5]. Several studies documented the acid lability of the IFN␣ in patient sera, a character- Mary Kirkland Center for Lupus Research, Hospital for Special Surgery and Department of Medicine, Weill Medical College of Cornell University, New York, istic that still has not been fully characterized but may NY, USA require effects of another serum protein [4,6]. More

Correspondence to Mary K. Crow, Hospital for Special Surgery, 535 East 70th recent studies, using enzyme-linked immunosorbent as- Street, New York, NY 10021, USA say to detect circulating IFN␣, have not been so suc- Tel: 212 606 1397; fax 212 774 2337; e-mail: [email protected] cessful, perhaps a function of the particular antibodies Current Opinion in Rheumatology 2004, 16:541–547 used in these assays to detect the cytokine or effects ␣ Abbreviations of proteins associated with the circulating IFN , such as anti-IFN antibodies or soluble IFN receptors IFN-␣ interferon-␣ PDC plasmacytoid dendritic cell [7••,8••,9,10].

541 542 Systemic lupus erythematosus and Sjögren syndrome

Expression of IFN␣ can also be assessed by measuring reaction analysis of SLE peripheral blood mononuclear specific mRNA. IFN␣ is not one protein but rather a cells to show that those genes that are increased in ex- family of highly related products encoded on the short pression in SLE blood are those that are preferentially arm of chromosome 9. There are at least 13 IFN␣ genes, induced by IFN␣, not those induced by IFN␥ [26]. With as well as IFN␤, IFN␬, IFN␶, and IFN␻, together com- the description of the new type III IFN gene family prising the type I IFNs [11••]. Complicating this picture (IFN␭), its gene products can also be considered candi- further are several recently described gene products date inducers of the genes overexpressed in SLE. termed IFN␭, or interleukin-28 and interleukin-29, now classified as type III IFNs [12•,13•,14]. The latter have some sequence similarity to the type I IFNs but are Induction of systemic lupus erythematosus encoded on a distinct chromosome and bind to a distinct by interferon-␣ receptor. Despite these differences, the type I and type Along with expression of IFN␣ and IFN␣-regulated III IFNs have very similar functional properties and tar- genes in SLE, support for a pathogenic role for IFN␣ in get genes, based on data currently available. Our labora- SLE, and perhaps other autoimmune diseases, comes tory is using quantitative real-time polymerase chain re- from clinical data derived from patients undergoing action to measure distinct IFN␣ gene products, as well as therapeutic administration of recombinant IFN␣. IFN␣ other less abundant transcripts for the other type I IFN has been used for approximately 15 years as a therapy for genes, along with IFN␭ gene products. This task is com- certain malignancies, including hairy cell leukemia and plicated by the likelihood that in SLE patients, the major multiple myeloma, and increasingly for hepatitis C in- cell population that produces IFN␣, the plasmacytoid fection. Its efficacy is most likely based on its capacity to dendritic cell (PDC), is recruited out of the peripheral promote effector functions mediated by tumor-specific blood and enriched in lymphoid organs and at other sites cytotoxic T cells and natural killer cells in the case of of disease, including skin and kidney, particularly in the malignancies and its direct antiviral effect in the case of setting of active lupus [15–18]. viral hepatitis. In the late 1980s, case reports emerged describing the development of lupus-associated autoan- Expression of interferon-induced genes in tibodies and even clinical lupus in some patients receiv- systemic lupus erythematosus ing this therapy [27]. Some patients treated with IFN␣ ␣ Although reliable quantification of IFN protein and developed other immune syndromes, including insulin- ␣ mRNA has been challenging, measurement of IFN - dependent diabetes, psoriasis, inflammatory arthritis, or induced genes has been used by several groups to pro- Sjögren syndrome. These reports have recently been re- vide a sensitive and relatively quantitative measure of viewed [28•]. Often the autoimmune disease was abro- ␣ functionally active IFN , or possibly of stimuli with gated after discontinuation of the IFN␣ therapy. It is ␣ similar effects to those of IFN [7••,8••,19–21]. Indeed, now accepted that induction of lupus autoantibodies and the expression of multiple genes that are regulated by a clinical lupus syndrome can be a complication of this ␣ IFN has provided compelling evidence of the primacy therapy. Of interest, recombinant IFN␤, frequently ad- ␣ of the IFN pathway in SLE. ministered to patients with multiple sclerosis, does not have the same effect. Together, these clinical data sup- Several previous reports documented increased expres- port the pathogenic potential of IFN␣, although it is ␣ sion of IFN -induced genes in SLE, including dsRNA- clear that other contributors, likely based on genetic, en- dependent protein kinase (PRKR) and oligoadenylate vironmental, and stochastic factors, are required for synthase, as well as Mx1, present in lupus-involved skin emergence of lupus in this setting. [18,22,23]. However, in the context of the numerous other documented alterations in lupus immune system function, these observations did not receive sufficient Mechanisms of induction of interferon-␣ in attention. New data derived from microarray analysis of systemic lupus erythematosus SLE peripheral blood cells, compared with those from The presence of circulating interferon-␣ documented in disease controls or healthy subjects, has emphasized the some studies of lupus patients, together with the com- dominance of the interferon signature in the global gene pelling demonstration of significant overexpression of a expression profile observed in SLE. These studies, in spectrum of genes induced by type I (and possibly type which cellular mRNAs are screened against thousands of III) IFNs, raises the question most relevant to the cause gene sequences, have reproducibly demonstrated that in of SLE: what are the stimuli for IFN␣ expression in SLE, IFN-induced genes are the most significantly over- SLE? Although the definitive answer to this question has expressed of all those assayed on the microarray not been established, candidate stimuli include immune [7••,8••,19–21,24,25]. Although these data could have complexes, along with immunostimulatory DNA and initially been interpreted as attributable to either type I RNA. A virus could be an exogenous trigger for IFN IFN (IFN␣) or type II IFN (IFN␥), our recent experi- pathway activation in SLE, similar to its effects in nu- ments have used quantitative real-time polymerase chain merous well-studied situations of viral infection. IFN␣ in SLE Crow and Kirou 543

Immune complexes chik in the murine B cell model, support the capacity of A recent series of careful studies by the group led by CpG containing immune complexes to induce the pro- Ronnblom and Alm have demonstrated the capacity of duction of IFN␣ as well as B cell activation and anti- immune complexes in SLE sera to trigger IFN␣ produc- chromatin autoantibodies with participation of TLR9 tion by PDCs [29–34]. That group has presented evi- [29–34,36•,37]. dence that autoantibodies associated with apoptotic cell fragments, DNA, or RNA can provide a stimulus that Another TLR, TLR3, is stimulated by dsRNA, includ- results in IFN␣ secretion [29–34]. Ronnblom et al. are ing the artificial polynucleotide poly(inosine-cytosine). now working to characterize the ingredients that are Very recent publications demonstrate the role of TLR7 most effective in activating IFN␣ production by PDCs and TLR8 in cellular responses to ssRNA [41•,42•]. We and the cellular receptors required. Fc receptors are at are currently studying the relation between activation of least one receptor class that contributes to cell activation the type I IFN pathway in peripheral blood mononuclear induced by these complexes, suggesting that internaliza- cells and the prevalence of autoantibodies among pa- tion of the immune complexes could be required for tients with SLE. Our preliminary data suggest that IFN induction of IFN␣ [35]. A similar data set developed pathway activation is highly correlated with the presence through study of murine B cell hybridomas with rheu- of antibodies specific for RNA binding proteins, whereas matoid factor or DNA specificity has also supported the other antibodies, such as those specific for phospholip- capacity of immune complexes, targeted to the cell sur- ids, are not associated with IFN pathway activation. We face and then internalized, to activate the immune sys- propose that immune complexes containing (1) dsRNA, tem [36•,37]. In the latter experiments, B cell receptor serving as a potential endogenous adjuvant; (2) RNA- ligation, along with immunostimulatory DNA, was nec- binding proteins, potential self-antigens; and (3) associ- essary to initiate B cell activation. ated immunoglobulin may use the TLR3 pathway to generate innate, followed by adaptive, immune system Immunostimulatory DNA and RNA activation. Even more intriguing is the possibility that The discovery of the Toll-like receptor (TLR) family of intracellular complexes, perhaps not requiring an anti- innate immune receptors has directed renewed attention body component, containing ssRNA and associated pro- to the important role of the innate immune response in teins could activate IFN production via the TLR7 or activation and maturation of antigen presenting cells, TLR8 receptor. preparing those cells for induction of antigen-specific adaptive T-cell-dependent immune responses [38]. This The explosion of new information regarding the regula- important receptor family continues to grow, and it is tory role of small endogenous RNAs, including mi- now clear that the stimuli for distinct members of the croRNA or small interfering RNA, has raised the possi- TLR family include endogenous ligands, as well as ex- bility that these RNAs could serve as endogenous ogenous microbial ligands [39•,40,41•,42•]. In addition adjuvant for induction of autoimmunity. Of considerable to receptor-ligand specificity, distinct patterns of cell ex- interest is the recent observation that small interfering pression and variable use of adaptor proteins by family RNAs can induce the same IFN gene expression signa- members contribute to distinct roles in host defense, and ture that is observed in SLE peripheral blood [47••]. likely also with regard to autoimmune disease. One of These small RNAs could potentially trigger cell activa- the first TLRs to be studied, TLR4, was shown to play tion and IFN production through TLR7 or TLR8. Al- a key role in immune system activation by lipopolysac- ternatively, TLR independent pathways of IFN produc- charide [43]. However, because lipopolysaccharide is not tion induced by RNA have been reported and act via a highly effective inducer of IFN␣, TLR4 may not be PRKR. These mechanisms could contribute to activation the most likely candidate for a mediator of IFN␣ path- of the IFN pathway in SLE [48,49•]. The differential way activation in SLE [44•]. In contrast, TLRs that have expression of various IFN isoforms in dendritic cell sub- been shown to trigger cell activation by DNA, single types after stimulation with distinct stimuli, including stranded RNA (ssRNA), or double stranded RNA TLR agonists or virus infection, indicate that it may be (dsRNA), are exciting candidates for transducers of the possible to elucidate the relevant stimuli that have acti- signals that induce IFN␣ in SLE [39•,40,41•,42•]. vated the IFN pathway in SLE [50•].

The laboratories of Pisetsky and Krieg are among those Interferon-␣ in murine lupus models that have provided important support for the immuno- In contrast to many aspects of altered immune regulation stimulatory role of oligodeoxynucleotides that are en- in autoimmune disease, in which murine models have riched in demethylated cytosine and guanosine se- served as preferred systems for study, the data support- quences, and it is now known that those CpG sequences ing a role for IFN␣ in SLE are arguably stronger in the act through TLR9 [39•,45,46]. The Ronnblom and Alm human system than in murine lupus models. Nonethe- data regarding DNA-containing immune complexes, less, previous and recent data using lupus mice are sup- along with those from Marshak-Rothstein and Shlom- portive. Poly(inosine-cytosine), a surrogate for dsRNA, 544 Systemic lupus erythematosus and Sjögren syndrome accelerates development of disease in the NZBxNZW function of ssRNA availability and be accompanied by F1lupus model [51].Recent reports have described the TLR-independent activation of the IFN pathway study of mice deficient in the IFN␣ receptor to support mediated by PRKR [41•,42•,48,49•]. Third, IFN␣ an important role for IFN␣ in lupus-like immune alter- production might be associated with particular autoanti- ations, production of lupus autoantibodies, and disease body specificities, reflecting the components of the im- [52•,53,54]. A caveat in interpretation of these studies is mune complex responsible for activation of the antigen- that the classic spontaneous murine models of SLE, the presenting cell. In this scenario, immune complexes NZBxNZW F1and the MRL/lpr, may differ in their containing dsRNA and its associated proteins would not capacity to produce distinct IFNs, including IFN␥,so only induce IFN␣ but would also target those compo- data derived from these strains cannot be readily com- nents to the antigen processing pathway and direct spe- pared. In fact, there is strong evidence of an important cific adaptive immune responses to its components, role for IFN␥ in murine SLE, particularly at the site of whereas patients with less significant activation of the lymphocyte and inflammatory cell infiltration in the kid- IFN pathway might express an adaptive immune re- ney [55–57]. It is likely that IFN␥ will also be important sponse directed at components of immune complexes as a driver of inflammation at the site of tissue damage in processed through other cellular pathways. Antigenic some lupus patients. Study of an induced model of lu- triggers of anti-phospholipid antibodies might be ex- pus, the pristane model, has provided preliminary data amples of complexes that are not strong activators of with suggestive similarity to those recently described in IFN␣. Finally, IFN␣ itself will be responsible for many human patients [58]. In that model, injection of the hy- of the manifestations of autoimmunity and inflammation drocarbon pristane induces the development of lym- characteristic of SLE through its direct and indirect ef- phoid aggregates enriched in expression of genes that are fects on immune system function, which are extensive regulated by IFN␣, including Mx1. It will be important and protean (Fig. 1). to define the involvement of TLR family members in that model. Data from murine lupus models have also Although some effects of IFN␣ on immune system func- supported a genetic contribution of IFN-regulated genes tion have been well characterized, others are being elu- to lupus susceptibility. Ifi202, a chromosome 1q-encoded gene that is induced by both IFN␣ and IFN␥, is poly- morphic and is differentially expressed in lupus and con- Figure 1. Potential mechanisms of induction of autoimmunity trol mice [59]. The mechanism by which Ifi202 and other IFN-induced genes contribute to altered immune function and autoimmunity will require further study.

Role of interferon-␣ in systemic lupus erythematosus pathogenesis As described, abundant data using several experimental approaches are providing strong support for a primary role for IFN␣ in the pathogenesis of SLE [60]. We propose that the contributions of IFN␣ to SLE can be framed based on several distinct but related mechanisms. First, IFN␣ can act to prime the immune system for augmented sensitivity to subsequent stimuli, whether endogenous (immune complex, products of tissue damage, or IFN␣ itself) or exogenous (virus) [61,62]. Targeting a macromolecular complex containing adjuvant-like factors (CpG DNA, This mechanism could in part explain variable disease dsRNA, ssRNA), associated self-proteins, and autoantibody to potential susceptibility among individuals and is supported by a antigen-presenting cells may induce cytokine production, including interferon-␣ microarray study showing highly variable but consistent (IFN␣), and effective processing of self-antigens for presentation to the adaptive immune response, resulting in downstream effects of IFN␣ and autoimmunity. patterns of IFN-induced gene expression among healthy Toll-like receptors (TLR) may selectively transduce signals triggered by the individuals [63•]. Second, IFN␣ production can reflect adjuvant-like component of these complexes, with CpG DNA activating TLR9, the TLR pathway and the adjuvant-like factor mediating dsRNA activating TLR3, and ssRNA activating TLR7 or TLR8. The cytokine ␣ profile produced will in part depend on the target genes regulated by the its induction. IFN induction through TLR9 might be respective TLRs. The autoantibody specificities produced may reflect the mediated by CpG DNA and be accompanied by the composition of the complexes activating specific TLRs. As an example, immune MyD88-dependent pathway used by TLR9 [36•]. IFN␣ complexes containing dsRNA, RNA-binding proteins, and some autoantibody would induce coordinate production of IFN␣ and anti-Ro antibody. In addition to production induced by activation of TLR3 might be me- these TLR-dependent pathways, a TLR-independent pathway mediated by diated by dsRNA and be accompanied by strong IFN- dsRNA binding to PRKR may activate IFN␣ production and prime the immune induced gene expression, given the distinct adaptors system for more vigorous responses to subsequent stimuli. anti-PL, ␣ anti-phospholipid antibody; anti-RNAbp, anti-RNA binding protein antibody; used by TLR3 in contrast to TLR9 [64,65]. IFN in- PRKR, dsRNA-dependent protein kinase. duced through TLR7 or TLR8 activation might be a IFN␣ in SLE Crow and Kirou 545 cidated as investigations of immune regulation move for- tiple stages: induction of a primed immune system, re- ward. It is striking that many of the effects of IFN␣ on flecting TLR pathway activation; generation of autoan- immune function mimic features of altered immune tibodies specific for extra- and intracellular complexes function that are characteristic of SLE. Of particular im- containing RNA or DNA; and direct effects on down- portance may be the capacity of IFN␣ to generate effec- stream immune functions. tive antigen-presenting cells. IFN␣ mediates maturation of dendritic cells and also pushes monocytes toward a Acknowledgments functional profile with increased capacity to stimulate The authors thank Christina Lee and Sandhya George for technical assistance in the experiments performed in our laboratory and Adrienne Davis and Dr. Jane allogeneic T cells [66,67•,68]. This myeloid cell state Salmon for providing the resources of the Hospital for Special Surgery Lupus Reg- may also be characterized by an augmented capacity to istry and Repository for our studies. The authors are most appreciative of the patients and healthy donors who participated in our research and the rheumatologists generate a peripheral T-cell repertoire enriched in auto- at Hospital for Special Surgery who facilitated these studies and provided careful reactive T cells with effector functions. Additional ac- clinical assessment of study patients. tions of IFN␣ include the induction of more IFN␣,as well as other pro-inflammatory cytokines [69]. IFN␣ can References and recommended reading Papers of particular interest, published within the annual period of review, support the survival of T helper cells but can also pro- have been highlighted as: mote apoptosis through effects on mitochondrial func- • Of special interest tion and by its induction of Fas ligand on NK cells [70]. •• Of outstanding interest ␣ Recent data have extended the impact of IFN on adap- 1 Hooks JJ, Moutsopoulos HM, Geis SA, et al.: Immune interferon in the circu- tive immunity by demonstrating its support of B-cell dif- lation of patients with autoimmune disease. N Engl J Med 1979, 301:5–8. ferentiation and immunoglobulin class switching [71,72]. 2 Tsokos GC, Liossis SN: Lymphocytes, cytokines, inflammation, and immune trafficking. Curr Opin Rheumatol 1998, 10:417–425. 3 Tsokos GC, Mitchell JP, Juang YT: T cell abnormalities in human and mouse Potential for therapeutic targeting of the lupus: intrinsic and extrinsic. 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Purpose of review TCR T-cell receptor TRAIL tumor necrosis factor-related apoptosis-inducing ligand T cells from patients with systemic lupus erythematosus have been shown to be activated in vivo and provide cognate and © 2004 Lippincott Williams & Wilkins 1040–8711 noncognate help to autoreactive B cells. In particular, T cells exhibit aberrant responses to stimuli with increased calcium influx and decreased production of interferon-␥ and T cells are thought to play a central role in the regulation interleukin-2. An imbalance in the proapoptotic/antiapoptotic of the immune system. In SLE, T cells display markers + mechanisms also seems to contribute to the persistence of of activation such as increased numbers of DR antigens autoreactive clones and the lack of productive immune [1] and increased levels of proto-oncogenes such as c- responses. The purpose of this review is to discuss recent myc [2], and are able to facilitate the production of im- studies that shed light into the pathogenetic mechanisms munoglobulins by B cells [3]. Furthermore, patients with underlying T-cell dysfunction in systemic lupus erythematosus. SLE have hypergammaglobulinemia and increased pro- Recent findings duction of T-cell–dependent IgG antidouble stranded Significant progress has been made in understanding the DNA antibodies [1]. Despite the presence of activated causes of the abnormal T-cell receptor and other surface immune cells, SLE patients exhibit deficient in vivo re- molecule-mediated signaling. Furthermore, investigators have sponse to new and recall antigens [4] and show a par- characterized better the intracellular and nuclear signaling ticular susceptibility to viral infections [5]. In this article, pathways that lead to abnormal cytokine production in lupus. we review recent studies that characterize functional Finally, efforts to correct these abnormalities in vitro have changes in T cells from patients with SLE and are yielded promising results. thought to contribute to the expression of disease pathol- Summary ogy. New findings in the pathophysiology of T cells in lupus and especially the application of novel techniques to correct Surface molecules immune cell aberrations on the transcriptional and translational T-cell receptor levels give hope for the development of rational treatments in Previous reports have indicated that SLE is character- systemic lupus erythematosus. ized by an imbalance between T-cytotoxic and T-helper response [1]. Levels of Epstein-Barr virus (EBV) load Keywords have been found elevated (40-fold increase) in patients systemic lupus erythematosus, T cells, T-cell receptor, with SLE [6]. Patients with SLE also have increased lev- + apoptosis, interleukin-2, ␨-chain els of EBV-specific CD4 T cells and a decreased number of EBV-specific CD8+ T cells, implying that EBV

Department of Cellular Injury, Walter Reed Army Institute of Research, Silver T cells in patients with SLE recognize through their Spring, Maryland, USA; and Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA T-cell receptor (TCR) autoantigens such as ribonucleoprotein particles and provide cognate help to autoreac- Correspondence to George C. Tsokos, MD, Department of Medicine, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, tive B cells, leading to production of autoantibodies. A MD 20814, USA single TCR from T-cell lines that recognized either U1- Tel: 301 319 9911; fax: 301 319 9133; e-mail: [email protected] 70kDa or Sm-B antigen, two antigenically dissimilar ri- Current Opinion in Rheumatology 16:548–552 bonucleoproteins, was shown to be able to cross-react

Abbreviations with both autoantigens [7•]. The investigators observed that the complementarity determining region 3 in TCRs AICD activation-induced cell death COX-2 cyclo-oxygenase 2 that were recognizing either autoantigen had significant CREM c-AMP response element modulator homology. This study supports the concept that TCR EBV Epstein-Barr virus FcR␥ Fc receptor ␥-chain plasticity plays a role in the apparent epitope spreading MAPK mitogen-activated protein kinase commonly seen in patients with SLE and other autoim- PKA protein kinase A SLE systemic lupus erythematosus mune diseases.

548 T lymphocytes in systemic lupus erythematosus Kyttaris and Tsokos 549

On engagement of an antigen with the TCR/CD3 com- of T cells with antigen-presenting cells at the level of the plex, a series of events leads to mobilization of intracel- immune synapse. T cells from patients with SLE lular calcium through the activation of the TCR/CD3 showed a preclustering of lipid rafts that contained TCR ␨-chain–ZAP 70 complex. Previous studies have shown ␨-chain and FcR␥-chain, whereas controls showed higher that despite a decrease in the levels of ␨-chain [8] in SLE concentration but more diffuse distribution of TCR T cells, the calcium response on stimulation is height- ␨-chain and no FcR␥-chain. The preclustering of these ened [4]. signaling molecule-rich lipid rafts was also shown to be partially responsible for the augmented calcium re- The decrease in the levels of TCR ␨-chain is caused by sponses observed in SLE T cells. both increased protein degradation through ubiquitination and decreased protein production. Elf-1, an Ets fam- Finally, transfection of T cells from patients with SLE ily transcription factor, was found to be responsible in with ␨-chain [16] led to correction of signaling aberra- part for the decreased production of ␨-chain mRNA and tions such as the increase in the Fc␥R protein, the de- protein [9]. Two types of defects in SLE T cells were crease in the NF-␬B, and the decreased interleukin-2 identified. In the first one, the active 98-kd form of Elf-1 production that have been observed in SLE T cells can was absent from SLE T cells. In the second type, al- be corrected by re-establishing the ␨-chain as the signal- though the 98-kd Elf-1 fraction was present, its binding transducing molecule of the T-cell receptor. to the ␨-chain promoter was deficient. Costimulatory molecules Another potential cause for lower levels of ␨-chain in It is well recognized that besides the engagement of the SLE T cells [10] is the decreased stability of an alterna- TCR with an antigen, a second stimulus is needed for tively spliced form of TCR ␨-chain mRNA (␨mRNA/as- the activation and proliferation of T cells. A recent report 3ЈUTR) that is predominant in SLE T cells [10,11]. Both [17] evaluated the possible role of tumor necrosis factor- the wild-type and the alternatively spliced mRNA were related apoptosis-inducing ligand (TRAIL) in T-cell ac- transfected in cells deficient of TCR ␨-chain. The cells tivation. The authors show that TRAIL, known as an transfected with the alternatively spliced mRNA showed apoptosis-inducer molecule, can enhance T-cell prolif- decreased stability of the ␨-chain mRNA, decreased ex- eration and secretion of interferon-␥, interleukin-2, and pression of the ␨-protein, and decreased production of CD25 (interleukin-2 receptor) after TCR engagement. interleukin-2 on activation compared with the cells trans- Using anti-CD3 antibodies and immobilized TRAIL re- fected with the wild-type ␨-chain mRNA. Thus, the phe- ceptor DR4-Fc, the authors stimulated T cells from pa- notype of the cells transfected with the ␨ mRNA/as- tients with SLE and controls. Only two of 20 patients 3ЈUTR is similar to T cells from patients with SLE. with SLE showed a particularly increased activation index on stimulation, whereas there was no difference in Furthermore, lCK, an important molecule for the phos- the amount of TRAIL expressed on the surface of T phorylation of ␨-chain on activation of the T cells, was cells between patients with SLE and controls. In another found to be decreased in T cells from patients with ac- report, Liu et al. [18] found that patients with SLE had tive SLE compared with controls [12]. In the same study, significantly fewer CD4+CD25+ T cells than healthy the investigators found increased ubiquitination of lCK controls and patients with rheumatoid arthritis. These and postulated that this is the main mechanism for the results make the role of TRAIL in the immunopathology reduction of its levels. The authors concluded that the of SLE unclear. Nevertheless, because genetically modi- decrease in lCK might contribute even further to the fied dendritic cells that overexpress TRAIL have been reduction of ␨-chain activity in SLE T cells. successfully used as treatment for collagen-induced arthritis in animals [19], further studies would be helpful in To explain the robust calcium influx despite the decreased delineating the role of TRAIL in SLE. expression of ␨-chain, investigators have searched for molecules that can substitute the ␨-chain in the CD3 Chemokine receptors complex. Indeed, one such molecule, the Fc receptor Inflammatory chemokines can bind to chemokine recep- ␥-chain (FcR␥), associates with the TCR/CD3 and takes tors on T cells and can regulate the immune response, the place of the ␨-chain in SLE T cells [13] but not in especially at areas of inflammation. There is a decrease controls. FcR␥ in association with the Syk kinase is able in CD4+ T cells expressing the CXCR3 and CCR2 che- to signal 100 times more effectively than the ␨-chain– mokine receptors in patients with SLE during disease ZAP 70 complex [14•]. This mechanism can help ex- exacerbations [20]. This observation suggests that acti- plain the robust calcium response on T-cell activation in vated T cells expressing these chemokine receptors ac- SLE T cells. cumulate in sites of inflammation, thus disappearing from the circulation. Indeed, increased CXCR3 expres- The same investigators examined the possible role of sion has been reported in the tubulointerstitial infiltrates lipid rafts [15] as a platform that facilitates the interaction but not the glomeruli of patients with lupus nephritis 550 Systemic lupus erythematosus and Sjögren syndrome

[21] and also in the skin of patients with discoid lupus kin-2 production by SLE T cells on activation [1]. De- [22]. Therefore, CXCR3 receptors could be targeted for creased translocation of the NF-␬B p65 subunit in the therapeutic interventions and be used as markers of dis- nucleus [27] and the binding of the transcription repres- ease activity, because their levels of expression in pe- sor c-AMP response element modulator (CREM) to the ripheral blood T cells fall during disease flares. promoter of the IL-2 gene [28] were found to be responsible for the decrease in the IL-2 gene transcription. Intracellular signaling Transfection of SLE T cells with the NF-␬B p65 sub- Binding of the surface signaling molecules, such as the unit resulted in reconstitution of the IL-2 promoter ac- TCR, to their ligands leads to the activation of a cascade tivity [27]. Along the same lines, transfection of SLE T of protein kinases and eventually the translocation of cells with a plasmid encoding antisense CREM resulted activated transcription factors to the nucleus that in turn in elimination of the repressor CREM and upregulation upregulate a variety of inducible genes [1]. of interleukin-2 production [29]. In a different set of experiments, the authors showed that CREM binding to Cedeno et al. [23] evaluated the Ras/Raf/mitogen- the promoter of c-fos in SLE T cells is responsible for the activated protein kinase (MAPK) cascade in patients decrease in the transcription of c-fos that in turn leads to with SLE. In T cells, on ligation of the TCR, hSos as- a decrease in the activity of AP-1 [30], another major sociates with Ras/Raf via the adapter protein Grb2. In transcription activator in T cells. The authors’ data point turn, Ras/Raf and eventually MAPK are activated. Using to the fact that CREM is a key repressor of interleukin-2 anti-CD3 antibody to activate the T cells, the authors and potentially other AP-1–dependent genes, such as show lower MAPK activity in SLE T cells compared interleukin-3 and GM-CSF. with controls. In contrast, when phorbol ester (a T-cell stimulator that leads to direct activation of Ras) is used, Deficient production of interleukin-2 by the activated the SLE and control T cells had similar MAPK activity. lupus T cell can account for the observed decrease in the The authors concluded that the observed deficiency in activation-induced cell death (AICD) in SLE. Xu et al. MAPK activity in activated SLE T cells is caused by [31•] have explored a different mechanism through aberrant transduction of the signal downstream of the which lupus T cells escape AICD and anergy. On acti- TCR but proximal to the activation of Ras. The authors vation, SLE but not control T cells upregulated the cy- further show that SLE T cells have decreased coupling clo-oxygenase 2 (COX-2) gene and CD40L. The authors of hSos with Grb2 that could explain the decreased ac- showed that when they blocked the COX-2 with cele- tivation of the Ras/Raf and eventually the MAPK path- coxib or niflumic acid, lupus T cells readily underwent way. apoptosis. In contrast, rofecoxib, another specific COX-2 inhibitor, did not have the same effect. The authors also Systemic lupus erythematosus T cells are also character- show that the inhibition of COX-2 caused apoptosis by ized by deficient protein kinase A (PKA) activity, an- augmenting Fas signaling and decreasing c-FLIP, a sur- other important regulator of T-cell activation [24]. Inter- vival molecule. Although the exact role of COX-2 in the estingly, the deficiency of the type II PKA (PKA-II) seen pathophysiology of SLE is still unclear, these observa- in 37% of patients with SLE is characterized by signifi- tions could have therapeutic implications. cant translocation of its RII ␤-subunit in the nucleus. The accumulation of the RII ␤-subunit of PKA-II not A different paradigm was described in mice. The inter- only causes a decrease in the activity of this enzyme in leukin-2 knockout mouse develops a syndrome that re- the cytosol but also interferes with gene transcription. sembles ulcerative colitis, whereas the Fas or Fas ligand- The authors showed [25] that PKA-RII␤ binds directly deficient mouse develops a lupuslike syndrome. Double to recombinant CREB, an important T-cell transcription mutant mice with both Fas/Fas ligand and interleukin-2 factor, and in turn inhibits CRE-dependent gene expres- deficiency (lpr+/+ IL2−/−) were shown to live substantially sion, such as the proto-oncogene c-fos. The same group longer than mice bearing only one of the two mutations also showed [26] that Jurkat T cells overexpressing a [32]. Furthermore, they did not display the major mani- phosphorylated form of PKA-RII␤ suppressed the pro- festations such as colitis or nephritis that are character- duction of interleukin-2 while upregulating the produc- istic of interleukin-2 and Fas/Fas ligand deficiencies, re- tion of CD154. These results taken together point to the spectively. Along the same lines, the genetic locus fact that increased translocation of RII␤ to the nucleus of around the centromere of chromosome 7 (Lmb3) [33] SLE T cells can account for some of the phenotypic can accelerate the clinical manifestations of Fas defi- abnormalities observed in these cells, such as the down- ciency in mice but is not sufficient to cause lupus in an regulation of interleukin-2. animal not genetically predisposed. On the other hand, a different strain of lupus-prone mice, the NZM2328, The regulation of interleukin-2 in SLE T cells has been shows a decrease of the known pathogenic autoantibod- extensively investigated in the authors’ laboratory. Early ies [34], such as double-strand DNA, and yet still have studies have shown a significant decrease in interleu- significant glomerulonephritis with immune complex de- T lymphocytes in systemic lupus erythematosus Kyttaris and Tsokos 551 position. Although these paradigms do not apply directly infection in systemic lupus erythematosus. J Immunol 2004, 172:1287– 1294. to human lupus because the pathogenetic pathways are 7 De Silva-Udawatta M, Kumar SR, Greidinger EL, et al.: Cloned human TCR different in most patients, they underscore the impor- • from patients with autoimmune disease can respond to two structurally distance of a balanced apoptotic pathway in the develop- tinct autoantigens. J Immunol 2004, 172:3940–3947. This article explores TCR plasticity in SLE. TCR from lupus T cells specific for one ment of tolerance and elimination of autoreactive T cell autoantigen is shown also to cross-react with another distinct autoantigen. This clones that can damage the tissues directly or indirectly concept can help explain the epitope spreading seen in many autoimmune condi- through activation of B cells. tions. 8 Liossis S-NC, Ding XZ, Dennis GJ, et al.: Altered pattern of TcR/CD3- mediated protein-tyrosyl phosphorylation in T cells from patients with sys- Finally, the altered state of histone acetylation has been temic lupus erythematosus: deficient expression of the T cell receptor zeta explored in association with T-cell function. In normal T chain. J Clin Invest 1998, 101:1448–1457. 9 Juang Y-T, Tenbrock K, Nambiar MP, et al.: Defective production of functional cells, CREM binding to the interleukin-2 promoter was 98-kDa form of elf-1 is responsible for the decreased expression of TCR-æ shown to correlate with increased recruitment of non- chain in patients with systemic lupus erythematosus. J Immunol 2002, acetylated histones, contributing potentially to the de- 169:6048–6055. crease in interleukin-2 production [35]. In the Fas- 10 Tsuzaka K, Fukuhara I, Setoyama Y, et al.: TCR zeta mRNA with an alternatively spliced 3Ј-untranslated region detected in systemic lupus erythemato- deficient mouse, trichostatin A, a histone deacetylase sus patients leads to the down-regulation of TCR zeta and TCR/CD3 com- inhibitor, was shown to ameliorate clinical disease [36]. plex. J Immunol 2003, 171:2496–2503. The recruitment of acetylated histones H3 and H4 in 11 Nambiar MP, Enyedy EJ, Fisher CU, et al.: Abnormal expression of various molecular forms and distribution of T cell receptor zeta chain in patients with genes such as interferon-␥, interleukin-12, interleukin-6, systemic lupus erythematosus. Arthritis Rheum 2002, 46:163–174. and interleukin-10 and downregulation of their trans- 12 Jury EC, Kabouridis PS, Abba A, et al.: Increased ubiquitination and reduced cription is shown to be the mechanism of action of expression of LCK in T lymphocytes from patients with systemic lupus ery- trichostatin A in mice. Taken together, these results thematosus. Arthritis Rheum 2003, 48:1343–1354. elude to the fact that altered recruitment of 13 Enyedy EJ, Nambiar MP, Liossis SN, et al.: Fc epsilon receptor type I gamma chain replaces the deficient T cell receptor zeta chain in T cells of patients acetylated/deacetylated histones could potentially ac- with systemic lupus erythematosus. Arthritis Rheum 2001, 44:1114–1121. count for the unique cytokine profile observed in both 14 Krishnan S, Warke VG, Nambiar MP, et al.: The FcR gamma subunit and Syk mice and humans with lupus. • kinase replace the CD3 zeta-chain and ZAP-70 kinase in the TCR signaling complex of human effector CD4 T cells. J Immunol 2003, 170:4189. The FcR␥-chain substitutes the ␨-chain in TCR effector T cells, resulting in signal- Conclusion ing through the TCR that can be 100-fold increased. This observation may help explain the heightened calcium response in the lupus T cell that is TCR ␨-chain– Studies over the period of the past few years have helped deficient. us understand the functional aberrations of T cells in 15 Krishnan S, Nambiar MP, Warke VG, et al.: Alterations in lipid raft composition patients with lupus. The T cell in SLE shows a pheno- and dynamics contribute to abnormal T cell responses in systemic lupus erythematosus. J Immunol 2004, in press. type of hyperexcitability with increased calcium re- 16 Nambiar MP, Fisher CU, Warke VG, et al.: Reconstitution of deficient T cell sponses but yet is unable to produce interleukin-2 on receptor zeta chain restores T cell signaling and augments T cell stimulation as readily as T cells from normal controls. On receptor/CD3-induced interleukin-2 production in patients with systemic lu- the contrary, it upregulates such genes as COX-2 and pus erythematosus. Arthritis Rheum 2003, 48:1948–1955. CD40L that help it escape AICD and provide help to 17 Tsai HF, Lai JJ, Chou AH, et al.: Induction of costimulation of human CD4 T cells by tumor necrosis factor-related apoptosis-inducing ligand: possible autoreactive B cells. Studies should be continued to un- role in T cell activation in systemic lupus erythematosus. Arthritis Rheum derstand further the molecular mechanisms behind these 2004, 50:629–639. aberrations and potentially design rational treatments to 18 Liu MF, Wang CR, Fung LL, et al.: Decreased CD4+CD25+ T cells in peripheral blood of patients with systemic lupus erythematosus. 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26 Elliott MR, Shanks RA, Brooks JW, et al.: Down-regulation of IL-2 production A novel mechanism through which lupus T cells escape AICD and anergy is explored in T Lymphocytes by phosphorylated protein kinase A-RII␤. J Immunol 2004, in this article. T cells from patients with SLE upregulate COX-2 on activation. Block- in press. ing that molecule with celecoxib induced apoptosis that was associated with increased Fas signaling. 27 Herndon TM, Juang Y-T, Solomou E, et al.: Electroporation-mediated gene transfer of p65 into T lymphocytes from systemic lupus erythematosus pa- 32 Xiao S, Sung SS, Fu SM, et al.: Combining Fas mutation with interleukin-2 tients leads to increased levels of interleukin-2 promoter activity. Clin Immunol deficiency prevents colitis and lupus: implicating interleukin-2 for auto- 2002, 103:145–153. reactive T cell expansion and Fas ligand for colon epithelial cell death. J Biol Chem 2003, 278:52730–52738. 28 Solomou EE, Juang Y-T, Gourley MF, et al.: Molecular basis of deficient IL-2 production in T cells from patients with systemic lupus erythematosus. J Im- 33 Kong PL, Morel L, Croker BP, et al.: The centromeric region of chromosome munol 2001, 166:4216–4222. 7 from MRL mice (Lmb3) is an epistatic modifier of Fas for autoimmune disease expression. J Immunol 2004, 172:2785–2794. 29 Tenbrock K, Juang Y-T, Gourley MF, et al.: Antisense cyclic adenosine 5Ј- 34 Waters ST, McDuffie M, Bagavant H, et al.: Breaking tolerance to double monophosphate response element modulator up-regulates IL-2 in T cells stranded DNA, nucleosome, and other nuclear antigens is not required for the from patients with systemic lupus erythematosus. J Immunol 2002, pathogenesis of lupus glomerulonephritis. J Exp Med 2004, 199:255–264. 169:4147–4152. 35 Tenbrock K, Juang Y-T, Tolnay M, et al.: The cyclic adenosine 5Ј- 30 Kyttaris VC, Juang Y-T, Tenbrock K, et al.: cAMP response element modulator monophosphate response element modulator suppresses IL-2 production in is responsible for the decreased expression of c-fos and AP- 1 binding in T stimulated T cells by a chromatin-dependent mechanism. J Immunol 2003, cells from patients with systemic lupus erythematosus. J Immunol 2004, in 170:2971–2976. press. 36 Mishra N, Reilly CM, Brown DR, et al.: Histone deacetylase inhibitors modu- 31 Xu L, Zhang L, Yi Y, et al.: Human lupus T cells resist inactivation and escape late renal disease in the MRL-lpr/lpr mouse. J Clin Invest 2003, 111:539– • death by upregulating COX-2. Nat Med 2004, 10:411–415. 552. EDITORIAL OVERVIEW Pediatric rheumatology workforce: a status update Raphael Hirsch

Division of Rheumatology, Children’s Hospital of Pittsburgh, Pittsburgh, ulty. The situation is even more distressing overseas, Pennsylvania, USA where many countries lack even a single pediatric rheu- Correspondence to Raphael Hirsch, MD, Division of Rheumatology, Children’s matologist. Hospital of Pittsburgh, 3705 Fifth Avenue, Pittsburgh, PA 15213, USA Tel: 412 692 5970; fax: 412 692 5054; e-mail: [email protected]

Current Opinion in Rheumatology 2004, 16:553–554 The reasons for this situation are multiple. Primarily, the lack of a critical mass reflects the newness of the spe- © 2004 Lippincott Williams & Wilkins cialty. This is compounded by the general shortage of 1040–8711 medical residents going into subspecialty training in general. In addition, pediatric rheumatologists are perceived Pediatric rheumatology is one of the newest and small- by residents in training as overworked and undercom- est of the pediatric subspecialties. The specialty focuses pensated. on musculoskeletal and autoimmune diseases of childhood, of which the most common is juvenile rheumatoid There is, however, reason for optimism. The need for arthritis. Pediatric rheumatology has been in a manpower pediatric rheumatologists is increasingly recognized by crisis since its inception as a recognized subspecialty by hospitals, medical schools, and community physicians. the American Board of Pediatrics in 1992. In the United Adult rheumatologists are often uncomfortable treating States, there are fewer than 200 board-certified pediatric young children with rheumatic diseases. More than 30 rheumatologists. There are only three or four centers academic centers in the United States are actively re- with four or more faculty and almost half of all US medi- cruiting for a pediatric rheumatologist. Both the Ameri- cal schools have no pediatric rheumatologist on their fac- can College of Rheumatology and the Arthritis Founda-

Table 1. Gender and location of medical school training of pediatric rheumatologists

Total AMG IMG

Year starting Total no. AMG, IMG, Male, Female, Male, Female, Male, Female, July 1 Level at level n, % n, % n, % n, % n, % n, % n, % n, %

1998 1 11 5, 45.5 6, 54.5 4, 36.4 7, 63.6 0, 0.0 5, 45.5 4, 36.4 2, 18.2 2 9 6, 66.7 3, 33.3 5, 55.6 4, 44.4 3, 33.3 3, 33.3 2, 22.2 1, 11.1 3 4 3, 75.0 1, 25.0 2, 50.0 2, 50.0 2, 50.0 1, 25.0 0, 0.0 1, 25.0 Total 24 14, 58.3 10, 41.7 11, 45.8 13, 54.2 5, 20.8 9, 37.5 6, 25.0 4, 16.7 1999 1 14 8, 57.1 6, 42.9 3, 21.4 11, 78.6 0, 0.0 8, 57.1 3, 21.4 3, 21.4 2 10 5, 50.0 5, 50.0 3, 30.0 7, 70.0 0, 0.0 5, 50.0 3, 30.0 2, 20.0 3 9 5, 55.6 4, 44.4 6, 66.7 3, 33.3 3, 33.3 2, 22.2 3, 33.3 1, 11.1 Total 33 18, 54.5 15, 45.5 12, 36.4 21, 63.6 3, 9.1 15, 45.5 9, 27.3 6, 18.2 2000 1 14 11, 78.6 3, 21.4 5, 35.7 9, 64.3 4, 28.6 7, 50.0 1, 7.1 2, 14.3 2 10 6, 60.0 4, 40.0 2, 20.0 8, 80.0 0, 0.0 6, 60.0 2, 20.0 2, 20.0 3 7 4, 57.1 3, 42.9 1, 14.3 6, 85.7 0, 0.0 4, 57.1 1, 14.3 2, 28.6 Total 31 21, 67.7 10, 32.3 8, 25.8 23, 74.2 4, 12.9 17, 54.8 4, 12.9 6, 19.4 2001 1 14 9, 64.3 5, 35.7 6, 42.9 8, 57.1 5, 35.7 4, 28.6 1, 7.1 4, 28.6 2 14 10, 71.4 4, 28.6 5, 35.7 9, 64.3 3, 21.4 7, 50.0 2, 14.3 2, 14.3 3 10 7, 70.0 3, 30.0 1, 10.0 9, 90.0 0, 0.0 7, 70.0 1, 10.0 2, 20.0 Total 38 26, 68.4 12, 31.6 12, 31.6 26, 68.4 8, 21.1 18, 47.4 4, 10.5 8, 21.1 2002 1 19 10, 52.6 9, 47.4 8, 42.1 11, 57.9 4, 21.1 6, 31.6 4, 21.1 5, 26.3 2 12 7, 58.3 5, 41.7 4, 33.3 8, 66.7 3, 25.0 4, 33.3 1, 8.3 4, 33.3 3 13 9, 69.2 4, 30.8 6, 46.2 7, 53.8 4, 30.8 5, 38.5 2, 15.4 2, 15.4 Total 44 26, 59.1 18, 40.9 18, 40.9 26, 59.1 11, 25.0 15, 34.1 7, 15.9 11, 25.0 2003 1 19 11, 57.9 8, 42.1 6, 31.6 13, 68.4 2, 10.5 9, 47.4 4, 21.1 4, 21.1 2 18 10, 55.6 8, 44.4 7, 38.9 11, 61.1 4, 22.2 6, 33.3 3, 16.7 5, 27.8 3 10 6, 60.0 4, 40.0 2, 20.0 8, 80.0 2, 20.0 4, 40.0 0, 0.0 4, 40.0 Total 47 27, 57.4 20, 42.6 15, 31.9 32, 68.1 8, 17.0 19, 40.4 7, 14.9 13, 27.7 AMG, American medical school graduates; IMG, international medical school graduates. Data are from the American Board of Pediatrics. 553 554 Pediatric and heritable disorders

Figure 1. Pediatric rheumatology fellows in training Figure 2. Age of pediatric rheumatologists in the United States

Data are from the American Board of Pediatrics.

period of time and suggests an increasing interest in the specialty by pediatric residents.

The average age of board-certified pediatric rheumatolo- Training level represents first, second, and third year fellows. Data are from the gists has decreased in recent years, to 49 years (Fig. 2). American Board of Pediatrics. Currently, nearly half of pediatric rheumatologists in the United States are 45 years old or younger. This represents an influx of new trainees into the workforce. tion actively support programs to promote pediatric As in many of the pediatric specialties, pediatric rheu- rheumatology training. matology has a majority of women (Table 1). Two thirds of specialists are women. More than half are graduates of Recent data from the American Board of Pediatrics is American medical schools. encouraging. During the past 7 years, there has been a steady increase in the number of pediatric rheumatology If these trends continue for the next few years, pediatric fellows in training (Fig. 1). Although the numbers are rheumatology as a specialty will survive and even thrive. still quite small, there were 19 first year fellows during Most encouraging for the future, the pediatric rheumatol- each of the past 2 years, compared with 10 in 1997. This ogy community is a cohesive group of individuals with tre- represents a near doubling in trainees over a very short mendous energy and unusual dedication to the specialty. Psychosocial aspects in pediatric rheumatology Daniel Kietz

Purpose of this article Introduction To review recent publications examining psychosocial Providing care for children and adolescents with rheu- adjustment to and coping with a pediatric rheumatic disease. matic diseases and their families has many complex psy- Recent findings chosocial implications. For example, special illness- The articles discussed illustrate important areas of related psychological challenges may arise at the time of psychological vulnerability and potential risk for disturbance in diagnosis, with disease exacerbation, or with changes in affected children and adolescents within their environment. the treatment plan. Long-term concerns may result from Summary incomplete control of disease activity, necessity to ad- Children and adolescents with rheumatic diseases and their here to a therapeutic regimen, and potential drug toxic- families face a multitude of psychosocial challenges. Some of ity. Also, premorbid conditions in families with a child these are related to the illness directly, some to treatment. who develops a rheumatic illness may limit the capacity There is need for more systematic research, including to deal effectively with these new challenges. The sub- multicenter studies, to identify psychosocial needs of patients ject of psychosocial aspects in pediatric rheumatology and their families. was last reviewed in this journal by Rapoff in 2001. This article reviews publications in the field of coping and Keywords adjustment of children with chronic rheumatic diseases psychosocial, pediatric rheumatic disease, coping, adjustment published during the interval. Topics for future research are presented. Curr Opin Rheumatol 16:555–559. © 2004 Lippincott Williams & Wilkins. Adjusting to life with a rheumatic illness A number of studies have examined adjustment of affected children and their families to a rheumatic disease. Results have been inconsistent. There has been contro- Children’s Hospital of Pittsburgh, Pennsylvania, USA versy about the prevalence of emotional difficulties in Correspondence to Daniel Kietz, MD, Division of Rheumatology, Children’s children and adolescents with rheumatic illnesses. Some Hospital of Pittsburgh, 3705 Fifth Avenue, Pittsburgh, PA 15213, USA studies have indicated that children are at significant risk Tel: 001 412 692 5081; fax: 001 412 692 5043; e-mail: [email protected] for adjustment problems, whereas other studies have Current Opinion in Rheumatology 2004, 16:555–559 shown that children and their families are doing well, Abbreviations suggesting a high degree of resilience. JRA juvenile rheumatoid arthritis Three articles in the January 2003 issue of the Journal of © 2004 Lippincott Williams & Wilkins 1040–8711 Pediatric Psychology [1–3], followed by two commentaries [4••,5•], have focused on the child with a rheumatic illness.

Gerhardt et al. [1] evaluated parental distress, family functioning, and social support from the perspective of caregivers of children with juvenile rheumatoid arthritis (JRA) and comparison caregivers without a chronically ill child. Parents of 64 children with JRA (64 mothers, 46 fathers) completed questionnaires and in-home interviews along with 64 matched comparison families. Pa- tients were assessed by pediatric rheumatologists and were rated in regard to the disease severity during the previous 6 months. The average time since diagnosis for children with JRA was 70 months. The reported results were that families of children with JRA generally reported levels of parental distress, family functioning, and social support similar to those of comparison families. 555 556 Pediatric and heritable disorders

Families of children with JRA were found to exhibit nalizing symptoms (such as depression and anxiety), but levels of adjustment quite similar to those for comparison not for externalizing symptoms or poor self-concept. Par- parents. However, mothers of children with JRA ex- ticipants with arthritis had significantly higher rates of ceeded the clinical cutoff on a self-report inventory mea- overall psychological adjustment problems when com- suring current psychological stress (SCL-90). The study pared with study-recruited control subjects, but not only had a limited number of children with more severe when compared with normative control subjects. Studies disease, which may have affected the ability to detect including children and adolescents with rheumatic dis- problems for families at higher risk for difficulties. Also, eases other than chronic arthritis demonstrated signifi- data were obtained at only one point in time at an aver- cantly larger differences from control subjects on overall age of 6 years after diagnosis, reflecting long-term ad- adjustment. The authors stress the importance of assess- justment rather than acute reactions. The authors of this ing for internalizing problems among youths with chronic article conclude that families of children with JRA ex- arthritis. hibited substantial resilience over the long term. Power et al. [6] studied the interaction between children Reiter–Purtill et al. [2] assessed the social functioning of with JRA and their mothers to look for any evidence of children with JRA and nonchronically ill control subjects potential interference of child-rearing styles with devel- who had been evaluated 2 years earlier [5a]. Their aim opment of autonomy and self-management in the child. was to examine the impact of disease severity and activ- The investigators were particularly interested in trends ity over time on the social functioning of children with toward overprotectiveness, control, and directiveness in JRA using peer, teacher, and self-reports in 57 children relation to disease severity. A total of 84 mother–child with JRA and 63 control subjects. The control group was pairs (42 JRA and 42 healthy; age range of children, 6 to recruited during the initial assessment by pairing each 13 years) were videotaped while interacting in a prob- child with JRA with a classmate who was the same race, lem-solving task. Based on physical therapy evaluations, gender, and age. The hypothesis was that, at the 2-year children in the JRA group were assigned to more severe follow-up, children with JRA would be identified as be- and milder subgroups. Mothers of children with more ing more socially withdrawn and isolated, as having severe arthritis were more directive of their children’s fewer friends, and as being less popular than their behavior during the task, showing higher rates of struc- friends. Disease severity at time 1 and 2 was rated by ture and rule setting. It is discussed in the conclusion pediatric rheumatologists as mild or moderate/severe. At how these differences in interactional style might impact the 2-year follow-up, the cross-sectional analysis re- the social development of children with JRA. Limita- vealed that children with JRA as a group were not dif- tions of the study were either one point-in-time obser- ferent from control subjects on any of the measures of vation or cross-sectional evaluation without longitudinal social reputation. It was felt that children with JRA ex- follow-up and the narrow experimental setting, raising hibited considerable psychological hardiness. For chil- questions about general applicability of findings. dren with more severe disease, like ratings declined during the 2-year period relative to children with mild Wagner et al. [7] analyzed child adjustment to a rheu- disease. Children with active disease were chosen fewer matic disease from a transactional perspective. They ex- times over the 2-year period as a best friend than chil- amined the question to what extent specific child cog- dren in remission. The authors conclude that children nitive appraisals, in particular illness intrusiveness, may with severe or active JRA may be at risk for difficulties influence the relation between global parental distress, with social acceptance over time and therefore they are child adjustment, and depressive symptoms. Illness inappropriate targets for interventions that ameliorate or trusiveness is characterized by perceived “illness- prevent these difficulties. induced barriers” across a variety of life domains. A multivariate transactional stress and coping approach was LeBovidge et al. [3] performed a meta-analysis of studies used. Participants were 45 children and adolescents (age of the psychological adjustment among children and ado- range, 9 to 17 years) diagnosed with JRD. Children com- lescents with chronic arthritis. Twenty-one studies with pleted measures of depressive symptoms (Children’s publication dates from 1974 to 2001 were selected. Five Depression Inventory), functional disability (Juvenile studies included participants with diseases other than Arthritis and Functional Assessment Report), and illness chronic arthritis including systemic lupus erythematosus, intrusiveness. Parents completed a brief measure of juvenile dermatomyositis, vasculitis, scleroderma, fibro- global distress (Brief Symptom Inventory). The pediatric myalgia and mixed connective tissue disease. The meta- rheumatologist provided functional disability ratings af- analysis included studies reporting overall adjustment ter a routine physical examination. The results showed problems, internalizing symptoms, externalizing symp- that both increased parental distress and child illness toms, or self-concept among youths with arthritis. The intrusiveness were associated with greater child depres- analysis showed that youths with arthritis displayed in- sive symptoms. The influence of general parental dis- creased risk for overall adjustment problems and inter- tress on child depressive symptoms was enhanced under Psychosocial aspects Kietz 557 conditions of increased child-reported illness intrusive- theory. The informants’ ideas and thoughts guided the ness. The authors interpret their results as further sup- interviews while they told their stories. The interviews port for a transactional concept of child adjustment to initiated by posing the question: What do you do all day chronic illness, with particular emphasis on children’s long? This open question was followed by questions perceived illness intrusiveness in the parent distress– such as: What do you do when you are in pain? child depressive symptoms relation. Limitations of the study include use of self-report inventories, modest The interview protocols were analyzed with the intent to sample size, and cross-sectional nature precluding the generate or identify concepts. They revealed that chil- determination of causal relationships among variables. It dren experienced an insecure life situation. The core is possible that depressive symptoms (in children) were category “oscillating between hope and despair” was actually antecedent in the process and resulted in both central in the data and related to four additional catego- increased negative cognitive appraisals (ie, illness intru- ries: labeled disturbed order in daily life, dependency on siveness) and greater parent distress. treatment, ambivalence related to environmental reactions, and uncertainty about the future. The authors con- Von Weiss et al. [8] studied the effect of daily hassles and cluded that chronic pain disturbed the children’s ordi- social support on adjustment in children with rheumatic nary way of life with interaction of psychological and diseases. Children with PRD (n = 160; age range, 8 to 17 physiologic processes. The environment’s response years) were recruited from three pediatric rheumatology could elicit, maintain, or decrease the experience of pain. centers and completed measures of daily hassles, social support, depressive symptoms, and state and trait anxi- Schanberg et al. [11••] also investigated children’s daily ety. Their parents completed measures of internalizing pain and other symptoms related to arthritis and how it and externalizing behaviors. The reported results show affected their lives. For a 2-month period, 41 children fewer daily hassles, and greater social support predicted with polyarticular juvenile arthritis completed daily dia- fewer adjustment problems. Among the sources of sup- ries. The daily diaries included measures of symptoms port, classmate and parent support were significant pre- and function (pain, stiffness, fatigue, activity reduction). dictors. Children with high classmate support had lower Children underwent initial and follow-up evaluations, in- levels of depression. The results are consistent with a cluding a joint count, laboratory testing, and completion “main model” for social support (social support is ben- of questionnaires assessing physical and psychosocial eficial irrespective of the level of stress). The study em- functioning. Children reported having pain an average of phasized the importance of parental and peer support for 73% of days, with most children (76%) reporting pain on successful adjustment of a child with a rheumatic dis- more than 60% of all days. Thirty-one percent reported ease. pain in the severe range. Increased daily symptoms, specifically pain intensity, number of painful locations, stiff- With respect to psychosocial impact of a chronic rheu- ness, and fatigue, were significant predictors of reduc- matic disease of childhood, the evaluation of quality of tions in school and social activities. Higher physician life in adulthood needs to be included. Foster et al. [9•] global assessment ratings, increased functional disability, performed a quality-of-life study in adults with JIA. The and increased anxiety were significantly associated with authors report 81 patients with a median age of 30 years increased daily pain. The incidence of flare (20% of chil- (range, 17 to 68 years), with a median disease duration of dren) in the sample was higher than expected. In their 21 years (range, 3 to 61 years). A total of 39% of patients conclusion, the authors point out that physicians need to had active disease. The academic achievement of pa- treat pain more aggressively in children with arthritis to tients with JIA was comparable, if not better, than that of preserve function in school and social domains, as well as local control subjects. The unemployment rates for pa- physical function. In addition, they emphasize the need tients were threefold higher than those for local control to screen for anxiety and address anxiety in the overall subjects. There was a trend, although not significant, therapeutic regimen. that patients with worse functional disability were more likely to be unemployed. Discussion These recent publications have underlined the impor- The child’s and adolescent’s perspectives tance of our awareness for the complexities of psychoso- Sallfors et al. [10] performed a qualitative study with the cial issues. More evidence has been provided [1] that aim to elucidate the life situation and psychosocial pro- many children with chronic arthritis and their families cesses of children with juvenile chronic arthritis. The adjust very well, particularly over time. Furthermore, focus of this study was directed at the child’s experiences most children and adolescents appear not to have signifi- of chronic pain and suffering, narrated by the children cant social difficulties in comparison with their peers. themselves. Taped, open, qualitative interviews with 22 However, there may be concern about some decline in children (age range, 6 to 17 years) were transcribed and social functioning, especially in children with more se- analyzed using the comparative method for grounded vere arthritis [2]. Children at risk for adjustment diffi- 558 Pediatric and heritable disorders culties may develop more internalizing symptoms, such dren with rheumatic diseases who may not be able to as anxiety or depression, rather than externalizing symp- attend school regularly. The challenges arising around toms [3]. A chronic rheumatic illness may influence the the times of transition out of school or back into school child–parent interaction and parenting styles, particu- are times of heightened stress that require research at- larly in regard to fostering autonomy and independence tention. Long-term psychosocial outcome, particularly [6]. Contributing factors of a child’s sense of vulnerabil- extended into adulthood, has not been studied system- ity toward experiencing illness intrusiveness are promis- atically. Are adults with a childhood rheumatic illness ing aims of investigation [7]. Parental and peer support “well equipped” and “ready” to struggle successfully appears essential for the child’s adjustment process [8]. with challenges in the “adult world?” Research patient The last two articles [10,11••] call our attention to the populations with chronic arthritis should be maintained significance of being attuned to patients’ very subjective as homogenous as possible. experience of their illness, particularly when experiencing pain. A child’s own words may be important to help Children and adolescents with other rheumatic illnesses recognize the high degree of symptom variability and to including systemic lupus erythematosus, juvenile derma- capture the pain experience, with its social consequences tomyositis, scleroderma, and vasculitis need to be stud- of reduced participation in school and leisure activities. ied with regard to their psychosocial issues. Considering the lower prevalence of these illnesses, multicenter na- Although many questions remain, these publications tional and international studies are called for. Even if provide more food for thought. Some of the data can only many of our children and adolescents may be doing well be taken as preliminary, and suggest the direction of with regard to psychosocial adjustment, we need to iden- future research. To arrive at observations with the high- tify those at risk and introduce intervention measures as est degree of relevance and validity, we need to define early as possible. We have little comprehensive knowl- clearly which patients need to be studied, at what point edge about what kinds of psychotherapies are being used in the time course of their illness, and with what means. for what indications in our patients. Which treatment approaches may be beneficial? Behavioral, cognitive, While awaiting further results from systematic research family oriented, group therapy, psychodynamic psycho- in the field of adjustment in children with rheumatic therapy, alone or in combination? Individual case stud- diseases, psychosocial care provided by the pediatric ies, especially longitudinally performed, may be highly rheumatology teams may be an integrated component of instructive, allowing us to achieve deeper understanding regular office visits. We have the opportunity to assess of the psychosocial challenges some of our children and mental and emotional well-being, foster psychological adolescents with a rheumatic disease are facing, how health, and be vigilant toward psychological conflict in a they are dealing with them, and how we can become nonpsychiatric environment. “Fostering Independence more effective in providing support. in Children with Rheumatic Disease” was the topic of an ACRclinical symposium by Schanberg, Anthony, and References and recommended reading Rittgers. It was demonstrated how the close relation to Papers of particular interest, published within the annual period of review, children, adolescents, and their families offers ongoing are highlighted as: opportunity to provide stimulation for healthy cognitive • Of special interest and emotional development. This may start with a com- •• Of outstanding interest prehensive psychosocial intake from the beginning, par- 1 Gerhardt C, Vannatta K, McKellop J, et al.: Comparing parental distress, family functioning, and the role of social support for caregivers with and without a ticularly once a diagnosis of a rheumatic illness has been child with juvenile rheumatoid arthritis. J Pediatr Psychol 2003, 28:5–15. confirmed. Anticipatory guidance needs to be provided 2 Reiter–Purtill J, Gerhardt C, Vannatta K, et al.: A controlled longitudinal study from the beginning. During clinic visits, patients may of the social functioning of children with juvenile rheumatoid arthritis. J Pediatr benefit from a more unstructured opportunity to find Psychol 2003, 28:17–28. their personal expression of their illness experience. 3 LeBovidge J, Lavigne J, Donnenberg G, et al.: Psychological adjustment of children and adolescents with chronic arthritis: a meta-analytic review. J Pe- Qualitative factors should be regarded as important as diatr Psychol 2003, 28:29–39. attempts to quantify discomfort using scales or other 4 Routh D: Commentary: juvenile rheumatic disease as a psychosocial stress- measures. •• or. J Pediatr Psychol 2003, 28:41–43. This excellent commentary compliments previous articles [1–3] for their high methodological standards and rigorous design. However, it raises questions about clini- Conclusion cal validity of findings. It is emphasized that research should be able to capture the individual dimension of the potentially profound psychosocial impact of a pediatric Many research tasks regarding psychosocial aspects in rheumatic illness. pediatric rheumatology remain to be addressed. Studies 5 Dahlquist L: Commentary: are children with JRA and their families at risk or looking at adjustment problems in children with chronic • resilient? J Pediatr Psychol 2003, 28:45–46. arthritis need to be conducted longitudinally, including This very helpful commentary points out the need for more precise definition of research goals, population targets, and methods. the time around diagnosis, periods of active disease, and 5a Noll R, Kaslowski K, Gerhardt C, et al.: Social, emotional, and behavioral families with children with more severe disease. With functioning of children with juvenile rheumatoid arthritis. Arthritis and Rheu- respect to social functioning, there still are many chil- matism 2000, 43:1387–1396. Psychosocial aspects Kietz 559

6 Power T, Dahlquist L, Thompson S, et al.: Interactions between children with 9 Foster H, Marshall N, Myers A, et al.: Outcome in adults with juvenile idio- juvenile rheumatoid arthritis and their mothers. J Pediatr Psychol 2003, • pathic arthritis: a quality of life study. Arthritis Rheum 2003, 48:767–775. 28:213–221. This paper demonstrates the importance of extending the perspective of psychosocial outcome studies of pediatric rheumatic illnesses into adulthood. 7 Wagner J, Chaney J, Hommel K, et al.: The influence of parental distress on 10 Sallfors C, Fasth A, Hallberg L: Oscillating between hope and despair—a child depressive symptoms in juvenile rheumatic diseases; the moderating qualitative study. Child Care Health Dev 2002, 28:495–505. effect of illness intrusiveness. J Pediatr Psychol 2003, 28:453–462. 11 Schanberg L, Anthony K, Gil K, et al.: Daily pain and symptoms in children with 8 Von Weiss R, Rapoff M, Varni J, et al.: Daily hassles and social support as •• polyarticular arthritis. Arthritis Rheum 2003, 48:1390–1397. predictors of adjustment in children with pediatric rheumatic disease. J Pedi- This excellent paper stresses the significance of the pediatric rheumatologist’s atr Psychol 2002, 27:155–165. heightened awareness of a child’s pain experience and anxiety. Update on childhood vasculitides Tracy V. Ting and Philip J. Hashkes

Purpose of review Introduction The purpose of this review is to provide an update on the new Vasculitis is defined as inflammation involving the blood developments in pediatric vasculitis. vessel wall. Most types of vasculitis in childhood are rare, Recent findings with the exception of Henoch–Scho¨nlein purpura (HSP), Because most childhood vasculitides are rare, few large Kawasaki disease (reviewed separately in this issue), and systematic studies have been done. Studies of Takayasu arteritis. Gardner–Medwin et al. [1] surveyed Henoch–Scho¨ nlein purpura have focused on pathogenesis the local population in the West Midlands, UK, in 2002 and outcome. Genetic associations and molecular changes and reported an estimated annual incidence of primary occurring during Henoch–Scho¨ nlein purpura, including vasculitis of 0.24 per 100,000 children (except HSPand cytokines, and endothelial and nitric oxide metabolism are Kawasaki disease), mainly in children of Asian origin. discussed. Risk factors for renal involvement and poor renal Vasculitides can be classified according to the size or outcome are described. Uncontrolled series of treatment histology of the blood vessel or by clinical manifesta- protocols for severe Henoch–Scho¨ nlein purpura nephritis are tions. The Chapel Hill Consensus Conference classifica- mentioned. Several studies have focused on the pathogenesis tion has not been validated in children. of other primary vasculitides, especially polyarteritis nodosa. Series describing the clinical manifestations of childhood Diagnosis is based on clinical criteria, well defined in vasculitis and case reports of uncommon manifestations of some childhood vasculitides (HSP, Kawasaki disease), as vasculitis in children are presented. The efficacy of new well as imaging, and histology. Laboratory tests are usu- therapies, including the use of thalidomide and biologic ally nonspecific. The utility of antineutrophil cytoplas- modifiers, has been shown in individual childhood cases; mic antibodies (ANCA) in children is not clear. In one however, there are no controlled studies of these agents. study the sensitivity of p-ANCA and c-ANCA for micro- Summary scopic polyangiitis and Wegener granulomatosis was Besides studies of Henoch–Scho¨ nlein purpura, advances in 100%, but the specificity was low. c- and p-ANCA were pediatric vasculitis are few as a result of the rarity of most also found in juvenile rheumatoid arthritis (27% of pa- vasculitides in childhood. Multicenter collaboration is tients), cystic fibrosis (42%), ulcerative colitis (70%), and necessary to substantially increase the scientific base of autoimmune hepatitis (84%) [2•]. investigating and treating childhood vasculitis. We review the relatively few recent developments in Keywords pediatric vasculitis. vasculitis, children, Henoch–Scho¨ nlein purpura Henoch–Scho¨ nlein purpura HSP, the most common vasculitis in children, classically Curr Opin Rheumatol 16:560–565. © 2004 Lippincott Williams & Wilkins. includes nonthrombocytopenic purpura, abdominal pain, arthritis, and glomerulonephritis.

Epidemiology, etiology, and pathophysiology Gardner–Medwin et al. [1] found an estimated annual Section of Pediatric Rheumatology, Department of Rheumatic Diseases, Cleveland Clinic Foundation, Ohio, USA incidence of 20.4 per 100,000 children, with a mode between 4 to 6 years (70.3/100,000). The association of HSP Correspondence to Philip Hashkes, MD, Department of Rheumatic Diseases A50, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA with familial Mediterranean fever (FMF) was supported Tel: 216 445 8525; fax: 216 445 7569; e-mail: [email protected] by Gershoni–Baruch et al. [3•], who identified an in- Current Opinion in Rheumatology 2004, 16:560–565 creased number of FMF gene mutations among Israeli children with HSP. Ten percent were homozygous or Abbreviations had a compound-homozygote FMF genetic defect. Most ANCA antineutrophil cytoplasmic antibodies BD Behc¸et disease included the M694V mutation [3•]. FMF familial Mediterranean fever HSP Henoch–Scho¨ nlein purpura HSPis associated with numerous triggers, primarily in- IL interleukin PAN polyarteritis nodosa fectious. Several recent studies have reiterated that upper respiratory tract infections precede HSPin 30 to 50% © 2004 Lippincott Williams & Wilkins 1040–8711 of cases, often group A Streptococcus [4,5•,6]. Masuda et al. 560 Childhood vasculitides Ting and Hashkes 561

[5•] have found increased levels of group A Streptococcus To differentiate HSPfrom testicular torsion, Ben–Sira antigens in the glomerular mesangium from patients and Laor [25] have described the sonographic features of with HSPnephritis compared with other types of glo- HSPscrotal disease. These include an enlarged, rounded merular disease. Eisenstein and Navon–Elkan [6] re- epididymis with thickened scrotal skin and hydrocele, ported the simultaneous occurrence of HSPand rheu- but with normal-appearing testes. matic fever in six patients. Eun et al. [26•] presented an 8 year-old boy with HSP Ayoub et al. [7] reported a possible association of HSP who developed seizures and changes in mental status. with Bartonella henselae infection. Antibodies to B. MRI revealed multifocal, high-intensity T2 images. In henselae were found in 12 of 18 HSPpatients (67%) as contrast to other reported cases, irregularities of several opposed to 8 of 57 healthy control subjects (14%; P < middle-size cerebral arteries were found by MR angiog- 0.0001). Other recently reported infectious triggers in- raphy. Rare complications of HSPrecently reported included hepatitis A [8] and Hemophilus parainfluenza [9]. cluded the development of cerebellar and pulmonary Two cases of HSPfollowing hepatitis B and meningo- hemorrhage [27,28]. coccal vaccination [10,11], and a case of azithromycin- induced HSPwere reported [12]. Unlike previous re- Two studies confirmed the benign nature of acute hem- ports, no evidence of preceding parvovirus B19 infection orrhagic edema of infancy associated with purpura, was found in 28 of 29 children with HSP[13]. edema, and fever in infants younger than 27 months [29•,30]. Amoli et al. [14,15] found an increase in the prevalence of human leukocyte antigen-DRB101 and a decrease in hu- Treatment man leukocyte antigen-DRB107 among patients with No new studies were published on the use of corticoste- HSP. They also found an increased prevalence of human roids for gastrointestinal disease and prevention of glo- leukocyte antigen-B35 and interleukin (IL)-8A allele merulonephritis. Several reports discussed the treatment polymorphism among HSPpatients with nephritis of severe nephritis. Flynn et al. [31] reported that treat- [14,15]. The severity of nephritis and renal outcome ment with prednisone and 12 weeks of oral cyclophos- were influenced by the IL-1␤ gene polymorphism. Pa- phamide resulted in a significant decrease in proteinuria tients with more severe disease carried the 511-T allele with preservation of renal function in 12 patients with [16•]. No associations were found between nitric oxide nephrotic-range proteinuria, 10 of whom had crescentic synthase polymorphisms and HSP[17]. However, an- nephritis. Kawasaki et al. [32•] reported 56 patients with other study identified higher levels of serum nitric oxide severe HSPnephritis treated with intravenous methyl- and urinary nitrate excretion during acute HSP[18]. En- prednisolone and urokinase pulse therapy. They found dothelial cell involvement as evident by increased endo- 100% renal survival during a follow-up of more than 10 thelin ET-1 and IgA antiendothelial cell antibodies were years. A significant decrease in the activity index (4.1 ± found during acute HSP[19,20]. Increased levels of ad- 1.9 to 2.5 ± 1.7) was found among 27 patients who un- renomedullin, a vasodilator molecule, were also found derwent pre- and posttherapy renal biopsies. Other se- during acute HSP[21]. ries reported the beneficial use of cyclosporin A for nephrotic-range proteinuria (seven patients) [33•] and for In a Turkish study, increased numbers of apoptotic pe- steroid-resistant HSP(two patients) [34]. Controlled ripheral neutrophils and lymphocytes were present dur- studies are required before these regimens become stan- ing the acute phase of disease, indicating that increased dard of care. apoptosis may have a role in the early control of inflammation in HSP[22•]. Intravenous pulse steroids were used to treat a 15-year- old boy with massive gastrointestinal bleeding with ileus Clinical manifestations [35]. Another 7-year-old boy with refractory, severe HSP A Thai review of 47 patients with HSPfound skin in- was successfully treated with leukocytopheresis [36]. A volvement in 100% of patients, gastrointestinal involve- recent study showed a lack of efficacy of vitamin E for ment in 75%, renal involvement in 47%, and joint in- HSP, despite evidence of oxidative damage and lipid volvement in 43% [23]. A Lithuanian series reported less peroxidation [37]. Conservative treatment of ileoileal in- gastrointestinal (38%) and renal involvement (13%) [4]. tussusception in HSPpatients is often adequate (three of six patients), but close observation is necessary [38]. Sano et al. [24] found that 97% of cases of HSPnephritis appeared within the first 3 months of disease. Risk fac- Prognosis tors included children older than 4 years, those with gas- Kawasaki et al. [39] looked at risk factors for developing trointestinal bleeding, purpura lasting more than 1 an “unfavorable” renal outcome, defined as hyperten- month, factor XIII activity less than 80% of normal, sion, proteinuria, and renal failure, in 114 patients fol- and/or those treated with factor XIII concentrate. lowed for 5 to 15 years. They found that patients with 562 Pediatric and heritable disorders nephritis, decreased factor XIII activity, hypertension, Polyarteritis nodosa and and renal failure at disease onset were at a higher risk for microscopic polyangiitis these outcomes. The 15-year renal survival rate was 96% Several studies have explored pathogenic processes in [39]. Garcia–Porrua et al. [40] recently confirmed that pediatric PAN and microscopic polyangiitis. An associa- adults with HSPhave a worse renal prognosis than chil- tion of specific V␤ T-cell receptor families (CD4-12, dren. Ronkainen et al. [41•] found that biopsy findings at CD17, and CD8-1) and the development of primary sys- onset did not predict the renal outcome. Patients with temic vasculitis, particularly PAN, have recently been low- to mid-grade histology had the worst outcomes described [50•]. Microparticle-containing molecules, in- [41•]. Algoet et al. [42] also found that 8 of 12 HSP dicating endothelial activation, were increased in chil- patients who underwent a renal biopsy 2 to 9 years after dren with active PAN, microscopic polyangiitis, and Ka- disease onset continued to have mesangial IgA deposits wasaki disease [51]. despite only minor renal findings in most patients. In an important long-term study (mean follow-up, 24.1 years), Recent studies have found an association of PAN with Ronkainen et al. [43] found that patients with significant FMF. Approximately 1% of patients with FMF develop glomerulonephritis at onset had a 4.7 risk of developing PAN [52]. These patients tend to be younger than chil- a poor renal outcome than patients with mild abnormali- dren with classic PAN and have a better prognosis. The ties. All patients without renal involvement did well. development of perirenal hematomas is particularly char- Women were at a 2.5-fold risk for a poor renal outcome, acteristic in these patients [53]. and 70% of the women developed pregnancy complications of hypertension and decreased renal function [43]. Cheung et al. [54] found a decrease in arterial distensibility of the brachial and radial arteries in 13 children with active PAN compared with the distensibility during Takayasu arteritis remission and with normal control subjects. Takayasu arteritis is the third most common childhood vasculitis. Case reports of unusual clinical manifestations Bakkaloglu et al. [55] examined the utility of p-ANCA include a child who presented with panuveitis and a testing in children with PAN. They found a 40% sensi- child initially thought to have juvenile rheumatoid ar- tivity in classic PAN (6 of 15 children) and positive thritis [44,45]. Also reported was a 17-year-old woman ANCA in all 10 children with MPO. ANCA levels were diagnosed via endovascular biopsy of the infrarenal aorta useful in following the disease course [55]. Ceruloplas- [46]. min levels were significantly elevated in children with active p-ANCA vasculitis compared with children with The features of pediatric Takayasu arteritis in 142 pa- c-ANCA vasculitis and HSP, particularly in patients with tients were recently described [47]. The mean age of severe renal disease. Ceruloplasmin levels correlated sig- onset was 11.4 years; 75% were female. The most com- nificantly with p-ANCA and antimyeloperoxidase levels, mon clinical and laboratory manifestations were hyper- and were decreased during remission [56]. tension (88%), cardiomegaly (74%), elevated sedimentation rate (61%), fever (40%), fatigue (40%), palpitations No controlled therapeutic studies were reported in chil- (25%), vomiting (25%), nodules (25%), abdominal pain dren. Successful treatment with interferon-␣ was re- (19%), arthralgia (19%), claudication (17%), weight loss ported in a 9-month-old girl with PAN related to mater- (17%), and chest pain (11%) [47]. The mean time to nally transmitted hepatitis B infection [57]. diagnose Takayasu arteritis was 19 months, longer than most adult series. The mortality rate was 33% (more than Wegener granulomatosis in adults). Similar clinical findings with an 8% mortality Wegener granulomatosis is characterized by the presence rate were seen in 24 Indian children followed for 3 to 72 of upper and lower respiratory tract disease with glomer- months [48]. ulonephritis. It is the most common granulomatous vasculitis in children, and it affects medium and small-size vessels. The angiographic findings in 26 children have been described [49]. The most common findings included ste- A series of 17 pediatric patients with Wegener granulo- nosis in all patients, mainly of the abdominal aorta. Sev- matosis (age range, 2 weeks to 14 years) was recently enteen of 26 (65%) also had aneurysms: fusiform (54%) reported [58]. The children’s ages were lower than in and saccular (31%). Percutaneous transluminal angio- previous pediatric series. Clinical manifestations were plasty was initially effective in treating stenosis in eight similar to adult cases, with nasal and sinus involvement patients [49]. No long-term follow-up was available. in 100%, respiratory in 87%, arthralgia in 53%, ocular in 53%, skin in 53%, gastrointestinal in 41%, and central No pediatric studies on the use of methotrexate or newer nervous system in 12%. Renal involvement was seen in antitumor necrosis factor agents have been published. 53% (less than in other series), whereas subglottic ste- Childhood vasculitides Ting and Hashkes 563 nosis was more frequent (41%). The follow-up period membrane and enteric features of pediatric BD [71,72]. was unclear, but one patient died, one was in drug-free However, symptoms of peripheral neuropathy were pres- remission, and other patients were stable while receiving ent in four of five children treated with thalidomide, and treatment. was irreversible in one patient [71]. Infliximab was effective in a 15-year-old girl with severe mucous mem- Unusual manifestations of Wegener granulomatosis, in- brane ulcers [73]. Cord blood stem cell transplantation in cluding intracranial bleeding in a 4-year-old girl and a 10-year-old girl with a myelodysplastic syndrome was pseudo tumor orbitae in a 7-year-old girl were recently also effective in curing her BD [74]. reported [59,60]. Central nervous system vasculitis The adult therapeutic regiments, including corticoste- A comprehensive review by Benseler and Schneider roids and cyclophosphamide for induction and metho- [75••] was recently published in this journal. Benseler et trexate for maintenance, have not been validated in chil- al. [76] reviewed the predictors of primary central ner- dren. vous system vasculitis progression in 62 children. High- risk factors included significant neurocognitive dysfunc- Behc¸et disease tion and severe headache at onset, MR findings of Behc¸et disease (BD) is a small-vessel immune complex multifocal parenchyma lesions with bilateral areas of in- vasculitis typically involving the oral and genital mucous farction, and MR angiographic findings of multiple ste- membranes, eyes, and skin, and often involving the mus- noses, with bilateral and peripheral vessel involvement. culoskeletal, central nervous, and gastrointestinal sys- Isolated stroke features were associated with a low risk of tems. progression [76]. Epidemiology BD is more frequent in East Asia and the Mediterranean. Secondary vasculitis Researchers in Korea and Turkey have reported that less Several cases of the development of vasculitis secondary than 10% of BD cases start in childhood (149 of 1697 to other diseases have been reported. A 16-year-old girl patients) [61,62]. A multinational study has found a sig- with congenital cyanotic heart disease was diagnosed nificantly greater familial aggregation in families with with infectious endocarditis after presenting with sys- pediatric cases of BD (12.3%) than adult BD (2.2%) [63]. temic vasculitis and glomerulonephritis [77]. A 16-year- Another study reported that siblings were affected in old girl with systemic lupus erythematosus was found to 33% of families with childhood BD (4 of 12 patients) have mononeuritis multiplex 4 years after diagnosis. [62]. Nerve biopsy confirmed vasculitis [78]. An 11-year-old girl with pre-B-cell acute lymphoblastic leukemia pre- Clinical manifestations sented with cutaneous lymphocytic vasculitis that re- The International Study Group diagnostic criteria for BD solved after chemotherapy [79]. A 9-year-old girl with in 1989 have not been validated in children [64]. In a systemic juvenile rheumatoid arthritis treated with series from Israel comparing pediatric with adult BD, etanercept developed purpura that resolved after etaner- children had uveitis more often, but less genital ulcer- cept discontinuation. Purpura did not recur after gradual ations, vascular thrombosis, arthralgia, and central ner- reintroduction of etanercept [80]. vous system involvement [65]. The spectrum of BD- related eye involvement was described in 36 Turkish Conclusion children. Panuveitis was the most common form, but There are still significant gaps in the understanding and more than 80% also had retinal vasculitis and/or infil- treatment of pediatric vasculitis. We are dependent, to a trates. Unlike earlier series, more than 50% of the chil- large degree, on the adult knowledge and experience. A dren had complications, including blindness in 17%, de- concerted multicenter, international effort is needed to spite aggressive immunosuppression given to 75% of the develop an independent understanding of the unique children [66•]. pathogenesis, clinical features, and therapeutic modalities of pediatric vasculitis. Case reports of pediatric BD included a 13-year-old boy with abdominal aortic aneurysm and superior sagittal si- References and recommended reading nus thrombosis [67], two cases of cerebral venous throm- Papers of particular interest, published within the annual period of review, bosis [68], and fatal hemoptysis in a 10-year-old child are highlighted as: [69]. • Of special interest •• Of outstanding interest Treatment 1 Gardner–Medwin JM, Dolezalova P, Cummins C, et al.: Incidence of He- noch–Scho¨ nlein purpura, Kawasaki disease, and rare vasculitides in children Current therapy includes colchicine, corticosteroids, and of different ethnic origins. Lancet 2002, 360:1197–1202. various immunosuppressive medications [70]. Two pa- 2 Bartunkova J, Tesar V, Sediva A: Diagnostic and pathogenetic role of anti- pers reported the efficacy of thalidomide for mucous • neutrophil cytoplasmic autoantibodies. Clin Immunol 2003, 106:73–82. 564 Pediatric and heritable disorders

This is a nice review and study of ANCA and its usefulness in Wegener granulo- 25 Ben-Sira L, Laor T: Severe scrotal pain in boys with Henoch–Scho¨ nlein pur- matosis, microscopic polyangiitis, and other nonvasculitic illnesses such as cystic pura: incidence and sonography. Pediatr Radiol 2000, 30:125–128. fibrosis, inflammatory bowel disease, and autoimmune hepatitis in both adults and children. 26 Eun SH, Kim SJ, Cho DS, et al.: Cerebral vasculitis in Henoch–Scho¨ nlein • purpura: MRI and MRA findings treated with plasmapheresis alone. Pediatr 3 Gershoni–Baruch R, Broza Y, Brik R: Prevalence and significance of muta- Int 2003, 45:484–487. • tions in the familial Mediterranean fever gene in Henoch–Scho¨ nlein purpura. The paper reports the radiologic findings in HSP-related cerebral vasculitis and J Pediatr 2003, 143:658–661. presents an interesting table reviewing other cases of HSP cerebral involvement. In certain populations, HSP may be the presenting sign for FMF. Seizures and hemiparesis are the most common clinical manifestations. 4 Sileikiene R, Tamakauskiene E, Baksiene D: Henoch–Scho¨ nlein purpura— 27 Paolini S, Ciappetta P, Piattella MC, et al.: Henoch–Scho¨ nlein syndrome and one of the most common types of systemic vasculitis in childhood. Medicina cerebellar hemorrhage: report of an adolescent case and literature review. (Mex) 2003, 39:476–479. Surg Neurol 2003, 60:339–342. 5 Masuda M, Nakanishi K, Yoshizawa N, et al.: Group A streptococcal antigen 28 Besbas N, Duzova A, Topaloglu R, et al.: Pulmonary haemorrhage in a 6-year- • in the glomeruli of children with Henoch–Scho¨ nlein nephritis. Am J Kidney Dis old boy with Henoch–Scho¨ nlein purpura. Clin Rheumatol 2001, 20:293– 2003, 41:366–370. 296. This study demonstrates that streptococcal antigens may have a pathogenic role in a significant proportion of patients with HSP nephritis. 29 Poyrazoglu HM, Per H, Gunduz Z, et al.: Acute hemorrhagic edema of infancy. • Pediatr Int 2003, 45:697–700. 6 Eisenstein EM, Navon–Elkan P: Acute rheumatic fever associated with He- This study reiterates the benign nature of this disorder, perhaps a variant of HSP in noch–Scho¨ nlein purpura: report of three cases and review of the literature. infancy. Acta Paediatr 2002, 91:1265–1267. 30 Caksen H, Odabas D, Kosem M, et al.: Report of eight infants with acute 7 Ayoub EM, McBride J, Schmeiderer M, et al.: Role of Bartonella henselae in infantile hemorrhagic edema and review of the literature. J Dermatol 2002, the etiology of Henoch–Scho¨ nlein purpura. 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J Dermatol Treat 2003, 14:179–181. lone and thrombolytic therapy when administered early for HSP nephritis. 33 11 Lambert EM, Liebling A, Glusac E, et al.: Henoch–Scho¨ nlein purpura follow- Ronkainen J, Autio–Harmainen H, Nuutinen M: Cyclosporin A for the treating a meningococcal vaccine. Pediatrics 2003, 112:e491. • ment of severe Henoch–Scho¨ nlein glomerulonephritis. Pediatr Nephrol 2003, 18:1138–1142. 12 Odemis E, Kalyoncu M, Okten A, et al.: Azithromycin-induced leukocytoclas- This small, uncontrolled series found that cyclosporin A was effective for otherwise tic vasculitis. J Rheumatol 2003, 30:2292. treatment-resistant HSP nephritis. 13 Heegaard ED, Taaning EB: Parvovirus B19 and parvovirus V9 are not asso- 34 Huang DC, Yang YH, Lin YT, et al.: Cyclosporin A therapy for steroid- ciated with Henoch–Scho¨ nlein purpura in children. Pediatr Infect Dis J 2002, dependent Henoch–Scho¨ nlein purpura. 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Clin Rheumatol 2003, 22:472–474. report and review of the literature. Pediatr Nephrol 2001, 16:1089–1092. 61 Bang D, Lee JH, Lee ES, et al.: Epidemiologic and clinical survey of Behçet’s 78 Ryan MM, Tilton A, DeGirolami U, et al.: Paediatric mononeuritis multiplex: a disease in Korea: the first multicenter study. J Korean Med Sci 2001, report of three cases and review of the literature. Neuromuscul Disord 2003, 16:615–618. 13:751–756. 62 Gul A, Inanc M, Ocal L, et al.: Familial aggregation of Behçet’s disease in 79 Jaing TH, Hsueh C, Chiu CH, et al.: Cutaneous lymphocytic vasculitis as the Turkey. Ann Rheum Dis 2000, 59:622–625. presenting feature of acute lymphoblastic leukemia. 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Purpose of review Correspondence to Nicolino Ruperto, MD, IRCCS G. Gaslini, Pediatria II - PRINTO, Largo Gaslini, 5, 16147 Genova Italy The purpose of this review is to highlight the problems and Tel: 39 010 382854; fax 39 010 393324; possible solutions for the conduct of international collaborative e-mail: [email protected] research for pediatric rheumatic diseases. Current Opinion in Rheumatology 2004, 16:566–570 Recent findings Abbreviations Pediatric rheumatic diseases are rare conditions associated JDM juvenile dermatomyositis with important sequelae on the quality of life and long-term JIA juvenile idiopathic arthritis outcome. The research aimed at studying new therapeutic JRA juvenile rheumatoid arthritis JSLE juvenile systemic lupus erythematosus approaches is difficult because of logistic, methodological, and MTX methotrexate ethical problems. To face these problems, two international PRCSG Pediatric Rheumatology Collaborative Study Group PRD pediatric rheumatic diseases networks have been founded: the Pediatric Rheumatology PRINTO Pediatric Rheumatology International Trials Organization Collaborative Study Group (or PRCSG) and the Paediatric © 2004 Lippincott Williams & Wilkins Rheumatology international Trials Organization (or PRINTO). 1040–8711 The two networks have the goal to promote, facilitate, and conduct high-quality research into pediatric rheumatic diseases. In particular they have been able to standardize the evaluation of response to therapy in juvenile idiopathic arthritis, Introduction juvenile systemic lupus erythematosus, and juvenile The pediatric rheumatic diseases (PRD) are rare condi- dermatomyositis; to draft clinical remission criteria in juvenile tions associated with substantial morbidity, consequence idiopathic arthritis; and to provide cross-cultural adapted and on the quality of life, and monetary costs. Many studies validated quality-of-life instruments like the Childhood Health of the impact and outcome of PRD have shown that this Assessment Questionnaire and the Child Health Questionnaire group of diseases is associated with greater morbidity and in 32 different languages. monetary cost than previously thought [1]. For example, Summary long-term outcome studies of children with juvenile id- The creation of large international trial networks such as iopathic arthritis (JIA) report that after a mean follow-up PRINTO and PRCSG, the definition of internationally of 15 years, the majority of the patients continue to ex- recognized and standardized outcome measures and perience some difficulties in daily livingactivities, and definitions of improvement, the validation of quality-of-life that moderate to severe pain is still present in 30% of instruments, and the adoption of adequate legislative patients [2,3]. There is also evidence of cumulative organ measures (pediatric rule) have created the basic premises for damage in patients with juvenile systemic lupus erythe- the best future assessment of pediatric rheumatic diseases. matosus (JSLE) [4•]. This progress now affords children with pediatric rheumatic diseases the same opportunities as adults to be treated with Certainly childhood chronic illnesses with high levels of drugs whose safety and efficacy have been assessed through morbidity should be the target of intense research aimed legitimate scientifically valid investigations. at amelioratingand/or curingthe disease. However, conductingclinical trials in PRD has proved difficult for a Keywords host of reasons. collaborative research, clinical trials, pediatric rheumatic diseases, quality of life Because of the rarity of the diseases, the only possibility of gathering a sufficient number of patients to obtain

Curr Opin Rheumatol 16:566–570. © 2004 Lippincott Williams & Wilkins. clinically and statistically valid results in a reasonable period of time is to perform multicenter studies on an international scale. The ethics of conductingany placebo-controlled trial, even in adults, has recently come under intense debate [5–9]. Parents often refuse entry IRCCS G. Gaslini, Universita` di Genova, Pediatria II-Reumatologia, Genova, Italy into studies because they are uncomfortable with the The studies performed by PRINTO have been supported with the following grants prospect of their child beingassignedby chance to pla- from the European Union: no. BMH4 983531, no. QLG1-CT-2000-00514, no. 2001CVG4-808, and no. AML/B7-311/97/0666/II-0246-FI. cebo. Securingfundingfor conductingclinical trials in 566 Research networks in pediatric rheumatology Ruperto and Martini 567

PRD has always been difficult because the pharmaceu- patients whose disease is resistant to nonsteroidal anti- tical industry has little interest in fundingthese trials as inflammatory drugs. a result of the small potential market. The PRCSG more recently developed a randomized withdrawal study design in collaboration with the Food Drugs available for the treatment of PRD have been and DrugAdministration that has been accepted by used in new dosages, new routes of administration, and regulatory agencies throughout the world as an accept- new combinations. Unfortunately, data regarding the able study design for use in the evaluation of new thera- safety and effectiveness of these new treatment regi- pies for children with JIA. This study design was used mens tend to be from small, open, anecdotal, uncon- successfully used by the PRCSG in performingthe first trolled, nonrandomized case series. Examples include trial of a biologic therapy in JIA [23]. the use of high-dose methotrexate (MTX) in recalcitrant JIA [10,11] and of MTX usage in juvenile dermatomyo- The Pediatric Rheumatology International sitis (JDM) [12]. Many of these new approaches to man- Trials Organization agement may represent improvements over existing The Pediatric Rheumatology International Trials Orga- standards, but without larger, systematic trials, the data nization (PRINTO) was founded by Alberto Martini and must remain suspect. Nicolino Ruperto in 1996, and initially included 14 Eu- ropean countries (now 43 countries with more than 170 The history of collaborative research in centers worldwide) [24]. PRINTO aims are to facilitate pediatric rheumatology and coordinate the development, conduct, analysis, and The Pediatric Rheumatology Collaborative reportingof clinical trials and outcome assessment stan- Study Group dardization in children with PRD. PRINTO was Founded in 1973 by Dr. Earl Brewer and led the follow- founded with the idea to perform clinical trials for PRD ingyears by Drs. Edward H. Giannini and Daniel J. with or without the support of pharmaceutical compa- Lovell, the purpose of the Pediatric Rheumatology Col- nies. In general, if a study is not supported by a phar- laborative Study Group (PRCSG) is to foster, facilitate, maceutical company, the design is that of a randomized, and conduct high-quality research in the field of pediat- actively controlled, and open-label clinical trial. If the ric rheumatology in North America. The activities of the study is supported by a pharmaceutical company and is PRCSG are governed by written bylaws, and oversight part of a clinical development program that aims at mar- and long-range planning is provided by the PRCSG ad- keting an agent, a more classic design is used. visory council. The PRCSG coordinatingcenter is located in Cincinnati, Ohio, USA. PRINTO is composed of academic and clinical centers actively engaged in the research/clinical care of children The main focus of the PRCSG in its early years was with PRD. PRINTO actually is composed of the most related to clinical trials of nonsteroidal antiinflammatory esteemed pediatric rheumatology researchers outside the drugs in juvenile rheumatoid arthritis (JRA) [13]. Their United States. PRINTO has four main vertical struc- pioneeringmethodologicalworks for the conduct of tures: the advisory council, which provides leadership clinical trials [14,15•16–18] set the basis for the further and guidance for PRINTO research activities; the inter- development of evidence-based collaborative research in national coordinatingcenter, with the main task of facil- PRD. itatingthe flow of logisticand scientific details needed to design, launch, and manage multicenter, multinational, collaborative studies; the national coordinatingcenters Indeed, duringthe ensuingyears, the PRCSG started (one per country), with the tasks of facilitatingthe par- work in the field of disease-modifyingantirheumatic ticipation of the greatest number possible of individual drugs [19] that led to the demonstration of the ineffec- centers and translatingall the forms to be completed by tiveness of penicillamine, hydroxychloroquine [20], and the parents/patients; and finally the individual clinical auranofin [21] in the treatment of severe JRA. It should sites, which constitute the main support structure for be noted that to reach an adequate sample size for these obtaininga critical mass of data for ongoingandfuture mentioned trials, it was necessary to establish an inter- research. In recent years the PRINTO and the PRCSG national collaboration between the United States and the have worked closely on various international collabora- former Soviet Union. tive projects detailed in the followingparagraphs.

Their seminal work led to a significant impact in the The American College of Rheumatology Pediatric 30 current clinical practice of the pediatric rheumatology definition of improvement for juvenile community, especially after the publication of the MTX idiopathic arthritis trial [22] in JRA, which demonstrated the efficacy of this Up until the late 1990s, the assessment of clinical re- drug at a dosage of 10 mg/m2/week. Since 1992, MTX sponse in JIA/JRA was not standardized. Multiple mea- has become the drugof choice for the treatment of JRA sures of outcome were in use and different trials used 568 Pediatric and heritable disorders different end points. Some of these end points had low shows that the plateau of efficacy of MTX in JIA is validity characteristics and were insensitive to change, reached with the parenteral administration of 15 some were redundant, and some were not reliable (poor mg/m2/week and that further increase in dosage is not reproducibility). Additionally, there was little consensus associated with any additional therapeutic benefit. regarding the amount of change in end points, which signifies clinically important improvement or worsening. This lack of standardization led to inefficient trials that From a methodological point of view, the trial was built required larger than necessary sample sizes, an increased on the current “standard of care” in such a way that the risk of statistical error, possible reportingbias, multiple cost of insurance coverage, the medication, clinic visits, or ambiguous interpretations of the results, and an in- and laboratory monitoringwere paid by the usual ability to compare multiple therapies usingmeta-analytic method of cost reimbursement for clinical care in each techniques. participatingcountry. The amount of data collected, in addition to that from routine follow-up, was minimal, and The main aim of this first combined effort conducted by all investigators volunteered their time and effort. The the PRCSG and PRINTO, under the guidance of Gian- study received no pharmaceutical industry support. nini, was to develop a standardized core set of measures and a definition of improvement for the evaluation of The next steps were to launch clinical trials in Europe response to therapy in JRA that would be accepted by and to prepare standardized tools for the outcome assess- the international community. ment of children with PRD to be used internationally among nations with different languages and cultures. There are six validated outcomes measures in the JIA core set [25] [26] that measure different domains of disease activity: the number of joints with active arthritis, The quality-of-life project for pediatric the number of joints with limited range of motion, the rheumatic diseases physician global evaluation of disease activity, the parent One particular problem for the conduct of international assessment of child’s overall well-being, a functional as- studies was the availability of parent/patient-reported sessment tool, and the Westergren erythrocyte sedimen- outcome for functional ability and quality-of-life assess- tation rate. To be classified as improved, a patient must ment. Thanks to the European Union (contract no. demonstrate at least 30% improvement from baseline in BMH4 983531), PRINTO has been able to adapt and at least three of any six JIA core set variables with no validate two questionnaires cross-culturally: the Child- more than one of the remainingvariables worsened by hood Health Assessment Questionnaire for functional more than 30%. The definition of improvement allows ability assessment in JIA and JDM, and the Child Health researchers and clinicians to dichotomize patients into Questionnaire for health-related quality-of-life evalua- responders or nonresponders. tion for all PRD. The project enrolled 6644 subjects (3235 patients with JIA and 3409 healthy children), with After its publication [26], the definition of improvement 32 validated versions of the Childhood Health Assess- was adopted by the Food and DrugAdministration as the ment Questionnaire and Child Health Questionnaire primary outcome for all clinical trials involvingchildren now available [29,30]. The Childhood Health Assess- with JIA, and was subsequently officially recognized by ment Questionnaire is now the functional assessment the American College of Rheumatology and was re- tool used for nearly all trials in JIA [23,28••]. named the ACR Pediatric 30 [27].

The methotrexate trial in juvenile idiopathic arthritis Disease activity and damage assessment in juvenile After the trial published by Giannini et al. [22], MTX systemic lupus erythematosus and became the disease-modifyingagentof choice in poly- juvenile dermatomyositis articular JIA. For children who did not respond to 10 Once the problem of a standardized approach for the mg/m2/week, it became common practice to use higher evaluation of response to therapy in JIA was resolved, the dose MTX (up to 30 mg/m2/week [11]), but no random- logical follow-up study was to conduct a similar project ized trial had confirmed this hypothesis. Knowledge of for two other chronic PRD: JSLE and JDM. With a sec- the optimal dosage of MTX in terms of efficacy and ond grant from the European Union (contract no. QLG1- safety is central to disease management. PRINTO, sup- CT-2000-00514), PRINTO, in with collaboration with ported by the European Union (contract no. BMH4 PRCSG, was able to propose validated core sets for the 983531), conducted a randomized, open-label, standard- evaluation of disease activity and damage [31••], and to of-care trial to evaluate the MTX efficacy and safety propose definitions of improvement to be used in future profile in intermediate versus higher doses for polyar- clinical trials in JSLE and JDM (manuscript in prepara- ticular JIA patients who failed to improve on the stan- tion). A total of 295 patients with JDM and 556 patients dard dose of MTX. The trial, now concluded [28••], with JSLE were evaluated from 41 countries. Research networks in pediatric rheumatology Ruperto and Martini 569

A Web site for families of children with pediatric ease define clinical remission on medication, whereas 12 rheumatic diseases months off medication define clinical remission off Collaborative research is usually set up with the objec- medication. tive of answeringspecific scientific questions, but the social aspect of research has to be taken into account as The pediatric rule well; in particular, the needs of the parents. The actual Most, if not all, of the PRD drugs are used off label in large availability of the Internet allows families to access most countries worldwide, meaningthat no indication for medical information quickly and easily, but this informa- pediatric use is reported on the druglabel. This problem tion is often not standardized, and is inaccurate and un- also concerns most drugs used in children, and it led the reliable. To address this problem, PRINTO, in collabo- Food and DrugAdministration to issue the so-called ration with the Paediatric Rheumatology European “pediatric rule” [33,34], by which manufacturers of prod- Society (and again supported by the European Union ucts likely to be used in children have to study those [contract no. 2001CVG4-808]), has recently finished a products in a relevant pediatric population. project with the goal of preparing a Web site directed to families and health professionals containingconsensus- Thanks to this very welcome legislative initiative, the defined information about PRD (in the format of fre- request for clinical trials duringthe last few years has quently answered questions), a list of pediatric rheuma- greatly increased, leading to the first registration of a tology centers, and a list of family help associations. All biologic agent for use in JRA [23]. Four other biologic information is available and has been translated into the agents are currently in ongoing trials involving member languages of all the countries belonging to the PRINTO countries of both the PRINTO and PRCSG networks. network (www.pediatric-rheumatology.printo.it; manuscript in preparation). In February 2002, the European Commission, in collaboration with the European Medical Evaluation Agency, Research training in pediatric rheumatology published a consultation paper, Better Medicines for Chil- Good collaborative clinical research requires qualified dren—Proposed Regulatory Actions in Paediatric Medicinal people around the world able to conduct studies in a Products, as a first step of the commission to address this standardized fashion [32]. PRINTO, with another grant problem [35]. More recently, a second consultation paper from the European Union (contract no. AML/B7- entitled Commission Consultation on a Draft Proposal for a 311/97/0666/II-0246-FI), has set up a research training European Parliament and Council Regulation (EC) on Me- program in pediatric rheumatology to support mainly dicinal Products for Paediatric Use [36] has been drafted to Latin America recipients (Argentina, Brazil, Chile, Costa guide the European parliament to the adoption of a simi- Rica, Cuba, and Mexico). For the 24 Latin American lar pediatric rule also by the European Commission. recipients, the course will take place in Genoa, Italy; Paris, France; Utrecht, the Netherlands; Goteborg, Swe- Conclusion den; and London, UK. The project will also allow four The creation of large, international trial networks such as trained pediatric rheumatology fellows from Genoa, PRINTO and PRCSG; the definition of internationally Italy, to spend some months in Latin America (Buenos recognized, standardized outcome measures and defini- Aires in Argentina, Rio de Janeiro and Botucatu in Brazil, tions of improvement for JIA, JSLE, and JDM; the cross- and Mexico City in Mexico) to standardize the outcome cultural adaptation and validation of quality-of-life in- assessment of patients participatingto common collabo- struments; and the adoption of adequate legislative rative studies. measures (pediatric rule) have created the basic premises for the best future assessment of the efficacy of new The clinical remission criteria for juvenile treatments for PRD. Therefore, children with rheumatic idiopathic arthritis diseases now have the same rights as adults: to be treated Duringthe last few years, PRINTO and PRCSG have with drugs whose safety and efficacy have been assessed. worked with the recently founded North American Childhood Arthritis and Rheumatology Research Alli- Acknowledgment ance to develop draft criteria for inactive disease and The authors thank Drs. Edward H. Giannini, Daniel J. Lovell, and Anna Tortorelli for clinical remission for select JIA categories. their revision of the manuscript.

Draft criteria for inactive disease include no active ar- References and recommended reading Papers of particular interest, published within the annual period of review, thritis; no fever, rash, serositis, splenomegaly, or gener- are highlighted as: alized lymphadenopathy attributable to JIA; no active • Of special interest uveitis; normal erythrocyte sedimentation rate or C- •• Of outstanding interest reactive protein; and a physician’s global assessment of 1 Allaire SH, DeNardo BS, Szer IS, et al.: The economic impacts of juvenile disease activity rated at the best score possible for the rheumatoid arthritis. J Rheumatol 1992, 19:952–955. instrument used. Six continuous months of inactive dis- 2 Ruperto N, Levinson JE, Ravelli A, et al.: Long-term health outcomes and 570 Pediatric and heritable disorders

quality of life in American and Italian inception cohorts of patients with juvenile nile rheumatoid arthritis. Results of the U.S.A.–U.S.S.R. double-blind, pla- rheumatoid arthritis. I. Outcome status. J Rheumatol 1997, 24:945–951. cebo controlled cooperative trial. Arthritis Rheum 1990, 33:466–476. 3 Ruperto N, Ravelli A, Levinson JE, et al.: Long-term health outcomes and 22 Giannini EH, Brewer EJ, Kuzmina N, et al.: Methotrexate in resistant juvenile quality of life in American and Italian inception cohorts of patients with juvenile rheumatoid arthritis. Results of the U.S.A.–U.S.S.R. double-blind, placebo- rheumatoid arthritis. II. Early predictors of outcome. J Rheumatol 1997, controlled trial. N Engl J Med 1992, 326:1043–1049. 24:952–958. 23 Lovell DJ, Giannini EH, Reiff A, et al.: Etanercept in children with polyarticular 4 Ravelli A, Duarte–Salazar C, Buratti S, et al.: Assessment of damage in juve- juvenile rheumatoid arthritis. 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Available at http://pharmacos. eudra.org/F2/pharmacos/docs/Doc2002/feb/cd_pediatrics_en.pdf. 20 Brewer EJ, Giannini EH, Kuzmina N, et al.: Penicillamine and hydroxychloroquine in the treatment of severe juvenile rheumatoid arthritis: results of the 36 European Commission: Commission Consultation on a Draft Proposal for a U.S.A.–U.S.S.R double-blind, placebo controlled trial. N Engl J Med 1986, European Parliament and Council Regulation (EC) on Medicinal Products 314:1269–1276. for Paediatric Use. Available at http://pharmacos.eudra.org/F2/pharmacos/docs/Doc2004/mar/Paediatric%20consultation%20document%20 21 Giannini EH, Brewer EJ, Kuzmina N, et al.: Auranofin in the treatment of juve- final%208%20March%2004.pdf. Remittive agents in pediatric rheumatology Nora G. Singer and Lisabeth V. Scalzi

Purpose of review Introduction Children with rheumatic diseases frequently require therapy Standard therapy with disease-modifying antirheumatic with disease-modifying antirheumatic drugs and/or biologic drugs and (DMARDs) and/or novel biologic agents has agents. Therapies that have been prospectively tested in been well established for treatment of most forms of adults are often used in children before full evaluation of their juvenile rheumatoid arthritis (JRA) but not for rarer safety and efficacy. Published experience that may report childhood conditions, such as systemic lupus erythema- “off-label” usage can be helpful in decision making, although tosus (SLE), juvenile dermatomyositis (JDM), or for very such reports do not reduce the need for prospective clinical uncommon conditions such as scleroderma, vasculitis, trials in children. The purpose of this review is to summarize and autoinflammatory genetic disorders. There have the recent published evidence regarding efficacy (and safety, been few prospective trials in children because the ill- when available) of standard and novel agents used in pediatric nesses are infrequently encountered and resources are rheumatic disease. not widely available to fund multiple sites. It is likely Recent findings that many of the new agents available for treatment of Etanercept, one of three currently available tumor necrosis adult rheumatic diseases will also be useful for pediatric factor-␣ inhibitors has a juvenile idiopathic arthritis indication. rheumatic diseases. This review summarizes the recently Novel “off-label” uses in children for interleukin-1 receptor available data that support or refute the hypothesis that agonist (Anakinra), antiinterleukin-6 receptor antibody (MRA), standard DMARDs and/or novel biologic agents are and rituximab (anti-CD20 monoclonal antibody) are discussed. helpful in treating children with rheumatic diseases. Summary This review summarizes the published evidence that supports Methotrexate the use of selected disease-modifying antirheumatic drugs and Methotrexate (MTX) has been the mainstay of therapy novel biologic agents in children with rheumatic diseases. in the management of children with JRA [1]. Although MTX is used as adjunctive therapy in other juvenile Keywords rheumatic conditions, its efficacy has not been estab- DMARDs, TNF-␣ inhibitors, IL-1 receptor antagonist, rituximab, lished prospectively in conditions other than JRA. Ab- IL-6 receptor antibody sorption of oral MTX varies from one patient to another and in the same individual at different times [2,3]. Sev- Curr Opin Rheumatol 16:571–576. © 2004 Lippincott Williams & Wilkins. enty-six percent of children with juvenile idiopathic arthritis (JIA) who switched from oral to subcutaneous dos- Department of Pediatrics and Internal Medicine, CASE School of Medicine and ing experienced at least 30% improvement in three of Rainbow Babies and Children’s Hospital/University Hospitals, Cleveland, Ohio, USA five outcome variables and had no significant increase in toxicity [4•]. Lahdenne et al. [5] retrospectively exam- Correspondence to Nora G. Singer, MD, Department of Pediatrics, CASE School of Medicine and Rainbow Babies and Children’s Hospital, Cleveland OH 44106, USA ined the histopathologic liver findings of 34 patients with Tel: 216 844 3237; fax: 216 844 7587; e-mail: [email protected] JIA treated with MTX and found that, using the Roenigk Current Opinion in Rheumatology 2004, 16:571–576 classification [6], 85% of the specimens were grade 1, whereas 12% of patients had grade 2. Higher cumulative Abbreviations doses of MTX were associated with grade 2 histology AZA azathioprine CYC cyclophosphamide (median dose, 4250 mg vs 1600 mg for grade 1 speci- DMARD disease-modifying antirheumatic drug mens) but elevation of liver enzymes (>2.5 times normal) IL interleukin IV intravenous did not correlate with the histologic grade [5]. Other JDM juvenile dermatomyositis toxicities, such as abnormalities on pulmonary function JIA juvenile idiopathic arthritis JRA juvenile rheumatoid arthritis tests in patients with JIA, do not appear to be linked to MMF mycophenolate mofetil the use of low-dose MTX [7]. MTX methotrexate SLE systemic lupus erythematosus soJIA systemic-onset juvenile idiopathic arthritis When and how to discontinue methotrexate in JIA is TNF tumor necrosis factor IL-6R interleukin-6R IL-1 RA interleukin-1 receptor antagonist controversial. A prospective study was performed on 25 children with either oligoarticular or polyarticular arthri- © 2004 Lippincott Williams & Wilkins 1040–8711 tis whose MTX was discontinued approximately 3.6 or 12.6 months after remission, while on therapy, was 571 572 Pediatric and heritable disorders achieved. Longer therapy with MTX did not prevent group compared with the CYC group [14]. There have relapses (occurred in 52% of all patients). But in the been two reports on the use of MMF in children with group treated for less than 1 year compared with the lupus nephritis who had failed previous therapy. MMF prolonged therapy group, there was a significantly higher was particularly useful in treating patients with membra- level of myeloid-related proteins-8 and -14 (secreted by nous glomerulonephritis [15,16]. A recent pharmacoki- synovial phagocytes), suggesting that normal myeloid- netic study in children treated with MMF examined 15 related protein-8 and -14 levels may help to predict pa- patients who had proteinuria associated with a variety of tients who can safely discontinue MTX [8••]. inflammatory rheumatic conditions. MMF treatment was associated with significant clinical improvement. The Small case series reports agree that early initiation of authors suggested that mycophenolic acid trough levels MTX for JDM prevent poor outcomes, such as the de- be drawn to guide dosing and reduce long-term side ef- velopment of calcinosis [9]. Fisler et al. [10] studied 35 fects of the medication. A dose of 900 mg/m2 was rec- children retrospectively and demonstrated that patients ommended [17•]. Studies using sequential therapy with whose muscle enzymes did not respond to pulse intra- CYC and MMF versus CYC or MMF versus CYC to venous methylprednisolone or high-dose oral prednisone evaluate safety and efficacy should be a high priority for within 6 weeks, and who were subsequently started on the pediatric rheumatology community. MTX, had reduced incidence of calcinosis compared with historical control subjects. Factors associated with Cyclophosphamide calcinosis included delayed diagnosis and therapy, a Identifying the optimum therapy for SLE nephritis in longer duration of elevated muscle enzymes, and longer children is essential. Thirty-eight SLE nephritis patients disease duration [10]. age 12 to 62 years (mean age, 26 years) were treated with steroids plus IV CYC monthly for 6 months and then MTX, as well as newer DMARDs/biologics, is used to quarterly for 2 years. A retrospective analysis demon- treat uveitis in children. Thirty-nine patients (mean age, strated that 5 of 38 developed end-stage renal disease, all 26.6 years), whose uveitis was unsuccessfully controlled of whom were in the juvenile age range (age range, 12 to even after 5 years of corticosteroid therapy, were treated 20 years; mean age, 17 ± 3 years). In this population a with MTX. Of those who tolerated MTX, 79% re- high chronicity index, presence of interstitial fibrosis, sponded in an average of 2.4 months. Continuation of and low C3 and high anti-DNA levels were all associated MTX for a mean of 20.9 months resulted in remission, with poor renal outcome [18]. Similar poor outcomes are subsequent discontinuation of MTX, and no recurrence described in nine children with SLE nephritis who were [11]. treated prospectively with monthly IV CYC (×6), then every 3 months for 36 months. At 5 years, 56% of the Finally, Rettig and Cron [12] reported that MTX in patients progressed to chronic renal failure and 22% reduced remission in a child with chronic nonrenal Henoch– quired dialysis [19]. In contrast, in a retrospective review Scho¨nlein purpura vasculitis. of 33 children (mean age, 11 years) with SLE nephritis treated with either corticosteroids ± AZA or steroids and Azathioprine IV CYC (500 mg/m2 monthly, then quarterly thereafter), In a long-term retrospective follow-up of 67 children the CYC-treated group had improved survival, better with SLE nephritis, 32 had World Health Organization growth, and longer protection of renal function and bet- class intravenous (IV) glomerulonephritis. Fifty-three ter protection of long-term renal function compared with percent were treated with prednisone plus azathioprine the AZA-treated group [20]. Larger controlled trials of (AZA) and 16% were treated with prednisone plus cy- CYC versus other DMARDs, such as MMF or AZA, clophosphamide (CYC). Twenty-four percent of the must be conducted before conclusions can be drawn re- AZA group had exacerbation of renal disease and regarding the best treatment for childhood SLE nephritis. quired CYC. For lupus nephritis other than World Health Organization class IV, AZA was by far the most CYC may also have a role in the management of JDM. A prescribed medication and was well tolerated with good retrospective case review of 12 patients with severe re- outcomes, only rarely requiring replacement with CYC fractory JDM treated with pulse CYC demonstrated sig- [13]. nificant improvement in muscle function and strength, skin disease, and LDH levels [21]. Larger studies need Mycophenolate mofetil to be completed to identify appropriate management of A recent study in adult patients with SLE nephritis who these patients. were treated with seven monthly infusions of CYC followed by oral AZA or mycophenolate mofetil (MMF) The role of CYC in the treatment of children with had an improved 6-year event-free survival rate com- Henoch–Scho¨nlein purpura (HSP) was examined retro- pared with quarterly intravenous CYC. In addition, the spectively in nine patients (age range, 6 to 15 years) who rate of relapse-free survival was higher in the MMF underwent biopsy that supported a diagnosis of IgA ne- Remittive agents in pediatric rheumatology Singer and Scalzi 573 phropathy secondary to HSP. Repeat renal biopsy (mean steroid dose [23]. No clear-cut effect was found in uveitis interval, 23 months) after treatment with high-dose oral associated with JIA in 10 children, and two children ex- corticosteroids and oral CYC (2 mg/kg up to 100 mg perienced worsening of uveitis [23]. In an open-label daily) revealed improvement in activity indices, tubu- study in which children received either etanercept or lointerstitial disease, proteinuria, creatinine clearance, infliximab, improvement in symptoms occurred in both and serum albumin [22]. Even though the numbers of groups, but the numbers of patients was small [27]. children treated with CYC were small, the data suggest Etanercept has been used successfully to treat systemic- that some children with severe proteinuric HSP nephritis onset JRA/systemic-onset JIA (soJIA), but has also failed may benefit from aggressive therapy including CYC and to improve soJIA [26,28]. Our experience is that etaner- corticosteroids to prevent end-stage renal disease [23]. cept may control articular symptoms better than systemic ones. Etanercept has also been proposed as therapy for Cyclosporin A macrophage activation syndrome, frequently regarded as Seventeen JIA patients with a suboptimal response to a complication of soJIA [29], but there is at least one MTX were prescribed cyclosporin A prospectively and report that implicates etanercept as precipitating macro- were treated for 6 to 30 months (median, 10 months) phage activation syndrome [30] and one report that in- [24]. At the end of combination therapy, 8 of 17 patients dicates that macrophage activation syndrome followed (47%) met the 30% preliminary definition of improve- infusion of infliximab [27]. Etanercept but has also been ment, including 4 of 17 (29%) who met the 70% prelimi- reported to induce cutaneous vasculitis in one child [31]. nary definition of improvement, and two (12%) achieved complete disease control [24]. In a retrospective review Infliximab of 32 patients, erythrocyte sedimentation rate and C- Infliximab is indicated for adult rheumatoid arthritis and reactive protein improved significantly by the addition of Crohn disease. In an open-label study of infliximab and cyclosporin A to MTX [23]. Koybayashi et al. [25] re- etanercept by Lahdenne et al. [27], infliximab was ad- ported that four of five patients with JDM and interstitial ministered to patients with extended oligoarticular ar- lung disease improved when cyclosporin A was used as a thritis (n = 3), polyarthritis (n = 8), psoriatic arthritis (n = steroid-sparing agent and suggested that cyclosporin A is 2), and soJIA (n = 1). Five patients withdrew, including a reasonable choice when treating JDM patients with at least one because of lack of efficacy. Three patients interstitial lung disease [25]. who experienced side effects switched to etanercept and had evidence of disease amelioration [27]. One patient Tumor necrosis factor-␣ inhibitors who was noncompliant with etanercept therapy had a Tumor necrosis factor (TNF)-␣ inhibitors that are ap- sustained response when switched to infliximab [27], proved for rheumatoid arthritis include etanercept, in- suggesting that in some clinical settings failure to re- fliximab, and adalimumab, but only etanercept has a la- spond to or side effects from one type of TNF-␣ blocker beled indication for JIA. Etanercept is a recombinant does not necessarily preclude use of a different category fusion protein in which two soluble TNF-␣ receptors are of TNF-␣ blocker. In our practice we have observed fused to the Fc portion of human IgG1. It is adminis- that, over time, increased amounts and/or frequency of tered subcutaneously one to two times per week, and it infliximab dosing may be required over time for symp- binds to soluble TNF-␣. Infliximab is a chimeric hu- tom control. At the Mayo Clinic, Colombel et al. [32] man–mouse anti-TNF-␣ monoclonal antibody that can reported the safety profile of infliximab in 500 consecu- bind both soluble and cell-bound TNF. Adalimumab is tive patients with Crohn disease, 28 of whom (6%) were a human monoclonal antibody directed against TNF- ␣ children (age range, 5 to 17 years). Forty-three patients that is similar to infliximab, but because it contains only experienced adverse events, which included three cases human protein sequence, it has not been associated with of drug-induced lupus and 18 infusion reactions (2 of the human antichimera antibodies that are sometimes in- 18 patients were Յ17 years old) [32]. Ten adult deaths duced after exposure to infliximab. Infliximab is admin- were reported during follow-up [32]. Three infections istered as an intravenous infusion every 4 to 8 weeks in and no serum sickness, malignancies, or deaths were re- a maintenance phase whereas adalimumab is adminis- ported in patients Յ17 years old [32]. Stephens et al. [33] tered subcutaneously every other week in general, but reported a 5.3% rate of infusion reactions in 82 pediatric may also be dosed weekly. Crohn disease patients who received 432 infusions. Dia- manti et al. [34] reported a 5.1% rate of infusion reaction Etanercept in 10 pediatric patients with Crohn disease who received A prospective study established that TNF-␣ inhibition is 98 infusions. Both the patients of Stephens et al. [33] and an effective strategy to control polyarticular JRA [26]. Diamanti et al. [34] had a high likelihood of being on Retrospective analysis showed that 31 children “resistant additional immunosuppressives (98% and 60% respec- to conventional DMARDs” had a positive response to tively), prescribed in part to suppress human–antimouse etanercept in that there was a trend toward discontinu- antibodies, and therefore are likely to resemble pediatric ation of other DMARDs and a lowering of oral cortico- rheumatology patients treated with infliximab. 574 Pediatric and heritable disorders

Adalimumab would otherwise be transduced via IL-1 receptors. The Adalimumab is effective at inhibiting both symptoms efficacy of this drug has been perceived to be suboptimal and joint destruction that occur in rheumatoid arthritis because of pharmacokinetic and pharmacodynamic limi- [35]. To date, experience with adalimumab is anecdotal tations. In rheumatoid arthritis, molar excess of IL-1 re- in children. We switched two soJIA children who had ceptor agonist is required to saturate IL-1 receptor be- become refractory to etanercept, to adalimumab with cause binding of IL-1B to small numbers of IL-1 good success. Therapy was temporarily held and IV acy- receptor can initiate IL-1-dependent signaling. In con- clovir was administered as a result of primary varicella trast to perceived limitation of IL-1 receptor agonist infection in one of the children. After resolution of the therapy for rheumatoid arthritis, it has been reported to infection, adalimumab was reinitiated without complica- be effective in alleviating symptoms related to a series of tion (unpublished data). autoinflammatory disorders that are associated with a mutation in NALP3/C1AS1/PYPAF1, which codes for a Thalidomide protein known both as NALP3 and cryopyrin. The pre- Thalidomide is a potent antiangiogenesis agent that is cise functions of the NALP3/cryopyrin protein is un- ␣ also known to inhibit TNF- and interleukin (IL-6) pro- known, but may be important in altering susceptibility to duction and possibly IL-1-dependent signaling [36–39]. apoptosis. Mutations of this protein are associated with It has been used in the treatment of adults with Behçet’s Muckle–Wells syndrome, familial cold autoinflammatory disease and with ankylosing spondylitis [40,41]. One rea- syndrome, and neonatal-onset multisystem inflammatory ␣ son that inhibiting TNF- blockade may not be a cure- disease or cutaneous articular syndrome. Anakinra has all in soJIA is that it appears that IL-6 may be the major been reported to alleviate inflammatory symptoms in proinflammatory cytokine driving the inflammatory re- four adults and one child, and in all patients was associ- ␣ sponse [42] and not TNF- and/or IL-1B. Two soJIA ated with a decline in serum amyloid, a marker of in- patients whose disease was refractory to combination flammation [46•,47]. Finally, why Anakinra appears to ␣ therapy with DMARDs and TNF- inhibitors re- be more effective in these syndromes, compared with sponded well to thalidomide [43•]. Steroids and other receptor agonist, remains somewhat of a conundrum. DMARDs were successfully weaned in both patients, and no adverse reactions to thalidomide were observed [43•]. In view of its potential for teratogenic effects, a Rituximab (Rituxan) rigorous training program for physicians and families Rituximab is a promising newcomer to the therapeutic must be completed before prescribing its use, and fre- armamentarium for autoimmune diseases. This chimeric quent monitoring is required. Nevertheless, for children anti-CD20 monoclonal antibody is composed of an IgG1 who have failed conventional therapy or combinations ␬ immunoglobulin consisting of murine heavy- and light- thereof, thalidomide remains a viable treatment option. chain-variable regions and human constant sequences [48]. Two open-label studies in adult SLE patients sug- Antiinterleukin-6 receptor antibody gest that more than one therapeutic regimen may be Because IL-6 is markedly elevated in soJIA, and its el- effective. One protocol used four successive weekly evation is likely the major cytokine that contributes to doses of 375 mg/m2 [49,50], whereas another used a com- fever and other systemic features, clinical use of IL-6 bination of high-dose corticosteroid, rituximab (500 blockade is clinically appealing. The anti-IL-6R mono- mg/m2), and cyclophosphamide (750 mg) [51]. There clonal antibody currently in clinical trials has been was a favorable response in both studies, especially in termed “MRA,” and its use as a one-time therapy to those patients who achieved a higher degree of B-cell interrupt the inflammatory cascade has been reported in depletion [49]. Manifestations that responded particu- two children with soJIA [44]. A phase II dose escalation larly well included fatigue, arthralgia/arthritis, serositis, study has been reported in abstract form: Children with and vasculitis [51]. Two case reports in young adults soJIA received three to seven doses of MRA depending with SLE demonstrate the rituximab may be considered on disease activity and this study suggested that the for rescue therapy. An 18-year-old woman with life- therapy was safe and efficacious [45]. Seven of 11 chil- threatening autoimmune hemolytic anemia who did not dren had a 70% JIA core set response after a single respond to steroids, IVIg, and cyclosporin, improved sub- 2-mg/kg infusion and one of three children receiving stantially with two doses of rituximab weekly at a dose of subsequent dosing at 2 mg/kg, three of five children at 4 375 mg/m2 [52], and a 19-year-old woman with progres- mg/kg, and three of three children at 8 mg/kg appear to sive World Health Organization class Vc nephritis who, have maintained a 70% JIA core set response [41]. despite CYC and steroids, received four weekly doses of rituximab (375 mg/m2), three doses of IV CYC (20 Anakinra mg/kg) every 28 days, and a tapering dose of steroids Anakinra, or IL-1 receptor antagonist, is a recombinant achieved complete remission and has been stable for 24 antiinflammatory protein that binds to the proinflamma- months on maintenance therapy with MTX, steroids, tory cytokine IL-1B and thus prevents signaling that and cyclosporin [53]. Rituximab (four weekly intrave- Remittive agents in pediatric rheumatology Singer and Scalzi 575 nous infusions of 375 mg/m2) is useful for the treatment 9 Al-Mayouf S, Al-Mazyed A, Bahabri S: Efficacy of early treatment of severe juvenile dermatomyositis with intravenous methylprednisolone and metho- of autoimmune hemolytic anemia in children and adults trexate. Clin Rheumatol 2000, 19:138–141. [54,55] and for immune-mediated thrombocytopenia in 10 Fisler RE, Liang MG, Fuhlbrigge RC, et al.: Aggressive management of juve- adults [56,57]. Targeting B-cell CD20 may be useful nile dermatomyositis results in improved outcome and decreased incidence therapeutically in a host of autoantibody-mediated dis- of calcinosis. J Am Acad Dermatol 2002, 47:505–511. 11 Kaplan–Messas A, Barkana Y, Avni I, et al.: Methotrexate as a first-line corti- eases. Binstadt et al. [58] described four pediatric pa- costeroid-sparing therapy in a cohort of uveitis and scleritis. Ocul Immunol tients with autoimmune disorders who responded to rit- Inflamm 2003, 11:131–139. uximab. The autoimmune manifestations that improved 12 Rettig P, Cron RQ: Methotrexate used as a steroid-sparing agent in non-renal included immune cytopenias, and neurologic manifesta- chronic Henoch–Scho¨ nlein purpura. Clin Exp Rheumatol 2003, 21:767– 769. tions (including seizures, inflammatory demyelination, 13 Hagelberg S, Lee Y, Bargman J, et al.: Longterm followup of childhood lupus hemiplegic migraines, and choreoathetosis secondary to nephritis. J Rheumatol 2002, 29:2635–2642. anticardiolipin antibodies), and were accompanied by 14 Contreras G, Pardo V, Leclercq B, et al.: Sequential therapies for proliferative the disappearance of anticardiolipin antibodies. All the lupus nephritis. N Engl J Med 2004, 350:971–980. children tolerated the infusions without side effects [58]. 15 Fu YF, Liu GL: Mycophenolate mofetil therapy for children with lupus nephritis refractory to both intravenous cyclophosphamide and cyclosporine. Clin Nephrol 2001, 55:318–321. Conclusion 16 Buratti S, Szer IS, Spencer CH, et al.: Mycophenolate mofetil treatment of The future of therapy for children with pediatric rheu- severe renal disease in pediatric onset systemic lupus erythematosus. J Rheu- matic diseases appears brighter than in the past. That matol 2001, 28:2103–2108. such children will have the opportunity to use therapy 17 Filler G, Hansen M, LeBlanc C, et al.: Pharmacokinetics of mycophenolate • mofetil for autoimmune disease in children. Pediatr Nephrol 2003, 18:445– that has been consistently demonstrated to be safe, ap- 449. propriately dosed, and efficacious in them will require A pharmacokinetic study in 15 patients demonstrated that 900 mg/m2 of MMF in two divided doses is appropriate, and that children should have trough levels of continued collaborative efforts on the part of patients, mycophenolic acid, the active metabolite, measured. parents, pediatric rheumatologists, industry, and the Na- 18 Cortes–Hernandez J, Ordi–Ros J, Labrador M, et al.: Predictors of poor renal tional Institutes of Health. This review should help to outcome in patients with lupus nephritis treated with combined pulses of provide data for clinicians who need to use these agents cyclophosphamide and methylprednisolone. Lupus 2003, 12:287–296. before prospective demonstration of their safety and ef- 19 Al Salloum AA: Cyclophosphamide therapy for lupus nephritis: poor renal survival in Arab children. Pediatr Nephrol 2003, 18:357–361. ficacy. Researchers should target areas in which clinical 20 Barbano G, Gusmano R, Damasio B, et al.: Childhood-onset lupus nephritis: studies are required. a single-center experience of pulse intravenous cyclophosphamide therapy. J Nephrol 2002, 15:123–129. References and recommended reading 21 Riley P, Maillard SM, Wedderburn LR, et al.: Intravenous cyclophosphamide pulse therapy in juvenile dermatomyositis. A review of efficacy and safety. Papers of particular interest, published within the annual period of review, Rheumatology (Oxford) 2004, 43:491–496. are highlighted as: 22 • Of special interest Tanaka H, Suzuki K, Nakahata T, et al.: Early treatment with oral immunosup- pressants in severe proteinuric purpura nephritis. 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J Rheumatol 2004, 31:179–182. 27 Subcutaneous MTX has a high likelihood of inducing clinical improvement in chil- Lahdenne P, Vahasalo P, Honkanen V: Infliximab or etanercept in the treat- dren with JIA who either failed or could not tolerate oral MTX. ment of children with refractory juvenile idiopathic arthritis: an open label study. Ann Rheum Dis 2003, 62:245–247. 5 Lahdenne P, Rapola J, Ylijoki H, et al.: Hepatotoxicity in patients with juvenile 28 ten Cate R, van Suijlekom–Smit LW, Brinkman DM, et al.: Etanercept in four idiopathic arthritis receiving longterm methotrexate therapy. J Rheumatol children with therapy-resistant systemic juvenile idiopathic arthritis. Rheuma- 2002, 29:2442–2445. tology (Oxford) 2002, 41:228–229. 6 Roenigk HH Jr: Liver toxicity of retinoid therapy. Pharmacol Ther 1989, 29 Prahalad S, Bove KE, Dickens D, et al.: Etanercept in the treatment of mac- 40:145–155. rophage activation syndrome. 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Although a longer treatment period of MTX did not prevent JIA relapses compared 32 Colombel JF, Loftus EV Jr, Tremaine WJ, et al.: The safety profile of infliximab with a shorter course, normal levels of myeloid-related proteins-8 and -14 may in patients with Crohn’s disease: the Mayo Clinic experience in 500 patients. predict those individuals who will be able to withdraw MTX successfully. Gastroenterology 2004, 126:19–31. 576 Pediatric and heritable disorders

33 Stephens MC, Shepanski MA, Mamula P, et al.: Safety and steroid-sparing 46 Hawkins PN, Lachmann HJ, Aganna E, et al.: Spectrum of clinical features in experience using infliximab for Crohn’s disease at a pediatric inflammatory • Muckle–Wells syndrome and response to anakinra. Arthritis Rheum 2004, bowel disease center. Am J Gastroenterol 2003, 98:104–111. 50:607–612. This report describes four adults and one child whose autoinflammatory symptoms 34 Diamanti A, Papadatou B, Knafelz D, et al.: Complications of infliximab therapy responded well to treatment with thalidomide. in children and adolescents affected by Crohn’s disease. Am J Gastroenterol 2003, 98:2812–2813. 47 Hawkins PN, Lachmann HJ, McDermott MF: Interleukin-1-receptor antagonist in the Muckle–Wells syndrome. N Engl J Med 2003, 348:2583–2584. 35 Weinblatt ME, Keystone EC, Furst DE, et al.: Adalimumab, a fully human antitumor necrosis factor alpha monoclonal antibody, for the treatment of rheu- 48 Reff ME, Carner K, Chambers KS, et al.: Depletion of B cells in vivo by a matoid arthritis in patients taking concomitant methotrexate: the ARMADA chimeric mouse human monoclonal antibody to CD20. Blood 1994, 83:435– trial. Arthritis Rheum 2003, 48:35–45. 445. 36 Gelati M, Corsini E, Frigerio S, et al.: Effects of thalidomide on parameters 49 Anolik J, Sanz I, Looney RJ: B cell depletion therapy in systemic lupus erythe- involved in angiogenesis: an in vitro study. J Neurooncol 2003, 64:193–201. matosus. Curr Rheumatol Rep 2003, 5:350–356. 37 Jin SH, Kim TI, Han DS, et al.: Thalidomide suppresses the interleukin 1beta- 50 Anolik JH, Campbell D, Felgar R, et al.: B lymphocyte depletion in the treat- induced NFkappaB signaling pathway in colon cancer cells. Ann N Y Acad ment of systemic lupus (SLE) phase I/II trial of rituximab (Rituxan) in SLE. Sci 2002, 973:414–418. Arthritis Rheum 2002, 46:S289. 38 Lee FC, Merchant SH: Alleviation of systemic manifestations of multicentric 51 Leandro MJ, Edwards JC, Cambridge G, et al.: An open study of B lympho- Castleman’s disease by thalidomide. Am J Hematol 2003, 73:48–53. cyte depletion in systemic lupus erythematosus. Arthritis Rheum 2002, 46:2673–2677. 39 Corral LG, Haslett PA, Muller GW, et al.: Differential cytokine modulation and T cell activation by two distinct classes of thalidomide analogues that are 52 Perrotta S, Locatelli F, La Manna A, et al.: Anti-CD20 monoclonal antibody potent inhibitors of TNF-alpha. J Immunol 1999, 163:380–386. (rituximab) for life-threatening autoimmune haemolytic anaemia in a patient with systemic lupus erythematosus. Br J Haematol 2002, 116:465–467. 40 Huang F, Gu J, Zhao W, et al.: One-year open-label trial of thalidomide in ankylosing spondylitis. Arthritis Rheum 2002, 47:249–254. 53 Fra GP, Avanzi GC, Bartoli E: Remission of refractory lupus nephritis with a protocol including rituximab. Lupus 2003, 12:783–787. 41 Shek LP, Lim DL: Thalidomide in Behçet’s disease. Biomed Pharmacother 2002, 56:31–35. 54 Zecca M, Nobili B, Ramenghi U, et al.: Rituximab for the treatment of refractory autoimmune hemolytic anemia in children. Blood 2003, 101:3857– 42 Keul R, Heinrich PC, Muller–Newen G, et al.: A possible role for soluble IL-6 3861. receptor in the pathogenesis of systemic onset juvenile chronic arthritis. Cy- tokine 1998, 10:729–734. 55 Quartier P, Brethon B, Philippet P, et al.: Treatment of childhood autoimmune haemolytic anaemia with rituximab. Lancet 2001, 358:1511–1513. 43 Lehman TJ, Striegel KH, Onel KB: Thalidomide therapy for recalcitrant sys- • temic onset juvenile rheumatoid arthritis. J Pediatr 2002, 140:125–127. 56 Shanafelt TD, Madueme HL, Wolf RC, et al.: Rituximab for immune cytopenia This case report describes two patients with uncontrolled systemic-onset JRA who in adults: idiopathic thrombocytopenic purpura, autoimmune hemolytic ane- improved on thalidomide. mia, and Evans syndrome. Mayo Clin Proc 2003, 78:1340–1346. 44 Yokota S: Interleukin 6 as a therapeutic target in systemic-onset juvenile id- 57 Stasi R, Pagano A, Stipa E, et al.: Rituximab chimeric anti-CD20 monoclonal iopathic arthritis. Curr Opin Rheumatol 2003, 15:581–586. antibody treatment for adults with chronic idiopathic thrombocytopenic purpura. Blood 2001, 98:952–957. 45 Yokata S, Miyamae T, Imagawa T, et al.: Phase II trial of anti-IL-6 receptor antibody (MRA) for children with systemic-onset juvenile idiopathic arthritis. 58 Binstadt BA, Caldas AM, Turvey SE, et al.: Rituximab therapy for multisystem Arthritis Rheum 2003, 48:S1070. autoimmune diseases in pediatric patients. J Pediatr 2003, 143:598–604. Update on pediatric systemic lupus erythematosus Dorothee Stichweha,b, Edsel Arcea,b and Virginia Pascuala,b

Purpose of review Tel: 214 820 9981; fax 214 820 4813; e-mail: [email protected]

The purpose of this review is to provide an update on the Current Opinion in Rheumatology 2004, 16:577–587 clinical manifestations of SLE in children. Emerging clues on Abbreviations the pathogenesis of the disease based on recent human DCs dendritic cells studies conducted both in children and adults, will also be IFN interferon summarized. LN lupus nephritis SLE systemic lupus erythematosus Recent findings TNF tumor necrosis factor Pediatric Rheumatologists caring for children with SLE face © 2004 Lippincott Williams & Wilkins many challenges. As the life expectancy of these patients 1040–8711 improves, new recognized complications such as accelerated atherosclerosis and hypertension emerge as major causes of morbidity. However, few longitudinal studies describing the Introduction long term outcome of these children, including the impact of Children represent ∼15–20% of all Systemic Lupus Ery- disease and treatment on their physical and psychological thematosus (SLE) patients. Although the presentation, development are available. Few prospective interventional clinical symptoms and immunological findings of pedi- studies have been carried out to assess the efficacy of atric SLE are similar to those of adult SLE patients, established and novel treatments in the pediatric population. children usually have a more severe disease at onset. Recently, basic studies aimed at understanding the immune They also have higher rates of organ involvement, and a alterations underlying this disease have been performed in more aggressive clinical course than adults [1–3]. As it children. These studies indicate an important role for has been reported for adults, ethnicity influences disease interferon-alpha (IFN-␣) in the pathogenesis of this disease incidence and clinical manifestations in children. Black and reveal an overall striking homogeneity of leukocyte gene and Hispanic children have a higher incidence of dis- expression profiles in children and adults with SLE. The ease. Black children have a greater prevalence and se- contribution of novel gene polymorphisms to disease verity of renal and neuro-psychiatric disease (NPSLE) susceptibility and the sequential breakdown of tolerance to [4]. They also present more frequently with discoid rash nuclear antigens that precedes clinical manifestations in and display higher titers of anti-DNAand anti-SSAan- patients with SLE are among the recent studies that are tibodies in association with an increased prevalence of helping us understand the complex SLE puzzle. cardiac disease [5]. Although no controlled studies are Summary available, our experience with Hispanic pediatric SLE SLE continues to cause significant morbidity in the pediatric patients in Texas suggests that, as their adult counter- age group. A better recognition of the age-specific parts [6,7], these children suffer from more severe dis- manifestations and long-term complications of this disease is ease and have a higher incidence of renal involvement required to improve its outcome. Understanding its unique compared with Caucasian patients. pathogenesis will hopefully lead to the development of better, more targeted and less toxic therapies. The diagnosis of SLE in children is based upon the same criteria used for adults [8,9]. As reviewed below, most of Keywords the clinical manifestations described in adult SLE can be systemic lupus erythematosus, childhood, pathogenesis, found in children. The prognosis of this disease in the clinical manifestations pediatric age has improved dramatically over the past two decades mainly due to the successful treatment of Curr Opin Rheumatol 16:577–587. © 2004 Lippincott Williams & Wilkins. lupus nephritis (LN). In fact, survival rates of 94% have been reported after a mean follow up of 11 years in pediatric patients with biopsy-proven LN treated with ei- a b Baylor Institute for Immunology Research, Dallas, Texas, and the UT ther cyclophosphamide (CYC) or azathioprine (AZA) Southwestern Medical Center, Dallas, Texas, USA [10]. However, as it has been pointed out in several re- Supported by grants from the National Institutes of Health R01- AR46589-01, cent reviews [11••,12•], essential aspects of the treat- NOI-AI-05412, the DANA Foundation and the Alliance for Lupus Research to V. Pascual. ment of these children deserve special attention. These include, among others, the psychological impact of living Correspondence to Virginia Pascual, Baylor Institute for Immunology Research, 3434 Live Oak, Dallas, TX 75204, USA with a chronic disease, growth retardation and changes in 577 578 Pediatric and heritable disorders

Table 1. Presenting manifestations in childhood-onset SLE physical appearance due to the disease or its therapy, the Clinical features Frequency (%) References potential short and long-term impact of subclinical neurocognitive dysfunction that may lead to learning deficits Constitutional* 40–74% [2,107,108] Arthritis/arthralgia 20–74% [2,109] in many of these children, and the recognition and es- Visceromegaly 15–74% [2,107,108] tablishment of measures to prevent and/or control the Renal involvement 20–82% [2,29,30,109] development of atherosclerosis. Malar rash 44–52% [2,107] Lymphadenopathy 15–30% [2,108,109] The next sections summarize recent reports on the clini- *(fever, fatigue, weight loss) cal manifestations of pediatric SLE and novel clues in the pathogenesis of this disease.

Clinical manifestations of childhood SLE The main presenting manifestations of SLE in children are summarized in Table 1. Table 2. Clinical manifestations of childhood-onset SLE Clinical manifestations Frequency (%) References Mucocutaneous manifestations are frequent in pediatric Cutaneous [2,13•,107,108] SLE (see Table 2). Isolated discoid lupus (DLE), and Malar rash 44–74% lupus whose sole manifestation is isolated skin disease, Oral ulcers 26–48% however, rarely occur in the pediatric population [13•]. Vasculitis 16–52% Photosensitivity 16–40% Interestingly, a high proportion of pediatric patients with Alopecia 7–48% DLE seem to later develop systemic disease (reviewed Discoid lesions 10–19% in [13•]). Arthritis 74–90% Ocular 20–35% [110] Keratoconjunctivitis sicca Cardiac disease is now being recognized as a significant Conjunctivitis Uveitis cause of morbidity and mortality in children with SLE. Episcleritis/scleritis Although its prevalence and natural history are largely Keratitis unknown, as there are no published longitudinal studies, Optic neuritis Ischemic optic neuropathy the spectrum of cardiac disease in children mirrors that of Ophthalmoplegia adult SLE, and silent cardiac abnormalities are a com- Retinal disease mon finding [14–17]. Accelerated atherosclerosis is defi- Cardiac [14–16,111] Pericarditis 5–26% nitely observed in SLE patients, and ischemic disease Myocarditis occurs in up to 16% of asymptomatic children [16]. In a Valvular disease recent series describing a cohort of 4,737 adult SLE pa- Coronary artery disease Silent abnormalities 16–42% tients from Sweden followed over 30 years, the younger Pulmonary 5–77% [22,27,28] patients in the series (aged 20–39 years at the first hos- Pleuritis 40–60% pital discharge) had a 16-fold increased risk of death from Pneumonitis 1–4% Pulmonary hypertension 5–14% coronary heart disease [18]. Aseries of risk factors for the Diffuse interstitial disease 3–8% development of atherosclerosis have been identified in Pulmonary hemorrhage 2% children with SLE. They are summarized in Table 3. Pulmonary embolism 30% “Shrinking lung syndrome” Rare Renal 30–80% Alarge proportion of pediatric SLE patients present with WHO class I 7.5–8% [4,29,30,34,112] WHO class II 14–21% antiphospholipid antibodies, and there is a significant WHO class III 2–36% WHO class IV 40–65% WHO class V 5–20% Table 3. Risk factors for premature cardiovascular disease in Central nervous system 20–95% [2,11,21,113,114] childhood-onset SLE Headache 43–72% Seizures 26–51% Elevated levels of homocystein Psychosis 10–12% Hyperinsulinemia Peripheral neuropathy 15–16% Hypertension Myelopathy 1% Nephrotic range proteinuria Cerebral vascular disease 12% Dyslipdemia Cognitive disorder 55% —increased LDL/LDL oxidizability Mood disorder 57% Arterial vasculitis Movement disorder 7–9% Immune complex-mediated cell damage Hematological 39% [2,19,107,108] Antiphopholipid antibodies Thrombocytopenia 8–74% Lupus anticoagulant Leukopenia 27–52% Up-regulated CD40–CD40 ligand Lymphopenia 30–59% Steroid-induced obesity Anemia 72–84% [115••–117] Systemic lupus erythematosus in children Stichweh et al. 579 relationship between the presence of a lupus anticoagu- may not always correlate with clinical manifestations, lant (LAC), but not anticardiolipin antibodies, and performing a renal biopsy is crucial for planning effective thrombotic events (TE) [19•]. Lifelong anticoagulation therapy [30]. In children, few studies have examined the has been recommended after an initial TE in these chil- ability of the NIH index to evaluate disease at diagnosis dren [20]. and to predict outcome [31–34•]. Anewer index focusing on changes in the tubulointerstitial compartment, in ad- NPSLE is one of the most common serious complica- dition to features already included in the activity (AI) tions of pediatric SLE [21] as it is associated with a and chronicity (CI) indexes, has recently been proposed higher morbidity and mortality [4]. It occurs in 20% to [35]. More studies are needed to demonstrate its predic- 30% of children and adolescents and in the majority of tive value. these patients it will manifest within the first year of disease (reviewed in [11,22]). Some of the most common Since the first report in 1968 predicting the 10-year sur- NPSLE symptoms in children are summarized in Table vival rate for children with LN to be 20% [36], the prog- II. In contrast to overt neurologic disease that is well nosis of LN has improved dramatically. In the last de- recognized, little is known about subclinical neurocogni- cade, a 5-year patient survival rate for children ranged tive dysfunction in these children. Two studies have between 78% and 92%. The 5-year kidney survival from demonstrated that these patients have specific deficits in the time of diagnosis varies according to different series these areas, as well as trends towards increased depres- from 44% to 93% (reviewed in [29,34]). In patients un- sive symptoms and somatic complaints [23,24]. On the dergoing renal transplantation, a recent survey found other end of the spectrum, functional imaging can be that although the allograft survival is no different for abnormal in otherwise asymptomatic lupus patients. children with LN compared with pediatric patients with Whether these abnormalities result from subclinical cen- other diagnoses, these children were 1.8 times more tral nervous system involvement, or simply reflect false likely to die compared with patients without SLE [37]. positive findings remains to be determined. As the survival among children and adolescents with The lung is involved in 5–77% [25–28] of children with SLE improves because of earlier diagnosis, recognition SLE, and pulmonary function studies are abnormal in of mild disease, and better approaches to therapy, these the majority of patients, with the most frequent alter- patients are now faced with considerable morbidity due ation being restrictive disease. Asymptomatic lung dis- to the sequelae of disease activity, side effects of medi- ease in pediatric SLE may in fact be more prevalent than cations and comorbid conditions. Standardized methods realized [26]. Pulmonary hemorrhage secondary to SLE which are validated in children are necessary to estimate is a relatively uncommon but very serious complication. this morbidity [38•]. Some of the currently available Mortality approaches 90% despite the use of high-dose tools are summarized in Table 5. corticosteroids and other immunosuppressive agents [27,28]. The classical triad of hemoptysis, abrupt fall in Treatment of pediatric SLE hemoglobin and new pulmonary infiltrates is not uni- Acomplete coverage of the different treatment options formly seen in current series. for pediatric SLE patients is beyond the scope of this review, but there are recent articles summarizing the controversies and advances in the management of SLE Lupus nephritis (LN) is one of the main clinical presen- in children [12•]. Overall, children and adult SLE pa- tations (up to 80%) of pediatric SLE and it determines tients receive similar treatments depending on the clini- the course and outcome of the disease [29]. Some of the cal manifestations and the presence/absence of major or- prognostic parameters associated with LN in children are gan involvement. Most children with SLE receive summarized in Table 4. Because pathological findings corticosteroids and hydroxycloroquine as first line of treatment. Immunosuppressive drugs are added when Table 4. Prognostic parameters associated with lupus there is major organ involvement. Intravenous cyclo- nephritis in children phosphamide, which is commonly used for proliferative Parameters renal disease and CNS involvement, has dramatically improved the survival of children with SLE over the past 20 Male sex years [10]. Mycophenolate mofetil is used to treat pedi- Black race Age at onset before pre-puberty atric LN. Although few studies are available in children Anemia [39,40], good results have been reported especially in Persistent hypertension children with membranous nephritis. In adult patients Impaired renal function Nephrotic syndrome with proliferative LN, a recent study showed that short- Class IV lupus nephritis term therapy with intravenous cyclophosphamide fol- Increased histologic index scores lowed by maintenance therapy with mycophenolate [29,31,33,34•,118,119] mofetil or azathioprine appears to be more efficacious 580 Pediatric and heritable disorders

Table 5. Health outcome measures used in childhood-onset SLE

Instrument Validation in pediatric SLE References

SLEDAI Yes [120] —measurement of disease activity —assesses 9 organ systems —uses 24 weighted attributes SLICC/ACR Yes [3,38•] —measurement of irreversible, accumulated organ damage —assesses 12 domains —uses 41 items ECLAM Yes [113] —measurement of disease activity —assesses 12 domains —uses 34 items BILAG Yes [120] —measurement of disease activity —assesses 8 organ-based systems SLAM Yes [120] —measurement of disease activity —assesses 7 domains —uses 31 items Core sets of measure No, validation currently in progress [121] —measurement of disease activity and organ damage —introduced a ‘growth and development’ domain —uses 41 items and safer than long-term therapy with intravenous cyclo- disease. The next section summarizes some of these sig- phosphamide alone [41••]. Similar studies are needed in nificant new findings as they apply to adult and pediatric pediatric patients. Some recent studies using different SLE. treatment modalities in children with predominantly LN are depicted in Table 6. Genetic factors Pathogenesis Strong familial aggregation in SLE is well established. The heterogeneity of the clinical manifestations in SLE Siblings of SLE patients display a 10–20 fold increased patients probably reflects the complexity of the disease risk of developing the disease compared to the general pathogenesis. This complexity, however, is starting to population [42]. Monozygous twins have a 24% concor- unravel with the discovery that cells other than lympho- dance rate compared with 2% in heterozygous pairs [43]. cytes are involved in the breakdown of tolerance that This concordance rate highlights the importance of en- drives autoimmunity in SLE. New technologies applied vironmental factors in the development of SLE. Overall, to genomic and gene expression studies in patients with however, familial autoimmunity is a risk factor for SLE, SLE have revealed novel gene mutations and cytokine and this risk increases with the number of first degree alterations that may explain many of the features of the relatives affected with an autoimmune disease other than

Table 6. Summary of recent experience with different treatment modalities for childhood SLE

Treatment No. patients Indications Outcome Reference

Cs and CYC 9 Nephritis class III/IV 8/9 Normal serum creatinine at 36 months [122] 5 patients relapsed within 2 yr after treatment 31.5% mortality Cs with/without AZA 19 Nephritis class II–IV* CRF/ESRD in 5 patients at 8 year follow up [112] 0% mortality Cs and CYC 14 Nephritis class II and IV** CRF-ESRD in 3 patients at 8 year follow up [112] CYC 18 Nephritis class III–IV Within 10 year follow up, 3 patients required [123] re-treatment with CYC and 1 progressed to ESRD CYC and MTX 5 Relapse in Nephritis class IV 100% clinical improvement at 4 year follow up [124] MMF 11 Nephritis refractory to Cs, AZA Clinical response only in 4/4 patients with class [39] and/or CYC V nephritis. High incidence of infection. MMF 10 Nephritis class IIa–IV Decreased proteinuria and increased GFR in 70% patients [40] MMF 1 Pulmonary hemorrhage Extubated [125] Rituximab 1 Thrombocytopenia Remission [126] 1 Multi-systemic lupus-like Remission [127] syndrome Cs, corticosteroids; AZA, azathioprine; CYC, cyclophosphamide; CsA, cyclosporine A; MMF, mycophenolate Mofetil; CRF, chronic renal failure; ESRD, end stage renal disease. *9/19 patients without renal biopsy. **3/14 patients without renal biopsy. Systemic lupus erythematosus in children Stichweh et al. 581

SLE from an odds ratio of 4.1 (1 relative) to 11.3 (two or pediatric SLE serum, healthy monocytes aggregate and more relatives) [44]. differentiate into CD14+DCs. The generation of these CD14+DCs depends on the presence of IFN-␣␤ in SLE HLAhaplotypes, complement components and Fc ␥ re- serum [54]. Indeed, IFN-␣ was suggested as a factor in ceptor polymorphisms have been associated with in- SLE pathogenesis more than 20 years ago, though no creased susceptibility to SLE (reviewed in [45,46•,47•]). link to SLE pathogenesis was established. Therapy with Homozygous deficiency of any of the early components IFN-␣ occasionally (4–19%) results in induction of anti- of the classical complement pathway (C1q, C1r, C1s, C4 nuclear antibodies, though it rarely (0.15–0.7%) results in and C2) predisposes to the development of SLE. These overt autoimmunity like thyroiditis, diabetes or SLE (re- deficiencies are in fact the strongest SLE susceptibility viewed in [57•]). The recent finding that IFN␣␤ acti- factors identified in humans, and there is a hierarchy of vate DCs, and the identification of the critical role of association of both disease prevalence and severity ac- immature DCs in the establishment of peripheral toler- cording to the missing protein. Thus, patients deficient ance provided a new twist in the study of SLE. Given in one of the C1-complex or C4 molecules exhibit the that myeloid DCs are under the permanent activation of strongest prevalence (>80%) and the most severe dis- IFN␣␤, it can be hypothesized that instead of deleting ease, while the strength of association and disease sever- the autoreactive T cells they might select them, there- ity decrease in C2-deficient patients (reviewed in fore contributing to the development of autoimmunity. [48••]). B cells and autoantibodies Aseries of genetic linkage studies using microsatellite Regardless of the age at presentation, SLE patients dis- markers and single nucleotide polymorphisms have more play hypergammaglobulinemia and increased serum au- recently identified al least 7 loci displaying significant toantibody titers. Indeed, both adult and pediatric SLE linkage to SLE. These include 1q23 (Fc␥RIIA, patients exhibit profound alterations in their blood B cell Fc␥RIIB, Fc␥RIIIA), 1q25-31, 1q41-42 (PARP or ADP- compartments [58], as conventional naïve and memory B ribosyltransferase), 2q35-37 (PDCD1), 4p16-15.2, 6p11- cell numbers are decreased and there is an expansion of 21 (MHC haplotypes), and 16q12 [46,47]. Among the CD38 expressing cells, which include oligoclonal plasma genes identified within these loci, PDCD1 codes for PD- cell precursors (PCP) [59]. Blood PCP from children with 1, an immunoreceptor with a tyrosine-based inhibitory SLE display a phenotype similar to that of PCPs found motif (ITIM). The natural ligands of PD-1, PD-L1 and in the blood during secondary immune responses [60], PD-L2, are members of the B7 family. Interaction of including isotype-switched and mutated Ig genes [59]. PD-1 with PD-L1 leads to inhibition of anti CD3- As opposed to normal immune responses that cause tran- induced T cell activation, and mice lacking PDCD1 de- sient elevations of these cells, blood PCPs are persis- velop an SLE-like disease [49•]. The PDCD1 polymor- tently elevated in children with SLE. This suggests that phism identified in a subgroup of SLE patients of Nordic SLE mature B cells are persistently driven to differen- and Mexican origin is located within the 4th intron of the tiate into plasma cells that migrate through the blood gene and disrupts the binding of PDCD1 to RUNX-1, a from the secondary lymphoid organs into the bone mar- transcription factor that plays an important role in hema- row, where they may become long-lived, or the end- topoiesis (reviewed in [50•]. Mutations in two additional organs where inflammation takes place (Arce et al. manu- RUNX-binding genes have been recently linked to two script in preparation). different autoimmune diseases, Psoriasis [50•,51] and Rheumatoid Arthritis [52]. Thus, three autoimmune dis- What drives these alterations in SLE B cells is starting to eases with quite different clinical manifestations may be understood. As we have described, type-1 IFN levels have a common molecular etiology [50•]. are elevated in the majority of pediatric SLE patients. This cytokine increases the expression of CD38 [61] and Immune alterations promotes the differentiation of dendritic cells (DCs) that Dendritic cells can directly act on the growth and differentiation of B SLE might be the autoimmune disease that has received cells [62–65]. Indeed, myeloid DCs trigger B cell growth the highest attention with regard to dendritic cells, in- and differentiation through IL-12 and IL-6 [66] as well cluding both myeloid and plasmacytoid DCs (mDCs and as BAFF/APRIL [67–69•]. Additionally, virus stimulated pDCs) (reviewed in [53]). Even though these cells are plasmacytoid DC (pDCs) precursors can induce the significantly decreased in the blood of children with SLE maturation of CD40-activated B cells into plasma cells. [54], pDCs accumulate in the skin at the site of SLE This effect is due to two pDC-derived cytokines: type I involvement [55,56]. The blood of pediatric SLE pa- IFN that promotes differentiation of activated B cells tients contains unusual CD14+ “monocytes” with prop- into plasmablasts, and IL-6 that permits plasmablasts to erties of DCs, i.e. their ability to induce naïve T lym- become antibody-secreting plasma cells [70]. The phocyte proliferation [54]. Accordingly, upon exposure to CD40-L signal required to activate pDCs in this system 582 Pediatric and heritable disorders might be provided by T cells, but other cell types may DCs. Several alterations in human SLE T cell signaling contribute as well. This is particularly relevant to SLE molecules have been recently described. (1) SLE T cells where CD40-L is spontaneously expressed by circulating express decreased levels of both the TCR ␨ chain T and B cells [71,72]. The role of CD40L is further [88,89], and the lymphocyte-specific protein tyrosine ki- highlighted by the observation that cells with plasma cell nase (LCK) [90]; restoration of normal ␨ chain levels by phenotype disappear from the blood of adult SLE pa- gene transfer experiments corrects their over excitable tients after treatment with a blocking anti-CD154 mAb phenotype [91]. (2) SLE T cells over-express the raft- [73••]. associated glycosphyngolipid GM1, suggesting an increased formation of lipid rafts. These cells also display Antibody gene expression studies from single B cells an increased raft localization of CD45, a tyrosine phos- from healthy individuals show that large numbers of de- phatase that regulates LCK activity. These alterations, veloping B cells in the bone marrow and recent emi- however, are reversed when SLE T cells are allowed to grants in the blood express self-reactive antibodies. The “rest” in vitro and they cannot be reproduced by expo- majority of self-reactive B cells, however, are removed sure to SLE serum, suggesting that they may be the from the healthy mature blood naïve B cell pool [74•]. In result of cell-cell contact in vivo [92]. SLE patients, a large proportion of mature bone marrow plasma cells may derive from autoreactive progenitors, as SLE T cells seem to use different mechanisms of sur- they express the VH4-34 gene [75] that we and others vival upon costimulation than normal T cells. Indeed, have found encoding autoantibodies of different speci- microarray profiling studies have recently shown that ac- ficities [76,77], including anti-dsDNAantibodies [78]. tivated T cells from SLE patients resist anergy and ap- Furthermore, the serum of SLE patients contains el- optosis by upregulating cyclooxygenase-2 (COX-2) ex- evated titers of 9G4, an idiotype encoded by the VH4-34 pression, which in turn increases c-FLIP (cellular gene, and these titers correlate with SLE disease activity homolog of viral FLICE inhibitory protein) and attenu- [79••]. ates FAS signaling. Only certain COX-2 inhibitors, however, seem able to induce autoreactive T cell apoptosis Recent prospective studies on stored serum samples and suppress the production of pathogenic autoantibod- from the U.S. Armed Forces personnel have shown that ies to DNAin lupus-prone mice [93•]. clinical SLE is preceded by the progressive accumulation of autoantibody specificities many years (up to 9 yr) Cytokine alterations before diagnosis. Anti-nuclear, anti-Ro, anti-La, and anti- In addition to type-I IFN, many cytokines like IL-6, phospholipid antibodies appear first, followed by anti- IL10, IL12 (p40) and IL-18 have been reported elevated dsDNAantibodies and then anti-Sm and anti-nuclear in the serum of SLE patients [94–98] and correlate with ribonucleoprotein antibodies [80••]. The observation disease activity. As reviewed earlier, the fact that some of that clinically overt disease develops closer to the time of these cytokines, i.e. IFN-␣, are very potent adjuvants of breakdown of tolerance against DNAand ribonucleopro- both the innate and adaptive immune systems explains teins has some potential pathogenic implications. First, many of the features of SLE [53]. Elevated serum levels immune complexes containing hypomethylated DNA of IFN-␣ can only be detected in ∼50% of pediatric SLE have been shown to co-engage the BCR and TLR-9 on patients, but microarray analysis of their PBMCs reveals autoreactive B cells leading to autoantibody secretion that the majority (>95%) of children with mild to severe [81,82]. Second, immune complexes containing anti- disease display an IFN-␣ gene signature [61]. Similar DNAand anti-RNP antibodies have been shown to ac- studies in adult SLE patients found IFN-␣ upregulated tivate pDCs to secrete IFN-␣ [83•,84], which in turn can genes in only 50% of the samples analyzed [99]. This induce the differentiation of B cells into antibody- difference might be due to the fact that pediatric pa- secreting plasma cells [70] and activate monocytes and tients had more severe disease and/or their blood was myeloid DCs [54,85], creating a self-amplifying patho- analyzed closer to the time of diagnosis before they had genic loop (Figure 1). received any treatment.

T cells Children with SLE also display increased levels of serum T cells from patients with SLE display increased and soluble TNF receptors (sTNF-R) [100,101] and accelerated signaling responses upon TCR/CD3 engage- FLT3-L [102]. Because FLT3-L mobilizes DCs from ment, suggesting that they are “primed” for activation the bone marrow, elevated levels of this cytokine in pe- and can respond faster to antigenic triggers than healthy diatric SLE serum may represent a compensatory T cells (reviewed in [86,87•]). SLE T cell hyper- mechanism triggered by the low levels of myeloid and reactivity could be intrinsic, i.e. genetically determined, plasmacytoid DCs in their blood [54]. Elevated levels of or result from abnormal in vivo exposure to cytokines antagonist sTNF-RI and sTNF-RII could also be pri- and/or interactions with antigen presenting cells like mary or secondary events in SLE. TNF, as opposed to Systemic lupus erythematosus in children Stichweh et al. 583

Figure 1. Roles played by both genetic and environmental factors in the development of pediatric systemic lupus erythematosus Both genetic and environmental factors play a fundamental role in the disease development. From the genetic perspective, mutations in inhibitory receptors on T cells may contribute to T cell hyperactivity and tolerance escape. Deficiency in apoptotic cell removal may provide DCs with an excessive load of nuclear antigens to present to T cells. These and other genetic alterations may contribute to a progressive loss of tolerance to nuclear antigens, which has been shown to sequentially precede the development of clinically overt disease. Some of these autoantibodies may form complexes able to activate both B cells, through the co-engagement of BCR and TLRs, and pDCs, which are the main producers of IFN-␣. IFN-␣, together with IL-6, promotes the differentiation of mature B cells into plasma cells, which will in turn increase autoantibody secretion and immune complex formation, closing this self-perpetuating loop. IFN-␣ will also activate monocytes and other myeloid DC precursors to become immunogenic DCs able to activate T and B cells. Viruses and other environmental triggers that can activate pDCs to secrete IFN-␣, will contribute to enhance any of these loops and precipitate the development of clinical disease.

FLT-3L, inhibits the bone marrow generation of pDCs. terial and induce the proliferation of autologous T cells Neutralization of this cytokine may therefore be a com- [54]. Furthermore, autoantigens have been shown to un- pensatory mechanism to react to the low numbers of dergo structural modifications during the process of ap- pDCs in SLE blood. This neutralization, however, may optosis that may render them particularly immunogenic have deleterious consequences in SLE, as TNF pro- under the above circumstances [106]. Defective clear- motes the maturation of pDCs, which in turn abrogates ance of apoptotic cells could be a major player in some the ability of these cells to secrete IFN-␣. Blocking TNF SLE patients, as the genetic deficiency of molecules that therefore sustains the production of IFN-␣. This cyto- participate in this process, like C1q, induces SLE. kine interplay may explain why a significant number of patients with arthritis and Crohn’s disease treated with CONCLUSION TNF antagonists develop some of the features of SLE, We have discussed various clinical aspects of pediatric including anti-dsDNa antibodies. In fact, we have ob- SLE and summarized some recent observations that pro- served that the PBMCs of children with Systemic Onset vide new insights into the pathogenesis of this disease in Juvenile Idiopathic Arthritis (SOJIA) treated with Inflix- humans. As depicted in Figure 1, both genetic and en- imab display an IFN-␣ signature (Palucka, K, Blank JP, vironmental factors play a fundamental role in the dis- Bennett L., et al., submitted) and some of them go on ease development. From the genetic perspective, muta- into developing serological features of SLE. tions in inhibitory receptors on T cells may contribute to T cell hyperactivity and tolerance escape. Deficiency in Apoptosis and SLE apoptotic cell removal may provide DCs with an exces- Abnormal presentation of apoptotic body-derived anti- sive load of nuclear antigens to present to T cells. These gens by immunogenic DCs and/or a failure in the normal and other genetic alterations may contribute to a progres- process of clearance of apoptotic material can contribute sive loss of tolerance to nuclear antigens, which has been to the development of SLE [103•]. In fact, a common shown to sequentially precede the development of clini- feature of the SLE autoantigens, especially chromatin cally overt disease. Some of these autoantibodies may and phospholipids, is that they are components of the form complexes able to activate both B cells, through the surface blebs of apoptotic cells [104]. Furthermore, there co-engagement of BCR and TLRs, and pDCs, which are is increasing evidence that apoptotic material is normally the main producers of IFN-␣. This cytokine, together taken up by immature DCs and cross-presented to in- with IL-6, promotes the differentiation of mature B cells duce T cell tolerance (reviewed in [105••]). Maturation into plasma cells, which will in turn increase autoanti- of the same DCs upon exposure to an inflammatory en- body secretion and immune complex formation, closing vironment may therefore lead to immunization with an- this self-perpetuating loop. IFN-␣ will also activate tigens derived from apoptotic cells. Such scenario may monocytes and other myeloid DC precursors to become take place in SLE, as DCs derived from monocytes ex- immunogenic DCs able to activate T and B cells. Vi- posed to IFN-␣ from SLE serum capture apoptotic ma- ruses, and other environmental triggers that can activate 584 Pediatric and heritable disorders pDCs to secrete IFN-␣, will contribute to enhance any 12 Tucker LB: Controversies and advances in the management of systemic lu- • pus erythematosus in children and adolescents. Best Pract Res Clin Rheu- of these loops and precipitate the development of clini- matol 2002, 16:471–480. cal disease. Nice and comprehensive review of therapeutic options for children with SLE 13 Moises-Alfaro C, Berron-Perez R, Carrasco-Daza D, et al.: Discoid lupus ery- • thematosus in children: clinical, histopathologic, and follow-up features in 27 As we understand better the pathogenesis of SLE, we cases. Pediatr Dermatol 2003, 20:103–107. will be able to design better, more targeted and less toxic Complete review of DLE in childhood treatments for our patients. Translating the advances in 14 Guevara JP, Clark BJ, Athreya BH: Point prevalence of cardiac abnormalities in children with systemic lupus erythematosus. J Rheumatol 2001, 28:854– basic immunology into the care of the children with SLE 859. remains however a formidable challenge. The Childhood 15 Gunal N, Kara N, Akkok N, et al.: Cardiac abnormalities in children with sys- Arthritis & Rheumatology Research Alliance (CARRA) temic lupus erythematosus. Turk J Pediatr 2003, 45:301–305. has been created to promote multi-site collaborative re- 16 Gazarian M, Feldman BM, Benson LN, et al.: Assessment of myocardial perfusion and function in childhood systemic lupus erythematosus. J Pediatr lationships among Pediatric Rheumatology Centers in 1998, 132:109–116. North America to facilitate studies on pediatric rheu- 17 Sandor GG, Hishitani T, Petty RE, et al.: A novel Doppler echocardiographic matic diseases. The Atherosclerosis Prevention in Pedi- method of measuring the biophysical properties of the aorta in pediatric pa- atric Lupus Erythematosus (APPLE) study that will tients. J Am Soc Echocardiogr 2003, 16:745–750. assess the role of statins in the prevention of atheroscle- 18 Bjornadal L, Yin L, Granath F, et al.: Cardiovascular disease a hazard despite improved prognosis in patients with systemic lupus erythematosus: results rosis in pediatric SLE patients has already been from a Swedish population based study 1964–95. J Rheumatol 2004, launched as a result of it. This study will involve the 31:713–719. largest cohort of pediatric SLE patients ever studied pro- 19 Schmugge M, Revel-Vilk S, Hiraki L, et al.: Thrombocytopenia and thrombo- • embolism in pediatric systemic lupus erythematosus. J Pediatr 2003, spectively. Many studies hopefully will follow to 143:666–669. brighten the future of children with SLE. Review of the most important factors that contribute to TE in children with SLE 20 Levy DM, Massicotte MP, Harvey E, et al.: Thromboembolism in paediatric lupus patients. Lupus 2003, 12:741–746. 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disease activity and damage assessment in juvenile systemic lupus erythe- cyclophosphamide for refractory childhood lupus nephritis. Ann Rheum Dis matosus and juvenile dermatomyositis. Rheumatology (Oxford) 2003, 2004, 63:321–323. 42:1452–1459. 125 Samad AS, Lindsley CB: Treatment of pulmonary hemorrhage in childhood systemic lupus erythematosus with mycophenolate mofetil. South Med J 122 Al Salloum AA: Cyclophosphamide therapy for lupus nephritis: poor renal 2003, 96:705–707. survival in Arab children. Pediatr Nephrol 2003, 18:357–361. 126 ten Cate R, Smiers FJ, Bredius RG, et al.: Anti-CD20 monoclonal antibody 123 Barinstein LO, Lehman KB, Thomas JA: Cyclophosphamide to treat severe (rituximab) for refractory autoimmune thrombocytopenia in a girl with systemic pediatric lupus nephritis. Arthritis Rheum 2003, 9. lupus erythematosus. Rheumatology (Oxford) 2004, 43:244. 127 Binstadt BA, Caldas AM, Turvey SE, et al.: Rituximab therapy for multisystem 124 Lehman TJ, Edelheit BS, Onel KB: Combined intravenous methotrexate and autoimmune diseases in pediatric patients. J Pediatr 2003, 143:598–604. Genetics of juvenile idiopathic arthritis: an update Sampath Prahalad

Purpose of review Abbreviations Juvenile idiopathic arthritis (JIA) refers to a collection of chronic ACE angiotensin-converting enzyme I/D insertion/deletion arthritides in children, and the major subtypes of JIA are similar JIA juvenile idiopathic arthritis to the subtypes of juvenile rheumatoid arthritis (JRA). Several JRA juvenile rheumatoid arthritis LD linkage disequilibrium genetic variants influencing susceptibility to JIA have been MHC major histocompatibility complex identified, including genes encoding the HLA molecules, MIF macrophage migration inhibitory factor PPAR peroxisome proliferator activated receptor cytokines, and other modulators of immune responses. This RANK receptor activator of nuclear factor-␬B review outlines the principles behind genetic studies and RANKL RANK ligand SNP single nucleotide polymorphism summarizes recent studies on the genetics of JIA. TDT transmission disequilibrium test Recent findings Th1 and 2 T-helper 1 and 2

Recent studies confirm the association/linkage between JIA © 2004 Lippincott Williams & Wilkins and the HLA region and provide evidence for additional loci 1040–8711 involved in susceptibility to JIA. Several studies suggest that polymorphisms in other candidate genes also influence susceptibility to JIA. In addition, some genetic variants seem to influence the phenotype of JIA. A genome-wide scan for JRA in Introduction 121 affected sibling pair families confirms that gene(s) in the Juvenile idiopathic arthritis (JIA) is a collection of phe- HLA region influence susceptibility to JRA and identifies other notypically heterogeneous chronic childhood arthropa- chromosomal regions that possibly influence susceptibility to thies [1]. JIA includes the subtypes of juvenile rheuma- JRA or subtypes of JRA. Functional studies suggest that toid arthritis (JRA) defined by the American College of biologic markers could be useful in defining the phenotype of Rheumatology: pauciarticular, polyarticular, and sys- individuals with JIA. Familial studies and gene expression temic arthritis [2]. JIA also includes psoriatic arthritis, profiling are useful tools in the dissection of the genetic basis enthesitis-related arthritis, and other arthritis. Both ge- of JIA. netic and environmental factors are believed to play a Summary role in the susceptibility to JIA. This review focuses on Although there are challenges to the identification of genetic studies from the past year that enhance our understand- factors underlying complex diseases such as JIA, considerable ing of the genetic basis of JIA. Comparing genetic stud- progress has been made in JIA genetics. Candidate gene ies of juvenile arthritis is complicated by the use of dif- studies remain important to identify genetic variants with small ferent classification criteria. However, when phenotypic to moderate effects on the JIA phenotype. information is provided, comparisons are possible, because the major subtypes (pauciarticular/oligoarticular, polyarticular, and systemic) refer to relatively homoge- Keywords neous subsets of juvenile arthritis. juvenile arthritis, genetics, association, linkage, familial Exploring the genetic basis of a complex disease Curr Opin Rheumatol 16:588-594. © 2004 Lippincott Williams & Wilkins. Association studies and linkage studies are used to identify genetic variants influencing complex diseases. Asso- ciation studies compare unrelated affected and unaf- Department of Pediatrics, Division of Immunology and Rheumatology, University of fected individuals within a population. Thus, an allele at Utah School of Medicine, Salt Lake City, Utah, USA a locus of interest is associated with a trait if it occurs at Supported by grants from The Val A. Browning Charitable Foundation, the Primary Children’s Medical Center Foundation, Child Health Research Career a significantly higher (or lower) frequency among af- Development Award, the Clinical Genetics Research Program, and The Children’s fected individuals (cases) compared with control indi- Health Research Center, Salt Lake City, Utah, USA viduals [3]. Transmission disequilibrium testing (TDT) is another method for determining association between a Correspondence to Sampath Prahalad, Division of Immunology and Rheumatology, marker at a locus of interest and a complex disease. The Department of Pediatrics, University of Utah School of Medicine, 30 North, 1900 East, Salt Lake City, UT 84132-2206, USA TDT measures the rate of transmission of a marker from Tel: 801 581 5319; fax: 801 585 9314; e-mail: [email protected] parents who are heterozygous for the marker to their Current Opinion in Rheumatology 2004, 16:588–594 affected offspring. TDT tests the hypothesis that a par- 588 Genetics of juvenile arthritis Prahalad 589 ent heterozygous for a disease-associated allele will JRA and 64 controls [16]. HLA-DR3 alleles were in- transmit that allele more often to an affected child than creased in children with pauciarticular JRA compared expected by chance [4,5]. An advantage of TDT is that, with controls. HLA-DRB1*0307 and *0308 were seen unlike traditional case-control studies, TDT is not af- only in JRA probands. HLA-DR8 was increased in JRA fected by population stratification, because the untrans- patients. HLA-DR11 was increased in the controls com- mitted alleles serve as controls within families. When an pared with patients; however, this was not significant. association between a marker and a disease is detected, This trend differs from the previously described in- it implies either that the marker is the disease allele or creased frequency of HLA-DR5 (HLA-DR5 includes that the marker is in linkage disequilibrium (LD) with HLA-DR11 and HLA-DR12 alleles) among pauciarticu- the disease allele. LD is a nonrandom association of al- lar JRA probands [5]. leles at two or more loci and is a measure of cosegrega- tion of alleles in a population [6]. Linkage studies exam- The presentation of certain peptides by susceptible ine whether markers linked to a disease locus are HLA molecules might be involved in JIA pathogenesis transmitted to affected individuals more often than ex- by activating autoreactive T cells [17]. Ihle et al. [18] pected by chance. Thus, while association studies test used a synthetic nonapeptide library to compare the pep- whether a disease phenotype and a marker allele show tide-binding motif of a JIA-susceptibility molecule correlated occurrence in a population, linkage studies (DQ7) with that of neutral (DQ5) or protective (DQ2) test whether they show correlated transmission within a molecules. A differential motif for the three molecules pedigree [3]. Fundamentally, both types of studies rely was deduced, implying that peptides that bind to the on the same principle, ie, the coinheritance of polymor- susceptible vs neutral/protective DQ molecules are mu- phisms linked to a disease allele [7]. tually exclusive. This suggests that differential peptide presentation by disease-associated or protective DQ mol- Polymorphisms in the HLA region ecules might play a role in JIA pathogenesis. Identifying Several genetic studies have focused on understanding peptides that potentially initiate the disease process the contribution of polymorphisms in the major histo- could lead to targeted therapeutic interventions. compatibility complex (MHC) to JIA/JRA susceptibility. The MHC region located on chromosome 6 is densely Non-HLA polymorphisms packed with more than 200 genes [8], many of which are In addition to the numerous associations between JIA essential to the immune system, including genes encod- and HLA variants, other non-HLA polymorphisms have ing HLA. Associations and linkage between HLA vari- ␭ been associated with JIA. The sibling recurrence risk ( s) ants and JIA are well recognized [9–12]. JIA is influenced for JRA has been estimated to be ∼15, and the HLA-DR both by HLA class I and class II alleles and efforts con- accounted for ∼17% of the risk for JRA [12]. This sug- tinue to identify other causative HLA variants. gests that other loci both within and outside the MHC An association between JIA and allele 5 at the microsat- influence the genetic risk for JIA. Hence, we and others ellite D6S265 in the HLA class I region has been de- are investigating candidate genes outside the HLA re- scribed, independent of LD with the DR8-DQ4 haplo- gion that underlie susceptibility to JIA. A comprehensive type [13]. Other alleles at D6S265 were investigated to review of non-HLA polymorphisms in JRA summarizes a determine if they modified the risk for JIA on different number of studies performed over several decades [19•]. haplotypes [14•]. Allele 6 at D6S265 was significantly The following are some of the studies from the past year. associated with JIA on the DRB1*1301-DQB1*0603 haplotype (odds ratio 5.5). In another study, 235 sporadic Several genes involved in immune responses were inves- ∼ ∼ JIA families (82 pauciarticular, 153 polyarticular) and 639 tigated in 200 patients each with RA and JRA and 400 controls were typed for 16 markers spanning the MHC controls [20•]. Subtype information on JRA patients was region [15•]. Case-control and TDT analyses demon- not provided. A single nucleotide polymorphism (SNP) strated strong evidence for a susceptibility locus near at position −318 of CTLA4 was associated with both RA D6S2447, a marker flanked by DQB1 and DRB1. HLA- and JRA, after correcting for multiple comparisons. This DRB1*08 was strongly associated and overtransmitted to SNP has previously been shown to be associated with pauciarticular and polyarticular JIA probands. In pauci- Wegener granulomatosis and type 1 diabetes mellitus articular probands, HLA-DRB1*11 was also associated [21,22]. Two other variants showed association with JRA and overtransmitted. Probands with polyarticular JIA (Table 1). Many of the other polymorphisms did not showed association with a more extensive region com- show associations with JRA, including some that have pared with pauciarticular JIA probands. The results from previously been associated with JRA or other autoim- these two studies suggest the presence of additional JIA mune disorders [23–26]. susceptibility locus/loci in the HLA class I region. Macrophage migration inhibitory factor (MIF) plays a In another study HLA-DR3 alleles were investigated role in the development of experimentally induced au- among 64 children with pauciarticular or polyarticular toimmune disease [27]. A SNP at position −173(G/C) of 590 Pediatric and heritable disorders

Table 1. Summary of non-HLA polymorphisms investigated in juvenile idiopathic and juvenile rheumatoid arthritis

Marker Variant Phenotype Population Design Cases Controls Association P value Study Comments

TNFa Microsatellite JRA German CC 142 388 Yes 0.02 [20] Allele 06 TNFA −238A/G JRA German CC 130 375 No NS [20] −308A/G JRA German CC 122 312 No NS [20] −857C/T JRA German CC 170 415 No NS [20] TNFR1 −609G/T JRA German CC 136 428 No NS [20] P12P JRA German CC 132 334 No NS [20] TNFR2 del15 JRA German CC 146 428 No NS [20] P < 0.05, uncorrected IKBL −332A/G JRA German CC 170 389 No NS [20] −132T/A JRA German CC 170 389 No NS [20] C224R JRA German CC 169 379 No NS [20] CTLA4 −318C/T JRA German CC 197 362 Yes 0.001 [20] T17A JRA German CC 197 362 No NS [20] PTPRC P57P JRA German CC 161 362 No NS [20] MIF −173G/C JRA German CC 150 390 No NS [20] Microsatellite JRA German CC 224 341 Yes <0.02 [20] 05 allele, 0507 genotype increased IFN-␥ Microsatellite JRA German CC 165 395 No NS [20] D17S795 D17S795 JRA German CC 173 416 No NS [20] D17S807 D17S807 JRA German CC 172 412 No NS [20] D17S1821 D17S1821 JRA German CC 173 412 No NS [20] IL13 R110Q JIA German CC 86 270 No NS [34] JIA vs asthma P = 0.007 MEFV M694V JIA + Turkish CC 59 + 12 100 Yes <0.005 [35] vasculitis ACE I/D poly- JRA Kuwaiti CC 82 48 Yes 0.003 [36] morphism IL6 −174G/C Sys JIA US, UK, TDT 222 — Yes 0.04 [31] In patients over French 5 years, P < 0.007 −174G/C Poly JIA US TDT 169 — No NS [31] −174G/C Oligo JIA US TDT 239 — No NS [31] AnTn tract Sys JIA UK TDT 100 — No NS [31] ACE, angiotension-converting enzyme; CC, case-control; CTLA, anti-cytotoxic T-lymphocyte antigen; IFN-␥, interferon-␥; IKBL, inhibitor of kappa light chain gene enhancer in B cells-like gene; IL, interleukin; JIA, juvenile idiopathic arthritis; JRA, juvenile rheumatoid arthritis; MEFV, familial Mediterranean fever; MIF, migration inhibitory factor; Oligo, oligoarticular; Poly, polyarticular; PTPRC, protein-tyrosine phosphatase receptor-type C; Sys, systemic; TDT, transmission disequilibrium testing; TNF, tumor necrosis factor. the MIF gene is associated with JIA [28]. The functional Atopic and autoimmune diseases are believed to be on relevance of this polymorphism was investigated in 136 opposite ends of the T-helper 1 and 2 (Th1-Th2) im- patients with systemic JIA [29••]. Patients carrying an mune spectrum [32,33]. JIA is characterized by a pre- MIF −173C allele (GC/CC genotypes) had significantly dominantly Th1 immune response whereas atopic dis- greater serum and synovial fluid levels of MIF compared eases are characterized by a predominantly Th2 re- with patients with the GG genotype. Those carrying an sponse. An R110Q polymorphism in the interleukin-13 MIF −173C allele also were likely to require longer daily gene, which encodes a Th2 cytokine, was typed in chil- corticosteroids, have a shorter response to intra-articular dren with asthma, atopy, JIA, or controls [34•]. Q110 was corticosteroids, and have a higher number of joints with associated with increased IgE levels in individuals with active arthritis, suggesting that the MIF-173C allele is a atopy/asthma. Q110 frequency did not differ between predictor of poor outcome in systemic JIA. JIA cases and controls, but Q110 was significantly less frequent in JIA probands compared with asthmatic pro- Interleukin-6 is another proinflammatory cytokine el- bands. This suggests that some genetic variants involved evated in children with systemic JIA [30]. Systemic JIA in susceptibility to some phenotypes might be protective cohorts from three countries (United States, United against others. Kingdom, and France) were typed for a SNP at position

−174, and an AnTn tract in this gene [31••]. TDT dem- Two genetic variants implicated in other inflammatory onstrated significant overtransmission of the −174G al- disease have been investigated in JIA. In an analysis of lele to systemic JIA probands. The other subtypes did mutations in the MEFV gene, which cause familial not show deviations of transmission from expectations. Mediterranean fever, probands with JIA/vasculitis had a This study demonstrates the need for testing sufficient significantly higher frequency of M694V mutation com- numbers of families. Individual cohorts failed to show an pared with Turkish controls [35]. In three JIA patients, association with the −174 variant, but the combined sys- MEFV mutations appeared to affect the phenotype. An- temic JIA cohort demonstrated a significant association. giotensin-converting enzyme (ACE), a component of the Genetics of juvenile arthritis Prahalad 591 renin-angiotensin system, is believed to play a role in Gene expression analysis inflammation. An insertion-deletion (I/D) polymorphism Gene expression profiling using microarrays is used to in the ACE gene, which influences plasma and tissue identify genes that are over- or underexpressed between ACE levels, was investigated in JRA [36]. A significant two groups (patients and controls or treated and un- increase in the I/I genotype was observed in JRA pro- treated individuals). Changes in gene expression are bands compared with controls. Thus, polymorphisms of complex and might reflect differences among individuals candidates influencing susceptibility to other diseases or subtype or activity of the disease, as well as effects of might also influence susceptibility or disease expression the disease or treatment. However, well-designed gene of JIA. expression studies could potentially illuminate specific pathways relevant to the pathophysiology of various dis- The number of association studies performed has in- orders. Analysis of differentially expressed genes in nine creased with increasing availability of polymorphism JRA patients and 12 controls demonstrated that patients data. The development of a genetic association database with active disease had upregulation of principal modu- that aims to collect, standardize, and archive genetic as- lators of both innate and adaptive immune responses sociation data should enhance the accessibility of asso- [41•]. In addition, serum levels of interferon-␥, a proin- ciation studies [37•]. It is crucial to establish standards flammatory cytokine, were dramatically increased in pa- for designing, implementing, interpreting, and reporting tients with active disease compared with controls. A dis- association studies. criminant function analysis identified several genes that discriminate the groups studied. Gene expression profil- Genome-wide scan for JIA ing by other groups has also identified groups of genes susceptibility loci likely to play important roles defining the phenotypes of Because multiple genes are likely to be responsible for JIA [42,43]. These studies demonstrate the power of ana- susceptibility to complex diseases like JIA, another strat- lyzing gene expression behavior in complex diseases egy for identifying susceptibility loci is to screen the such as JIA. human genome for linkage to the disease. Results of linkage studies are reported as LOD (logarithm of odds) Defining the phenotype: functional studies scores. The traditional LOD score threshold for positive For some complex diseases, examining phenotypes that linkage in a genome-wide scan has been 3.3 (P < reflect the disease process has facilitated identification of 0.00002) [38]. Some authors have suggested setting a less genes influencing susceptibility or pathogenesis. These stringent lower threshold for a subset of the sibpairs, and phenotypes, termed intermediate phenotypes, define a confirming positive linkages in a second data set [39]. A genetically more homogeneous population for analysis. genome-wide scan provided evidence for linkage in 121 To date, the influence of candidate loci on intermediate sibpair JRA families [40••]. Genotype data was collected phenotypes for JIA has not been examined, in part be- for HLA-DRand 386 microsatellite markers. Multipoint cause the definition of the most appropriate intermediate nonparametric linkage analysis was performed on the en- phenotypes for JIA is unclear. Functional studies are im- tire cohort, as well as after stratification by disease onset, portant to delineate such intermediate phenotypes. course, onset age, and selected HLA-DRB1 alleles. Pedigree disequilibrium testing revealed a strong asso- Apoptosis is important for the induction of peripheral ciation at the DRB1 locus, with overtransmission of the T-cell tolerance, and defective T-cell apoptosis might DR8 haplotype (P < 0.000002). In contrast, HLA-DR4 result in autoimmune disease. Two studies demon- and DR7 were undertransmitted to affected sibpairs. strated increased apoptosis of peripheral blood T cells in children with JIA [44,45]. In one study, an increased The strongest evidence for linkage to JRA was near the apoptosis index was seen in children with systemic JIA, HLA-DRB1 locus, with a LOD score of 2.26. Three active disease, or increased inflammatory markers [44]. other regions had LOD scores over 1.5. Analyses after In the other study, the percentage of T cells expressing stratification identified 17 chromosomal regions with CD95(fas), a molecule involved in apoptosis modulation, LOD scores over 1.5, including several over 2.0. For was much higher in the synovial fluid than in the pe- early-onset pauciarticular and polyarticular disease, evi- ripheral blood in JIA patients [45]. Systemic T-cell ap- dence for linkage was found at chromosomes 7q11 and optosis was higher in JIA whereas a substantial number 19p13, respectively. Stratification for the presence of of synovial T cells survived locally, despite expressing HLA-DR8 in the affected siblings resulted in highly sig- CD95. CD95 could serve as a target for apoptosis induc- nificant linkage at 2p25 with a LOD score of 6.0. Many tion in autoreactive T cells, or cells infiltrating inflamed regions identified on subtype stratification were unique joints in children with JIA could be resistant to CD95- to JRA. These data confirm that gene(s) in the HLA ligand-mediated apoptosis. region influence susceptibility to JRA and suggest that other chromosomal regions influence susceptibility to Several studies have focused on molecules playing roles JRA or subtypes of JRA. in inflammatory processes in JIA, such as ␣(1,3) fucosyl- 592 Pediatric and heritable disorders

transferase, RANK (receptor activator of nuclear factor- phenotype), incomplete penetrance (the presence of a ␬B), and neprilysin in peripheral blood or synovial fluid predisposing allele does not necessarily lead to the de- of individuals with JIA [46,47,48•]. Another study found velopment of JIA), and polygenic inheritance (JIA might that the lymphocyte-to-neutrophil ratio at presentation require the simultaneous presence of mutations in mul- was lowest in patients with active disease, especially tiple genes). These challenges are common to other with polyarticular course [49]. These studies suggest that complex diseases as well. The identification of suscep- biologic markers could be useful in defining the pheno- tibility variants in other complex diseases, exemplified types of individuals with JIA, and possibly their relatives, by Alzheimer disease (APOE4), inflammatory bowel dis- to aid in the dissection of genetic factors that underlie ease (NOD2, SLC22A4, SLC22A5), asthma (ADAM33), JIA susceptibility and expression. and type 2 diabetes (PPAR-␥; peroxisome proliferator activated receptor) is encouraging [56–60]. Given the Defining the phenotype: family studies large number of plausible candidate genes that could be Twin and family studies also provide evidence for a ge- involved in susceptibility to JIA and other immune- netic component to a disease. The phenotypes of 164 mediated diseases, it is important to prioritize candidate JRA-affected sibpairs investigated by Moroldo et al. genes for study. Linkage studies identify chromosomal [50••] showed a high concordance for onset type, con- regions that often contain several genes. Knowledge firming earlier findings [51]. Familial aggregation of sev- about the pathophysiology of JIA will enable us to search eral manifestations was assessed, and a sporadic JRA for functional candidates within these regions. Another ␭ cohort was used to determine the S for several manifes- way to find functionally important variants might be to ␭ tations. S was high for tenosynovitis, rheumatoid factor, identify genes that have been acted on by natural selec- anemia, and positive antinuclear antibodies. Siblings de- tion [61]. Such an approach would have the added ad- veloped disease at the same onset age. With the excep- vantage of the ability to evaluate the effects of haplo- tion of number of joints at onset among children with types in addition to SNPs on the phenotype. Strategies polyarticular JRA, the other clinical features including such as accurate description of the phenotype, identifi- onset age did not differ between the sporadic and mul- cation of intermediate phenotypes, performing replica- tiplex cases. However, a Finnish study suggested a sig- tion studies in different cohorts, family studies, and us- nificant difference in onset age between sporadic and ing sufficient numbers of subjects to adequately power multiplex JIA cases [52]. Another study identified an studies will all facilitate identification of genetic variants increased frequency of inflammatory arthritis among the that contribute to susceptibility and expressivity of JIA. parents of JIA-affected sibpairs [53], similar to an earlier observation of increased prevalence of inflammatory ar- References and recommended reading thritis among relatives of JRA-affected sibpairs compared Papers of particular interest, published within the annual period of review, with relatives of sporadic JRA probands [54]. Such stud- have been highlighted as: ies are necessary to understand differences in the phe- • Of special interest notypes between sporadic and familial JIA. •• Of outstanding interest 1 Petty RE, Southwood TR, Baum J, et al.: Revision of the proposed classification criteria for juvenile idiopathic arthritis: Durban, 1997. J Rheumatol 1998, Despite the description of sibpairs and twins with JIA, 25(10):1991–1994. extended JIA pedigrees are rare [11]. One way to identify 2 Cassidy JT, Levinson JE, Bass JC, et al.: A study of classification criteria for a such families is to link records in clinical databases and diagnosis of juvenile rheumatoid arthritis. Arthritis Rheum 1986, 29:274– population genealogic databases. We performed a proba- 281. bilistic record-linking analysis in Utah, linking a database 3 Lander ES, Schork NJ: Genetic dissection of complex traits. Science 1994, of children with JIA and the Utah population database 265:2037–2048. [55]. Four extended families with five cases of JIA each 4 Spielman RS, McGinnis RE, Ewens WJ: Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus were identified. All five individuals in one cluster had (IDDM). Am J Hum Genet 1993, 52:506–516. oligoarthritis, and four had a very similar onset age. The 5 Moroldo MB, Donnelly P, Saunders J, et al.: Transmission disequilibrium asa median onset age among patients in these clusters was test of linkage and association between HLA alleles and pauciarticular-onset lower than the rest of the JIA cohort, similar to an earlier juvenile rheumatoid arthritis. Arthritis Rheum 1998, 41:1620–1624. observation [52]. Our study also demonstrated the famil- 6 Tabor HK, Risch NJ, Myers RM: Opinion: Candidate-gene approaches for ial aggregation of JIA and provided a population-based studying complex genetic traits: practical considerations. Nat Rev Genet 2002, 3:391–397. estimate of the recurrence risk for first-degree relatives ∼ 7 Cardon LR, Bell JI: Association study designs for complex diseases. Nat Rev of 30. Genet 2001, 2:91–99.

8 The MHC Sequencing Consortium: Complete sequence and gene map of a Conclusion human major histocompatibility complex. Nature 1999, 401:921–923. There are several challenges to the identification of ge- 9 Ploski R: Immunogenetic polymorphism and disease mechanisms in juvenile netic markers underlying susceptibility to complex dis- chronic arthritis. Rev Rhum Engl Ed 1997, 64(suppl 10):127S–130S.

eases [3]. Some examples include genetic heterogeneity 10 Howard JF, Sigsbee A, Glass DN: HLA genetics and inherited predisposition (mutations in different genes might each result in JIA to JRA. J Rheumatol 1985, 12:7–12. Genetics of juvenile arthritis Prahalad 593

11 Glass DN, Giannini EH: Juvenile rheumatoid arthritis as a complex genetic association with systemic-onset juvenile chronic arthritis. J Clin Invest 1998, trait. Arthritis Rheum 1999, 42:2261–2268. 102:1369–1376. 12 Prahalad S, Ryan MH, Shear ES, et al.: Juvenile rheumatoid arthritis: linkage to 31 Ogilvie EM, Fife MS, Thompson SD, et al.: The −174G allele of the interleu- HLA demonstrated by allele sharing in affected sibpairs. Arthritis Rheum •• kin-6 gene confers susceptibility to systemic arthritis in children: a multicenter 2000, 43:2335–2338. study using simplex and multiplex juvenile idiopathic arthritis families. Arthritis Rheum 2003, 48:3202–3206. 13 Smerdel A, Lie BA, Ploski R, et al.: A gene in the telomeric HLA complex Transmission disequilibrium test analysis of polymorphisms in the interleukin-6 distinct from HLA-A is involved in predisposition to juvenile idiopathic arthritis. gene demonstrates significant association of −174G allele with systemic JIA co- Arthritis Rheum 2002, 46:1614–1619. horts from United States, United Kingdom, and France. The effect was mainly due 14 Smerdel A, Lie BA, Finholt C, et al.: An additional susceptibility gene for ju- to children with onset after 5 years of age. • venile idiopathic arthritis in the HLA class I region on several DR-DQ haplo- 32 Romagnani S: Human TH1 and TH2 subsets: doubt no more. Immunol Today types. Tissue Antigens 2003, 61:80–84. 1991, 12:256–257. This study examined alleles at D6S265 to see if they influence susceptibility to JIA on different DQ-DR haplotypes and suggested the presence of additional suscep- 33 Prahalad S: Atopy, autoimmunity, and the TH1/TH2 balance. J Pediatr 2000, tibility loci in the HLA class I region. 137:446–449. 15 Runstadler JA, Saila H, Savolainen A, et al.: Analysis of MHC region genetics 34 Heinzmann A, Jerkic SP, Ganter K, et al.: Association study of the IL13 variant • in Finnish patients with juvenile idiopathic arthritis: evidence for different lo- • Arg110Gln in atopic diseases and juvenile idiopathic arthritis. J Allergy Clin cus-specific effects in polyarticular vs pauciarticular subsets and a shared Immunol 2003, 112:735–739. DRB1 epitope. Genes Immun 2003, 4:326–335. Association study examining two phenotypes thought to be mutually exclusive. Al- This is a nice study that used both a case-control and a TDT design to evaluate lele predisposing to atopic/asthmatic diseases was significantly lower in patients several markers spanning the MHC. Provides evidence for additional susceptibility with JIA, adding further evidence to the divergent disease associations with loci for JIA in the HLA class I region. Th1/Th2 immune responses. 16 Alsaeid KM, Haider MZ, al-Awadhi AM, et al.: Role of human leukocyte anti- 35 Ozen S, Bakkaloglu A, Yilmaz E, et al.: Mutations in the gene for familial Medi- gen DRB1*0307 and DRB1*0308 in susceptibility to juvenile rheumatoid terranean fever: do they predispose to inflammation? J Rheumatol 2003, arthritis. Clin Exp Rheumatol 2003, 21:399–402. 30:2014–2018. 17 Wedderburn LR, Patel A, Varsani H, Woo P: Divergence in the degree of 36 Alsaeid K, Haider MZ, Ayoub EM: Angiotensin converting enzyme gene in- clonal expansions in inflammatory T cell subpopulations mirrors HLA- sertion-deletion polymorphism is associated with juvenile rheumatoid arthritis. associated risk alleles in genetically and clinically distinct subtypes of child- J Rheumatol 2003, 30:2705–2709. hood arthritis. Int Immunol 2001, 13:1541–1550. 37 Becker KG, Barnes KC, Bright TJ, Wang SA: The genetic association data- 18 Ihle J, Fleckenstein B, Terreaux C, et al.: Differential peptide binding motif for • base. Nat Genet 2004, 36:431–432. three juvenile arthritis associated HLA-DQ molecules. Clin Exp Rheumatol This is a description of the genetic association database. Over 5900 records de- 2003, 21:257–262. scribing association studies in over 1600 genes are included. This will be a powerful resource for meta-analysis, because both positive and negative studies are 19 Rosen P, Thompson S, Glass D: Non-HLA gene polymorphisms in juvenile included. • rheumatoid arthritis. Clin Exp Rheumatol 2003, 21:650–656. A comprehensive review of non-HLA polymorphisms. Odds ratios calculated for 38 Lander E, Kruglyak L: Genetic dissection of complex traits: guidelines for each of the published association studies facilitate comparison of the magnitude of interpreting and reporting linkage results. Nat Genet 1995, 11:241–247. the association of different alleles. 39 John S, Hajeer A, Marlow A, et al.: Investigation of candidate disease suscep- 20 Miterski B, Drynda S, Boschow G, et al.: Complex genetic predisposition in tibility genes in rheumatoid arthritis: principles and strategies. J Rheumatol • adult and juvenile rheumatoid arthritis. BMC Genet 2004, 5:2. 1997, 24:199–201. 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Arthritis Rheum 2003, 48:1171–1176. 45 Knipp S, Feyen O, Ndagijimana J, Niehues T: Ex vivo apoptosis, CD95 and CD28 expression in T cells of children with juvenile idiopathic arthritis. Rheu- 28 Donn R, Alourfi Z, De Benedetti F, et al.: Mutation screening of the macro- matol Int 2003, 23:112–115. phage migration inhibitory factor gene: positive association of a functional polymorphism of macrophage migration inhibitory factor with juvenile idio- 46 De Benedetti F, Pignatti P, Biffi M, et al.: Increased expression of alpha(1,3)- pathic arthritis. Arthritis Rheum 2002, 46:2402–2409. fucosyltransferase-VII and P-selectin binding of synovial fluid T cells in juvenile idiopathic arthritis. 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49 Ronchezel MV, Hacbarth ET, Len CA, et al.: Low density neutrophils in pa- 55 Prahalad S, O’Brien E, Fraser AM, et al.: Familial aggregation of juvenile idio- tients with juvenile idiopathic arthritis. J Investig Allergol Clin Immunol 2003, pathic arthritis and type 1 diabetes. Arthritis Rheum 2003, 48(suppl 9):S102. 13:103–107. 56 Hugot JP, Chamaillard M, Zouali H, et al.: Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature 2001, 50 Moroldo MB, Chaudhari M, Shear ES, et al.: Juvenile rheumatoid arthritis af- 411:599–603. •• fected sib pairs: extent of clinical phenotype concordance. Arthritis Rheum 2004. In press. 57 Altshuler D, Hirschhorn JN, Klannemark M, et al.: The common PPARgamma The clinical phenotypes of the largest collection of JRA-affected sibpairs are de- Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. scribed in this paper. The phenotypes are also compared with a cohort of sporadic Nat Genet 2000, 26:76–80. JRA probands. 58 Van Eerdewegh P, Little RD, Dupuis J, et al.: Association of the ADAM33 51 Moroldo MB, Tague BL, Shear ES, et al.: Juvenile rheumatoid arthritis in af- gene with asthma and bronchial hyperresponsiveness. Nature 2002, fected sibpairs. Arthritis Rheum 1997, 40:1962–1966. 418:426–430. 59 52 Saila HM, Savolainen HA, Kotaniemi KM, et al.: Juvenile idiopathic arthritis in Peltekova VD, Wintle RF, Rubin LA, et al.: Functional variants of OCTN cation multicase families. Clin Exp Rheumatol 2001, 19:218–220. transporter genes are associated with Crohn disease. Nat Genet 2004, 36:471–475. 53 Saila H, Savolainen A, Kauppi M, et al.: Occurrence of chronic inflammatory 60 Corder EH, Basun H, Lannfelt L, et al.: Attenuation of apolipoprotein E Epsi- rheumatic diseases among parents of multiple offspring affected by juvenile lon4 allele gene dose in late age. Lancet 1996, 347:542. idiopathic arthritis. Clin Exp Rheumatol 2003, 21:263–265. 61 Bamshad M, Wooding SP: Signatures of natural selection in the human ge- 54 Prahalad S, Shear ES, Thompson SD, et al.: Increased prevalence of familial nome. Nat Rev Genet 2003, 4:99–111. EDITORIAL OVERVIEW Galectin-3 in osteoarthritis: when the fountain of youth doesn’t deliver its promises Pascal Reboul, Johanne Martel-Pelletier and Jean-Pierre Pelletier

Osteoarthritis Research Unit, Hôpital Notre-Dame, Centre hospitalier de and in most instances this is coincidental with aging, it l’Université de Montréal Montre´al, Que´bec, Canada may be asked if these changes, to some extent, may be Correspondence to Pascal Reboul, Osteoarthritis Research Unit, Hôpital related to molecular and/or structural changes of the joint Notre-Dame, Centre hospitalier de l’Université de Montréal, 1560, rue Sherbrooke Est, Montréal, Québec, Canada, H2L 4M1 tissues that can occur during the aging process. The Tel: 514 890 8000 ext. 28942; fax: 514 412 7583; alarming statistics on the aging that will occur in the e-mail: [email protected] world population during the next decade [7] remind us Current Opinion in Rheumatology 2004, 16:595–598 how important and urgent the need is to improve our knowledge of the etiogenesis of OA and to find a cure for © 2004 Lippincott Williams & Wilkins 1040–8711 this degenerative joint disease. Nevertheless, some progress in the understanding of the onset of OA has been made that was particularly related to the cartilage matrix In the last few decades, osteoarthritis (OA) research has breakdown. become a very exciting field of medical investigation. Ideas regarding the pathophysiology of this disease have moved from a wear and tear view to one of organ failure The alterations taking place within the cartilage extra- involving all of the major articular tissues [1••]. Today, cellular matrix are, in part, related to the action of a there is an understanding that the interaction among number of catabolic or oxidative factors, which have al- these tissues is not only responsible for maintaining the ready been extensively investigated [1••,8]. These fac- normal biology and function of the healthy joint, but also tors are believed to play an important role in the changes actively participates in the progressive structural changes in the biomechanical properties of cartilage and periar- taking place during the course of the disease. The tissues ticular soft tissues [9], which could contribute to disease involved include the cartilage, synovial membrane, sub- progression [10,11]. In addition, several changes, not pro- chondral bone, and other connective tissues, such as liga- teolytic in nature, have been described and may have ments and tendons [1••,2,3]. Therefore, it has become some significance in the appearance and/or progression obvious that OA is a disease of global organ failure. of OA [12••]. It has been hypothesized that the reexpression of molecules, normally present at the develop- The origin of the disease is wide-ranging and encom- mental stages, may also be a possible contributing factor passes mechanical, genetic, traumatic, and biochemical in OA [13]. In fact, molecules present in the early stages factors. There is a general consensus that the initial of the development of life, responsible for producing changes likely originate in the articular cartilage [2]. youth and beauty, may find themselves to be undesir- However, several recent findings suggested the involve- able or ineffective at rejuvenating the tissular and cellu- ment of subchondral bone, even in the early stages [4–6]. lar biology of diseased cartilage and chondrocytes later in In fact, there is still an ongoing debate as to whether life. Molecules, such as bone morphogenic proteins, col- these changes happen before or after those occurring at lagenase-3 (MMP-13), gene coding for wingless and the cartilage level. Moreover, because OA is of a multiple frizzled proteins, for example, respond to the healing etiogenesis, it may be that either cartilage or subchondral signal and are found at a higher level on human OA bone or both may be involved in the initiation of this cartilage [14–16]. Another potential factor, galectin-3, disease. Conversely, the role of synovial inflammation as may be of particular interest because this protein may a risk factor for disease progression seems to be more induce changes both in chondrocyte metabolism and in widely accepted, and substantial evidence from a num- the cartilage matrix/chondrocyte relation. ber of clinical studies supports this concept [3]. Galectin-3 is an animal lectin belonging to the galectin Osteoarthritis, a multifactorial disease in origin, is the superfamily. Galectins, like other lectins, recognize a result of an imbalance between the anabolic and cata- glycosylation structure with neither enzymatic nor im- bolic metabolism of articular joint tissue. Because carti- mune activity [17]. Galectins recognize lactose/galactose lage is one of the primary organ failures in this disease, residues by their carbohydrate recognition domain. 595 596 Osteoarthritis

Among all galectins cloned to date, galectin-3 is the tion of reducing sugar such as glucose with free amino unique protein having the particularity of possessing an acid in lysine and arginine residues, and the subsequent N-terminal domain sharing a high degree of homology covalent liaison between the sugar and amino acid leads with collagen (Fig. 1). This domain is involved in the to the formation of AGEs [12••]. However, other path- multimerization of galectin-3. The galectin-3 gene was ways, such as oxidative stress [33], could possibly add to mapped on human chromosome 14 (14q21-22) and codes the formation of the AGEs. All proteins are prone to for a soluble protein of 30 kDa [18,19]. Galectins includ- AGE formation, and AGEs tend to accumulate more pre- ing galectin-3 are found in a large number of tissues [20]. dominantly in proteins with long half-lives. Data from the literature also suggest that galectin-3, depending on its subcellular localization, is involved in a Studies have reported the presence of an increased level variety of processes such as RNA splicing [21] differen- of AGEs in aging cartilage, mainly in collagens [12••,35– tiation [22], apoptosis [23–25], and cell–cell or cell– 37]. The presence of AGEs in collagen is most likely matrix interactions [26–29]. related to its slow turnover in cartilage. Increased levels of AGEs were also found in OA cartilage [38], and this elevated level could possibly be associated with a greater We have recently demonstrated that in OA chondro- risk of developing the disease [12••]. Indeed, urinary cytes, the level of galectin-3 expression is increased [30]. secretion of AGEs (pentosidine) was found to be higher Moreover, in these cells, this protein is also localized at in OA patients and appears to be a good predictor of the the cell surface. This is a new finding for articular carti- presence of the disease [39]. lage chondrocytes because in hypertrophic chondrocytes where galectin-3 is highly expressed, it is located only at There are many hypotheses on the potential mecha- the intracellular level [31••]. The localization of galec- nisms by which AGEs could lead to the development of tin-3 at the chondrocyte surface is correlated with the OA. Among these hypotheses, there is one concerning presence of integrin-␤1expression, the level of which is the accumulation of AGEs in cartilage collagens possibly also increased in OA cartilage [32]. This preferential sur- being responsible for changes in the mechanical proper- face localization could correlate with a cell metabolic ties of the tissue [9–11]. Indeed, an increase in cartilage state where galectin-3 acts as an interface between the stiffness and fragility because of the collagen network extracellular matrix and the cells. Indeed, although correlates with AGE levels [11]. The AGE cross-linking speculative, it is possible that galectin-3 competes for of collagen increases the susceptibility of the collagen different ligands localized either at the chondrocyte sur- network to mechanical damage [40]. In diabetic patients, face or in the extracellular matrix leading to chondrocyte this phenomenon is also believed to be an important risk adhesion. Among potential ligands for galectin-3, there factor for the development of OA, more particularly, are the advanced glycation end products (AGEs), which where the accumulation of AGEs in tissues is more pro- are increased both in the aging process and in OA carti- nounced [41]. AGEs may also influence the metabolism lage [33,34]. of chondrocyte, at least in part, through their binding to specific cellular receptors (Fig. 2) [42]. In addition to Recent work suggests that AGEs may be responsible for galectin-3, two other AGE receptors, AGE-R1and AGE- the abnormal regulation of the OA chondrocyte metabo- R2, have been identified in chondrocytes whereas the lism and for the remodeling of the cartilage matrix other specific one, RAGE, was absent (P. Reboul, un- [12••]. Formation of AGEs results from the condensa- published observation, June 2002). The presence of AGE receptors on chondrocytes is important because it has been shown that the AGE/receptor complex is an Figure 1. Fourteen mammalian galectins were cloned efficient means to clear off AGEs in other tissues, such as the kidney [42]. Therefore, the presence of this complex at the chondrocyte surface could represent an adaptation of OA chondrocytes to reduce AGE levels in the diseased cartilage. The novel localization of galectin-3 in OA chondrocytes might also play a role in the regulation of adhesive molecules in the extracellular matrix. Galectin-3 could interact with several ligands, such as fibronectin and integrin, present either in the extracellular matrix or at the cell

Comparison of the amino acid sequences of galectins suggests a classification surface, and may lead to a regulation in the adhesion of into 3 subfamilies: the prototype group (galectin-1, -2, -5, -7, -10, -11 and -13), chondrocytes and modification of internal signals. An- the tandem repeat group (galectin-4, -6, -8 and -12), and the chimera group other part of the regulation of the adhesiveness mediated (galectin-3). (Modified from Barondes et al.: J Biol Chem 1994;269:20807– 20810; reproduced with permission.) by galectin-3 is the susceptibility of its N-terminal domain to cleavage by matrix metalloproteinases (MMPs), Editorial: Galectin-3 in OA Reboul et al. 597

Figure 2. Summary of galectin-3 functions in the joint Free galectin-3 may act as a chemoattractant for leukocytes. At the chondrocyte surface, galectin-3 could be an advanced glycation end products–receptor or an adhesive molecule (cell–cell or cell–matrix interaction, or both), whereas galectin-3 could play a role as an antiapoptotic molecule at the chondrocyte intracellular level. Moreover, extracellular galectin-3 may be cleaved by matrix metalloproteinases (MMPs), such as MMP-2, -9 and -13, which may modify its roles.

in rheumatoid arthritic joints was associated with disease particularly by MMP-2, MMP-9, and MMP-13 [30,43]. activity and joint destruction [44••]. The galectin-3 N-terminal domain allows it to multimer- ized, but when this domain was cleaved, galectin-3 was It could be hypothesized that the increased expression of no longer able to bridge cells or bridge cells with the galectin-3 in OA could be predominantly considered as a nearest extracellular matrix molecules. Furthermore, the means by which the cartilage, and perhaps other OA joint cleavage of galectin-3 could reduce its functionality by tissues, rejuvenates itself through the reexpression of decreasing the clearance of AGEs. factors involved in the early development of the joint structure. Obviously this propensity to repair is not effec- The intracellular role of galectin-3 is not yet well defined tive, at least not to expectations. In-depth investigations in chondrocytes. In other cells, galectin-3 has been dem- into the entire phenomenon allow greater perspective of onstrated to be a very potent antiapoptotic factor, its the interesting differences between the developmental action being somewhat similar to Bcl-2 [23]. As sug- and the adult period in the tissular environment. There- gested by Colnot et al. [31••], galectin-3 could also con- fore, continued studies may help provide important in- tribute to chondrocyte survival. Therefore, in OA, galec- formation for the better understanding of the disease tin-3, along with other factors, could be responsible for process and the failure of OA cartilage in properly repair- the relatively low level of chondrocyte apoptosis found in ing functional tissue with similar biochemical composi- vivo in this disease. tion and biomechanical properties when compared with normal. Finally, recent findings by Ohshima et al. [44••] indicate, in inflamed OA synovia, the presence of an increased In summary, the most recent findings in the pathophysi- level of galectin-3 at the synovial lining cell. This study ology of OA bring an interesting insight into the ways by showed that the galectin-3 median concentration was which the diseased joint tissues and cells attempt to ad- about 25 ng/mL in serum from OA patients, but it just to their changing environment. To protect and repair reached 80 ng/mL in synovial fluids. Although there is these tissues, some of those changes, such as the ones some variability in their results, it clearly suggests that an described in the present review, are still under explora- increased local production of galectin-3 was performed in tion. We definitely need to better understand the rem- the OA joint. Furthermore, the authors emphasized that edies Mother Nature is using to treat OA if we hope to galectin-3 was noticeably present during inflammatory develop new strategies aimed at creating an effective phases of OA where leukocyte infiltration was present. disease-modifying treatment. These results agree with data reporting an association with the role of galectin-3 in inflammation and its che- Acknowledgments moattractive properties for monocytes and macrophages The authors thank Heather Yampolsky for her invaluable secretarial assistance. [45], hence an induced production of proinflammatory Pascal Reboul is a recipient of a New Investigator Award from the Canadian Ar- cytokines in the joint. These findings correlated well thritis Society. Some data presented in the manuscript came from studies supported by grants from the Canadian Arthritis Society (TAS 01/0033) and the Ca- with the ones indicating that the presence of galectin-3 nadian Institute of Health and Research (MOP-64401). 598 Osteoarthritis

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Purpose of review Introduction Accumulating evidence indicates that every tissue contains Recent advances in our understanding of the biology of stem cells. Our understanding of the biology of stem cells stem cells have attracted the attention of the entire bio- reveals that these cell populations have a critical role in the medical research community [1–4]. It is rarely seen that homeostasis and repair of tissues. Besides the local stem cell basic scientists and clinicians are moving in concert, try- niches, additional compartments in the body such as the bone ing to bridge the gap between “bench and bedside,” and marrow may serve as reservoirs for stem cell populations. On to unravel the secrets of stem cell populations in devel- more extensive tissue damage, and guided by local repair opment, growth, homeostasis, and disease. Adult stem responses, “reparative” cell populations are mobilized from cells are found in most adult tissues. It has been sug- more distant stem cell reservoirs and migrate to the site of gested that they can participate in tissue homeostasis and injury, thereby contributing in many aspects of local tissue in many steps of tissue reparative responses. repair. Recent findings Adult stem cells have more restricted potential than em- Osteoarthritis has long been regarded as an imbalance bryonic stem cells, although recent findings have re- between destructive and reparative processes. The lack of vealed the existence of adult marrow-derived pluripotent repair of the weight-bearing articular cartilage and the stem cells with a differentiation potential close to em- associated subchondral bone changes are considered of bryonic stem cells [5]. Because this paper deals with the critical importance in the progression of the disease. Recent potential role of stem cells in osteoarthritis (OA), and findings indicate a depletion and/or functional alteration of thus in joint or joint-associated tissues, the focus of this mesenchymal stem cell populations in osteoarthritis. These review will be on adult mesenchymal stem cells (MSCs). preliminary data suggest that in joint diseases such as Indeed, MSCs have the capacity to differentiate into osteoarthritis, it is of importance to investigate further the cells of the mesodermal lineages such as cartilage, bone, involvement of the stem cell pool in the mechanisms fat, and muscle. MSCs have typically been derived from contributing to joint homeostasis and driving disease bone marrow [6,7]. However, reports have described the progression. presence of MSCs in several other tissues, including fat Summary and synovial membrane [8,9], making these cell popula- In view of the emerging body of evidence pointing to a tions, by virtue of their presence in the joint environ- potential therapeutic utility of stem cell technology, it is not ment, relevant to the role and potential therapeutic use surprising that local delivery of mesenchymal stem cells has of MSCs in joint diseases such as OA. been explored as a therapeutic approach in animal models of Characterization of mesenchymal osteoarthritis. stem cells There has been accumulating evidence that the prolif- Keywords erative activity and osteogenic potential of bone marrow- mesenchymal stem cells, cartilage, bone, joint homeostasis, derived MSCs diminish with age [10–12]. Regardless of tissue repair an age-associated decline in stem cell number and function, the concept that MSCs may be deficient or may Curr Opin Rheumatol 16:599–603. © 2004 Lippincott Williams & Wilkins. behave differently in chronic diseases has been supported by the findings that MSCs from osteoporotic pa- Department of Rheumatology, University Hospitals KULeuven, Leuven, Belgium tients have significantly reduced osteogenic activity [13]. Correspondence to Frank P. Luyten, MD, PhD, Department of Rheumatology, In contrast, cultures of bone marrow MSCs from OA University Hospitals KULeuven, Herestraat 49, B-3000 Leuven, Belgium Tel: 32 16 346341; fax: 32 16 346343; e-mail: [email protected] patients did not show altered in vitro behavior when compared with normal individuals [14]. Recently, a more Current Opinion in Rheumatology 2004, 16:599–603 comprehensive study has reported a significant reduction Abbreviations in the proliferation rate of OA-derived bone marrow ACI autologous chondrocyte implantation MSCs, and in their chondrogenic and adipogenic differ- MSCs mesenchymal stem cells entiation in vitro [15]. Interestingly, there was no differ- OA osteoarthritis RA rheumatoid arthritis ence in osteogenic activity. These findings were independent of the site of harvest and appeared to be disease © 2004 Lippincott Williams & Wilkins 1040–8711 and not age related. 599 600 Osteoarthritis

Contrasting data have been reported on the effect of modifications, such as protein phosphorylation, may be joint inflammation on MSC populations. Synovial MSCs, more informative. defined by morphologic appearance and characterized by the expression of bone morphogenetic protein receptor In vivo functional analysis of mesenchymal Ia (Alk3), have been demonstrated in rheumatoid arthri- stem cells tis (RA) synovium but not synovium obtained from pa- Very little has been reported on the in vivo biology of tients with OA [16]. More important, the same authors MSCs in diseased tissues such as the joints in OA and detected similar cells in the initial stages of collagen- the role of the microenvironment on their in vivo biologic induced arthritis, a well-characterized mouse model of behavior. There is little doubt that the functional analy- RA [17]. The number of presumed MSCs is increased on sis of MSCs derived from the different tissue sources of passaging in in vitro cultures of adherent synovial cells. the joint, and studied in a relevant environment mim- More MSC-like cells are found in RA cell cultures than icking early or advanced disease, will be of great impor- compared with OA-derived cultures. Interestingly, it ap- tance. These tissue-derived MSCs may be of local origin, pears that the number of MSCs characterized by in vitro and thus may be considered “niche” MSCs. However, multilineage potential is larger in OA than in RA synovial some cells of the tissue stem cell pool may have been fluid [18•]. recruited from a distance, and they may have very different functions linked to the severity of the disease These preliminary data are certainly provocative and state and its progression. Manipulating the stem cell provide a strong impetus to investigate further the role of compartment and thereby modulating and possibly slow- MSCs in OA. Some questions remain regarding the re- ing down disease progression in an in vivo model may producibility of these findings. More important, the re- then be the proof-of-principle concept to convince the ports solely demonstrate that, in OA, MSCs respond dif- scientific community that stem cells are a therapeutic ferently to specific in vitro conditions, such as in the target in a disease such as OA. presence of fetal bovine serum. The issue becomes more complex, because the data indicate that not only bone Assessing the functions of the stem cell pool appears to marrow MSCs may be of importance in OA, but synovial be more complex. Stem cells, by local activation or re- membrane-derived MSCs [9,19•], MSCs derived from cruitment from a distance, may be involved in the res- the infrapatellar fat pad [20], and even articular cartilage- toration of tissue homeostasis. Some examples are the derived progenitor cell populations [21•,22,23,24•] may low-frequency replacement of hepatocytes by bone mar- as well. Therefore, we are beginning to address the ques- row-derived stem cells, even in the absence of liver in- tion if indeed in OA there is an altered stem cell com- jury [26]. There is sufficient proof of principle in the partment in OA, and if so, whether this is associated with contribution of stem cells to local tissue repair, as seen in the development and progression of the disease. The models of skeletal muscle repair [19•,27] and cardiac characterization of the stem cell compartment in OA re- muscle repair [28,29]. These regulatory and repair func- quires a systematic and careful analysis of the stem cell tions may be mediated by an autocrine mechanism (ie, pool involved. This includes the study of the presence of the direct contribution to the differentiated functional cell surface markers on freshly obtained MSC popula- cell pool). However, a paracrine mechanism such as re- tions, as well as the distribution of these cells and asso- leasing specific regulatory instructions to the microenvi- ciated markers in the tissue compartments. For instance, ronment, or even an endocrine mechanism, may play a it has been recently reported that the synovium of end- role. The release of specific chemokines from injured stage osteoarthritic joints contains subpopulations (3 to liver can recruit distinct stem cell populations to the site 10%) of adherent cells expressing triplicate combinations of injury [30]. Most interesting, and of relevance to ar- of cell surface markers associated with the MSC pheno- thritic disease and OA, is the potential immunoregulato- type, such as CD9/CD44/CD54/CD90/CD166 [25•]. On ry role of stem cell populations [31–33]. This surprising cultivation and expansion, the relative amount of these functional role may be mediated by the release of spe- subpopulations markedly increased values up to 50%, or cific signaling molecules, such as transforming growth by a factor of three to seven. These findings also em- factor-␤ and hepatocyte growth factor by the MSC cell phasize the importance of the characterization of cell population, which points again toward the potential criti- products for therapeutic use. cal paracrine functions of the stem cell populations in vivo. The biggest challenge is the link of a marker profile to a predictable function and behavior in the microenviron- In OA, the data with respect to functional characteristics ment of the diseased joint. Currently available cell sur- of stem cell populations are still preliminary. MSCs pre- face markers may not be sufficient to discriminate be- pared from bone marrow taken from patients undergoing tween physiology and disease. The expression of specific joint replacement for OA indicated a reduced prolifera- intracellular genes, such as transcriptional regulators, or tive activity, and reduced chondrogenic and adipogenic the production of secreted proteins and posttranslational differentiation in vitro, independent of age and the site Mesenchymal stem cells in osteoarthritis Luyten 601 of harvest [15]. These findings suggest a possible asso- the expansion process is a major limitation and results in ciation, but do not indicate a causal relation. Indeed, this an inconsistent cellular product [42]. Interestingly, a altered stem cell behavior may be a secondary event, and more careful analysis and characterization of expanded a result of a prolonged disease progression, or may even cell populations convincingly demonstrates the presence be caused by the long-term intake of nonsteroidal anti- of multipotent stem cells in these expanded cell popu- inflammatory drugs. In addition, activation of stem cells lations, and indicates that their relative amount will de- at specific sites in the joint may contribute to the phe- pend on the culture conditions [21•,22,23]. In addition, it notype of OA. Periosteal and entheseal cartilage and is important to remember that ACI is performed for car- bone formation leading to the formation of osteophytes tilage defects in an otherwise healthy joint. Therefore, can be considered a repair response to stabilize the dam- the potential role and success of ACI in an OA joint is aged joint. Signals from the stressed or damaged joint unclear, as is the impact of the influence of this proce- leading to osteophytosis include proinflammatory cyto- dure on the development and progression of OA. The kines and morphogens/growth factors such as bone mor- variability of the outcome of the ACI procedure is influ- phogenetic proteins and/or transforming growth factors enced by several factors, including the quality of the cell [34]. It is remarkable that such repair efforts are appar- population and surgical skill, but also by the joint micro- ently more successful than effective articular cartilage environment. Loss of joint homeostasis and OA are cre- repair by endogenous stem cells in the cartilage. ating a very different microenvironment, and thus will influence cell engraftment and tissue differentiation. Therapeutic use of mesenchymal Nonetheless, retrospective data indicate a potential for stem cells long-term tissue repair using these cell-based approaches Several therapeutic opportunities for using the adult in the joint environment [38,39]. Careful, prospective, stem cell pool can be recognized. Most important, long-term follow-up is required to confirm and extend mechanistic insights are required to manipulate the stem these findings. MSCs are easy to isolate, expandable, and cell pool in vivo, involving enhanced and appropriate have a broad differentiation potential, and thus are at- stem cell activation, stem cell recruitment, stem cell tractive for their use in cell-based therapies as a potential homing, and in situ stem cell differentiation. A better replacement for expanded chondrocytes in an ACI pro- understanding of the stem cell pool leads to the isolation cedure. They can be isolated from multiple sources, in- and expansion of well-defined multipotent stem cells ex cluding bone marrow, fat, or synovium. Indeed, the rou- vivo, and their use in tissue repair by relatively simple tine use of needle arthroscopy allows us to obtain means, including local injection or by more complex synovial biopsies easily and prepare synovial-derived methods such as the generation of tissue replacement MSCs for joint tissue repair. Evidence was reported on parts and subsequent local implantation. the multipotency of synovial-derived MSCs in vitro and in vivo [9,19•,43•,44•]. Additional data will have to be Very little is known on the mechanisms of action of the generated to demonstrate the potential superiority of stem cell pool in arthritic diseases such as OA. Circum- these local “niche”-derived stem cells over more “ge- stantial data have indicated the recruitment of stem cells neric” bone marrow-derived stromal cells for specific with specific characteristics during the early phase of clinical applications, such as their use in OA joint repair. inflammatory destructive joint disease such as RA There are indications in other applications that niche- [17,35,36]. However, the potential roles of these stem derived stem cells may indeed have advantages [45,46]. cell populations are far from clear. This new field of The use of resident stem cells, properly responding to research requires more comprehensive approaches, in- the environmental signals, may be an important factor for cluding genetic models allowing stem cell tracking, in their successful therapeutic use. situ identification of the stem cell populations, and mi- crodissection technology. The proper choice of the source of MSCs is not trivial. It Treatments with cell-based products are reaching the has been reported that under specific conditions, the clinical arena, with some success. In the field of joint chondrogenic potential of bone marrow-derived MSCs surface repair, autologous chondrocyte implantation was superior over adipose-derived cells [47]. In addition, (ACI), as a promising treatment for deep symptomatic the in vitro behavior may not necessarily reflect their in cartilage defects, is based on mostly retrospective studies vivo biology, as was recently demonstrated using syno- [37–39]. Very recent prospective studies confirm the vial-derived MSCs [43•]. Some authors have advocated good clinical outcome of ACI to some extent, but posi- the use of MSCs as a platform of overexpressing growth tioning this treatment versus other standard treatments factors such as bone morphogenetic protein-2 for the re- such as microfracture and mosaicplasty is unclear [40,41]. pair of local cartilage defects [48]. Although apparently However, there is an important lack of understanding of fairly successful in repairing cartilage lesions, the associ- the repair in this application. In addition, dedifferentia- ated effects of these growth factors on neighboring cells tion of the articular cartilage-derived cells resulting from populations, resulting in side effects or “unforeseen 602 Osteoarthritis events” such as osteophyte formation, may limit the 6 Friedenstein AJ, Piatetzky–Shapiro II, Petrakova KV: Osteogenesis in trans- plants of bone marrow cells. J Embryol Exp Morphol 1966, 16:381–390. value of this approach. 7 Pittenger MF, Mackay AM, Beck SC, et al.: Multilineage potential of adult human mesenchymal stem cells. Science 1999, 284:143–147. Regardless of the origin of the stem cell populations, a 8 Zuk PA, Zhu M, Mizuno H, et al.: Multilineage cells from human adipose tissue: remarkable potential application was recently reported in implications for cell-based therapies. Tissue Eng 2001, 7:211–228. a large animal model of OA [49••]. OA-like disease was 9 De Bari C, Dell’Accio F, Tylzanowski P, et al.: Multipotent mesenchymal stem cells from adult human synovial membrane. Arthritis Rheum 2001, 44:1928– induced by medial meniscectomy and resection of the 1942. anterior cruciate ligament in the knee joint of goats. Lo- 10 Oreffo RO, Bord S, Triffitt JT: Skeletal progenitor cells and ageing human cal delivery of labeled adult stem cells, isolated from populations. Clin Sci (Lond) 1998, 94:549–555. bone marrow, to injured joints resulted in engraftment in 11 Majors AK, Boehm CA, Nitto H, et al.: Characterization of human bone mar- meniscus, fat pad, and synovium. This led to the regen- row stromal cells with respect to osteoblastic differentiation. J Orthop Res 1997, 15:546–557. eration of a meniscallike tissue and retardation of tissue 12 Quarto R, Thomas D, Liang CT: Bone progenitor cell deficits and the age- destruction, particularly in the articular surface of in this associated decline in bone repair capacity. Calcif Tissue Int 1995, 56:123– model. It is noteworthy that no stem cells were engrafted 129. in the articular cartilage. These data indicate that, be- 13 Rodriguez JP, Garat S, Gajardo H, et al.: Abnormal osteogenesis in osteopo- cause OA is very often a local disease, restricted to one or rotic patients is reflected by altered mesenchymal stem cells dynamics. J Cell Biochem 1999, 75:414–423. a few large weight-bearing joints, there are opportunities 14 Oreffo RO, Bennett A, Carr AJ, et al.: Patients with primary osteoarthritis for these local cell-based treatments. In addition, the show no change with ageing in the number of osteogenic precursors. Scand engrafted stem cells may also be used to modulate spe- J Rheumatol 1998, 27:415–424. cific signaling pathways locally, thereby contributing by 15 Murphy JM, Dixon K, Beck S, et al.: Reduced chondrogenic and adipogenic activity of mesenchymal stem cells from patients with advanced osteoarthritis. a paracrine mechanism to more successful tissue repair Arthritis Rheum 2002, 46:704–713. and prevention of disease development [50]. 16 Marinova–Mutafchieva L, Taylor P, Funa K, et al.: Mesenchymal cells expressing bone morphogenetic protein receptors are present in the rheumatoid ar- Conclusion thritis joint. Arthritis Rheum 2000, 43:2046–2055. OA is a common disease and is associated with the loss of 17 Marinova–Mutafchieva L, Williams RO, Funa K, et al.: Inflammation is preceded by tumor necrosis factor-dependent infiltration of mesenchymal cells in homeostasis of the joint tissues, particularly the articu- experimental arthritis. Arthritis Rheum 2002, 46:507–513. lar cartilage and underlying bone. The insufficient re- 18 Jones EA, English A, Henshaw, et al.: Enumeration and phenotypic charac- parative response of articular cartilage resulting from a • terization of synovial fluid multipotential mesenchymal progenitor cells in inflammatory and degenerative arthritis. Arthritis Rheum 2004, 50:817–827. reduction in cell number, and the loss of phenotypic This paper demonstrates careful analysis and characterization of MSCs in synovial stability, are major components contributing to disease fluids of different patient populations. progression. Local activation, recruitment, and/or local 19 De Bari C, Dell’Accio F, Vandenabeele F, et al.: Skeletal muscle repair by • adult human mesenchymal stem cells from synovial membrane. J Cell Biol delivery of the appropriate stem cell populations are cur- 2003, 160:909–918. rently opportunities in the search for new therapeutic Experimental data demonstrate the in vivo myogenic potential of synovial-derived approaches contributing to the restoration of joint ho- MSCs in animal models of muscle damage and disease. 20 Wickham MQ, Erickson GR, Gimble JM, et al.: Multipotent stromal cells de- meostasis and repair. Understanding the mechanisms of rived from the infrapatellar fat pad of the knee. Clin Orthop 2003, 196–212. action of these stem cell-based approaches is critical in 21 Dell’Accio F, De Bari C, Luyten FP: Microenvironment and phenotypic stabil- their development toward clinical applications. Using • ity specify tissue formation by human articular cartilage-derived cells in vivo. the stem cells as a platform for local gene delivery may Exp Cell Res 2003, 287:16–27. This report provides in vivo evidence of the crucial role of microenvironmental be a promising treatment approach for the future. In the signals on cell plasticity and behavior. long term, stem cell technology will allow us to engineer 22 Barbero A, Ploegert S, Heberer M, et al.: Plasticity of clonal populations of an array of musculoskeletal substitutes, with the biologic dedifferentiated adult human articular chondrocytes. Arthritis Rheum 2003, prosthesis as a dream. 48:1315–1325. 23 Tallheden T, Dennis JE, Lennon DP, et al.: Phenotypic plasticity of human articular chondrocytes. J Bone Joint Surg Am 2003, 85A(suppl 2):93–100. References and recommended reading 24 Dowthwaite GP, Bishop JC, Redman SN, et al.: The surface of articular car- Papers of particular interest, published within the annual period of review, • tilage contains a progenitor cell population. J Cell Sci 2004, 117:889–897. are highlighted as: This is an excellent paper on the characterization of articular cartilage-derived stem • Of special interest cells. •• Of outstanding interest 25 Fickert S, Fiedler J, Brenner RE: Identification, quantification and isolation of • mesenchymal progenitor cells from osteoarthritic synovium by fluorescence 1 Weissman IL: Translating stem and progenitor cell biology to the clinic: bar- automated cell sorting. Osteoarthritis Cartilage 2003, 11:790–800. riers and opportunities. Science 2000, 287:1442–1446. This is a comprehensive analysis of synovium-derived MSCs using established cell surface markers in patients with end-stage OA. 2 Korbling M, Estrov Z: Adult stem cells for tissue repair—a new therapeutic concept? N Engl J Med 2003, 349:570–582. 26 Theise ND, Badve S, Saxena R, et al.: Derivation of hepatocytes from bone marrow cells in mice after radiation-induced myeloablation. 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29 Jackson KA, Majka SM, Wang H, et al.: Regeneration of ischemic cardiac 41 Knutsen G, Engebretsen L, Ludvigsen TC, et al.: Autologous chondrocyte muscle and vascular endothelium by adult stem cells. J Clin Invest 2001, implantation compared with microfracture in the knee—a randomized trial. J 107:1395–1402. Bone Joint Surg Am 2004, 86:455–464.

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31 Di Nicola M, Carlo–Stella C, Magni M, et al.: Human bone marrow stromal 43 De Bari C, Dell’Accio F, Luyten FP: Failure of in vitro-differentiated mesen- cells suppress T-lymphocyte proliferation induced by cellular or nonspecific • chymal stem cells from the synovial membrane to form ectopic stable carti- mitogenic stimuli. Blood 2002, 99:3838–3843. lage in vivo. Arthritis Rheum 2004, 50:142–150. 32 Kuroiwa T, Kakishita E, Hamano T, et al.: Hepatocyte growth factor amelio- Data indicate differences in the in vitro and in vivo behavior of MSCs. These find- rates acute graft-versus-host disease and promotes hematopoietic function. J ings emphasize the importance of the characterization of MSC populations, includ- Clin Invest 2001, 107:1365–1373. ing their in vivo biology. Therapeutic use of stem cells in patients should be preceded by preclinical studies in models relevant to the therapeutic application. 33 Krampera M, Glennie S, Dyson J, et al.: Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their 44 Seto H, Kamekura S, Miura T, et al.: Distinct roles of Smad pathways and p38 cognate peptide. Blood 2003, 101:3722–3729. • pathways in cartilage-specific gene expression in synovial fibroblasts. J Clin Invest 2004, 113:718–726. 34 Scharstuhl A, Vitters EL, van der Kraan PM, et al: Reduction of osteophyte This paper presents very interesting findings with respect to the role of bone mor- formation and synovial thickening by adenoviral overexpression of transform- phogenetic signaling in chondrogenesis and stem cell differentiation. ing growth factor beta/bone morphogenetic protein inhibitors during experimental osteoarthritis. Arthritis Rheum 2003, 48:3442–3451. 45 Snyder EY, Park KI: Limitations in brain repair. Nat Med 2002, 8:928–930.

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Purpose of review Introduction Osteoarthritis has been considered a degenerative disease. Osteoarthritis is a common chronic joint disease. This However, recent evidence supports involvement of disease has been described as a noninflammatory degen- immunologic mechanisms in this pathophysiology: for example, erative one and it results from the imbalance between inflammation of synovial tissue is observed in osteoarthritis. In degradation and repair in the articular cartilage and sub- osteoarthritis, the proinflammatory cytokine interleukin-1, which chondral bone. Aging, genetic factors, and loading of me- is produced by activated synoviocytes and mononuclear cells chanical stress contribute to the imbalance. However, in and has catabolic effects on chondrocytes, is one of the most addition to these factors, the involvement of immuno- involved. The immune reaction would require driving antigens. logic mechanisms has been recently suggested. We re- This review describes autoantigens in osteoarthritis and view autoantigens recently reported in patients with os- discusses their roles in triggering and/or perpetuating synovitis teoarthritis (OA)and discuss the roles of autoimmunity and joint cartilage destruction in osteoarthritis. in this disease process. Recent findings Several autoantigens/autoantibodies have been reported in Involvement of immunologic mechanisms osteoarthritis, such as the cartilage intermediate layer protein. in osteoarthritis Furthermore, recent comprehensive proteomic surveillance has Genetic linkage revealed that comparable numbers of autoantigens were There is widespread agreement that OA is considered a detected in osteoarthritis and rheumatoid arthritis, and that heterogeneous disease. No genetic linkage has been some of them were recognized predominantly in osteoarthritis generally established in OA. However, linkages between rather than in rheumatoid arthritis. In addition, it was revealed HLA haplotypes and subgroups of OA have been re- that the cartilage intermediate layer protein immunization of ported. Wakitani et al. [1] reported that HLA-Cw4 was mice developed calcification of tendons, thus indicating that associated with generalized OA, and HLA-Cw1 and autoimmunity modulates functions of target molecules. Cw10 were negatively correlated with generalized GOA. Summary Merlotti et al. [2•] reported an association of HLA-B35- Osteoarthritis-specific autoantigens may drive chronic synovitis DQ1, B40-DQ1, and DR2-DQ1 with increased OA risk. and may thereby contribute to production of cytokines to Riyazi et al. [3•] reported that the HLA-DR2 allele was upregulate proteases, which lead to chondrocyte and cartilage more common in patients with interpharyngeal OA and damage. In addition, autoimmunity may damage joint that HLA-DR4 was negatively associated with interpha- components by modulating functions of the target molecules. ryngeal OA. Because HLAs are polymorphologic molecules that present antigenic peptides to T cells, these Keywords observations support involvement of immunologic path- osteoarthritis, autoantibody, autoantigens, synovitis ways at the onset of OA. Again, these linkage analyses were done by selecting subgroups of OA, and different Curr Opin Rheumatol 16:604–608. © 2004 Lippincott Williams & Wilkins. linkages were observed among the subgroups. Thus, involvement of immunologic mechanisms would be differ- Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan ent between the subgroups of OA.

Correspondence to Tomohiro Kato, MD, PhD, Division of Immunoregulation, Department of Bioregulation, Institute of Medical Science, St. Marianna University Synovitis in osteoarthritis School of Medicine, Sugao 2-16-1, Miyamae-ku, Kawasaki, Kanagawa 216-8512, Japan Chronic synovitis is generally observed in OA. Even Tel: 81 44 977 8111, ext. 4209; fax: +81 44 978 2036; e-mail: though synovitis in OA is milder than in rheumatoid [email protected] arthritis (RA), an infiltration of lymphocytes with acti- Current Opinion in Rheumatology 2004, 16:604–608 vated phenotypes was observed [4,5]. The synovitis in

Abbreviations OA has often been considered a secondary phenomenon in the joints. However, Saxne et al. [6•] recently reported CILP cartilage intermediate layer protein GPI glucose-6-phosphate isomerase that C-reactive protein serum increased in patients with OA osteoarthritis early stages of OA, without causing an increase in carti- RA rheumatoid arthritis TPI triose phosphate isomerase lage oligomeric protein. This indicates that inflammation is a component of the early events leading to the clinical © 2004 Lippincott Williams & Wilkins 1040–8711 stage of OA. Furthermore, the authors found oligoclonal 604 Neoantigens in osteoarthritic cartilage Kato et al. 605 accumulation of T cells and B cells in the inflamed sy- autoimmunity to the cartilage link protein [17]. How- novitis [7,8], indicating that antigen-specific immune re- ever, Austin et al. [18] reported that frequencies of hu- actions occur in OA synovitis. In addition, Oehler et al. moral immunity to cartilage link protein were not signifi- [9] reported four different basic patterns of synovial re- cantly different among RA patients, OA patients, or actions: hyperplasia, inflammatory, fibrotic, and detritus- normal individuals. rich synoviopathy. In the OA-inflamed synovium, the proinflammatory cytokines interleukin-1 and tumor ne- The G1 domain proteoglycan aggrecan crosis factor-␣ are produced by activated synovial cells Cellular immunity to the G1 domain proteoglycan aggre- and mononuclear cells. They were found to upregulate can is reported in RA [16]. Immunization of mice with matrix metalloprotease gene expression in chondrocytes the G1 domain produced progressive arthritis [19]. Cel- [10]. These cytokines may have pivotal roles in the deg- lular autoimmunity to the G1 domain has been detected radation of cartilage. in 45.8% of OA patients [14].

Autoantigen/autoantibodies in osteoarthritis As mentioned earlier, synovitis is an essential component Cartilage intermediate layer protein of OA from its early stages. In this regard, Jasin [11] Distribution of cartilage intermediate layer protein reported that OA cartilage tissue contains three times (CILP)is limited to the middle layer of cartilage, and the more IgM and IgG than normal cartilage tissues. This C-terminal half of the molecule is homologous to nucleo- indicates that antibodies are synthesized locally by the tide triphosphohydrolase [20,21]. The expression of cells infiltrating the inflamed joints. Furthermore, oligo- CILP is upregulated in the elderly [21] and in early-stage clonal accumulation of T cells and B cells suggests local OA patients. We previously demonstrated that about one production of Ig’s through antigen-specific immune re- tenth of patients tested positive for anti-CILP autoanti- actions [4,5]. Even though much remains to be known bodies in both RA and OA [22]. Furthermore, immuni- about the antigens that drive the synovitis in OA, it has zation of mice with human CILP produced chronic sy- been reported that autoantigens found in this disease novitis but not destruction of cartilage and bone [22]. could be the candidates for the synovitis-driving antigens. The following are reported autoantigens in OA. YKL-39 YKL-39 is a homologous protein to human chondrocyte Chondrocyte membrane protein (HC)gp-39. Sekine et al. [23] reported that the autoanti- In early studies, serum antibodies to chondrocyte mem- body to YKL-39 was detected in 8% of patients with RA, brane proteins were reported [12,13], but specific anti- and Tsuruha et al. [24] found that about 11% of patients gens have not been identified. tested positive for the autoantibody in both RA and OA. Furthermore, immunization of mice with YKL-39 caused Collagen II mild synovitis [25]. Collagen II is one of the major autoantigens in human and animal models of RA. Autoimmunity to collagen II Other joint-related antigens has also been reported in OA. Jasin [11] reported that Osteopontin, secreted mainly from chondrocytes, is sug- 50% of specimens from OA cartilage contained autoan- gested to be involved in the ossification and remodeling tibodies to collagen II, and that this was comparable with of bone, and in the regulation of cytokine profiles as a those found in RA (60%). They also reported that about T-helper 1 cytokine [26]. Sakata et al. [27] detected au- 90% of dogs with OA with spontaneous cruciate ligament toantibodies to osteopontin in both OA and RA. rupture had both anticollagen I and anticollagen II antibodies [14]. Moreover, Osborne et al. [15] reported an increase in anticollagen II antibodies in 26% of OA pa- Considering the genetic linkages between HLA and sub- tients and in 63% of traumatized horses. Anticollagen II groups of OA, the synovitis with infiltration of antigen- antibodies would be increased easily by destruction of specific T and B cells, and the production of cytokines, cartilage, and collagen II would be one of the autoanti- one could define as follows a possible pathway of the gens that drive self-perpetuating synovitis and chronic autoimmunity to the cartilage-related components that cartilage degradation in OA. Immunization of mice or contribute to the pathology of OA (Fig. 1). First, me- other animals with collagen II produces severe inflam- chanical stress produces microdamage of cartilage, which matory destructive arthritis (a well-known model of in- is usually repaired. However, when the microdamage re- flammatory arthritis of collagen-induced arthritis), which leases self-antigens, this elicits breakdown of immune is more comparable with RA than OA. tolerance to the antigens and leads to chronic synovitis, in which driving antigens are supplied as far as cartilage Cartilage link protein tissue exists. Activated synoviocytes and infiltrating Cellular autoimmunity to the cartilage link protein was monocytes produce cytokines like interleukin-1 and tu- detected in 34% of RA patients [16]. The same group mor necrosis factor-␣, which then upregulate matrix me- reported that 42.4% of OA patients possessed cellular talloproteases in chondrocytes. Finally, increased matrix 606 Osteoarthritis

Figure 1. Possible involvement of autoimmunity in the sively. We then carried out such experiments in which pathogenesis of osteoarthritis we evaluated OA-specific autoantigens in comparison with RA, using proteomics [28••]. Proteins were sepa- rated from cultured human articular chondrocytes by two-dimensional electrophoresis, and the autoantibodies from 20 OA and 20 RA serum samples were detected by Western blot analysis. Data revealed that 19 protein spots were recognized by the OA group but not by the RA group, whereas 11 spots were recognized only by RA serum samples. This indicates that the overall profile of autoimmunity in OA differs from that in RA. Autoimmu- nity in OA would be compatible with that of RA.

One such protein was triose phosphate isomerase (TPI), which was identified in our proteomic surveillance and mass finger-printing. By enzyme-linked immunosorbent assay and Western blot analysis, using recombinant human TPI, the IgG type anti-TPI autoantibodies were detected in 24.5% of sera as well as in 24.1% of synovial metalloproteases and other proteases digest cartilage ma- fluid from OA patients, but less than 6% was detected in trix and help release more antigens (Fig. 1, gray arrows). patients with RA or systemic lupus erythematosus. Thus, predominant recognition of TPI as an autoantigen in OA However, several points need to be clarified. First, some was confirmed. Furthermore, we identified another au- of the autoantigens described here give rise to severe toantigen, fibulin-4, a matrix protein produced from destructive arthritis, such as RA, when animals are im- chondrocytes, that was recognized in OA three times munized with them. Collagen II and the G1 domain of more frequently than in RA (Xiang Y, et al., manuscript proteoglycan aggrecans could be included in this cat- in preparation), confirming the existence of OA- egory. On the other hand, immunization of other auto- dominant autoimmunity. Interestingly, the autoimmu- antigens like YKL-39 and CILP produces chronic but nity to fibulin-4 may contribute to the OA pathophysi- only mild synovitis. Thus, the arthritic genesis of each of ology as described in Figure 1, because fibulin-4 is a the autoantigens is different. Autoantigens that produce component of cartilage. mild nondestructive arthritis appear to be suitable for OA-driving antigens. However, as observed in the case of However, the TPI finding suggests a new enigma. In- collagen-induced arthritis, some mouse strains are sensi- deed, TPI is a ubiquitous protein and a housekeeping tive whereas others are resistant to immunization of col- glycolytic enzyme that converts D-glyceraldehyde-3- lagen II. This reflects that the arthritic genesis of the phophate and dihydroxyacetone phosphate. Although autoantigens should be evaluated within the context of the anti-TPI autoantibodies are found in OA, it remains genetic backgrounds. This should also be applied to hu- unclear whether they play substantial roles in the devel- mans, and genetic backgrounds of individual patients opment of OA. Parenthetically, it is known that the with OA should be taken into account. autosomal recessive disease of TPI deficiency is characterized by chronic hemolytic anemia, neurologic distur- Second, the autoimmunity to these joint-related antigens bances, susceptibility to bacteria infection, and cardio- is detected more frequently in RA than in OA or, at most, myopathy [29,30]. The decreased production of ATP at nearly equal frequencies in these two diseases. This and the accumulation of dihydroxyacetone phosphate, supports the traditional viewpoint that autoimmunity to however, failed to explain the hemolytic anemia [31]. In the cartilage-related proteins in OA and RA is simply an chondrocytes, the energy production is mainly depen- epiphenomenon that reflects the severity of synovial in- dent on anaerobic metabolism [32]. Because the anaero- flammation. However, the range and/or severity of auto- bic condition needs greater amounts of glucose than the immunity does not always correlate with the degree of aerobic condition to produce the same level of energy, inflammation, even in autoimmune diseases. For in- interconversion from dihydroxyacetone phosphate to stance, myasthenia gravis, caused by antiacetylcholine D-glyceraldehyde-3-phophate by TPI could be of critical receptor antibodies, does not present apparent inflam- importance in these cells. In this context, the stressed matory signs. Furthermore, most of the reported autoan- condition of OA may increase the need for TPI. Accord- tigens in OA were first found in patients with RA and in ingly, we observed that the mRNA of TPI in cultured patients with OA thereafter. To our knowledge, few tri- chondrocytes was increased by the stimulation with in- als have been performed to find OA-specific autoanti- terleukin-1␤, one of the major proinflammatory cyto- gens or to search for autoantigens in OA comprehen- kines involved in OA. Thus, if the anti-TPI autoimmu- Neoantigens in osteoarthritic cartilage Kato et al. 607 nity inhibits enzymatic activity of TPI, this could result the C-terminal half of the molecule is homologous to in chondrocyte alterations. nucleotide triphosphohydrolase.

Alternatively, TPI as an antigen can be important in In addition, an interesting concept suggesting that auto- generating chronic inflammation in OA, even if this in- antibodies can compensate pathologic immune reactions flammation is milder than in RA. Recently, glucose-6- has been proposed. Wildbaum et al. [39••] suggested phosphate isomerase (GPI), a ubiquitously expressed that autoimmunity to proinflammatory mediators may re- protein and one of the glycolytic enzyme cascade, was strain, at some point, the consequence of self-destructing demonstrated to be a pathogenic autoantigen in a K/BxN immunity and may thus be beneficial. In the rat adju- murine arthritis model. Interestingly, the anti-GPI auto- vant-induced arthritis model, the authors evidenced that antibodies were detected in a subset of RA patients [33– the antitumor necrosis factor-␣ autoantibodies generated 35]. The reasons why the antibodies induce joint- during adjuvant-induced arthritis prevented exacerba- specific autoimmune disease to a ubiquitous cytoplasmic tion of adjuvant-induced arthritis in vivo. In OA, such enzyme could be explained by the following studies. beneficial autoimmunity has not yet been demonstrated. Maccioni et al. [36] generated anti-GPI monoclonal an- However, some candidates could play a role in that re- tibodies from spontaneously activated B cells in the lym- gard. For example, because osteopontin is a Th1 cyto- phoid organs of arthritic K/BxN mice and injected them kine, antiosteopontin antibodies may play a role in trying into healthy recipients. They found that pathogenicity of to balance Th1/Th2 in OA synovitis. an antibody depends on the ability to form antibody/GPI multimers by simultaneous recognition of different epi- In summary, although the inflammation in OA is much topes. Moreover, Matsumoto et al. [37] observed deposits less severe than in RA, autoimmune phenomena are ob- of GPI /anti-GPI and C3 on the lining of the articular served as frequently as in RA. Autoantigens are detected cavity and cartilage surface in both arthritic mice and more predominantly in patients with OA than in those human arthritic joints. In contrast with joints, kidney with RA, and cause mild, chronic arthritis in immunized glomeruli showed that C3 was not located with GPI– animals. The roles of autoantigens in OA include supply anti-GPI IgG complexes. Based on these phenomena, of antigens to synovitis, and pathologic or beneficial the authors speculated that GPI could be passively trans- modulation of functions of target molecules. Further ferred from the serum into synovial fluid and deposited studies are required to elucidate immunologic mecha- onto the surface of cartilage, which would start inflam- nisms in OA. mation. 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J Rheumatol •• mediators restrains the consequences of self-destructive immunity. Immunity 2002, 29:1459. 2003, 19:679. This article provides a novel concept of beneficial autoantibodies. The authors 25 Sakata M, Masuko–Hongo K, Tsuruha J, et al.: YKL-39, a human cartilage- demonstrated that antitumor necrosis factor-␣ autoantibodies generated during related protein, induces arthritis in mice. Clin Exp Rheumatol 2002, 20:343. adjuvant-induced arthritis prevents exacerbation of arthritis. Angiogenesis in osteoarthritis and spondylosis: successful repair with undesirable outcomes David A. Walsh

Purpose of review © 2004 Lippincott Williams & Wilkins 1040–8711 Osteoarthritis and spondylosis are frequently described as “wear-and-tear” arthritis, apparently contradicting modern management, which focuses on continuing and progressive Introduction exercise. Laboratory findings, including the growth of new Osteoarthritis describes a group of joint diseases of un- blood vessels, encourage comparisons with repair processes. known etiology. It is a major source of pain and disability This review aims to place recent evidence in the context of in humans as well as in many animal species, including previous work emphasizing the dynamic nature of tissues in horses and dogs. Diagnosis is based on clinical features of these conditions. pain and stiffness associated with joint crepitus, bony Recent findings swelling, and deformity. Radiologic changes include Synovitis has now become recognized as a common and joint space narrowing, subchondral sclerosis, and mar- important feature of osteoarthritis, and vascular growth is ginal osteophytes. Chronic low back pain is often asso- enhanced in osteoarthritic synovia when infiltrating ciated with similar radiologic change, spondylosis, with macrophages generate angiogenic factors. As the molecular osteoarthritis of the facet joints, marginal osteophytes at balance between angiogenic and antiangiogenic factors is the vertebral end plates, and disc space narrowing. disturbed, new blood vessels are permitted to grow into normally avascular structures, such as the articular cartilage Osteoarthritis and spondylosis are commonly described and intervertebral disc. Angiogenesis is a key factor in new using terms such as wear-and-tear arthritis, degenerative bone formation in osteophytes and at the osteochondral disease, joint failure, or aging. This biomechanical model junction, thereby contributing to radiologic disease has led to important and effective treatments, not the progression. Innervation of new blood vessels may contribute least of which is joint replacement surgery. However, for importantly to chronic pain. joints such as those in the spine, where surgery may be Summary less effective, labeling the condition as “wear and tear” Reconceptualizing osteoarthritis and spondylosis as reparative or “degenerative” implies that, like a car, with continued processes provides a pathologic model consistent with current use over many years, symptoms and structural damage advice to exercise, when exercise facilitates repair. Repair will inevitably deteriorate. By contrast, inexorable de- does not, however, lead to normal tissue, and understanding cline is not an inevitable consequence of diagnosing os- the mechanisms by which changes in joint innervation may teoarthritis or spondylosis. Despite the outward appear- occur as a consequence of angiogenesis should lead to novel ance of bone swelling in the hands, hand pain is often not therapies that alleviate the common symptoms of these highly a major source of disability in nodal osteoarthritis. prevalent conditions. Chronic low back pain seems to cause a peak of disability in late working life, and may be less bothersome with Keywords advancing years thereafter. Back pain, neovascularization, pathologic, nerve growth, Contrary to these common descriptions of presumed eti- endochondral ossification, inflammation ology in osteoarthritis and spondylosis, clinical and radiologic appearances may perhaps be better described in Curr Opin Rheumatol 16:609–615. © 2004 Lippincott Williams & Wilkins. terms of “repair” rather than “wear and tear.” Inflamma- tion, fibrosis, and new bone formation are key compo-

Academic Rheumatology, University of Nottingham, UK nents of repair, and may explain pain, stiffness, osteophytosis, and subchondral sclerosis. Conceptualization of Correspondence to David A. Walsh, Academic Rheumatology, University of Nottingham, Clinical Sciences Building, City Hospital, Hucknall Road, Nottingham these processes as active and reparative rather than pas- NG5 1PB, UK sive and degenerative is consistent with therapeutic ad- Tel: 44 0 115 840 4727; fax: 44 0 115 840 4732; e-mail: [email protected] vice to exercise, whereby exercise facilitates the repair response. Conversely, prescription of exercise for wear- Current Opinion in Rheumatology 2004, 16:609–615 and-tear arthritis would be a little like advising someone Abbreviation with an old car to drive more miles if they wanted it to VEGF vascular endothelial growth factor last longer! 609 610 Osteoarthritis

A distinction must be drawn between repair, which leads would lead to intermittent vascular compression, with to functional but abnormal tissue, and resolution, in associated hypoxic reperfusion cycles. which the tissue returns to normality. Repair in the lumbar spine may lead to a strong back. Unfortunately, how- Avascularity of the articular cartilage appears to be main- ever, it may also lead to persistent pain and consequent tained through the production of antiangiogenic factors chronic disability and psychological distress. Radiologic by chondrocytes, and a cartilaginous matrix that that is severity in osteoarthritis and spondylosis displays poor hostile to vascular invasion [4,5]. Antiangiogenic factors correlation with clinical symptoms. This would be ex- derived from articular cartilage and chondrocytes have pected if the changes represent the outcome of repair, included tissue inhibitors of matrix metalloproteinases, whereas the process of repair contributes to symptoms. A thrombospondin, chondromodulin-1, and leukemia in- cutaneous laceration is painful while it repairs, but we hibitory factor [6–9]. would not expect a patient’s symptoms to correlate closely with the number or size of scars that they display on their skin. Nonetheless, understanding the processes Sensory nerves in synovium and subchondral bone com- that lead to radiologic change in osteoarthritis and spon- prise predominately perivascular unmyelinated C fibers, dylosis may help us develop disease-modifying treat- containing neuropeptides such as substance P and calci- ments that could reduce the burden of these conditions tonin gene-related peptide [10–13]. Angiogenesis and in the long term. innervation share common molecular mechanisms [14•,15]. It is not surprising, therefore, that avascular Angiogenesis, the formation of new blood vessels from a structures, such as articular cartilage and intervertebral preexisting vasculature, is a central component of the disc, are also normally not innervated. In other words, repair process. Recent advances in understanding the although periarticular structures may be highly inner- extent, nature, and mechanisms of angiogenesis in os- vated, the articular cartilage and intervertebral disc can- teoarthritis and spondylosis have shed new light on po- not normally be a source of pain. tential mechanisms of symptoms and disease progression. This review aims to place angiogenesis within the Localization of angiogenesis context of attempted repair within the joint. As a part of in osteoarthritis repair, angiogenesis may seem like a good idea, but, in Cartilage and bone the joint, may have the undesirable outcomes of per- Angiogenesis can be recognized most easily as vascular petuating pain and accelerating disease progression. invasion into avascular structures. Vascular breaching of the tidemark, with invasion of vessels into the more su- Vascularization and innervation of the perficial, noncalcified articular cartilage, is a recognized normal joint feature of osteoarthritis. Indeed, loss of tidemark integ- The normal synovial joints and intervertebral discs are rity contributes to well-established scoring systems for unusual in containing large, avascular structures (articu- the histologic severity of osteoarthritis [16]. lar cartilage and nucleus pulposus) that depend, for their metabolic support, on adjacent, highly vascular structures. Articular cartilage is normally apposed to the Vascular structures within articular cartilage or osteo- highly vascular normal synovium and may also gain phytes are derived through angiogenesis from blood ves- metabolic support in its deeper layers from the adjacent sels within the subchondral bone. Given the distance subchondral bone [1]. that a blood vessel must grow from the subchondral bone before it reaches the tidemark, increased vascularization The intervertebral disc has a unique structure compris- of the calcified cartilage would be expected to precede ing an inner nucleus pulposus and an outer annulus fi- loss of tidemark integrity in early osteoarthritis. Quanti- brosus surrounded by spinal ligaments. Metabolic sup- fication of vascular invasion in articular cartilage is not, port for the intervertebral disc derives largely from blood however, without technical difficulties. For a vessel vessels at the periphery of the annulus fibrosus, and within articular cartilage to be counted as new, it should partly through the central portion of the vertebral end not have been present in the predisease, normal joint. plates [2]. Blood vessels are found in the outer region of Blood vessels have been reported within the calcified the annulus fibrosus of radiologically normal discs, layer of articular cartilage near the osteochondral junc- whereas the inner annulus fibrosus and the nucleus tion even in “normal” specimens [16]. However, the pulposus are avascular [3]. boundary between normality and mild disease may be impossible to define in conditions as common as osteo- Avascularity of articular cartilage and the intervertebral arthritis. We cannot be certain, at present, whether in- disc may maintain structural integrity and permit high creasing vascularization of the calcified articular cartilage mechanical loading. If cartilage and discs were vascular- is an early feature of osteoarthritis or whether this rep- ized, mechanical loading of these compressible tissues resents normal variation. Angiogenesis in arthritis Walsh 611

Measurement of angiogenesis by quantifying the vascu- novitis [28•]. Synovia displaying increased macrophage larization of articular cartilage is further hampered by a infiltration also display increased indices of endothelial phenomenon of “moving goal posts.” New vessels at the cell proliferation and increased vascular densities. osteochondral junction are consistently associated with new bone formation, seen as osseous cuffs to the fibro- The extent to which inflammatory angiogenesis leads to vascular channels. Advancing ossification through the increased synovial vascular density is limited by concur- deep layers of articular cartilage obliterates the original rent vascular regression, as indicated by increased indi- osteochondral junction of the normal joint. In addition, ces of endothelial cell death [21]. Vascular turnover is the original “normal” tidemark can be impossible to lo- therefore much more rapid than would be expected from calize after reduplication along the advancing front of the relatively small changes observed in vascular densi- calcified articular cartilage. Similarly, early vasculariza- ties. High vascular turnover leads to a change in the tion of the osteophyte can be difficult to delimit. Vascu- quality of the synovial microvasculature. The immature lar invasion of the chondrophyte is associated with an vascular bed displays increased expression of integrin ␣ ␤ advancing edge of endochondral ossification and bone v 3, vascular endothelial growth factor (VEGF) and its remodeling, which obliterates the original bony joint receptors, and a sparsity of perivascular nerves [21,22,29]. margin [17]. In rheumatoid arthritis, vascular turnover leads to redistribution of vessels, with higher densities in the deeper Synovium synovial layers and vascular rarefaction at the synovial Vascular proliferation within the synovium is now a well- surface [30,31]. It is not yet known whether a similar recognized feature of inflammatory arthritis [18–20]. En- vascular redistribution occurs in inflamed osteoarthritic dothelial cell proliferation, markers of vascular immatu- synovia. rity, and altered vascular distribution and morphology all have been noted in synovia from patients with rheuma- Spine toid arthritis or psoriatic arthritis. Early evidence for sy- Delimiting normality and pathologic change is difficult novial angiogenesis or expression of angiogenic factors in in the spine, as it is in the knee. Indeed, statistically, osteoarthritis was derived from studies in which osteoar- disease of the intervertebral disc could be considered a thritic samples were used as control tissues [21–23]. Cau- normal, albeit undesirable, finding. During the develop- tion should be exercised before generalizing the findings ment of radiologic spondylosis, vascular invasion may from these studies to osteoarthritis as a whole. Osteoar- proceed into the nucleus pulposus with associated matrix thritis represents a cluster of diseases with some abnor- change and replacement of normal disc tissue. Vascular malities that may be shared with rheumatoid arthritis, invasion of the intervertebral disc may occur through the whereas others may be unique to osteoarthritis or rheu- vertebral end plate or through the annulus fibrosus matoid arthritis respectively. The premise behind using [13,32]. Vascular invasion of vertebral osteophytes prob- osteoarthritic tissues as controls is often that osteoarthri- ably occurs in much the same way as in other joints. tis is a “degenerative” rather than an “inflammatory” disease. As a consequence, osteoarthritic control samples Regulation of angiogenesis in in some studies may have been selected to exclude those osteoarthritis and spondylosis cases with evidence of inflammation, to ensure diagnos- Angiogenesis results from a change in the balance be- tic integrity [24]. When control tissues have been ob- tween pro- and antiangiogenic factors. Endothelial cell tained from cases postmortem, there is often no com- proliferation is extremely rare in normal resting tissues, ment on macroscopic osteoarthritic changes. Mild and the normal vasculature is maintained by vascular osteoarthritic changes are commonly observed postmor- survival factors that that are currently incompletely un- tem. Far from being insignificant, these may indicate derstood. It is likely that pericytes and matrix inter- early disease and give important insights into disease actions play important roles in this long-term vascular mechanisms. survival [33,34•]. Expression of angiogenic and antiangiogenic factors is low in resting tissues such as the syno- An inflammatory component is now increasingly recog- vium, and in the articular cartilage [20,35]. In the chronic nized in osteoarthritis [25–27]. Severe histologic evi- synovitis seen in osteoarthritis, there is concurrent up- dence of chronic synovitis is found in approximately one regulation of both pro- and antiangiogenic factors, with third of unselected cases undergoing total joint replace- the balance in favor of angiogenesis [20]. ment, even when clinical evidence of synovitis is absent [28•]. Early studies indicated that angiogenesis in syno- Regulators of angiogenesis in rheumatoid arthritis have via from some patients with osteoarthritis may be as in- been discussed in detail elsewhere [20,36]. It remains tense as in patients with rheumatoid arthritis [21]. Sub- possible that molecular regulation of angiogenesis in os- sequently, more detailed research confirmed that teoarthritis differs from that in other forms of synovitis, synovial angiogenesis is a feature of osteoarthritis that such as rheumatoid arthritis or psoriatic arthritis. This correlates with other histologic evidence of chronic sy- hypothesis remains to be tested in interventional studies, 612 Osteoarthritis and the key molecular mediators of angiogenesis have cates and becomes incomplete in osteoarthritis. This ab- not been categorically defined in any of these conditions. sence of barriers raises the possibility of transfer of factors from the synovium to the osteochondral junction Synovial angiogenesis in osteoarthritis correlates with during osteoarthritis. Osteochondral angiogenesis may histologic synovitis and, particularly, with macrophage be regulated, to some extent, by factors that are pro- infiltration in the synovium [28•]. Macrophages within duced within the synovium, although this hypothesis re- inflamed osteoarthritic synovium express a variety of mains to be formally tested. proangiogenic factors, including VEGF. Many angiogenic factors are also proinflammatory, and correlations Chondrocytes have been identified as major regulators of found between angiogenesis, inflammation, and factor angiogenesis during endochondral ossification in growing expression are not able to define precisely which factors long bones [47]. Transformation of chondrocytes to a are primarily important for angiogenesis within the in- hypertrophic phenotype is associated with the expres- flamed synovium. sion of angiogenic factors such as VEGF. Chondrocyte- derived angiogenic factors are believed to stimulate the Studies on synovial fluids have provided some evidence growth of new blood vessels into channels within the of the relative importance of specific angiogenic factors ossifying cartilage. Inhibition of VEGF and its signal in rheumatoid arthritis. Synovial fluids can induce angio- transduction pathways during endochondral ossification genic phenotypes in endothelial cells in vitro, and can in long bones prevents vascular invasion of the epi- stimulate angiogenesis in vivo in animal models, al- physial cartilage [47,48]. However, the specific role of though some samples have greater potency than others angiogenesis inhibition in these effects is not yet clear, [37,38]. Synovial fluids from patients with osteoarthritis because VEGF may directly stimulate chondrocytes and display lower angiogenic potential than those from pa- osteoblasts. Other molecules may be equally important tients with rheumatoid arthritis, although this may sim- for this vascular invasion, including matrix metallopro- ply reflect different degrees of inflammation in selected teinases-9 and -13 [49,50]. Chondrocyte hypotrophy is cases [39]. recapitulated at the osteochondral junction in osteoarthritis. Cells at the osteochondral junction display mor- The stimulation of in vitro “angiogenesis” may be phologic characteristics of hypertrophic chondrocytes, blocked by specific inhibitors of particular molecular and may express collagen X and alkaline phosphatase as pathways. Most of these studies have used synovial flu- well as VEGF [35]. ids from patients with rheumatoid arthritis, demonstrating substantial inhibition of angiogenic activity by block- Explants of articular cartilage exhibit resistance to vas- ing each of VEGF, tumor necrosis factor-␣, hepatocyte cular invasion in vitro, and this antiangiogenic phenotype growth factor, secreted phospholipase A2, interleukin-18, is impaired in osteoarthritis [5,51•]. Downregulation of fractalkine, and stromal cell-derived factor-1 [39–44,45•]. those antiangiogenic factors that are produced by normal These data suggest a degree of redundancy and overlap chondrocytes may, in part, explain loss of angiogenesis between angiogenic factors. resistance in osteoarthritic cartilage. Cell–matrix interactions may also be important. High-molecular weight hy- The synovial vasculature provides metabolic support for aluronic acid is antiangiogenic, and is a major constituent the articular cartilage, and this is facilitated by the ab- of normal synovial fluid, articular cartilage, and nucleus sence of barriers between the synovial stroma and the pulposus. Low-molecular weight hyaluronic acid may chondrocyte [1]. The synovium is not a true membrane. stimulate angiogenesis [52,53]. Reductions in the me- It is derived from mesoderm, and lacks a basement mem- dian molecular weights of hyaluronic acid during syno- brane between the subsynovium and synovial lining vitis and in osteoarthritis are well recognized [54]. cells. This absence of a basement membrane permits exchange of solutes and regulatory factors between sy- Hypoxia and angiogenesis novial stroma and synovial fluid compartments, although Hypoxia is a major driver of angiogenesis in a variety of expression of membrane peptidase by lining cells limits tissues, including retinopathy and in tumors. Rheuma- diffusion of more labile peptides such a bradykinin and toid synovitis is associated with synovial hypoxia, as evi- substance P [46]. denced by direct measurements of low oxygen tensions and by the expression of hypoxia inducible factor-1␣ and Similarly, there is an exchange of fluid between the sy- hypoxia-responsive genes such as VEGF and angiopoi- novial cavity and the articular cartilage. Cycles of com- etin [23,55,56•]. The articular cartilage experiences low pression during exercise force fluid in to and out of the oxygen tensions even in normal joints. Despite this, cartilage matrix, and solutes pass with the fluid by mass chondrocytes in situ in normal cartilage do not display transport [1]. The tidemark at the junction between cal- high expression of hypoxia inducible factor-1␣ or hyp- cified and noncalcified cartilage may provide a barrier to oxia-responsive genes, indicating a degree of hypoxia re- solute transfer in normal joints. This tidemark redupli- sistance in these cells under normal conditions [35,57•]. Angiogenesis in arthritis Walsh 613

Further reduction in oxygen tensions during disease, or gene-related peptide-containing sensory nerves, which loss of hypoxia resistance may, however, be an important grow into the cartilage from the adjacent subchondral stimulus to angiogenesis. bone [11,12]. Similarly, the bony core of osteophytes contains peptidergic sensory nerves, and fine, unmyelin- Oxygen tensions are reduced during synovitis because of ated sensory nerves also accompany blood vessels into increased metabolic demand from the synovium, and re- the intervertebral disc [13,61–63]. distribution of the blood flow away from the synovial surface and therefore away from the already hypoxic ar- C-fibers transmit pain sensations often described as ticular cartilage. Metabolic support to the deep layers of “burning” and “sustained” (slow conducting), and these articular cartilage derives from the subchondral bone, descriptors are commonly used by patients with osteoar- and impairment of subchondral blood flow may also con- thritis or chronic low back pain to describe some aspects tribute to the progression of osteoarthritis. Occlusion of of their pain. There may be good reasons why normal the subchondral blood flow leads to osteoarthritic articular cartilage and intervertebral discs are aneural. changes in animal models and may be important in the Mechanical or metabolic stimulation of the aberrant human conditions of avascular necrosis and osteochon- nerves in these structures may contribute to the sus- dritis [58,59]. tained pain that is experienced by the patient, even in the absence of ongoing inflammation or repair. Articular hypoxia may contribute to cartilage changes by impairing chondrocyte metabolism and synthetic activ- Nerve growth is itself associated with altered sensory ity, and may play an important role through stimulation function. Regenerating nerves may display increased of angiogenesis. It remains to be determined whether sensitivity to mechanical and chemical stimulation and angiogenesis is able to relieve hypoxia by reinstating may display altered expression of neurotransmitters and blood flow, or whether disadvantages of angiogenesis neuromodulators in the cell bodies of the dorsal root outweigh those potential benefits. ganglia [64]. Increased vascular turnover is associated with apparent loss of neuronal immunoreactivity, consis- Clinical consequences of angiogenesis tent with retraction of nerve terminals from inflamed Angiogenesis may contribute both to symptoms and to regions of the synovium [10]. Regrowth of sensory nerve disease progression in osteoarthritis and spondylosis. terminals is observed in animal models of synovitis [65]. Much has been written about the potential facilitation of The numbers of cell bodies and dorsal root ganglia have inflammation by angiogenesis, and this remains prob- not displayed major changes during synovitis in animal able, although currently it is still unproved [20,36]. It is models [66]. This, together with evidence of nerve re- often difficult to distinguish between direct effects of growth, suggests that neurite retraction rather than actual angiogenesis and coincidental proinflammatory effects of cell death is the predominant cause of neuronal deple- angiogenic factors such as VEGF and interleukin-1. tion in inflamed synovium. This increased neurite turn- Nonetheless, new blood vessels display hyperpermeabil- over that accompanies vascular turnover during synovitis ity to solutes and high expression of cell adhesion mol- may therefore contribute to sensitization and the pain ␣ ␤ ecules such as e-selectin and integrin v 3. Inflammation experience. may contribute to the pain experienced by patients with osteoarthritis or spondylosis, as indicated by the symp- Vascular invasion is an essential component of endo- tomatic efficacy of nonsteroidal antiinflammatory agents. chondral ossification [67]. New vessels invade cartilage prior to its transformation into bone, and inhibition of Angiogenesis may be viewed teleologically as a part of angiogenesis prevents endochondral ossification both in the repair response, and it may be reasonably asked, If the growth plate and during ectopic ossification in animal this repair is successful, why does pain persist? One pos- models [48,68]. New bone formation at the osteochon- sible explanation is suggested by the observation that dral junction is localized in a cuff around fibrovascular angiogenesis is typically followed by innervation of new channels, and this advancing edge of ossification through vessels by fine, unmyelinated sensory nerves [60]. In- the calcified cartilage contributes to the thickening of deed, angiogenesis and innervation are closely associated the subchondral plate that is characteristic of osteoarthri- processes both during development and in the adult tis. [14•]. Environments that are hostile to vascularization, such as the glycosaminoglycan-rich intervertebral disc, The subchondral bone plays an important part in the are also resistant to innervation. Because osteoarthritis pathogenesis of osteoarthritis. Thickening of the sub- and spondylosis are associated with the vascularization of chondral plate alters mechanical loading through articu- these normally avascular and aneural structures, they are lar cartilage, and changes in subchondral blood flow and also associated with their neoinnervation. Blood vessels intraosseous pressure have been implicated in osteoar- invading the articular cartilage and crossing the tidemark thritis disease progression [58,59,69]. Bone formation may be accompanied by substance P- and calcitonin within the cartilaginous matrix of osteophytes similarly 614 Osteoarthritis appears to recapitulate developmental endochondral os- 5 Fenwick SA, Gregg PJ, Rooney P: Osteoarthritic cartilage loses its abilityto remain avascular. Osteoarthritis Cartilage 1999, 7:441–452. sification, and angiogenesis may contribute to osteo- 6 Lotz M, Moats T, Villiger PM: Leukemia inhibitory factor is expressed in carti- phyte growth [17,70]. 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Purpose of review Current Opinion in Rheumatology 2004, 16:616–622 The pathophysiology of osteoarthritis is the result of an Abbreviations imbalance between anabolic and catabolic pathways. This C/EBP CCAAT/enhanced-binding protein imbalance is the result of the activation of joint cells by COX cyclooxygenase IL interleukin inflammatory mediators, matrix components, and mechanical JNK Jun NH2-terminal kinase stress. All these mediators act through specific receptors that MMP matrix metalloproteinase MAPK mitogen-activated protein kinase transmit the signals to the nucleus to activate the transcription MKK MAPK kinase of matrix metalloproteinases and inflammatory genes. Targeting NF nuclear factor NO nitric oxide these signaling pathways in osteoarthritis is considered a OA osteoarthritis novel approach to modulate this imbalance. PPAR peroxisome proliferator activated receptor RA rheumatoid arthritis Recent findings TNF tumor necrosis factor Although many signaling pathways are necessary for © 2004 Lippincott Williams & Wilkins physiologic cell life, it is now well established that a few are 1040–8711 more specifically induced in an inflammatory environment. In osteoarthritis, the nuclear factor-␬B and mitogen-activated protein kinase pathways have been shown to play a Introduction predominant role in the expression of metalloproteinases and Osteoarthritis (OA) results from a failure of chondrocytes inflammatory genes and proteins. Also involved in the within the joint to synthesize a good-quality matrix and activation of osteoarthritic cells are other molecules interacting to maintain a balance between synthesis and degradation with one or several signaling pathways, such as nitric oxide, of the extracellular matrix. The change in the quality of peroxisome proliferator-activated receptor-␥ ligands, or C/EBP the matrix is mainly the result of dedifferentiation of transcriptional factors. Based on this knowledge, specific chondrocytes, whereas the imbalance between synthesis inhibitors for some of these signaling pathways have been and degradation of the extracellular matrix is caused by designed and include p38 mitogen-activated protein kinase or increased synthesis of proteinases and decreased ana- nuclear factor-␬B inhibitors. Experimental studies evaluating bolic effects of growth factors, mainly from chondrocytes cartilage degradation in arthritis models are promising, but also from synovial tissue and subchondral bone. although fewer have been done specifically in osteoarthritis Moreover, chondrocyte apoptosis is enhanced in OA, re- models. ducing the capacity of cartilage to repair lesions. Proin- Summary flammatory mediators synthesized by OA chondrocytes Targeting signaling pathways in osteoarthritis did not seem and synovial cells bind to specific receptors on chondro- feasible a few years ago because of the complexity of the cytes causing transcription of many genes involved in the multiple intracellular pathways, mainly physiologic, defined by a degradative process [1]. Targeting the intracellular path- high degree of redundancy and cross-talk. However, important ways activated between the receptors and gene expres- advances in the knowledge of chondrocyte and synoviocyte sion is an attractive concept to treat OA [2•,3], because signaling in osteoarthritis have been achieved in recent years different proinflammatory mediators can share common and suggest that inhibitors of specific signaling pathways intracellular pathways. It will be interesting to determine could shortly provide effective treatments for this disease. whether a single inhibitor could inhibit the effects of multiple deleterious mediators. This review describes Keywords the major intracellular pathways activated in OA, high- osteoarthritis, signaling pathways, NF-␬B, MAP kinases, nitric lighting potential therapeutical targets. oxide, PPAR-␥ ligands, C/EBP transcriptional factors Role of nuclear factor-␬B and therapeutical Curr Opin Rheumatol 16:616–622. © 2004 Lippincott Williams & Wilkins. perspectives in osteoarthritis Nuclear factor (NF)-␬B is a transcription factor found as homodimers and heterodimers of a family of 5 proteins University Pierre & Marie Curie and Department of Rheumatology, UFR (p65, c-Rel, RelB, p50/p105, and p52/p100), the most Saint-Antoine, AP-HP, Paris, France abundant dimer being p50-p65 [4]. NF-␬B is present in Correspondence to Francis Berenbaum, UMR CNRS 7079, University Pierre & the cytosol in an inactive form and is bound to a family Marie Curie (Paris VI), 7 quai St Bernard 75252 Paris Cedex 5, France of inhibitory proteins named I-␬B. When interleukin Tel: +33 0149282520; fax: +33 0149282513; e-mail: [email protected] (IL)-1 or tumor necrosis factor (TNF)-␣ bind to their 616 Signaling transduction Berenbaum 617 specific receptors, a complex cascade is activated, involv- investigated for arthritis by many pharmaceutical com- ing reactive oxygen species [5]. One of their effects is panies [9,33,34••,35,36]. However, the methods used for phosphorylation of I-␬B. Phosphorylated I-␬B can bind testing these molecules are done on experimental mod- to ubiquitin before undergoing degradation in the pro- els of RA but not of OA. teasome. NF-␬B is released from I-␬B and can be translocated to the nucleus, where it can activate the tran- Role of mitogen-activated protein kinase scription of various genes having a NF-␬B response and therapeutic perspectives element. More than 150 NF-␬B-responsive genes have in osteoarthritis been identified [6]. These include genes for cytokines, In parallel with the NF-␬B pathway, IL-1 and TNF␣ can matrix metalloproteinases (MMPs), adhesion molecules, activate another signal transduction pathway involving acute phase reactants, I-␬B, p50, c-rel, cyclooxygenase-2 the enzyme mitogen-activated protein kinase (MAPK). (COX-2), and ESE-1. The latter is a transcription factor MAPKs work in a cascade composed of three protein belonging to the Ets family, involved in inducible nitric kinase modules: MAPK kinases (MKK) kinases phos- oxide synthase and COX-2 gene expression, and ex- phorylate MAPK kinases (MKKs), which in turn phos- pressed in cartilage and OA synovial tissue [7]. NF-␬Bis phorylate MAPKs. To date, 12 MAPKs, seven MKKs, already considered a potential therapeutic target for the and 14 MKK kinases have been identified [37,38]. In treatment of inflammatory joint diseases, such as rheu- addition, the p38 MAPK exists as four isoforms (p38␣ matoid arthritis (RA). Indeed, NF-␬B is critical for the MAPK, p38␤ MAPK, p38␦ MAPK, and p38␥ MAPK), initiation and perpetuation of chronic synovitis, for the which probably differ in their substrate specificity. It is synovial hyperplasia and for providing antiapoptotic sig- noteworthy that the p38␤ isoform increases the activa- nals [8,9]. However, less information is available for OA. tion of activating protein-1 transcriptional activities whereas the p38␥/␦ inhibits or has no effect on the Within chondrocytes, this pathway is indispensable to stimulation [39•]. the expression of MMP-1 [10], MMP-3 [11], and MMP- 13 [11–13]. The suppressive effect of insulinlike growth Although the number of possible combinations is theo- factor-1 on MMP-13 expression is due in part to the retically very high, in reality each effector selects certain downregulation of NF-␬B activity [14], which modulates combinations. For instance, IL-1 and TNF-␣ preferen- IL-1-, IL-17- and NO-induced apoptosis [15–19]. Fi- tially activate the p44/42 MAPK modules (or ERK), the nally, for IL-1 to inhibit the expression of SOX-9, a tran- Jun NH2-terminal kinases (JNKs), and p38 MAPK. scription factor involved in chondrocyte differentiation, These three modules cause activation and/or synthesis of activation of the NF-␬B pathway is required [20]. various transcription factors such as activating protein-1 or C/EBP. It has been demonstrated that the JNK, Mechanical signals play an integral role in cartilage ho- p44/42, and p38 MAPK pathways are specifically acti- meostasis. Overloading is a major risk factor for OA, in vated by IL-1 within chondrocytes [40]. The JNK [41] which chondrocytes are activated by mechanoreceptors and p38 MAPK [42,43] pathways are involved in the present at the cell surface. Mechanical signals trigger, IL-1-induced activation of chondrocyte COX-2 [44] and either in chondrocytes or in bone cells, the activation or MMP-13 [12]. Expression of MMP-1 needs p38 in chon- the inhibition of many signaling pathways [21], including drocytes [12], and ERK pathways in chondrocytes and in NF-␬B, and depend on the intensity of the mechanical synoviocytes [12,45]. Induction of the MMP-13 gene by stress [22••]. In chondrocytes, low magnitude prevents TNF-␣ is mediated by ERK, p38, and JNK MAPK in IL-1-induced nuclear translocation of NF-␬B, whereas articular chondrocytes [11]. The p38 MAPK pathway is high magnitude induces its transactivation and thus pro- also involved in IL-1-induced inducible nitric oxide syn- inflammatory gene induction [23]. thase expression [46,47] and in chondrocyte apoptosis [48•,49,50]. Recently, p44/42 MAPK and p38 MAPK Interestingly, some products launched for the treatment were shown to be involved in the IL-1-induced micro- of symptoms in OA have shown inhibitory effects on the somal prostaglandin E synthase-1 expression in OA NF-␬B pathway. Diacerhein [24,25], glucosamine chondrocytes [51•]. Besides IL-1, many effectors in- [26,27], and N-acetylglucosamine [28] are all capable of volved in the activation of chondrocytes are also capable inhibiting the IL-1-induced NF-␬B activation in human of inducing MAPK activities. In vitro, TNF-␣ suppresses chondrocytes. Rofecoxib, a specific COX-2 inhibitor, type II collagen expression via p44/42 MAPK and NF- dose-dependently inhibits DNA binding capacity of NF- ␬B [52]. Fibronectin fragments [53,54,55], oncostatin M ␬B in macrophages [29•]. Dexamethasone inhibits NF- [56], endothelial growth factor [57], vascular endothe- ␬B DNA binding in OA synovial tissue [30]. Surpris- lial growth factor [58], integrins [53], IL-17 [59], reac- ingly, green tea polyphenols [31] and the chinese herbal tive oxygen species [60], prostaglandin E2 [61], and ex- remedy Tripterygium wilfordii [32] also counteract IL-1- tracellular ATP [62] activate one or several MAPKs in induced NF-␬B activation in human chondrocytes. Spe- chondrocytes. On the other hand, MAPKs are critical cific small-molecule inhibitors of the NF-␬B pathway are signaling pathways for the control of chondrocyte 618 Osteoarthritis

differentiation, proliferation, and matrix synthesis in- drocyte apoptosis have been published during the past duced by growth factors. p38 signaling is necessary for few years [47,87,88•]. insulinlike growth factor-1-induced and Smad-induced Studies involving NO inhibitors also raise some discrep- type II collagen expression [63,64•,65–67]. ERK is nec- ancies. Several drugs with antiinflammatory properties, essary for gp39-induced type II collagen expression [68] including nonsteroidal antiinflammatory drugs, immuno- (Personal communication). Interestingly, the inhibitory suppressive agents, and tetracyclines, attenuate the ac- effect of insulinlike growth factor-1 on fibronectin frag- tivity of NO [89,90]. However, selective inhibition of ments- or IL-1-induced MMP-13 expression is due, at inducible nitric oxide synthase can attenuate [91,92] or least in part, to the inhibition of the MAPK pathway [14]. exacerbate [93] erosive joint diseases, depending on the Taken together, these data suggest multiple pivotal roles experimental model. for members of the MAPK family in chondrocyte activation, differentiation/proliferation, and chondrocyte apop- Role of peroxisome proliferator activated tosis. receptor-␥, and peroxisome proliferator activated receptor-␥ ligands, and therapeutic perspectives in osteoarthritis Several trials with inhibitors for p38 MAPK are ongoing Peroxisome proliferator activated receptor (PPAR)-␥ is a in RA, based on the demonstration of efficacy in experi- nuclear receptor that is activated by fatty acids and ara- mental arthritis models [69–72]. Inhibitors for the spe- chidonic acid metabolites. Thiazolidinediones such as cific p38␣ MAPK isoform have been recently designed rosiglitazone, troglitazone, certain nonsteroidal antiin- and exhibit antiinflammatory properties [73]. JNK inflammatory drugs, L-tyrosine-based compounds, and hibitors have also demonstrated preventive effects on FMOC-L-leucine are the main classes of synthetic the destruction of bone and cartilage destruction in RA PPAR-␥ ligands. PPAR-␥ forms a heterodimer with the [74–76]. However, little is known about the effect of retinoic X receptor. Several studies have shown that these compounds in OA models. Like their effect on activation of PPAR-␥ may interfere with several signal- NF-␬B, green tea polyphenols counteract IL-1-induced ing pathways regulating the expression of proinflam- JNK activation in human OA chondrocytes [32]. Re- matory genes, such as those controlled by the MAPK, ␬ cently, it has been demonstrated that phenyl N-tert- NF- B, signal transducers and activators of transcription butylnitrone, a spin-trap agent, downregulates the IL-1- (STATs), activating protein-1, and the NF of activated T induced MMP-13 expression via the inhibition of the cells [94]. Consequent to the inhibition of these signal- ␥ JNK pathway in OA chondrocytes [77]. Interestingly, ing pathways, PPAR- activators modulate the produc- one experimental study focused on the therapeutic ef- tion of inflammatory cytokines, chemokines, and cell ad- fect of a specific ERK inhibitor, PD198306, in rabbit hesion molecules, thereby limiting the recruitment of experimental OA. Pelletier et al. [78••] demonstrated a inflammatory cells. Interestingly, Cuzzocrea et al. dem- significant reduction of structural changes (cartilage de- onstrated [95•] that rosiglitazone was capable of amelio- struction and osteophyte width), but also severity of sy- rating the clinical signs of inflammation and the histo- novial inflammation compared with placebo. logic lesions in the collagen-induced arthritis model. ␦ The PGJ2 family, including PGJ2, -(12)-PGJ2, and 15- deoxy-␦-[12,14]-PGJ (15d-PGJ ), are metabolites of Role of nitric oxide and therapeutic 2 2 PGD . They have been known as powerful inhibitors of perspectives in osteoarthritis 2 cell proliferation and viral replication until 15d-PGJ was Redox-based regulation of gene expression emerges as a 2 found to be a natural ligand for PPAR-␥. Several new fundamental regulatory mechanism in chondrocytes and pharmacologic actions of the PGJ family have since synoviocytes. Generation and action of free radicals such 2 been found, such as a proapoptotic effect on synovio- as NO, superoxide, and H O highlights the impact of 2 2 cytes [96] or an antiapoptotic effect on chondrocytes and redox regulation on cellular signal transduction and gene synoviocytes [97], and inhibitory effects on inflammatory expression [79]. Thus, NO has been suggested as a po- arthritis [93]. These effects were PPAR-␥-dependent or tent modulator of intracellular signal transduction. For -independent. 15d-PGJ inhibits IL-1-induced MMP-13, example, MAPK activation observed in OA cartilage is 2 COX-2, NO production, and proteoglycan degradation in dependent on NO production [80,81]. In this disease, chondrocytes [98–101] and IL-1-induced microsomal the excessive production of NO by IL-1 or shear stress prostaglandin E synthase-1 in synoviocytes [102]. It is [82] inhibits matrix synthesis and promotes its degrada- noteworthy that PPAR-␥ ligands induce the basal level tion. Furthermore, by reacting with oxidants such as su- of COX-2 expression [96,103]. peroxide anion, NO promotes cellular injury and renders

the OA synoviocyte [83] and chondrocyte susceptible to In conclusion, 15d-PGJ2 at therapeutic concentrations cytokine-, aging-, and hydrostatic pressure-induced ap- could be of potential interest in counteracting the in- optosis [84–86]. However, several contradictory results flammatory component observed in OA, but more data on the role of NO in cartilage degradation and in chon- are expected in OA animal models. Signaling transduction Berenbaum 619

Role of C/EBP factors and therapeutic Conclusion perspectives in osteoarthritis Targeting signaling pathways in OA did not seem fea- C/EBP transcription factors are involved in the regula- sible a few years ago because of the complexity of the tion of gene transcription by IL-6 and they control in- multiple intracellular pathways, mainly physiologic, de- flammation [104]. The C/EBP family includes three fined by a high degree of redundancy and cross-talk. main members: C/EBP-␣, C/EBP-␤, and C/EPB-␦. The However, important advances in the knowledge of chon- relation between IL-1␤ and C/EBP factors has also been drocyte and synoviocyte signaling in OA have been studied, and positive regulations in the interaction with achieved in recent years. Inducible signaling pathways in NF-␬B have been reported [105,106]. However, induc- different articular cells exposed to inflammatory media- tion of C/EBP binding to DNA by proinflammatory tors or mechanical stress have been recently discovered, cytokines correlates with the accumulation of prostaglan- such as the MAPK and the NF-␬B pathways. The dis- din E2, and both effects are reversed by antiinflamma- coveries reviewed in this paper give hope that specific tory cytokines [107]. C/EBP factors act with NF-␬B signaling inhibitors may be found with less toxicity than to induce the transcription of many acute-phase response those in development in RA. Success in developing spe- genes in response to proinflammatory cytokines, and cific inhibitors will be achieved if we can more accurately this effect is based on direct protein–protein interac- determine the cell specificity in the expression and actions [108,109,110]. tivity of the signaling pathways induced by biochemical and physical inflammatory mediators. Enhanced nuclear staining for C/EBP-␤ has been observed in monocyte/macrophages from rheumatoid syno- References and recommended reading vitis [111], and its binding activity to DNA is correlated Papers of particular interest, published within the annual period of review, with serum C-reactive protein levels [112]. In chon- are highlighted as: • Of special interest drocytes, C/EBP-␤ and C/EBP-␦ are critical for the •• Of outstanding interest stimulation of COX-2 and sPLA2 by IL-1 [42,113]. Fur- 1 Chakraborti S, Mandal M, Das S, et al.: Regulation of matrix metalloprotein- thermore, the antiinflammatory drug salicylate, at phar- ases: an overview. Mol Cell Biochem 2003, 253:269–285. macologic concentration, is capable of suppressing pros- 2 Malemud CJ, Islam N, Haqqi TM: Pathophysiological mechanisms in osteo- ␤ arthritis lead to novel therapeutic strategies. Cells Tissues Organs 2003, taglandin E2 synthesis by blocking the C/EBP- binding • 174:34–48. to the COX-2 promoter [114]. 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Purpose of review Abbreviations

Prostaglandin E2 (PGE2) is by far the major prostanoid COX cyclooxygenase EP prostaglandin receptor synthesized in the joint and plays an important role in IL interleukin inflammation and pathogenesis of arthritis. Moreover, LPS lipopolysaccharides MAPEG membrane-associated proteins involved in eicosanoid and glutathione increased levels of PGE2 have been detected in serum and metabolism synovial fluids from arthritic patients. Little was known about NO nitric oxide PGE2 prostaglandin E2 the enzyme(s) involved in the isomerization of PGH2 into PGE2 PGES prostaglandin E2 synthase synthesis until recent identification of PGE synthase (PGES). PPAR peroxisome proliferator-activated receptor Several isoforms were characterized, among which microsomal TNF tumor necrosis factor PGES-1 (mPGES-1) has received much attention, because © 2004 Lippincott Williams & Wilkins this enzyme is inducible and functionally linked with 1040–8711 cyclooxygenase-2. This review focuses on recent findings regarding the regulation of mPGES-1 expression and the possible role of this enzyme in arthritis. Recent findings Introduction Various in vitro and in vivo studies demonstrated that Prostaglandin E (PGE ) plays an important role in the ␤ 2 2 proinflammatory stimuli, such as interleukin-1 and tumor physiopathology of arthritis, and excessive production of necrosis factor-␣ upregulate the expression of mPGES-1 at PGE2 has been reported in serum and synovial fluids of the protein and mRNA level. Promoter analysis indicates that rheumatoid arthritic and osteoarthritic patients. In addi- the transcription factor Egr-1 is involved in the positive tion to its proinflammatory actions, PGE2 may contribute regulation of mPGES-1. Studies from mPGES-1-deficient mice to joint damage by promoting matrix metalloproteinase and animal models of inflammatory arthritis strongly suggest a production, osteoclastic bone resorption, and angiogene- role of mPGES-1 in the production of PGE2 and the sis. The critical role of PGE2 in the pathology of arthritis pathogenesis of arthritis. was substantiated in animal models of arthritis and mice Summary lacking cyclooxygenase-2 (COX-2) or PGE2 receptors This article reviews the regulation of mPGES-1 expression and [1,2]. Until recently, COX activity had been considered provides evidence for a role of mPGES-1 in inducible PGE2 the key step in PG synthesis. However, metabolism of production and arthritis. Future studies using selective arachidonic acid (substrate) by COX (COX-1 or COX-2) inhibitors of mPGES-1 activity or expression would clarify the yields only the unstable intermediary PGH2, which can role of this enzyme in arthritis. ␣ be further metabolized into PGE2, PGD2, PGF2 , PGI2 (prostacyclin), or thromboxane A2. The enzyme respon- Keywords sible for the isomerization of PGH2 into PGE2 was little PGE2, mPGES-1, arthritis known until recent identification of PGE synthase

At least three distinct PGES isoforms have been identi- Osteoarthritis Research Unit, Centre Hospitalier de l’Université de Montréal, Hôpital Notre-Dame, Montréal, Québec, Canada fied, including cytosolic PGES (cPGES) [3], microsomal PGES-1 (mPGES-1) [4–6], and mPGES-2 [7]. cPGES is Supported by research grants from the Canadian Institutes of Health Research (CIHR, IMH-63168), the Fonds de Recherche en Santé du Québec (FRSQ, JC constitutively and ubiquitously expressed and is prefer- 2836), and the Centre de Recherche du Centre Hospitalier de l’Université de entially coupled with COX-1, promoting immediate pro- Montréal (CR-CHUM). duction of PGE2 [3,8]. By contrast, mPGES-1 is mark- Correspondence to Hassan Fahmi, Osteoarthritis Research Unit Centre, edly upregulated by proinflammatory stimuli and is Hospitalier de l’Université de Montréal, Hôpital Notre-Dame, 1560 Sherbrooke Street East, Montréal, Québec, Canada H2L 4M1 functionally coupled with COX-2, promoting delayed Tel: 514-890-8000; fax: 514-412 7583; e-mail: [email protected] PGE2 synthesis [5]. mPGES-2, the most recently iden- Current Opinion in Rheumatology 2004, 16:623–627 tified PGES, is ubiquitously expressed in diverse tissues and is functionally linked to both COX-1 and COX-2. However, the role of mPGES-2 in physiology and disease pathogenesis remains elusive [9].

623 624 Osteoarthritis

This review discusses the function and the regulation of terestingly, the upregulation of mPGES-1 expression can mPGES-1 expression as well as its potential role in arthritis. be prevented by dexamethasone treatment [5,12,18,19]. Thus, inhibition of mPGES-1 expression may be part of Biology of microsomal prostaglandin E2 synthase-1 the mechanisms by which glucocorticoids exert their an- Microsomal prostaglandin E2 synthase-1, originally des- tiinflammatory and antiarthritic effects. Indomethacin, ignated MGST1-L1 (for membrane-bound GST1-like- NS-398, rofecoxib, or meloxicam prevented IL-1␤- 1), is a member of the MAPEG (for membrane-associated induced mPGES expression, an effect that was reversed proteins involved in eicosanoid and glutathione metabo- by exogenous PGE2, indicating that PGE2 may partici- lism) superfamily, which includes others proteins in- pate in a positive feedback loop for mPGES-1 induction. volved in arachidonic acid metabolism, such as 5-lipoxy- The enhancing effect of PGE2 was associated with an genase-activating protein and leukotriene C synthase. 4 increase in cAMP level via the EP2 and EP4 receptors The gene for human mPGES-1 maps to chromosome [21]. IL-1␤ and TNF-␣ have been shown to induce the 9q34.3, is divided into three exons and two introns, and expression of mPGES-1 in rat [5] and mouse [22] osteo- spans 14.8 kb [10]. blasts. In a mouse coculture system of osteoblasts and bone marrow, an antisense oligonucleotide blocking The cDNA for human mPGES-1 encodes a protein com- mPGES-1 expression inhibited not only PGE produc- posed of 152 amino acid residues (∼16 kDa). The cofac- 2 tion, but also osteoclastogenesis and bone resorption, tor glutathione is essential for mPGES-1 enzymatic ac- suggesting strong evidence for a link between mPGES-1 tivity and exhibits an apparent structure-stabilizing expression and bone resorptive disorders [22]. In human function [4,5,11]. Mutation of Arg110, a residue well con- articular chondrocytes, the expression of mPGES-1 is also served in all members of the MAPEG family, abrogates upregulated by IL-1␤ (X. Li, personal communication). mPGES-1 activity, indicating an essential role of this residue for catalytic function [5]. Although the sequence In virtually all systems studied, the induction of mPGES-1 identity of mPGES-1 with 5-lipoxygenase-activating pro- expression by proinflammatory stimuli was correlated with tein and leukotriene C synthase is less than 20% at the 4 increased expression of COX-2 and PGE2 production, sug- amino acid level, MK-866, an inhibitor of 5-lipoxygen- gesting functional coupling of mPGES-1 with COX-2. ase-activating protein, and leukotriene C4 were found to Indeed, HEK293 cells cotransfected with COX-2 and inhibit mPGES-1 activity with IC values of 3.2 and 1.2 50 mPGES-1 produce much higher amounts of PGE2 than µmol/L, respectively [6]. COX-inhibitory nonsteroidal cells transfected with either enzyme alone [5]. Moreover, antiinflammatory drugs, sulindac sulfide and NS-398, immunohistochemical analyses showed that the subcellular but not acetaminophen (paracetamol), inhibit mPGES-1 localization of mPGES-1 and COX-2 almost overlap in the activity with an IC50 of 80 and 20 µmol/L, respectively perinuclear membrane [5,23]. The intracellular signaling [12,13]. Finally, the prostaglandin D2 metabolite 15- pathways that lead to upregulation of mPGES-1 are still ⌬12,14 deoxy- -PGJ2 (15d-PGJ2) and some polyunsaturated unclear. Recent data suggest a regulatory role for Erk and fatty acids were also reported to inhibit the activity of p38 MAP kinase [18] and phosphatidylcholine phospholi- mPGES-1 [14]. pase C [24]. More complete characterization of the mechanisms involved in the regulation of mPGES-1 expression Regulation of microsomal prostaglandin E 2 should suggest new approaches to modulate this promising synthase-1 expression in isolated cells therapeutic target. Since the identification of mPGES-1, a variety of stimuli were reported to upregulate the expression of mPGES-1 Features of microsomal prostaglandin E2 in vitro. Lipopolysaccharides (LPS) time- and dose- synthase-1 promoter dependently induce the expression of mPGES-1 in in- The human mPGES-1 promoter lacks a TATA box and flammatory cells, such as rat [5] and mouse [15] perito- contains several potential transcription factor–binding neal macrophages, as well as human vascular smooth sites, including two GC-boxes, two tandem Barbie muscle cells [16]. LPS-induced mPGES-1 expression in boxes, and an aryl hydrocarbon response element. Al- mouse macrophages is mediated via a Toll-like Receptor though IL-1␤ activated the human mPGES-1 promoter 4-MyD88-dependent pathway [15]. The proinflammatory in transient transfection experiments [10,18], the cis- cytokines, interleukin (IL)-1␤ and tumor necrosis factor elements or transcription factors involved in mPGES-1 (TNF)-␣, upregulate mPGES-1 expression in umbilical activation still are not clearly identified. vein endothelial cells [17] and orbital fibroblasts isolated from patients with thyroid-associated ophthalmopathy [18]. A recent published paper [25] has demonstrated that the mouse mPGES-1 promoter contains several tran- The induction of mPGES-1 expression has been exam- scription factor binding sites, including two GC-boxes, ined in articular joint tissues. Human synovial fibroblasts C/EBP, AP-1, and glucocorticoid-responsive elements from patients with rheumatoid arthritis express low lev- (GRE). The binding of early growth response factor-1, els of mPGES-1, and this expression is strongly induced an inducible transcription factor, to the proximal GC box by IL-1␤ and to a lesser extent by TNF-␣ [19–21]. In- is a key event that directs the regulatory expression of mPGES-1 and arthritis Fahmi 625

␤ ␣ mPGES-1 in response to LPS, IL-1 , TNF- , and phor- marked reduction in PGE2 production, and the levels of ␤ bol ester [25]. Catley et al. [26•] found that IL-1 in- PGE2 in the urine of knockout mice were decreased by duces mPGES-1 expression via the transcription factor 78% compared with control animals. However, COX-2 NF-␬B in A549 cells. On the other hand, Uematsu et al. protein expression was not significantly different in both

[15] reported that LPS failed to induce mPGES-1 ex- cell types, suggesting that NO may modulate PGE2 pro- pression in macrophages from NF-IL6-deficient mice. duction via COX-2-independent mechanisms. Indeed,

However, the mPGES-1 promoter contains neither Devaux et al. [33] showed that the induction of PGE2 NF-␬B- nor NF-IL6-responsive elements, suggesting production by LPS in vivo was not associated with an that these transcription factors may regulate mPGES-1 increase in COX-2 protein expression and was mediated expression via mechanisms that do not involve their di- by NO-dependent induction of mPGES-1 expression. rect interaction with the mPGES-1 promoter. It is also Further studies are necessary to better understand the ␬ possible that NF- B- or NF-IL6-responsive elements, or precise role of NO in PGE2 production. both, lie outside of the promoter regions analyzed in Microsomal prostaglandin E synthase-1 expression these studies. Further analyses are required to address 2 the exact role of NF-␬B and NF-IL6 in the expression of in animal models of arthritis and pyresis mPGES-1. Recent data from animal models demonstrate that mPGES-1 is important in PGE2 production, arthritis, and Microsomal prostaglandin E2 synthase-1 pyresis. The most persuasive evidence comes from stud- and peroxisome proliferator- activated ies using mPGES-1-deficient (mPGES−/−) mice. receptor ␥ Another factor that may contribute to mPGES-1 regula- The expression of mPGES-1 has been examined in a rat tion is the peroxisome proliferator- activated receptor ␥ model of adjuvant-induced arthritis (AIA), a condition (PPAR␥). PPAR␥ is a ligand-activated transcription fac- that mimics many of the clinical and pathologic features tor and belongs to the nuclear-hormone-receptor super- of human rheumatoid arthritis. Five days after adjuvant family. Recent evidence has indicated an important role treatment, the level of mPGES-1 was strongly induced for PPAR␥ in the control of various types of inflamma- in the treated paw, whereas no mPGES-1 was detected tory responses. PPAR␥ is activated by the prostaglandin in the naive rat paw [6]. Using the same animal model, Claveau et al. [34••] showed that adjuvant administration D2 metabolite 15d-PGJ2 and synthetic antidiabetic thia- zolidinedione drugs (e.g., troglitazone). PPAR␥ ligands resulted in a prompt and marked increase in the level of have been shown to inhibit a number of inflammatory mPGES-1 in the affected paw. The increase was visible events such as the production of IL-1␤, TNF-␣, and at 4 hours, peaked during the first 3 days, and remained IL-6 by monocytes/macrophages, as well as the produc- elevated during the progression of inflammation. Inter- tion of IL-2 by T lymphocytes. We and others have estingly, the increase in mPGES-1 level coincided with demonstrated that PPAR␥ ligands inhibit the expression local increases in COX-2 expression and PGE2 produc- of the inducible nitric oxide synthase, matrix metallopro- tion. In contrast, the levels of cPGES, mPGES-2, and teinase-1, matrix metalloproteinase-13, and COX-2 in COX-1 were only slightly affected, suggesting that over- human synovial fibroblasts and chondrocytes [27]. Simi- expression of mPGES-1 may contribute to the pathogen- ␤ esis of arthritis [34••]. larly, 15d-PGJ2 and troglitazone inhibit IL-1 -induced mPGES-1 expression in human synovial fibroblasts Recently, mPGES-1-deficient (mPGES−/−) mice were (Cheng S, et al., personal observation, February, 2004). generated by homologous recombination. These animals Moreover, 15d-PGJ and other natural PPAR␥ ligands 2 display no abnormalities compared with wild-type con- such as docosahexaenoic acid and eicosapentaenoic acid trols. However, LPS-induced PGE production was al- were reported to inhibit mPGES-1 activity [14]. Thus, 2 most completely abrogated both in vivo and in vitro.In both the expression and activity of mPGES-1 appear to contrast, the production of TNF-␣ and IL-6 was unaf- be an additional target for the antiinflammatory effects of fected, confirming that mPGES-1 is essential for PGE PPAR␥ ligands. 2 production [15•,35••]. The impact of mPGES-1 deletion

Prostaglandin E2/nitric oxide cross-talk was also evaluated in collagen-induced arthritis, another In addition to PGE2, nitric oxide (NO) also plays a criti- model of human rheumatoid arthritis. In contrast to the cal role in the inflammatory and catabolic processes as- wild-type mice, mPGES−/− mice exhibit reduced inflam- sociated with arthritis. Interestingly, a cross-talk between matory responses (edema and erythema) and are pro-

NO and PGE2 has been reported in several systems, but tected from histopathological deterioration (hyperplasia, the relevance of this cross-talk remain controversial. loss of proteoglycan, and bone and cartilage erosion) as- Pharmacological inhibition of inducible nitric oxide syn- sociated with arthritis. Moreover, inflammatory pain and thase was reported, depending on the study, to enhance inflammatory responses associated with delayed-type hy-

or to decrease the production of PGE2 [28–31]. Marnett persensitivity were also decreased, indicating that et al. [32] have shown that peritoneal macrophages from mPGES-1 is involved in both acute and chronic inflam- inducible nitric oxide synthase–deficient mice had a mation [35••]. 626 Osteoarthritis

There is accumulating evidence that increased produc- HEK293 cells led to cellular transformation, which is tion of PGE2 in the central nervous system plays a crucial evidenced by rapid proliferation, morphologic change, role in fever, a common sign of various inflammatory pilling up, and formation of solid tumors in nude mice disorders. This increase can be induced by proinflamma- [47]. The expression of mPGES-1 is upregulated in co- tory stimuli such as LPS, IL-1␤, IL-6, and TNF-␣ [36]. lorectal tumors [48], endometrial adenocarcinoma [49], Animal models of pyresis have been used to examine the non–small cell lung cancer [50], head and neck squa- expression of mPGES-1 in the brain and address its role mous cell carcinoma [51], and gastric carcinoma [52]. Ad- in fever. Ek et al. [37] observed increased expression of ditional studies are warranted to determine whether mPGES-1 and COX-2 in blood vessels throughout the mPGES-1 represents a pharmacological target for pre- brain after IV treatment with IL-1␤. Similarly, LPS in- venting or treating cancer. jection caused a marked increase of mPGES-1 expression in brain endothelial cells, which was associated with Conclusion a COX-2-dependent increase in PGE2 levels in the ce- Overproduction of PGE2 clearly plays a central role in rebrospinal fluid [23]. Further studies demonstrated that the pathogenesis of arthritis. Great progress has been mPGES-1 and COX-2 are induced by LPS in rat spinal made over the past several years in the understanding of cord, dorsal root ganglia, and skin, an effect that was the mechanisms of PGE2 production. The identification inhibited by dexamethasone [38]. Moreover, mice with of COX-2 as a key enzyme in PGE2 synthesis resulted in targeted mPGES-1 gene disruption do not produce the introduction of several COX-2-selective inhibitors. PGE2 and fail to develop fever in response to LPS, but Although these drugs have decreased gastrointestinal maintained their pyretic capacity to administered PGE2 toxicity compared with classical nonsteroidal antiinflam- [39••]. These results provide conclusive evidence that matory drugs, they may still have adverse effects such as mPGES-1 plays a key role in PGE2 production and fever renal toxicity and increased risk of cardiovascular events and suggest a new approach to treat fever by inhibiting and thrombosis. Therefore, more selective inhibitors of mPGES-1. PGE2 synthesis may prove useful. The recent findings described in this review strongly suggest that mPGES-1

Microsomal prostaglandin E2 synthase-1 may serve as a therapeutic target not only in arthritis, but in tumorigenesis also in other inflammatory disorders and cancer. A large body of evidence suggests an important role of

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Purpose of review MMP matrix metalloproteinase LOX lipoxygenase This review discusses the recent literature on drugs used for LT leukotriene symptomatic pain relief in patients with osteoarthritis (OA) as NSAID nonsteroidal anti-inflammatory drug OA osteoarthritis well as potential mechanisms underlying their pharmacologic PG prostaglandin action. TNF tumor necrosis factor

Recent findings © 2004 Lippincott Williams & Wilkins Recent research has shed light on the molecular mechanisms 1040–8711 underlying the contribution of prostaglandins to pain sensation. Moreover, the role of the enzymes cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) in inflammation and subsequent structural changes of joints has been clarified. Based on the Introduction: role of eicosanoids in pain COX-1/COX-2 hypothesis, various selective COX-2 inhibitors and inflammation with improved gastrointestinal tolerability as compared with About a decade ago, the enzyme cyclooxygenase (COX) conventional nonsteroidal anti-inflammatory drugs (NSAIDs) was demonstrated to exist as two distinct isoforms. have been established for the symptomatic treatment of OA in COX-1 is constitutively expressed as a “housekeeping” recent years. Rational therapy with these compounds should enzyme in nearly all tissues and mediates physiologic be based on their diverse pharmacokinetic characteristics. responses (eg, cytoprotection of the stomach, platelet ag- Among the traditional NSAIDs, the mode of action of gregation). Conversely, COX-2, expressed by cells in- aceclofenac has been recently clarified in that the compound volved in inflammation (eg, macrophages, monocytes, was shown to elicit preferential inhibition of COX-2 as a result synoviocytes) has emerged as the isoform that is primar- of limited but sustained biotransformation to diclofenac. Novel ily responsible for the synthesis of prostanoids involved mechanisms have also been proposed to account for the in acute and chronic inflammatory states [1]. Current action of acetaminophen. Finally, there is evidence from animal research suggests that factors such as inflammation and models to suggest that the dual LOX/COX inhibitor licofelone changes in subchondral bone may play a larger role in the may stop disease progression in OA. Clinical studies are pathophysiology of osteoarthritis (OA) than previously under way to establish this compound for treatment of OA. thought. Some new aspects concerning the contribution Summary of prostaglandin (PG) E to the inflammatory process of It is anticipated that new insights into the pathophysiology of 2 the joint have been recently clarified. PGE2 has been OA as well as novel therapeutics will improve the proposed to regulate the production of interleukin (IL)- pharmacologic options in OA. 6, macrophage colony-stimulating factor, and vascular endothelial growth factor by IL-1-stimulated human sy- Keywords novial fibroblasts through the activation of EP2 and EP4 osteoarthritis, pain, cyclooxygenase-2, 5-lipoxygenase receptors with an increase in cyclic AMP [2]. Moreover,

induction of synovial COX-2-derived PGE2 has been Curr Opin Rheumatol 16:628–633. © 2004 Lippincott Williams & Wilkins. proposed to represent one mechanism by which IL-1 modulates cartilage proteoglycan degradation in OA [3]. Finally, COX-2-dependent prostanoids seem to be in- Department of Experimental and Clinical Pharmacology and Toxicology, Emil–Fischer-Center, Friedrich-Alexander-University Erlangen-Nuremberg, volved in the apoptotic cell death of human osteoarthritic Fahrstrasse 17, D-91054 Erlangen, Germany synoviocytes by nitric oxide [4]. Correspondence to Dr. Burkhard Hinz, Department of Experimental and Clinical Pharmacology and Toxicology, Emil–Fischer-Center, Moreover, it has become increasingly clear that, apart Friedrich-Alexander-University Erlangen-Nuremberg, Fahrstrasse 17, D-91054 Erlangen, Germany from sensitizing peripheral nociceptors, PGs may also Fax: 49 9131 8522774; act in the central nervous system to produce hyperal- e-mail: [email protected] gesia. Experimental data suggest that COX inhibitors Current Opinion in Rheumatology 2004, 16:628–633 (COXibs) act primarily in the dorsal horn to cause anal- Abbreviations gesia (for review see Hinz and Brune [5]). Here, noci- COX cyclooxygenase ceptor signals are transferred to secondary neurons, COXib selective COX-2 inhibitor which propagate the signals to the higher centers of the CYP cytochrome P-450 IL interleukin central nervous system. The sensation of pain is then 628 Pain and osteoarthritis Hinz and Brune 629 assembled in the cortex. COX-2 is expressed constitu- acid derivative lumiracoxib has gained permission to en- tively in the dorsal horn of the spinal cord and becomes ter the European market recently. All of these selective upregulated briefly after a trauma, such as damage to a inhibitors block predominantly COX-2, although they limb, in the corresponding sensory segments of the spi- differ with respect to their selectivity. However, it may nal cord [6]. Compelling evidence suggests that the in- be assumed that the existing differences in selectivity duction of spinal cord COX-2 expression may facilitate are of minor clinical importance because at recom- transmission of the nociceptive input. Two recent pub- mended clinical dosages even celecoxib, the substance lications can explain how PGE2 facilitates pain sensation. displaying the lowest degree of selectivity, inhibits only Baba et al. [7] showed that PGE2 directly depolarizes COX-2, but not platelet COX-1, in vivo in humans. In wide dynamic range neurons in the deep dorsal horn. line with their COX-1-sparing effect, recently performed More convincingly, Ahmadi et al. [8] demonstrated that endoscopic studies revealed a significantly improved gas-

PGE2 at significantly lower concentrations reduces the trointestinal safety even for the novel COX-2 inhibitors inhibitory tone of the neurotransmitter glycine onto neu- valdecoxib [16,17], etoricoxib [18,19], and lumiracoxib rons in the superficial layers of the dorsal horn, thereby [20,21]. causing a disinhibition of spinal nociceptive transmission. All five COXibs are relatively lipophilic compounds. Whereas the sulfonamides and methylsulfones are non- Other arachidonic acid metabolites contributing to the acidic compounds, lumiracoxib is a phenylacetic acid de- development of OA are leukotrienes (LTs). LTB4 and rivative. Differences in physicochemical characteristics the cysteinyl LTs are potent mediators of inflammation, are reflected in different pharmacokinetic behavior. Ac- causing increased activation, recruitment, migration, and cordingly, the volume of distribution of the nonacidic adhesion of immune cells. In a recent study, LTB4 has compounds is equal or above body weight, whereas that been shown to increase the production and release of the of lumiracoxib is, as with other acetic acid derivatives, proinflammatory cytokines tumor necrosis factor (TNF) around 15% of body weight. The nonacidic compounds and IL-1 [9]. Both cytokines are thought to mediate distribute almost equally throughout the body with the damage to cartilage by increasing the expression of ma- exception of celecoxib, which is likely to be sequestered trix metalloproteinases (MMPs) and by reducing the re- in body fat due to its extremely high lipophilicity. The pair of damaged cartilage by chondrocytes. Owing to in- acidic compound lumiracoxib apparently mimics diclof- creased TNF and IL-1 expression, LTB4 is currently enac and indomethacin, which reach high concentrations thought to be involved in stimulation of bone resorption in the bloodstream, kidney, liver, and inflamed tissue in OA [9,10]. but comparatively lower concentrations in other compartments (for review see Hinz and Brune [5]). The With particular emphasis on drugs interfering with the physicochemical differences are also reflected in other biosynthesis of PGs and LTs, new developments in this pharmacokinetic parameters. As might be expected from field, as well as new insights into the mode of action of its very high lipophilicity, celecoxib is absorbed rela- new agents and traditional drugs, will be discussed in the tively slowly and incompletely. It undergoes consider- following chapters. able first-pass metabolization (20 to 60% oral bioavail- ∼ Selective cyclooxygenase-2 inhibitors ability) and its rate of elimination (t50% 6 to 12 hours) Therapy with nonsteroidal anti-inflammatory drugs appears to be very variable [22,23••]. Rofecoxib and val- (NSAIDs) has long been the cornerstone of pharmaco- decoxib show higher degrees of bioavailability. They dif- logic management of OA. However, many patients with fer in their elimination half-life, with rofecoxib being ∼ OA are at increased risk of developing clinically signifi- eliminated more slowly (t50% 15 to 18 hours) than val- ∼ cant adverse events associated with NSAIDs, in particu- decoxib (t50% 6 to 10 hours). Etoricoxib encounters only ∼ lar upper gastrointestinal complications including symp- slow metabolic elimination (t50% 20 to 26 hours), tomatic and complicated ulcers. The rationale for the whereas lumiracoxib is eliminated much faster, with an development of selective inhibitors of the COX-2 isoen- elimination half-life of about 5 hours. Indirect evidence zyme was the hypothesis that selective inhibition of suggests that all substances reach sufficiently high con- COX-2 might have therapeutic actions similar to those of centrations in the central nervous system to counter in- NSAIDs, but without causing the gastrointestinal side flammatory pain by blocking COX-2 within about an effects (for review see Hinz and Brune [1]). hour. The fast absorption of etoricoxib appears to cause its fast onset of action. Selective COX-2 inhibitors currently used are the sulfonamides celecoxib, valdecoxib, and parecoxib (prodrug All five compounds are eliminated predominantly by of valdecoxib) as well as the methylsulfones rofecoxib metabolization. Whereas celecoxib, valdecoxib, etori- and etoricoxib (for reviews see Cochrane et al. [11], Ding coxib, and lumiracoxib are metabolized in a first step by and Jones [12], Ormrod et al. [13], Ahuja et al. [14], and oxidative drug metabolism involving cytochrome P450 Chavez and DeKorte [15]). Further, the phenylacetic (CYP) enzymes such as CYP3A, CYP2C9, CYP2D6, and 630 Osteoarthritis

CYP1A2, rofecoxib is, in a first step, metabolized by cy- tively, COXibs plus low-dose aspirin appears a possible toplasmic reductases. Moreover, all five compounds ap- option, although clinical data (outcome studies) are not pear to interfere with the metabolization of other drugs. yet available. Interestingly celecoxib and possibly also valdecoxib interfere with the activity of CYP2D6. Accordingly, cele- Traditional nonsteroidal coxib has recently been shown to inhibit the metabolism anti-inflammatory drugs of the CYP2D6 substrate metoprolol, the most widely Apart from the selective COX-2 inhibitors, another ␤ used -blocker [23••]. This interaction is likely to also NSAID, aceclofenac, has been launched in some coun- occur with the concomitant administration of sedatives, tries as an anti-inflammatory and analgesic drug with ef- serotonin reuptake inhibitors, tricyclic antidepressants, ficacy similar to that of other NSAIDs (for review see and some neuroleptics. Moreover, some antiarrhythmic Dooley et al. [30]). Based on data from clinical trial re- drugs are also metabolized via CYP2D6. Conversely, the ports, aceclofenac seems to possess an improved gastro- interference of CYP3A4 by etoricoxib and CYP1A2 by intestinal tolerability, although the safety of this drug rofecoxib appears of minor importance because CYP3A is remains to be established in large endoscopic studies. As inducible and many drugs metabolized by CYP3A are compared with the structurally related diclofenac, ace- also substrate of other CYP enzymes. Similarly, few clofenac contains an additional esterified acetoxy side drugs are metabolized via CYP1A2. Of relative impor- chain. The mode of action of aceclofenac, as well as the tance appears only theophylline. Indeed, there is infor- reason for its improved gastrointestinal tolerability, are mation that rofecoxib might interfere with the metabo- currently unknown. It has been suspected that aceclof- lization of this compound, which may be relevant in enac may act predominantly by suppressing the synthe- asthma therapy. sis of proinflammatory cytokines or by other mechanisms independent of COX inhibition. However, these actions cannot explain the entire pharmacologic activity of the On the basis of their diverse pharmacokinetic character- compound. In a recent study [31••], it has been shown istics, a rational use of different COXibs in different that aceclofenac itself is inactive in terms of COX inhi- clinical settings is recommended. Accordingly, the slow bition but interferes with prostanoid formation in vivo absorption and variable first-pass metabolization of cele- and in vitro following conversion to its active metabolite coxib should preclude this compound from the treatment diclofenac. The amount of diclofenac generated after ad- of acute pain. Rofecoxib and valdecoxib may be used but ministration of 100 mg of aceclofenac can cause an al- need to be given in higher dosages [24,25]. Etoricoxib most complete inhibition of the COX-2 enzyme but only appears particularly promising for this indication; how- a partial and short-term suppression of the COX-1 iso- ever, final data are lacking. This is even more the case form. In comparison with a 75-mg dose of a sustained- with lumiracoxib. On the basis of experiences gathered release diclofenac formulation, aceclofenac was associ- with diclofenac, a structural analogue, the administration ated with a pronounced COX-1-sparing effect. of lumiracoxib in salt form to facilitate fast absorption appears promising for the treatment of acute pain. How- ever, all COXibs will find a suitable indication in OA The apparently improved COX-2 selectivity of aceclof- pain. Accordingly, valdecoxib at 5 mg and 10 mg once enac as compared with diclofenac raises several ques- daily [26], as well as etoricoxib 60 mg once daily [27,28], tions. According to double-blind comparative trials, the were found to possess a similar efficacy in treating symp- efficacy of aceclofenac 100 mg twice daily is similar to tomatic OA of the knee or hip as compared with tradi- that of diclofenac 50 mg 3 times daily in patients with tional NSAIDs. Moreover, lumiracoxib at 400 mg once rheumatoid arthritis and OA of the knee [30]. Moreover, daily was recently reported to cause significant improve- a recently published double-blind study has shown that ments in OA pain intensity and functional status [29]. aceclofenac, 100 mg twice daily, is at least as effective as The selection of COXibs should be based on the phar- 75 mg of resin-bound diclofenac twice daily in lowering macokinetic parameters. Obviously if patients are satis- pain in patients with acute low back pain suffering from fied with one daily dose of celecoxib or lumiracoxib degenerative spinal disorders [32]. Conversely, aceclof- (Յ 200 mg), which displays the shortest elimination half- enac would be expected to possess much lower anti- life, they may benefit because the fast elimination will inflammatory and analgesic activity by virtue of the low allow the kidney to recover from temporary COX-2 in- plasma levels of its metabolite diclofenac compared with hibition. Of course, if two daily doses are required, or the levels of diclofenac obtained by the direct dosing of very high doses are given once daily, this possible ad- a clinically effective dose of diclofenac. There are several vantage is likely to vanish. Moreover, all COXibs must possible explanations concerning this matter. First, un- not be given to patients with cardiovascular risk factors. der long-term treatment with aceclofenac, 4Ј-hydroxy- In these patients, classical NSAIDs plus proton-pump diclofenac, which occurs at higher steady-state concen- inhibitors plus low-dose aspirin (given once daily, not trations in aceclofenac- than in diclofenac-treated together with the NSAID) might be preferred. Alterna- volunteers, may contribute to COX-2 inhibition [30]. Pain and osteoarthritis Hinz and Brune 631

Second, mechanisms distinct from COX-2 inhibition Acetaminophen could contribute to the activity of aceclofenac. Accord- According to a recent update of the American College of ingly, aceclofenac has been shown to stimulate glycos- Rheumatology guidelines for OA, acetaminophen re- aminoglycan synthesis in osteoarthritic cartilage, whereas mains first-line therapy because of its cost, efficacy, and diclofenac had no measurable effect [33,34]. Likewise, safety profiles [41]. Acetaminophen provides effective recent studies indicate that 4Ј-hydroxy-aceclofenac but relief of pain for many patients with OA and has been not diclofenac possesses putative chondroprotective demonstrated to be safe in a wide range of populations, properties attributable to suppression of IL-1-mediated providing less severe or no gastrotoxic side effects as MMP production and proteoglycan release [35,36]. How- compared with NSAIDs [42]. Conversely, randomized ever, in a previous long-term clinical trial including ace- trials have now demonstrated that NSAIDs and COXibs clofenac- and diclofenac-treated patients with OA, both provide superior efficacy compared with acetaminophen drugs have been associated with suppression of IL-1 proin patients with OA [43]. In contrast to NSAIDs and duction by blood mononuclear cells [37], raising doubts COXibs, the analgesic and antipyretic mode of action of concerning the proposed selectivity of aceclofenac in acetaminophen is still debated. Due to its nonacidic suppressing cytokine formation. Likewise, aceclofenac chemistry, the drug reaches higher concentrations within and diclofenac have been recently classified as NSAIDs, the central nervous system as compared with the acidic showing a highly pronounced inhibitory effect on L- antipyretic analgesics (eg, aspirin, indomethacin) that ac- selectin surface expression in neutrophils [38]. The re- cumulate in peripheral compartments with acidic extra- sults of this study indicate that diphenylamine seems to cellular pH (eg, inflamed tissue) (for review see Hinz and be the structural core of these NSAIDs, accounting for Brune [5]). Evidence supporting a central analgesic their downregulatory activity on L-selectin leukocyte ex- mode of action has already previously been demon- pression. It has been suggested that the mechanism un- strated by the finding showing that acetaminophen may derlying this PG-independent effect involves uncou- inhibit nociception-induced spinal PG synthesis [44]. pling of mitochondrial oxidative phosphorylation. Recently, acetaminophen has been shown to inhibit a newly discovered COX isoform, derived from the same Clearly, more research is needed to understand how the gene as COX-1 and referred to as COX-3 [45]. However, proposed mechanisms may work in a coordinated fashion until now COX-3 has been detected at relatively small to contribute to the pharmacologic action of aceclofenac. amounts in the cerebral cortex of dogs. Moreover, studies In particular, a wider clinical experience and further ef- indicating a pharmacologically different regulation of ficacy studies are required before the role of aceclofenac COX-3 as compared with the other two isoenzymes have relative to diclofenac can be determined. However, apart been performed using canine COX-3 and murine COX-1 from the efficacy concern, metabolic formation of diclof- and -2 enzymes. To clarify the impact of acetaminophen enac may be favorable through avoiding high initial on COX-3-dependent PG production, further experi- plasma peaks of diclofenac that may confer a high degree ments must be performed using the human COX isoen- of COX-1 inhibition. zymes. In this context it is noteworthy that COX-3 inhibition by acetaminophen is weak and not specific. It remains to be determined whether the improved Accordingly, inhibition of COX-3 was observed at con- COX-2 selectivity profile of 100 mg aceclofenac may be centrations above those inhibiting monocyte COX-2 in of clinical relevance in view of previous observations re- the human whole blood assay. Moreover, PGs derived porting a lower incidence of gastric and duodenal muco- from COX-2 but not from COX-1 have been proposed to sal damage and less gastrointestinal bleeding with oral be involved in the maintenance of central analgesic aceclofenac than with oral diclofenac. An improved gas- states. Finally, the existence of a full-length, catalytically trointestinal tolerability of aceclofenac was supported by active form of COX-3 in humans has been recently ques- the SAMM study [39] showing a significantly lower in- tioned by two independent groups [46,47•]. cidence of gastrointestinal adverse events with aceclofenac (100 mg twice daily) than with diclofenac (75 mg Apart from the COX-3 enzyme, another possible mode twice daily). In line with this study, the findings of the of action of acetaminophen was suggested in 2002. This European Observational Cohort Study validated aceclof- theory is based on accumulating evidence that acetamin- enac, in everyday clinical practice, as an effective, well- ophen inhibits the COX enzymes by reducing the higher tolerated, and well-accepted therapy for both acute and oxidation state of these proteins. Thus, it was hypoth- chronic inflammatory and degenerative disease [40]. esized that peroxides, by oxidizing the enzyme to its However, as stated previously, the safety of aceclofenac catalytically active state, would oppose the action of acet- awaits further confirmation in large, prospective clinical aminophen. Boutaud et al. [48] have readdressed this trials using ulcers, bleeds, and the incidence of upper issue and showed that high levels of peroxides overcome gastrointestinal perforation/obstruction as primary end- the inhibitory effect of acetaminophen on the COX en- points. zymes in platelets and immune cells. As such, 12- 632 Osteoarthritis

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Licofelone is a competitive inhibitor of 5-LOX, COX-1, 8 Ahmadi S, Lippross S, Neuhuber WL, Zeilhofer HU: PGE2 selectively blocks and COX-2 [49] that is currently being developed for the inhibitory glycinergic neurotransmission onto rat superficial dorsal horn neurons. Nat Neurosci 2002, 5:34–40. treatment of OA. The development of the compound 9 He W, Pelletier JP, Martel-Pelletier J, et al.: Synthesis of interleukin 1␤, tumor was based on the theory that increases in the production necrosis factor-␣, and interstitial collagenase (MMP-1) is eicosanoid dependent in human osteoarthritis synovial membrane explants: interactions with of cysteinyl LTs and LTB4 may contribute to gastroin- antiinflammatory cytokines. 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Ann Rheum Dis 2004, 63:78–83. 36 Yamazaki R, Kawai S, Mizushima Y, et al.: A major metabolite of aceclofenac, 51 Boileau C, Martel-Pelletier J, Jouzeau JY, et al.: Licofelone (ML-3000), a dual 4Ј-hydroxy aceclofenac, suppresses the production of interstitial pro- inhibitor of 5-lipoxygenase and cyclooxygenase, reduces the level of cartilage collagenase/proMMP-1 and pro-stromelysin-1/proMMP-3 by human rheuma- chondrocyte death in vivo in experimental dog osteoarthritis: inhibition of pro- toid synovial cells. Inflamm Res 2000, 49:133–138. apoptotic factors. J Rheumatol 2002, 29:1446–1453. 37 Gonzalez E, de la Cruz C, de Nicolas R, et al.: Long-term effect of nonsteroidal 52 Pelletier JP, Boileau C, Brunet J, et al.: The inhibition of subchondral bone anti-inflammatory drugs on the production of cytokines and other inflamma- resorption in the early phase of experimental dog osteoarthritis by licofelone is tory mediators by blood cells of patients with osteoarthritis. Agents Actions • associated with a reduction in the synthesis of MMP-13 and cathepsin K. 1994, 41:171–178. Bone 2004, 34:527–538. 38 Gomez-Gaviro MV, Gonzalez-Alvaro I, Dominguez-Jimenez C, et al.: Struc- A study showing concomitant inhibition of bone resorption and suppressionof ture-function relationship and role of tumor necrosis factor-alpha-converting MMP-13 levels by the LOX/COX inhibitor licofelone. Sports and osteoarthritis Joseph A. Buckwalter and James A. Martin

Purpose of review Introduction Participation in sports improves general health but increases Participation in sports provides entertainment and plea- the risk of osteoarthritis. This review analyzes the relationships sure and improves general health [1••]. Unfortunately, among increased joint use, joint injuries, and injury-induced vigorous physical activity increases the risk of joint inju- joint degeneration that causes posttraumatic osteoarthritis. ries [2••–4••,5]. Damage to joint articular surfaces, me- The purpose is to help people who participate in sports nisci, ligaments, and capsules causes acute tissue damage minimize their risk of joint degeneration. and can lead to permanent joint instability or incongruity Recent findings of the articular surface [6,7•]. Joint instability and articu- Participation in sports that cause minimal joint impact and lar surface incongruity cause repetitive increased contact torsional loading by people with normal joints and stress on articular surfaces that can initiate or accelerate neuromuscular function may cause osteophyte formation, but it joint degeneration [7•]. Injury-induced joint degenera- has minimal, if any, effect on the risk of osteoarthritis. In tion causes joint pain and dysfunction, the clinical syn- contrast, participation in sports that subject joints to high drome of posttraumatic osteoarthritis [2••,7•,8]. Joint levels of impact and torsional loading increases the risk of degeneration generally progresses over years to destroy injury-induced joint degeneration. People with abnormal joint the articular cartilage, leaving only bone wearing against anatomy or alignment, previous joint injury or surgery, bone for bearing surfaces, and causes increasing pain, osteoarthritis, joint instability, articular surface incongruity or loss of mobility, and deformity [6,8]. dysplasia, disturbances of joint or muscle innervation, or inadequate muscle strength have increased risk of joint Review of the evidence concerning the relationships damage during participation in athletics. among joint use, joint injuries, and posttraumatic osteo- Summary arthritis suggests approaches to decreasing the risk of Gaining the benefits of participation in athletics while injury-induced joint degeneration [2••]. The most im- minimizing the risk of osteoarthritis requires understanding of portant sources of evidence are experimental studies in the relationships between sports participation and joint injury animals and clinical and epidemiologic studies of ath- and the relationships between joint injury and joint letes. degeneration. People who wish to participate in sports should have an evaluation of their joint structure and function, muscle Experimental studies strength, and neuromuscular function, and people with a Animal experiments show that the increased joint use history of joint injury or mild osteoarthritis should select sports and impact loading produce different results and that the that have limited risk of accelerating joint degeneration. effects of joint use differ between normal joints and abnormal joints. Keywords sports, posttraumatic osteoarthritis, articular cartilage Increased use of normal joints Life-long moderate running with added weight did not Curr Opin Rheumatol 16:634–639. © 2004 Lippincott Williams & Wilkins. cause joint degeneration in beagles [9]. Animals were divided into two groups: exercised animals (running 4 km/day with jackets weighing an average of 11.5 kg, Department of Orthopaedics and Rehabilitation, University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA 130% of the adult animal’s weight, 5 days a week for 550 weeks) and control animals (cage activity for 550 weeks). Supported by award P50 AR48939 National Institutes of Health Specialized Center on Research for Osteoarthritis (http://poppy.obrl.uiowa.edu/Specialized The joints of animals participating in the exercise regi- Center of Research/SCOR.htm). men did not differ grossly or microscopically from the

Correspondence to Joseph A. Buckwalter, MD, University of Iowa Hospitals, joints of animals limited to cage activity, and mechanical Department of Orthopaedics, 01008 JPP, IA City, IA 52242, USA testing of the articular cartilage did not show any differ- Tel: 319 356 2595; fax: 319 356 8999; e-mail: [email protected] ences between exercised and control animals. Current Opinion in Rheumatology 16:634–639 In a series of investigations of the effects of running © 2004 Lippincott Williams & Wilkins 1040–8711 without added weight, the results depended on the distance the dogs ran. Moderate running (4 km/d, 5 days a week for 40 weeks) increased cartilage thickness, proteo- 634 Sports and osteoarthritis Buckwalter and Martin 635 glycan content, and indentation stiffness [10–12]. More to resume limited joint use as soon as the joint is stable strenuous running (20 km/d, 5 days a week for 15 weeks) and the acute injury response has subsided. decreased cartilage thickness and proteoglycan content. Longer-term strenuous running (40 km/d for as long as 1 Mechanical joint instability caused by disruption of liga- year) decreased cartilage proteoglycan concentration and ments and joint capsules, or possibly increased joint lax- indentation stiffness and stimulated remodeling of sub- ity, may also increase the risk of articular surface injury or chondral bone, but these animals did not develop degen- degeneration with normal joint use. Experimental mod- erative joint disease [13]. These studies suggest that re- els of joint degeneration show that mechanical instability petitive running alters articular cartilage composition and created by transection of the anterior cruciate ligament mechanical properties, but it does not accelerate joint and meniscectomy can lead to progressive joint degen- degeneration. This observation supports the concept eration [27]. These studies have not defined the mecha- that joints can adapt to increased use [14•]. nisms responsible for degeneration of the articular surface in unstable joints, but possible adverse effects of Impact loading of normal joints joint instability include altering the congruence and re- In contrast with the possible adaptive effects of running, gions of contact of the opposing articular surfaces, in- in vivo repetitive impact loading of normal animal joints creasing the number and intensity of rapidly applied im- caused degenerative changes [15,16]. These results show pact loadings, and increasing shear and compression that repetitive impact loading is more likely to cause forces on some regions of the cartilage. joint degeneration than increased joint use. Joint instability combined with loss of sensory innerva- Abnormal joints tion can dramatically increase the susceptibility of joints Although increased physical activity apparently does not to degeneration with use [28,29]. Sensory denervation by adversely affect normal animal joints, joint use may cause dorsal root ganglionectomy did not cause degenerative further damage or prevent optimal healing of injured joint disease in dogs allowed to resume activity as toler- joints. Normal levels of joint use may also cause articular ated and followed for 16 months, but ganglionectomy surface injury and degeneration in unstable joints; in followed by anterior cruciate ligament transection led to subluxed, dysplastic, incongruous, or malaligned joints; severe degenerative changes within 3 weeks of ligament and in joints that do not have normal innervation [2••]. transection [28]. Partial loss of joint innervation also accelerated the development of degenerative joint disease Even mild joint injuries may alter cartilage metabolism in dogs with anterior cruciate ligament transection [29]. and matrix composition. Chondrocytes have the capacity These studies indicate that sensory denervation acceler- to detect these alterations and restore the matrix ates the degeneration of unstable joints. They also sug- [2••,17–19], but joint loading may interfere with this gest that neurologic disorders or partial joint denervation process. In one investigation [20], cast immobilization of at the time of surgery could accelerate joint degeneration a leg for 6 weeks increased knee joint articular cartilage in humans [29]. water content and decreased cartilage thickness, proteoglycan synthesis, and proteoglycan aggregation. Resump- Sports, joint injury, and joint degeneration tion of normal activities appeared to reverse these Comparison of the risk of joint degeneration in runners changes slowly, but running 6 miles a day prevented and people who participate in sports with greater levels reversal of the proteoglycan aggregation defect and fur- of joint impact and torsional loading indicates that sports ther decreased cartilage thickness. Other work shows vary in the risk of joint degeneration. Joint abnormalities that forced activity after enzymatically induced articular increase the risk of joint degeneration. cartilage injury or anterior cruciate ligament transection [21,22,23•] can cause joint degeneration, whereas immo- Running bilization after these injuries may prevent degeneration. Because many runners can recall how long and how often Experimental studies of osteochondral repair in primates they have run, studies of these people provide one of the show that joint immobilization followed by active motion best opportunities to examine the relation between in- produces repair tissue that more closely resembles a nor- creased sports related joint use and joint degeneration in mal articular cartilage than early passive motion [24••]. humans [30]. In one investigation, 41 long-distance run- Taken together, these experimental observations indi- ners were compared with 41 matched controls [31,32]. cate that limited active motion, rest, or even immobili- Runners with a mean age of 60 years who had run an zation of injured joints immediately after injury may pro- average of 180 minutes a week for 12 years did not have duce better results than forced motion and loading soon a greater prevalence of osteoarthritis. Another investiga- after injury. However, prolonged immobilization of joints tion compared 17 people with a mean age of 56 years adversely affects articular cartilage, bone, and ligament who had run an average of 28 miles per week for 12 years metabolism and mechanical properties [23•,25,26] and with 18 nonrunners [33]. Runners had no more com- leads to muscle atrophy. For this reason, it is reasonable plaints of pain and swelling of the hips, knees, ankles, 636 Osteoarthritis and feet than nonrunners, and radiographic examinations generative disease in association with running [46]. In of the joints of the two groups did not show any differ- this investigation, 20 people with a mean age of 39 years ences. The hip joints of 74 former championship dis- who had run an average of 62 miles a week for 20 years tance runners with a mean age of 55 years who had com- were examined clinically and radiographically. Six of the peted for an average of 21 years showed no greater 20 had evidence of degenerative joint disease. All of prevalence of osteoarthritis than controls [34]. these people had genu varum, and four had a history of previous knee injury. Radiographic degenerative However, other investigations suggest that regular run- changes were associated with genu varum, a history of ning increases the risk of osteoarthritis [35••]. A study of previous severe joint injury, and more years of long- long-distance runners with a mean age of 42 years did distance running. Other factors that may increase the risk show more radiographic evidence of hip degenerative of joint degeneration include joint incongruity caused by disease in the runners than in bobsled competitors or previous injury or joint dysplasia, muscle weakness, neu- nonathletes [36], and increased running pace was associ- rologic deficits, and increased weight [2••]. ated with increased radiographic evidence of joint degeneration. Furthermore, a retrospective cohort study of Studies of people with knee ligament and meniscal in- 81 female former elite athletes ranging in age from 40 to juries indicate that after these injuries, the risk of devel- 65 years showed that the former athletes (runners and oping degenerative changes increases [2••], and the time tennis players) had a twofold to threefold increased interval between joint injury and the development of prevalence of radiographic abnormalities in their joints, osteoarthritis may be significantly shorter in older people primarily osteophytes [37]. In analyzing these studies, it [47]. This latter observation supports the concept that is important to recognize that the presence of osteo- age increases the risk of articular cartilage degeneration, phytes is not sufficient to establish the diagnosis of os- possibly because of loss of the ability of chondrocytes to teoarthritis. maintain and restore the articular surface [17,48,49,50••]. The age-related decline in chondrocyte function The studies of runners indicate that, as suggested by the [49,50••] may be accelerated by joint injuries and re- experimental studies of the effects of running in dogs, sidual joint instability after injury caused by increased running causes relatively little increased risk of joint de- oxidative damage to chondrocytes [51••,52••]. generation in normal joints. Increased joint use may stimulate osteophyte formation, but it rarely causes in- Decreasing the risk of joint injury juries that lead to joint degeneration. and degeneration The combination of information from experimental stud- Impact and torsional loading ies with information from clinical investigations makes it People who participate in sports that subject joints to possible to identify sports that increase the risk of joint more intense impact and torsional loading than running degeneration. Table 1 groups sports by estimated inten- have an increased prevalence of joint degeneration [2••]. sity, rate, and frequency of impact and torsional loading Participants in American football have an increased inci- of joints [2••]. dence of degenerative change in multiple joints, possibly caused by joint injuries [38]. One investigator reported Review of currently available clinical, epidemiologic, and that more than 80% of American football players with a experimental studies suggests that several interventions history of a knee injury had evidence of osteoarthritis 10 can decrease the risk of joint degeneration in athletes to 30 years after competing [38]. Baseball pitchers appear [2••]. Appropriate diagnosis, treatment, and rehabilita- to be at increased risk of osteoarthritis of the elbow and tion after injury should decrease the risk of subsequent shoulder [39], competitive soccer players have been joint injury and posttraumatic osteoarthritis. More stud- shown to have an increased prevalence of osteoarthritis ies are needed to determine when or whether people in the lower extremity joints compared with age- with joint injuries should return to competitive sports. matched controls [40–42,43•], and javelin throwers and Other measures that may help preserve normal joint high jumpers appear to have an increased risk of hip structure and function include selection of sports that do osteoarthritis [44•]. not require high levels of joint impact and torsional loading; training and exercise programs that avoid high fre- Abnormal joints quency, rate, and intensity of joint impact and torsional Joint instability, malalignment, or disturbances of me- loading and injury; use of sports and exercise equipment chanical function caused by loss of normal ligament or that minimizes joint impact loading; and decrease in meniscal function may initiate or accelerate the devel- body weight in people with greater than ideal body opment of degenerative changes with participation in weight for their height and age [2••]. Maintaining or sports [2••,45•]. A study of 20 middle-aged runners with improving muscle strength and tone and general condi- knee pain for at least 3 months suggested that joint ab- tioning should help prevent joint injury and minimize normalities may be related to the development of de- articular surface loading caused by muscle weakness and Sports and osteoarthritis Buckwalter and Martin 637

Table 1. Estimated intensity of joint impact and torsional loading

Level joint loading Activities

Low • Recreational swimming • Golf • Stationary cycling, rowing, or skiing • Walking • Tai Chi • Water aerobics • Low impact aerobics • Calisthenics • Downhill skiing Moderate • Bowling • Sailing • Fencing • Speed walking • Bicycling • Cross-country skiing • Rowing • Table tennis • Ice skating • Canoeing • Rock climbing • Hiking • Doubles tennis • Horseback riding • Weight lifting • In-line skating High • Baseball/softball • Lacrosse • Basketball/volleyball • Soccer • American football • Rugby • Handball/racquetball • Singles tennis • Competitive running • Squash

fatigue, and alternating sports or exercise activities will Measures that may decrease the intensity and frequency decrease the number of repetitions of the same pattern of impact and torsional loading of joints include use of of joint loading and motion. sports equipment that decreases joint impact loading, like impact-absorbing shoes and playing surfaces; main- Conclusion taining or improving muscle strength, tone, and general People who participate in sports have increased risk of conditioning so that muscle contractions help protect osteoarthritis compared with sedentary people. This in- joints from injury and high impact; and decreasing body creased risk is caused primarily by joint injuries, and weight. In addition, people who have a joint injury experimental evidence and clinical experience show that should seek appropriate treatment and rehabilitation be- joints are most commonly injured by impact and tor- fore returning to sports. Activities such as bicycling, row- sional loading. Injury-induced joint degeneration causes ing, swimming, golf, and running do not appear to in- the clinical syndrome of posttraumatic osteoarthritis, and crease the risk for development of osteoarthritis in sports that subject joints to repetitive high levels of im- people with normal muscle strength and normal joints. pact and torsional loading increase the risk of joint injury. Not all athletes, or former athletes, who develop osteo- References and recommended reading arthritis have a clear history of joint injury, but it is likely Papers of particular interest, published within the annual period of review, have been highlighted as: that at least some of these people had unrecognized joint • Of special interest damage. •• Of outstanding interest 1 Hunt A: Musculoskeletal fitness: the keystone in overall well-being and injury People with abnormal joint anatomy or alignment, pre- •• prevention. Clin Orthop 2003, 409:96–105. This article stresses the health benefits of musculoskeletal fitness. Musculoskeletal vious significant joint injury or surgery, joint instability, fitness improves the metabolic capabilities of children and adults and helps them above average body weight, disturbances of joint or maintain an ideal body weight. It also may decrease the risk of musculoskeletal disorders such as muscle sprains, lower back pain, osteoarthritis, osteoporosis, muscle innervation, or inadequate muscle strength have shoulder instability, and knee instability and pain. increased risk of degenerative joint disease from activi- 2 Buckwalter JA: Sports, joint injury, and posttraumatic osteoarthritis. J Orthop ties that subject their joints to loads greater than those •• Sports Phys Ther 2003, 33:578–588. A review of the evidence concerning sports-related joint injuries and injury-induced that result from normal activities of daily living, espe- joint degeneration. The current article is based on this previously published manu- cially activities that involve repetitive impact or torsion. script. These people and people with early osteoarthritis can 3 Garrick JG, Requa RK: Sports and fitness activities: the negative conse- •• quences. J Am Acad Orthop Surg 2003, 11:439–443. benefit from regular physical activity, including some This article raises important questions about the adverse consequences of sports sports, but they should have a careful evaluation of their participation. The author stresses that even in the absence of injury, participation in sports during childhood and adolescence increases the likelihood of developing joint structure and function before participating in ath- osteoarthritis. He also notes that although return to sports participation has been letic competition or intense exercise programs. In most accepted as a measure of success of treatment of sports injuries, few efforts have been made to document long-term consequences of continued participation after instances, they would be best advised to select physical joint injury. activities that maintain joint motion and muscle strength 4 Kujala UM, Marti P, Kaprio J, et al.: Occurrence of chronic disease in former with minimal impact or torsional loading, thereby gain- •• top-level athletes: predominance of benefits, risks or selection effects? Sports Med 2003, 33:553–561. ing improved general health and mobility with minimal Competitive athletes have lower overall morbidity risk and enjoy better self-rated increased risk of osteoarthritis. health in later years compared with the general population and matched controls. 638 Osteoarthritis

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47 Roos H, Adalberth T, Dahlberg L, et al.: Osteoarthritis of the knee after injury function in the increased incidence of joint degeneration and decreased capacity to the anterior cruciate ligament or meniscus: the influence of time and age. for cartilage repair with age. Osteoarthritis Cartilage 1995, 3:261–267. 51 Martin JA, Klingelhutz AJ, Moussavi-Harami F, et al.: Effects of oxidative dam- 48 Martin JA, Scherb MB, Lembke LA, et al.: Damage control mechanisms in •• age and telomerase activity on human articular cartilage chondrocyte senes- articular cartilage: the role of the insulin-like growth factor I axis. Iowa Orthop cence. J Gerontol A Biol Sci Med Sci 2004, 59:B324–B336. J 2000, 20:1–10. This experimental study demonstrates how oxidative damage of chondrocyte nuclear DNA may cause a decline in chondrocyte function. Joint injury and exces- 49 Martin JA, Buckwalter JA: Telomere erosion and senescence in human articu- sive articular surface loading can cause oxidative damage to chondrocytes. This lar cartilage chondrocytes. J Gerontology A Biol Sci Med Sci 2001, may help explain how joint degeneration develops after joint injury and how exces- 56:B172–B179. sive joint loading can cause degeneration of the articular surfaces. 50 Martin JA, Buckwalter JA: The role of chondrocyte senescence in the patho- 52 Martin JA, Brown TD, Heiner A, et al.: Post-traumatic osteoarthritis: the role of •• genesis of osteoarthritis and in limiting cartilage repair. J Bone Joint Surg Am •• accelerated chondrocyte senescence. Biorheology 2004, in press. 2003, 85(suppl 2):106–110. A presentation of evidence that excessive articular surface loading can accelerate This article reviews the evidence of a decline in the efficacy of cartilage repair with the age-related loss of chondrocyte function. Accelerated loss of chondrocyte increasing age. It then analyzes the role of an age-related loss of chondrocyte function may contribute to injury-induced joint degeneration. Bibliography Current World Literature Vol 16 No 5 September 2004

This bibliography is compiled by clinicians Contents Pediatric and heritable disorders from the journals listed at the end of this publication. It is based on literature entered Systemic lupus erythematosus and 649 Psychosocial aspects in pediatric into our database between May 1, 2003 Sjörgren syndrome rheumatology and April 30, 2004 (articles are generally 649 Update on pediatric vasculitides added to the database about two and a half 640 SLE trials: successes and issues months after publication). In addition, the 650 International research networks in bibliography contains every paper annotated 641 B cells in human and murine SLE pediatric rheumatology: the PRINTO by reviewers; these references were perspective 641 Update on human SLE genetics obtained from a variety of bibliographic 650 Agents used to induce remission in databases and published between the 642 Apoptosis in SLE pediatric rheumatology: what is the beginning of the review period and the time evidence? of going to press. The bibliography has been 643 Cerebral inflammation and grouped into topics that relate to the reviews 650 Update on pediatric SLE degeneration in SLE in this issue. 650 Genetics of juvenile idiopathic 643 Antibodies, autoimmunity, and SLE arthritis: an update • Papers considered by the reviewers to be of special interest. 643 Interferons: their place in SLE 651 Coping mechanisms in children with •• Papers considered by the reviewers to chronic rheumatic diseases be of outstanding interest. 644 T cells 651 Kawasaki Disease The number in square brackets following a 644 Origin of autoimmunity in Sjögren 651 Hypermobility selected paper, for example [7], refers to its syndrome number in the annotated references of the 651 Miscellaneous corresponding review. 644 CNS pathology in SLE: current Osteoarthritis insights Current Opinion in Rheumatology 652 Galectin-3 in osteoarthritis: when the 2004, 16:640–663 644 Salivary involvement in Sjögren fountain of youth doesn;t deliver its syndrome promises © 2004 Lippincott Williams & Wilkins ISSN 1040–8711 645 Pulmonary involvement in Sjögren 652 Use of stem and mesenchymal cells syndrome for osteoarthritic cartilage regeneration 653 Role of neo-antigen in osteoarthritic 645 Cardiac vascular disease in SLE cartilage 645 Genetics of Sjögren syndrome 653 Angiogenesis in osteoarthritis 645 Treatment of SLE 653 Signaling transduction: target in osteoarthritis 646 Outcome in SLE 654 MPGES-1 as a novel target for 646 Treatment of Sjögren syndrome arthritis 654 Pain and osteoarthritis: new drugs 646 Outcome of Sjögren syndrome and conservative therapies 646 Sex hormones and lupus 657 Sports and osteoarthritis 646 Antiphospholipid antibody syndromes 658 Prostaglandin synthetase in articular joint tissue and biochemical 647 Clinical manifestations of lupus assessment

647 Cytokines in lupus 659 Clinical feature, associations, causes, and epidemiology 647 Clinical manifestations of Sjögren 661 Radiological investigation and syndrome surgical interventions 648 Miscellaneous 663 Miscellaneous

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