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VOLUME 6 NUMBER 2 2008 WWW.ADVANCESINRHEUMATOLOGY.COM

INTERNATIONAL JOURNAL OF ADVANCES IN RHEUMATOLOGY

Editors-in-Chief Michael E Weinblatt, Boston, MA, USA Ferdinand C Breedveld, Leiden, The Netherlands

Pharmacogenetics of Tumor Necrosis Factor Serum Autoantibodies in Rheumatoid Arthritis Antagonists in Rheumatoid Arthritis Raimon Sanmartí, Maria Victoria Hernández, José A Gómez- Hamid Bashir and Prabha Ranganathan Puerta, Eduard Graell, and Juan D Cañete Cardiovascular Aspects of Rheumatoid Arthritis Case Study: Just Another Case of Neuropsychiatric Michael T Nurmohamed Systemic Lupus Erythematosus? Leroy R Lard, Darius Soonawala, Abraham Schoe, and Irene Speyer

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Faculty Disclosures The following are relevant financial relationships declared by the journal’s Editors-in-Chief, Editors, and Editorial Board members. Ferdinand C Breedveld: Abbott, Schering- Plough, Wyeth. Michael E Weinblatt: Abbott, Alza, Amgen, AstraZeneca, BioAssets, Biogen Idec, Bristol-Myers Squibb, CanFite, Celgene, Centocor, CombinatoRx, Critical Therapeutics, Eisai, EntreMed, Genentech, Gilead, Lilly, Merrimack, Merck, Millennium, Novartis, Pfizer, Praecis, Proprius, Rigel, Roche, Sanofi-Aventis, Scios, Serono, Synta, TAP, Trubion, Wyeth, UCB, Vascular Biogenics. Tom Huizinga: None declared. Peter Nigrovic: None declared. Eric Ruderman: Abbott, Amgen, Biogen Idec, Bristol-Myers Squibb, Genentech, Roche. Hendrik Schulze-Koops: Abbott, Aspreva, Essex, Roche, Wyeth. Cornelia F Allaart: None declared. Steven Abramson: Amgen, GlaxoSmithKline, Novartis, Pfizer. Carol Black: None declared. Gerd Burmester: Abbott, Essex, Merck, Novartis, Pfizer, Roche, Sanofi-Aventis, UCB, Wyeth. Maxime Dougados: Abbott, Bristol- Myers Squibb, Roche, Wyeth. Paul Emery: Abbott, Amgen, Bristol-Myers Squibb, Centocor, Roche, Schering-Plough, Wyeth. Daniel Furst: Abbott, Amgen, Bristol-Myers Squibb, Centocor, Genentech, Merck, Novartis, Roche, UCB. Mark Genovese: Biogen Idec, Bristol-Myers Squibb, Genentech, Roche, Serono, Wyeth. Gabriel Herrero- Beaumont: None declared. Joachim Kalden: Abbott, Roche, Schering-Plough, Wyeth. Arthur Kavanaugh: Abbott, Amgen, Biogen Idec, Bristol-Myers Squibb, Centocor, Genentech. Edward Keystone: Abbott, Amgen, AstraZeneca, Bristol-Myers Squibb, Novartis, Pfizer, Roche, Schering-Plough, Wyeth. Lars Klareskog: Abbott, Astra-Zaneca, Bristol-Myers Squibb, Roche, Schering-Plough, Wyeth. Vicente Rodriguez-Valverde: Abbott, Bristol-Myers Squibb, Schering-Plough. Josef Smolen: Abbott, Bristol-Myers Squibb, Centocor, Roche, Sanofi-Aventis, Schering-Plough, Wyeth. Désirée van der Heijde: Abbott, Amgen, Bristol-Myers Squibb, Centocor, Chugai, Dainippon Sumitomo, GlaxoSmithKline, Roche, Schering-Plough, UCB, Wyeth. Editorial Policy International Journal of Advances in Rheumatology is an independent journal published by Remedica Medical Education and Publishing. Editorial control is the sole responsibility of the Editors-in-Chief, Editorial Advisory Board, and the Editors. Before publication, all material submitted to the journal is subjected to rigorous review by the Editors-in-Chief, Editorial Advisory Board, Editors, and/or independent reviewers for suitability of scientific content, scientific accuracy, scientific quality, and conflict of interest.

Aims and Scope International Journal of Advances in Rheumatology is designed to bring a critical analysis of the world rheumatology literature, written by clinicians, for clinicians, to an international, multidisciplinary audience. Our mission is to promote better understanding of rheumatological medicine across the global healthcare system by providing an active forum for the discussion of clinical and healthcare policy issues. Leading Articles - These major review articles are chosen to reflect topical clinical and healthcare issues in rheumatology. All contributions undergo a strict editorial review process. Clinical Reviews - The most important papers from the best of the international literature on rheumatology are systematically selected by an internationally recognized panel of experts. The Editors then prepare concise and critical analyses of each paper, and, most importantly, place the findings into clinical context. Meeting Reports - International Journal of Advances in Rheumatology also provides incisive reportage from the most important international congresses.

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Editors-in-Chief Ferdinand C Breedveld, MD Contents Professor of Rheumatology, Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands Michael E Weinblatt, MD Leading Articles Professor of Medicine, Harvard Medical School, Division of Rheumatology, Pharmacogenetics of Tumor Necrosis Factor Immunology and Allergy, Brigham and Women’s Hospital, Boston, MA, USA Antagonists in Rheumatoid Arthritis: An Update Hamid Bashir and Prabha Ranganathan 34 Editors Tom WJ Huizinga, MD Professor, Department of Rheumatology, Leiden University Medical Center, Cardiovascular Aspects of Rheumatoid Arthritis Leiden, The Netherlands Michael T Nurmohamed 40 Peter Nigrovic, MD Director, Center for Adults with Pediatric Rheumatic Illness, Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital Serum Autoantibodies in Rheumatoid Arthritis Boston, MA, USA Raimon Sanmartí, Maria Victoria Hernández, Eric M Ruderman, MD José A Gómez-Puerta, Eduard Graell, Associate Professor, Division of Rheumatology, Northwestern University and Juan D Cañete 47 School of Medicine, Chicago, IL, USA Hendrik Schulze-Koops, MD, PhD Professor, Division of Rheumatology, University of Munich, Munich, Germany Case Study Just Another Case of Neuropsychiatric Case Study Editor Systemic Lupus Erythematosus? Cornelia F Allaart, MD, PhD Leroy R Lard, Darius Soonawala, Associate Professor, Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands Abraham Schoe, and Irene Speyer 53

Editorial Advisory Board Clinical Reviews Steven B Abramson, MD Treatment Strategies 57 Professor of Medicine and Pathology, New York University School of Medicine, New York, NY, USA Carol M Black, MD Genetics 60 Professor of Rheumatology, Department of Rheumatology, Royal Free Hospital, London, UK Pathogenesis 61 Gerd R Burmester, MD Professor of Medicine, Department of Rheumatology and Clinical Immunology, Charite University Hospital, Humboldt-University of Berlin, Berlin, Germany Infectious and Malignant Complications 63 Maxime Dougados, MD Professor of Rheumatology, Department of Rheumatology, Hospital Cochin, Cardiovascular Risk 65 Paris, France Paul Emery, MD ACR Professor of Rheumatology, Academic Department of Musculoskeletal Prognosis and Assessment 66 Disease, Department of Rheumatology, Leeds General Infirmary, Leeds, UK Daniel E Furst, MD Carl M Pearson Professor of Rheumatology, UCLA Medical School, Miscellaneous 68 Los Angeles, CA, USA Mark C Genovese, MD Meeting Report Assistant Professor of Medicine, Division of Rheumatology, Stanford EULAR 2008 70 University Medical Center, Palo Alto, CA, USA Gabriel Herrero-Beaumont, MD Professor of Rheumatology, Inflammation Research Unit, Fundacion Jimenez Diaz, Universidad Autonoma, Madrid, Spain Joachim R Kalden, MD Professor of Internal Medicine, University of Erlangen-Nuremberg, Erlangen, Germany Arthur F Kavanaugh, MD Professor of Medicine, Division of Rheumatology, Allergy and Immunology, Center for Innovative Therapy, UCSD, La Jolla, CA, USA Edward Keystone, MD Professor of Medicine, University of Toronto, Director, Center for Advanced Therapeutics in Arthritis, Mount Sinai Hospital, Toronto, ON, Canada Lars Klareskog, MD Professor of Rheumatology, Department of Medicine, Karolinska Hospital, Karolinska Institute, Stockholm, Sweden Vicente Rodriguez-Valverde, MD Professor of Medicine and Chief, Rheumatology Service, Hospital Universitario Marqués de Valdecilla, Facultad de Medicina, Universidad de Cantabria, Santander, Spain Josef S Smolen, MD Professor, 2nd Department of Medicine, Krankenhaus Lainz, Vienna, Austria Désirée van der Heijde, MD Professor of Rheumatology, Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands RT404_2_Rheum_6.2_05.qxd 10/9/08 16:44 Page 34

Pharmacogenetics of Tumor Necrosis Factor Antagonists in Rheumatoid Arthritis: An Update

Hamid Bashir, MD, and Prabha Ranganathan, MD Department of Medicine, Washington University School of Medicine, St Louis, MO, USA LEADING ARTICLE Rheumatoid arthritis (RA) is a chronic inflammatory disease with a worldwide prevalence of approximately 1%. There is good agreement on early intervention and tight control of the disease, and prevention of irreversible joint damage. However, despite the introduction of targeted biological therapy, 25–30% of RA patients do not respond to treatment. Individualizing treatment decisions can be problematic because of a lack of predictability of patients’ response to therapy. The results of recent investigations indicate that differential drug responses may be explained by genomic variations between individual patients; this represents a rapidly evolving field called “pharmacogenomics”. Incorporation of such genomic data in clinical practice may lead to individualized treatment of RA with more efficient use of the tumor necrosis factor (TNF) antagonists. This review highlights recent literature on the pharmacogenetics of TNF blockers in RA and the issues that surround pharmacogenomic applications in the future. Int J Adv Rheumatol 2008;6(2):34–9.

Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory the crucial roles of these cytokines in inflammation in RA has disease of unknown etiology that is associated with led to the development of targeted biological therapies, such progressive disability and an increased mortality rate. The as agents that block the action of TNF-α. These biological primary site of pathology is the synovium of the joints, which treatments have revolutionized the treatment of RA. becomes inflamed and proliferates to form a pannus [1]. Randomized clinical trials have shown that these agents yield Many cell populations, including monocytes, macrophages, significant clinical benefit in patients with inadequate B cells, T cells, endothelial cells, and fibroblasts, participate in responses to other disease-modifying drugs [6,7]. the ongoing inflammatory process [2]. B cell–T cell Despite the widespread use of these novel therapeutic interactions are integral to the inflammatory process in RA; B regimens, only 50–70% of patients receiving anti-TNF cells may function as antigen presenting cells and provide therapy achieve at least an ACR20 response during clinical important co-stimulatory signals required for CD4+ T cell trials, suggesting that there remains a significant proportion clonal expansion and effector functions [3,4]. RA is thought of patients that does not respond [8]. As these drugs are to be initiated by T lymphocytes recognizing antigens in the expensive and have the potential to cause serious toxicity synovial tissue. Activated T cells, macrophages, and [9–12], identifying patients most likely to respond favorably fibroblasts produce pro-inflammatory cytokines that play a is desirable. There has been a growing interest in recent key role in the synovitis and tissue destruction in RA. Tumor years in pharmacogenetic approaches to identifying such necrosis factor-α (TNF-α) and interleukin-1 (IL-1) are the two patients. These approaches are particularly relevant in RA major pro-inflammatory cytokines that enhance synovial where long-term therapy is required and several therapeutic proliferation and stimulate secretion of other inflammatory options exist without a universal drug of choice. cytokines, matrix-degrading metalloproteinases, adhesion Inherited differences in drug effects and drug metabolism

molecules, and prostaglandin E2 – all of which are were first documented in the 1950s [13,14]. These concepts instrumental in tissue destruction in RA [5]. Recognition of evolved into a field of research called “pharmacogenetics”, which focuses on the interactions between genetic variations Address for correspondence: Prabha Ranganathan, Division of and drug effects in individuals. Pharmacogenetics has been Rheumatology, Washington University School of Medicine, 660 South rediscovered by a broader spectrum of academia and industry, Euclid Avenue, Campus Box 8045, St Louis, MO 63110, USA. creating the term “pharmacogenomics”. This term applies to Email: [email protected] genome-wide approaches (rather than single or multiple genes

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of interest) that are used to identify genetic variations that polymorphisms in genes encoding proteins related to TNF-α govern response to medications [15]. Unlike other factors that have been identified that may be associated with treatment influence drug response, inherited determinants offer the outcomes in RA [24–26]. Several SNPs have been described advantage of remaining stable throughout a person’s lifetime in the TNF locus (Fig. 1), both within the TNF gene itself and [16]. Inter-individual differences in drug response may be in proximity to it [27,28]. Among these, SNP –308 A/G in caused by common genetic variations (called polymorphisms) the promoter region of TNF has been the most widely in genes encoding drug-metabolizing enzymes, drug studied for its effects on treatment responses to TNF blockers transporters, or drug targets. These genetic variants of interest in RA patients. This polymorphism may influence the binding come in many forms; single nucleotide polymorphisms (SNPs) of transcription factors and control TNF production after are the most common, with possibly 15 million in the human lipopolysaccharide (LPS) stimulation [25,29,30]. Another genome. SNPs are caused by a difference in one base-pair in promoter SNP, TNF –857 C/T, may directly affect the the DNA sequence, which may result in a change in the transcription efficiency of the TNF gene [24] although its function or quantity of the transcribed protein depending on effects on cellular levels of TNF remain controversial [31,32]. the nucleotide change and the location [15]. There are Another category of polymorphisms described in the TNF >30 families of drug-metabolizing enzymes in humans, and locus are the DNA microsatellites, which are highly essentially all are encoded by genes with genetic variants, polymorphic and serve as genetic markers. Microsatellites are many of which translate into functional changes in the proteins repeat sequences of the bases A and T found in the intronic encoded [16]. portions of DNA. Although they are not transcribed into mature mRNA, they can alter DNA folding and conformation TNF blockers in RA and hence the transcription of various enzymes and proteins. TNF-α belongs to a family of proteins important in immune The TNF locus has five such microsatellites, TNFa–e, further regulation and programmed cell death. It has a key role in designated based on the number of repeat sequences [33]. the inflammatory process in RA and is expressed by many Genetic polymorphisms have also been described for other cells within the immune system. TNF-α is involved in cytokines and their receptors, such as IL-1, IL-10, and the Fc stimulating cytokine (including its own) production, in gamma (Fcγ) receptor. For example, the gene encoding the enhancing the expression of adhesion molecules, and in IL-1 receptor antagonist (IL-1ra), IL1RN, has a variable allelic neutrophil activation; it is also a costimulator of T cell polymorphism. The IL1RN*2 allele has been described as a activation and antibody production by B cells [17–19]. It factor determining severity in several autoimmune diseases and induces an array of biological responses in innate as well as has paradoxically been associated with increased production of adaptive immunity by binding to one of two receptors: TNF- IL-1ra by monocytes in vitro [34]. The Fcγ receptor found on RI (subsequently referred to as the p55 TNF receptor) and the surface of cells in the immune system binds the Fc portion TNF-RII (the p75 TNF receptor). These receptors are of an Ig molecule and affects several cell-specific functions, expressed on nearly all human cells [20]. such as phagocytosis, degranulation, antibody dependent cell- Three anti-TNF agents (TNF blockers) are currently mediated cytotoxicity, cytokine release, and regulation of approved for use in the treatment of RA. Etanercept is a antibody production [35]. Fcγ receptor polymorphisms may fusion protein consisting of two p75 TNF receptors linked to alter Fcγ receptor function by enhancing or diminishing its the Fc portion of human immunoglobulin G1 (IgG1). This affinity for Igs [36]. The most frequent polymorphism of Fcγ agent binds to soluble TNF-α and lymphotoxin-α (LT-α), receptor IIIA, a subclass of Fc receptor, is a point mutation thereby preventing binding of these molecules to their cell- affecting amino acids in codon 158 in the extracellular surface receptors. However, etanercept does not bind to domain [37]. transmembrane TNF-α or induce lysis of target cells. Besides etanercept, two monoclonal antibodies against TNF-α are TNF promoter polymorphisms available: the chimeric antibody infliximab, and the fully Fonseca et al. demonstrated that RA patients with the –308 humanized antibody adalimumab. These two monoclonal G/G genotype had a better response to infliximab treatment antibodies directly bind TNF-α on the cell surface, fix than those who had the A/A or A/G genotype [38]. They complement, and induce lysis of the target cells [21–23]. studied the influence of the TNF –308 A/G polymorphism on long-term responses to infliximab in a prospective fashion in Pharmacogenetic studies of TNF blockers in RA 22 consecutive patients. Patients who had the A/A or Pharmacogenetic studies of anti-TNF therapies in RA have A/G genotype were compared with those who had the involved the obvious candidate gene, TNF, coding for TNF-α, G/G genotype. After 24 months of treatment with and the genes encoding TNF-α receptors. In recent years, infliximab, patients with the –308 G/G genotype had a

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Figure 1. Chromosomal location of the TNF-α gene and polymorphisms in the region.

TNF HLA Class I locus HLA Class II

Telomere Centromere 320 kb 850 kb

Microsatellite markers found in the TNF gene locus include TNFa, TNFb, TNFc, TNFd and TNFe

a b c LT-α TNF-α LT-β de

+249 +365 +720 –375 –244 –163 –70 +488

–308 –238 Single nucleotide polymorphisms in the Single nucleotide polymorphisms in the region of the LT-α gene region of the TNF-α gene

HLA: human leukocyte antigen; LT-α: lymphotoxin-α; TNF-α: tumor necrosis factor-α. Redrawn with permission from [28].

significantly better response (mean decrease in DAS28 –2.4; Kang et al. studied several genetic polymorphisms within p<0.01) than patients in the other groups. The study the TNF and LT-α gene region and showed that the –857 also demonstrated that the TNF –308 A/G genotype was C/T SNP in the promoter region of the TNF gene was associated with sustained (>1 year) high disease activity associated with response to etanercept [40]. In this study, 70 and functional decline despite treatment with infliximab, Korean patients were examined to determine whether these suggesting that carrying the A allele may portend a more polymorphisms were associated with treatment outcome severe disease course in RA with a poorer response with etanercept. Patients were divided into responders and to treatment. non-responders according to the ACR20 and ACR70 Guis et al. reported that RA patients with the –308 G/G response criteria. Only the –857 C/T SNP was significantly genotype responded better to etanercept than patients with associated with response; the frequency of the T allele was the –308 A/G or A/A genotypes [39]. The study involved 86 5% in the ACR20 non-responders and 39% in the ACR70 RA patients who were treated with etanercept and responders (odds ratio [OR] 12, 95% confidence interval genotyped for the –308 A/G TNF polymorphism. Patients [CI] 1.4–105; p=0.0077). Among ACR70 responders, there were subdivided into group A (A/A and A/G genotypes) and were more carriers of the T allele (39%) than the C allele group G (G/G genotype). The clinical response to etanercept (13%), although this did not reach statistical significance. in groups A and G was compared after 6 and 12 months, Moreover, the ratio of ACR70 responders to ACR20 non- using the DAS28. After a 6-month treatment period, 55.6% responders among the T-allele carriers was >10-fold higher of patients in group A and 82.4% of patients in group G than in the C allele homozygotes (OR 12, 95% CI 1.2–120; had a DAS28 improvement of >1.2 (p=0.027). After 1 year p=0.033), indicating that this SNP may be a useful genetic of treatment, among 48 patients followed up, 47% of marker for predicting response to etanercept. patients in group A and 87% in group G maintained an A recent pharmacogenetic study by Miceli-Richard improvement in DAS28 >1.2 (p=0.005). et al. suggested that a particular TNF haplotype

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Table 1. Summary of pharmacogenetic studies of TNF antagonists in RA. Gene/polymorphism Postulated function of polymorphism Possible clinical effect Reference TNF –857 Transcription/production of TNF-α TNF –857 T-allele was associated with [40] positive response to etanercept in RA

TNF –308 Transcription/production of TNF-α TNF –308 GG was associated with positive [38,39] response to infliximab and etanercept in RA

TNF –238 Transcription/production of TNF-α TNF –238 G-allele was associated with [41] negative response to adalimumab in RA

IL10 microsatellites Regulation of IL-10 production IL10 microsatellites IL10.G13 and [42] IL10.R2-G13 haplotype were associated with a decreased response to etanercept in RA

FcγRIIIA-158 Binding to IgG leading to phagocytosis FcγRIIIA-158 F-allele was associated [37] with positive response to various TNF blockers in RA and psoriatic arthritis

HLA-DRB1 SE Influence on severity and susceptibility to RA Number of HLA-DRB1 SE copies associated [43] with increased likelihood of selection for infliximab therapy in RA

IgG: immunoglobulin G; IL-10: interleukin-10; FcγRIIIA: Fcγ receptor type IIIA; HLA: human leukocyte antigen; RA: rheumatoid arthritis; SE: shared epitope; TNF-α: tumor necrosis factor-α.

(–238G/–308G/–857C) may be associated with a lower rate of 0.05–0.61, and OR 0.14, 95% CI 0.04–0.50, respectively). response to adalimumab in RA patients [41]. The investigators These results suggest that microsatellite polymorphisms in the studied 388 patients receiving adalimumab alone or in IL10 gene may play a role in determining response to combination with a disease-modifying antirheumatic drug etanercept in RA patients. (DMARD). All patients were genotyped for the HLA-DRB1 shared epitope (SE) alleles and three TNF gene polymorphisms Fcγ receptor polymorphisms (–238A/G, –308A/G, and –857C/T). Extended haplotypes Tutuncu et al. investigated the Fcγ receptor type IIIA (FcγRIIIA) spanning the HLA-DRB1 and TNF loci were constructed. polymorphism and demonstrated that the FcγRIIIA-158 F allele Neither the number of HLA-DRB1 SE copies nor the presence was a marker of favorable response to anti-TNF therapy [37]. of the three individual TNF polymorphisms was significantly The study was designed to assess the clinical outcome in 35 associated with an ACR50 response to adalimumab at 12 patients with RA and psoriatic arthritis treated with the three weeks. However, the –238G/–308G/–857C haplotype was anti-TNF agents (adalimumab, etanercept, and infliximab). associated with a lower rate of ACR50 response to Each patient’s rheumatologist was asked to categorize the adalimumab at this time point (34% vs. 50% in patients patient as a good responder or a poor responder based on without the haplotype; p=0.003). physician’s global assessment of disease activity. All patients were genotyped for the FcγRIIIA-158 polymorphism. The IL-10 microsatellite polymorphisms distribution of the FcγRIIIA-158 genotype was as follows: F A recent study by Schotte et al. looked at microsatellite homozygous (F/F) 31.5%, V homozygous (V/V) 11.5%, and polymorphisms in the IL10 gene as predictors of response to VF heterozygous (V/F) 57%. Among very good responders etanercept therapy [42]. The IL10 microsatellites IL10.R and (n=23), the distribution of alleles was as follows: F/F 48%, IL10.G were genotyped in 50 RA patients. Patients were V/V 13%, and V/F 39%. Among non-responders (n=12), the treated for up to 4 years with etanercept and the treatment distribution of alleles was as follows: F/F 0%, V/V 8%, and response was assessed by the EULAR criteria. IL10.R3 and the V/F 92% (p<0.01). Thus, the FcγRIIIA-158 F allele appeared to IL.R3-G9 haplotype were associated with a good response to be a marker of response to anti-TNF therapy. etanercept (OR 5.5, 95% CI 1.6–18, and OR 5.1, 95% CI 1.5–18, respectively). In addition, IL10.G13 and the IL10.R2- IL-1RN/SE polymorphisms G13 haplotype were more common among patients with a Marotte et al. investigated IL1RN and TNF polymorphisms in moderate or no response to etanercept (OR 0.18, 95% CI 198 RA patients and found that these polymorphisms did

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not predict the clinical response to infliximab [43]. The study challenge to the incorporation of pharmacogenetic testing sought to determine whether the response to infliximab was into clinical care is not the availability of technologies to associated with SE carrier status or selected cytokine gene determine large numbers of genotypes, but rather the polymorphisms in IL1RN and TNF (including the –308G/A precise definition of drug-response phenotypes. Large, well- promoter polymorphism). The response to infliximab was powered clinical trials are needed before genotype-guided defined using ACR response rates. Neither SE carrier status therapy can be incorporated into routine clinical care [15]. nor the polymorphisms predicted response to infliximab. Furthermore, rather than single SNP association studies, However, the authors demonstrated an association between large multicenter studies examining composite SNPs and selection for infliximab treatment and SE status, in that haplotypes may be more useful in defining the genotypes patients with the SE were almost twice as likely to be that determine drug response. With rapid advances in the selected for infliximab treatment (OR 1.89, 95% CI International HapMap Project (www.hapmap.org) and the 1.35–2.65; p<0.001). In addition, a dose effect was dedication of major funding agencies to pharmacogenetics observed between the SE copy number and selection for research (www.nigms.nih.gov/pharmacogenetics), such infliximab treatment; patients with one SE copy were 1.5 studies should be feasible and available in the near future. times more likely (OR 1.58, 95% CI 1.09–2.27; p=0.01) and patients with two copies three times more likely (OR 2.96, Disclosures 95% CI 1.92–4.56; p<0.001) to be selected for infliximab The authors have no relevant financial interests to disclose. treatment than those with no copies of the SE allele. References Discussion 1. Felson DT, Zhang Y, Hannan MT et al. The incidence and natural history of knee osteoarthritis in the elderly. The Framingham Osteoarthritis Study. Arthritis Rheum Although biological therapies blocking TNF-α constitute a 1995;38:1500–5. 2. Panayi GS. The pathogenesis of rheumatoid arthritis: from molecules to the whole patient. major advance in the management of RA, selection of RA Br J Rheumatol 1993;32:533–6. patients for these therapies is still empirical and there are no 3. Takemura S, Braun A, Crowson C et al. Lymphoid neogenesis in rheumatoid synovitis. standard guidelines. Pharmacogenetic testing has significant J Immunol 2001;167:1072–80. 4. Dörner T, Burmester GR. The role of B cells in rheumatoid arthritis: mechanisms and potential to optimize therapy with these agents in RA therapeutic targets. Curr Opin Rheumatol 2003;15:246–52. patients, but there are certain facts about the studies 5. Firestein GS. Etiology and Pathogenesis of Rheumatoid Arthritis. 6th edition. Kelley’s Textbook of Rheumatology. S Ruddy, ED Harris, CB Sledge et al., editors. WB Saunders reviewed in this article that need to be considered (Table 1). Company, Philadelphia, PA. 921–966. 6. Weinblatt ME, Kremer JM, Bankhurst AD et al. A trial of etanercept, a recombinant tumor Most of these studies had small sample sizes and hence were necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving underpowered, raising questions about the validity and methotrexate. N Engl J Med 1999;340:253–9. 7. Maini RN, Breedveld FC, Kalden JR et al. Therapeutic efficacy of multiple intravenous generalizability of the results. In addition, considerable infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low- contradiction exists amongst the available studies. For dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum 1998;41:1552–63. 8. Hyrich KL, Watson KD, Silman AJ et al. Predictors of response to anti-TNF-alpha therapy example, some studies showed a positive association among patients with rheumatoid arthritis: results from the British Society for between the TNF –308 G/G genotype and response to Rheumatology Biologics Register. Rheumatology (Oxford) 2006;45:1558–65. 9. Askling J, Fored CM, Brandt L et al. Time-dependent increase in risk of hospitalisation with infliximab and etanercept [38,39], while others demonstrated infection among Swedish RA patients treated with TNF antagonists. Ann Rheum Dis no such association [40,43]. More importantly, given the 2007;66:1339–44. 10. Breedveld FC, Weisman MH, Kavanaugh AF et al. The PREMIER study: a multicenter, central role of TNF in the pathophysiology of RA, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, polymorphisms in the TNF locus may potentially influence aggressive rheumatoid arthritis who had not had previous methotrexate treatment. disease severity and this fact should be taken into account Arthritis Rheum 2006;54:26–37. 11. Klareskog L, van der Heijde D, de Jager JP et al.; TEMPO (Trial of Etanercept and when interpreting such pharmacogenetic data. For instance, Methotrexate with Radiographic Patient Outcomes) study investigators. Therapeutic effect α of the combination of etanercept and methotrexate compared with each treatment alone Fonseca et al. observed that the TNF- –308 A/G genotype in patients with rheumatoid arthritis: double-blind randomised controlled trial. Lancet was associated with high disease activity and functional 2004;363:675–81. 12. Maini RN, Breedveld FC, Kalden JR et al.; Anti-Tumor Necrosis Factor Trial in Rheumatoid decline, despite treatment with infliximab [38]. Hence, it may Arthritis with Concomitant Therapy Study Group. Sustained improvement over two years in physical function, structural damage, and signs and symptoms among patients with be difficult to differentiate between the effects of the TNF rheumatoid arthritis treated with infliximab and methotrexate. Arthritis Rheum polymorphisms on RA disease activity and severity, and 2004;50:1051–65. 13. Kalow W, Maykut MO. The interaction between cholinesterases and a series of local response to anti-TNF therapy. anesthetics. J Pharmacol Exp Ther 1956:116:418–32. 14. Weinshilboum R. Inheritance and drug response. N Engl J Med 2003;348:529–37. 15. Lanfear DE, McLeod HL. Pharmacogenetics: using DNA to optimize drug therapy. Am Fam Summary Physician 2007;76:1179–82. In summary, although the results of recent pharmacogenetic 16. Evans WE, McLeod HL. Pharmacogenomics – drug disposition, drug targets, and side studies on the TNF antagonists in RA are intriguing, they effects. N Engl J Med 2003;348:538–49. 17. Podolsky DK. Inflammatory bowel disease. N Engl J Med 2002;347:417–29. remain hypothesis-generating and need to be replicated and 18. Feldmann M, Brennan FM, Maini RN. Role of cytokines in rheumatoid arthritis. Ann Rev validated in larger patient populations. The greatest Immunol 1996;14:397–440.

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19. Choy EH, Panayi GS. Cytokine pathways and joint inflammation in rheumatoid arthritis. 33. Udalova IA, Nedospasov SA, Webb GC et al. Highly informative typing of the human TNF N Engl J Med 2001;344:907–16. locus using six adjacent polymorphic markers. Genomics 1993;16:180–6. 20. Rigby WF. Drug insight: different mechanisms of action of tumor necrosis factor 34. Perrier S, Coussediere C, Dubost JJ et al. IL-1 receptor antagonist (IL-1RA) gene antagonists – passive-aggressive behavior? Nat Clin Pract Rheumatol 2007;3:227–33. polymorphism in Sjogren’s syndrome and rheumatoid arthritis. Clin Immunol 21. Elliott MJ, Maini RN, Feldmann M et al. Treatment of rheumatoid arthritis with chimeric Immunopathol 1998;87:309–13. monoclonal antibodies to tumor necrosis factor alpha. Arthritis Rheum 1993;36:1681–90. 35. Binstadt BA, Geha RS, Bonilla FA. IgG Fc receptor polymorphisms in human disease: 22. Maini RN, Elliott MJ, Brennan FM et al. Monoclonal anti-TNF alpha antibody as a probe of implications for intravenous immunoglobulin therapy. J Allergy Clin Immunol pathogenesis and therapy of rheumatoid disease. Immunol Rev 1995;144:195–223. 2003;111:697–703. 23. Coenen MJ, Toonen EJ, Scheffer H et al. Pharmacogenetics of anti-TNF treatment in 36. de Haas M, Koene HR, Kleijer M et al. A triallelic Fc gamma receptor type IIIA patients with rheumatoid arthritis. Pharmacogenomics 2007;8:761–73. polymorphism influences the binding of human IgG by NK cell Fc gamma RIIIa. J Immunol 1996;156:2948–55. 24. van Heel DA, Udalova IA, De Silva AP et al. Inflammatory bowel disease is associated with a TNF polymorphism that affects an interaction between the OCT1 and NF(-kappa)B 37. Tutuncu Z, Kavanaugh A, Zvaifler N et al. Fcgamma receptor type IIIA polymorphisms transcription factors. Hum Mol Genet 2002;11:1281–9. influence treatment outcomes in patients with inflammatory arthritis treated with tumor necrosis factor alpha-blocking agents. Arthritis Rheum 2005;52:2693–6. 25. Louis E, Franchimont D, Piron A et al. Tumour necrosis factor (TNF) gene polymorphism influences TNF-alpha production in lipopolysaccharide (LPS)-stimulated whole blood cell 38. Fonseca JE, Carvalho T, Cruz M et al. Polymorphism at position –308 of the tumour culture in healthy humans. Clin Exp Immunol 1998;113:401–6. necrosis factor alpha gene and rheumatoid arthritis pharmacogenetics. Ann Rheum Dis 2005;64:793–4. 26. Waldron-Lynch F, Adams C, Amos C et al. Tumour necrosis factor 5’ promoter single nucleotide polymorphisms influence susceptibility to rheumatoid arthritis (RA) in 39. Guis S, Balandraud N, Bouvenot J et al. Influence of –308 A/G polymorphism in the tumor immunogenetically defined multiplex RA families. Genes Immun 2001;2:82–7. necrosis factor alpha gene on etanercept treatment in rheumatoid arthritis. Arthritis Rheum 2007;57:1426–30. 27. Ranganathan P. Pharmacogenomics of tumor necrosis factor antagonists in rheumatoid arthritis. Pharmacogenomics 2005;6:481–90. 40. Kang CP, Lee KW, Yoo DH et al. The influence of a polymorphism at position –857 of the tumour necrosis factor alpha gene on clinical response to etanercept therapy in 28. Knight JC, Kwiatkowski D. Inherited variability of tumor necrosis factor production and rheumatoid arthritis. Rheumatology (Oxford) 2005;44:547–52. susceptibility to infectious disease. Proc Assoc Am Physicians 1999;111:290–8. 41. Miceli-Richard C, Comets E, Verstuyft C et al. A single tumour necrosis factor haplotype 29. Baseggio L, Bartholin L, Chantome A et al. Allele-specific binding to the –308 single influences the response to adalimumab in rheumatoid arthritis. Ann Rheum Dis nucleotide polymorphism site in the tumour necrosis factor-alpha promoter. Eur J 2008;67:478–84. Immunogenet 2004;31:15–9. 42. Schotte H, Schluter B, Drynda S et al. Interleukin 10 promoter microsatellite 30. Bouma G, Crusius JB, Oudkerk Pool M et al. Secretion of tumour necrosis factor alpha and polymorphisms are associated with response to long term treatment with etanercept in lymphotoxin alpha in relation to polymorphisms in the TNF genes and HLA-DR alleles. patients with rheumatoid arthritis. Ann Rheum Dis 2005;64:575–81. Relevance for inflammatory bowel disease. Scand J Immunol 1996;43:456–63. 43. Marotte H, Pallot-Prades B, Grange L et al. The shared epitope is a marker of severity 31. Uglialoro AM, Turbay D, Pesavento PA et al. Identification of three new single nucleotide associated with selection for, but not with response to, infliximab in a large rheumatoid polymorphisms in the human tumor necrosis factor-alpha gene promoter. Tissue Antigens arthritis population. Ann Rheum Dis 2006;65:342–7. 1998;52:359–67. 32. Higuchi T, Seki N, Kamizono S et al. Polymorphism of the 5’-flanking region of the human tumor necrosis factor (TNF)-alpha gene in Japanese. Tissue Antigens 1998;51:605–12.

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Cardiovascular Aspects of Rheumatoid Arthritis

Michael T Nurmohamed, MD, PhD Departments of Internal Medicine and Rheumatology, VU University Medical Centre; Department of Rheumatology, Jan van Breemen Institute, Amsterdam, The Netherlands

The increased mortality rate in rheumatoid arthritis (RA) is predominantly due to atherosclerotic cardiovascular (CV) disease. LEADING ARTICLE CV morbidity is also elevated in comparison with the general population. This increased CV risk may be caused by a greater prevalence of CV risk factors, under-treatment of these risk factors, or RA itself – particularly its chronic inflammatory component. However, CV risk factors only partly explain the enhanced CV risk and it is becoming increasingly acknowledged that the inflammatory process in RA plays a pivotal role. This is probably related to the fact that atherosclerosis also has an inflammatory component and RA accelerates this process. Equally, it is possible that effective suppression of inflammation by disease-modifying antirheumatic drugs and/or biological agents could lower the CV risk. There is now accumulating evidence that the enhanced CV risk in RA is similar to that observed in type 2 diabetes, and RA should therefore be seen as a new CV risk factor for which appropriate risk management is mandatory. Int J Adv Rheumatol 2008;6(2):40–6.

The mortality rate in rheumatoid arthritis (RA) is higher than rate becomes more apparent after 10 years of disease that in the general population, and standardized mortality duration) [1,5]. Another possible explanation for this ratios (SMRs) range from 1.3–3.0 [1]. This increased discrepancy might be the more intensive treatment of RA mortality rate is largely attributable to cardiovascular disease employed nowadays, which leads to a longer overall life (CVD), principally atherosclerosis. CV morbidity also appears expectancy. Nevertheless, this survival improvement remains to be at least two-fold greater in RA in comparison with the below that of the general population; thus, SMRs remain general population [2]. The raised CV risk in RA may have enhanced. This is illustrated by a recent study in which no several causes. Firstly, the prevalence of CV risk factors, such reduction in mortality rate was observed; in fact, a relative as dyslipidemia, diabetes mellitus, hypertension, a higher increase in comparison with the general population was seen body mass index (BMI), a higher waist-to-hip ratio, or lack [6]. The mortality rates between 1965 and 2005 were of physical activity, may be increased. Secondly, in chronic relatively constant at 2.4 and 2.5 per 100 person-years for diseases, unrelated disorders such as hypertension are female and male RA patients, respectively. In contrast, the frequently under-treated [3,4]. Finally, the chronic expected mortality rate in female population control subjects inflammatory process in RA might itself mediate a higher declined from 1.0 in 1965 to 0.2 per 100 person-years in CV risk. 2000. For male subjects, these figures were 1.3 and 0.2 per 100 person-years in 1965 and 2000, respectively. These Cardiovascular mortality findings indicate a widening mortality gap between RA Most studies indicate that the risk of dying from CV disease patients and the general population. in RA, particularly coronary heart disease, is increased by more than two-fold in comparison with the general Cardiovascular morbidity population. However, some recent reports described no As stated above, several investigations have indicated an enhanced mortality rate in RA, which might be due to the elevated rate of CVD in RA. In a prospective Dutch study, inclusion of inception cohorts (as the enhanced mortality the magnitude of this enhanced CV risk relative to that conferred by type 2 diabetes – a well-established CV risk Address for correspondence: Michael T Nurmohamed, Departments of factor – was investigated [2]. The prevalence of CVD was Internal Medicine and Rheumatology, VU University Medical Centre, determined in 353 RA patients in the CARRÉ (Cardiovascular De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands. Research and Rheumatoid Arthritis) study, and in Email: [email protected] participants of a population-based cohort study on CVD and

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its risk factors (the Hoorn study). Non-diabetic RA patients might solve this problem. In this regard, congestive heart (n=294) were compared with non-diabetic, non-RA failure is generally the result of either systolic or diastolic individuals (n=258), and individuals with type 2 diabetes ventricular dysfunction, and an increased frequency of left (n=194) from the Hoorn study. The adjusted odds ratios ventricular diastolic dysfunction has been found in patients (OR) for CVD were 3.1 in RA patients and 2.3 in individuals with long-standing RA who do not have CV risk factors or with type 2 diabetes in comparison with non-diabetic clinically evident CV manifestations [15]. Moreover, an individuals. This investigation indicates that the prevalence increased frequency of subclinical pulmonary hypertension of CVD in RA is at least comparable with its prevalence in has also been identified in these patients compared with diabetes, and is increased at least two-fold relative to the matched controls. general population. Stroke Myocardial infarction Wolfe et al. reported the results of a US survey of CVD in RA patients who experience a myocardial infarction (MI) have 9093 RA patients and 2479 osteoarthritis patients [16]. an approximately doubled rate of multivessel coronary disease Compared with osteoarthritis patients, RA patients had an in comparison with MI patients without RA, indicating OR of 1.7 (95% CI 1.3–2.2) for current stroke and an OR of accelerated atherosclerosis in RA [7]. In addition, the case 1.1 (95% CI 0.9–1.2) for lifetime stroke. In contrast, fatality rate in RA patients following an MI is almost two-fold Solomon et al. followed 25 385 British Columbian adults greater than that in individuals without RA [8,9]. It is also with RA over 5 years and found an incidence rate per important to realize that RA patients are less likely to report 1000 years of 5.1 in RA and 2.7 in non-RA subjects, angina and are twice as likely to have a silent MI and sudden resulting in a rate ratio of 1.9 (95% CI 1.7–2.1) [17]. death in comparison with the general population [10]. Another database investigation in 11 633 RA patients in the To date, two follow-up studies with CV endpoint UK, with a follow-up of 5 years, revealed an incidence rate assessment have been published. In the first, 234 patients of stroke of 7.0 per 1000 patient-years and a relative risk of with RA were followed up for 1 year, and 15 CV events 1.4 (95% CI 1.3–1.5) versus non-RA subjects [18]. These (predominantly MIs) occurred during 252 patient-years [11]. data strongly suggest that the risk for stroke is enhanced in As a comparator group, >4600 participants of a community- RA patients, although the increase may be less in based cohort were followed for up to 8 years; in this group, comparison with the risk for an MI. 200 CV events occurred. The age- and sex-adjusted incidence risk ratio of CV events associated with RA was 4.0 Peripheral arterial disease (95% confidence interval [CI] 1.86–8.43), which decreased A database investigation from an integrated US health plan to 3.2 when adjusting for CV risk factors. The second study including 28 208 RA patients revealed a prevalence of considered the 3-year follow-up of the CARRÉ investigation peripheral arterial disease of 4.7 in RA patients and 1.7 in [12]. In that analysis, CV events were reported in 9% of the matched controls (OR 2.3; 95% CI 2.3–2.6) [19]. Liang et RA patients and in 4% of the general population. The age- al. found a 30-year cumulative incidence rate of peripheral and gender-adjusted relative risk (RR) of a CV event was 2.0 arterial disease of 20% in 609 incident RA patients who (95% CI 1.3–3.1). were diagnosed during 1955–1994 and followed up to the year 2000 [20]. This is approximately 30% higher than Congestive heart failure would have been expected from prevalence data in non-RA One of the first investigations revealing an increased subjects [20]. In an elegant study, Del Rincón et al. likelihood of congestive heart failure in RA indicated an investigated the stiffness of limb arteries as a marker for RR of 1.6 during follow-up of 450 RA patients and 450 peripheral arterial disease in 234 RA patients and 102 control subjects [13]. A much larger sample of patients came control subjects [21]. Among the RA patients, 66 of 931 from the National Data Bank for Rheumatic Diseases [14]. A arteries (7%) were incompressible and 30 (3%) were total of 13 171 RA patients and 2568 osteoarthritis patients obstructed; for the control subjects, the percentages were were followed over a 2-year period; heart failure was 0.7% and 1%, respectively. observed in 461 (3.9%) of those with RA and in 87 (2.3%) osteoarthritis patients. Other database investigations have Preclinical atherosclerosis indicated similar results. However, an important pitfall of the It is increasingly acknowledged that carotid artery intima- heart failure studies is that diagnosis has always been based media thickness (IMT) is an important marker for early, on clinical criteria, rendering it less reliable. Obviously, the preclinical atherosclerosis and a strong predictor of future use of echocardiography for assessment of heart failure CV events. IMT is assessed non-invasively with

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echocardiographic techniques (carotid ultrasound). In a in patients with RA is contradictory but it appears that there landmark study of 4476 general population persons is an inverse relationship between disease activity and lipid followed for 6 years, every 0.20 mm increase of the levels [29]. maximum IMT of the common carotid artery was associated with a 30% increase in the incidence of new CV events [22]. When does the dyslipidemia start? Consequently, carotid artery IMT in RA has been assessed by Dyslipidemia is already present in early RA and so the question several investigators. One of the first studies was conducted of whether or not this phenomenon starts in the preclinical by Japanese researchers who found significantly increased phase of the disease has emerged. Hence, the present author common carotid IMT in 138 RA patients (mean age and colleagues have investigated the lipid profile over time, 55 years) in comparison with 94 matched controls (mean and its relationship with inflammation, in subjects who later age 52 years), with values of 0.64 mm and 0.58 mm, developed RA [30]. Future RA patients displayed 4% higher respectively (p<0.05) [23]. TC, 9% lower HDL-C, and 17% higher triglyceride levels than Accurate longitudinal data on the progression of subclinical matched controls (p≤0.05), at least 10 years before the onset atherosclerosis in RA are still sparse, but data were recently of symptoms. Although the differences between the various indirectly derived from a cross-sectional investigation. del lipid values were small, they are clinically relevant, particularly Rincón et al. found that the rate at which the IMT increased in the light of results from other studies [31]. was related to disease duration and ranged from 0.15 mm/ 10 years among RA patients with a disease duration of Functional properties of lipid particles <7 years, to 0.30 mm/10 years in RA patients with a disease Protecting LDL from oxidation is one the anti-atherogenic duration of >20 years [24]. Therefore, patients with prolonged roles of normal HDL. This anti-inflammatory HDL is distinct RA have more advanced atherosclerosis than patients of the from the so-called pro-inflammatory HDL, which is devoid of same age but who have a shorter disease duration, which these properties and may actually promote atherosclerosis. suggests that RA accelerates atherosclerosis. This is in line with Indeed, in a small study that included 48 women with RA and the observation that atherosclerosis represents a chronic 72 healthy subjects, McMahon and colleagues showed that inflammatory process of the artery and, therefore, that longer pro-inflammatory HDL was detected more frequently in RA RA disease duration will lead to a greater atherosclerotic patients (20%) than in control subjects (4%) [32]. burden (discussed below in “Atherosclerosis and inflammation”). Gonzalez-Juanatey and colleagues recently Antirheumatic treatment and lipid profile found that carotid artery IMT had a high predictive power for Treatment with disease-modifying antirheumatic drugs the development of CV events over a 5-year follow-up period (DMARDs) has beneficial effects on the lipid profile in in 47 patients with RA who did not have clinically evident CV patients with early active RA [33]. These agents do mediate disease at the time of the carotid ultrasonography an increase in TC, but they induce a more pronounced evaluation [25]. increase in HDL-C, resulting in a lower (more favorable) An emerging technique for assessing coronary athero- atherogenic index (TC/HDL-C ratio), which is an important sclerosis, including preclinical disease, is the determination of prognostic CV risk factor. coronary artery calcification by computed tomography [26]; Investigations of tumor necrosis factor (TNF)-blocking the presence of such coronary calcifications is a strong agents reveal a transient increase in TC and HDL-C levels, predictor of subsequent coronary heart disease. Chung et al. mostly accompanied by improvement of the atherogenic found coronary calcification in 61% of patients with index, during the first few months of the treatment. established RA, 43% of early RA patients, and in 38% of Thereafter, the results become divergent between the control subjects [27]. The OR for more severe coronary studies (reviewed in [33]). This may be due to differences in calcification was 3.4 in patients with established disease. The disease activity, changes in co-medication (particularly relationship between coronary calcification and RA disease prednisone), dietary intake, and physical activity. Hence, duration was recently confirmed in another study [28]. future studies should appropriately address these potential confounders in order to reach valid conclusions. Cardiovascular risk factors in RA Dyslipidemia Lifestyle factors and medical comorbidities Increased levels of total cholesterol (TC) and low-density Smoking is an important risk factor for CV disease in the lipoprotein cholesterol (LDL-C), and a decreased level of general population. It is conceivable that smoking might high-density lipoprotein cholesterol (HDL-C) are associated play a role in CV disease in RA as it increases the with a higher CV risk. The available literature on lipid profiles susceptibility for the development of RA as well its severity

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[34]. A recent investigation revealed that smoking was more binding of (modified) LDL-C to the endothelium and muscle prevalent in RA patients and that there was an increased CV cells. Modified LDL-C accumulates within macrophages risk in these subjects compared with that in non-smoking RA resulting in the formation of foam cells and subsequent fatty patients [35]. However, the effect of smoking was streaks. This lesion progresses and a fibrous cap is formed, significantly less than that observed in control (non-RA) which consists of smooth muscle cells and a collagen matrix subjects (hazard ratio [HR] for CV disease was 1.3 and 2.2 that separates the atherosclerotic plaque lesion from the for smoking vs. non-smoking RA patients and smoking vs. arterial lumen [40,41]. non-smoking controls, respectively). During this process, the arterial wall becomes thicker; Published data on the prevalence of type 2 diabetes in RA however, initially, the lumen remains unaltered owing to are not concordant; however, as there is increasing evidence dilatation. Accumulation and activation of macrophages and T for elevated rates of insulin resistance in RA [36], it is lymphocytes leads to the release of several mediators causing conceivable that the prevalence of diabetes might be further damage, and, ultimately, narrowing of the artery does enhanced. Similarly, data regarding hypertension in RA are occur. Platelet activation by the dysfunctional endothelium contradictory and no conclusions can be reached with respect results in the formation of thromboxane – a potent the contribution of body mass index to the CV risk in RA. vasoconstrictor and platelet aggregator. Finally, plaque rupture In summary, the abovementioned evidence is not and thrombosis leads to unstable angina or MI. This process uniform, adequate comparative investigations are lacking, accounts for up to 70% of the acute coronary syndromes [41]. and studies are limited by a lack of control for important The cellular interactions that are seen in the development of confounders. Nevertheless, the prevalences of hypertension atherosclerosis are similar to those observed in chronic and smoking appear to be increased in RA patients. inflammatory diseases such as RA, which might explain the Very recently, a systematic review investigated the increased CV risk in patients with RA. In keeping with this effectiveness of exercise interventions in patients with RA view, high-resolution B-mode ultrasound of the common [37]. Unfortunately, no studies investigating the effect of carotid artery identified a strong correlation between the exercise interventions in relation to CV disease in RA were carotid IMT and markers of systemic inflammation in patients identified. Therefore, further studies are required to address with RA and in healthy subjects [24,42]. this topic. Antirheumatic treatment and CV risk in RA Under-treatment of hypertension in RA Acetaminophen It is well known that comorbidity is under-treated in patients Chan et al. examined the relationship between acetaminophen with chronic diseases [38]. Moreover, it is known that use and major CV events in a prospective cohort of 70 971 comorbidities in patients with RA do not differ from women [43]. Frequent usage, defined as on ≥22 days/month, comorbidities observed in other chronic diseases [39]. Thus was linked with an elevated risk of CV events. The highest risk far, just one study has addressed this topic [4], with a total was associated with the intake of ≥15 tablets per week (RR of 400 consecutive RA patients investigated for 1.7, 95% CI 1.1–2.6), with 69% of patients taking tablets of hypertension and antihypertensive drug use. Hypertension ≥500 mg acetaminophen. The observed association might be was present in 71% of the patients; only 61% of these mediated through the induction of hypertension due to received antihypertensives. These results clearly indicate that cyclooxygenase-2 (COX-2) inhibition [44]. future research in this area is necessary. Glucocorticoids Atherosclerosis and inflammation The place of glucocorticoids in RA therapy is a continuing Formerly, atherosclerosis was seen as an accumulation of lipids matter of debate in view of their associated CV side effects, within the arterial wall. However, during the last few decades, which include hypertension, dyslipidemia, insulin resistance, it has become acknowledged that atherosclerosis represents a and diabetes. These side effects are particularly linked to chronic inflammatory process in the artery (Fig.1). Endothelial prolonged exposure to high-dose glucocorticoids, with dysfunction is the first step of atherosclerosis and is induced by hypertension demonstrated to be especially prominent in different cardiovascular risk factors, e.g. oxidized LDL-C, patients receiving ≥7.5 mg/day prednisone for a period of smoking, hypertension, or diabetes. The endothelium becomes ≥6 months [45]. Conversely, low-dose glucocorticoids might more permeable to lipoproteins and acquires procoagulant have beneficial effects on the lipid profile [46]. rather than anticoagulant properties. Increased permeability to There is no doubt that corticosteroids rapidly and inflammatory and muscle cells also occurs. Inflammatory effectively suppress inflammation in RA and their use may mediators such as TNF-α and interleukin-1 cause increased be justified as a short-term treatment, e.g. as a “bridging

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Figure 1. Effects of T cell activation on plaque inflammation. Antigens presented by macrophages and dendritic cells (antigen- presenting cells) trigger the activation of antigen-specific T cells in the artery. Most of the activated T cells produce Th1 cytokines (e.g. IFN-γ), which activate macrophages and vascular cells, leading to inflammation. Regulatory T cells modulate the process by secreting anti-inflammatory cytokines (such as IL-10 and TGF-β). Coronary artery

Adhesion Migration Endothelium

Regulatory T cell Inhibitory cytokines

Processing Antigen- presenting cell Th1

Antigen- Th1 cytokines presenting cell

Processing

Inflammation

Antigens: oxidized LDL, heat-shock proteins, microbes Smooth- muscle cell

IFN-γ: interferon-γ; IL-10: interleukin-10; LDL: low-density lipoprotein; TGF-β: transforming growth factor-β; Th1: type 1 helper T cell. Redrawn with permission from [41].

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therapy” during the period between the initiation of and adjusted rate ratio was 0.46 in anti-TNF-treated compared response to DMARDs [47]. The debate regarding the use of with non-anti-TNF treated subjects. From a larger British corticosteroids continues. cohort study, the risk of an MI was markedly reduced when comparing anti-TNF responders with the non-responders Nonsteroidal anti-inflammatory drugs (incidence ratio 0.36) [58]. and COX-2-selective inhibitors During the last decade there has been an ongoing debate as Cardiovascular risk management in RA to whether or not COX-2-selective inhibitors (COXIBs) are In summary, RA should be seen as a new CV risk factor, for associated with an enhanced CV risk, particularly MIs. which CV-risk management (CV-RM) is mandatory. CV-RM is Several large-scale, placebo-controlled trials have generally performed on the basis of the 10-year absolute risk demonstrated that COXIBs are accompanied by an for a (fatal) CV-event, which is derived from a CV risk formula approximately two-fold enhanced CV risk [48,49]. based on several CV risk factors. Examples include the There are many observational database studies indicating Framingham risk calculator and the Systematic Coronary Risk either an increased on no increased CV risk with Evaluation (SCORE). Treatment with statins and/or nonsteroidal anti-inflammatory drug (NSAID) therapy. antihypertensives is then initiated at above a certain threshold, Observational investigations have inherent methodological e.g. a 10-year CV-mortality risk of ≥10%. Thus far, CV risk problems that can only be addressed by the performance of function scores are not available for patients with RA and, large-scale, randomized investigations. However, such therefore, existing CV risk functions such as SCORE should be studies have not been conducted with NSAIDs. As an adapted, for example by a multiplier, so that they can be used alternative (albeit a second-best option), meta-analyses with to assess the CV risk in RA patients. Regular CV risk screening meta-regression techniques of comparative trials of NSAIDs appears to be appropriate for RA patients and lifestyle and COXIBs can be employed in order to reach valid recommendations should be given to every patient. Treatment conclusions regarding the CV risks associated with NSAID with statins and/or antihypertensives should be considered use. From one such study, and a large controlled when the 10-year CV risk is above a certain value. In addition, investigation comparing a COXIB with a non-naproxen aggressive suppression of the inflammation is recommended NSAID, it appears that non-naproxen NSAIDs confer a to further lower the CV risk [59]. similar CV risk to COXIBs [50,51]. Disclosures DMARDs The author has no relevant financial interests to disclose. In a prospective investigation of 1240 patients in which 190 patients died during a follow-up of 18 years, the CV References mortality rate was 70% lower in patients receiving 1. Van Doornum S, McColl G, Wicks IP. Accelerated atherosclerosis: an extraarticular feature of rheumatoid arthritis? Arthritis Rheum 2002;46:862–73. methotrexate than in those who did not receive the drug 2. van Halm VP, Peters MJ, Voskuyl AE et al. Rheumatoid arthritis versus diabetes as a risk [52]. Another study revealed that patients who do not factor for cardiovascular disease, a cross sectional study. The CARRE Investigation. Ann Rheum Dis 2008; [Epub ahead of print]. respond to methotrexate treatment have a poor prognosis 3. Boers M, Dijkmans B, Gabriel S et al. Making an impact on mortality in rheumatoid [53]. Not only is CV mortality reduced by methotrexate; arthritis: targeting cardiovascular comorbidity. Arthritis Rheum 2004;50:1734–39. 4. Panoulas VF, Douglas KM, Milionis HJ et al. Prevalence and associations of hypertension from two case–control studies, it appears that the use of and its control in patients with rheumatoid arthritis. Rheumatology (Oxford) methotrexate is also associated with less CV morbidity 2007;46:1477–82. 5. Ward MM. Recent improvements in survival in patients with rheumatoid arthritis: better [54,55]. outcomes or different study designs? Arthritis Rheum 2001;44:1467–9. 6. Gonzalez A, Maradit Kremers H, Crowson CS et al. The widening mortality gap between rheumatoid arthritis patients and the general population. Arthritis Rheum TNF-blocking agents 2007;56:3583–7. Jacobsson et al. linked a Swedish database – in which 921 of 7. Warrington KJ, Kent PD, Frye RL et al. Rheumatoid arthritis is an independent risk factor for multi-vessel coronary artery disease: a case control study. Arthritis Res Ther 1430 patients received TNF-blockers – with a national 2005;7:R984–91. mortality register. The adjusted HR for death was 0.65 when 8. Van Doornum S, Brand C, King B et al. Increased case fatality rates following a first acute cardiovascular event in patients with rheumatoid arthritis. Arthritis Rheum comparing TNF blockade versus no TNF blockade [56]. In an 2006;54:2061–8. earlier study, these investigators determined the incidence of 9. Södergren A, Stegmayr B, Lundberg V et al. Increased incidence of and impaired prognosis after acute myocardial infarction among patients with seropositive rheumatoid arthritis. MIs in 983 RA patients, of whom 531 underwent treatment Ann Rheum Dis 2007;66:263–6. with TNF blockers [57]. There were 13 CV events in the 10. Maradit-Kremers H, Crowson CS, Nicola PJ et al. Increased unrecognized coronary heart disease and sudden deaths in rheumatoid arthritis: a population-based cohort study. anti-TNF-treated patients resulting in 14 CV events per 1000 Arthritis Rheum 2005;52:402–11. person-years, compared with 35 CV events per 1000 11. del Rincón ID, Williams K, Stern MP et al. High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors. Arthritis person-years in RA patients not treated with anti-TNF. The Rheum 2001;44:2737–45.

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12. Peters MJ, van Halm VP, Voskuyl AE et al. Prospective study reveals rheumatoid arthritis to 36. Gonzalez-Gay MA, Gonzalez-Juanatey C, Martin J. Rheumatoid arthritis: a disease be an important independent risk factor for incident cardiovascular disease. Ann Rheum associated with accelerated atherogenesis. Semin Arthritis Rheum 2005;35:8–17. Dis 2008;67(Suppl II):309. 37. Metsios GS, Stavropoulos-Kalinoglou A, Veldhuijzen van Zanten JJ et al. Rheumatoid 13. Gabriel SE, Crowson CS, O’Fallon WM. Comorbidity in arthritis. J Rheumatol arthritis, cardiovascular disease and physical exercise: a systematic review. Rheumatology 1999;26:2475–9. (Oxford) 2008;47:239–48. 14. Wolfe F, Michaud K. Heart failure in rheumatoid arthritis: rates, predictors, and the effect 38. Redelmeier DA, Tan SH, Booth GL. The treatment of unrelated disorders in patients with of anti-tumor necrosis factor therapy. Am J Med 2004;116:305–11. chronic medical diseases. N Engl J Med 1998;338:1516–20. 15. Gonzalez-Juanatey C, Testa A, Garcia-Castelo A et al. Echocardiographic and Doppler 39. Kroot EJ, van Gestel AM, Swinkels HL et al. Chronic comorbidity in patients with early findings in long-term treated rheumatoid arthritis patients without clinically evident rheumatoid arthritis: a descriptive study. J Rheumatol 2001;28:1511–7. cardiovascular disease. Semin Arthritis Rheum 2004;33:231–8. 40. Ross R. Atherosclerosis – an inflammatory disease. N Engl J Med 1999;340:115–26. 16. Wolfe F, Freundlich B, Straus WL. Increase in cardiovascular and cerebrovascular disease 41. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med prevalence in rheumatoid arthritis. J Rheumatol 2003;30:36–40. 2005;352:1685–95. 17. Solomon DH, Goodson NJ, Katz JN et al. Patterns of cardiovascular risk in rheumatoid 42. Gonzalez-Gay MA, Gonzalez-Juanatey C, Pineiro A et al. High-grade c-reactive protein arthritis. Ann Rheum Dis 2006;65:1608–12. elevation correlates with accelerated atherogenesis in patients with rheumatoid arthritis. 18. Watson DJ, Rhodes T, Guess HA. All-cause mortality and vascular events among patients J Rheumatol 2005;32:1219–23. with rheumatoid arthritis, osteoarthritis, or no arthritis in the UK General Practice Research Database. J Rheumatol 2003;30:1196–1202. 43. Chan AT, Manson JE, Albert CM et al. Nonsteroidal antiinflammatory drugs, acetaminophen, and the risk of cardiovascular events. Circulation 2006;113:1578–87. 19. Han C, Robinson DW Jr, Hackett MV et al. Cardiovascular disease and risk factors in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. 44. Hinz B, Cheremina O, Brune K. Acetaminophen (paracetamol) is a selective J Rheumatol 2006;33:2167–72. cyclooxygenase-2 inhibitor in man. FASEB J 2008;22:383–90. 20. Liang KP, Liang KV, Matteson EL et al. Incidence of noncardiac vascular disease in 45. Panoulas VF, Douglas KM, Stavropoulos-Kalinoglou A et al. Long-term exposure to rheumatoid arthritis and relationship to extraarticular disease manifestations. Arthritis medium-dose glucocorticoid therapy associates with hypertension in patients with Rheum 2006;54:642–8. rheumatoid arthritis. Rheumatology (Oxford) 2008;47:72–5. 21. del Rincón I, Haas RW, Pogosian S et al. Lower limb arterial incompressibility and 46. Boers M, Nurmohamed MT, Doelman CJ et al. Influence of glucocorticoids and disease obstruction in rheumatoid arthritis. Ann Rheum Dis 2005;64:425–32. activity on total and high density lipoprotein cholesterol in patients with rheumatoid arthritis. Ann Rheum Dis 2003;62:842–5. 22. O’Leary DH, Polak JF, Kronmal RA et al. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study 47. Vis M, Nurmohamed MT, Wolbink G et al. Short term effects of infliximab on the lipid Collaborative Research Group. N Engl J Med 1999;340:14–22. profile in patients with rheumatoid arthritis. J Rheumatol 2005;32:252–5. 23. Kumeda Y, Inaba M, Goto H et al. Increased thickness of the arterial intima-media 48. Bresalier RS, Sandler RS, Quan H et al. Cardiovascular events associated with rofecoxib in detected by ultrasonography in patients with rheumatoid arthritis. Arthritis Rheum colerectal adenoma chemoprevention trial. N Engl J Med 2005;352:1092–102. 2002;46:1489–97. 49. Solomon SD, McMurray JJ, Pfeffer MA et al.; APC Study Investigators. Cardiovascular risk 24. Del Rincón I, Williams K, Stern MP et al. Association between carotid atherosclerosis and associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J markers of inflammation in rheumatoid arthritis patients and healthy subjects. Arthritis Med 2005;352:1071–80. Rheum 2003;48:1833–40. 50. Kearney PM, Baigent C, Godwin J et al. Do selective cyclo-oxygenase-2 inhibitors and 25. Gonzalez-Juanatey C, Llorca J, Martin J et al. Carotid intima-media thickness predicts the traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? development of cardiovascular events in patients with rheumatoid arthritis. Semin Arthritis Meta-analysis of randomised trials. BMJ 2006;332:1302–8. Rheum 2008; [Epub ahead of print]. 51. Cannon CP, Curtis SP, FitzGerald GA et al.; MEDAL Steering Committee. Cardiovascular 26. Greenland P, LaBree L, Azen SP et al. Coronary artery calcium score combined with outcomes with etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid Framingham score for risk prediction in asymptomatic individuals. JAMA 2004;291:210–5. arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme: a randomised comparison. Lancet 2006;368:1771–81. 27. Chung CP, Oeser A, Raggi P et al. Increased coronary-artery atherosclerosis in rheumatoid arthritis: relationship to disease duration and cardiovascular risk factors. Arthritis Rheum 52. Choi HK, Hernan MA, Seeger JD et al. Methotrexate and mortality in patients with 2005;52:3045–53. rheumatoid arthritis: a prospective study. Lancet 2002;359:1173–7. 28. Kao AH, Krishnaswami S, Cunningham A et al. Subclinical coronary artery calcification and 53. Krause D, Schleusser B, Herborn G et al. Response to methotrexate treatment is associated relationship to disease duration in women with rheumatoid arthritis. J Rheumatol with reduced mortality in patients with severe rheumatoid arthritis. Arthritis Rheum 2008;35:61–9. 2000;43:14–21. 29. White D, Fayez S, Doube A. Atherogenic lipid profiles in rheumatoid arthritis. N Z Med J 54. van Halm VP, Nurmohamed MT, Twisk JW et al. Disease-modifying antirheumatic drugs 2006;119:U2125. are associated with a reduced risk for cardiovascular disease in patients with rheumatoid arthritis: a case control study. Arthritis Res Ther 2006;8:R151. 30. van Halm VP, Nielen MM, Nurmohamed MT et al. Lipids and inflammation: serial measurements of the lipid profile of blood donors who later developed rheumatoid 55. Suissa S, Bernatsky S, Hudson M. Antirheumatic drug use and the risk of acute myocardial arthritis. Ann Rheum Dis 2007;66:184–8. infarction. Arthritis Rheum 2006;55:531–6. 31. Menotti A, Kromhout D, Blackburn H et al. Forty-year mortality from cardiovascular 56. Jacobsson LT, Turesson C, Nilsson JA et al. Treatment with TNF blockers and mortality risk diseases and all causes of death in the US Railroad cohort of the Seven Countries Study. in patients with rheumatoid arthritis. Ann Rheum Dis 2007;66:670–5. Eur J Epidemiol 2004;19:417–24. 57. Jacobsson LT, Turesson C, Gulfe A et al. Treatment with tumor necrosis factor blockers is 32. McMahon M, Grossman J, FitzGerald J et al. Proinflammatory high-density lipoprotein as a associated with a lower incidence of first cardiovascular events in patients with rheumatoid biomarker for atherosclerosis in patients with systemic lupus erythematosus and arthritis. J Rheumatol 2005;32:1213–8. rheumatoid arthritis. Arthritis Rheum 2006;54:2541–9. 58. Dixon WG, Watson KD, Lunt M et al.; British Society for Rheumatology Biologics Register 33. Nurmohamed MT. Atherogenic lipid profiles and its management in patients with Control Centre Consortium, Silman AJ, Symmons DP; British Society for Rheumatology rheumatoid arthritis. Vasc Health Risk Manag 2007;3:845–52. Biologics Register. Reduction in the incidence of myocardial infarction in patients with rheumatoid arthritis who respond to anti-tumor necrosis factor alpha therapy: results from 34. Goodson NJ, Farragher TM, Symmons DP. Rheumatoid factor, smoking, and disease the British Society for Rheumatology Biologics Register. Arthritis Rheum severity: associations with mortality in rheumatoid arthritis. J Rheumatol 2008;35:945–9. 2007;56:2905–12. 35. Gonzalez A, Maradit Kremers H, Crowson CS et al. Do cardiovascular risk factors confer 59. Peters MJ, Symmons DP, McCarey DW et al. Cardiovascular risk management (CV-RM) in the same risk for cardiovascular outcomes in rheumatoid arthritis patients as in non- patients with rheumatoid arthritis and other types of inflammatory arthritis. Ann Rheum rheumatoid arthritis patients? Ann Rheum Dis 2008;67:64–9. Dis 2008;67(Suppl II):310.

46 INTERNATIONAL JOURNAL OF ADVANCES IN RHEUMATOLOGY Vol 6 No 2 2008 LEADING ARTICLE 47 Vol 6 No 2 2008 Vol HEUMATOLOGY R citrulline, an amino acid generated by a post-translational citrulline, an amino acid generated by which involves deimination of the modification process, by the enzyme peptidylarginine natural amino acid arginine to the is related of autoantibodies deiminase [4]. This group as antiperinuclear factor, previously antibodies recognized regularly are ACPA antikeratin, or antifilaggrin antibodies. assay (ELISA) detected by an enzyme-linked immunosorbent The first ELISA using synthetic peptides containing citrulline. filaggrin from test using synthetic cyclic peptides derived its sensitivity to increase (the CCP1 test) was improved antigenic (CCP2 test) [5]. Other synthetic and non-synthetic these antibodies, substrates have been used to detect fibrin [7], and a more including citrullinated vimentin [6] and assay (CCP3) has been developed [8]. anti-CCP recent prognostic) These tests have similar diagnostic (and probably the allowing the same reactivity, but not properties, observed more are which possibility of discrepancies, due mostly to commonly in non-RA samples and are in the substrates used rather than other technical differences [9–11]. reasons Diagnostic value have confirmed the In the last 5 years, many reports The second generation important diagnostic value of ACPA. anti-CCP assay (CCP2) – the best known and the most widely used test – has a sensitivity similar to that of RF (60–80%), but has a higher specificity (>95%) [12]. of RF-negative RA patients test 30–40% Approximately meta-analysis In a recent positive in the CCP2 assay. including 37 studies of anti-CCP antibodies and 50 studies specific than it was concluded that anti-CCP is more on RF, DVANCES IN A (2):47–52. 6 2008; OURNAL OF J NTERNATIONAL I Int J Adv Rheumatol Serological markers other than RF have been investigated markers other than RF have been Serological Anti-citrullinated protein/peptide antibodies a are antibodies (ACPA) Anti-citrullinated protein/peptide against peptides containing of autoantibodies directed group Unit, Raimon Sanmartí, Arthritis for correspondence: Address 170, Villarroel Rheumatology Service, Hospital Clinic of Barcelona, Spain. Email: [email protected] Barcelona, Rheumatoid arthritis (RA) is a common inflammatory disease Rheumatoid arthritis (RA) is a common 1940s, an antibody of autoimmune pathogenesis. Since the G (IgG), against the Fc portion of immunoglobulin directed by been measured known as rheumatoid factor (RF), has patients, and has a various methods in the sera of RA 65–80%, but a limited sensitivity of approximately in various autoimmune RF may be positive specificity. healthy infections, and also in some and chronic disorders is currently RF However, subjects, particularly in the elderly. American College of the only autoantibody included in the for the diagnosis Rheumatology 1987 classification criteria associated with more of RA [1]. Positivity for RF has been articular and extra-articular disease [2]. severe in RA, but most have shown a poor diagnostic sensitivity and in the last decade, a new class of 1). However, specificity (Table has against citrullinated proteins autoantibodies directed to date, as the most specific markers of RA identified emerged and have been shown to have important diagnostic and discusses the review [3]. The present properties prognostic autoantibodies other than RF described thus far in the sera of with particular patients with RA and their clinical relevance, emphasis on autoantibodies against citrullinated proteins. Arthritis Unit, Rheumatology Service, Hospital Clinic of Barcelona, Barcelona, Spain Barcelona, of Barcelona, Service, Hospital Clinic Arthritis Unit, Rheumatology factor arthritis (RA). At present, rheumatoid in the sera of patients with rheumatoid antibodies have been found Various classification of RA, but its of Rheumatology criteria for the included in the American College (RF) is the only autoantibody and specificity have been described in recent degrees of sensitivity with different specificity is limited. New autoantibodies due to directed against citrullinated peptides has also recently gained acceptance years and a new class of autoantibodies in RA, are and prognostic value. These, together with other autoantibodies found and diagnostic their high specificity, discussed in this review. Raimon Sanmartí, MD, Maria Victoria Hernández, MD, José A Gómez-Puerta, MD, MD, José A Gómez-Puerta, Hernández, MD, Maria Victoria Raimon Sanmartí, MD, PhD MD, and Juan D Cañete, Eduard Graell, Serum Autoantibodies in Autoantibodies Serum Arthritis Rheumatoid RT404_2_Rheum_6.2_05.qxd 10/9/08 16:44 Page 47 Page 16:44 10/9/08 RT404_2_Rheum_6.2_05.qxd RT404_2_Rheum_6.2_05.qxd 10/9/08 16:44 Page 48

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Table 1. Sensitivity and specificity of autoantibodies in the autoantibodies predict a worse radiographic outcome in early sera of patients with RA according to different studies. RA. The presence of anti-CCP (determined by the CCP2 test) Autoantibodies Sensitivity (%)* Specificity (%)* at baseline is associated with erosive disease and radiographic progression to a greater extent than RF [5,12,19]. Other RF 65–80% 85% studies suggest that not only the presence, but also the levels, ACPA 60–75% 95–98% of these antibodies correlate with joint damage [20]. Levels of Anti-RA33 30–35% 96% anti-CCP seem to remain stable over the course of the disease, but may decrease (especially in those with early RA) due to Anti-collagen type II 30% NE antirheumatic therapy with disease-modifying antirheumatic Anti-GPI 15–64% 70% drugs (DMARDs) or tumor necrosis factor-α (TNF-α) Anti-BiP 63–73% 65–99% antagonists, although the potential association of this decrease with clinical response is not clear [21]. This prognostic value is Anti-calpastatin 5–83% 96% also seen in the RF-negative RA population. ACPA have not Anti Ro (SSA) 3–15% NE been associated with the frequency or severity of extra- Antiphospholipid/ 12–48% NE articular features [2], although an association with serositis and anticardiolipin pulmonary fibrosis was suggested in a Greek study [22]. ANCA 0–70% NE Pathogenic significance ACPA: anti-citrullinated protein antibodies; ANCA: antineutrophil cytoplasmic The pathophysiological role of ACPA is unknown, although antibodies; GPI: glucose-6-phosphatase isomerase; BiP: endoplasmic reticulum chaperone binding protein; NE: not established; RA: rheumatoid arthritis; it is proven that the antibodies may be present years before RF: rheumatoid factor. *Values of sensitivity/specificity may differ according to the first clinical signs of RA [23]. In recent years, an the cutoff values or rheumatoid or control populations used. association between ACPA and the rheumatoid (shared) epitope and the HLA-DRB04 genotype has been RF in the diagnosis of RA [13]. However, anti-CCP demonstrated [24]. Smoking has also been identified as a autoantibodies have been described in up to 10% of predisposing factor for RA, but only in anti-CCP-positive patients with other diseases [14], including psoriatic arthritis, patients, and has a strong correlation with the DRB04 Sjögren’s syndrome (SS), and systemic lupus erythematosus genotype [25,26]. Citrullinated proteins have been found in (SLE), emphasizing that they are not pathognomonic for RA. the synovium of patients with RA and other inflammatory In these other diseases, anti-CCP may be a marker of joint diseases, probably as a consequence of apoptosis due persistent or more severe polyarthritis. Only in palindromic to inflammation [12,27]. However, the immunological rheumatism is the frequency of anti-CCP similar to that response to the generation of ACPA seems to be very observed in RA, suggesting that this disorder may be specific for RA, in particular for carriers of the shared epitope considered as an abortive form of RA [15]. [10]. A direct role for ACPA in joint damage has recently ACPA have been shown to be useful in discriminating been suggested [28,29]. the evolution to RA (or to persistent and erosive arthritis) in patients with early undifferentiated arthritis (UA). The Anti-RA-33 antibodies diagnostic utility of these tests in early arthritis clinics is Anti-RA-33 antibodies, which are directed against the clearly seen in a 3-year follow-up study of 318 patients with heterogeneous nuclear ribonucleoprotein A2 (hnRNP-A2) UA [16], in which 93% of patients who were anti-CCP- that is involved in mRNA transport and the regulation of positive at inclusion evolved to having RA, in comparison alternative splicing, have recently been identified as a with just 25% of anti-CCP-negative patients (odds ratio potentially specific serological marker for RA [30]. They have [OR] 38). Other studies confirm this potential predictive role been found in nearly 35% of patients with established RA of anti-CCP, which is higher than that of RF [17]. Visser et but not in control subjects [31]. In early RA, their sensitivity al. found that anti-CCP was the highest-weighted factor of is approximately 30% [32], and in undifferentiated seven variables that predicted persistent arthritis after polyarthritis later classified as RA, anti-RA33 antibodies have 2 years of follow-up in a series of 524 patients with early shown a higher specificity than RF [32], suggesting that they arthritis [18]. are early antibodies in RA, and are more specific than RF. Although anti-RA33 antibodies were initially thought to Prognostic value be a useful early, specific marker for RA, they are not strictly Several reports have studied the predictive value of ACPA for specific for RA as they are also found in nearly 20% of joint damage in RA and almost all have shown that these patients with SLE and 40–60% of patients with mixed

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connective tissue disease (MCTD) [33], mainly in those with cytokine and growth factor activities. Increased levels of erosive disease [34]. However, in SLE and MCTD, they anti-GPI antibodies have been found in the serum and usually occur together with antibodies to U1-small nuclear synovial fluid of RA patients [42], with a prevalence ranging ribonucleoprotein particle (U1-snRNP) or Sm. Anti-RA33 between 14.8% [43] and 64% [42]. without concomitant anti-U1-snRNP antibodies have a Anti-GPI antibodies are not specific for RA relative to specificity for RA of 96% [33]. One study has found that other rheumatic diseases [44,45], and no differences anti-RA-33 antibodies do not have a significant impact on between early and established RA have been identified radiographic outcomes [35]. [43,46]. However, increased concentrations of anti-GPI have been found in RA patients with extra-articular Anti-collagen type II antibodies manifestations such as nodules, vasculitis, or Felty’s The possibility that an immune response directed against syndrome [46]. No correlation between anti-GPI and other joint-related antigens such as type II collagen could play a RA-associated antibodies, such as ACPA, has been found role in the pathogenesis of RA has been hypothesized in [43,45]. Furthermore, anti-GPI do not predict radiographic recent years. It has been suggested that an immune progression in very early arthritis. Therefore, anti-GPI response to a foreign antigen that shares some epitopes antibodies provide only weak discrimination of RA from present in type II collagen could produce antibodies not only non-RA rheumatic disorders and are not a predictive factor to the antigen but also to the shared epitopes, producing for structural damage [45]. joint inflammation by the binding of antibodies to the epitope on the collagen cartilage. The specific expression of Anti-BIP antibodies type II collagen in articular cartilage and its ability to induce Autoantibodies against endoplasmic reticulum chaperone destructive arthritis in animal models reinforces this binding protein (anti-BIP), also called p68, have been found hypothesis [36]. in the serum and synovial fluid of RA patients [47]. BIP Anti-collagen type II (anti-CII) antibodies have been stimulates synovial T cell proliferation, and its expression demonstrated in serum and synovial fluid of approximately could be induced by a number of cellular stress mechanisms 30% of patients with RA [37], although lower frequencies such as ischemia, heat shock proteins, or cytokines [48]. have also been detected in patients with other rheumatic The sensitivity of anti-BIP for established RA is 63–73% diseases, including SLE and systemic sclerosis (SSc), among and the specificity is 71–99% [47,48]. In early RA patients, others. In RA patients, a direct correlation between serum the sensitivity of anti-BIP is 66% and the specificity is 65% and synovial fluid titers of anti-CII and acute phase reactants [48]. The sensitivity of anti-BIP to predict the onset of RA – has been found [38]. Anti-CII have been found mainly in before disease onset – is 45%, and the specificity 65%. No early RA [39], and seem to have the potential to destroy correlation between anti-BIP and RF has been observed cartilage in the early stages of RA. Besides the possible [47]. Anti-BIP antibodies have also been detected in patients implication of anti-CII in the pathogenesis of RA, they could with SS [49]. Recently, a reduction in serum anti-BIP levels be a useful marker of cartilage destruction in some patients was described in RA patients after biological therapy with and could offer early information, before the disease TNF-α blockers [50]. However, no data on anti-BIP and becomes clinically evident. disease progression or severity in early RA are available. Although some reports have suggested that anti-CII could be predictive of a more severe outcome [40], no Anti-calpastatin differences with controls have been found in patients before Calpastatin, the endogenous inhibitor of the intracellular, the onset of RA [41]. This may be because anti-CII might calcium-activated cysteine proteases calpain I and II is widely only be produced after the onset of articular inflammation distributed in the cytoplasmic fraction of almost all caused by other mechanisms. Thus, after breakdown of mammalian cells [51]. Elevated levels of extracellular calpain cartilage, exposure of collagen to the immune system could have been reported in inflamed synovium, suggesting that generate secondary antibodies against cartilage, and anti-CII calpain could be secreted by synovial cells and might play a could contribute to the perpetuation of inflammation. role in cartilage degradation in RA [52]. Recently, various reports have associated anti-calpastatin antibodies with RA Anti-GPI antibodies [53], venous thrombosis [54], and autoimmune infertility Anti-GPI antibodies are directed against glucose-6- [55], although epitope mapping in calpastatin remains phosphate isomerase, a cytosolic enzyme that catalyzes the controversial. Mimori et al. detected anti-calpastatin interconversion of D-glucose-6-phosphate and D-fructose 6- antibodies in 57% of RA patients and in lower percentages phosphate, which are essential bodily reactions. GPI also has of patients with SLE, polymyositis/dermatomyositis, or SSc,

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and healthy controls [53]. Another study determined IgG artery intima-media thickness and antiphospholipid (aPL) in anti-calpastatin antibodies in 58 RA patients and 24 subjects a selected group of 70 patients with RA (non-diabetic, non- with osteoarthritis (OA), 18 with SLE, 19 with SSc, and five hypertensive, premenopausal women) and compared them with SS, using a modified ELISA [56]. IgG anti-calpastatin with age- and sex-matched controls [67]. There was a antibodies were found in 48 (83%) out of 58 patients with significantly higher internal carotid artery intima-media RA and in only two patients with OA. IgG anti-calpastatin thickness and a greater number of plaques in RA patients antibodies are both sensitive (83%) and specific (96%) for compared with controls. IgG and IgM aCL were present in RA. In contrast, sera from patients with other systemic 15.7% of RA patients compared with 5% of the control β rheumatic diseases showed lower sensitivities (6% in SLE, group, whilst anti- 2GPI antibodies were positive in 30% of 0% in SSc, and 20% in SS). Antibodies against C-terminal RA patients compared with 7.5% of controls. Seriolo et al. peptide and calpastatin domain I have been found in only a evaluated aPL and plasma levels of protein S in 184 patients small proportion of RA patients and have not been with RA and extra-articular involvement [68]. Thirty-five associated with radiographic progression [57]. (19%) had at least one type of aPL. Lupus anticoagulant Recently, a strong association between anti-calpastatin was present in seven patients with concomitant aCL antibodies, using an ELISA with purified synovial calpastatin positivity. Thrombotic events were diagnosed in 34% of as a substrate, and HLA-DRB alleles has been demonstrated aCL-positive patients with RA. Low free protein S levels [58]. The HLA-DRB1*0404 allele was very strongly were found in 22 of 184 RA patients; 11 of those who had associated with anti-calpastatin in RA sera. Eighty-three low free protein S levels and were positive for aCL. RA percent of patients expressing both HLA-DRB1*0404 and patients with positive aCL and a history of arterial and/or HLA-DRB1*0401 were positive for antibodies against venous thromboses showed lower levels of free protein S synovial calpastatin. compared with patients with positive aCL but no history of thrombosis. aCL has also been found in a small proportion Anti-Ro (SSA) antibodies of patients with RA who were treated with TNF-α Anti-Ro (SSA) antibodies are associated with a variety of antagonists. The clinical implications of these drug-induced autoimmune diseases including SS, SLE, subacute cutaneous aCL are unknown, but the majority of patients exhibit no lupus, neonatal lupus, SSc, and RA. The reported frequency clinical features related to antiphospholipid syndrome [69]. of anti-Ro in RA varies widely (3–15%), possibly due to differences in methods and study groups [59–61]. Anti-Ro Antineutrophil cytoplasmic antibodies antibodies have been associated with extra-articular Antineutrophil cytoplasmic antibodies (ANCA) are directed manifestations such as xerophthalmia, xerostomia, scleritis, against lysosomal enzymes of human neutrophils and oral ulcers, purpuric vasculitis, amyloidosis, and specific monocytes and have been identified in various vasculitides, autoantibody profiles including hypergammaglobulinemia, especially in Wegener’s granulomatosis and microscopic cryoglobulins, anti-double stranded DNA, and anti- polyangiitis. ANCA (perinuclear ANCA [pANCA] and mitochondrial antibodies. Boire et al. found that patients cytoplasmic ANCA [cANCA]) have been detected in the sera with anti-Ro antibodies had more severe disease and a of 0–70% of RA patients [70–72]. ANCA antibodies from RA greater requirement for immunosuppressive drugs [61], patients recognize different antigens in the nucleus and while their genetic profile showed a lower frequency of cytoplasm, of which lactoferrin is the most common [73]. It HLA-DR4 than anti-Ro-negative patients, although these has been suggested that ANCA occur especially in RA results were not confirmed by another study [60]. Anti-Ro patients with longstanding, severe disease who are positive antibodies have also been identified as predictive markers of for RF and ANA. An association between ANCA and penicillamine and gold salt toxicity in RA [62]. vasculitic and pulmonary involvement has also been proposed [70,71]. Mustila et al. evaluated the prevalence of Antiphospholipid antibodies ANCA in patients with early (<12 months) RA [70]. pANCA The frequency of anticardiolipin antibodies (aCL) in RA were found in 40 (50%) patients and atypical cANCA in patients ranges from 12% to 48% [63–66]. aCL have three (4%) patients at study entry. pANCA were significantly shown a correlation with high levels of C-reactive protein more frequent in RF-positive patients. There was no and repeated miscarriages, RF and antinuclear antibodies correlation between ANCA and clinical disease activity. (ANA), extra-articular manifestations, nodules, and During follow-up, radiographic erosions (Larsen score) hemolytic anemia in patients with RA [63–66]. advanced more rapidly in pANCA-positive patients. Anti- aCL have been linked with a higher risk of atherosclerosis myeloperoxidase (MPO), a pANCA-specific antibody, was in patients with RA. Pahor et al. evaluated internal carotid determined in 97 patients with RA. Anti-MPO were detected

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14. Fabien N, Olsson NO, Goetz J et al. Prevalence of autoantibodies to cyclic citrullinated in 12 (12%) patients and were associated with nodules, lung peptide in patients with rheumatic diseases other than rheumatoid arthritis: a French multicenter study. Clin Rev Allergy Immunol 2008;34:40–4. involvement, and a higher swollen joint count [72]. 15. Sanmartí R, Cañete JD, Salvador G. Palindromic rheumatism and other relapsing arthritis. Best Pract Res Clin Rheumatol 2004;18:647–61. 16. van Gaalen FA, Linn-Rasker SP, van Venrooij WJ et al. Autoantibodies to cyclic citrullinated Conclusion peptides predict progression to rheumatoid arthritis in patients with undifferentiated Since the first description of RF >50 years ago, various arthritis: a prospective cohort study. Arthritis Rheum 2004;50:709–15. 17. Vallbracht I, Rieber J, Oppermann M et al. Diagnostic and clinical value of anti-cyclic autoantibodies have been found in the sera of RA patients. citrullinated peptide antibodies compared with rheumatoid factor isotypes in rheumatoid The majority of these have been shown to be more arthritis. Ann Rheum Dis 2004;63:1079–84. 18. Visser H, le Cessie S, Vos K et al. How to diagnose rheumatoid arthritis early: a prediction prevalent in RA than in other rheumatic diseases or healthy model for persistent (erosive) arthritis. Arthritis Rheum 2002;46:357–65. subjects although their sensitivity and specificity (Table 1) 19. Forslind K, Ahlmén M, Eberhardt K et al. Prediction of radiological outcome in early rheumatoid arthritis in clinical practice: role of antibodies to citrullinated peptides (anti- have consistently been shown to be lower than that of RF, CCP). Ann Rheum Dis 2004;63:1090–5. and few appear to have prognostic significance. Variable 20. Bongi SM, Manetti R, Melchiorre D et al. Anti-cyclic citrullinated peptide antibodies are highly associated with severe bone lesions in rheumatoid arthritis anti-CCP and bone results have been obtained for some of these damage in RA. Autoimmunity 2004;37:495–501. autoantibodies, such as those directed against calpastatin, 21. Bobbio-Pallavicini F, Caporali R, Alpini C et al. Predictive value of antibodies to citrullinated peptides and rheumatoid factors in anti-TNF-alpha treated patients. Ann N Y Acad Sci owing to technical difficulties and the characteristics of the 2007;1109:287–95. antigenic substrate used. 22. Alexiou I, Germenis A, Koutroumpas A et al. Anti-cyclic citrullinated peptide-2 (CCP2) autoantibodies and extra-articular manifestations in Greek patients with rheumatoid However, in the last decade, ACPA have been identified arthritis. Clin Rheumatol 2008;27:511–3. as the most specific serological marker of RA, with 23. Nielen MM, van Schaardenburg D, Reesink HW et al. Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. interesting diagnostic and prognostic properties. These Arthritis Rheum 2004;50:380–6. 24. van Gaalen FA, van Aken J, Huizinga TW et al. Association between HLA class II genes autoantibodies are now a useful tool for the diagnosis of RA and autoantibodies to cyclic citrullinated peptides (CCPs) influences the severity of in clinical practice and their role in the disease process and rheumatoid arthritis. Arthritis Rheum 2004;50:2113–21. 25. Klareskog L, Stolt P, Lundberg K et al. A new model for an etiology of rheumatoid arthritis: joint damage merits further investigation. smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum 2006;54:38–46. 26. van der Helm-van Mil AH, Verpoort KN, le Cessie S et al. The HLA-DRB1 shared epitope Disclosures alleles differ in the interaction with smoking and predisposition to antibodies to cyclic The authors have no relevant financial interests to disclose. citrullinated peptide. Arthritis Rheum 2007;56:425–32. 27. Makrygiannakis D, af Klint E, Lundberg IE et al. Citrullination is an inflammation- dependent process. Ann Rheum Dis 2006;65:1219–22. References 28. Kuhn KA, Kulik L, Tomooka B et al. Antibodies against citrullinated proteins enhance tissue injury in experimental autoimmune arthritis. J Clin Invest 2006;116:961–73. 1. Arnett FC, Edworthy SM, Bloch DA et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 29. Hill JA, Bell DA, Brintnell W et al. Arthritis induced by posttranslationally modified 1988;31:315–24. (citrullinated) fibrinogen in DR4-IE transgenic mice. J Exp Med 2008;205:967–79. 2. De Rycke L, Peene I, Hoffman IE et al. Rheumatoid factor and anticitrullinated protein 30. Steiner G, Hartmuth K, Skriner K et al. Purification and partial sequencing of the nuclear antibodies in rheumatoid arthritis: diagnostic value, associations with radiological autoantigen RA33 shows that it is indistinguishable from the A2 protein of the progression rate, and extra-articular manifestations. Ann Rheum Dis 2004;63:1587–93. heterogeneous nuclear ribonucleoprotein complex. J Clin Invest 1992;90:1061–6. 3. van Venrooij WJ, Zendman AJ, Pruijn GJ. Autoantibodies to citrullinated antigens in (early) 31. Hassfeld W, Steiner G, Hartmuth K et al. Demonstration of a new antinuclear antibody (anti- rheumatoid arthritis. Autoimmun Rev 2006;6:37–41. RA33) that is highly specific for rheumatoid arthritis. Arthritis Rheum 1989;32:1515–20. 4. Schellekens GA, de Jong BA, van den Hoogen FH et al. Citrulline is an essential constituent 32. Hassfeld W, Steiner G, Graninger W et al. Autoantibody to the nuclear antigen RA33: a of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies. marker for early rheumatoid arthritis. Br J Rheumatol 1993;32:199–203. J Clin Invest 1998;101:273–81. 33. Hassfeld W, Steiner G, Studnicka-Benke A et al. Autoimmune response to the spliceosome. 5. van Gaalen FA, Viser H, Huizinga TW. A comparison of the diagnostic accuracy and An immunologic link between rheumatoid arthritis, mixed connective tissue disease and prognostic value of the first and second anti-cyclic citrullinated peptides autoantibody systemic lupus erythematosus. Arthritis Rheum 1995;38:777–85. (CCP1 and CCP2) test for rheumatoid arthritis. Ann Rheum Dis 2005;64:1510–2. 34. Mediwake R, Isenberg DA, Schellekens GA et al. Use of anti-citrullinated peptide and anti- 6. Mathsson L, Mullazehi M, Wick MC et al. Antibodies against citrullinated vimentin in RA33 antibodies in distinguishing erosive arthritis in patients with systemic lupus rheumatoid arthritis: higher sensitivity and extended prognostic value concerning future erythematosus and rheumatoid arthritis. Ann Rheum Dis 2001;60:67–8. radiographic progression as compared with antibodies against cyclic citrullinated peptides. 35. Combe B, Dougados M, Goupille P et al. Prognostic factors for radiographic damage in Arthritis Rheum 2008;58:36–45. early rheumatoid arthritis. Arthritis Rheum 2001;44:1736–43. 7. Pérez ML, Gómara MJ, Ercilla G et al. Antibodies to citrullinated human fibrinogen 36. Trentham DE, Townes AS, Kang AH. Autoimmunity to type II collagen an experimental synthetic peptides in diagnosing rheumatoid artritis. J Med Chem 2007;50:3573–84. model of arthritis. J Exp Med 1977;146:857–68. 8. Luis Caro-Oleas J, Fernández-Suárez A, Reneses Cesteros S et al. Diagnostic usefulness of 37. Clague RB. Autoantibodies to cartilage collagens in rheumatoid arthritis. Do they a third-generation anti-cyclic citrulline antibody test in patients with recent-onset perpetuate the disease or are they irrelevant? Br J Rheumatol 1989;28:1–5. polyarthritis. Clin Chem Lab Med 2007;45:1396–401. 38. Kim WU, Yoo WH, Park W et al. IgG antibodies to type II collagen reflect inflammatory 9. Vander Cruyssen B, Nogueira L, van Praet J et al. Do all anti-citrullinated protein/peptide activity in patients with rheumatoid arthritis. J Rheumatol 2000;27;575–81. antibody (ACPA) tests measure the same? Evaluation of discrepancy between anti- 39. Mullazehi M, Mathsson L, Lampa J et al. High anti-collagen type-II antibody levels and citrullinated protein/peptide antibody tests in patients with and without rheumatoid induction of proinflammatory cytokines by anti-collagen antibody-containing immune arthritis. Ann Rheum Dis 2008;67:542–6. complexes in vitro characterise a distinct rheumatoid arthritis phenotype associated with 10. Bizzaro N, Tonutti E, Tozzoli R et al. Analytical and diagnostic characteristics of 11 2nd- acute inflammation at the time of disease onset. Ann Rheum Dis 2007;66:537–41. and 3rd-generation immunoenzymatic methods for the detection of antibodies to 40. Cook AD, Rowley MJ, Mackay IR et al. Antibodies to type II collagen in early rheumatoid citrullinated proteins. Clin Chem 2007;53:1527–33. arthritis. Correlation with disease progression. Arthritis Rheum 1996;39:1720–7. 11. Coenen D, Verschueren P, Westhovens R et al. Technical and diagnostic performance of 6 41. Möttönen T, Hannonen P, Oka M et al. Antibodies against native type II collagen do not assays for the measurement of citrullinated protein/peptide antibodies in the diagnosis of precede the clinical onset of rheumatoid arthritis. Arthritis Rheum 1988;31:776–9. rheumatoid arthritis. Clin Chem 2007;53:498–504. 42. Schaller M, Stohl W, Tan SM et al. Raised levels of anti-glucose-6-phosphate isomerase 12. Vossenaar ER, Walther J, van Venrooij. Anti-CCP antibodies, a highly specific marker for IgG in serum and synovial fluid from patients with inflammatory arthritis. Ann Rheum Dis (early) rheumatoid arthritis. Clin Applied Immunol Rev 2004;4:239–62. 2005;64:743–9. 13. Nishimura K, Sugiyama D, Kogata Y et al. Meta-analysis: diagnostic accuracy of anti-cyclic 43. Matsumoto I, Lee DM, Goldbach-Mansky R et al. Low prevalence of antibodies to citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis. Ann Intern glucose-6-phosphate isomerase in patients with rheumatoid arthritis and a spectrum of Med 2007;146:797–808. other chronic autoimmune disorders. Arthritis Rheum 2003;48:944–54.

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44. Herve CA, Wait R, Venables PJ. Glucose-6-phosphate isomerase is not a specific 59. Cavazzana I, Franceschini F, Quinzanini M et al. Anti-Ro/SSA antibodies in rheumatoid autoantigen in rheumatoid arthritis. Rheumatology (Oxford) 2003;42:986–8. arthritis: clinical and immunologic associations. Clin Exp Rheumatol 2006;24:59–64. 45. Jouen F, Vittecoq O, Leguillou F et al. Diagnostic and prognostic values of anti glucose-6- 60. Schneeberger E, Citera G, Heredia M et al. Clinical significance of anti-Ro antibodies in phosphate isomerase antibodies in community-recruited patients with very early arthritis. rheumatoid arthritis. Clin Rheumatol 2008;27:517–9. Clin Exp Immunol 2004;137:606–11. 61. Boire G, Ménard HA, Gendron M et al. Rheumatoid arthritis: anti-Ro antibodies define a 46. van Gaalen FA, Toes RE, Ditzel HJ et al. Association of autoantibodies to glucose-6- non-HLA-DR4 associated clinicoserological cluster. J Rheumatol 1993;20:1654–60. phosphate isomerase with extraarticular complications in rheumatoid arthritis. Arthritis 62. Tishler M, Nyman J, Wahren M et al. Anti-Ro (SSA) antibodies in rheumatoid arthritis Rheum 2004;50:395–9. patients with gold-induced side effects. Rheumatol Int 1997;17:133–5. 47. Bläss S, Union A, Raymackers J et al. The stress protein BIP is overexpressed and is a major 63. Fort JG, Cowchock FS, Abruzzo JL et al. Anticardiolipin antibodies in patients with B and T cell target in rheumatoid arthritis. Arthritis Rheum 2001;44:761–71. rheumatic diseases. Arthritis Rheum 1987;30:752–60. 48. Bodman-Smith MD, Corrigall VM, Berglin E et al. Antibody response to the human stress 64. Keane A, Woods R, Dowding V et al. Anticardiolipin antibodies in rheumatoid arthritis. Br J protein BIP in rheumatoid arthritis. Rheumatology (Oxford) 2004;43:1283–7. Rheumatol 1987;26:346–50. 49. Bodman-Smith MD, Corrigal VM, Chan C et al. Anti-BIP antibodies in the serum of 65. Wolf P, Gretler J, Aglas F et al. Anticardiolipin antibodies in rheumatoid arthritis: their patients with autoimmune disease. Immunology 2003;107(Suppl 1):OP203. relation to rheumatoid nodules and cutaneous vascular manifestations. Br J Dermatol 50. Mavropoulos JC, Cuchacovich M, Llanos C et al. Anti-tumor necrosis factor-alpha therapy 1994;131:48–51. augments dipeptidyl peptidase IV activity and decreases autoantibodies to GRP78/BIP and 66. Merkel PA, Chang YC, Pierangeli SS et al. The prevalence and clinical associations of phosphoglucose isomerase in patients with rheumatoid arthritis. J Rheumatol anticardiolipin antibodies in a large inception cohort of patients with connective tissue 2005;32:2116–24. diseases. Am J Med 1996;101:576–83. 51. Rantapää-Dahlqvist S. Diagnostic and prognostic significance of autoantibodies in early 67. Pahor A, Hojs R, Holc I et al. Antiphospholipid antibodies as a possible risk factor for rheumatoid arthritis. Scand J Rheumatol 2005;34:83–96. atherosclerosis in patients with rheumatoid arthritis. Immunobiology 2006;211:689–94. 52. Yamamoto S, Shimizu K, Shimizu K et al. Calcium-dependent cysteine proteinase (calpain) 68. Seriolo B, Accardo S, Garnero A et al. Anticardiolipin antibodies, free protein S levels and in human arthritic synovial joints. Arthritis Rheum 1992;35:1309–17. thrombosis: a survey in a selected population of rheumatoid arthritis patients. 53. Mimori T, Suganuma K, Tanami Y et al. Autoantibodies to calpastatin (an endogenous Rheumatology (Oxford) 1999;38:675–8. inhibitor for calcium-dependent neutral protease, calpain) in systemic rheumatic diseases. 69. Bobbio-Pallavicini F, Alpini C, Caporali R et al. Autoantibody profile in rheumatoid arthritis Proc Natl Acad Sci USA 1995;92:7267–71. during long-term infliximab treatment. Arthritis Res Ther 2004;6:R264–72. 54. Schlosser U, Lackner KJ, Scheckenhofer C et al. Autoantibodies against the protease 70. Mustila A, Paimela L, Leirisalo-Repo M et al. Antineutrophil cytoplasmic antibodies in inhibitor calpastatin: a new risk factor for venous thrombosis? Thromb Haemost patients with early rheumatoid arthritis: an early marker of progressive erosive disease. 1997;77:11–3. Arthritis Rheum 2000;43:1371–7. 55. Wang LF, Wei SG, Miao SY et al. Calpastatin gene in human testis. Biochem Mol Biol Int 71. Tur BS, Süldür N, Ataman S et al. Anti-neutrophil cytoplasmic antibodies in patients with 1994;33:245–51. rheumatoid arthritis: clinical, biological, and radiological correlations. Joint Bone Spine 56. Iwaki-Egawa S, Matsuno H, Yudoh K et al. High diagnostic value of anticalpastatin 2004;71:198–202. autoantibodies in rheumatoid arthritis detected by ELISA using human erythrocyte 72. Cambridge G, Williams M, Leaker B et al. Anti-myeloperoxidase antibodies in patients with calpastatin as antigen. J Rheumatol 2004;31:17–22. rheumatoid arthritis: prevalence, clinical correlates, and IgG subclass. Ann Rheum Dis 57. Vittecoq O, Pouplin S, Krzanowska K et al. Rheumatoid factor is the strongest predictor of 1994;53:24–9. radiological progression of rheumatoid arthritis in a three-year prospective study in 73 Brimnes J, Halberg P, Jacobsen S et al. Specificities of anti-neutrophil autoantibodies in community-recruited patients. Rheumatology (Oxford) 2003;42:939–46. patients with rheumatoid arthritis (RA). Clin Exp Immunol 1997;110:250–6. 58. Auger I, Roudier C, Guis S et al. HLA-DRB1*0404 is strongly associated with anticalpastatin antibodies in rheumatoid arthritis. Ann Rheum Dis 2007;66:1588–93.

52 INTERNATIONAL JOURNAL OF ADVANCES IN RHEUMATOLOGY Vol 6 No 2 2008 CASE STUDY 53 /L), an 9 , 2 L with a total protein μ Vol 6 No 2 2008 Vol /L), and platelet count (170x10 9 , Darius Soonawala, MD , Darius Soonawala, 1 mol/L. Liver enzymes were unremarkable. Spinal tap unremarkable. mol/L. Liver enzymes were HEUMATOLOGY μ R The patient’s laboratory tests on admission showed a laboratory tests on The patient’s The electrocardiogram showed a sinus tachycardia of showed a sinus tachycardia The electrocardiogram 3 opening pressure was normal, and the spinal fluid leukocyte opening pressure count was 2.0 cells per 3 Examination clonazepam received On admission, the patient had already unconscious with a for generalized convulsions. She was 180/100 was pressure Glasgow coma scale of 8. Her blood (bpm), and her mmHg, pulse rate 130 beats/min heart revealed was 39.1ºC. Auscultation of the temperature consistent with the normal heart tones with a murmur Examination of the lungs known mitral valve insufficiency. no abnormalities. Neurological and abdomen revealed or asymmetric no signs of meningitis examination revealed fixed to the left. the head and eyes were deficit; however, white blood cell normal hemoglobin level (8.3 mmol/L), count (12.6x10 erythrocyte sedimentation rate of 31 mm/h, C-reactive erythrocyte and an international normalized level of 3 mg/L, protein ratio (INR) of 4.0. Her sodium concentration was slightly level (133 mmol/L) and the elevated creatinine decreased stable at remained insufficiency) renal (due to her chronic 146 concentration of 1.19 g/L. Blood, urine, sputum, and spinal all negative for abnormalities. were fluid cultures 120 bpm without abnormalities. Chest radiography and A no irregularities. ultrasound of the abdomen also revealed embolism or did not indicate cardiac ultrasound cardiac Computed tomography active Libman–Sachs endocarditis. imaging (MRI; both (CT) scanning and magnetic resonance Gadolinium contrast) of the brain and with standard only old lesions consistent with the previous revealed DVANCES IN A OURNAL OF J Intensive Care Unit, Leiden University Medical Centre, Leiden, and Leiden, Medical Centre, Unit, Leiden University Intensive Care 2 (2):53–6. , and Irene Speyer, MD , and Irene Speyer, 2 6 NTERNATIONAL I 2008; The current admission was due to sudden onset of The current Departments of Rheumatology and Departments of Rheumatology Netherlands Hospital, Hague, The Bronovo Department of Rheumatology, Abraham Schoe, MD Abraham Schoe, Address for correspondence: LR Lard, Department of Rheumatology, LR Lard, for correspondence: Address PO Box 9600, 2300 RC, Leiden, Leiden University Medical Centre, The Netherlands. Email: [email protected] Case was admitted descent woman of Moroccan A 45-year-old convulsions. authors’ hospital with persistent to the present lupus erythematosus She had a history of systemic of arthritis, discoid skin (SLE) based on the presence (ANA), antibodies to lesions, positive antinuclear antibodies Coombs test. In 1998, double-stranded DNA, and a positive an intra-uterine fetal death due to she suffered and in 2005, she was treated antiphospholipid syndrome Health lupus nephritis (World for biopsy-proven grade V). In 2006, she had a middle cerebral Organization with a grade four mitral valve insufficiency artery stroke in this resulted due to Libman–Sacks endocarditis; of SLE and a relapse left-sided spastic hemiparesis with was treated glomerulonephritis for which she and azathioprine. high-dose methylprednisolone epileptic fits for subject suffered the After the stroke acid was started. which valproic by 1 day of progressive generalized convulsions preceded had been no fever or signs of abdominal pain. There deficit. On admission, her infection, or neurological 5 mg prednisone medication consisted of phenprocoumon, times daily, azathioprine 50 mg three twice daily, acid 70 alendronic 400 mg once daily, hydroxychloroquine amlodipine acid 500 mg twice daily, mg per week, valproid atorvastatin peridonpril 8 mg once daily, 10 mg once daily, and pantoprazole 20 mg once daily. 10 mg once daily, Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands Leiden University Medical Centre, Department of Rheumatology, Int J Adv Rheumatol 1 3 PhD Cornelia F Allaart, MD, Case Study Editor: Case Study presented by: Leroy R Lard, MD, PhD by: Leroy R Lard, Case Study presented Just Another Case of Neuropsychiatric Case Another Just Erythematosus? Lupus Systemic RT404_2_Rheum_6.2_05.qxd 10/9/08 16:44 Page 53 Page 16:44 10/9/08 RT404_2_Rheum_6.2_05.qxd RT404_2_Rheum_6.2_05.qxd 10/9/08 16:44 Page 54

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Table 1. Clinical manifestations of AP with the estimated infectious origin during immunosuppressive therapy, or by incidence [2]. active SLE. Clonazepam and carbamazepine were administered Clinical manifestations Incidence (%) intravenously and broad spectrum antibiotics were started. Over the next few days her fever subsided and she was awake Abdominal pain 85–95 and responsive. The laboratory results remained unchanged. Vomiting 43–88 One week later she developed a flaccid paresis of the right arm Constipation 48–84 and leg together with phatic problems. New MRI of the brain and cervical spine (standard and with Gadolinium contrast) Diarrhea 5–12 showed no signal abnormalities, no mass in the cervical cord, Pain in extremities, back, unchanged abnormalities in the brain, and no new ischemic chest, neck, or head 50–70 lesions. This could neither prove nor rule out neuropsychiatric Paresis 42–68 SLE (NPSLE). Due to the clinical deterioration in spite of the current treatment, active NPSLE was considered the most likely Respiratory paralysis 9–20 diagnosis. Therefore, methylprednisolone 1000 mg/day for Mental symptoms 40–58 3 days was initiated, followed by 60 mg/day of prednisone. Convulsions 10–20 The anti-epileptic drugs were continued intravenously. Initially, Tachycardia 28–85 a mild clinical improvement seemed to occur; however, during the next 2 days she had two more seizures. The paresis Hypertension 36–55 progressed to flaccid tetraparesis, soon followed by a critical Fever 9–37 respiratory failure for which an intensive care unit (ICU) admission was needed for mechanical ventilation. After AP: acute porphyria. exclusion of vascular or infectious causes, the neurological deterioration was thought to be due to active NPSLE in the Table 2. Common drugs that are unsafe and safe in patients form of Guillain–Barré syndrome (GBS). However, serial nerve with porphyria [2]. conduction studies showed axonal rather than demyelinating Unsafe Safe findings, and needle electromyography showed no spontaneous activity. In other words, the typical GBS pattern Alcohol Acetaminophen was not observed. Nevertheless, treatment was started with Barbiturates Aspirin intravenous immunoglobulin and cyclophosphamide pulse 2 Carbamazepine Gabapentin therapy (750 mg/m ) [1]; prednisone 60 mg/day and the anti- epileptic drugs were continued. Unfortunately, no Clonazepam Glucocorticoids improvement was observed. Diclofenac Insulin In the ICU, the patient’s urine was noted to have an Estrogens Narcotic analgesics orange/reddish color, and at that moment acute porphyria (AP) was considered. Testing revealed elevated urine levels of total Phenytoin Penicillin porphyria of 24 306 nmol/24 h (normal <210 nmol/24 h), Progesterone Atropine porphobilinogen of 269 μmol/24 h (normal <9 μmol/24 h), Calcium channel blockers Phenothiazines and δ-aminolevulinic acid (δ-ALA) of 300 μmol/24 h (normal <53 μmol/24 h). Fecal coproporphyrin levels were significantly Sulfonamide antibiotics Ranitidine elevated, with 86 nmol/g coproporphyrin I (normal Valproic acid Streptomycin <5.4 nmol/g) and 691 nmol/g coproporphyrin III (normal <2 nmol/g). This led to the diagnosis of an AP attack due to hereditary coproporphyria (HCP) and not that of NPSLE. All of ischemic stroke and old brain white matter lesions centrally the symptoms, namely the preceding abdominal pain, the on both sides. No tumor or hematoma was found on the convulsions, fever, hypertension, sinus tachycardia, tetraparesis, brain scans. Thus far, no obvious causes for the persistent and respiratory failure, could be attributed to the AP (Table 1) convulsions and the fever were identified. [2]. The initial attack may have been caused by the use of medication. Valproic acid and calcium channel blockers are Management and further progress candidates for triggering an attack (Table 2) [2]. The clinical At this point, our differential diagnosis was convulsions due to course deteriorated by further administration of clonazepam her past stroke currently triggered by high fever of unknown and phenytoin, which are known to be porphyrinogenic drugs.

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Figure 1. Schematic representation of the heme synthesis. AP due to HCP is caused by a deficiency of the enzyme coproporphyrinogen oxidase.

Mitochondria Cytoplasm

Aminolaevulinic acid synthase Aminolaevulinate dehydratase

Glycine + Succinyl Co-A D-aminolaevulinic acid Prophobilinogen

Prophobilinogen deaminase

Hydroxymethylbilane Coproporphyrinogen oxidase Uroporphyrinogen III synthase Protoporphyrinogen IX Uroporphyrinogen III Protoporphyrinogen oxidase Uroporphyrinogen decarboxylase Protoporphyrin IX Coproporphyrinogen III Ferrochelatase

Heme

AP: acute porphyria; CoA: co-enzyme A; HCP: hereditary coproporphyria.

Following the diagnosis of HCP, all porphyrinogenic attack of porphyria. However, infections, certain hormones medication was stopped and hematin was started and drugs, and dietary changes can trigger an attack of AP intravenously [2]. Unfortunately, awaiting possible beneficial by inducing the synthesis of cytochrome P450, which response, the patient developed cyclophosphamide-induced consequently increases the heme oxygenase activity. This leucopenia, making her susceptible to infections. The patient leads to an abnormal accumulation of the toxic porphyrins. suffered from multiple episodes of ventilator-associated The most common known drugs that can trigger AP are pneumonia and ultimately died due to a Gram-negative sepsis. anti-epileptic drugs such as valproic acid, phenytoin, and clonazepam, which were administrated to our patient. Discussion Treatment of mild AP attacks consists of a high HCP is one of four types of AP. It is a rare, autosomal- carbohydrate diet or a glucose 10% infusion (≥300 g daily), dominant metabolic disorder of the production of heme – which reduces the activity of heme oxygenase. In severe AP the oxygen-binding prosthetic group of hemoglobin. It is attacks, hematin must also be given intravenously at a characterized by a deficiency of the enzyme dosage of 3–4 mg/kg per day for ≥4 days [2,3]. These are coproporphyrinogen oxidase (CPO). Heme synthesis begins not curative drugs, but they can shorten attacks and reduce in the mitochondrion, proceeds into the cytoplasm, and ends the intensity of an attack by inhibiting ALA synthase and in the mitochondrion (Fig. 1). Without CPO, heme synthesis thus the accumulation of toxic precursors. Side effects are cannot progress, and the metabolite porphyrin accumulates rare but can be serious, for instance severe coagulopathy in the cytoplasm, which is toxic. Accumulation of these and anaphylactic reactions. Discontinuing porphyrinogenic metabolites causes the characteristic neurovisceral and/or drugs is essential. As many anti-epileptic drugs exacerbate photosensitizing symptoms. The exact mechanism leading to this condition, the treatment of convulsions in these patients these symptoms remains unclear. Even with the genetic is difficult. Some benzodiazepines are safe, and, when used disorder, in unchallenged conditions there still is a 50% CPO in conjunction with gabapentin, offer a possible regimen for enzyme activity, which is sufficient to prevent an acute convulsion control [2,4].

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Several reports have described the co-appearance of unknown diseases, especially if the response to treatment is (cutaneous) porphyria in patients with SLE [5,6]. Allard et al. not what may have been expected. It is also an illustration of even describe a high prevalence of presence of ANA in the hazard of the doctor’s detachment/dissociation from the patients with AP [6]. However, this appears to be an patient’s bedside. Advanced technical tests may be considered unfortunate coincidence rather than a specific for diagnoses and response to treatment, but in this case, the pathophysiological relationship. As the most common unusual color of the urine went unnoticed until the patient had symptoms of AP (abdominal pain, vomiting, tachycardia, a urinary catheter in the ICU. As one of the physicians involved and fever) are not especially specific, and because SLE was a with the care for this patient, I am entitled to be critical. Since likely cause of the neurological symptoms in this case, this case occurred, we have considered AP and tested for it in porphyria was not initially considered in this patient. Many two other patients with atypical manifestations of NPSLE. They symptoms could be attributed to an active NPSLE. Indeed, both tested negative, and the diagnosis of NPSLE was finally the lack of new lesions on a cerebral MRI does not exclude confirmed. Given the rarity of AP, I hope that we will not an active NPSLE [7]. However, the poor response to high- forget this case when the next patient is admitted in several dose immunosuppressive therapy, and the electromyography years time. that was not consistent with typical GBS, should have triggered suspicions of an alternative, even more rare, Disclosures diagnosis, at an earlier stage. The patient might still have The authors have no relevant financial interests to disclose. responded to the treatment of AP; however, in the meantime the NPSLE treatment had made her even more References vulnerable to the infectious complications, which ultimately 1. Gourley MF, Austin HA 3rd, Scott D et al. Methylprednisolone and cyclophosphamide, alone or in combination, in patients with lupus nephritis. A randomized, controlled trial. resulted in her death. AP should be included in the Ann Intern Med 1996;125:549–57. differential diagnosis of atypical NPSLE, especially when 2. Anderson KE, Bloomer JR, Bonkovsky HL et al. Recommendations for the diagnosis and treatment of the acute porphyrias. Ann Intern Med 2005;142:439–50. presenting with acute neuropathy. 3. Kochar DK, Pal M, Kochar SK et al. Acute intermittent porphyria presenting with neurological emergency: review of six cases. Neurol India 2007;55:413–5. 4. Kauppinen R. Porphyrias. Lancet 2005;365:241–52. Case Study Editor’s comments 5. Filiotou A, Vaiopoulos G, Capsimali V et al. Acute intermittent porphyria and systemic This is a report of the unfortunate result of a missed diagnosis. lupus erythematosus: report of a case and review of the literature. Lupus 2002;11:190–2. 6. Allard SA, Charles PJ, Herrick AL et al. Antinuclear antibodies and the diagnosis of systemic It highlights that making a differential diagnosis needs to go lupus erythematosus in patients with acute intermittent porphyria. Ann Rheum Dis beyond the obvious and most likely, and should include, even 1990;49:246–8. 7. Jennings JE, Sundgren PC, Attwood J et al. Value of MRI of the brain in patients with systemic if as a final thought, the rare, the unlikely, and the relatively lupus erythematosus and neurologic disturbance. Neuroradiology 2004;46:15–21.

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CLINICAL REVIEWS Commentary and Analysis on Recent Key Papers

Clinical reviews were prepared by Tom Huizinga, MD, Peter Nigrovic, MD, Eric Ruderman, MD, and Hendrik Schulze-Koops, MD

TREATMENT STRATEGIES least every 6 months. After a median follow-up of 5.3 years (range 1–7.5 years), 81% (21 of 26) of the patients demonstrated a clinically beneficial response. The Kaplan–Meier Long-term follow-up results after autologous estimated survival rate at 5 years was 96.2% (95% confidence haematopoietic stem cell transplantation for severe interval [CI] 89–100%) and at 7 years, 84.8% (95% CI systemic sclerosis 70.2–100%). The event-free survival rate, defined as survival Vonk MC, Marjanovic Z, van den Hoogen FH et al. without mortality, relapse, or progression of SSc resulting in Ann Rheum Dis 2008;67:98–104. major organ dysfunction, was 64.3% (95% CI 47.9–86%) at 5 years and 57.1% (95% CI 39.3–83%) at 7 years. Despite modern therapies, the high mortality rate in This study confirms that autologous HSCT in selected patients with systemic sclerosis (SSc; a 5-year mortality rate patients with severe diffuse SSc results in sustained of 30%) requires the development of novel therapeutic improvement of skin thickening and stabilization of organ approaches. In the present study, the authors report the function up to 7 years after transplantation. 1. Farge D, Passweg J, van Laar JM et al.; EBMT/EULAR Registry. Autologous stem cell results of intensive myelo- and immunosuppression transplantation in the treatment of systemic sclerosis: report from the EBMT/EULAR followed by autologous hematopoietic stem cell Registry. Ann Rheum Dis 2004;63:974–81. transplantation to treat severe SSc. Address for reprints: MC Vonk, Department of Rheumatology, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, Since 1996, approximately 140 patients with systemic sclerosis The Netherlands. Email: [email protected] (SSc) have undergone hematopoietic stem cell transplantation (HSCT). Early results of Phase I/II clinical trials showed that The comparative one-year performance of anti- HSCT is feasible in carefully selected patients with diffuse SSc. tumor necrosis factor α drugs in patients with A follow-up study of 57 patients revealed a positive response rheumatoid arthritis, psoriatic arthritis, and at 3 years in about 66% of the patients with a mortality rate ankylosing spondylitis: results from a longitudinal, of 8.7% [1]. Based on these data, the present authors observational, multicenter study initiated an analysis of the long-term follow-up results of the Heiberg MS, Koldingsnes W, Mikkelsen K et al. Dutch and French patients from two Phase I/II trials. Arthritis Rheum 2008;59:234–40. The specific aims of this analysis were to evaluate the survival rates and the durability of responses at up to 7 years of What is the “survival” of anti-tumor necrosis factor therapy follow-up in SSc patients treated with HSCT. A total of 26 in clinical practice, and what are the predictors of successful patients were followed up. The mobilization and collection of long-term use of such therapy? The authors address this peripheral blood stem cells (PBSC) was performed with 4 g/m2 question in an observational Norwegian cohort and find of cyclophosphamide followed by human granulocyte-colony that patients with rheumatoid arthritis tend to require a stimulating factor (G-CSF) 4–5 days later. At least 9.5 million change in regimen sooner than patients with psoriatic CD34+ cells per kg had to be collected by successive daily arthritis or ankylosing spondylitis. Concomitant apheresis to obtain 7 million stem cells after positive selection. methotrexate use was associated with greater longevity Conditioning was performed at least 4 weeks later using of therapy. cyclophosphamide at 50 mg/kg/day from day –5 to day –2 prior to PBSC injection. To assess the survival and disease Therapy with anti-tumor necrosis factor (anti-TNF) agents is response to treatment, clinical evaluation was conducted at often highly successful in patients with rheumatic illnesses, but

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not all patients remain on therapy in the long-term. Reasons clinical trial to assess a therapeutic effect of glucosamine for discontinuation include inefficacy and adverse events, sulfate, 1500 mg daily for 2 years, in patients with hip OA among others. recruited through primary care practices. Patients referred The present group used a Norwegian disease-modifying for screening evaluation at the study center were eligible if antirheumatic drug registry to track the course of >1200 they met American College of Rheumatology hip OA criteria courses of anti-TNF therapy to assess factors associated with with Kellgren/Lawrence scores <4 (the most severe), were early discontinuation. They found that the underlying not awaiting hip surgery, and were not receiving diagnosis was a powerful predictive factor, such that patients glucosamine therapy. Standardized radiographs were with rheumatoid arthritis (RA) had significantly reduced obtained at baseline and 24 months, clinical questionnaires treatment longevity compared with patients with psoriatic were completed every 3 months, and compliance was arthritis (PsA) or ankylosing spondylitis (AS). The crude assessed by self report and pill counts. Patients and assessors 1-year drug survival rates were 65.4%, 77.3%, and 77.5% were blinded to the treatment group. Criteria for clinically respectively (although the difference between PsA and RA important changes in pain and function (Western Ontario lost significance when adjusted for potential confounders). and McMaster Osteoarthritis Index [WOMAC]) scores, and Among the three drugs (adalimumab, etanercept, and joint narrowing, were defined in advance. infliximab), etanercept enjoyed the best crude survival rates, Out of 417 patients referred from general practitioners, but this drug was often the first that was tried, and the 222 patients with a mean age of approximately 63 years survival advantage evaporated when only TNF-naïve were enrolled in the study. Over 93% were available for recipients were considered. Factors associated with earlier final assessment. At 24 months, no significant differences termination of therapy included female gender and higher were noted between glucosamine and placebo arms in pain, disease activity. The use of methotrexate correlated with a function, joint space narrowing, or pain medication use; substantially reduced rate of discontinuation (hazard ratio 95% confidence intervals excluded the pre-determined 0.53; 95% confidence interval 0.43–0.65); no subgroup clinically important difference values. Restriction of analysis analysis was presented as to whether this advantage accrued to patients with excellent (>80%) adherence to therapy did differentially across anti-TNF agents. Interestingly, the not change these results. methotrexate effect was absent in patients with AS. While it remains formally possible that this study missed Improvement in health-related quality of life with TNF a clinical subpopulation that responds well to glucosamine – therapy was greater in PsA and AS – particularly in the latter, because such patients might already be taking the accounting perhaps for the improved duration of therapy in supplement and would, therefore, be excluded from the trial these patients. – the data are extremely convincing that no substantial benefit for hip OA can be expected from glucosamine in the Address for reprints: MS Heiberg, Department of Rheumatology, Diakonhjemmet Hospital, Box 23 Vinderen, 0319 Oslo, Norway. dose regimen assessed. Email: [email protected] Address for reprints: RM Rozendaal, Department of General Practice, Erasmus Medical Center, Room Fg 351, PO BOX 2040, 3000 CA Effect of glucosamine sulfate on hip osteoarthritis: Rotterdam, The Netherlands. Email: [email protected] a randomized trial Rozendaal RM, Koes BW, van Osch GJ et al. Immunosuppressive therapy in lupus- and mixed Ann Intern Med 2008;148:268–77. connective tissue disease-associated pulmonary arterial hypertension: a retrospective analysis of The role of glucosamine in the treatment of osteo- twenty-three cases arthritis (OA) remains controversial. Only a few studies Jais X, Launay D, Yaici A et al. have investigated its efficacy in hip OA. In this Arthritis Rheum 2008;58:521–31. methodologically pristine, 2-year, randomized, double- blind clinical trial free of industry support, patients with Connective tissue disease-associated pulmonary arterial hip OA recruited from primary care offices demonstrated hypertension may be successfully managed with a no benefit from therapy. treatment protocol that begins with immunosuppressive therapy and corticosteroids in less severely affected The utility of oral glucosamine for the management of patients, reserving pulmonary vasodilators for those osteoarthritis (OA) remains uncertain, given conflicting who progress or have severe functional limitations results of published clinical trials. Most of these studies have at presentation. been conducted in knee OA. The present authors designed a

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Pulmonary arterial hypertension (PAH) can be a life- Comparison of the clinical efficacy and safety of threatening complication of various collagen vascular diseases, subcutaneous versus oral administration of including progressive systemic sclerosis (PSS), systemic lupus methotrexate in patients with active rheumatoid erythematosus (SLE), and mixed connective tissue disease arthritis: results of a six-month, multicenter, (MCTD). Therapy for PAH has focused on the use of randomized, double-blind, controlled, Phase IV trial pulmonary vasodilators to counteract vascular hyper-reactivity. Braun J, Kästner P, Flaxenberg P et al. However, recent evidence has pointed to the involvement of Arthritis Rheum 2008;58:73–81. an immune-mediated inflammatory process in the development and progression of PAH in patients with Subcutaneous methotrexate (MTX) is clinically more CTD, suggesting that immunosuppressive therapy may have effective than oral MTX in MTX-naïve rheumatoid arthritis a role in the management of PAH in at least some of patients, although both methods of administration produce these patients. substantial clinical benefits in this population. In a previous publication, the authors of this manuscript reported on their treatment of a group of patients with PAH Low-dose methotrexate (MTX) therapy for rheumatoid related to either SLE or MCTD [1]. They found that a subset arthritis (RA) may be administered orally or via of these patients responded to immunosuppressants and subcutaneous injection. While the latter method is glucocorticoids alone, without the addition of pulmonary associated with better bioavailability of the medication and vasodilators. They proposed that patients who were New has been used for patients with gastrointestinal toxicity from York Heart Association functional class I or II, as well as oral dosing, there is uncertainty about whether those who were class II but had at least a near normal subcutaneous dosing of MTX generally results in greater cardiac index, should be treated with immunosuppressants clinical efficacy. and glucocorticoids initially, adding vasodilators only if they In the current study, the authors identified 375 biological failed to respond. They also proposed that those patients agent-naïve patients with active RA randomized to receive with worse functional class should be treated with a 15 mg/week of MTX either orally or subcutaneously, in a combination of immunosuppressants, glucocorticoids, and blinded fashion for 16 weeks. At week 16, patients who had pulmonary vasodilators, although they acknowledged the not achieved an ACR20 response had their dose escalated lack of evidence that the first two were beneficial. from 15 mg orally to 15 mg subcutaneously for those In the current manuscript, the authors report on the first originally on oral therapy, and from 15 mg subcutaneously 23 consecutive patients treated according to their proposed to 20 mg subcutaneously for those originally on algorithm, including 16 who met criteria for treatment with subcutaneous therapy. The primary outcome of the study immunosuppressive therapy alone and seven who were was overall ACR20 response at 24 weeks. Higher levels of treated with a combination of immunosuppressives and response were also assessed. vasodilators. Eight of the first group met defined criteria for At week 24, 78% of those initially treated with response (functional class I or II along with hemodynamic subcutaneous MTX had achieved an ACR20 response improvement at the conclusion of therapy), and six of the compared with 70% of those initially treated with oral MTX, eight non-responders subsequently improved with the a difference that was statistically significant. The difference addition of pulmonary vasodilators. Four of the seven in ACR70 response was also statistically significant at 41% patients in the second group responded to the versus 33%, although the difference in ACR50 response was combination therapy. not. Fourteen per cent of the patients, approximately The authors conclude that a subset of patients with equally split between the two treatment groups, had an CTD-associated PAH may respond to treatment aimed at the escalation of therapy at week 16 after not meeting an immune mechanisms presumably responsible for their ACR20 response. Interestingly, patients with disease disease. They propose a sequence of therapy that appears to duration of >1 year had the highest response to be successful in their retrospective, uncontrolled series. subcutaneous MTX. Overall, adverse events were similar Randomized, controlled trials in this population will between the two groups; those treated with oral MTX determine whether their approach should become standard reported more diarrhea, while those treated with of care. subcutaneous MTX reported more loss of appetite. 1. Sanchez O, Sitbon O, Jais X et al. Immunosuppressive therapy in connective tissue The authors conclude that subcutaneous MTX is more diseases-associated pulmonary arterial hypertension. Chest 2006;130:182–9. effective than oral MTX for RA, although the latter certainly Address for reprints: M Humbert, Service de Pneumologie et appears effective enough to support its initial use if it is more Réanimation Respiratoire, Hôpital Antoine-Béclère, 157 rue de la Porte de Trivaux, 92140 Clamart, France. Email: [email protected] convenient for the patient. The results with both routes of

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administration confirm the effectiveness of MTX as initial the SRMs, with a large SRM for physician global, HAQ, SF- monotherapy for RA. 36 physician component score, SF-36 bodily pain and fatigue. For the more physical parameters (physician global, Address for reprints: J Braun, Rheumazentrum Ruhrgebiet, Landgrafenstrasse 15, 44652 Herne, Germany. SF-36 bodily pain, pain intensity, and HAQ), the relative Email: [email protected] efficiencies in relation to the TJC for detecting a treatment effect were greater, in contrast to the assessment of Responsiveness of patient reported outcomes psychological components. In general, most of the PROs including fatigue, sleep quality, activity limitation, showed good concordance with both American College of and quality of life following treatment with Rheumatology criteria and European League Against abatacept for rheumatoid arthritis Rheumatism response criteria. Significant treatment Wells G, Li T, Maxwell L et al. differences between abatacept and placebo were found for Ann Rheum Dis 2008;67:260–5. all core set measures and PROs. The differences were substantial in most cases, with significant but smaller On the basis of the ATTAIN (Abatacept Trial in Treatment differences noted for PROs associated with the more of Anti-TNF Inadequate Responders) study, the present psychological attributes. authors validate that patient-reported outcomes for Address for reprints: G Wells, Department of Epidemiology and evaluating treatments for rheumatoid arthritis can be Community Medicine, University of Ottawa, 451 Smyth Road, Ottawa, used to detect improvements that are important to ON, KIH 8M5, Canada. Email: [email protected] patients. Physical assessments are more responsive to an effective treatment than psychological assessments. GENETICS Patient-reported outcomes (PROs) assess health, wellbeing, and treatment response from the perspective of the patient The additive effect of individual genes in predicting and may differ from the clinical manifestations. Therefore, risk of knee osteoarthritis the present authors evaluated the responsiveness of PROs, Valdes AM, Doherty M, Spector TD. including the Short Form 36-item survey (SF-36), activity Ann Rheum Dis 2008;67:124–7. limitation, fatigue, and sleep with respect to clinical measures in rheumatoid arthritis (RA) patients. Data were Clinically relevant risk factors for osteoarthritis (OA) are obtained from the ATTAIN (Abatacept Trial in Treatment of obesity, with odds ratios (OR) of 3–18, and knee injury, Anti-TNF Inadequate Responders) study, which evaluated with OR ranging from 5–16. The OR conferred by the efficacy and safety of abatacept on a background of genetic risk factors have been found to be small, disease-modifying antirheumatic drug (DMARD) treatment indicating that genetics is perhaps more relevant in the in patients with active RA who were anti-tumor necrosis elucidation of biologically relevant pathways than in factor (anti-TNF) treatment “failures”. Assessments included disease management. With large-scale genetic testing, tender joint count (TJC), health assessment questionnaire this may change. Indeed, the current study indicates (HAQ), and clinical parameters. Multiple PROs including some additive effect of individual genetic risk factors in health-related quality of life (measured by the SF-36) and the prediction of risk for OA. sleep quality were assessed. The ability to detect a treatment effect was evaluated by the treatment difference (abatacept Genetic factors are determinants of osteoarthritis (OA), but vs. placebo), percentage improvement relative to baseline most individual genetic associations appear modest. The scores, standardized response mean (SRM), and the relative genotypes for 36 single nucleotide polymorphisms (SNPs) in efficiency for assessing an outcome’s ability to detect a 17 candidate genes previously associated with OA were treatment effect relative to the TJC. analyzed in 298 men and 305 women diagnosed with knee The PROs and quality of life (SF-36) indicated great OA, and in 297 male and 299 female control subjects. The impairment at baseline. The mean changes from baseline in odds ratio (OR) for individuals in the top quartile of the the study outcomes were larger for the abatacept group. “genetic risk” variable, compared with those in the bottom The largest relative percent improvements were found for quartile was found to be approximately 9 (95% confidence acute phase reactants and the PRO activity limitation, interval [CI] 5.20–14.49) for women, and about 5 (95% CI whereas the more psychological PROs (e.g. mental health 3.10–8.27) for men. and mental component score) gave the smallest relative Although these data indicate a relatively large effect, the percent improvement. Similar trends could be observed for odds between individuals in the lower versus the upper half of

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the distribution according to these known genetic risk factors A minor allele of the SNP rs13277113 in the region was only approximately 3. Nevertheless, the fact that upstream from the transcription initiation site of the gene additivity of genetic risk factors was observed is encouraging. encoding BLK and C8orf13 was associated with a risk for developing the disease both in the US and Swedish Address for reprints: AM Valdes, Twin Research Unit, St Thomas’ –10 Hospital Campus, Kings College London, Lambeth Palace Road, case–control series (odds ratio [OR] 1.39; p=1x10 ), and London, SE1 7EH, UK. also with altered levels of messenger RNA in B cell lines. In addition, variants on chromosome 16p11.22, near the genes Association of systemic lupus erythematosus with encoding integrin alpha M (ITGAM, or CD11b) and integrin C8orf13-BLK and ITGAM-ITGAX alpha X (ITGAX), were associated with SLE in the combined Hom G, Graham RR, Modrek B et al. sample (rs11574637; OR 1.33; p=3x10–11). Both associations N Engl J Med 2008;358:900–9. were confirmed in the replication study. Thus, two new genetic loci for SLE susceptibility were Identification of genetic factors involved in the identified and associated with reduced expression of BLK pathogenesis of autoimmune diseases such as systemic and increased expression of C8orf13. lupus erythematosus (SLE) is of obvious importance. In Address for reprints: TW Behrens, Genentech, 1 DNA Way, the present study, the authors performed a genome-wide 45-3B, South San Francisco, CA 94080, USA. scan of samples from patients with SLE and control Email: [email protected] subjects in order to identify disease-related genes.

Systemic lupus erythematosus (SLE) is a chronic autoimmune PATHOGENESIS disease with very strong genetic and environmental components. A number of genes: interferon regulatory Inhibition of monocyte chemoattractant protein-1 factor 5 (IRF5) and signal transducer and activator of ameliorates rat adjuvant-induced arthritis transcription 4 (STAT4), and some human leukocyte Shahrara S, Proudfoot AE, Park CC et al. antigen-DR (HLA-DR) alleles have already been associated J Immunol 2008;180:3447–56. with the disease. In this report, the results of a genome-wide single nucleotide polymorphism (SNP) scan in SLE patients The therapeutic inhibition of monocyte chemoattractant and control subjects are described. protein-1 (MCP-1)/CCL2 and RANTES/CCL5 was A total of 1861 samples from control subjects were examined in rat adjuvant-induced arthritis. Treatment of genotyped on the Illumina Human Hap550 Genotyping rats with an inhibitor of MCP-1 (P8A-MCP-1) resulted in Bead-Chip (Illumina Inc., San Diego, CA, USA). A total of amelioration of the disease, whereas inhibition of 1465 samples (464 from cases and 1001 from control RANTES or its corresponding receptors (using 44AANA47- subjects) were genotyped on the HumanHap550v1 chip, RANTES and Met-RANTES) had no effect. and 1875 samples (1015 from cases and 860 from controls) were genotyped on the HumanHap550v3 chip. An The chemokines RANTES/CCL5 and monocyte additional, independent set of 1722 samples that were chemoattractant protein-1 (MCP-1)/CCL2 regulate the genotyped on the HumanHap550 BeadChip was obtained chemotaxis of monocytes and T lymphocytes. They are highly from public data repositories. Analysis of the genotyped expressed in rheumatoid arthritis (RA) synovial tissue and are samples was performed in serial phases. After applying the thought to be involved in the pathogenesis of the disease data-quality filters, series one consisted of 411 case subjects through the promotion of leukocyte migration into the and 1047 control subjects, series two consisted of 595 cases synovial tissue. In this study, the effects of inhibition of and 1516 controls, and series three comprised 305 case RANTES and MCP-1 were examined in rat adjuvant-induced subjects and 777 controls. A total of 502 033 SNPs were arthritis (AIA) – an animal model of RA. After the onset of advanced into analyses. In a replication study consisting of AIA, the modified chemokines P8A-MCP-1 and 44AANA47- 793 case subjects and 857 control subjects from Sweden, RANTES, two inhibitors of endogenous MCP-1 and RANTES, two specific SNPs, namely rs11574637 and rs13277113, respectively, were administered intraperitoneally, separately, or were genotyped by the use of fluorescent single-base in combination, for 7 or 14 days. Measurement of ankle extension assays. To examine the functional consequences circumferences and articular index (AI) scores revealed of the finding, the authors analyzed gene expression of B improved clinical signs of AIA after treatment with P8A- lymphoid tyrosine kinase (BLK) and C8orf13 (chromosome MCP-1. Furthermore, P8A-MCP-1 decreased joint 8p23.1) in B cell lines transformed by the Epstein–Barr virus. inflammation, synovial lining, and bone destruction as

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determined by histology, X-rays, and real-time reverse alone. However, this group reports a novel mechanism by transcriptase-polymerase chain reaction (RT-PCR) for the which Tregs could impact upon the effector arm of the markers associated with bone destruction (receptor activator immune system as well. In this article, they show that Tregs of nuclear factor-κ ligand and matrix metalloproteinase-9). express high surface levels of the p75 tumor necrosis factor Downregulation of proinflammatory mediators and a (TNF) receptor TNFRII, the same molecule that forms the TNF- reduction in the number of macrophages in the synovial tissue binding site of etanercept. Upon activation, Treg cells begin to could be observed by enzyme-liked immunosorbent assay shed this receptor via cleavage of the extracellular portion of (ELISA) and immunostaining. As RANTES and MCP-1 induce the molecule, which then binds soluble TNF to prevent it from chemotaxis through activation of p38 mitogen-activated reaching its targets on the surface of other cells. In a functional protein kinase, the amount of phosphorylated p38 was assay, the authors show that Treg cells derived from mice investigated by immunostaining and Western blot analysis. deficient in TNFRII lack the ability to antagonize TNF. Further, Reduced activation of p38 was detected in rats treated with pharmacological blockade of the enzyme responsible for P8A-MCP-1. In contrast, treatment with 44AANA47-RANTES cleaving TNFRII from the surface results in excess accumulation had no effect on the evaluated features. Furthermore, the of this receptor on the surface of Treg cells. combination of P8A-MCP-1 and 44AANA47-RANTES was not No in vivo data are shown to demonstrate the importance more effective than P8A-MCP-1 alone. Administration of of TNFRII release by Treg cells in inflammatory diseases. Met-RANTES, an antagonist for RANTES receptors, did not Nevertheless, the authors introduce a compelling potential ameliorate clinical signs either. mechanism by which Treg cells could limit autoimmunity at the These results indicate that post-disease onset treatment level of tissue inflammation and injury, in addition to their with P8A-MCP-1 ameliorates AIA. The authors suggest that critical role in the maintenance of self-tolerance. MCP-1 is critical for the progression of AIA, whereas RANTES Address for reprints: R Toes, Department of Rheumatology, Postal Zone may be of limited importance in the pathogenesis of RA. C1-R, Leiden University Medical Center, PO BOX 9600, 2300 RC, Leiden, The Netherlands. Email: [email protected] Address for reprints: S Shahrara, Northwestern University Feinberg School of Medicine, Department of Medicine, Section of Rheumatology, McGaw Pavillion, 240 East Huron, Suite 2220, Chicago, IL 60611, USA. A followup study of antiphospholipid antibodies Email: [email protected] and associated neuropsychiatric manifestations in 137 children with systemic lupus erythematosus Cutting edge: TNFR-shedding by CD4+ CD25+ Avcin T, Benseler SM, Tyrrell PN et al. regulatory T cells inhibits the induction of Arthritis Rheum 2008;59:206–13. inflammatory mediators Van Mierlo GJ, Scherer HU, Hameetman M et al. Antiphospholipid (aPL) antibodies can induce J Immunol 2008;180:2747–51. neurological disease via cerebrovascular thrombosis and potentially other mechanisms. The present authors Regulatory T cells (Treg cells) help to prevent investigated the association of aPL antibodies with autoimmunity by limiting the activity of other neuropsychiatric systemic lupus erythematosus (SLE) in β lymphocytes. Recently, experimental evidence in mice 137 children. Anti- 2-glycoprotein I antibodies were has suggested that Treg cells can also limit antigen- somewhat more common among patients with independent inflammation. In this article the authors neuropsychiatric SLE, and lupus anticoagulant was found report that activated Treg cells can shed substantial at an elevated frequency in patients with stroke. quantities of the tumor necrosis factor (TNF) receptor TNFRII, thereby dampening inflammation driven by The pathogenesis of neuropsychiatric manifestations of innate immune lineages such as macrophages. systemic lupus erythematosus (SLE) remains uncertain. Since antiphospholipid (aPL) antibodies may have neurological Regulatory T cells (Treg cells) represent an important and effects above and beyond the promotion of cerebrovascular heterogeneous population of lymphocytes that are capable of thrombosis, this group examined a cohort of children with blocking the action of other lymphocytes through direct SLE tested regularly for these antibodies for a potential contact as well as production of soluble mediators, such as association between aPL and neuropsychiatric lupus. Of 175 interleukin-10 (IL-10) and transforming growth factor-β patients seen at the Toronto Pediatric Lupus Clinic (The (TGF-β). In general, these cells have been regarded as a Hospital for Sick Children, Toronto, ON, Canada), 137 met “brake” on adaptive immunity, while leaving innate immune the entry criteria of aPL testing within the first 3 months cells such as neutrophils, macrophages, and mast cells largely after diagnosis and longitudinal follow-up within the clinic.

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Overall, 66% of children had aPL antibodies at presentation, adult psoriatic arthritis (PsA) develop malignancy at a rate β including anticardiolipin (aCL) in 65%, anti- 2-glycoprotein I greater than expected for the general population, the β (anti- 2GPI) in 41%, and lupus anticoagulant (LAC) in 26%. authors examined a prospective, well-documented registry Approximately 70% of these patients remained persistently of >680 PsA patients for the incidence and nature of first positive, while new positives were detected over the course malignancies occurring after entry into the cohort. To of observation in 20% of the remaining patients (mean capture malignancies not recorded in the registry or after follow-up 31 months). Neuropsychiatric SLE was loss to follow-up, the authors queried an Ontario (Canada) documented in 26% of patients, ranging from headache cancer registry for data on the same patients. Of 665 (the most common) to transverse myelitis. However, patients included in the analysis, 68 (10.2%) developed a evidence for an association between aPL status and malignancy meeting study criteria. Comparison of the risk of neuropsychiatric disease was scarce. Evaluation of potential malignancy overall, and of common types of malignancy associations between aPL antibodies (considered individually considered separately, showed no change from malignancy or collectively, at presentation or over the course of disease) incidence in the general Ontario population, as determined and different neuropsychiatric manifestations identified a through a provincial cancer registry (standard incidence ratio plausible association between LAC positivity and stroke (four 0.98, 95% confidence interval 0.77–1.24). Patients who of five stroke patients compared with 18 of 79 patients developed malignancy did not differ statistically from those β without stroke tested for LAC; p=0.015). Anti- 2GPI without across a wide spectrum of parameters, though use antibodies were positive at some point in 48% of patients of biologics in the population was limited. with neuropsychiatric manifestations compared with 25% of Together the data indicate that PsA, unlike RA, exhibits patients without (p=0.02). Chorea was noted in two no clear association with an overall elevated risk of patients, both of whom were LAC-positive. General disease malignancy, but the number of cases was too small to activity, as assessed by SLE disease activity index, tended to evaluate elevated risk in specific cancer subtypes. track with aCL titer but not with anti-β GPI titer. 2 Address for reprints: D Gladman, Centre for Prognosis Studies These findings are of potential interest but, in virtue of in the Rheumatic Diseases, Toronto Western Hospital, 1E-410B, the very large number of hypotheses tested in this 399 Bathurst Street, Toronto, ON, M5T 2S8, Canada. exploratory study, will require validation in other cohorts. Email: [email protected]

Address for reprints: ED Silverman, Division of Rheumatology, The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, Morbidity and mortality in rheumatoid arthritis ON, MSG 1XA, Canada. Email: [email protected] patients with prolonged therapy-induced lymphopenia: twelve-year outcomes Lorenzi AR, Clarke AM, Wooldridge T et al. INFECTIOUS AND MALIGNANT Arthritis Rheum 2008;58:370–5. COMPLICATIONS The current armamentarium of drugs against rheumatoid Prevalence of malignancy in psoriatic arthritis arthritis (RA) consists of agents that modulate the immune Rohekar S, Tom BD, Hassa A et al. system at increasingly sophisticated levels, such as tumor Arthritis Rheum 2008;58:82–7. necrosis factor blockade, costimulation blockade, and B cell depletion. Whether such interventions are safe can only be learned from long-term observations. In the early Rheumatoid arthritis, particularly when highly 1990s, patients were treated with the lymphocytotoxic inflammatory, has been associated with an increased risk monoclonal antibody alemtuzumab (anti-CD52) with the for certain malignancies. These authors examined a hope that lymphocyte depletion and reconstitution would prospective registry of >680 patients with adult psoriatic result in autoreactive lymphocytes being replaced by a arthritis to determine whether a similar association exists. tolerant immune system. In these patients, it was observed They found none. that despite continued lymphopenia >11 years after Rheumatoid arthritis (RA) and, potentially, antirheumatic therapy, no excess mortality or unusual infection-related therapies have been associated with a higher risk of morbidity occurred. These data are reassuring for the long- lymphoma and potentially certain other malignancies. In term outcomes of current immunomodulatory therapies addition, psoriasis has been associated with an increased risk for RA. for skin malignancy in some studies, although the area In an analysis of 53 rheumatoid arthritis (RA) patients remains controversial. To examine whether patients with treated with the lymphocytotoxic monoclonal antibody

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alemtuzumab (anti-CD52) and 102 control subjects selected 2002, there were too few exposures to these drugs to obtain from the European League Against Rheumatism database of meaningful data. patients with rheumatic disorders (matched for disease Address for reprints: S Bernatsky, Division of Clinical Epidemiology, severity), lymphopenia was found to persist in the patients McGill University Health Centre, 687 Pine Avenue West, V Building, treated with anti-CD52 after >11 years of follow-up. Montreal, QC, H3A 1A, Canada. However, no adverse clinical consequences were observed, with a mortality rate ratio of 1.2 (95% confidence interval The risk of herpes zoster in patients with 0.72–1.98). The causes of death were similar to those that rheumatoid arthritis in the United States and the would be expected in a hospital-based RA cohort. No United Kingdom opportunistic infections were noted, and only three Smitten AL, Choi HK, Hochberg MC et al. infections were documented following 36 elective Arthritis Rheum 2007;57:1431–8. orthopedic procedures.

Address for reprints: JD Isaacs, Musculoskeletal Research Group, Analysis of US and UK databases shows an increased risk Institute of Cellular Medicine, Newcastle University, Newcastle-upon- of herpes zoster in rheumatoid arthritis patients, which is Tyne, UK. Email: [email protected] further increased with the use of disease-modifying antirheumatic drugs or corticosteroids. Hematologic malignant neoplasms after drug exposure in rheumatoid arthritis Assessing and quantifying the underlying risk of specific Bernatsky S, Clarke AE, Suissa S. infections in rheumatoid arthritis (RA) is essential to Arch Intern Med 2008;168:378–81. understanding the added risk that may be attributable to disease-modifying antirheumatic drug (DMARD) therapy in Hematological malignancies seem to occur more these patients. While herpes zoster has been suggested to be frequently in patients with rheumatoid arthritis (RA). more common in patients with RA, the evidence for this is However, it is unclear whether there is a link with limited, as is any firm evidence linking specific RA therapies to disease-modifying antirheumatic drug (DMARD) an increased risk of herpes zoster. In the current cohort study, exposure. In a large, case–control study of 619 cases (RA the authors use data from a US managed-care database plus hematological neoplasms) and 6190 controls (RA (PharMetrics claims database) and the UK General Practice alone, approximately matched in terms of disease Research Database (GPRD) to examine the rate of herpes severity but without hematological neoplasms) the zoster. The PharMetrics database included 122 272 patients greatest relative risk (about 2.2) for hematological with RA between 1998 and 2002, and the GPRD included malignant neoplasms was noted after use of 38 621 RA patients from 1990–2001. Compared with non-RA cyclophosphamide. The only other significant risk ratios patients, the adjusted hazard ratio for herpes zoster was 1.91 (RR) were for azathioprine use although this was in the PharMetrics database and 1.65 in the GPRD, both of marginal (the 95% confidence interval was 1.01–2.03). which had 95% confidence intervals that did not cross 1. No increased RR were found for the use of methotrexate Using nested, case–control analysis the authors were able or antimalarial agents. to show that treatment was associated with herpes zoster in both databases. In the PharMetrics database, current use of This case–control study involved subjects from a cohort of both biological and non-biological DMARDs alone was 23 810 patients with rheumatoid arthritis assembled from associated with a statistically increased risk of herpes zoster, administrative databases covering the population of the state with odds ratios (ORs) of 1.52 and 1.34, respectively. The of Quebec, Canada, in the period 1980–2003. Cases that had combination of biological and traditional DMARDs was also hematological malignant neoplasms were ascertained from associated with increased risk, although this was not physician billing and hospitalization records. Patients were statistically significant, possibly because the number of matched for age and sex with 10 control subjects and clinical subjects on both therapies was too low. In the GPRD, which variables and concomitant medications were taken into did not include any patients taking biological DMARDs, the account, in order to diminish the possibility that the use of non-biological DMARDs was associated with a underlying disease led to hematological malignancies. During statistically increased risk of herpes zoster (OR 1.27). Oral the study, hematological malignant neoplasms developed in corticosteroid use increased the risk of herpes zoster in both 619 patients, including lymphomas in 346 patients, leukemia databases, regardless of DMARD use. in 178 patients, and multiple myelomas in 95 patients. Owing These data from two large databases suggest that RA is to the fact that biological agents first appeared in Quebec in independently associated with an increased risk for the

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CARDIOVASCULAR RISK

development of herpes zoster, and that this risk may be menopausal state. Similarly, non-traditional CAD risk factors, magnified by the use of corticosteroids, as well as both present in up to 30% of patients at enrolment, accumulated biological and non-biological DMARDs. This suggests that over the 3 years of follow-up: body mass index increased by RA patients may be candidates for the zoster vaccine, which 54.3%, waist:hip ratio >0.8 by 79.5%, low physical activity may be particularly appropriate early in the disease course by 71.6%, family history of CAD by 40.8%, and nephrotic before initiation of therapies that may preclude the use of syndrome by 82.8%. The Framingham 10-year risk profile live vaccines. was higher in men than in women with SLE both at entry and at 3 years. It decreased in men over the 3-year Address for reprints: KA Chan, Department of Epidemiology, Harvard School of Public Health, 677 Huntington Avenue, Boston, MA 02115, observation period and remained constant in women. With USA. Email: [email protected] regard to the use of medications, the treatment of hypertension and hypercholesterolemia, and the use of antimalarials and immunosuppressives increased over 3 CARDIOVASCULAR RISK years, whereas corticosteroid use increased only slightly. The authors conclude that CAD risk factors accumulate Accumulation of coronary artery disease risk in SLE patients from the early stages of the disease. Thus, factors over three years: data from an international they require careful monitoring, starting at diagnosis, in inception cohort order to be properly managed. Urowitz MB, Gladman D, Ibanez D et al. Address for reprints: MB Urowitz, Centre for Prognosis Studies, Toronto Arthritis Rheum 2008;59:176–80. Western Hospital, IE-409, 399 Bathurst Street, Toronto, ON, M5T 2S8, Canada. Email: [email protected] Risk factors for coronary artery disease (CAD) are present in one-third of patients with systemic lupus erythematosus Rheumatoid arthritis is associated with a high (SLE) at the initial presentation of the disease, and increase prevalence of hypothyroidism that amplifies its greatly during its early phase. Therefore, patients need to cardiovascular risk be carefully monitored for proper management of CAD risk Raterman HG, van Halm VP, Voskuyl AE et al. factors, from the diagnosis of SLE. Ann Rheum Dis 2008;67:229–32.

Coronary artery disease (CAD) affects up to 10% of patients Hypothyroidism has been linked to an increased risk of with systemic lupus erythematosus (SLE) and CAD risk factors cardiovascular disease (CVD), as has rheumatoid arthritis are predictive of myocardial infarction, adverse renal (RA). In the cohort of RA patients investigated by these outcomes, and mortality in SLE patients. Therefore, the authors, hypothyroidism was found to be more prevalent present investigators monitored CAD risk factors in SLE than expected, and patients with both RA and patients during the early phase of the disease, i.e. during the hypothyroidism appeared to be at an elevated risk for first years after the diagnosis. A total of 278 patients from the CVD. The results are thought-provoking but arise from a Systemic Lupus International Collaborating Clinics (SLICC) small sample and will require replication before definitive registry (a multicenter, international, inception cohort of newly conclusions can be drawn. diagnosed SLE patients) were followed-up over a 3-year period for their clinical, laboratory, and CAD risk factors, Hypothyroidism has been identified in some studies as a which were documented at enrolment and annually. cardiovascular risk factor, operating via factors such lipid The SLE patients included in the study were profile, blood pressure elevation, and effects on the representative of the total SLICC cohort of 935 patients in endothelium. These authors examined a prospective cohort terms of their demographic features, CAD risk factor of 358 rheumatoid arthritis (RA) patients for the prevalence differences, and medications. The remaining patients from of hypothyroidism and its potential effect on cardiovascular the cohort had not yet completed 3 years of follow-up. At disease (CVD) in a population already at an elevated risk enrolment, almost one-third of the patients had some because of RA. They found that 6.8% of patients had classical CAD risk factors such as hypertension (39.2%), “clinical hypothyroidism” (defined as an established hypercholesterolemia (36.3%), or ever smoking (37.4). Over physician diagnosis of hypothyroidism or the satisfaction of the 3 years of follow-up, all classical CAD risk factors a published criteria set), in excess of the 2.7% expected for increased by up to 60% of levels at enrollment: 48.6% for the Dutch population in general (p<0.001). Of these 16 hypertension, 65.3% for hypercholesterolemia, 36.7% for women, six (37.5%) had CVD, defined to include either smoking, 55.6% for diabetes, and 37.2% for post- coronary, cerebrovascular, or peripheral vascular disease,

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compared with 13% among the euthyroid members of the the charts of >11 000 visits made by 310 patients with SLE RA cohort (p=0.05). After adjusting for potential to the Montreal General Hospital, Montreal, QC, Canada. A confounders – the hypothyroid patients were, on average, 6 higher past-year corticosteroid dose was independently years older and were all female – the odds ratio for CVD associated with a significantly higher overall 2-year CHD was around 3–4. risk. Moreover, corticosteroid use was associated with higher The authors suggest these data “demonstrate” a higher levels of conventional risk factors such as total serum risk for CVD in patients with co-incident RA and cholesterol, high-density lipoprotein (HDL) cholesterol, low- hypothyroidism, and recommend consideration of screening density lipoprotein cholesterol, apolipoprotein B (ApoB), for hypothyroidism in patients with RA. However, the triglycerides, systolic blood pressure (BP), body mass index, confidence with which this conclusion is reached is quite out and blood glucose. Higher past-year lupus disease activity of proportion to the evidence presented. The authors’ was also independently associated with higher overall 2-year conclusions derive from four excess CVD diagnoses among CHD risk. Furthermore, it was associated with lower HDL these 16 older women – had there been only three, the cholesterol levels, and higher values for systolic BP, ApoB, effect size would have been non-significant (p=0.047 → triglycerides, and blood glucose. p=0.13; calculated by this Editor). The nature of the CVD Address for reprints: M Abrahamowicz, Division of Clinical events is not described, nor is their temporal onset vis a vis Epidemiology, Royal Victoria Hospital, 687 Pine Avenue West, either RA or hypothyroidism. Further, the definition of V Building, Montreal, QC, H3A 1A1, Canada. “clinical hypothyroidism” used in this series raises genuine Email: [email protected] concerns for confounding, since patients might be more likely to receive a formal diagnosis if under regular medical care for another problem, for example CVD. Accordingly, PROGNOSIS AND ASSESSMENT while this article remains provocative and should motivate further research, the conclusions are in no way sufficiently Immunologic markers as potential predictors of robust to justify present action by clinicians. systemic autoimmune disease in patients with idiopathic scleritis Address for reprints: MT Nurmohamed, VU University Medical Centre, departments of International Medicine and Rheumatology, PO BOX 7057, Lin P, Bhullar SS, Tessler HH et al. 1007 MB Amsterdam, The Netherlands. Email: [email protected] Am J Ophthalmol 2008;145:463–71.

Recent corticosteroid use and recent disease Scleritis is a painful inflammatory condition of the eye that activity: independent determinants of coronary can be infectious, idiopathic, or secondary to autoimmune heart disease risk factors in systemic lupus conditions such as rheumatoid arthritis and Wegener’s erythematosus? granulomatosis. The authors investigated the utility of Karp I, Abrahamowicz M, Fortin PR et al. testing for rheumatoid factor and antineutrophil cytoplasmic Arthritis Rheum 2008;59:169–75. antibody in patients referred to a university-based referral clinic, and found that both tests performed well. During the last decade, a dramatic increase in the incidence of coronary heart disease (CHD) has been Scleritis manifests as a painful red or purple discoloration of observed in patients with systemic lupus erythematosus the sclera, and can progress to sight-threatening scleral (SLE). In this retrospective study, it was observed that necrosis. Causes include infections such as herpes and recent use of corticosteroids and recent lupus activity are syphilis as well as autoimmune diseases such as rheumatoid independently associated with higher values for several arthritis (RA), Wegener’s granulomatosis (WG), and lupus. well-recognized CHD risk factors and with overall 2-year The present authors conducted a retrospective review of 119 CHD risk. These data indicate that novel steroid-sparing scleritis patients seen at a university clinic, of whom 91 had drugs should be indicated in the care of SLE patients. no evident cause at initial evaluation. Over subsequent follow-up, 11 of these 91 patients were diagnosed with RA The pathogenesis of the markedly elevated risk of coronary and five with WG. Since the general procedure in the clinic heart disease (CHD) in systemic lupus erythematosus (SLE) was to assess both rheumatoid factor (RF) and patients is unknown. In particular, the causal roles of antineutrophil cytoplasmic antibody (ANCA), the authors corticosteroid therapy and SLE disease activity, and whether were able to review the predictive value of these tests for their putative effects are mediated through conventional risk the subsequent development of disease. Of the 70 patients factors, are unclear. To this end, data were obtained from tested for RF, 19 (27%) were positive, of whom 10 went on

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to receive a diagnosis of RA, whereas only one of 51 RF- patients with high levels of anti-CCP (OR 9.9) were more negative patients did so. Thus, the positive predictive value likely to develop radiographic progression than patients with of RF in this setting was 52.6%, with a negative predictive no anti-CCP antibodies. No independent effects were value of 98%. RF was predictive even among patients who observed for IgA RF, whereas after stratification for ESR it reported no joint symptoms. ANCA testing was performed was suggested that an additional effect was observed for RF in 70 patients and was positive in seven, of whom three and anti-CCP antibodies. developed WG. Two ANCA-negative patients also Address for reprints: SW Syversen, Department of Rheumatology, developed WG, giving positive and negative predictive Diakonhjemmet Hospital, PB 23 Vindem, N-0319 Oslo, Norway. values of 42.9% and 96.8%, respectively. Email: [email protected] The authors conclude that both tests are useful in this clinical setting, but caution that the prevalence of RA and Development and validation of a patient-based WG may be lower in non-tertiary-care clinics, changing the disease activity score in rheumatoid arthritis that test characteristics. Whether these tests would provide can be used in clinical trials and routine practice similar benefits for patients seen in a rheumatology office, Choy EH, Khoshaba B, Cooper D et al. where clinical skills in the global assessment for RA and WG Arthritis Rheum 2008;59:192–9. are presumably more advanced than in an ophthalmology office, remains an open question. Patient-based disease activity scores, either with or Address for reprints: DA Goldstein, University of Illinois at Chicago, without the inclusion of a sedimentation rate, correlate Department of Ophthalmology, 1905 West Taylor Street, L131 L.I.E.R.I., with the 28-joint Disease Activity Score (DAS28) and M/C 648, Chicago, IL 60612, USA. Email: [email protected] may be useful both in clinical trials and clinical practice.

High anti-cyclic citrullinated peptide levels and an As the evidence grows to support the value of objective algorithm of four variables predict radiographic disease activity measures in rheumatoid arthritis (RA), progression in patients with rheumatoid arthritis: patient-based disease activity scoring systems, once the results from a 10-year longitudinal study province of clinical trials, are increasingly being used in Syversen SW, Gaarder PI, Goll GL et al. clinical practice. In practice, the acceptability of these Ann Rheum Dis 2008;67:212–7. measurements may be limited by the perception that their complexity limits the ease with which they can be Prediction of joint damage is important for helping the incorporated into routine patient management. However, in clinician in terms of guiding treatment decisions. In a cohort clinical trials the key limitation of these measurements is the study from Norway in which follow-up of 125 patients was high degree of interobserver variability. While this can often available for 10 years, the presence of autoantibodies (anti- be addressed using a single clinician to score disease activity, cyclic citrullinated peptide [anti-CCP] and immunoglobulin this solution may be impractical in many situations. M rheumatoid factor), erythrocyte sedimentation rate, and In this paper the authors describe the development and female gender were independent predictors of radiographic validation data for an RA disease activity score that is driven by progression. Interestingly, the patients with high levels of the patients’ own assessments, a method that would address anti-CCP were especially prone to radiographic progression, both the complexity and interobserver variability concerns. indicating that the anti-CCP levels may add more They developed two patient-based disease activity scores, one information than the mere presence of anti-CCP. with (PDAS1) and one without (PDAS2) a sedimentation rate. Both include the patients’ own assessments of swollen and A cohort of 238 patients with rheumatoid arthritis (RA) was tender joints, as well as visual analogue scales for pain and followed longitudinally for 10 years. For 125 of the patients, general health and a health assessment questionnaire (HAQ). radiographs of the hands were available both at baseline The PDAS1 and the PDAS2 correlated well with the and after 10 years. Baseline sera were analyzed for C- DAS28 in both the development cohort of 204 patients and reactive protein, erythrocyte sedimentation rate (ESR), anti- the validation cohort of 322 patients. The PDAS1, PDAS2, cyclic citrullinated peptide (anti-CCP), immunoglobulin A and the DAS28 all showed similar sensitivity to change, rheumatoid factor (IgA RF), and IgM RF. Anti-CCP (OR 4.0) although there was a floor effect with the two PDAS scores, was the strongest independent predictor of radiographic suggesting a decreased sensitivity to change at lower levels progression. Female gender (OR 3.3), a high ESR (OR 3.2), of disease activity. and a positive IgM RF (OR 3.1) were also independent The authors conclude by suggesting that these predictors. Patients with low levels of anti-CCP (OR 2.6) and measurements may have utility in clinical trials,

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epidemiological studies, and clinical practice. They suggest In this basic science study, synovial tissue specimens that these scores may be particularly valuable in the last case obtained from inflamed knee joints of 57 RA patients (34 by involving patients in the assessment of their own disease, anti-CCP positive, 23 anti-CCP negative) who underwent an important factor in optimizing care. The one caveat the arthroscopy were analyzed for several histological features authors note in the use of these scores is that they may not along with immunohistochemistry by two independent be accurate in detecting remission or near-remission. observers. In addition, standard anteroposterior (AP) knee radiographs obtained within 3 months before or after the Address for reprints: EH Choy, Sir Alfred Baring Garrod Clinical Trials Unit, Academic Department of Rheumatology, King’s College London, synovial tissue sampling were scored for the severity of joint Weston Education Centre, Cutcombe Road, London SE5 9RJ, UK. damage using the Kellgren/Lawrence (K/L) scale Email: [email protected] (range 0–4). Synovial tissue samples from anti-CCP-positive patients Differences in synovial tissue infiltrates between revealed a higher number of infiltrating lymphocytes (61.6 anti-cyclic citrullinated peptide-positive vs. 31.4 cells/high-power field [hpf]; p=0.01) expressing rheumatoid arthritis and anti-cyclic citrullinated more CD3, CD8, CXCL12, and CD45RO. The difference in peptide-negative rheumatoid arthritis the mean number of infiltrating lymphocytes remained van Oosterhout M, Bajema I, Levarht EW et al. demonstrable after correction for disease activity using the Arthritis Rheum 2008;58:53–60. 28-jount count disease activity score (DAS28). While there was no difference in vascularity, anti-CCP-positive patients The authors of this study analyzed and compared showed a thicker synovial lining layer (mean score 2.1 vs. synovial tissue infiltrates from patients with rheumatoid 3.3; p=0.002) and a decreased extent of fibrosis (mean score arthritis (RA) who were anti-cyclic citrullinated peptide 1.2 vs. 2.0; p=0.04). No difference in absolute K/L scores (anti-CCP)-positive with those from anti-CCP-negative between the groups was observed, but more anti-CCP- RA subjects. The results demonstrate differences in positive patients had a K/L score of >1. The evaluation of synovial tissue infiltrates from patients with anti-CCP- synovial tissue of 31 patients (18 anti-CCP positive) positive versus anti-CCP-negative disease, particularly obtained at earlier time points (mean of 3.8 years before the with regard to lymphocyte infiltration. index biopsy) revealed that the difference in the mean lymphocyte counts was also present at the time of the Anti-cyclic citrullinated peptide (anti-CCP) autoantibodies – earlier arthroscopy, with 76.7 cells/hpf in anti-CCP-positive highly specific serological markers for rheumatoid arthritis patients compared with 26.7 cells/hpf in anti-CCP-negative (RA) – often precede the onset of disease symptoms and are patients (p=0.008). thought to be involved in disease pathogenesis. While the The authors concluded that inflamed synovial tissue in clinical presentation of RA patients with or without anti-CCP anti-CCP-positive RA patients is different from that in anti- antibodies is similar at baseline, the progression to erosive CCP-negative patients, particularly with respect to disease occurs predominantly in anti-CCP-positive patients. infiltrating lymphocytes, and shows a higher rate of local Since only sparse information is available on the pathological joint destruction, which together might reflect differences in features of synovitis in anti-CCP-positive compared with underlying pathophysiological mechanisms. anti-CCP-negative patients, evaluation of synovial tissue Address for reprints: M van Oosterhout, Leiden University Medical infiltrates might help to clarify the role of anti-CCP Center, Department of Rheumatology, C4R, PO Box 9600, 2300 antibodies in synovial inflammation. Leiden, The Netherlands. Email: [email protected]

68 INTERNATIONAL JOURNAL OF ADVANCES IN RHEUMATOLOGY Vol 6 No 2 2008 MEETING REPORT 69 3.2, 64% vs. 41%; ≤ 3.2) who had not previously ≥ Vol 6 No 2 2008 Vol [4]. Lancet HEUMATOLOGY R One-year results from the COMET (Combination of from One-year results An interim analysis of a German, 5-year, multicenter, An interim analysis of a German, 5-year, The multicenter trial, BeSt (Behandel Strategieen), Methotrexate and Etanercept in Active Early Rheumatoid and Etanercept Methotrexate Paul Emery by Professor presented Arthritis) trial were This is the first major (University of Leeds, Leeds, UK) [3]. as DAS28 remission clinical trial in patients with RA to use moderate-to- early, an endpoint, and involved patients with active RA (DAS28 severe, prospective study of the efficacy and safety of adalimumab study of the efficacy prospective in the setting of day-to-day rheumatology practice was [5]. A total of 4640 patients with long-standing presented included at RA (mean disease duration 12 years) were baseline. After 24 months of adalimumab therapy (data for in clinical available), 20% of patients were 824 patients were in (DAS28 <2.6) and considerable improvements remission Adalimumab was also achieved. physical function were generally well-tolerated among these patients. with the aim of disease of tight control the effect addressed strategy for early RA of determining the optimal treatment this investigation were patients. Five-year data from (Leiden University Naomi Klarenbeek by Dr presented Medical Center) [6]. Longitudinal data analysis showed that an initial combination of methotrexate with those treated and infliximab had significantly better Health Assessment used methotrexate. Subjects were randomized to Subjects were used methotrexate. plus alone (n=268) or methotrexate methotrexate 50% of 50 mg/week (n=274). At 1 year, etanercept achieved remission recipients plus methotrexate etanercept with 28% of those who received (DAS28 <2.6) compared alone (p<0.001). In addition, a greater methotrexate of patients in the combination therapy group proportion achieved low disease activity (DAS28 p<0.001). Radiographic non-progression was achieved in p<0.001). Radiographic non-progression 59% of and recipients plus methotrexate 80% of etanercept (p<0.001). Rates of severe group the methotrexate-only similar between the two treatment adverse events were published have subsequently been These trial results groups. in the DVANCES IN A OURNAL OF J NTERNATIONAL I Another group of investigators from The Netherlands investigators from of Another group Remission in rheumatoid arthritis is that remission demonstrated A number of presentations of rheumatoid an achievable goal in a significant proportion (Leiden der Woude arthritis (RA) patients. Diane van Leiden, The Netherlands) University Medical Center, data on disease-modifying antirheumatic drug presented and independent disease remission, (DMARD)-free in patients at the for achieving such remission, predictors an average follow-up Leiden Early Arthritis Clinic [1]. During 69 of 454 of 8.2 years and a total of 3817 patient-years, DMARD- RA achieved patients (15.2%) with recent-onset defined as persistent (>1 year) absence of remission, free use of DMARDs. Independent synovitis without concurrent remission of DMARD-free for the achievement predictors included old age, low body mass index, low erythrocyte sedimentation rate, non-smoking, and the absence of anti- cyclic citrullinated peptide antibodies. study involving a cohort of DMARD- performed a prospective RA patients in daily clinical practice [2]. naïve, recent-onset approach using a step-up, tight-control treated Patients were followed by sulfasalazine, with with methotrexate, at week 24 if remission adalimumab added to methotrexate <2.6) had not been [DAS28] (28-joint Disease Activity Score in the achieved. The estimated median time to first remission 169 patients available for the analysis was 25 weeks, with the 15.5% at week of patients in remission: following percentages 8, 22.2% at week 12, 30.7% at week 20, 38.8% at week 24, 52.1% at week 36, and 51.0% at weeks 48–52. The Annual European League Against Rheumatism (EULAR) League The Annual European all over the world attracts rheumatologists from Congress the meeting in and this year >13 000 delegates attended submitted for were Paris, France. A total of 3435 abstracts a 9% representing at the congress, for presentation review in a continued interest 2007, and reflecting from increase A in the field of rheumatology. clinical and scientific research this at the Congress; wide range of topics was covered a few of the key presentations. discusses report Paris, France, 11–14 June 2008 Paris, France, Editorial Team The Remedica Annual European Congress of Congress European Annual 2008) (EULAR Rheumatology RT404_2_Rheum_6.2_05.qxd 10/9/08 16:44 Page 69 Page 16:44 10/9/08 RT404_2_Rheum_6.2_05.qxd RT404_2_Rheum_6.2_05.qxd 10/9/0816:44Page70 MEETING REPORT DMARD therapy. biological agentsandinthose whoreceived traditional malignancy recurrence was similarinpatientstreated with time elapsedsincetheonsetofmalignancy. Therateof biological agentsirrespective ofpriormalignancies,andthe cancer [9].Theinvestigatorsfoundthatpatientsreceived daily rheumatologypracticeinpatientswithahistory of biologicals register assessedtheuseofbiologicalagentsin ability toreach definitiveconclusions. concluded thatthesmallnumberofcancersprecluded their However, thiswasnotstatisticallysignificant andtheauthors increased riskofmalignancyinetanercept-treated patients. malignancy of1.84(95%CI0.79–4.28),suggestingan recipients andinsevencontrols, resulting inahazard ratiofor control therapy. Malignancieswere detectedin26etanercept 3316 patients,2233received etanercept and1072received analysis ofrandomizedcontrolled trials[8].From atotalof Rochester, MN,USA)andcolleagues,whopresented ameta- in RAwasalsoinvestigatedbyEricMatteson(MayoClinic, elevated riskoflymphomainpatientswithRA”. related toTNFantagonistexposure orifitreflects the unknown ifthehigher-than-expected rateoflymphomais 1.82–6.16). Theresearchers statedthat“itiscurrently however, theSIRforlymphomawas3.53(95%CI Surveillance EpidemiologyandEndResults(SEER)database; matched datafrom theNationalCancerInstitute (95% confidenceinterval[CI]0.78–1.22),calculatedusing standard incidenceratio(SIR)formalignancywas0.98 control/methotrexate-treated patientsinearliertrials.The serious infectionswere similartothoseseenin randomized controlled clinicaltrials.Theoverallratesof control patients from thedouble-blindphaseofincluded RA patientswere similartothesevere adverseeventratesin respectively. Theoverallratesofsevere adverseeventsinthe and 9years(inongoingNorthAmericanstudies), patients estimatedtobecontinuingonetanercept at3years years ofetanercept exposure, with57–71%and35–43%of were basedon atotalof2054patientsand9763patient- controlled trials inEurope andNorthAmerica[7].Theresults who were enrolled inopen-labelextensionsofdouble-blind, analysis ofpatientswithDMARD-refractory RAorearly The safetyoflong-termetanercept usewasassessedinan Etanercept Safety ofanti-TNFs therapy regimens. sequential monotherapyorstep-upcombination remission rateat5years,compared withthosewhoreceived Questionnaire scores, andaslightlyhigherdrug-free 70 R EMEDICA An analysisofRApatientsincludedinaGerman The riskofmalignancyassociatedwithetanercept therapy E DITORIAL T EAM I NTERNATIONAL J UNLOF OURNAL A VNE IN DVANCES radiographic progression atupto144weeks. open-label adalimumabledtosustainedinhibition of responders intheADEPTstudy, continuedtreatment with Associates, Seattle,WA, USA)[13].Ininitialadalimumab were presented byPhilipMease(SeattleRheumatology ADEPT (AdalimumabEffectiveness inPsoriatic ArthritisTrial), an open-labelextensionofthe24-week,PhaseIIItrial, no casesoftuberculosis ordemyelinatingdisorders. between thetwotreatment periods.Inaddition,there were exposure periods,identifiednosignificantdifferences adverse eventsratesbetweenthedouble-blindand3-year treatment [12].Comparisonofadverseeventsandsevere double-blind phase)wassustainedatupto3yearsof international Societycriteria)observedat24weeks(inthe (20% improvement inAssessmentSpondyloarthritis statistically significantreduction inASsignsandsymptoms University MedicalCenter),demonstratedthatthe Spondylitis), presented byDesireé vanderHeidje(Leiden Evaluating Long-termEfficacy andSafetyforAnkylosing (95% CI1.90–6.81). for etanercept, theSIRformalignantlymphomawas3.81 all malignancies;however, similarlytothatdescribedabove database forcomparison,was0.89(95%CI0.68–1.13) rates ofseriousinfectionswere low. TheSIR,usingtheSEER safety signalswere observedinthisinterimanalysis,andthe for adverseeventsand5.7%lackofefficacy. Nonew 11.7% ofpatients(n=400)withdrew from thestudy, 4.0% in theReActstudywere sustainedinReAlise.Overall, clinical improvements withadalimumabtreatment observed [11]. Datawere availablefor3421patients.Therapidinitial University andHumboldtofBerlin,Germany) by Gerd Burmester (CharitéUniversityHospitaloftheFree Arthritis) [10].AninterimanalysisofReAlisewaspresented Rheumatic TherapyinPatientswithActiveRheumatoid Adalimumab whenAddedtoInadequateStandard Anti- ReAct (AStudytoAssesstheSafetyandEfficacy of years inpatientswithRAwhohadpreviously participatedin term safetyandeffectiveness ofadalimumabforupto5 Prescribed Humira)wasundertakentoevaluatethelong- Treated inStudyM02-497[ReAct]andSubsequently Follow-up PatientswithRheumatoidArthritisFormerly ReAlise (AFive-Year, Post-MarketingObservationalStudyto Adalimumab GO-FORWARD (GolimumabforSubjects withActiveRA golimumab, were presented attheCongress. Theresults of Data from PhaseIIItrials of theanti-TNFantibody, Golimumab Novel agents Data onradiographicprogression inpatientsentered into An open-labelextensionofATLAS (AdalimumabTrial R HEUMATOLOGY Vol 6No22008 RT404_2_Rheum_6.2_05.qxd 10/9/08 16:44 Page 71

EULAR 2008

Despite methotrexate), presented by Edward Keystone ACR70 responses at week 24 [18]. Professor Graeme Jones (Toronto University, Toronto, ON, Canada), showed that (University of Tasmania, Tasmania, Australia) and colleagues golimumab plus methotrexate was significantly more also reported safety data from the study. Severe adverse efficacious than methotrexate alone in subjects with active events and serious infections were slightly higher in those RA [14]. In GO-AFTER (Golimumab after Former anti-TNF treated with tocilizumab compared with methotrexate (4% Therapy Evaluated in RA), 461 patients with active RA who vs. 3% and 1.4% vs. 0.7%, respectively). In contrast, had previously received at least one anti-TNF agent (65% elevation in liver enzymes occurred more frequently in the had failed one, 25% failed two, and 10% failed three) were methotrexate group than in the tocilizumab arm (4% vs. 2%). randomized to placebo, golimumab 50 mg subcutaneously, The results of RADIATE (A Randomized, Double-Blind or 100 mg subcutaneously every 4 weeks. Josef Smolen Study of Safety and Reduction in Signs and Symptoms (University of Vienna, Vienna, Austria) presented data from During Treatment With Tocilizumab Versus Placebo, in the study [15]. Prior anti-TNF therapy had been Combination With Methotrexate, in Patients With Moderate discontinued due to lack of efficacy in approximately 60% to Severe Active Rheumatoid Arthritis and Inadequate of patients. Among this subgroup, 35.7% and 42.7% of Response to Anti-TNF Therapy) were presented by Professor patients in the golimumab 50 mg and golimumab 100 mg Emery. Tocilizumab plus methotrexate therapy was groups had a 20% improvement in American College of demonstrated to be efficacious in the treatment of refractory Rheumatology criteria (ACR20 response) at week 14 RA patients, irrespective of the number of, or most recently compared with 17.7% of the placebo group (p=0.006 and failed anti-TNF treatment [19]. p<0.001, respectively). Adverse event and severe adverse event rates were similar across the treatment groups. This INCB18424 study is the first to demonstrate that a patient who fails on William Williams (Incyte Inc., Wilmington, DE, USA) and up to three anti-TNF-α agents may be successfully treated colleagues presented results from a 28-day proof-of-concept with another. trial of INCB18424, an orally available janus-associated Arthur Kavanaugh (University of California–San Diego, kinase (JAK) inhibitor, in eight patients with active RA [20]. La Jolla, CA, USA) presented data from GO-REVEAL (A Six subjects received the inhibitor, while two received Multicenter, Randomized, Double-Blind, Placebo-Controlled placebo. Four of the six INCB18424-treated subjects Trial of Golimumab, a Fully Human Anti-TNF-α Monoclonal achieved at least an ACR20, three achieved at least an Antibody, Administered Subcutaneously in Subjects with ACR50, and two achieved an ACR90 response. Three Active Psoriatic Arthritis) [16]. Golimumab was significantly patients achieved a DAS28 score <2.6, and the mean DAS28 more efficacious in improving the signs and symptoms of score decreased from 6.0±0.32 to 3.29±0.99 by day 28. psoriatic arthritis (PsA) at week 24 compared with placebo, This is the first demonstration of clinical activity of a and its efficacy was maintained at week 52. At week 24, selective JAK inhibitor in RA. 2.4% of golimumab-treated patients experienced severe adverse events compared with 6.2% of placebo recipients. References In a separate presentation of data from GO-REVEAL [17], 1. van der Woude D, Brand R, Toes RE et al. Risk factors for DMARD-free remission in RA, lessons from an inception cohort. Ann Rheum Dis 2008;67(Suppl II):48. treatment with golimumab significantly improved psoriatic 2. Kuper I, Hoekstra M, ten Klooster P et al. Remission can be achieved in 50% of early rheumatoid arthritis patients after 25 weeks in daily clinical practice. Ann Rheum Dis nail changes, dactylitis score, and enthesitis score in patients 2008;67(Suppl II):48. with active PsA (all p<0.001 compared with placebo). 3. Emery P, Breedveld F, Hall S et al. Clinical remission, radiographic non-progression, and normalized function with the combination of etanercept and methotrexate in the treatment of early active rheumatoid arthritis: 1-year results of the COMET trial. Ann Tocilizumab Rheum Dis 2008;67(Suppl II):50. 4. Emery P, Breedveld FC, Hall S et al. Comparison of methotrexate monotherapy with a Several Phase III trials of tocilizumab, an anti-interleukin-6 combination of methotrexate and etanercept in active, early, moderate to severe rheumatoid arthritis (COMET): a randomised, double-blind, parallel treatment trial. Lancet (anti-IL-6) receptor antibody, were presented at this year’s 2008; [Epub ahead of print]. Congress. The AMBITION (Actemra™ [Tocilizumab] versus 5. Tony H, Wassenberg S, Krause A et al. Adalimumab (Humira®) is effective and well- tolerated in patients with rheumatoid arthritis (RA): disease activity and physical function Methotrexate Double-Blind Investigative Trial in results from a German database of RA patients receiving adalimumab. Ann Rheum Dis Monotherapy) investigators assessed the efficacy and safety 2008;67(Suppl II):188. 6. Klarenbeek NB, Güler-Yüksel M, van der Kooij SM et al. Clinical outcomes of four different of tocilizumab monotherapy versus methotrexate treatment strategies in patients with recent-onset rheumatoid arthritis: 5-years results of the BEST-study. Ann Rheum Dis 2008;67(Suppl II):187. monotherapy in patients with active RA who had not failed 7. Klareskog L, Moreland LW, Cohen SB et al. Safety and efficacy of over 10 years of previous methotrexate or biological treatment. Tocilizumab continuous etanercept therapy in patients with rheumatoid arthritis in North America and Europe. Ann Rheum Dis 2008;67(Suppl II):175. monotherapy (8 mg/kg every 4 weeks) was found to be 8. Bongartz T, Warren FC, Mines D et al. Etanercept therapy in rheumatoid arthritis and the superior to a standard escalating dose of methotrexate, with risk of malignancies. Ann Rheum Dis 2008;67(Suppl II):51. 9. Strangfeld A, Listing J, Herzer P et al. RA patients with prior malignancy under treatment higher proportions of patients achieving ACR20, ACR50, and with biologics. Ann Rheum Dis 2008;67(Suppl II):332.

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10. Bombardieri S, Ruiz AA, Fardellone P et al.; Research in Active Rheumatoid Arthritis 16. Kavanaugh A, Mease P, Krueger GG et al. Golimumab, a new, human, TNF alpha antibody (ReAct) Study Group. Effectiveness of adalimumab for rheumatoid arthritis in patients with administered subcutaneously every 4 weeks in psoriatic arthritis patients: 52-week efficacy a history of TNF-antagonist therapy in clinical practice. Rheumatology (Oxford) and safety results of the randomized, placebo-controlled GO-REVEAL study. Ann Rheum 2007;46:1191–9. Dis 2008;67(Suppl II):99. 11. Burmester GR, Matucci Cerinic M, Mariette X et al. Safety and effectiveness of adalimumab 17. Gladman D, Kavanaugh A, McInnes I et al. Golimumab, a new human TNF-alpha (Humira®) is maintained in patients with rheumatoid arthritis — three-year results of realise, a antibody, administered every 4 weeks as a subcutaneous injection in psoriatic arthritis: nail, post-marketing observational study. Ann Rheum Dis 2008;67(Suppl II):176. enthesitis, and dactylitis response in the randomized, placebo-controlled, GO-REVEAL 12. van der Heijde D, Sieper J, Dijkmans BA et al.; for the ATLAS Study Group. Three-year safety study. Ann Rheum Dis 2008;67(Suppl II):526. and efficacy results from the adalimumab (Humira®) trial evaluating long-term efficacy and 18. Jones G, Gu JR, Lowenstein M et al. Tocilizumab monotherapy is superior to methotrexate safety in ankylosing spondylitis (ATLAS). Ann Rheum Dis 2008;67(Suppl II):519. monotherapy in reducing disease activity in patients with rheumatoid arthritis: the 13. Mease PJ, Ory P, Sharp JT et al. Adalimumab (Humira®) sustains inhibition of joint damage ambition study. Ann Rheum Dis 2008;67(Suppl II):89. for more than 2 years in patients with psoriatic arthritis (PsA). Ann Rheum Dis 19. Emery P, Keystone E, Tony H et al. Tocilizumab (TCZ) significantly improves disease 2008;67(Suppl II):99. outcomes in patients with rheumatoid arthritis whose anti-TNF therapy failed: the radiate 14. Keystone E, Genovese MC, Klareskog L et al. Golimumab, a new human anti-TNF-alpha study. Ann Rheum Dis 2008;67(Suppl II):127. monoclonal antibody, administered subcutaneously every 4 weeks in patients with active 20. Williams WV, Scherle P, Shi J et al. Initial efficacy of INCB018424, a selective janus kinase1 rheumatoid arthritis despite methotrexate: week 24 results of the randomized, double- & 2 (JAK1&2) inhibitor in rheumatoid arthritis (RA). Ann Rheum Dis 2008;67(Suppl II):62. blind, placebo-controlled, GO-FORWARD study. Ann Rheum Dis 2008;67(Suppl II):185. 15. Smolen J, Kay J, Doyle MK et al. Golimumab, a new human anti-TNF-alpha monoclonal antibody, subcutaneously administered every 4 weeks in patients with active rheumatoid arthritis who were previously treated with anti-TNF-alpha agent(s): results of the randomized, double-blind, placebo-controlled, GO-AFTER study. Ann Rheum Dis 2008;67(Suppl II):50.

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