Chronic Recurrent Multifocal Osteomyelitis a Concise Review and Genetic Update

Chronic Recurrent Multifocal Osteomyelitis A Concise Review and Genetic Update

Hatem I. El-Shanti, MD; and Polly J. Ferguson, MD

Chronic recurrent multifocal osteomyelitis is an autoinflam- tifocal osteomyelitis (CRMO) is an autoinflammatory matory disorder characterized by bone pain and fever, a bone disease characterized by bone pain and fever with an course of exacerbations and remissions, and a frequent as- unpredictable course of exacerbations and spontaneous re- sociation with other inflammatory conditions. Because its missions. It is one type of nonbacterial osteitis and is fre- etiology is largely unknown, the diagnosis is still based on quently associated with other inflammatory conditions clinical criteria; treatment is empiric and not always success- 11,51,79 ful. The diagnosis is supported by the presence of osteolytic such as pustulosis palmoplantaris (PPP), Sweet syn- 4,29,78 65,82,98 lesions with surrounding sclerosis apparent on radiographs, drome, and psoriasis. Most of the originally 23 and silent asymptomatic lesions frequently appear on reported patients are from Scandinavian countries ; how- nuclear scans. The histologic findings in bone biopsies are ever, patients of other ethnicities were later reported.75 nonspecific, showing inflammatory changes with granulo- Chronic recurrent multifocal osteomyelitis became rec- cytic infiltration. Several observations suggest the contribu- ognized as a separate clinical entity under the name sym- tion of genetic factors to the etiology of chronic recurrent metric osteomyelitis in 1972.35 Because symmetry was not multifocal osteomyelitis. Indeed, mutations in LPIN2 cause a always present, the name chronic recurrent multifocal os- syndromic form of chronic recurrent multifocal osteomyeli- 13 tis known as Majeed syndrome, while mutations in pstpip2 teomyelitis was suggested and then adopted by the medi- cause a murine form of the disorder. The roles played by cal community. Different terms are used to describe dis- LPIN2 and the human homolog of pstpip2, PSTPIP2, in the orders with nonbacterial osteitis, including SAPHO (syno- etiology of chronic recurrent multifocal osteomyelitis are un- vitis, acne, pustulosis, hyperostosis, and osteitis) certain but are currently being investigated. We emphasize syndrome,9,28,58 pustulotic arthroosteitis,44–46,48 and the need to validate diagnostic clinical criteria and develop chronic sclerosing osteomyelitis,59 all probably represent- new pathogenesis-based targeted therapy. ing the same pathogenetic mechanism.5 Osteitis is a com- Level of Evidence: Level IV, therapeutic and prognostic mon feature in both SAPHO syndrome and CRMO and study. See the Guidelines for Authors for a complete descrip- the latter is believed the pediatric presentation of the tion of levels of evidence. former.2,58 However, children with SAPHO syn- drome10,62,96 and adults with CRMO are described.86 The etiology of CRMO is unknown, but is unlikely due Autoinflammatory diseases are a group of disorders char- to infection, immune deficiency, or autoimmunity. Several acterized by seemingly unprovoked inflammation in the observations, such as affected siblings,8,32,79 concordant absence of high-titer autoantibodies or antigen-specific T monozygotic twins,39 and a recent association study,39 cells.92 They include the hereditary periodic fever syn- suggest contribution of genetic factors to the etiology of dromes and are believed caused by disturbances in the CRMO. The presence of an autosomal recessive syn- regulation of innate immunity.61,74 Chronic recurrent mul- dromic form of CRMO31,68–70 called Majeed syndrome further supports this suggestion. Another observation is From the Department of Pediatrics, University of Iowa Carver College of the presence of a spontaneously occurring mouse model 17,30,43 Medicine, Iowa City, IA. with clear autosomal recessive inheritance (cmo). The authors have received funding from NIH/NIAMS: 1 R21 AR053924-01 Recently, two genes have been identified to play a role in (HIE); NIH/NIAMS: 1 R03 AR051130-01 (PJF); and Carver Medical Re- search Initiative Grant, University of Iowa (HIE, PJF). the etiology of CRMO, LPIN2 being responsible for 31 Correspondence to: Hatem I. El-Shanti, MD, Department of Pediatrics, Uni- Majeed syndrome, and pstpip2 being responsible for the versity of Iowa Carver College of Medicine, 200 Hawkins Drive, W125 GH, cmo mouse.30 Iowa City, IA 52242. Phone: 319-356-2674; Fax: 319-356-3347; E-mail: [email protected]. In this review, we provide an overview of the clinical DOI: 10.1097/BLO.0b013e3180986d73 and management aspects of CRMO and discuss the iden-

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Clinical Orthopaedics 2 El-Shanti and Ferguson and Related Research tified genes that play a role in its etiology. Although a proposed in a recent study that included a sizable cohort genetic contribution to the etiology of CRMO has been with sterile osteomyelitis.50 Patients were grouped as: (1) suggested, we here present an overview of the two recently acute nonbacterial osteomyelitis (symptoms for less than 6 identified genes that are responsible for a syndromic hu- months with one or more bone lesions); (2) chronic non- man form of CRMO and for a murine form. We also bacterial osteomyelitis (symptoms for more than 6 months discuss and speculate on the role of these two genes in without remissions with one or more bone lesions); or (3) bone inflammation. CRMO (multiple bone lesions or one bone lesion with PPP and recurrence). Search Strategy The most consistent laboratory abnormality is the el- evation of the erythrocyte sedimentation rate.12,88,97 The We performed a PubMed search of the MEDLINE bio- white blood cell count may or may not be elevated.88 medical literature, using the terms chronic recurrent mul- TNF-␣ was elevated (> 25 pg/mL) in 66% of patients with tifocal osteomyelitis (141 references), LPIN2 (10 refer- 50 ences), PSTPIP1 or PSTPIP2 (30 references), SAPHO CRMO. All cultures of blood, bone biopsies, and pus- syndrome (29 references), chronic sclerosing osteomyeli- tules were negative for fungal and bacterial growth, including mycobacterium, mycoplasma, and anaerobes.88 tis (94 references), and pustulotic arthroosteitis (15 refer- 91 ences). Our searches of articles published in the English There have been suggestions of a viral etiology which is supported by the response to interferon treatment in a few language revealed considerable overlap in articles identi- 3,33 fied under the different search terms, and we reviewed the patients. However, there is otherwise little or no data articles for pertinence to our review article. We also supporting a role of viruses in the disease process or the searched articles in French or German languages. We re- successful treatment with interferon. viewed the abstracts of the articles published in these lan- Radiographs usually show irregular osteolytic le- guages and obtained and utilized the articles that added sions (radiolucency) with surrounding sclerosis 11–13,25,29,34,35,37,41,42,63,64,77,79,84,89,90,100 any information to this review.8 Due to the rarity of these (Fig 1). There conditions, we elected to include all studies in our analy- is increased uptake on nuclear scans using Tc-99, and sis, however, when information overlapped we referenced silent asymptomatic lesions may appear as well (Fig the most recent articles built on conclusions or reports of 2).25,29,34,37,42,64,77,79,84,89,90,100 A computed tomography previous articles. We also extracted information and views scan or an MRI scan may be required to confirm the di- from the abstract book, presentations, posters, and discus- agnosis.37,42,54,63,67,85,89 MRI can be helpful in determin- sions from the fourth international meeting on autoinflam- ing disease activity and extent of disease, and can be used matory disorders, “FMF and Beyond,” held in Bethesda, to help guide the bone biopsy procedure.53 MD, USA, on November 6–10, 2005. A bone biopsy taken from an active lesion usually shows nonspecific inflammatory changes Clinical Picture with granulocytic infiltration (Fig 13,24,25,29,34,35,37,41,42,63,64,79,84,89,90,100 The classic clinical picture of chronic recurrent multifocal 3). Examination of osteomyelitis is dominated by periodic bone pain and fe- biopsies at different stages showed CRMO begins as an ver. There is a slight female predominance. The age at acute inflammatory process with a predominance of poly- onset of symptoms ranges from infancy to 55 years with a morphonuclear (PMN) leukocytes plus evidence of osteo- median age of 10 years.12 The onset is almost always clastic bone resorption with or without multinucleated gi- 12 insidious with pain and tenderness, whereas the swelling ant cells. At a later stage, the inflammatory infiltrate and fever are not always present.20,23 At any one time, the shows predominance of lymphocytes, plasma cells, histio- 12 number of osteomyelitis lesions is variable, ranging from cytes, and PMN leukocytes. New bone formation is evi- two to 18.71,97 The course of disease is characterized by denced by fibrosis around foci of inflammation, irregular periodic waxing and waning of symptoms over a duration bone marrow space, and increased osteoblast activity.63 of 1 to 20 years.20,23,25,27 The inflammatory lesions are Progressive sclerosis and hyperostosis occur mostly in the localized in a distribution that is similar to the hematog- clavicle and occasionally in the tibia, femur, metatarsal, enous osteomyelitis of childhood usually in the metaphy- jaw, and ischiopubic bones.55,63 Sometimes biopsies show ses of long bones and the clavicle.12 The involvement of acute, subacute, and chronic nonspecific osteomyelitis other bone sites, such as the vertebrae,6,23 the mandible,23 mixed in the same lesion.22,76,89 Histologic changes cor- and the frontal and sphenoid bones99 is less frequently related poorly with clinical features but relatively well reported. Many individuals develop a very similar clinical with radiographic findings.22 Skin biopsy from pustular picture but with monofocal inflammatory lesions or mul- lesions showed intraepidermal collection of neutrophils tifocal nonrecurring lesions. A clinical classification was with mild hyperkeratosis.79

Fig 1. Multiple lytic lesions with surrounding sclerosis are seen in the ankle and hind foot of a female patient with chronic Fig 2. A bone scan from a child with longstanding chronic recurrent multifocal osteomyelitis. This radiograph demon- recurrent multifocal osteomyelitis shows increased uptake strates typical lesions in the distal tibia, talus, and calcaneus noted in the third right rib, left proximal femur, and right first (arrows). Diffuse osteopenia is also present. metatarsal.

In general, CRMO has a self-limited course causing major symptoms but leaving most affected individuals with no permanent long-term skeletal abnormali- After its original description, it became recognized 12,13,16,20,22,25,34,54,55,97 that CRMO can be associated with other disorders, mostly ties. However, sequelae are re- 11,13,50 ported in some cases in the form of residual joint of an inflammatory nature, including PPP ; general- 16 55 ized pustulosis involving the trunk, groin, thighs, and changes, ankylosis of the sacroiliac joints, growth dis- 84 4,29,70,78 80 buttocks ; Sweet syndrome ; psoria- turbance, thoracic outlet syndrome, disuse atrophy of the 20,50,51,63,65,80,82,98 muscles,77 and evolution into a spondyloarthropathy with sis ; pyoderma gangrenosum with or without inflammatory bowel disease19,78; SAPHO syn- unusual features such as unilateral sacroiliitis in the ab- 15,57,60,93 98 drome ; recurrent sterile subcutaneous absence of the HLA-B27 association. Several reports sug- 84 7,14,19,50 gested the sequelae of CRMO are not as benign as previ- scesses ; and inflammatory bowel disease. ously thought,27,51,72 and in one followup study, a considerable proportion of patients were at risk for physical and Diagnosis psychological complications resulting from the prolonged For the diagnosis of classic CRMO, all of the following course despite the apparently good physical outcome.47 criteria should be met: (1) multifocal bone lesions; (2)

Fig 3A–B. Bone biopsies from (A) a human and (B) a cmo mouse reveal a similar histologic picture with evidence of bone destruction (dead bone in panel A) accompanied by a mixed inflammatory infiltrate. prolonged clinical course over several years with remis- helpful in reducing the pain, swelling, and restricted sions and exacerbations; (3) lack of response to antimicro- mobility.20,36,37,42,51,63,83,84,89,100 However, many patients bial therapy; and (4) radiographic examination showing continue to have evidence of active disease despite multiple foci of osteolysis surrounded by sclerosis.12,63,88 improved pain and need additional antiinflammatory Based on clinical observations, a suggestion for a new agents. Steroids have been used with reported ben- classification of nonbacterial osteitis, and review of the efit.12,13,29,73,78,79 There are two reports of clinical im- available literature, a panel of major and minor diagnostic provement using interferon ␣ or interferon ␥.3,33 Tumor criteria was proposed50 (Table 1). The study suggests the necrosis factor-␣ blocking agents such as infliximab have general diagnosis of nonbacterial osteitis is reached if two been reported to provide clinical improvement in the treat- major criteria or one major criterion plus three minor cri- ment of CRMO.19,26 Bisphosphonates have also been used teria are found.50 Applying the proposed diagnostic crite- for CRMO with reported success by several groups,50,62,96 ria, the authors found the fewer the criteria that were met, however, no response to treatment with bisphosphonates the more likely the diagnosis of acute nonbacterial osteitis has also been reported.38,50 In general, antibiotics do not was reached. The more the criteria that were met, the more have an effect on CRMO symptoms; however, a German likely the diagnosis of CRMO was reached.50 However, study reported improvement in seven of 13 patients with this scheme of diagnosis has not been clinically validated CRMO treated with azithromycin.13,25,52,56,63,87,89 The and prospective studies examining the application of these improvement reported with this macrolide antibiotic is criteria are needed to evaluate the usefulness of this diag- probably attributable to its antiinflammatory effects.49 nostic approach. Etiology Treatment The etiology of CRMO is currently unknown. Cultures are The treatment of CRMO remains empiric due to the lack uniformly negative, and there is typically no response to of controlled studies. Nonsteroidal antiinflammatory drugs antibiotic therapy, making an infectious etiology highly (NSAIDs) are the first line of therapy resulting in clinical unlikely. In addition, there is no evidence for immune improvement in most treated patients. NSAIDs are often deficiency or autoimmunity.63 An early report13 did not

TABLE 1. Proposed Major and Minor Diagnostic Criteria for Nonbacterial Osteitis Major Diagnostic Criteria Minor Diagnostic Criteria

Radiologically proven osteolytic/sclerotic Normal blood cell count and good general bone lesion state of health Multifocal bone lesions CRP and ESR mildly to moderately elevated PPP or psoriasis Course is longer than 6 months Sterile bone biopsy with signs of Hyperostosis inflammation and sclerosis Association with other autoimmune diseases other than PPP or psoriasis Grade I or II relatives with autoimmune or autoinflammatory disorders or with NBO

PPP = pustulosis palmoplantaris; NBO = nonbacterial osteitis

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Number 000 06-01113 2007 CRMO: Review and Genetic Update 5 support hereditary or autoimmune etiologic factors. How- ever, there are currently several observations that point to the genetic etiology of CRMO. First, there are at least three reports of affected siblings with normal parents, thus suggesting autosomal-recessive inheritance.8,32,79 Second, a published study39 reports one monozygotic twin pair concordant for CRMO and another monozygotic twin pair in which CRMO was diagnosed in one and PPP was diagnosed in the other, both pairs with normal parents. In the same paper, the authors mention they have seen a child with CRMO whose father developed chronic noninfectious osteomyelitis of the sternum as an adult. In another report,50 there was more than one member affected with sterile osteomyelitis in 6% of the families that comprised their cohort. These family relationships were: father and son, monozygotic twin sisters, two pairs of sisters, and two sisters and their father. Multiple affected family members were also observed. Third, it has been recently shown, through an association study, there is a susceptibility locus on chromosome 18q21.3-22.39 Fourth, the autosomal- recessive Majeed syndrome, in which CRMO is the main component,68–70 is the result of mutations in LPIN2.1,31 The role of genetic factors in the etiology of CRMO is Fig 4. Tail kinks (arrows) are shown in a 4-month-old cmo potentiated by the presence of a spontaneously occurring (chronic multifocal osteomyelitis) mouse. mouse model (cmo) with clear autosomal-recessive inheritance.17 These mice develop tail kinks by 6 to 8 weeks of age and hind foot deformities by 3 months of age (Fig 4). ity to microtubule destabilizing agents.94 The role of hu- Males and females are equally affected.17 The caudal and man lipin2 in fat metabolism is not clear, because LPIN1 spinal vertebrae in these mice are partially or completely mutations have not been reported in patients with lipodys- destroyed by an inflammatory infiltrate composed of mac- trophy.18 Based on suggested mechanism for pyrin, the rophage and PMN cells by 3 to 4 weeks of age.43 Subse- protein implicated in the archetypal autoinflammatory dis- quently, there is resorption of both cancellous and cortical orders, familial Mediterranean fever,61 we hypothesize bone by osteoclasts followed by reactive new bone forma- lipin2 plays a role in the regulation of the innate immune tion with associated fibrosis; these findings are very simi- system, and the defect in the protein would lead to in- lar to those seen in human CRMO.43 The gene responsible creased production of proinflammatory signals. One way for the murine cmo phenotype has been identified to be this could occur would be if lipin2 plays a role in promot- pstpip2.30 ing apoptosis in polymorphonuclear leukocytes and its Majeed syndrome is an autosomal-recessive disorder normal function were to curtail the inflammatory milieu. characterized by CRMO and congenital dyserythropoietic Mutations in LPIN2 would then lead to a disturbed func- anemia, which has been clearly described in three families tion and persistence of inflammation. An alternative hy- with seven affected individuals.1,68–70 Homozygosity pothesis is based on the observation that LPIN2 expression mapping, parametric linkage analysis, and various muta- is upregulated in response to oxidative stress in lung mac- tion detection techniques led to the identification of LPIN2 rophages.95 Mutations in LPIN2 would disturb its protec- as the gene responsible for the Majeed syndrome pheno- tive function against oxidative stress, and the oxidative type.31 Little is known about the function of LPIN2.It stress would lead to inflammation secondary to tissue shares a lipin domain with the human ortholog of murine damage. Both hypotheses assume there is tissue-specific lpin1, which plays a role in fat metabolism.81 Studies of redundancy in the role played by lipin2 and its related the fission yeast (Schizosaccharomyces pombe) Ned1 pathway in the downregulation of inflammation with a gene, which belongs to an evolutionary conserved gene lower level of redundancy in skin and bone. family that includes the mammalian LPIN genes, revealed Mutations in pstpip2 have been identified in two mutant mutations have a high incidence of chromosome misseg- mouse lines, which have chronic osteomyelitis as the main regation, aberrantly shaped nuclei, overdeveloped endo- phenotype. The first mouse model is a spontaneous mutant plasmic reticulum-like membranes, and increased sensitiv- model described in 1991 and named the cmo (chronic

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Clinical Orthopaedics 6 El-Shanti and Ferguson and Related Research multifocal osteomyelitis) mouse.17 The gene locus was such as affected siblings, a syndromic monogenic disorder mapped by RFLP analysis to a 21 cM location on murine with CRMO as a prominent phenotypic feature, and a chromosome 18.17 The gene was subsequently identified spontaneously occurring mouse model led to the identifi- using a backcross breeding strategy followed by direct cation of two genes that play a role in the etiology of sequencing of candidate genes in the refined region. A CRMO. The role of mutations in LPIN2 has been proven missense mutation (L98P) in pstpip2 was detected, which to cause the syndromic form of CRMO called Majeed was predicted to be deleterious by protein modeling and syndrome, and mutations in pstpip2 cause a murine form the leucine in the ninety-eighth amino acid position is of the disorder, cmo. There are currently ongoing studies highly conserved across species.30 Independent confirma- to delineate the contribution of common or rare variations tion that mutations in pstpip2 caused the phenotype came in LPIN2 and PSTPIP2 to the etiology of CRMO and its shortly thereafter when Grosse et al40 reported an ENU associated inflammatory conditions. The goals of these mutant mouse (Lupo mouse) with an overlapping phe- studies are to better understand the pathophysiology of notype that also had homozygous missense mutation in CRMO and to guide the treatment modalities, based on the pstpip2. The Lupo mouse showed inflammation in a simi- understanding of the bone inflammatory process. Identi- lar tissue distribution as the cmo mouse but with variable fying the pathway involved in bone inflammation will aid severity. This difference in severity may be explained by in identifying other genes that play a role in the etiology of the different mutations in Pstpip2 domains or other factors CRMO, which is clearly a heterogeneous and multifacto- relating to the different genetic backgrounds of the mice. rial condition. The human PSTPIP2 is located on 18q21.1, in the vicinity The diagnosis of CRMO has been hampered by the lack of the region identified by the association study.39 Its role of a specific diagnostic test and the reliance on clinical in human CRMO has been examined in a limited number criteria and recurrence of the disease to reach a firm di- of patients50 but is currently under study in our laboratory agnostic conclusion. Algorithms for the clinical diagnosis in a larger number of patients. have been proposed but remain to be validated for ex- Pstpip2 is a proline-serine-threonine phosphatase inter- tended clinical use. As mentioned above, the current treat- acting protein (also called MAYP—macrophage actin- ment modalities are empiric with varying degrees of suc- associated tyrosine phosphorylated protein) that belongs to cess. There is an obvious need for appropriately designed the Pombe CDC15 homology family of proteins that are drug trials that are supported by deeper understanding of important in actin-based cellular functions.66 Pstpip2/MAYP the pathophysiology of CRMO. Identifying all genes con- is highly expressed in macrophages.40 As predicted, un- tributing to the etiology of CRMO will undoubtedly pro- der- or overexpression of pstpip2/MAYP in mouse macro- vide the framework for studies of the pathophysiology and phages (in vitro) affects the ability to rearrange the cyto- the interaction of those genes with the environment to skeleton to form filopodia and membrane ruffles and also produce the phenotype. It may also lead to individualiza- affects cell motility.21 The level of pstpip2/MAYP in wild- tion of treatment modalities based on an etiology-based type mouse macrophages increases with LPS stimulation, classification. but this response to LPS is dampened in the Lupo mouse In this review, we provided an outline for the clinical in which MAYP expression is threefold lower than wild presentation and the management aspects of CRMO and type.40 The exact mechanism has not been elucidated, but discussed the genetic factors contributing to its etiology. it appears mutations in pstpip2 lead to an inflammatory We outlined the need for validation of clinical schemes for phenotype by disrupting normal macrophage function; the diagnosis of this disorder and the deeper understanding thus, wild-type pstpip2/MAYP appears to play an anti- for its underlying pathophysiology. This in turn can proinflammatory role in normal immunologic function of the vide the basis for treatment trials that have a high rate of monocytic cell lineage. Both LPIN2 and PSTPIP2 are ex- success, or individualization of the treatment based on an pressed in macrophages95 and the Lupo mouse is a macro- etiologic classification of the disorder. phage-mediated autoinflammatory disorder40 suggesting a common pathway for down-regulation of bone and skin Acknowledgment inflammation. We thank Dr. Jeffrey C. Murray for his help and guidance. DISCUSSION References CRMO is an autoinflammatory disorder of bone that is 1. Al-Mosawi ZS, Al-Saad KK, Ijadi-Maghsoodi R, El-Shanti HI, often associated with other inflammatory conditions. Al- Ferguson PJ. A splice site mutation confirms the role of LPIN2 in Majeed syndrome. Arthritis Rheum. 2007;56:960–964. though its etiology is currently unknown, evidence for 2. Anderson SE, Heini P, Sauvain MJ, Stauffer E, Geiger L, Johnston causative genetic factors is emerging. Several observations JO, Roggo A, Kalbermatten D, Steinbach LS. Imaging of chronic

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