Chronic Recurrent Multifocal Osteomyelitis

Joint Bone Spine 78 (2011) 555–560

Review Chronic recurrent multifocal osteomyelitis

Julien Wipff a,∗, Catherine Adamsbaum b, André Kahan a, Chantal Job-Deslandre a a Service de rhumatologie A, université Paris Descartes, AP–HP, hôpital Cochin, 27, rue du Faubourg-Saint-Jacques, 75014 Paris, France b Service de radiologie, université Paris Descartes, AP–HP, hôpital Saint-Vincent-de-Paul, 27, rue du Faubourg-Saint-Jacques, 75014 Paris, France article info abstract

Article history: Chronic recurrent multifocal osteomyelitis (CRMO), also known as chronic nonbacterial osteomyelitis, is Accepted 6 January 2011 an orphan disease that manifests as recurrent flares of inflammatory bone pain with or without a fever. Available online 26 March 2011 The pain is related to one or more foci of nonbacterial osteomyelitis. To distinguish unifocal CRMO from a tumor or an infection, a bone biopsy is required in nearly all patients and a trial of antibiotic therapy Keywords: in many. CRMO is now considered the pediatric equivalent of SAPHO syndrome, and recent data sug- Osteitis gest that CRMO should be classified among the autoinflammatory diseases. The treatment of CRMO is not Osteomyelitis standardized. Although no randomized placebo-controlled trials are available, there is general agreement Autoinflammatory disease that nonsteroidal antiinflammatory drugs constitute the best first-line treatment and that bisphospho- SAPHO syndrome ␣ Pediatric rheumatology nates and biotherapies such as TNF antagonists are effective in the most severe forms. Although CRMO is considered a benign disease, recent data suggest an up to 50% rate of residual impairments despite optimal management. © 2011 Société franç aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.

1. Introduction occurrence of attacks of multifocal bone pain), and investigations must then be performed to rule out the main differential diagnoses Chronic recurrent multifocal osteomyelitis (CRMO), also known (mainly infectious osteomyelitis, bone tumor, and Langerhans cell as chronic nonbacterial osteomyelitis, is an orphan disease histiocytosis). (OMIM#259680) whose prevalence is estimated at 1–2/106 (Orphanet.net) but may well be higher. CRMO was first described in 1972 by Giedon et al. [1]. The disease manifests as recurrent flares of 2.1. Clinical features inflammatory bone pain related to the presence of multiple foci of aseptic osteomyelitis. CRMO is widely believed to constitute the The mean age at CRMO onset is 10 years [3–5] and girls are pediatric equivalent of Synovitis, Acne, Pustulosis, Hyperostosis, affected more often than boys [3–7]. The mean time from symp- Osteitis (SAPHO) syndrome described in 1987 [2]. Initially, CRMO tom onset to the diagnosis of CRMO is 18 months, with a range of was thought to share similarities with the spondylarthropathies, a few weeks to a few years [3,5]. based on the links between CRMO and SAPHO syndrome and on The most suggestive feature is bone pain predominating in the presence in a substantial number of CRMO patients of psoriasis the metaphyses and epiphyses of the long bones. The main sites or chronic inflammatory bowel disease (Crohn’s disease or ulcera- of involvement, in order of decreasing frequency, are the distal tive colitis). However, recent genetic data from mice with chronic tibia, proximal tibia, pelvis, proximal femur, clavicle, and calcaneus multifocal osteomyelitis (cmo) and humans with Majeed syndrome [3–5,7,8]. The prevalence of vertebral involvement in retrospective (CRMO with dyserythropoietic anemia) suggest that CRMO may studies ranged from 4 to 30% [3–5,7,9]. Involvement of the ster- belong to the vast family of autoinflammatory diseases. Here, we num, clavicle, or mandible is particularly suggestive of CRMO. There discuss recent data on the clinical features, outcomes, imaging may be a fever during the attacks of bone pain. Some patients have study findings, nosology, and management of CRMO. extraarticular manifestations such as psoriasis [4,10], palmoplantar pustulosis [3,6,7,10], Crohn’s disease [4,7,11–14], acne [15],or 2. Diagnosing chronic recurrent multifocal osteomyelitis Sweet’s syndrome [16,17]. Although CRMO occurs at a young age, studies have shown that the disease remains active in 25 to 59% The diagnosis of CRMO rests on a convergence of positive and of cases after a median follow-up of more than 10 years [3,4,18]. negative findings. A number of features suggest CRMO (chiefly the CRMO was long believed to resolve without leaving any conse- quential residual impairments. Recent data suggest, however, that physical impairments may persist in up to 50% of patients [4]. ∗ Corresponding author. Tel.: +33 1 58 41 25 59; fax: +33 1 58 41 24 49. They consist chiefly in chronic pain and bone deformities, some- E-mail address: [email protected] (J. Wipff). times with limb length abnormalities. These physical abnormalities

1297-319X/$ – see front matter © 2011 Société franc¸ aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved. doi:10.1016/j.jbspin.2011.02.010 556 J. Wipff et al. / Joint Bone Spine 78 (2011) 555–560 may have a major psychological impact, and visible deformities (clavicle, mandible) may require plastic surgery to improve the patient’s appearance [3,4]. Furthermore, there is evidence that CRMO may evolve into spondyloarthropathy with clinical and radiological sacroiliitis [6,10].

2.2. Laboratory tests

During the attacks of bone pain, about two-thirds of patients have laboratory evidence of systemic inﬂammation with elevations in the erythrocyte sedimentation rate, C-reactive protein (CRP) level, leukocytes, and ﬁbrinogen [3]. However, the increases are usually moderate [3,19].

2.3. Radiological ﬁndings

Many studies are ongoing to evaluate the role for imaging studies in CRMO. The recent introduction of whole-body magnetic resonance imaging (MRI) warrants a reappraisal of the relative roles for each imaging technique. Radiography is the first-line imaging study in pediatric patients with a limp or pain possibly originating in the bone. The radiographs are often normal initially in CRMO. The first changes are usually seen in the metaphyses, near the growth plates. Later on, osteolytic, sclerotic, or mixed lesions develop, generally with no periosteal reaction [19]. However, the radiological findings vary widely, with some patients having breached cortices and/or periosteal apposi- tions [5] suggesting a tumor, particularly if the lesion is unifocal. The main differential diagnoses are osteomyelitis, primary bone tumors, lymphomas, and Langerhans cell histiocytosis. Diaphyseal lesions visible only as cortical thickening have been reported [19]. The prevalence of spinal involvement varies considerably, from 3 to 25%, depending on the study [3,20]. A literature review suggests that the vertebral lesions may predominantly affect the thoracic spine, followed by the lumbar spine then the cervical spine [21]. One or more vertebral bodies are involved, while the disks are intact [21]. Vertebra plana and crush fractures may develop [7,8], and the main differential diagnosis is Langerhans cell histiocytosis. The presence of multiple bone lesions and involvement of the metaphyses strongly suggest CRMO, obviating the need for a bone biopsy. Multiple lesions that are not visible on radiographs can be detected using either radionuclide bone scanning or whole- body MRI (Fig. 1). Radionuclide bone scanning may show multiple asymptomatic foci of increased uptake [22]. A map of the lesions at the time of the diagnosis can be obtained (Fig. 2), and the number of lesions may reflect the risk of persistent symptoms [3]. Early radionuclide uptake suggests inflammation and late uptake bone Fig. 1. (a) Radiograph of the right ankle showing an osteolytic lesion due to chronic sclerosis. The main limitations of radionuclide bone scanning are recurrent multifocal osteomyelitis in the distal tibial metaphysis without involve- the normally high uptake in the growth plates and patient exposure ment of the growth plate; (b) radiograph of the right ankle showing a sclerotic lesion to radiation. due to chronic recurrent multifocal osteomyelitis in the distal tibial metaphysis without involvement of the growth plate. Whole-body MRI is more sensitive than radionuclide bone scanning. However, the long acquisition time and high cost limit the use surgical or imagery-guided bone biopsy to rule out an infection (via of this investigation. MRI delineates the anatomy of the bone lesions cultures) or tumor. This invasive investigation is usually unneces- (Fig. 3) and soft tissues. Inflammatory CRMO lesions generate low sary in patients with multiple lesions. signal on T1 images and high signal on T2 images. A recent study Bone biopsies from CRMO lesions [7,25] show nonspecific showed that metaphyseal lesions were accompanied with epiphy- osteitis. Initially, there is an infiltrate composed of neutrophils and seal lesions in 67% of cases [8,23]. The identification of patients with giant cells, as well as areas of osteolysis. Subsequently, histology epiphyseal involvement may be helpful, as these patients may be shows reactive bone formation, sclerosis, and a predominantly lym- at increased risk for growth disturbances [24]. Another advantage phocytic infiltrate [25]. In some studies, these two stages could not of MRI is detection of synovial involvement near the bone lesions be separated, as acute, subacute, and chronic changes coexisted [7,8,23]. within the same specimens [26,27].

2.4. Histological features 2.5. Diagnostic score

Children with a solitary bone lesion whose clinical and radio- Jansson et al. recently developed a score to assist in the diag- logical features raise concern or lack speciﬁcity should undergo a nosis of CRMO while diminishing the number of unnecessary bone J. Wipff et al. / Joint Bone Spine 78 (2011) 555–560 557

Fig. 2. Radionuclide bone scan: note the multiple high-uptake foci (right ankle, left ﬁbula, right half of the pelvis, and right hip) in this patient with chronic recurrent multifocal osteomyelitis. biopsies [28]. They used a retrospective cohort of 224 patients, of whom 102 had CRMO and 122 had other diseases including benign and malignant bone tumors and bacterial osteomyelitis. The clinical score is based on weighted variables and can range from 0 to 63. When used in a diagnostic algorithm based on the presence of pain, abnormalities on standard radiographs, and/or one or more abnormalities on a whole-body imaging study, the score helps to diagnose CRMO and to avoid an unnecessary bone biopsy [28]. A prospective study in a larger cohort is needed to validate this algorithm.

3. Pathophysiology of chronic recurrent multifocal osteomyelitis

The pathophysiology of CRMO is unclear, and consequently the nosology of the disease remains ill defined. Until recently, CRMO was classified among the enthesitis-related forms of juvenile idio- Fig. 3. Magnetic resonance imaging in a patient with chronic recurrent multifocal pathic arthritis or juvenile spondyloarthropathy, according to the osteomyeliti; (a) whole-body image showing multiple foci of osteomyelitis, some of which are distributed symmetrically; (b) image of the ankle showing inflamma- Edmonton classification scheme [29]. A number of arguments sug- tory metaphyseal and epiphyseal lesions; and (c) image of the left femur showing gest that CRMO may belong to the spondyloarthropathy spectrum: involvement of the diaphysis with a soft tissue reaction. associations have been reported with psoriasis [4,10], sacroiliitis [6], and Crohn’s disease [4,7,11–14]; CRMO can evolve into spondyloarthropathy [10], and enthesitis may be the starting point for many features such as aseptic osteomyelitis and palmoplantar skin the bone lesions. However, there are a number of discordant facts, lesions. such as the absence of an association with HLA B27 [5,7]. Fur- Recent evidence indicates that CRMO is probably one of thermore, some of the clinical features of CRMO suggest a link the autoinflammatory diseases. First, spondyloarthropathies may with a highly distinctive form of spondyloarthropathy known as share similarities with autoinflammatory diseases. In 2006, McG- SAPHO syndrome. It has been suggested that CRMO may consti- onagle et al. [30] suggested a continuum from pure autoimmune tute a pediatric form of SAPHO syndrome. These two entities share disease to pure autoinflammatory disease. Disorders located 558 J. Wipff et al. / Joint Bone Spine 78 (2011) 555–560 toward the middle of this continuum exhibit both autoimmune and autoinflammatory features; they consist chiefly of spondyloarthropathies and associated diseases such as psoriasis and uveitis. Second, associations have been reported between CRMO and both Sweet’s syndrome [16,17,31,32] and Crohn’s disease [4,7,11–14], two multifactorial autoinflammatory diseases [30]. However, no associations were found between the NOD2/CARD15 gene polymorphisms implicated in Crohn’s disease and CRMO [33]. Third, although most cases of CRMO are sporadic, several facts suggest a genetic component. In several families, two affected children were born to unaffected parents [34,35], suggesting autosomal recessive inheritance. Affected monozygous twins born to unaffected parents have been reported [36], as well as a case in a child whose father had aseptic osteomyelitis confined to the sternum [36]. The histological findings in CRMO suggest a link with autoinflammatory disease: the inflammatory infiltrates usually seen early in the disease are composed chiefly of neutrophils, the key cells in autoinflammatory diseases such as PAPA syndrome, together with giant cells and foci of osteolysis [7,25]. Fig. 4. Diagram of the NALP3 (cryopyrin) inflammasome components involved in Studies of murine models of CRMO led to the identification of a the autoinflammatory diseases. The NALP3 inflammasome is a protein complex region of interest and subsequently of one of the causative genes. composed of NALP3 (inactive form folded over its leucine-rich region or LRR), the There are two murine models, cmo mice [37–39] and Lupo mice ASC protein, and Cardinal. NALP3 binds to the ASC protein via its pyrin domain [40]. A study in cmo mice identified a 21cM region of interest on (PyD) and to Cardinal via its NACHT-associated domain (NAD). The NALP3 inflammasome then binds to pro-caspase 1, allowing its cleavage and the release of active chromosome 18 [37]. The same group subsequently showed that caspase 1, which in turn activates interleukin-1 (IL-1) or interleukin-18 (IL-18). the cmo phenotype was due to a mutation in the pstpip2 gene Pyrin regulates the NALP3 inflammasome pathway. Pyrin may compete with NALP3 coding for proline-serine-threonine phosphatase-interacting pro- and pro-caspase 1 to bind ASC, thereby inhibiting the activation of this signaling tein 2, located on chromosome 18 [39]. Although the exact role pathway. Furthermore, proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1) binds to and inhibits pyrin. Mutations in the gene for PSTPIP1 that are for the pstpip2 protein remains unknown, a study in the Lupo known to increase the affinity of the protein for pyrin have been identified in an model showed that the causative mutation induced abnormalities autoinflammatory disorder (PAPA syndrome). in innate immunity [40] and that the pstpip2 protein was expressed in the monocyte cell line, which is the key cell line involved in innate immunity. These data are supported by the results of studies in bism shows an abundance of connective tissue and osteoclast-type humans. Mutations in the PSTPIP1 gene for a protein involved in cells. Two genes have been implicated in cherubism, SH3BP2 [44] regulating pyrin are responsible for the autoinflammatory disease and PTPN11 [45]. Although the role for these genes remains unclear, known as PAPA syndrome (OMIM#604416). This disease manifests a murine model for cherubism is characterized by abnormal acti- as progressively destructive aseptic arthritis with neutrophil infil- vation of cells involved in innate immunity (macrophages) with trates and skin lesions such as cystic acne, aseptic dermal abscesses, an excess of osteoclasts [46]. DIRA is a more recently described and/or pyoderma gangrosum [41]. PSTPIP1 binds to pyrin, a regu- Mendelian autoinflammatory disease characterized by multifocal lator that inhibits the NALP3 inflammasome. The two mutations aseptic foci of osteolysis, periostitis, and pustulosis. Symptom onset described as causing PAPA syndrome may prevent PSTPIP1 from occurs at a younger age than in CRMO, and the phenotype is more binding to the inhibitory phosphatases PSP-PEST and PTP-HSCF. severe, with a fatal outcome in three of nine patients. DIRA is char- Loss of this negative feedback effect mediated by dephosphory- acterized by expansile lesions of the ribs, a feature not found in lation may lead to excessive binding of PSTPIP1 to pyrin, and CRMO. Several mutations have been identified in the IL1RN gene therefore, to activation of the downstream NALP3 inflammasome encoding an IL-1 receptor antagonist protein [47]. pathway (Fig. 4) [42]. Finally, susceptibility regions have been identified on chro- Recent genetic studies further support the classification of mosome 18 in two other diseases that share varying degrees of CRMO among the autoinflammatory diseases. In 2002, a study that similarity with CRMO, familial expansile osteolysis and familial used the family trio design (n = 27) demonstrated an association Paget’s disease of bone. In both diseases, the phenotype has been between an allele (166pb) of the D18S60 microsatellite polymor- ascribed to mutations in the TNFRSF11A (RANK receptor activator phism and CRMO [36]. This polymorphism is located in the region of nuclear factor kappa B) gene at 18q22.1 [48,49]. of the human chromosome 18 that is homologous to the region associated with the murine cmo phenotype [36–38]. A copy of the 4. Treatment rare allele was identified in a single control compared to 11 of 27 patients with CRMO. In addition, the 166pb allele was prefer- The treatment of CRMO is not standardized. Although no ran- entially transmitted to children with CRMO (P = 0.003). In 2005, domized controlled trials are available, there is general agreement Ferguson et al. identified the gene responsible for Majeed syn- about several points. NSAIDs are the accepted first-line medica- drome (OMIM#609628), a recessive autosomal disease manifesting tions for CRMO. NSAIDs are used either during the attacks or as as severe CRMO with closely spaced attacks of florid osteomyelitis maintenance therapy to prevent attacks. None has been proven and dyserythropoietic anemia [43]. Majeed syndrome is caused by superior over the others, but all are indisputably effective. In five a mutation in the LPIN2 gene at 18p11.31. The functional role for patients given indomethacin to treat CRMO, the clinical and radi- LPIN2 in Majeed syndrome remains unknown. ological response was excellent after 4 years of follow-up [50].In Multifocal inflammatory bone disease is a manifestation shared patients with primary or secondary failure of NSAID therapy, one by CRMO and two autosomal dominant Mendelian diseases, or two other NSAIDs should be tried as the susceptibility to NSAIDs cherubism (OMIM#118400) and deficiency of the IL-1 receptor varies across patients. antagonist (DIRA) (OMIM#612852). A greater degree of osteolysis When NSAID therapy is inadequate, the main treatment options in cherubism is the main difference with CRMO. Histology in cheru- are bisphosphonates and TNF␣ antagonists. There is anecdotal J. Wipff et al. / Joint Bone Spine 78 (2011) 555–560 559 experience with other drugs such as azithromycin, interferon, Disclosure of interest sulfasalazine, methotrexate, intravenous immunoglobulins, and colchicine [3–8]. Oral glucocorticoid therapy is probably effective The authors have no conflicts of interest to declare. [51,52] but should be used only in limited dosages and dura- tions, given the adverse effects of long-term glucocorticoid therapy References on growth in these patients who are usually adolescents. Evi- dence that bisphosphonates might be effective was first reported [1] Giedion A, Holthusen W, Masel LF, et al. Subacute and chronic “symmetrical” in 2004 [53] and was confirmed by several subsequent publications osteomyelitis. Ann Radiol (Paris) 1972;15:329–42 [in multiple languages]. [3–5,9,54–56]. In nine patients, the pain resolved almost com- [2] Chamot AM, Benhamou CL, Kahn MF, et al. 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