Autoinflammatory Bone Disorders

CHAPTER

48

 

Autoinflammatory Bone Disorders Polly J. Ferguson, Ronald M. Laxer

Autoinflammatory disorders (discussed in Chapter 47) result from aberrant activation of the innate immune system.1,2 They occur in the absence of high titer autoantibodies or autoreactive lymphocytes, thus distinguishing them from the classic autoimmune disorders.1,3 The concept of autoinflammatory disorders was proposed in 1999, following the identification of the genetic basis of the prototypic periodic fever syndromes, familial Mediterranean fever and TRAPS (TNF receptor-associated periodic syndrome).1,4-6 There are now more than 30 disorders that are thought to be autoinflammatory, most of which affect children; included are a group of disorders that have bone inflammation as a main phenotypic feature, including chronic recurrent multifocal osteomyelitis (CRMO); synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome; Majeed syndrome; deficiency of interleukin-1 receptor antagonist (DIRA); and cherubism.1,7,8

CHRONIC RECURRENT MULTIFOCAL OSTEOMYELITIS Overview In 1972, Giedion recognized what is now commonly referred to as chronic recurrent multifocal osteomyelitis (CRMO) as a distinct clinical entity when he described four children with noninfectious multifocal osteomyelitis who presented with subacute and chronic symmetric osteomyelitis.9 The term chronic recurrent multifocal osteomyelitis was coined by Probst, Bjorksten, and Gustavson to describe the recurrent nature of the illness.10,11 Since that time, the term has been commonly used for this clinical entity despite the fact that the disease is neither always multifocal nor recurrent. The co-occurrence of CRMO with pustulosis palmoplantaris (PPP) was reported in 1967 in a child with bilateral clavicular osteitis, but it was Bjorksten et al. who firmly established the association with CRMO and PPP.11,12 The association of CRMO with PPP has been confirmed by others and descriptions of additional dermatologic associations with CRMO including psoriasis vulgaris, severe acne, generalized pustulosis and Sweet syndrome followed shortly thereafter.13-22 Subsequently, reports of the co-occurrence of CRMO and inflammatory bowel disease emerged as well as the observation that CRMO may evolve into spondyloarthropathy over time in some patients, suggesting that CRMO might best fit in the spondyloarthropathy family of disorders.23-36 Recently, the identification of the genetic basis for a subgroup of earlyonset CRMO cases and for murine models of disease has defined CRMO as an autoinflammatory syndrome.7,37-45

NOMENCLATURE It is difficult to review the CRMO literature because many terms have been utilized to describe similar clinical entities. Names that have been

used to describe cases of sterile inflammatory bone disorders that occur in the presence or absence of skin or intestinal inflammation are listed in Box 48-1.35,46-59 The most common terms utilized in the literature are CRMO and SAPHO syndrome. SAPHO is an acronym proposed in 1987 by Chamot et al. as a broad umbrella term to denote a clinical syndrome characterized by inflammation of the bone, joint, and skin.60,61 The SAPHO syndrome encompasses bone inflammation in the form of sterile osteomyelitis or as hyperostosis; inflammation of the skin, including acne or pustulosis and inflammation of the joint in the form of synovitis. SAPHO syndrome is the term most frequently utilized by adult rheumatologists, whereas the pediatric community has primarily utilized the term CRMO.33,47,62-65 SAPHO syndrome and CRMO may well be the same disorder presenting in different age groups (CRMO in childhood and SAPHO in adults) or it may be that they are distinct disorders that are part of the same disease spectrum. Another problem with the term CRMO is that sometimes the disease process is unifocal or is multifocal without recurrence, thus limiting the accuracy of the diagnostic term for many patients’ clinical course. For instance, in a German cohort of 89 patients with at least one noninfectious inflammatory bone lesion, approximately 20% had bone inflammation in one location with disease duration longer than 6 months without recurrence (unifocal nonrecurrent), nearly 45% of patients had classic CRMO with multiple bone lesions with recurrent flares with remissions (recurrent multifocal), and the remaining 35% had persistent multifocal bone inflammation for longer than 6 months without remissions (persistent multifocal).66 In addition, some children present with unifocal disease, yet over time develop classic multifocal recurrent disease.66 Similarly, in a cohort reported by Girschick et al. of 30 pediatric patients with sterile osteitis, 30% had unifocal nonrecurrent disease, 10% had unifocal recurrent disease, 30% had multifocal nonrecurrent disease and 30% had classic CRMO.67 Because of this, several authors have proposed other names, including chronic nonbacterial osteomyelitis (CNO) and chronic nonbacterial osteitis (NBO).66,67 In this chapter, we will utilize the term CRMO.

Incidence, Geographic and Racial Distribution CRMO is a rare disorder. Several hundred cases have been reported in the literature, but the incidence of the disease is unknown. Early reports of CRMO were predominantly from Scandinavia. However, review of the literature suggests a worldwide distribution of disease affecting multiple ethnicities and races.12,13,66,68

Age at Onset and Sex Ratio CRMO is primarily a disease of young girls, with peak onset between 7 to 12 years of age.66,69 Females are affected at a rate two to four times more often than males.34,66,67,69-72 The majority of cases occur in

627

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SECTION FIVE  Arthritis Related to Infection

BOX 48-1  Alternative Diagnostic Labels • • • • • • • • • • • • •

Chronic recurrent multifocal osteomyelitis Chronic sclerosing osteitis Pustulotic arthrosteitis Chronic multifocal cleidometaphyseal osteomyelitis Chronic symmetrical osteomyelitis Chronic multifocal symmetrical osteomyelitis Sternocostoclavicular hyperostosis Sternoclavicular pustulotic osteitis Diffuse sclerosing osteomyelitis Multifocal recurrent periostitis Bone lesions of acne fulminans Clavicular hyperostosis and acne arthritis Chronic nonbacterial osteomyelitis

childhood but adults can be affected and are more likely to be reported as SAPHO syndrome.62,71,73 Onset of CRMO prior to the age of 2 years is unusual and should prompt an evaluation for a syndromic form of CRMO, including DIRA and Majeed syndrome.37-39,41

Etiology and Pathogenesis CRMO best fits into the category of autoinflammatory disorders, a group of innate immune system disorders in which there are “seemingly unprovoked” episodes of inflammation.1,3,74 In most cases of CRMO (and SAPHO), bone inflammation occurs in the absence of an identifiable trigger. Cultures of the bone are typically sterile, antibiotic therapy is rarely accompanied by clinical improvement, and antiinflammatory medications improve the condition.66,69-72,75-80 Despite the inability to culture an organism in the vast majority of cases, many have postulated that the osteitis is driven or triggered by exposure to a microbial agent. There are a few reports of bone cultures growing organisms including Propionibacterium acnes, Mycoplasma, and various Staphylococcus species.26,27,69,76-78,80-87 However, in many cases it is unclear whether it is a contaminated specimen or a true infection.80 In a cohort of adults with inflammatory osseous anterior chest wall lesions, most of whom also had palmoplantar pustulosis, Propionibacterium acnes was cultured in bone biopsy samples from 7 of the 15 patients, suggesting that for this population of adult patients infection may have played a role in pathogenesis.85 However, in children with CRMO and for most adults with SAPHO syndrome, the vast majority of cultures of pustules and bone are negative.69,78,79,86 Girshick et al. looked for evidence of microbial infection in 25 patients with chronic nonbacterial osteomyelitis, all of whom had a bone biopsy performed as part of their diagnostic evaluation.67 All biopsies were sent for aerobic and anaerobic bacterial, mycobacterial, and fungal organisms. Eubacterial polymerase chain reaction was performed on 12 of the 25 bone biopsy samples, yet no bacterial ribosomal DNA was detected.67 Serologic testing for evidence of Borrelia burgdorferi, Salmonella, Yersinia enterocolitica, Campylobacter jejuni and Streptococcus pyogenes showed no evidence of acute or chronic infection with any of these microbes.67 Supporting the lack of an active infection as an etiology in CRMO or SAPHO syndrome, prolonged antimicrobial therapy rarely results in clinical improvement.69,70,88,89 Schilling et al. reported that 7 of 13 patients with CRMO treated with azithromycin had rapid clinical and radiologic improvement.86,90 However, azithromycin has a known antiinflammatory effect, and so a response to azithromycin does not necessarily support an active infection in CRMO.91,92 Bjorksten et al. and Jurik et al. reported that approximately 25% of CRMO patients reported trauma preceding the development of chronic bone inflammation,11,73 suggesting tissue

damage as another possible trigger, although this has not been found in most series. The precise immunologic basis of CRMO remains unknown. There is no evidence of immune deficiency in the vast majority of children and the lack of high titer autoantibodies suggests that it does not have an autoimmune basis.69,77 Although a German cohort was noted to have a positive ANA greater than or equal to 1 : 120 in approximately one third of cases, this hasn’t been found other cohorts.66 There is no significant association with HLA-B27 positivity.66,69,77 There are reports of neutrophil dysfunction in CRMO; however, the role of neutrophils in these disorders has not been fully studied.11,73,93 There are two murine models of CRMO, which are both due to mutations in proline-serine-threonine phosphatase interacting protein-2 (Pstpip2) gene. The chronic multifocal osteomyelitis (cmo) mouse lacks detectable Pstpip2 and the mice develop multifocal osteomyelitis beginning at 6 to 8 weeks of age.40,43 Mouse models of CRMO have demonstrated that the adaptive immune system is not needed for disease development40,42,94 supporting the autoinflammatory nature of the disease. Recently, two groups demonstrated dysregulation of the IL-1 pathway in the pathogenesis of disease in the cmo mouse.44,45 In this model, both groups demonstrated that the inflammatory phenotype was IL-1 dependent, as the mice were completely protected if the cmo mice lacked a functional IL-1 receptor (IL-1RI).44,45 Yet, disease occurred in the absence of a functional Nlrp3 inflammasome and occurred in cmo.caspase-1 knockout mice.44,45 Further, using a genetic approach, they demonstrated that it is IL-1β, not IL-1α, that is needed for disease.44,45 Cmo neutrophils, but not cmo bone marrow–derived macrophages, secreted increased IL-1β in response to ATP, silica, and P. aeruginosa when compared to wild-type neutrophils.44 The aberrant neutrophil response could be inhibited by serine protease inhibitors.44 These results demonstrate that bone disease in the cmo mouse is an inflammasome-independent, IL-1β– mediated disease44,45 and implicates neutrophils and neutrophil serine proteases in disease pathogenesis.44 In addition, the discovery that infantile-onset noninfectious multifocal osteitis associated with generalized pustulosis (deficiency of the interleukin-1 receptor antagonist [DIRA]) is due to IL-1 pathway dysregulation lends additional support to the notion that CRMO, SAPHO, and related disorders are autoinflammatory.38,39 Many authors have noted the tendency for CRMO or SAPHO syndrome to evolve into a picture consistent with spondyloarthropathy over time.27,47,64,72,95 Rohekar and Inman point out that SAPHO syndrome has many features that fit into the spondyloarthropathy family with features that suggest it lies in the spectrum of disease between ankylosing spondylitis and psoriatic arthritis (Fig. 48-1).33,36 The connection between CRMO and inflammatory bowel disease also supports the contention that CRMO is part of the spondyloarthropathy spectrum of disease. Crohn disease and ulcerative colitis have both been reported in conjunction with CRMO and SAPHO syndrome.24-26,28-32,36 When inflammatory bowel disease (IBD) is associated with CRMO, pyoderma gangrenosum may accompany the inflammatory gut and bone disease.21,32,96 The link between gut inflammation and spondyloarthropathies is well established, with endoscopic gastrointestinal inflammation detectable in greater than 40% of spondyloarthropathy patients.97,98 In three CRMO cohorts, 13% of affected individuals had a first- or second-degree relative with Crohn disease, further supporting the link between IBD and autoinflammatory bone disease.7,66,70

Role of Genetics in CRMO Pathogenesis There is evidence that genetics plays a prominent role in susceptibility to CRMO. There are reports of affected siblings, concordant

CHAPTER 48  Autoinflammatory Bone Disorders monozygotic twins (with unaffected parents), as well as parent/child duos.15,49,59,66,93,99 There are also reports of first degree relatives with CRMO in one and PPP or psoriasis in at least one other.7,66,73,99,100 Golla et al. performed an association study in CRMO and found evidence for a susceptibility locus on chromosome 18q21.3-22.99 More recently, Hofmann et al. detected an association with a promotor polymorphism in the IL-10 gene that has been associated with high IL-10 production.101 Further support for a genetic basis of CRMO comes from animal models of the disease. Two single gene murine models of disease and a canine model all develop spontaneous sterile multifocal osteomyelitis.40,42,43,102 And finally, up to half of the first and second degree relatives of individuals with CRMO have another inflammatory disorder, most often some form of psoriasis (palmar plantar pustulosis or psoriasis vulgaris) or inflammatory bowel disease.7,66,103 Definitive proof that CRMO can be genetically determined came when LPIN2 was identified as the causative gene for Majeed syndrome, followed by the identification of autosomal recessive mutations in pstpip2 in two murine models of disease (Fig. 48-2) and by the identification of mutations in IL1RN in infants with DIRA.37-40,42

Severe acne

PPP CRMO IBD

GP Psoriasis

Ankylosing spondylitis

FIGURE 48-1  Overlapping features of the main inflammatory disorders associated with CRMO. CRMO, Chronic recurrent multifocal osteomyelitis; GP, generalized pustular psoriasis; IBD, inflammatory bowel disease; PPP, palmoplantar pustulosis.

A

629

Clinical Manifestations of CRMO The typical clinical presentation of CRMO is local bone pain with or without fever.11,27,69,72 The pain is typically worse at night. Onset is usually insidious, although some patients present with acute pain.11,27,76 Tenderness, swelling, or warmth are often present overlying the involved bone but may be absent.11,27,34,69,76-78,104 At any one time, the number of osteomyelitis lesions can vary from one to 18.69 The symptoms may be intermittent or chronic and persistent, lasting from months to as long as 20 years.69,70,105 However, many individuals instead have chronic unremitting symptoms that may vary in severity.70 The disease may affect virtually any bone of the body, but the metaph­ yseal regions of the long bones, clavicle, vertebral bodies and pelvis are the most commonly affected sites.27,66,67,69,70,103,106,107 Involvement is symmetric in 25% to 40% of individuals.66,69 The local swelling involving the soft tissues adjacent to the inflamed bone may mimic arthritis when the lesions affect the metaphyseal regions of the long bones.27 Clavicular lesions often present with marked swelling and tenderness, most often involving the medial one third of the bone (Fig. 48-3).11,72,73,108 When the pelvis or vertebrae are involved, the patient presents with pain (local or referred), limp, or pelvic girdle weakness.72 Synovitis may accompany the bone lesions and can occur distant from the sites of bone involvement.66,67,103 In one study 80% of patients had been diagnosed with arthritis in joints adjacent to the lesion; some had synovial biopsies that revealed histologic evidence of synovitis.67 Fever accompanies the bone pain at presentation in 17% to 33% of patients.34,69,73,103 Most often the affected individuals appear well, although many complain of malaise and fatigue.72,73 Twenty-five percent of CRMO patients present with an extra osseous manifestation, most commonly a pustular rash on the palms and soles(Fig. 48-4).27,67,69 The majority of affected individuals have modest elevations of the erythrocyte sedimentation rate and C-reactive protein.66,69,73,80 White blood cell counts are typically normal or only mildly elevated.27,66,69 High titer autoantibodies are typically absent and there is no strong association with HLA-B27.34,67,69,76 Tumor necrosis factor alpha (TNFα)66,101 and interleukin-6 were elevated in the serum of patients with CNO, suggesting a role for these cytokines in the pathogenesis of the disease.66,101

Radiographic Studies Very early in the disease plain films may be normal or only show osteopenia; however, increased uptake on technetium bone scan or

B

FIGURE 48-2  Tail kinks and hindfoot deformities in the cmo mouse model of CRMO. A, A cmo mouse with segmental swelling of the tail, swollen hindfoot, and increased erythema of the left ear. B, Swelling and deformity in the hindfoot and digits accompanied by thickening and discoloration of the nails in a cmo mouse. The swelling of the digits resembles dactylitis.

630

SECTION FIVE  Arthritis Related to Infection

A

B

C

D

E

FIGURE 48-3  Clavicular involvement in CRMO. Adolescent female with unilateral clavicular involvement. A, Plain radiograph of the right clavicle at presentation reveals widening of the medial two thirds, with associated periosteal reaction. B, Corresponding CT scan of the right clavicle demonstrates expansion of the medial right clavicle with areas of increased sclerosis accompanied by a surrounding periosteal reaction (arrow). C, Flare of disease 18 months later showing further clavicular enlargement (clinical photo). D, Plain radiograph of the right clavicle at that time demonstrates marked interval sclerosis and thickening. E, MRI at the same time shows increased signal intensity on fat-suppressed contrast-enhanced T1-weighted images of the right medial clavicle consistent with continued inflammation. (Images courtesy Dr. P. Babyn.)

A

B

FIGURE 48-4  Palmoplantar pustulosis. Pustules in various phases of healing on the soles of an individual with CRMO (A) and PPP (B).

evidence of marrow edema on MRI can be seen at this stage. Mixed osteolytic and sclerotic lesions, with a predilection for the metaphyses of the long bones, are one of the most common radiologic findings (Fig. 48-5).10,72,105,109,110 Periosteal reaction may be present10,80; involvement of the small tubular bones is more likely to be accompanied by a significant periosteal reaction than is typically seen in the long bones.80,110 Cortical thickening or progressive sclerosis of the lesions occurs later in the course of the disease, followed by gradual normalization of the radiographic appearance over several years.10,66,70,72,80,105,110

Epiphyseal involvement is unusual but may occur and when present may lead to premature epiphyseal fusion.80,110 Likewise, diaphyseal involvement is unusual but is typically adjacent to involved metaphyseal regions.72 Clavicular lesions are typically located in the medial clavicle and may have a lytic destructive appearance with periosteal new bone formation when the disease is active.72,108,111 As the lesions heal, the clavicle becomes increasingly sclerotic in appearance.72,108 Repeated periods of remission and active disease often results in progressive

CHAPTER 48  Autoinflammatory Bone Disorders

A

631

B

FIGURE 48-5  Typical lesions of CRMO. A, Osteolytic lesion with surrounding sclerosis in the metaphyseal area of the distal fibula (short arrow) and the distal tibia (long arrow). B, Osteolytic lesion with surrounding sclerosis in the calcaneus (arrow).

A

B

FIGURE 48-6  Pelvic involvement in CRMO. A, Plain film of the right pelvis demonstrates expansion of the ischium without visible osteolytic lesions (arrow). B, CT of the region demonstrates expansion of the ischium with sclerosis and osteolytic lesions on the right (arrow).

clavicular sclerosis and hyperostosis.55,72 Vertebral lesions typically display erosion of vertebral plates sometimes accompanied by reduced intervertebral space, which can mimic infectious spondylodiscitis.10,11,72,112,113 Alternatively, a destructive lytic lesion involving a vertebral body may precede its collapse.72,114 Vertebra plana may be seen.36,79,115 Involvement of the bones of the pelvis may occur at joint surfaces or synchondroses and often have a sclerotic appearance (Fig. 48-6).72 Sacroiliitis may also occur as part of the osseous pelvic lesions (Fig. 48-7).27,34,70,72,110 Asymptomatic lesions are common and can be screened for by technetium bone scan.72,79,80,109 MRI is very useful for gauging activity and extent of the bone lesions and is preferred over bone scan for diagnosis and subsequent management.72,110,116 In addition, it provides information about the extent of soft tissue involvement.72,110 Active lesions typically have high signal intensity on T2-weighted images and on short tau inversion recovery (STIR) images accompanied by decreased signal intensity on T1 weighted images.72 The ability to more clearly discern the extent of soft tissue involvement makes STIR images extremely useful.72,110 Whole body MRI with STIR images offer an alternative to bone scan for detecting asymptomatic lesions (see Chapter 9.).106,107,110,117-122 The advantage of MRI over bone scan is that the lesions of CRMO often occur in the metaphyseal regions of the long bones and are often symmetric. In a growing child, symmetric inflammatory lesions in the metaphyses may be read

as normal increased uptake due to metabolic activity in the open growth plate. An additional benefit of MRI is that it spares radiation exposure. A reasonable radiographic approach in a child with suspected CRMO would be to start with plain radiographs of symptomatic regions, perform a whole body MRI with STIR images (or bone scan if whole body MRI is not possible) to detect asymptomatic lesions, obtain plain radiographs of the additional lesions and utilize site specific MRI to further delineate extent of disease as needed.

Histology Histologic findings in the bone vary depending on the age of the lesion with neutrophils prominent in early lesions while a mixed inflammatory infiltrate consisting primarily of lymphocytes and plasma cells with various degrees of sclerosis and fibrosis are present later.11,69,71,73,76,77 Abscess formation surrounded by lymphocytes and increased osteoclasts with signs of bone resorption also can be seen early.71 Later, there is a predominance of lymphocytes, accompanied by plasma cells, histocytes, and a few neutrophils.69,71,73,77 Noncaseating granulomas have been reported in some biopsies.11,71 Multinucleated giant cells, necrotic bone, areas of new bone formation, and fibrosis can also be seen in late lesions.69,71,73,77 The histopathologic picture may vary within the same sample, and it is therefore important to evaluate multiple sections from each biopsy specimen.77

632

SECTION FIVE  Arthritis Related to Infection

A

marginal sclerosis; absence of fever; lesion in a vertebra, clavicle or sternum; the presence of a radiographic-proven lesion, and C-reactive protein level greater than or equal to 1 mg/dl were suggestive of CRMO. A clinical score can then be calculated that ranges from 0 to 63 with a score of greater than or equal to 39 generating a positive predictive value of 97% and a sensitivity of 68% in their cohort.66 The differential diagnosis includes infectious osteomyelitis; malignant bone tumors, including primary intraosseous lymphoma, osteosarcoma, Ewing sarcoma, leukemia, and neuroblastoma; benign bone lesions, including osteoid osteoma and osteoblastoma; Langerhans cell histiocytosis; Rosai-Dorfman disease; psoriatic arthritis or spondyloarthropathy; hypophosphatasia; and immune deficiency.10,90,117,133-138 Biopsy is often needed to exclude an infectious etiology and to exclude the possibility of malignancy. It is difficult to definitively rule out malignancy based on the clinical picture and imaging. MRI of the affected region is helpful to guide the site to biopsy.72 The best site to biopsy is the site that is felt to give the best diagnostic information with the lowest chance for functional or cosmetic consequences.117 In some cases, a biopsy may not be needed. This occurs when a child has classic radiographic findings of CRMO (particularly if the clavicle is one of the bones involved) and has a comorbid condition such as Crohn disease or psoriasis.

Treatment

B FIGURE 48-7  Involvement of the pelvis with sacroiliitis and osteomyelitis of the ilium. A, Unilateral sacroiliitis is present with sclerosis of the SI joint that is most prominent on the iliac side of the joint (arrow). There is associated increase sclerosis of the left ilium with multiple moth eaten lesions scattered throughout the left side of the pelvis. B, CT scan shows marked expansion of the left ilium with multiple small osteolytic lesions with surrounding sclerosis on the left (arrow).

Associated Inflammatory Conditions There is a firm association of CRMO with inflammatory disorders of the skin and gut. These include palmoplantar pustulosis,11,12,15,22,23 psoriasis vulgaris,13,23 generalized pustulosis,123 Sweet syndrome,18-21 severe acne14,17 and pyoderma gangrenosum.32,70,96 An association also exists with inflammatory bowel disease, most often Crohn disease but also with ulcerative colitis and celiac disease.24-26,28-32,66,70,124 Peripheral arthritis has been reported with CRMO often adjacent to active bone lesions but can involve joints distant to the osteitis35,66,67,70; sacroiliac joint disease has also been reported.27 Other disorders that have been reported in individuals with CRMO include Takayasu arteritis,34,125,126 Wegener granulomatosus,70,75 sclerosing cholangitis,26,70 Ollier disease,70 myositis,103,106,127,128 Still disease,129 tumoral calcinosis,130 and parenchymal lung disease.131,132

Differential Diagnosis There are no validated diagnostic criteria and no diagnostic test for CRMO. Jansson et al. developed a clinical score to aid in differentiating nonbacterial osteitis from other bone lesions. They found that a normal complete blood count; symmetric bone lesions; lesions with

Nonsteroidal antiinflammatory drugs (NSAIDs) are used as a first line treatment strategy in CRMO, providing some degree of symptomatic relief in up to 80% of patients.34,66,67,69,108,139 Indomethacin may be more effective than other NSAIDs.140 However, many children continue to have symptoms despite NSAIDs.34,66,67,78,103 In one long-term follow-up study of 22 individuals with CRMO, only 9% had a good response to NSAIDs with 27.2% having no response at all.78 Beck et al. prospectively followed a group of children with CRMO and gauged their response to antiinflammatory medications (most often naproxen) during the first year of treatment. They found that 43% of individuals treated with naproxen were symptom-free at 6 months after starting treatment.141 This was accompanied by a statistically significant decrease in pain, functional impairment, and swelling and by more than 50% reduction in radiologically apparent lesions at 12 months.141 However, 100% of those with arthritis continued to have active synovitis at 3 months; at 6 months that figure was 50%.141 Two out of 7 patients (28%) in this cohort with spinal involvement developed pathologic fractures during the 12 months of follow-up.141 This suggests that NSAIDs alone may not be optimal for individuals who present with arthritis or spinal involvement. The decision to escalate medical therapy must take into consideration the fact that most lesions resolve without significant sequelae, and spontaneous remission can occur (Fig. 48-8).67,70 Indications for escalation include persistent pain that affects normal activities, frequent recurrences, and functional limitations. Second-line treatment agents that have been utilized include corticosteroids, azathioprine, disease-modifying antirheumatic drugs (DMARDs), bisphosphonates, biologics, and other immune modulators.66,117,142,143 Most individuals obtain symptomatic relief with corticosteroids, but side effects limit their usefulness in long-term disease management.34,67 There are reports of improvement in patients with CRMO or SAPHO treated with methotrexate, sulfasalazine, colchicine, hyperbaric oxygen, cal­ citonin, azithromycin, interferon-α, interferon-γ, TNF-α inhibitors, IL-1 blocking agents, and bisphosphonates; however, there is no randomized trial of any of these agents, and there are also reports of treatment failures.26,27,34,66,70,80,86,103,139,144-148 Borzutsky et al. performed a retrospective analysis of 70 patients with CRMO/CNO and found that the estimated probability to response was 57% for NSAIDs,

CHAPTER 48  Autoinflammatory Bone Disorders

2007

2007

I

2010

2004

2010 II

III FIGURE 48-8  Spontaneous resolution of lesions in an 8-year-old girl with CRMO over a 3-year time span. Plain radiographs of the ankle (I and II) and wrist (III) of a female with CRMO whose parents decided to stop treatment after only a couple of days of an NSAID. Over the span of 3 years there is spontaneous healing of all of her bone lesions. (Courtesy Dr. Marilyn Ranson.)

633

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SECTION FIVE  Arthritis Related to Infection

66% for sulfasalazine, 91% for methotrexate, 91% for TNF inhibitors, and 95% for corticosteroids. No individuals were treated with bisphosphonates.103 The rate of clinical remission (defined as resolution of pain, normalization of inflammatory markers, and radiologic improvement) was highest in the TNF inhibitor group at 46%, followed by corticosteroids at 37%; clinical remission was only achieved in 20% in the methotrexate group, 18% in the sulfasalazine group, and 13% in the NSAID group.103 For NSAID-resistant disease, there are case reports of marked improvement following treatment with TNF-α blocking agents29,66,103,149-156 and bisphosphonates.143,150,152,157-165 The data are strongest regarding the use of bisphosphonates in recalcitrant bone lesions. There is now information in the literature on more than 50 individuals with CRMO, CNO of the jaw, or SAPHO treated with various bisphosphonates with a positive response to initial treatment reported in most of the individuals treated (Fig. 48-9).66,150,152,157-169 In the series of Miettunen et al., nine patients with CRMO were treated with pamidronate with a mean resolution of

MRI abnormalities of 6 months. Four of the nine subsequently flared but all responded to retreatment.157 There are also reports in the literature of failure to respond to bisphosphonates as well as failure to respond to TNF inhibitors.66,159,161,168 Surgical approaches to treatment have included curettage or partial resection of the involved bone; however, surgical intervention is typically limited to obtaining tissue for cultures and histology. The optimal treatment strategy for CRMO remains unknown, and safety questions remain with the long-term use of both TNF inhibitors as well as with bisphosphonates in children. The use of IL-1 inhibitors to treat CRMO remains largely unexplored and needs further investigation given the successful treatment of sterile bone inflammation in both DIRA and Majeed syndrome with these agents.38,39,170 All children should remain physically active despite ongoing inflammation. Referral to a physical therapist may be needed to regain strength and range of motion lost due to inactivity and guarding the extremity; this is especially true for those with a delay in diagnosis and treatment.

A

B

C FIGURE 48-9  Plain radiographs of the left humerus. 10-year-old girl with noninfectious osteomyelitis of the left tibia diagnosed 7 months previously presents with a several-month history of left arm pain. A, Initial radiograph shows marked proximal expansion with lateral cortical thickening extending down the proximal half of the humerus. She improved clinically on naproxen. B, Eighteen months later, she had a recurrence of pain with significant radiologic progression showing areas of lucency and sclerosis with extensive medullary expansion now involving almost the entire humerus. C, Plain radiograph taken 1 year after a 1-year course of intravenous pamidronate shows significant healing of the humerus lesion. (Courtesy Dr. Paul Babyn.)

CHAPTER 48  Autoinflammatory Bone Disorders

635

employment, educational achievement, and participating in recreational sporting activities has been reported in a few cases.70,105

Long-Term Outcome For most affected individuals, the disease waxes and wanes with periods of exacerbations and remissions, but with resolution of the disease process after several years; reportedly leaving most with no long-term sequelae (Fig. 48-10).67,69 However, several long-term follow-up (f/u) studies suggest that CRMO might be more persistent, lasting well over a decade in some,70,71,105 and not as benign as previously reported. For instance, the percentage of individuals with continued disease activity at follow-up ranges from 0% in a German cohort (mean f/u = 5.6 years),67 18% in an Australian cohort (mean f/u = 6.2 years),78 25% in a Finish cohort (mean f/u = 7.5 years),75 26% in an Canadian/Australian cohort (mean f/u = 12.4 years),70 57% in a French cohort (mean f/u = 5.3 years),34 and 100% in a Dutch cohort (mean f/u = 5.5 years).73 Pathologic fractures, most often of a vertebral body, occurred in 49% of a German cohort.66 Long-term skeletal deformities, particularly leg length discrepancy, have been reported in up to 58% in one study.80,105 Other long-term musculoskeletal abnormalities include residual hyperostosis and sclerosis of the bones, difficulty with mastication (following mandibular involvement), valgus deformity of the knee, vertebral collapse, persistent muscle atrophy, thoracic outlet syndrome, persistent arthritis, and evolution into spondyloarthropathy.66,67,69,70,75,105,171 Disease recurrence may occur as long as 6 years after the last episode of osteitis.10,105 Difficulty with

DISTINCT GENETIC AUTOINFLAMMATORY BONE SYNDROMES (TABLE 48-1) Majeed Syndrome The classic clinical triad in Majeed syndrome (OMIM reference #609628) includes early onset CRMO, congenital dyserythropoietic anemia, and a neutrophilic dermatosis (consistent with Sweet syndrome) (Fig. 48-11).19 This is a rare syndrome with only three unrelated Arabic families and one Turkish family identified to date.19,41,68,170 Affected individuals from all four families have homozygous mutations in the gene LPIN2.37,41,170 Onset of the inflammatory bone disease is typically prior to the second birthday.41,68,170 Bone pain with or without fever is the typical presenting feature. The histology and radiographic findings are identical to those of CRMO.19,41,68 Cultures are negative and there is no improvement with antibiotic therapy.19,68 Individuals with Majeed syndrome have varying degrees of anemia ranging from mild to transfusion dependent.19,41,68,170 The red cells are typically microcytic.19,172 Bone marrow biopsy reveals evidence of dyserythropoiesis with bi- and tri-nucleated normoblasts.41,68,170 No other cell lines appear to be affected. Other laboratory abnormalities

TABLE 48-1  Autoinflammatory Bone Disorders CRMO Ethnicity

Extraosseous Manifestations

Worldwide, but mostly European Uncommon Metaphyses of long bones > vertebrae, clavicle, sternum, pelvis, others PPP, psoriasis, IBD, others

Family History of Inflammatory Disorders Inheritance

Psoriasis, PPP, arthritis, IBD, others Not clear

Gene Defect Protein Name Protein Function

Unknown Unknown Unknown

Cytokine Abnormalities

↑ serum TNF-α

Fever Sites Of Osseous Involvement

MAJEED SYNDROME

CMO AND LUPO MICE

DIRA

CHERUBISM

European, Puerto Rican, Arabic Uncommon Anterior rib ends, metaphyses of long bones, vertebrae, others Generalized pustulosis, nail changes, lung disease, vasculitis

Worldwide

Cervical lymphadenopathy

Dermatitis, extramedullary hematopoiesis, splenomegaly

No known associations

No known associations

Heterozygotes normal

Autosomal recessive

Autosomal recessive

Autosomal recessive

LPIN2 LIPIN2 Fat metabolism: (PAP enzyme activity), ↑ message to oxidative stress, unknown role in mitosis Not tested

IL1RN IL-1Ra Antagonist of IL-1 receptor

Autosomal dominant; incomplete penetrance SH3BP2 ≫ PTPN11 SH3BP2 ↑ myeloid cell response to M-CSF and RANKL, ↑ TNF-α expression in macrophages ↑ serum TNF-α in mouse model

cmo: ↑serum IL-6, MIP-1α, TNF-α, CSF-1, IP-10Lupo: ↑serum MIP-1α, IL-4, RANTES, TGF-β

Arabic Common Similar to CRMO

Dyserythropoietic anemia, Sweet syndrome, HSM, growth failure Psoriasis in some obligate carriers

↑ IL-1α, IL-1β, MIP-1α, TNF-α, IL-8, IL-6 ex vivo monocyte assay; skin reveals ↑ IL-17 staining

No Mandible > maxilla, rarely ribs

Occurs in various backgrounds Not assessed Vertebrae, hind feet > forefeet

Pstpip2 PSTPIP2 (MAYP) Macrophage proliferation, macrophage recruitment to sites of inflammation, cytoskeletal function

CRMO, Chronic recurrent multifocal osteomyelitis; HSM, hepatosplenomegaly; IBD, inflammatory bowel disease; IL, interleukin; MCSF, macrophage colony-stimulating factor; MIP, macrophage inflammatory protein; PPP, palmoplantar pustulosis; RANTES, regulated on activation, normal T cell expressed and secreted; TGF, transforming growth factor; TNF, tumor necrosis factor; ↑, increase.

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SECTION FIVE  Arthritis Related to Infection

I

III

II

IV

FIGURE 48-10  Radiographic resolution of distal femur lesion in a girl with CRMO over a 5-year time span. In 2002, there is an osteolytic lesion with surrounding sclerosis adjacent to the growth plate in the left distal femoral metaphysis (I). Minimal change is seen in the lesion 1 year later (2003; II ). In 2004, the lesion begins to heal with significant sclerosis (III ). In 2007, the lesion is nearly completely healed and the bone mineral density is nearly normal (IV).

CHAPTER 48  Autoinflammatory Bone Disorders

637

A Delayed

R

B

C

FIGURE 48-11  CRMO and dyserythropoietic anemia in Majeed syndrome. A, Affected male with contractures and failure to thrive. B, Technetium (Tc-99m) bone scan of a female with Majeed syndrome demonstrating increased radiotracer uptake in the metaphyses of the long bones of the lower extremities consistent with osteomyelitis. C, Dyserythropoiesis with multiple bi-nucleated erythrocyte precursors in the bone marrow from a child with Majeed syndrome.

include leukocytosis, thrombocytosis, and a raised erythrocyte sedimentation rate.19,41,68,170 Despite the evidence that the protein LIPIN2 is involved in fat metabolism, no lipid abnormalities have been reported in children with Majeed syndrome.41 Cutaneous manifestations include a neutrophilic dermatosis consistent with Sweet syndrome in two affected individuals.19 Interestingly, several of the carrier parents have psoriasis, which suggests that LIPIN2 may play a role susceptibility to psoriasis.7 Treatment with corticosteroids results in only partial clinical improvement in the inflammatory bone and skin disease; anemia is less responsive to treatment. However, undesirable long-term steroidinduced side effects limit their long-term usefulness.19,41 Nonsteroidal antiinflammatory medications provide some degree of pain relief but do not produce disease control.68 Colchicine was tried in three individuals without significant clinical improvement.19 Permanent joint contractures and growth disturbance have been reported after years of chronic inflammation (Fig 48-11).68 However, Herlin et al. recently reported prompt and sustained improvement in two brothers treated with anakinra who flared upon its discontinuation, followed

by rapid improvement when treated with the IL-1β blocking agent canakinumab.170 Both boys had previously failed to respond to TNF-α inhibition. This suggests that Majeed syndrome is an IL-1β (not IL-1α) driven disease. The role of LIPIN 2 in inflammation of the bone and skin remains ill defined. All three members of the LPIN gene family act as phosphatidate phosphatases (PAP) and can act as transcription regulators.173-177 Rue et al. demonstrated in vitro that one of the Majeed syndrome– causing mutations, p.Ser734Leu (S734L), abolishes the PAP activity of LIPIN2,178 suggesting that the inflammatory phenotype may result from the loss of PAP activity. Valdearcos et al. found that in a cell line, under expression of LPIN2 resulted in increased production of proinflammatory cytokines when exposed to excessive quantities of saturated fatty acid (palmitic acid), and overexpression of LPIN2 in this setting was associated with lower levels of proinflammatory cytokines.179 This suggests that LIPIN2 plays a role in the immune response to saturated fatty acids. Yet, how aberrant function in these lipid pathways genes causes autoinflammatory disease of the bone remains unknown.180 LIPIN2 may play a role in responses to oxidative

638

SECTION FIVE  Arthritis Related to Infection

stress because it is highly upregulated in animal models of tissue damage, including paraquat-induced pulmonary injury and 2,3,7,8tetrachlorodibenzo-p-dioxin induced liver injury.181,182 Ned1 is an LPIN ortholog that when mutated in yeast Schizosaccharomyces pombe results in aberrantly shaped nuclei.183 This suggests that LIPIN2 may be involved in mitosis as there are frequent bi- and tri-nucleated pronormoblasts in the bone marrow of children with Majeed syndrome.184

Deficiency of the Interleukin-1 Receptor Antagonist Deficiency of the interleukin-1 receptor antagonist (DIRA) (OMIM reference #612852) is an autosomal recessive autoinflammatory disorder that is cause by mutations in IL1RN that encodes the interleukin-1 receptor antagonist [IL-1Ra].38,39 Affected individuals do not produce functional IL-1Ra, resulting in marked dysregulation of IL-1 pathway signaling.38,185 DIRA presents in infancy (usually within the first few weeks of life) with pustular rash, sterile osteitis, and periostitis, typically in the absence of fever.38,39 Half of the infants have been born near-term premature (31 to 36 weeks’ gestation).38,39,186,187 Respiratory problems (respiratory distress, apnea, or aspiration pneumonia) were present in half of the infants shortly after birth.38,39,185,186,188,189 Hepatomegaly was reported in five of the nine infants in one study.38 All infants had elevated inflammatory markers including white blood cell counts in the 20,000 to 60,000 cells/mm3 range, erythrocyte sedimentation rates up to 115 mm/hr, thrombocytosis ranging from 500,000 to 1,000,000 platelets/mm3 and C-reactive protein levels up to 30 mg/dl.38,39,185-188,190,191 The majority of affected infants received prolonged courses of antibiotics for presumed sepsis without clinical improvement.38,39,185,186,188-190 Clinical improvement was noted in most (but not all) when treated with sizeable doses of corticosteroids.38,39,185,188-190 Inflammation of the skin has been present in 95% of the affected infants and varies in severity from a few clusters of pustules to severe wide-spread generalized pustulosis to ichthyosiform lesions; pustules were only present transiently in one child.38,39,185-191 Histologically, involved skin displays a predominantly neutrophilic infiltration of the epidermis and dermis, acanthosis, hyperkeratosis, parakeratosis and subcorneal pustule formation.38,39,185,187,189 Cultures of the skin lesions are generally negative; however, two infants had positive cultures from pustules, one methicillin-resistant Staphylococcus aureus cultured on one occasion39 and the other coagulase-negative Staphylococcus.188 Other reported mucocutaneous manifestations included pathergy, oral ulcers, and pyoderma gangrenosum.38,185 Nail abnormalities (nail pits, onychomadesis, nail shedding, and anonychia) have been reported in nearly half of the children.38,187,190,191 There may be no objective evidence of osteitis on examination but the infant may appear to be in pain with movement. Only 33% of infants had objective swelling on musculoskeletal examination.186,188,190 Marked radiologic abnormalities were present in all affected children. Common findings included multifocal osteolytic lesions, marked periostitis, widening of the medial clavicle, and flaring of the anterior rib ends (Fig. 48-12).38,39 Multifocal osteolytic lesions involving the long bones were present in most affected children.38,39,185-187,190,191 Involvement of the vertebrae occurred in approximately 25% of children, resulting in vertebral collapse, gibbus deformity, nonunion of the odontoid, C1-C2 instability, and vertebral fusion.38,185,187 Bone biopsies reveal neutrophilic infiltration with bone destruction, fibrosis, sclerosis, reactive new bone formation, and scattered osteoclasts.38,39,185 Cultures of the bone were negative for anaerobes, aerobes, fungi, and acid-fast bacilli in all biopsies tested.38,39,185 Pulmonary involvement occurs in approximately 50% of infants, most often transient respiratory distress in the perinatal period. How­ ever, life-threatening lung disease has been reported in four patients

FIGURE 48-12  Chest radiograph in a patient with DIRA. Male infant with multiple bony abnormalities including expansion of the medial clavicles R > L (long arrow ) and widening of the anterior rib ends (small arrows). Patchy opacifications are seen in the lung fields. This child developed interstitial lung disease. (Courtesy Dr. P. Babyn.)

including interstitial lung disease in two infants (pulmonary fibrosis found at autopsy in one and classic computed tomography findings of ground-glass opacities in the other)38,39 and systemic inflammatory response syndrome (SIRS) requiring mechanical ventilation in two others (one of whom died of respiratory failure).186,189 Venous thrombosis, either spontaneous or associated with a indwelling catheter, have been reported in four cases.39,185,188,191 Less common complications include CNS vasculitis, cardiomyopathy, marked abdominal distension with caput medusa, conjunctival injection, hypotonia, and developmental delay.38,191 Failure to thrive is reported in one third of patients.38,185,187,190,191 Antibiotics are ineffective in DIRA and most, but not all, children improved when treated with high doses (2 mg/kg/day) of cortico­ steroids.38,39,185,188,191 Prior to the discovery that children with DIRA were deficient in the interleukin-1 receptor antagonist, several steroidsparing agents were utilized unsuccessfully, including nonsteroidal antiinflammatory drugs, intravenous gamma globulin, metho­ trexate, cyclosporine, azathioprine, etanercept, thalidomide, and interferon-γ.38,190 An empiric trial of anakinra in one child led to dramatic and rapid disease improvement, and it was this observation that led investigators to sequence IL-1 pathway genes leading to the discovery of gene defect.38 Mononuclear cells from DIRA patients produce high levels of inflammatory cytokines (including MIP-1α, TNF-α, IL-8 and IL-6) in vitro.38,39,185 Left untreated, the unopposed action of IL-1 results in life-threatening systemic inflammation that predominately affects skin and bone.38 Treatment with anakinra results in prompt and dramatic improvement within days of the initiation of treatment.38,39,187-191 There is limited information about long-term outcome in this condition given that it was unrecognized as a distinct clinical entity until its description in 2009. The disease is potentially fatal with a 33% mortality rate including the siblings of reported mutation-positive cases(38, 186, 190, 191). Most deaths occurred in the first 2 years of

CHAPTER 48  Autoinflammatory Bone Disorders life and were attributed to multisystem failure due to SIRS.38,186 One child lived until he was 9.5 years of age; he was treated with corticosteroids, methotrexate, and cyclosporin but ultimately died of respiratory failure secondary to chronic interstitial lung disease.38 Permanent skeletal deformities and failure to thrive occurred in several of the children prior to initiation of anakinra.38,191 Allergic reaction to anakinra may occur in those who have complete deficiency of the protein and desensitization therapy may allow continued treatment; alternatively, other IL-1 blocking agents may be utilized. Outcomes should improve significantly with early recognition accompanied by prompt initiation of appropriate treatment. Once the diagnosis of DIRA is made, genetic counseling should be offered to each family so that they understand the recurrence risk. When genetic testing for IL1RN mutations is commercially available, determination of carrier status and prenatal diagnosis (if desired) would be options for family members of affected individuals.

Cherubism Cherubism is an autosomal dominant autoinflammatory disorder (OMIM reference #118400) that is almost exclusively confined to the jaw.192-196 The disorder was described by Jones in 1933. Most children present between 2 and 7 years of age with symmetric, progressive, nontender bony enlargement of the jaw without associated systemic symptoms.192,194,195,197,198 The expansion of the mandible and maxilla causes a chubby cheeked appearance and an upward gaze; features that Jones felt were thought to be reminiscent of paintings of cherubs in Renaissance art.198,199 The jaw hypertrophy is disfiguring and associated with significant dental problems, including malocclusion and loss of dentition with secondary difficulty with mastication in severely affected individuals.198,199 The bony enlargement of the jaw begins to slowly regress after the onset of puberty.198 Regression may be accompanied by marked sclerosis, which may never fully resolve. Lymphadenopathy may be present during the active phase of the disease.198 Extra gnathic bone involvement is rare, but there are reports of lesions in the ribs, humerus, femur, and tibia.198,200,201 Radiographs reveal large multilocular, cystic appearing lesions predominately affecting the mandible with less severe involvement of the maxilla.198,199,202-204 The lesions may appear osteolytic or radiopaque with a coarse trabecular pattern associated with thinning of the cortices.202,203 Computerized tomography reveals osseous expansile lesions, cortical scalloping, dental derangement, and many show secondary maxillary sinus disease.198,205,206 MRI examination reveals extensive homogeneous isointense (to skeletal muscle) lesions on T1 images and hypointense on fast spin-echo T2-weighted images with fat suppression.206 Histologically, there are abundant osteoclasts interspersed throughout dense fibrostromal connective tissue without accompanying features of osteomyelitis.197,207,208 There have been no effective medical or surgical treatments. A gene defect was identified in 2001, when heterozygous mutations in the SH3 binding protein-2 (SH3BP2) were discovered in affected individuals from 12 affected families.192 Mutations in SH3BP2 account for the vast majority of gene defects found in individuals with cherubism; however, mutations in PTPN11 can also result in a cherubism phenotype.209 To further understand the pathophysiology of cherubism, Ueki et al. created a murine cherubism model by knocking in the most common human SH3BP2 mutation.210 One copy of the knockin allele resulted in a surprisingly normal mouse.210 However, mice homozygous for the knockin allele (double knockin) had widespread bone disease with osteoclast-rich inflammatory jaw lesions, systemic myeloid inflammation, and extensive trabecular bone loss throughout the remainder of the skeleton.210 The inflammatory phenotype in cherubism mice occurs independent of a functioning

639

adaptive immune system, is dependent on the presence of TNF-α, and is mediated by hematopoietically derived myeloid cells.210 Cherubism mutations have been found to abolish the recognition of SH3BP2 by tankyrase, an enzyme that normally targets SH3BP2 for ubiquitylation and subsequent degradation.211-213 This results in increased stability of mutant SH3BP2 with enhanced activation of SCR, SYK, and VAV pathways, with resultant hyperactivation of osteoclasts.211,213 These suggest that TNF-α and or SRC inhibition might prove to be an effective therapy for this disfiguring disease.214 However, a recent report of two children treated with the TNF-α antagonist adalimumab did not prevent lesion expansion in active cherubism.215

SUMMARY Sterile bone inflammation is the cardinal feature of the autoinflammatory bone disorders. Many affected individuals also have a chronic inflammatory condition of the skin or intestinal tract, suggesting common immunologic pathways are involved in CRMO, psoriasis, and inflammatory bowel disease. A genetic defect has been found in two syndromic forms of CRMO and in a mouse model of the disease. The information learned from these single gene disorders implicates the innate immune system in the pathogenesis of CRMO and related disorders.

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CHAPTER 48  Autoinflammatory Bone Disorders 187. K. Minkis, I. Aksentijevich, R. Goldbach-Mansky, et al., Interleukin 1 receptor antagonist deficiency presenting as infantile pustulosis mimicking infantile pustular psoriasis, Arch. Dermatol. 148 (6) (2012) 747– 752. 188. M. Stenerson, K. Dufendach, I. Aksentijevich, et al., The first reported case of compound heterozygous IL1RN mutations causing deficiency of the interleukin-1 receptor antagonist, Arthritis Rheum. 63 (12) (2011) 4018–4022.

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189. C. Schnellbacher, G. Ciocca, R. Menendez, et al., Deficiency of interleukin-1 receptor antagonist responsive to anakinra, Pediatr. Dermatol. 30 (6) (2013) 758–760. PubMed PMID: 22471702. 190. W. Sakran, S.A. Shalev, H. El-Shanti, Y. Uziel, Chronic recurrent multifocal osteomyelitis and deficiency of interleukin-1-receptor antagonist, Pediatr. Infect. Dis. J. 32 (1) (2013) 94.

Entire reference list is available online at www.expertconsult.com.

CHAPTER 48  Autoinflammatory Bone Disorders

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