Sternocostal involvement in chronic recurrent multifocal osteomyelitis associated with ulcerative colitis

Chronic recurrent multifocal osteomyelitis (CRMO) is a chronic, relapsing, inflammatory, non-infectious disorder of the skeletal system and is of unknown origin. Early diagnosis of the disease is essential to exact treatment. The relationship between inflammatory bowel disease and CRMO is understood as extraintestinal rheumatic manifestations. CRMO associated with ulcerative colitis (UC) is very rarely reported. This case is first report of sternocostal involvement in CRMO associated with UC.     

Chronic Recurrent Multifocal Osteomyelitis Associated with Chronic Inflammatory Bowel Disease in Children

Chronic recurrent multifocal osteomyelitis(CRMO) is a rare disease of children characterized byaseptic inflammation of the long bones and clavicles. Noinfectious etiology has been identified, and CRMO has been associated with a number of autoimmunediseases (including Wegener's granulomatosis andpsoriasis). The relationship between CRMO andinflammatory bowel disease is poorly described. Throughan internet bulletin board subscribed to by 500pediatric gastroenterologists, we identified sixinflammatory bowel disease patients (two with ulcerativecolitis, four with Crohn's colitis) with confirmed CRMO. In all cases, onset of the bony lesionspreceded the onset of bowel symptoms by as much as fiveyears. Immunosuppressive therapy for the bowel diseasegenerally resulted in improvement of the bone inflammation. Chronic recurrrent multifocalosteomyelitis should be considered in any inflammatorybowel disease patient with unexplained bone pain orareas of uptake on bone scan. CRMO may be a rareextraintestinal manifestation of inflammatory bowel disease;alternatively, certain individuals may be geneticallypredisposed to the development of bothdiseases.     

Das SAPHO-Syndrom: Klinisch-rheumatologische und radiologische Differenzierung und Klassifizierung eines Krankengutes von 86 Fällen

Synovitis (inflammatory arthritis), acne (pustulosa), pustulosis (psoriasis, palmoplantar pustulosis), hyperostosis (acquired), and ostitis (bland osteomyelitis) are symptoms forming the acronym SAPHO, which is a syndrome of nosologic heterogeneity. All entities forming the SAPHO syndrome are connected by a non-obligate dermatoskeletal association with an aseptic pustulous character. 86 cases were analyzed clinically, radiologically and by histology/histopathology. 31 adult patients showed the typical triad of pustulosis palmo-plantaris (psoriatica, PPP), sterno-costo-clavicular hyperostosis (SCCH), and "productive" spondylopathy, which we define as entity I. spondarthritis hyperostotica pustulopsoriatica (Spond.hyp.pp). Twelve adolescent and 13 adult patients showed entity no. II: chronic recurrent multifocal osteomyelitis (CRMO), being characterized by non-purulent osteomyelitis of plasma-cell sclerotic type, potentially being a reactive inflammatory process. 50% of the adult patients with CRMO showed PPP. Differentiation between these two entities is possible by detection of ossifying enthesiopathy in cases of Spond. hyp.pp and primarily chronic osteomyelitis in cases of CRMO. Two more entities or abortive forms of group I and II are III: the inflammatory syndrome of the anterior chest-wall (ACW syndrome) and IV: the more productive form of isolated sterno-costoclavicular hyperostosis (SCCH). Both are connected quite frequently to HLA-B-27-independent forms of spondarthritis and to pustulous dermatosis. More rarely we find osteo-articular symptoms in cases of acne pustulosa, which form group V: acne-associated spondarthritis and CRMO in the case of acne. Adult forms of CRMO with different forms of appearance (lumosacro-iliac hyperostosis with retroperitobeal fibrosis, pelvic type with affection of the hip-joint) are described. The immunologic theory of a "reactive osteomyelitis" potentially triggered by saprophytes is described. The inverse acne triad is brought in a context of skin symptoms. A case of intercurrent postpartum symptoms together with ulcerative colitis is described. Three cases of patients with Crohn's disease are described. Clinical features, radiological findings, and histopathological elements are brought together to determine the connections between the different entities and the possibilities of differentiation. With these elements together with bone-scan, it is often not necessary to obtain a bone specimen. Therapeutical possibilities, especially concerning CRMO, are discussed. "SAPHO syndrome" is more a sign-post on the way to a more subtle diagnosis when it comes to hyperostotic, skin-associated diseases, and it needs interdisciplinary work to clear the situation.     

Serum biomarkers for the diagnosis and monitoring of chronic recurrent multifocal osteomyelitis (CRMO)

Chronic recurrent multifocal osteomyelitis (CRMO), the most severe form of chronic nonbacterial osteomyelitis, is an autoinflammatory bone disorder. A timely diagnosis and treatment initiation is complicated by the absence of widely accepted diagnostic criteria and an incomplete pathophysiological understanding. The aim of this study was to determine biomarkers for the diagnosis and follow-up of CRMO. Serum of 56 CRMO patients was collected at the time of diagnosis. As controls, sera from treatment-naïve age-matched patients with Crohn’s disease (N = 62) or JIA (N = 28) as well as healthy individuals (N = 62) were collected. Multiplex analysis of 25 inflammation markers was performed. Statistical analysis was performed using Kruskal–Wallis and Mann–Whitney U tests, canonical discriminant analysis, and mixed model variance analysis. Mostly monocyte-derived serum proteins were detectable and differed significantly between groups: IL-1RA, IL-2R, IL-6, IL-12, eotaxin, MCP-1, MIP-1b, RANTES. Multicomponent discriminant analysis allowed for the definition of algorithms differentiating between CRMO, Crohn’s disease, and healthy controls. Persistently high levels of MCP-1, IL-12, sIL-2R correlated with incomplete remission in follow-up samples from CRMO patients. Discrimination algorithms allow differentiation between patients with CRMO or Crohn’s disease, and healthy individuals. IL-12, MCP-1, and sIL-2R can act as markers for treatment response. Though confirmation of our findings in larger multiethnical cohorts is warranted, they may prove valuable to differentiate between otherwise healthy individuals or Crohn’s disease patients with “bone pain” and CRMO patients. The elevation of mainly monocyte-derived pro-inflammatory serum proteins supports the hypothesis of pro-inflammatory monocyte/macrophages driving inflammation in CRMO.     

Pamidronate treatment of chronic noninfectious inflammatory lesions of the mandible in children

Noninfectious inflammatory lesions of the mandible occur in chronic recurrent multifocal osteomyelitis (CRMO). Diffuse sclerosing osteomyelitis of the mandible (DSOM) is a condition thought to be a localized form of CRMO. Recently, bisphosphonate therapy, and particularly intravenous pamidronate, has been proposed as a treatment for patients with both CRMO and DSOM who do not improve with nonsteroidal antiinflammatory drug treatment. We report our experience using pamidronate in 2 children with chronic noninfectious osteomyelitis affecting the mandible. We describe the clinical and radiographic features and the treatment, side effects, and clinical and radiographic responses. Our experience suggests that pamidronate is an effective second-line therapy.     

Osteomielitis de pie diabético: ¿es posible un manejo conservador?

Introduction

The aim of the present study is to determine the proportion of foot ulcers, complicated by osteomyelitis in diabetic patients, that heal without amputation. Furthermore, an attempt is made to analyze the main clinical and microbiological characteristics of episodes, and to identify potential predictive factors leading to the failure of conservative treatment.

Methods

A prospective observational study was carried out between 2007 and 2009 on diabetic patients with a foot lesion and attending a diabetic foot clinic. A percutaneous bone biopsy was required to be included in the study.

Results

A total of 81 episodes of diabetic foot osteomyelitis in 64 patients were evaluated. Staphylococcus aureus (28/81) and coagulase negative Staphylococcus (22/81) were the most frequent organisms isolated. Among the gramnegative group (34/81), non-fermenting gram negative bacteria were the most prevalent organisms isolated (14/81). Conservative treatment was successful in 73% of episodes. After a logistic regression analysis using the most significant prognostic variables, only lesion size greater than 2 cm independently predicted failure of conservative treatment. Culture guided antibiotic treatment was associated with a better prognosis.

Conclusion

Conservative treatment, including culture-guided antibiotics, is successful without amputation in a large proportion of diabetic patients with diabetic foot osteomyelitis. Considering empiric therapy directed at non-fermenting gramnegative bacteria could be advisable in some cases, because they are frequently isolated in our setting.     

Azithromycin: Eine anti-inflammatorische Wirksamkeit im Einsatz bei der chronischen rekurrierenden multifokalen Osteomyelitis? Eine vorläufige Mitteilung

In this preliminary communication we report our experience with Azithromycin in patients with Chronic Recurring Multifocal Osteomyelitis (CRMO). Seven out of 13 patients, mainly teenager, showed a fast clinical improvement after they were started on Azithromycin. The immediate therapeutic effect of Azithromycin in patients with CRMO was surprising and lead us to the hypothesis that Azithromycin could have an antiphlogistic in addition to it's antibiotic effect in this disease setting. In patients with reactive chronic pelvic osteomyelitis Azithromycin obviously had a direct influence on the sympathic coxitis. Half of the patients reported an immediate reduction of pain and a significant improvement in range of movement after they were started on Azithromycin. In all cases the clinical and radiographic signs on MRI showed a reduction of the inflammatory process. Experimental animal models have recently shown that macrolids have independent additional antiinflammatory and immunomodulatory effects. The assumed local immunomodulatory effect of Azithromycin potentially is an additional activity to the already known synergistic antimicrobial and antiinflammatory effect. Right now we are in the process of collecting data from patients with SAPHO Syndrome who underwent bone-biopsies for microbiologic and histomorphologic investigations. All patients with the growth of propionibacterium acnes were started on a long-term antibiotic therapy with Azithromycin. This study will possibly help to answer the question of the additional antiphogistic/immunomodulatory effect of Azithromycin in this disease entity and the related CRMO.     

Chronic non-bacterial osteomyelitis in children

BACKGROUND: Chronic recurrent multifocal osteomyelitis (CRMO) in children is a chronic non-suppurative inflammation involving multiple sites. Some children affected by chronic non-bacterial osteomyelitis (CNO) do not have multiple lesions or a recurrent course. OBJECTIVE: To characterise the long term outcome of children with the full spectrum of CNO. METHODS: 30 children diagnosed with CNO were followed up for a mean of 5.6 years and their disease assessed using a clinical score, multiple imaging, and a diagnostic biopsy, including extensive microbial analysis. RESULTS: 9 patients had unifocal non-relapsing disease, 3 unifocal lesions with relapses, 9 multifocal lesions without relapses, and 9 multifocal lesions with relapses (CRMO). Granulocytes were present significantly more often in CRMO than in unifocal and non-recurrent lesions. Pustulosis was more common in multifocal cases regardless of recurrence. Mean duration of treatment in 15 children with a single occurrence was 9.2 months. Naproxen treatment was generally effective. Naproxen treatment in 12 patients with relapses lasted 25 months. However, 7 of these were not effectively treated with naproxen alone. Five were treated with oral glucocorticoids for 27 days in addition to naproxen, which induced remission in four, lasting for at least 1.5 years. Longitudinal growth of affected bones was not altered, except for the development of hyperostosis. CONCLUSION: CNO is a spectrum of inflammatory conditions, with CRMO being the most severe. Most children with CNO have a favourable outcome of the disease. Oral glucocorticoids may be necessary in severe recurrent cases.     

Childhood chronic recurrent multifocal osteomyelitis: pamidronate therapy decreases pain and improves vertebral shape

OBJECTIVE: Chronic relapsing multifocal osteomyelitis (CRMO) results in significant morbidity, especially in those with vertebral collapse. Symptomatic benefit with intravenous pamidronate (PAM) has been shown; however, few studies have demonstrated radiological benefit. We describe clinical and radiological data on 7 pediatric cases of CRMO treated with PAM. METHODS: Retrospective chart review on all children with CRMO treated with PAM. Response to PAM was measured by subjective reports and radiology including vertebral morphometry. RESULTS: Seven patients (1 male) presented with bone pain at a median age of 8 years (range 5-14). Symptoms had been present for a median of 18 months (range 11-51) before PAM therapy. All patients had involvement of multiple nonspinal sites, 5 children had spinal involvement with vertebral fractures, and 5 had joint involvement. Six cases had symptomatic improvement within 6 months of starting PAM, which was sustained during PAM therapy (median 26 mo, range 6-41) and persisted in the 4 cases who had ceased treatment for the duration of followup (27 mo, range 18-51). The least benefit was seen in the 3 cases with synovial joint involvement. The 3 cases with spinal radiological followup showed modeling of vertebral fractures and in one patient improvement in kyphosis. No radiological improvement in nonspinal lesions was seen. CONCLUSION: PAM therapy was associated with symptomatic improvement and vertebral modeling in children with CRMO. We suggest that children with bone pain and/or spinal involvement be considered for PAM therapy early after diagnosis.     

Die chronische rekurrierende multifokale Osteomyelitis in Assoziation mit chronisch entzündlichen Darmerkrankungen: Die enteropathische CRMO

The enterogenic reactive arthritides and entheropathic spondyloarthropathies are well-known entities. The so-called gut iteropathy concept offers an interesting working hypothesis to link the gut inflammation and the lymphocytic infiltration of the synovium. However, the association of rheumatic diseases belonging to the entity of the SAPHO syndrome with inflammatory bowel diseases (IBD) has only been rarely described in the literature. Among 138 cases of our (heterogenic) SAPHO cohort, we detected 5 patients (1 male, 4 females) with a proven association of SAPHO syndrome with IBD (in 4 cases Crohn's disease, in 1 case ulcerative colitis). Two patients belonged to the juvenileadolescent form and 3 to the adult form of SAPHO syndrome. In all cases the underlying osteoarticluar disease was classified as chronic recurrent multifocal osteomyelitis (CRMO), 2 of them presenting as inflammatory anterior chest wall syndrome. There was a strong association with psoriatic pustular dermatitis. Thus, we present 5 cases of "enteropathic CRMO" demonstrating several analogies to the enteropathic spondyloarthropathies. Both disease entities have in common i) metachronic development with osteoarticluar manifestations often preceding the gastrointestinal disease; ii) Crohn's like lesions that may develop from the stomach to the colon; iii) concomittent or intermittent skin pustulosis which mostly resolves; iiii) the gastrointestinal disease that often dominates the whole syndrome namely in the longterm follow-up. We suggest to transfer the hypothesis of the gut-synovium axis of enteropathic spondyloarthropathies to the entity of CRMO. This concept offers an opportunity to link the target organs gut mucosa, bone marrow and the skin via homing of antigen specific lymphocytes. This concept may help to better understand the pathogenesis of the "Skibo" (i. e., skin-bone) disease CRMO.     

Synovitis,acne, pustulosis,hyperostosis, osteitis (SAPHO), and chronic recurrent multifocal osteomyelitis (CRMO): A tale of two cases

BackgroundSAPHO (Synovitis Acne Pustulosis Hyperostosis Osteitis) and CRMO (Chronic Recurrent Multifocal Osteomyelitis) are chronic relapsing osteoarticular disorders with common dermatological manifestations.Aim of the workTo describe a case of SAPHO in an adult and CRMO in a child.Cases presentationCase 1: A 32-year old man presented with dull aching low back pain for 2 years with morning pain/stiffness. On examination there were acneform lesions on the face, tenderness over thoracic spine and swelling of left sternoclavicular joint. Plain x-rays showed sclerosis/widening/irregularity of sternoclavicular joint, sclerosis/irregularity of endplate, loss of disc space with syndesmophytes in mid/lower dorsal spine (D6-11) and sclerosis in middle of left tibia. Magnetic resonance imaging (MRI) spine showed cortical erosions and marrow edema (D6-L1) with findings suggestive of aseptic/inflammatory spondylodiscitis. A bone scan showed increased uptake D7-D12 and mid-third tibia (hyperostosis). Biopsy from D6/D7 showed normal histopathology. Case 2: A 10-year-old girl presented with pain/swelling of right foot for 2 months, pain/swelling of left shoulder and sternoclavicular joint with pustular acne on the face. There was swelling/tenderness over right 5th metatarsal base and left sternoclavicular joint as well as tenderness over proximal humerus. ESR was 65 mm/1^sthr. Plain x-rays showed punched-out lytic lesions surrounded by sclerosis in metatarsal base and metaphysis of humerus. Patient was diagnosed as CRMO.ConclusionSAPHO and CRMO are rare and their diagnosis is sometimes not easy. SAPHO can present as aseptic spondylodiscitis. Both conditions can be diagnosed with clinical and radiological features. A biopsy is necessary for ruling out other conditions.     

Evolution of chronic recurrent multifocal osteitis toward spondylarthropathy over the long term

OBJECTIVE: To retrospectively assess, with a sufficiently long followup (mean 11.6 years; median 9 years), the long-term outcome of chronic recurrent multifocal osteitis (CRMO), a multifocal, inflammatory bone disease. METHODS: Patients included were 8 children/adolescents and 7 adults with no family history of rheumatic disease who had been diagnosed as having CRMO between 1979 and 1995. Ten patients had undergone at least 1 bone biopsy of the lesions, with histologic examination and multiple cultures. In 1996, in addition to an in-depth interview, 12 patients underwent an extensive physical examination, laboratory evaluation, HLA-A, B, C, and DR typing, bone radiography and scintigraphy, and computed tomography scan of the sternoclavicular and sacroiliac joints. RESULTS: Remission was observed in 3 patients. The other 12 patients developed various associations of vertebral (n = 10), sacroiliac (n = 6), anterior thoracic (n = 7), peripheral articular (n = 2), enthesopathic (n = 4), or dermatologic (palmoplantar pustulosis in 3 cases and psoriasis in 2) involvements. Spine involvement was the most common and occurred the earliest (median time to appearance after the onset of osteitis 5.63 years). Clinical sacroiliitis was always unilateral. No patients carried the HLA-B27 haplotype. CRMO responded well to nonsteroidal antiinflammatory drugs. Twelve patients met the European Spondylarthropathy Study Group criteria for spondylarthopathy. CONCLUSION: After 10 years, CRMO had usually evolved to spondylarthropathy, but with certain features not usually seen in the latter: predominantly, unilateral sacroiliitis, no familial form, and no link with HLA-B27.     

Chronic recurrent multifocal osteomyelitis and psoriasis—A report of a new association and review of related disorders

In summary, we have described two patients with CRMO and psoriasis, and have reviewed the musculoskeletal manifestations associated with pustular eruptions of the palms and soles. In view of the frequent occurrence of PPP in patients with CRMO, we suggest that the occurrence of psoriasis in our two patients is more than coincidence, and that noninfectious, inflammatory lesions of bone may be another musculoskeletal manifestation of psoriasis. This rare association, as well as the association of PPP with disorders associated with new bone formation, may shed new insights on the relatively common finding of periosteal elevation associated with psoriatic arthritis and the occasional severe juxta-articular osteolytic destructive bone lesions seen in psoriatic arthritis.     

Current Understanding of the Pathogenesis and Management of Chronic Recurrent Multifocal Osteomyelitis

Chronic recurrent multifocal osteomyelitis (CRMO) is an inflammatory disorder that primarily affects children. Its hallmark is recurring episodes of sterile osteomyelitis. The clinical presentation is insidious onset of bone pain with or without fever. Laboratory studies typically reveal nonspecific evidence of inflammation. Radiologic imaging and histologic appearance resemble those of infectious osteomyelitis. There is a strong association with inflammatory disorders of the skin and intestinal tract in affected individuals and their close relatives, suggesting a shared pathophysiology and supporting a genetic component to disease susceptibility. Two genetic syndromes have CRMO as a prominent phenotype—Majeed syndrome and deficiency of the interleukin-1 receptor antagonist—and suggest that interleukin-1 may be a key cytokine in disease pathogenesis. This review briefly summarizes the main clinical and radiologic aspects of the disease and then focuses on genetics and pathophysiology and provides an update on treatment.     

Chronic recurrent multifocal osteomyelitis: a case report

Chronic recurrent multifocal osteomyelitis (CRMO) is a recognized condition that usually affects children and adolescents. It's characterized by insidious onset of local swelling and pain in affected bones. Clinical, biological and especially radiological abnormalities are suggestive of septic osteomyelitis, so the diagnosis is delayed. Bone biopsy with culture is certainly necessary to rule out bacterial osteomyelitis and bone tumor. Authors report the case of a 27-years old man in whom the diagnosis of CRMO was done after 14 years course.     

Association of chronic non-bacterial osteomyelitis with Crohn’s disease but not with CARD15 gene variants

Chronic non-bacterial osteomyelitis (CNO) is an inflammatory, non-infectious disorder of the skeletal system with unknown etiology. Besides bone-inflammation, patients may present with inflammatory involvement of other tissues. Chronic recurrent multifocal osteomyelitis (CRMO) is the most severe form of CNO. We describe the occurrence of Crohn’s disease (CD) in four patients, previously diagnosed with CRMO. Mutations in CARD15, encoding the NOD2 protein, have recently been found in patients with CD. Based on the occurence of CNO and CD in these four and several reported patients, we hypothesized that CD and CRMO might share a common autoinflammatory process. Thus, we searched for CD associated CARD15 gene variants R702W, G908R and 1007fs in 29 CNO patients, 4 of them additionally diagnosed with CD. In the latter one out of the four showed compound heterozygosity for the gene variants R702W and 1007fs. The allele frequency in the 25 patients diagnosed with CNO but not CD was not different from that already reported in healthy people (R702W 4.0%, G908R 2.0%, 1007fs 2.0%). The occurrence of non-bacterial bone inflammation and granulomatous intestinal inflammation seems to represent an extended phenotype of CD, which partly might be explained by potential disease causing mutations in CARD15. However, CNO without intestinal inflammation is not associated with common CARD15 gene variants. Therefore, other variants of genes coding for proteins involved in innate immunity and inflammation might predispose for the occurrence of CNO.     

Inflammasome-independent IL-1β mediates autoinflammatory disease in Pstpip2-deficient mice

Chronic recurrent multifocal osteomyelitis (CRMO) is a human autoinflammatory disorder that primarily affects bone. Missense mutation (L98P) of proline-serine-threonine phosphatase-interacting protein 2 (Pstpip2) in mice leads to a disease that is phenotypically similar to CRMO called chronic multifocal osteomyelitis (cmo). Here we show that deficiency of IL-1RI in cmo mice resulted in a significant reduction in the time to onset of disease as well as the degree of bone pathology. Additionally, the proinflammatory cytokine IL-1β, but not IL-1α, played a critical role in the pathology observed in cmo mice. In contrast, disease in cmo mice was found to be independent of the nucleotide-binding domain, leucine-rich repeat-containing family, pyrin domain-containing 3 (NLRP3) inflammasome as well as caspase-1. Neutrophils, but not bone marrow-derived macrophages, from cmo mice secreted increased IL-1β in response to ATP, silica, and Pseudomonas aeruginosa compared with neutrophils from WT mice. This aberrant neutrophil response was sensitive to inhibition by serine protease inhibitors. These results demonstrate an inflammasome-independent role for IL-1β in disease progression of cmo and implicate neutrophils and neutrophil serine proteases in disease pathogenesis. These data provide a rationale for directly targeting IL-1RI or IL-1β as a therapeutic strategy in CRMO.Chronic recurrent multifocal osteomyelitis (CRMO) is a sterile inflammatory disorder that affects children and presents with bone pain due to sterile osteomyelitis (1). The etiology of the disease is unknown, but it is associated with Crohn disease, inflammatory arthritis, and psoriasis in affected individuals and their close relatives, suggesting a shared pathophysiology and supporting a genetic contribution to disease (2). There are two autosomal recessive disorders that present with neonatal- or infant-onset sterile osteitis that are histologically similar to the bone disease in CRMO and clinically improve with IL-1 blockade (3, 4). Majeed syndrome, caused by mutations in LPIN2, presents with CRMO, congenital dyserythropoietic anemia, and sterile neutrophilic dermatosis (5). Deficiency of the IL-1 receptor antagonist (DIRA) is caused by mutations in IL1RN, which encodes the IL-1 receptor antagonist (3), resulting in dysregulation of the IL-1 pathway. Affected individuals present with neonatal-onset cutaneous pustulosis, marked elevation of inflammatory markers, sterile multifocal osteitis, and periostitis (3).There are two autosomal recessive murine models of CRMO both due to mutations in proline-serine-threonine interacting protein 2 (Pstpip2) (6–8). The mutation (L98P) present in the chronic multifocal osteomyelitis (cmo) model results in no detectable expression of Pstpip2, a protein expressed predominantly in the cells of the myeloid lineage, and leads to disease that resembles human CRMO (6, 9). The development of osteomyelitis in the cmo mouse is hematopoietically driven and develops in the absence of lymphocytes, consistent with an autoinflammatory mechanism of disease (9). Although it is known that cmo mice have a dysregulated innate immune system, it is not clear what inflammatory pathway is critical for disease.Mutations within NLRP3 (also known as NALP3 or cryopyrin) are associated with the autoinflammatory Muckle-Wells syndrome, familial cold autoinflammatory syndrome, and neonatal-onset multisystem inflammatory disease, collectively known as cryopyrin-associated periodic syndrome (10). These NLRP3 mutations result in a constitutively active form of NLRP3 that leads to increased inflammasome activation with a resultant increase in secretion of IL-1β (10). A diverse array of agonists has been identified that are capable of activating NLRP3, which results in the assembly of the NLRP3 inflammasome composed of NLRP3, the adaptor molecule apoptosis-associated speck-like protein containing a CARD (ASC), and caspase-1 (11). The activation of the inflammasome leads to the activation of caspase-1, with the resultant processing of pro-IL-1β and pro-IL-18 to their mature and secreted forms (12). However, the role of the NLRP3 inflammasome in the pathogenesis of cmo remains unknown.Given the evidence that IL-1 is important in the pathogenesis of sterile bone inflammation in humans (3, 4), we investigated the role of IL-1 in the pathogenesis of sterile osteomyelitis in the cmo mouse. Here we demonstrate that deficiency of IL-1RI (interleukin-1 receptor type I) or IL-1β in cmo mice resulted in delayed onset of disease and an attenuation of disease severity. In contrast, disease progression in cmo mice was found to be independent of the NLRP3 inflammasome, and in vitro findings support a role for neutrophil serine proteases in the abnormally increased secretion of IL-1β. Taken together these data demonstrate an inflammasome-independent role for the IL-1 pathway in the disease pathogenesis of cmo.     

Consensus Treatment Plans for Chronic Nonbacterial Osteomyelitis Refractory to Nonsteroidal Antiinflammatory Drugs and/or With Active Spinal Lesions

Objective

To develop standardized treatment regimens for chronic nonbacterial osteomyelitis (CNO), also known as chronic recurrent multifocal osteomyelitis (CRMO), to enable comparative effectiveness treatment studies.

Methods

Virtual and face‐to‐face discussions and meetings were held within the CNO/CRMO subgroup of the Childhood Arthritis and Rheumatology Research Alliance (CARRA). A literature search was conducted, and CARRA membership was surveyed to evaluate available treatment data and identify current treatment practices. Nominal group technique was used to achieve consensus on treatment plans for CNO refractory to nonsteroidal antiinflammatory drug (NSAID) monotherapy and/or with active spinal lesions.

Results

Three consensus treatment plans (CTPs) were developed for the first 12 months of therapy for CNO patients refractory to NSAID monotherapy and/or with active spinal lesions. The 3 CTPs are methotrexate or sulfasalazine, tumor necrosis factor inhibitors with optional methotrexate, and bisphosphonates. Short courses of glucocorticoids and continuation of NSAIDs are permitted for all regimens. Consensus was achieved on these CTPs among CARRA members. Consensus was also reached on subject eligibility criteria, initial evaluations that should be conducted prior to the initiation of CTPs, and data items to collect to assess treatment response.

Conclusion

Three consensus treatment plans were developed for pediatric patients with CNO refractory to NSAIDs and/or with active spinal lesions. Use of these CTPs will provide additional information on efficacy and will generate meaningful data for comparative effectiveness research in CNO.