Chronic Recurrent Multifocal Osteomyelitis Patients Research Articles

Spine Involvement and Vertebral Deformity in Patients Diagnosed with Chronic Recurrent Multifocal Osteomyelitis.

Chronic recurrent multifocal osteomyelitis (CRMO) is an inflammatory disorder of bone, typically arising adjacent to the physes of long bones but also seen throughout the skeleton. For patients with spinal involvement, CRMO lesions can cause compression deformities with a range of severity from minimal anterior wedging to circumferential height loss, known as vertebra plana. This study examines a large cohort of CRMO patients to determine the prevalence of spine involvement and vertebral deformity. This is a retrospective review of all patients with a diagnosis of CRMO seen at our institution between January 2003 and December 2020. These patients were identified through a prospectively maintained database of all CRMO patients seen at the institution. A retrospective review was undertaken to identify all patients with spinal involvement and determine the prevalence of CRMO in the spine and its effects on vertebral height and deformity. Of 170 patients included in this study, 48 (28.2%) were found to have spinal involvement. Among patients with spinal involvement, vertebral body lesions were identified in 27 (56.3%) patients. The remaining lesions were in the sacrum or posterior elements. Radiographic evidence of the vertebral body height loss was noted in 23 of these 27 patients. This cohort of CRMO patients demonstrates that 28% of patients have spinal involvement, and 48% of those patients have vertebral body height loss. While the ideal treatment for spinal CRMO has yet to be determined, imaging studies, including whole-body MRI and spine-specific MRI, are useful in identifying vertebral lesions and deformities. Identification and surveillance of these lesions are important as the disorder has a relapsing and remitting course, and patients can develop significant vertebral body height loss. Once deformity has developed, we have seen no evidence of reconstitution of the height of the collapsed vertebra. Bisphosphonates have been successful in preventing the progression of vertebral body height loss. Level II: Retrospective study investigating spinal involvement and prevalence of vertebral body deformity in patients diagnosed with CRMO.

Chronic Osteomyelitis of Clavicle as a Primary Manifestation of CRMO in an Adolescent: A Case Report

Background: Chronic recurrent multifocal osteomyelitis (CRMO) is an auto-inflammatory bone disorder characterized by aseptic, mono- to multi-focal inflammation of the bones, yet its etiology remains undetermined. Diagnosis of CRMO is often challenging due to its overlapping signs and symptoms with other bone disorders, leading to potential long-term deformities. Increasing awareness of the various presentations of CRMO is crucial for timely diagnosis and management. Case presentation: A 14-year-old girl presented to our center with recurrent left clavicle pain, persisting for more than 3 years before referral. She had received multiple courses of analgesics. Physical examination revealed a hard, fixed mass in the medial third of the left clavicle, painless to palpation, with no inflammatory signs. MRI showed diffuse multiple hypo-signal lesions of the medial third of the left clavicle, blowing the bone cortex with infiltration of the soft tissues. Differential diagnoses were ruled out through bone biopsy, and laboratory tests. The patient responded favorably to treatment with Methotrexate, and Indomethacin, with no relapse observed during one year of follow-up. Conclusions: Uncommon presentations of CRMO can pose challenges in diagnosis, potentially leading to prolonged diagnostic processes. Increasing awareness among specialists regarding these presentations can facilitate earlier diagnosis and more effective treatment of CRMO patients.

Diagnostic Role of FDG PET/CT in Pediatric Patients With Chronic Recurrent Multifocal Osteomyelitis.

Chronic recurrent multifocal osteomyelitis (CRMO), or chronic nonbacterial osteomyelitis, is difficult to diagnose. The accurate diagnosis of CRMO relies on comprehensive imaging examinations because of its multifocal nature. In this regard, 18 F-FDG PET/CT has demonstrated significant utility in inflammatory diseases. This study tries to determine the value of FDG PET/CT in the evaluation of CRMO. We retrospectively collected imaging data from pediatric CRMO patients who underwent FDG PET/CT scans. Lesions exhibiting abnormal metabolism with/without structural abnormalities on FDG PET/CT were identified as CRMO lesions, and their location and SUV max were recorded. A total of 21 pediatric patients with CRMO were included in this study. The median age at diagnosis was 9.4 years. Total 131 foci of abnormal activity were identified using FDG PET/CT imaging. The distribution pattern showed a higher prevalence of lower limbs and pelvis involvement. Among all identified lesions, abnormalities were detected on both PET and CT images of 93 lesions, whereas exclusively positive findings on 18 F-FDG PET alone were observed for 38 of them. Our study findings suggest a higher prevalence of lesions in the bones of the lower limbs and pelvis among children with CRMO. Compared with CT scans, FDG PET exhibits superior sensitivity in detecting these lesions.

Extra-osseous manifestations in chronic recurrent multifocal osteomyelitis: a retrospective study.

Extra-osseous (EO) manifestations are poorly characterized in chronic recurrent multifocal osteomyelitis (CRMO). This study aimed to further define the frequency, characteristics and treatment of EO events in CRMO and whether different phenotypes can be distinguished and benefit from special management. This multicentre retrospective study included CRMO patients followed in several paediatric rheumatology departments in France between 2015 and 2022. EO manifestations were defined as skin lesions, gastrointestinal manifestations, arthritis, enthesitis, sacroiliitis, uveitis, vasculitis and fever. At the last visit, the physician defined CRMO as active in the presence of clinical manifestations including both osseous and EO symptoms. We included 133 patients; 87 (65.4%) were girls and the median age at first symptoms was 9.0 years (interquartile range 7.0-10.0). EO manifestations were described in 90 (67.7%) patients, with a predominance of skin lesions [n = 51/90 (56.7%)], followed by sacroiliitis [n = 38/90 (42.2%)], enthesitis [n = 21/90 (23.3%)], arthritis [n = 14/90 (15.6%)] and gastrointestinal manifestations [n = 6/90 (6.7%)]. The use of non-steroidal anti-inflammatory drugs and bisphosphonates did not differ by the presence or not of EO manifestations. Biologics were taken more frequently by patients with than without EO manifestations (P < 0.001); TNF inhibitors were used in 33 (36.7%) EO-positive patients. Under this treatment, 18 (54.5%) patients achieved complete remission of osseous and EO manifestations. At the last visit, more EO+ than EO- patients were on treatment (P = 0.009), with active disease in 58 (64.4%) patients. The analysis of EO manifestations in CRMO delineates two groups of patients in terms of severity and treatments used. Our study opens up new pathophysiological leads that may underlie the wide range of CRMO phenotypes.

Chronic Recurrent Multifocal Osteomyelitis: A Comprehensive Literature Review.

Chronic recurrent multifocal osteomyelitis (CRMO) is a non-infectious, inflammatory disorder of the bones. CRMO typically affects children, with a predisposition to females. Bone-related pain is often felt in the metaphysis of long bones, particularly of the lower extremities, but it can also target other sites at varied time intervals. Patients are likely to complain of tenderness and swelling that may cause considerable disability and adversely impact quality of life. There are three main pathophysiological mechanisms that have been hypothesized to drive CRMO including imbalanced cytokine expression, increased inflammasome activation, and enhanced osteoclast differentiation. Therapies have been based on targeting and suppressing these key players in CRMO patients.The first step in management involves pain control. Non-steroidal anti-inflammatory drugs should provide initial relief, albeit temporarily. It is imperative to initiate immunosuppressive medication that will help limit bone involvement and thereby prevent the development of fractures or leg-length discrepancies, for example. The purpose of this literature review is to study the pathophysiology of CRMO and carefully dissect the agents that have been previously employed in the management of CRMO patients. This could allow for the purposeful formulation of individualized care plans and improving the overall well-being of patients. The authors included a multitude of PubMed-indexed articles published from 2000 onwards in this review.

Correlation between the Clinical Course of CRMO Lesions and the Imaging Characteristics on Follow-up MRIs

Objective: To evaluate the correlation between the clinical course of chronic recurrent multifocal osteomyelitis (CRMO) lesions and their imaging characteristics on follow-up MRIs. Material and Methods: Two musculoskeletal fellowship-trained radiologists retrospectively reviewed the initial and follow-up MRI images of 9 CRMO patients who were treated in our institution from 2008 to 2018. Evaluation of clinical course was based on symptomatology, lab results and physical examination and was compared to MRI findings, on follow-up MRIs. Results: Thirty-five CRMO lesions in 9 patients were identified. Patient’s ages ranged from 4 to 15 years with a mean age of 10 years (S.D.±3.22). Six of the 9 patients were female. Only 21 of 35 lesions had been longitudinally followed by MRI. Of the 39 follow-up MRI exams, there was clinical improvement 15 times, and 24 times there was no clinical improvement confirmed by the clinician. Three MRI features: 1) bone marrow edema (BME) size, 2) BME signal intensity and 3) periosteal edema, significantly correlated with the clinical course (p-value&lt;0.001). When there was the improvement of all these three findings, the correlation with clinical improvement was high with 80% sensitivity and 100% specificity. The area under the receiver operator characteristic curve was 0.90 (95% confidence interval 0.795-1.005). Fourteen silent clinical lesions were also identified. Conclusion: Bone marrow edema and periosteal edema correlated best with the clinical course of CRMO patients on follow-up MRIs.

Colchicine as rescue treatment in two pediatric patients with chronic recurrent multifocal osteomyelitis (CRMO).

Chronic recurrent multifocal osteomyelitis (CRMO) is a rare idiopathic autoinflammatory bone disease characterised by noninfective inflammation of bones. Diagnostic approach is challenging and requires exclusion of other causes such as malignancies or infections. Nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids are usually applied as first-line therapy in CRMO patients; however, some cases require more intensive therapy with second-line agents to control disease activity. We hereby describe the use of colchicine as a nonconventional second-line disease-modifying antirheumatic drug in two pediatric patients with CRMO refractory to NSAIDs and corticosteroids. Our data indicate that colchicine might prove an important area for future research as a potential therapeutic option with easy administration, low cost, and a good safety profile in CRMO patients refractory to first-line therapy.

O007. Register of hereditary auto-inflammatory diseases in a pediatric rheumatology unit

Abstract Background Autoinflammatory diseases (AID) are a group of genetic syndromes resulting from an excessive activation of the innate immune system, caused by mutations in genes regulating the inflammatory pathways and can involve several organs. The aim of this study is to evaluate the clinical, paraclinical, epidemiogical and genetic data of Moroccan patients with confirmed AID, in order to allow a first experience of AID registry in our unit. Material We have retrospectively analyzed 30 cases of patients in our unit over a period of 13 years (between 2006 and 2019), according to inclusion criterias (recurrent fever &amp;gt; 3 episodes and a CRP &amp;gt; 40mg/L) and having excluded immune deficiency, autoimmune disease, neoplasia and infectious diseases. Results The mean age of our patients at 1st consultation was 6.9 years (with extremes ranging from 8 months to 14 years). Consanguinity was reported in 16 cases, and unknown in one case of an adopted child. The patients were classified as follows: 66% of cases with Familial Mediterranean Fever (FMF) including 1 case with a characteristic phenotype of Marshall/Periodic Fever Aphtous Pharyngitis Adenitis (PFAPA) syndrome, 16% of cases with Mevalonate Kinase Deficiency (MKD), 10% of cases with Chronic Recurrent Multifocal Osteomyelitis (CRMO), 1 patient with Familial Pustular Psoriasis (FPP) and another symptomatic patient with Muckle Wells syndrome. An association with Henoch Schonlein purpura was reported in 30% of cases and with periarteritis nodosa in 1 case in FMF patients. The mean diagnostic delay was 3 years (with extremes ranging from 1 month to 12 years). The main clinical features found in our patients included fever (83%), abdominal pain (90%), arthralgia (83%), arthritis (46%), adenopathies (40%), aphtous (30%) and other specific signs. Genetic analysis revealed that M694V was the most frequent mutation (60%), followed by A744S (15%), E148Q (10%), K695R (10%) and P369S/ R408Q (5%) in all FMF patients, and V337I found in 1 patient with MKD while the 4 others were confirmed basing on a high rate of urinary mevalonic acid. CRMO patients were confirmed by radiological and histological analysis. The case of FPP was confirmed histologically by skin biopsy and the patients with Muckle Wells and PFAPA syndroms were diagnosed basing on characteristic clinical features. Therapeutically, all FMF patients were treated with colchicine in addition of corticosteroids in 1 case of PFAPA syndrome. Patients with MKD received targeted therapy (Anakinra, Etanercept) and Ibuprofen in 1 case. CRMO patients were treated with targeted therapy and NSAIDs. The case of FPP was treated with Methotrexate combined with Etanercept and the patient with Muckel Wells Syndrome received corticosteroid therapy combined with Azathioprine and then Anakinra. The clinical and biological evolution was considered favorable in 76% of cases, partial in 13% of cases and 3 death cases were reported. Conclusion AIDs remain rare genetic syndromes whose lack of knowledge explains the late diagnostic delay. Therefore, it is necessary for any pediatrician to know how to evoke an AID in front of recurrent fever with free intervals, clinical features and inflammatory syndrome, in order to choose the optimal treatment as well as to make the genetic counseling. Abbreviations AID: Auto-Inflammatory Disease CAPS: Cryopyrin Associated Periodic Syndromes CARD14: Caspase Recruitment Domain Family Member 14 CIAS1: Cold-Induced Autoinflammatory Syndrome 1 CRMO: Chronic Recurrent Multifocal Osteomyelitis CRP: C-Reactive Protein CT scan: Computerized Tomography scan DNA: DeoxyriboNucleic Acid ESR: Erythrocyte Sedimentation Rate FMF: Familial Mediterranean Fever FPP: Familial Pustular Psoriasis IL-1β: Interleukine-1beta IL-17A: Interleukine 17A MEFV: Mediterranean fever gene MKD: Mevalonate Kinase Deficiency MVK: Mevalonate Kinase MW: Muckle Wells NALP3: NAcht Leucine-rich repeat Protein 3 NLRP3: NOD-like receptor family, pyrin domain containing 3 NSAID: Non-Steroidal Anti Inflammatory Drugs PFAPA: Periodic Fever Aphtous Pharyngitis Adenitis PRINTO: Pediatric Rheumatology INternational Trials Organization SAA: Serum Amyloid A TRAPS: TNF Receptor Associated Periodic Syndroms TNF: Tumor Necrosis Factor

Role of Diagnostic Imaging in Chronic Recurrent Multifocal Osteomyelitis (CRMO) in Children: An Observational Study.

The aim of this single-center observational study was to analyze the applicability of various imaging studies to the diagnosis and further evaluation of patients with chronic recurrent multifocal osteomyelitis (CRMO). The analysis included the data of 10 patients with CRMO treated between 2016 and 2021. The mean ages of the patients at the first manifestation of CRMO and ultimate diagnosis were 10 years and 7 months and 11 years and 10 months, respectively. Conventional radiography demonstrated focal loss of bone density in only 30% of the patients. Computed tomography showed disseminated foci with non-homogeneous osteolytic/osteosclerotic structure, with a massive loss of cortical layer and strong periosteal reaction. On magnetic resonance imaging (MRI), most patients presented with multifocal hypodense areas on T1-weighted images, with the enhancement of signal on T-weighted and STIR sequences. The duration of follow-up varied between 3 months and 3 years. In 40% of the patients, both clinical symptoms and the abnormalities seen on MRI resolved completely, whereas another 50% showed partial regression of clinical and radiological manifestations. MRI findings, co-existing with characteristic clinical manifestations, play a pivotal role in establishing the ultimate diagnosis of CRMO. MRI can also be used to monitor the outcomes of treatment in CRMO patients.

Mast cells enhance sterile inflammation in chronic nonbacterial osteomyelitis.

ABSTRACTChronic nonbacterial osteomyelitis (CNO) is an autoinflammatory bone disease, and patients with active or recurrent bone inflammation at multiple sites are diagnosed with chronic recurrent multifocal osteomyelitis (CRMO). The Chronic multifocal osteomyelitis (CMO) mouse model develops IL-1β-driven sterile bone lesions reminiscent of severe CRMO. The goal of this study was to evaluate the potential involvement of mast cells in CMO/CRMO. Here, we show that mast cells accumulate in inflamed tissues from CMO mice and that mast cell protease Mcpt1 can be detected in the peripheral blood. A transgenic model of connective tissue mast cell depletion (Mcpt5-Cre:Rosa26-Stopfl/fl-DTa) was crossed with CMO mice and the resulting mice (referred to as CMO/MC–) showed a significant delay in disease onset compared with age-matched CMO mice. At 5-6 months of age, CMO/MC– mice had fewer bone lesions and immune infiltration in the popliteal lymph nodes that drain the affected tissues. In bone marrow-derived mast cell cultures from CMO mice, cytokine production in response to the alarmin IL-33 was elevated compared with wild-type cultures. To test the relevance of mast cells to human CRMO, we tested serum samples from a cohort of healthy controls and from CRMO patients at diagnosis. Interestingly, mast cell chymase was elevated in CRMO patients as well as in patients with oligoarticular juvenile arthritis. Tryptase-positive mast cells were also detected in bone lesions from CRMO patients and patients with bacterial osteomyelitis. Together, our results identify mast cells as cellular contributors to bone inflammation in CMO/CRMO and provide rationale for further study of mast cells as therapeutic targets.

Chronic recurrent multifocal osteomyelitis in children: a single center experience over five years.

Sağ E, Sönmez HE, Demir S, Bilginer Y, Ergen FB, Aydıngöz Ü, Özen S. Chronic recurrent multifocal osteomyelitis in children: a single center experience over five years. Turk J Pediatr 2019; 61: 386-391. Chronic recurrent multifocal osteomyelitis (CRMO) is a rare disease characterized by sterile bone inflammation. It is an orphan disease with many unclear aspects in terms of diagnosis, treatment and follow-up. The aim of this study was to report our experience of pediatric CRMO patients. Children who were diagnosed with CRMO, and were followed-up between January 2008 and January 2017, were included in this study. There were 15 CRMO patients (8M/7F) with a median age at diagnosis of 9.0 years (range: 0.6-15.0). Bone pain was the most common presenting symptom. All of the patients had multifocal bone lesions. Vertebrae (66.7%) and femur (66.7%) were the most commonly affected bones. Eight of the patients also had sacroiliitis; however, only one of them was HLA-B27 positive. Whole-body magnetic resonance imaging (MRI) was used as a diagnostic tool in 13 patients revealing bone marrow edema (84.6%), osteitis (69.2%), and periosteal reaction (61.5%). All patients were initially treated with non-steroidal anti-inflammatory drugs (NSAIDs), however, disease-modifying anti-rheumatic drugs, anti-TNF agents or pamidronate were added to therapy due to inadequate treatment response. Clinical remission was achieved in 12 patients (1 with NSAIDs, 3 with methotrexate, 1 with pamidronate and 7 with an anti-TNF agent). During the follow-up period, relapses were observed in four patients who presented with pain and/or a newly formed bone lesion on MRI. Eventually, however, all of these patients also reached remission. CRMO is a chronic disease which may have a progressive or relapsing-remitting course. Improvement of the knowledge about this rare disease may help to enlighten the unknowns of the disease.

Clinical experiences in Turkish paediatric patients with chronic recurrent multifocal osteomyelitis.

Sözeri B, Aktay Ayaz N, Yıldız Atıkan B, Karadağ ŞG, Çakan M, Argın M, Sezak M. Clinical experiences in Turkish paediatric patients with chronic recurrent multifocal osteomyelitis. Turk J Pediatr 2019; 61: 879-884. Chronic recurrent multifocal osteomyelitis (CRMO) is a clinical entity which occurs mainly in children and adolescents with recurrent episodes of pain occurring over several years. Cause and physiopathology of disease is still uncertain. We aim to assess clinical characteristics and treatment options, need and response to anti-inflammatory therapies in children diagnosed chronic recurrent multifocal osteomyelitis Demographic data and clinical features of seventeen children diagnosed with CRMO in 2 pediatric rheumatology centers in Turkey were reviewed retrospectively. The diagnosis was based on clinical findings, radiological images and histopathological and microbiological studies. A total of 17 patients were included in the study. The median age of diagnosis was 9.6±4.2 years. The mean follow-up time was 31.6 months (range 6-35 months). Most patients (n: 10) had a recurrent multifocal disease course ( > 6 months), 6 patients had a persistent course and a patient had only one episode of CRMO. MEFV gene mutations were detected in 4 patients whose clinical features reduced with colchicine therapy. All patients had received nonsteroidal anti-inflammatory drugs but only one had complete response. Thirteen children with NSAID failure subsequently received corticosteroids, sulfasalazine, methotrexate, Anti TNF α drugs, or a combination of these drugs. This study is the largest cohort of pediatric CRMO patients in our country. Clinical evolution and imaging investigations should be closely done to avoid delays in diagnosis. Ethnic differences create changes in the presentation of the disease and response to treatment.

Serum Interleukin-6 and CCL11/Eotaxin May Be Suitable Biomarkers for the Diagnosis of Chronic Nonbacterial Osteomyelitis.

Chronic recurrent multifocal osteomyelitis (CRMO), the most severe form of chronic nonbacterial osteomyelitis (CNO), is an autoinflammatory bone disorder. In the absence of diagnostic criteria or biomarkers, CNO/CRMO remains a diagnosis of exclusion. The aim of this study was to identify biomarkers for diagnosing multifocal disease (CRMO). Sera from 71 pediatric CRMO patients, 11 patients with osteoarticular infections, 62 patients with juvenile idiopathic arthritis (JIA), 7 patients with para-infectious or reactive arthritis, and 43 patients with acute leukemia or lymphoma, as well as 59 healthy individuals were collected. Multiplex analysis of 18 inflammation- and/or bone remodeling-associated serum proteins was performed. Statistical analysis included univariate ANOVA, discriminant analysis, univariate receiver operating characteristic (ROC) analysis, and logistic regression analyses. For 14 of 18 blood serum proteins, significant differences were determined between CRMO patients, at least one alternative diagnosis, or healthy controls. Multi-component discriminant analysis delivered five biomarkers (IL-6, CCL11/eotaxin, CCL5/RANTES, collagen Iα, sIL-2R) for the diagnosis of CRMO. ROC analysis allowed further reduction to a core set of 2 biomarkers (CCL11/eotaxin, IL-6) that are sufficient to discern between CRMO, healthy controls, and alternative diagnoses. Serum biomarkers CCL11/eotaxin and IL-6 differentiate between patients with CRMO, healthy controls, and alternative diagnoses (leukemia and lymphoma, osteoarticular infections, para-infectious arthritis, and JIA). Easily accessible biomarkers may aid in diagnosing CRMO. Further studies testing biomarkers in larger unrelated cohorts are warranted.

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.

Altered expression of IL-10 family cytokines in CRMO result in enhanced inflammasome activation

Chronic recurrent multifocal osteomyelitis (CRMO) is the most severe presentation of the autoinflammatory bone disorder chronic nonbacterial osteomyelitis (CNO). The pathophysiology of CNO remains to be determined. We recently demonstrated reduced activation of mitogen-activated protein kinases ERK1 and 2 in monocytes from CRMO patients responsible for impaired activation of the transcription factor signaling protein (Sp-)1. This resulted in failure to express the immuno-modulatory cytokine IL-10. The IL10 gene, together with its homologues IL19 and IL20, is organized in the 145 kb spanning IL10 cytokine cluster on chromosome 1q32. In most cells, including monocytes, IL-10 cytokine family members are co-regulated in response to certain stimuli. IL-10 and IL-19 mainly have immune-modulating functions, while IL-20 acts as a pro-inflammatory cytokine contributing to inflammatory bone-loss. The NLRP3 inflammasome is a multi-protein complex forming in response to innate stimuli, subsequently mediating the cleavage and release of IL-1β. Enhanced inflammasome activation in IL-10 deficient mice was linked with bone-loss. Convincing evidence of this mechanism playing a role in CNO, however, is lacking.

Altered expression of IL-10 family cytokines in monocytes from CRMO patients result in enhanced IL-1β expression and release

Chronic recurrent multifocal osteomyelitis (CRMO) is characterized by reduced activation of protein kinases ERK1 and 2 in monocytes resulting in impaired IL-10 expression. IL10 and its homologs IL19 and IL20 are organized in the IL10 cluster on chromosome 1q32. IL-10 and IL-19 are immune-regulatory cytokines, while IL-20 acts in a pro-inflammatory manner. The NLRP3 inflammasome, a multi-protein complex forming in response to innate stimuli, mediates IL-1β cleavage and release. Here, we investigated IL-10-related cytokine expression in CRMO monocytes, underlying molecular events, and effects on inflammatory responses. We observed reduced anti-inflammatory IL-10 and IL-19 expression, and enhanced IL-20 expression in CRMO monocytes. Reduced IL-10 and IL-19 expression was associated with impaired Sp-1 recruitment to regulatory regions, contributing to NLRP3 inflammasome activation, which may induce inflammatory bone-loss. Our findings underscore the importance of balanced receptor-, cell-, and tissue-specific cytokine expression for immune homeostasis, providing additional arguments for cytokine blocking strategies in CRMO.

Chronic recurrent multifocal osteomyelitis: A rare entity.

Chronic recurrent multifocal osteomyelitis (CRMO) is an auto-inflammatory disease which is characterised by non-infectious bone lesions at multiple sites which have a relapsing nature. Our aim is to examine the role of radiology in diagnosis and management of CRMO patients who have been managed at the Mater Children's Hospital. This is a retrospective analysis of patients who have been managed with CRMO at the Mater Hospital since 2002. Inclusion criteria included a final diagnosis of CRMO. Exclusion criteria were a diagnosis more likely than CRMO. Medical images for each patient were evaluated for lesion features, location of lesion, number of bony lesions and whether or not the radiographic appearance would be characteristic of CRMO. Initially, 17 patients were included in the study; however, seven patients were excluded due to a more likely alternative diagnosis. In total, 24 lesions were detected; the most common anatomical sites were the spine (25%), feet (25%), ribs (16.7%) and femur (12.5%). Plain radiography lacked sensitivity, but it was important in initial screening and evaluating progress of lesions. MRI is important for targeted investigation and further evaluation of lesions. Bone scintigraphy is useful for detecting other affected sites. Due to the exposure to radiation, computed tomography is generally avoided. The combination of imaging modalities plays a large role in CRMO diagnosis. CRMO lesions usually appear ill defined with no pathognomonic features. The distribution of bony lesions can aid diagnosis, with lower limbs and clavicles commonly affected.

G357 Chronic recurrent multifocal osteomyelitis (crmo): the value of whole body mri demonstrated by a series of 13 adult and 34 paediatric patients

Aim To assess the role of whole-body MRI (WB MRI) in the diagnosis and management of patients with Chronic Recurrent Multifocal Osteomyelitis (CRMO). CRMO is a benign and non-infective autoinflammatory bone disorder characterised by multiple and recurrent inflammatory bone lesions. No universal diagnostic criteria exist. Methods Retrospective review of CRMO cases diagnosed at this hospital between 2008 to 2014. Cases were identified from patient records, and clinical information was collated from radiology and histopathology records and individual case notes. Results Forty seven CRMO patients were identified who had had WB MRI, of these 34 were paediatric patients up to the age of 18 years. The number of WB MRI scans per case ranged from 1 to 5 [mean 1.5]. WB MRI identified multifocal lesions in 30 patients. The clavicle, tibia and femur were most frequently involved. All cases were managed with non-steroidal anti-inflammatory medication or bisphosphonates. No children required steroid or anti-TNF treatment or surgical resection. Conclusions In the absence of specific diagnostic criteria, WB MRI in combination with clinical assessment can aid in the diagnosis of CRMO. WB MRI has almost entirely replaced bone biopsy in the diagnosis of CRMO at our institution.

A large national cohort of French patients with chronic recurrent multifocal osteitis.

To document more fully the characteristics of chronic recurrent multifocal osteomyelitis (CRMO) in pediatric patients, to collect data on the outcomes and management of the disease, and to define prognostic factors. One hundred seventy-eight patients were included (123 female patients and 55 male patients), with a mean ± SD age at diagnosis of 10.9 ± 2.9 years. Inclusion criteria were a diagnosis of CRMO, evidence of at least one lesion of osteitis confirmed by imaging, and development of the syndrome before age 18 years. Longitudinal clinical and imaging studies revealed that only 12 of 178 CRMO patients (7%) had unifocal lesions at the last medical visit. We were able to apply the clinical chronic nonbacterial osteomyelitis score to 110 of 178 patients (62%), which indicated that bone biopsy could have been avoided in 27 cases (25%). At the last medical visit, disease was in remission in only 73 of 171 patients (43%) (41% receiving therapy) after a mean ± SD of 47.9 ± 38.9 months; 44 of 171 patients (26%) experienced sequelae. Using cluster analysis, the CRMO cohort was separated into 3 homogeneous phenotypes (severe, mild, and intermediate). Patients with the severe phenotype had the worst prognosis. This group was entirely composed of male patients, most of whom had the multifocal form of CRMO and inflammatory syndrome. Patients with the mild phenotype had the best prognosis. This group was primarily composed of female patients with a unifocal form of CRMO and infrequent clavicle involvement and inflammatory syndrome. Patients with the intermediate phenotype had a good prognosis but greater reliance on treatment. This group primarily included female patients with multifocal lesions and inflammatory syndrome. This is the largest CRMO cohort described in the literature to date. Clinical evolution and imaging investigations confirmed the multifocal pattern of the disease. Three distinct subgroups of CRMO patients were distinguished, with very different prognoses.

Deregulation of the IL-1β axis in chronic recurrent multifocal osteomyelitis.

BackgroundThis study aims to investigate the inflammasome response in peripheral blood mononuclear cells (PBMCs) and the expression of inflammasome components in bone biopsies from patients with chronic recurrent multifocal osteomyelitis (CRMO).MethodsThe expression of inflammasome components mRNAs was evaluated in PBMCs isolated from 15 CRMO patients and 13 healthy controls by quantitative real-time PCR. The Interleukin (IL)-1β released in the medium of PBMC cultures after treatment with lipopolysaccharides (LPS) alone or LPS and ATP was measured by ELISA. Immunohistochemical staining for Apoptosis-associated Speck-like protein (ASC), caspase-1 (CASP-1), Nod-like receptor protein-3 (NLRP3) and IL-1β expression was performed in bone biopsies from CRMO patients.ResultsmRNA levels of ASC, CASP-1 and IL-1β were significantly higher in freshly isolated PBMCs from CRMO patients in active disease than in healthy controls. CASP-1 and IL-1β transcript levels were significantly higher also in PBMCs from CRMO patients in remission compared to healthy controls. PBMCs from CRMO patients in active disease stimulated in vitro with LPS showed a significant increase in IL-1β release compared to healthy control cells. Immunohistochemistry staining of bone tissue revealed the expression of inflammasome components in CRMO osteoclasts.ConclusionsOur data suggest that an abnormal regulation of IL-1β axis may be involved in CRMO pathogenesis.