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Objectives: This study aimed to analyze the influence of drug factors on the efficacy of bisphosphonate for chronic nonbacterial osteomyelitis to provide a reference for clinical treatment and promote clinical rational drug use by evaluation of effectiveness and safety of bisphosphonate treatment of chronic nonbacterial osteomyelitis., Methods: Literature on the treatment of chronic nonbacterial osteomyelitis by using bisphosphonate was collected and analyzed from PubMed, Medline, Embase, Cochrane, ISI Web of Knowledge, CNKI, VIP, and Wanfang databases., Results: A total of 489 cases were collected, with an average complete response rate of clinical presentation, laboratory tests and imaging findings of 80.37%, 80.56% and 79.22%, respectively. Except for opadronate, risedronate, ibandronate, pamidronate, alendronate, neidronate and zoledronate showed good efficacy, and the average complete response rates were 100%, 100%, 81.64%, 87.50%, 69.23% and 69.23%, respectively.The study found that in the pamidronate group, the average complete response rate of 0.5-1 mg/kg (maximum single dose≤60 mg) subgroup and the frequency of administration once every 3 months subgroup were better than other subgroups., Conclusions: Bisphosphonate could be used to treat chronic nonbacterial osteomyelitis, which of efficacy were affected by different drug types, dose and frequency of administration. The optimal dose and frequency of administration of pamidronate were 0.5-1 mg/kg (maximum single dose≤60 mg) and once every 3 months, respectively.

Background: Chronic Nonbacterial Osteomyelitis (CNO) is a rare auto-inflammatory disease that mainly affects children, and manifests with single or multiple painful bone lesions. Due to the lack of specific laboratory markers, CNO diagnosis is a matter of exclusion from different conditions, first and foremost bacterial osteomyelitis and malignancies. Whole Body Magnetic Resonance (WBMR) and bone biopsy are the gold standard for the diagnosis. Although the association with Inflammatory Bowel Disease (IBD) has been reported in the literature, cases of CNO in celiac patients have never been described before., Case Presentation: We report about a girl of 3 years and 8 months of age who presented with severe bone pain, slight increase of inflammatory markers, micro-hematuria and high calprotectin values. Her personal medical history was uneventful, apart from low weight growth. She had never complained of abdominal pain or other gastro-intestinal symptoms. WBMR showed the classical features of multifocal CNO, and biopsy confirmed the diagnosis. Celiac disease (CD) was suspected on the basis of antibody screening, and confirmed by gut biopsy. With gluten-free diet the patient achieved rapid and complete symptom remission together with healing of all the bone lesions proven by WBMR. Three years after the onset of the disease the girl is healthy and totally asymptomatic, still on clinical and radiological follow-up., Conclusions: Based on our experience, the diagnostic work-up of new cases of CNO should include the screening test for CD and, according to the literature, the possibility of IBD should also be properly ruled out. When CNO and CD coexist, gluten-free diet, combined with antinflammatory therapy, could be able to completely reverse bone lesions, shortening the duration of medical treatment. Because the diseases' onset is seldom simultaneous, patients with CNO and IBD deserve a properly extended follow-up. Finally, the analysis of the relationship between CNO and autoimmune intestinal diseases provides a unique opportunity to understand the pathophysiological pro-inflammatory network underlying both types of disorders and it is necessary to make the most suitable therapeutic choice., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: The parents of the child described in this case report gave their written consent for publication (kept in the medical records). Competing interests: The authors declare that they have no competing interest., (© 2025. The Author(s).)

Chronic nonbacterial osteomyelitis (CNO) is an uncommon autoinflammatory disorder. Significant effort has recently been spent to better define and treat this disorder including development of consensus treatment protocols, validate disease activity tools, and refining classification criteria. However, the underlying immunopathogenesis of the disease remains elusive. In this report, we describe the simultaneous onset of CNO in siblings. A pathogenic gene mutation was not identified, and these sisters lacked a similar biomarker profile. This report highlights that if a genetic predisposition for CNO exists, it may be related to complex polygenic or multifactorial mechanisms of disease evolution., (© Japan College of Rheumatology 2024. Published by Oxford University Press.)

Objectives: 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., Methods: 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., Results: 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., Conclusion: 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., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To present MRI distribution of active osteitis in a single tertiary referral center cohort of patients with chronic nonbacterial osteomyelitis (CNO)., Methods: Two musculoskeletal radiologists retrospectively reviewed MRI examinations of all patients with a final clinical diagnosis of CNO over 15 years. Sites of active osteitis at any time during the course of disease were divided into seven groups: (A) mandible, sternum, clavicles, or scapulas; (B) upper extremities; (C) subchondral sacrum and ilium immediately subjacent to sacroiliac joints (active osteitis denoting "active sacroiliitis" here); (D) pelvis and proximal 1/3 of femurs (excluding group C); (E) bones surrounding knees including distal 2/3 of femurs and 1/2 of proximal tibias and fibulas; (F) distal legs (including distal 1/2 of tibias and fibulas), ankles, or feet; (G) spine (excluding group C). Temporal changes of lesions in response to treatment (or other treatment-related changes such as pamidronate lines) were not within the scope of the study., Results: Among 97 CNO patients (53 males [55%], 44 females; age at onset, mean ± SD, 8.5 ± 3.2 years; age at diagnosis, 10.3 ± 3.3 years), whole-body (WB) MRI was performed in 92%, mostly following an initial targeted MRI (94%). A total of 557 (346 targeted and 211 WB) MRIs were analyzed. Biopsy was obtained in 39 patients (40%), all consistent with CNO or featuring supporting findings. The most common locations for active osteitis were groups D (78%; 95% CI 69‒85%) and C (72%; 95% CI 62‒80%)., Conclusion: Pelvis and hips were preferentially involved in this cohort of CNO patients along with a marked presence of active sacroiliitis., Clinical Relevance Statement: When suggestive findings of CNO are identified elsewhere in the body, the next targeted site of MRI should be the pelvis (entirely including sacroiliac joints) and hips, if whole-body MRI is not available or feasible., Key Points: • Heavy reliance on MRI for diagnosis of CNO underscores the importance of suggestive distribution patterns. • Pelvis and hips are the most common (78%) sites of CNO involvement along with active sacroiliitis (72%). • Pelvis including sacroiliac joints and hips should be targeted on MRI when CNO is suspected., (© 2024. The Author(s), under exclusive licence to European Society of Radiology.)

Chronic nonbacterial osteomyelitis (CNO), an autoinflammatory bone disease primarily affecting children, can cause pain, hyperostosis and fractures, affecting quality-of-life and psychomotor development. This study investigated CNO-associated variants in P2RX7, encoding for the ATP-dependent trans-membrane K + channel P2X7, and their effects on NLRP3 inflammasome assembly. Whole exome sequencing in two related transgenerational CNO patients, and target sequencing of P2RX7 in a large CNO cohort (N = 190) were conducted. Results were compared with publicly available datasets and regional controls (N = 1873). Findings were integrated with demographic and clinical data. Patient-derived monocytes and genetically modified THP-1 cells were used to investigate potassium flux, inflammasome assembly, pyroptosis, and cytokine release. Rare presumably damaging P2RX7 variants were identified in two related CNO patients. Targeted P2RX7 sequencing identified 62 CNO patients with rare variants (32.4%), 11 of which (5.8%) carried presumably damaging variants (MAF <1%, SIFT "deleterious", Polyphen "probably damaging", CADD >20). This compared to 83 of 1873 controls (4.4%), 36 with rare and presumably damaging variants (1.9%). Across the CNO cohort, rare variants unique to one (Median: 42 versus 3.7) or more (≤11 patients) participants were over-represented when compared to 190 randomly selected controls. Patients with rare damaging variants more frequently experienced gastrointestinal symptoms and lymphadenopathy while having less spinal, joint and skin involvement (psoriasis). Monocyte-derived macrophages from patients, and genetically modified THP-1-derived macrophages reconstituted with CNO-associated P2RX7 variants exhibited altered potassium flux, inflammasome assembly, IL-1β and IL-18 release, and pyroptosis. Damaging P2RX7 variants occur in a small subset of CNO patients, and rare P2RX7 variants may represent a CNO risk factor. Observations argue for inflammasome inhibition and/or cytokine blockade and may allow future patient stratification and individualized care., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Chronic non-bacterial osteomyelitis (CNO) is a rare, non-infection- related inflammatory disorder that affects children and teens. Clinical manifestations of CNO range widely from moderate, time-limited, monofocal inflammation of the bone to extreme multifocal or chronically active inflammation of the bone., Objectives: The main aim of this study was to explore the correlation between musculoskeletal (MSK) symptoms and health-related quality of life (HRQoL) in patients with CNO., Methods: Children and adults with CNO and their parents were asked to answer a web-based survey. The survey consisted of multiple questions centered around demographic, clinical and therapeutic data, MSK discomfort form based on the Nordic MSK Questionnaire and HRQoL based on Pediatric Quality of Life Inventory-4 (PedsQL-4) and PedsQL rheumatology module. The inclusion criteria included diagnosis of CNO before the age of 18. Patients who had malignancies or any chronic rheumatic, MSK, neurological disease prior to CNO onset were excluded., Results: There was a total of 68 participants, mostly females (66.2%), with median age 14 years and median disease duration 4.75 years. The median number of bones affected by CNO was 5 and ranged from 1 to 24 bones. Among the studied patients, 45 patients (66.2%) had MSK manifestations at the last month. The most commonly affected part was ankle and feet (26.5%). Regarding HRQoL, patients with MSK manifestations had lower scores than did patients without in PedsQL-4 (p < 0.001) including domains of physical functioning (p < 0.001), emotional functioning (p = 0.033), social functioning (p < 0.001) and school functioning (p = 0.007) in addition to lower scores in PedsQL rheumatology module (p < 0.001) including domains of pain and hurt (p < 0.001), daily activities (p < 0.001), treatment (p = 0.035), worry (p = 0.001) and communication (p < 0.001)., Conclusion: MSK manifestations have a negative impact on HRQoL in CNO patients. So, early identification and treatment are highly recommended., (© 2024. The Author(s).)

Chronic non-bacterial osteomyelitis (CNO) is an autoinflammatory bone disorder mostly affecting children and adolescents. Although it is considered a rare disease, CNO is likely to be the single most common autoinflammatory bone disease in childhood, underdiagnosed and underreported due to a lack of awareness of the condition in both medics and patients and the absence of validated diagnostic criteria. The exact underlying pathogenesis of CNO remains unknown, making targeted treatment difficult. This issue is exacerbated by the lack of any randomised control trials, meaning that treatment strategies are based solely on retrospective reviews and case series. This review summarises the current concepts in pathophysiology, the clinical features that help differentiate important differential diagnoses, and an approach to investigating and managing children with CNO. Ultimately, the timely and thorough investigation of children and young people with CNO is vitally important to exclude important mimics and initiate appropriate management that can prevent the complications of persistent inflammatory bone disease., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Introduction: Chronic non-bacterial osteomyelitis (CNO) is an autoinflammatory bone-disease of unknown origin. The National Pediatric Rheumatologic Database (NPRD) collects long-term data of children and adolescents with rheumatic diseases including CNO., Objective: To assess characteristics, courses, and outcomes of CNO with onset in childhood and adolescence and to identify outcome predictors., Methods: From 2015 to 2021 patients with a confirmed diagnosis of CNO, who were registered in the NPRD during their first year of disease and at least one follow-up visit, were included in this analysis and observed for up to 4 years., Results: Four hundred patients with recent diagnosis of CNO were enrolled in the NRPD during the study period. After 4 years, patient data documentation was sufficient to be analyzed in 81 patients. A significant decline of clinical and radiological lesions is reported: at inclusion in the registry, the mean number of clinical lesions was 2.0 and 3.0 MRI lesions per patient. A significant decrease of manifestations during 4 years of follow-up (mean clinical lesions 0.5, p < 0.001; mean MRI lesions 0.9 (p < 0.001)) was documented. A significant improvement of physician global disease activity (PGDA), patient-reported overall well-being, and childhood health assessment questionnaire (C-HAQ) was documented. Therapeutically, an increase of disease-modifying anti-rheumatic drugs over the years can be stated, while bisphosphonates rather seem to be considered as a therapeutic DMARD option in the first years of disease. Only 5-7% of the patients had a severe disease course as defined by a PGDA >  = 4. Predictors associated with a severe disease course include the site of inflammation (pelvis, lower extremity, clavicle), increased erythrocyte sedimentation rate, and multifocal disease at first documentation. The previously published composite PedCNO disease activity score was analyzed revealing a PedCNO70 in 55% of the patients at 4YFU., Conclusion: An improvement of physician global disease activity (PGDA), patient reported overall well-being and imaging-defined disease activity measures was documented, suggesting that inactivity of CNO disease can be reached. PedCNO score and especially PGDA, MRI-defined lesions and in a number of patients also the C-HAQ seem to be reliable parameters for describing disease activity. The identification of risk factors at the beginning of the disease might influence treatment decision in the future., (© 2023. The Author(s).)

Objective: Prospective comparative effectiveness research (CER) in chronic nonbacterial osteomyelitis (CNO) is lacking. Our objectives were to (1) determine the use and safety of each consensus treatment plan (CTP) regimen for CNO, (2) assess the feasibility of using the Chronic Nonbacterial Osteomyelitis International Registry (CHOIR) data for CER, and (3) develop and validate a CNO clinical disease activity score (CDAS) using CHOIR., Methods: Consenting children or young adults with CNO were enrolled into CHOIR. Demographic, clinical, and imaging data were prospectively collected. The CNO CDAS was developed through a Delphi survey and nominal group technique. External validation surveys were administered to CHOIR participants., Results: One hundred forty (78.2%) CHOIR participants enrolled between August 2018 and September 2020 received at least 1 CTP regimen. Baseline characteristics from different CTP groups were well matched. Patient pain, patient global assessment, and clinical CNO lesion count were key variables included in the CNO CDAS. The CDAS showed a strong correlation with patient/parent report of difficulty using a limb, back, or jaw and patient/parent report of disease severity, but a weak correlation with patient/parent report of fatigue, sadness, and worry. The change in CDAS was significant in patients reporting disease worsening or improvement ( P < 0.001). The CDAS significantly decreased after initiating second-line treatments from median 12.0 (IQR 8.0-15.5) to 5.0 (IQR 3.0-12.0; P = 0.002). Although second-line treatments were well tolerated, psoriasis was the most common adverse event., Conclusion: The CNO CDAS was developed and validated for disease monitoring and assessment of treatment effectiveness. CHOIR provided a comprehensive framework for future CER., (Copyright © 2023 by the Journal of Rheumatology.)

Background: Chronic nonbacterial osteomyelitis (CNO) is a rare, and impactful auto-inflammatory bone disease occurring in children and adults. Clinical care for CNO is challenging, as the condition lacks validated classification criteria and evidence-based therapies. This study aimed to map the current diagnostic and therapeutic practices for CNO in adults, as a first step towards a standardized disease definition and future consensus treatment plans., Methods: A primary survey was spread among global rheumatological/bone networks and 57 experts as identified from literature (May 2022), covering terminology, diagnostic tools (clinical, radiological, biochemical) and treatment steps. A secondary survey (sent to primary survey responders in August 2022) further queried key diagnostic features, treatment motivations, disease activity and treatment response monitoring., Results: 36 and 23 physicians completed the primary and secondary survey respectively. Diagnosis was mainly based on individual physician assessment, in which the combination of chronic relapsing-remitting bone pain with radiologically-proven osteitis/osteomyelitis, sclerosis, hyperostosis and increased isotope uptake on bone scintigraphy were reported indicative of CNO. Physicians appeared more likely to refer to the condition as synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome in the presence of joint and skin pathology. MRI was most frequently performed, and the preferred diagnostic test for 47%. X-rays were second-most frequently used, although considered least informative of all available tools. Typical imaging features reported were hyperostosis, osteitis, osteosclerosis, bone marrow edema, while degeneration, soft tissue calcification, and ankylosis were not regarded characteristic. Inflammation markers and bone markers were generally regarded unhelpful for diagnostic and monitoring purposes and physicians infrequently performed bone biopsies. Management strategies diverged, including indications for treatment, response monitoring and declaration of remission. Step-1 treatment consisted of non-steroidal anti-inflammatory drugs/COX-2 inhibitors (83%). Common step 2-3 treatments were pamidronate, methotrexate, and TNF-a-inhibition (anti-TNFα), the latter two regarded especially convenient to co-target extra-skeletal inflammation in SAPHO syndrome. Overall pamidronate and anti-TNFα and were considered the most effective treatments., Conclusions: Following from our survey data, adult CNO is a broad and insufficiently characterized disease spectrum, including extra-osseous features. MRI is the favoured imaging diagnostic, and management strategies vary significantly. Overall, pamidronate and anti-TNFα are regarded most successful. The results lay out current practices for adult CNO, which may serve as backbone for a future consensus clinical guideline., (© 2023. The Author(s).)

Objective: Chronic nonbacterial osteomyelitis (CNO) is an autoinflammatory bone disorder that predominantly affects children and young people. The pathophysiology and molecular mechanisms of CNO remain poorly understood, and diagnostic criteria and biomarkers are lacking. As a result, treatment is empiric and follows personal experience, case series and expert consensus plans., Methods: A survey was designed to gain insight on clinician and patient experiences of diagnosing and treating CNO and to collate opinions on research priorities. A version containing 24 questions was circulated among international expert clinicians and clinical academics (27 contacted, 21 responses). An equivalent questionnaire containing 20 questions was shared to explore the experience and priorities of CNO patients and family members (93 responses)., Results: Responses were used to select topics for four moderated roundtable discussions at the "International Conference on CNO and autoinflammatory bone disease" (Liverpool, United Kingdom, May 25-26 th , 2022). The group identified deciphering the pathophysiology of CNO to be the highest priority, followed by clinical trials, necessary outcome measures and classification criteria. Surprisingly, mental wellbeing scored behind these items., Conclusions: Agreement exists among clinicians, academics, patients and families that deciphering the pathophysiology of CNO is of highest priority to inform clinical trials that will allow for the approval of medications for the treatment of CNO by regulatory agencies., (© 2023. The Author(s).)

Objectives: To determine the influence of HLA-B27 positivity on risk of developing chronic nonbacterial osteomyelitis (CNO)., Methods: HLA-B*27 genotype was assessed in 3 European CNO populations and compared with local control populations (572 cases, 33,256 controls). Regional or whole-body MRI was performed at diagnosis and follow-up in all cases which reduces the risk of disease misclassification. Genotyping was performed using either next generation DNA sequencing or PCR based molecular typing. Statistical analysis used Fisher's exact test with Bonferroni correction and a fixed effects model for meta-analysis of odds ratios., Results: HLA-B*27 frequency was higher in all 3 populations compared with local controls (combined odds ratio (OR) = 2.2, p-value = 3 × 10 -11 ). This association was much stronger in male compared with female cases (OR = 1.99, corrected p-value = 0.015). However, the HLA-B*27 status was not statistically significantly associated with co-occurrence of psoriasis, arthritis or inflammatory bowel disease., Conclusion: Carriage of HLA-B*27 is associated with greater risk of developing CNO, particularly in male cases., (© 2023. The Author(s).)

Background/aim: Chronic nonbacterial osteomyelitis (CNO) is a rare disease of unknown etiology and most commonly occurs during childhood or adolescence. The purpose of this study is to collect data on the clinical features, outcomes, and management of the disease and to identify the factors affecting recurrence., Materials and Methods: This is a retrospective multicenter cross-sectional study of pediatric patients diagnosed with CNO. A total of 87 patients with a diagnosis of CNO followed for at least 6 months in 8 pediatric rheumatology centers across the country between January 2010 and December 2021 were included in this study., Results: The study included 87 patients (38 girls, 49 boys; median age: 12.5 years). The median follow-up time was 20 months (IQR: 8.5-40). The median time of diagnostic delay was 9.9 months (IQR: 3-24). Arthralgia and bone pain were the most common presenting symptoms. Multifocal involvement was detected in 86.2% of the cases and a recurrent course was reported in one-third of those included in the study. The most commonly involved bones were the femur and tibia. Vertebrae and clavicles were affected in 19.5% and 20.6% of cases, respectively. The erythrocyte sedimentation rate (ESR) values of 60.9% of the patients were above 20 mm/h and the C-reactive protein values of 44.8% were above 5 mg/L. The remission rate was 13.3% in patients using nonsteroidal antiinflammatory drugs and 75.0% in those using biological drugs. Vertebral and mandibular involvement and high ESR values at the time of diagnosis were associated with recurrence., Conclusion: In this multicenter study, CNO with vertebral and mandibular involvement and high ESR at diagnosis were associated with recurrence., (© TÜBİTAK.)

Chronic nonbacterial osteomyelitis (CNO) is a chronic, sterile, inflammatory disease. It primarily presents with nonspecific bone pain and swelling but ultimately can cause bone destruction and deformities, if left untreated. The involvement of the cranial bones (apart from the mandible) is rare in CNO. In this report, we present a rare case of CNO affecting facial and cranial bones presenting as facial palsy with a review of the literature about similar affection. A 10-year-old, previously healthy female was initially evaluated for swelling of the left side of her face with slight tenderness on palpation, but no fever. Her complete blood count was unremarkable, her inflammatory markers were elevated (C-reactive protein 7.5 mg/dl and erythrocyte sedimentation rate 104 mm/h), and CT of facial and skull bones and MRI of brain showed a destructive osseous process involving the left maxillary, zygomatic, sphenoid bones and the clivus. Bone biopsy of the left maxilla showed fibrous dysplasia with abscess formation, most consistent with an infectious aetiology (acute osteomyelitis). She was started on oral clindamycin for a 3-month course. The facial swelling improved after starting clindamycin, but on her sixth week of treatment, she developed right-sided Bell's palsy. An MRI of the brain showed hyperenhancement of the right seventh cranial nerve. A month later, she was evaluated for right wrist and knee swelling, pain, and limitation of movement. Skeletal survey and MRI showed multifocal lesions with mixed sclerosis and lucency. Her inflammatory markers continued to be elevated. Another bone biopsy of the right radius showed similar findings of destruction with no evidence of malignancy. She was ultimately diagnosed with CNO. She was started on nonsteroidal anti-inflammatory drugs with gastric protection and regular follow-up. Over more than a year of follow-up, the patient's inflammatory markers remain normal, and joint swelling/limitation has remained in remission. We found five additional cases in the literature that presented with a similar presentation. To our knowledge, our patient is the first reported case in the USA involving the cranial/facial bones apart from the mandible presenting with facial palsy. The affection of the facial bones (apart from the mandible) in CNO is very rare, but the awareness of such a presentation by the clinician is an important aspect of reaching the diagnosis., (© Japan College of Rheumatology 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Chronic nonbacterial osteomyelitis (CNO) is a rare autoinflammatory bone disease that is gaining recognition from clinicians and researchers. We aim to publish data from our cohort of patients with CNO living in the northwestern United States to increase the awareness of specific demographics, characteristics, and presentation of this rare disease., Methods: A retrospective chart review was performed of our electronic medical records. Patients with complete chart records who met criteria for a diagnosis of CNO from 2005 to 2019 were included. Extracted data including patient demographics, bone biopsy results, and lesion locations on advanced imaging were analyzed. King County census data were used to calculate the annual new case rate within our center., Results: A total of 215 CNO cases were diagnosed at our large tertiary pediatric hospital. The majority of cases were of White race residing in Washington's most populous county, King County. Most cases were diagnosed in 2016 to 2019, showing a significant increase in the annual case rate from 8 to 23 per million children in King County, though there did not appear to be a seasonal predilection. Biopsy rate decreased from 75% to 52%. One hundred fifty-two (71%) children had family history of autoimmunity. With increasing use of whole-body magnetic resonance imaging (WB-MRI), results showed 68% had multiple lesions., Conclusion: CNO has been diagnosed at an increased rate in recent years. WB-MRI may assist in identifying other lesions that may be asymptomatic on presentation. Bone biopsy is still required in some children at the time of diagnosis., (Copyright © 2022 by the Journal of Rheumatology.)

Chronic nonbacterial osteomyelitis (CNO) can cause significant morbidity, including bone pain and damage. In the absence of clinical trials, treatments include non-steroidal anti-inflammatory drugs, corticosteroids, TNF-inhibitors (TNFi) and/or bisphosphonates. In a retrospective chart review in the United Kingdom and Germany, we investigated response to TNFi and/or pamidronate. Ninety-one patients were included, receiving pamidronate (n = 47), TNFi (n = 22) or both sequentially (n = 22). Patients with fatigue [p = 0.003] and/or arthritis [p = 0.002] were more frequently treated with TNFi than pamidronate. Both therapies were associated with clinical remission at 6 months, and reduction of bone lesions on MRI at 12 months. While not reaching statistical significance, pamidronate resulted in faster resolution of MRI lesions. Fewer flares were observed with TNFi. Failure to respond to pamidronate was associated with female sex [p = 0.027], more lesions on MRI [p = 0.01] and higher CRP levels [p = 0.03]. Randomized clinical trials are needed to confirm observations and generate evidence., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: To explain the central role of magnetic resonance imaging (MRI) in the diagnosis and follow-up of chronic nonbacterial osteomyelitis (CNO) in children and adolescents, centering on practical technical aspects and salient diagnostic features., Recent Findings: In the absence of conclusive clinical features and widely accepted laboratory tests, including validated disease biomarkers, MRI (whether targeted or covering the entire body) currently plays an indispensable role in the diagnosis and therapy response assessment of CNO. Whole-body MRI, which is the reference imaging standard for CNO, can be limited to a short tau inversion recovery (STIR) coronal image set covering the entire body and a STIR sagittal set covering the spine, an approximately 30-min examination with no need for intravenous contrast or diffusion-weighted imaging. The hallmark of CNO is periphyseal (metaphyseal and/or epi-/apophyseal) osteitis, identified as bright foci on STIR, with or without inflammation of the adjacent periosteum and surrounding soft tissue. Response to bisphosphonate treatment for CNO has some unique MRI findings that should not be mistaken for residual or relapsing disease. Diagnostic features and treatment response characteristics of MRI in pediatric CNO are discussed, also describing the techniques used, pitfalls encountered, and differential diagnostic possibilities considered during daily practice., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: The aim of this study was to evaluate demographic, clinical, laboratory, imaging, histopathology characteristics, and treatment responses of children with Chronic nonbacterial osteomyelitis (CNO)., Methods: Retrospective multi-center case series study of pediatric patients diagnosed with CNO treated at five tertiary centers in south China., Results: Totally there were 18 patients diagnosed as CNO between 2014 and 2020. The median age of onset was 9.2 years (range 3.7-13.1) and 55.6% were female. Median delay in diagnosis was 10.9 months (range 1.0-72.0). The most frequent presenting symptoms were bone pain (100%) and fever (44.4%). Most patients had more than one lesion (median of 5, range 1-7). Most frequently affected bones were tibiofibula (88.9%) and femur (77.8%). The MRI characteristics mainly presented as bone edema and hyperintensity in bone marrow. Bone biopsy was conducted in 11 patients (61.1%) with inflammatory cells infiltration manifested as chronic osteomyelitis, and none showed bacterial infection or tumor. In treatment, non-steroid anti-inflamatory drugs (NSAIDs) is used as the first-line drug followed by steriods, methotexate (MTX), salazosulfadimidine (SASP), Bisphosphonates and TNF-α inhibitor. Two refractory cases received combination therapy with Bisphosphonates and TNF-α inhibitor, and achieved good therapeutic effect., Conclusions: The present study described a multicenter series of CNO from south China and highlighted the clinical features, laboratory tests, imaging characteristics and treatment outcomes. Increasing awareness of this disease is important to decrease time to diagnosis, improve access to treatment, and reduce complications., (© 2021. The Author(s).)

Objective: To assess the first-year features of patients with chronic nonbacterial osteomyelitis (CNO)., Methods: Patients with a diagnosis of CNO, disease duration of under 13 months, and first registration in the German National Pediatric Rheumatologic Database (NPRD) between 2009 and 2018 were included in this cross-sectional analysis., Results: Of 774 documented patients, 62.8% were female, and all patients had a median age of 11 years. The most affected clinical sites were the tibia (29.7%), pelvis (28.0%), and femur (27.8%). HLA-B27 was positive in 48 of 314 analyzed patients (15.3%). In 406 patients, an X-ray was performed at the first visit; X-ray results showed osteosclerosis/-lysis in 34.0% and hyperostosis in 14.5% of the patients. MRI scans (focal and whole-body scans) were performed in 648 patients, and 81.5% showed a positive TIRM/STIR signal. A total of 84.7% of the patients were administered nonsteroidal anti-inflammatory drugs, 9.6% were administered oral glucocorticoids, 10.8% were administered disease-modifying anti-rheumatic drugs (DMARDs), and 6.1% were administered bisphosphonates. An evaluation of the patient's questionnaire showed an overall well-being (NRS 0-10) of 2.0. The PedCNO disease "activity" score revealed a 70% improvement in variables in 43% of patients in the initial 1-year follow-up. Copresentation with diagnostic criteria of pediatric enthesitis-related arthritis was rare., Conclusion: To our knowledge, the NPRD cohort seemed to be the largest cohort of children and adolescents suffering from CNO worldwide. Most patients were treated effectively with NSAIDs, and only a small group of patients was administered additional medication. The patient-defined measures of disease activity had a moderate impact on patients' daily lives., Trial Registration: Not applicable., (© 2021. The Author(s).)

Chronic nonbacterial osteomyelitis, or its most severe form, chronic recurrent multifocal osteomyelitis, is an autoinflammatory bone disease that causes skeletal inflammation characterized by bone pain and swelling that primarily affects children. It is a diagnosis of exclusion and its clinical presentation may mimic underlying infectious processes and malignancy. Clinical suspicion for this diagnosis and timely referral to pediatric rheumatology is crucial to achieve earlier diagnosis, appropriate treatment, and improved quality of life of affected patients and families. This article focuses on recent insights into the pathogenesis of chronic nonbacterial osteomyelitis and outlines recent advances and ongoing research., Competing Interests: Disclosure F. Nuruzzaman has nothing to disclose. Y. Zhao - Consultant for Novartis. P.J. Ferguson - Consultant for Novartis., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Based on the recently developed ChRonic nonbacterial Osteomyelitis MRI Scoring tool (CROMRIS), we developed a radiological activity index (RAI-CROMRIS) to obtain a quantification of the overall bone involvement in individual patients., Methods: Whole Body Magnetic Resonance Imaging (WB-MRI) images were scored according to parameters included in the RAI-CROMRIS: bone marrow hyperintensity, signal extension, soft tissue/periosteal hyperintensity, bony expansion, vertebral collapse. These parameters were evaluated for each bone unit yielding a score from 0 to 7 and summed up as RAI-CROMRIS including all bone units. We assessed clinical disease activity using a physician global assessment (PGA) and radiological findings in 76 treatment-naïve patients; 46 of 76 were evaluated at 6 and 12 months after initial WB-MRI. Quantitative variables were compared using the Mann-Whitney U test for unmatched groups and the Wilcoxon signed-rank test for paired groups. Correlation was evaluated using Spearman's rank coefficient (r s )., Results: There was a significant correlation between RAI-CROMRIS and PGA (r s  = 0.32; p = 0.0055), between RAI-CROMRIS and presence of elevated erythrocyte sedimentation rate (p = 0.013) and C-reactive protein (p = 0.0001) at baseline. The RAI-CROMRIS decreased from a median of 17 at baseline to 12 at 6 months (p = 0.004) and remained stable (median 11) at 12 months. A correlation between the RAI-CROMRIS and the PGA was observed at baseline (r s  = 0.41; p = 0.004) and during follow up at 6 months (r s  = 0.33; p = 0.025) and 12 months (r s  = 0.38; p = 0.010). The baseline RAI-CROMRIS (median 20) was significantly higher in patients who subsequently received bisphosphonates than in patients who received other treatments (median 12) and decreased significantly after bisphosphonates (p = 0.008)., Conclusions: The RAI-CROMRIS was correlated with clinical and laboratory measures of disease activity showing significant short-term changes following treatment with bisphosphonates. This tool could be used in clinical practice and clinical trials after validation., (© 2021. The Author(s).)

Objective: A working group was established to develop a core domain set (CDS) for Chronic Nonbacterial Osteomyelitis (CNO) and Synovitis, Acne, Pustulosis, Hyperostosis, Osteitis (SAPHO) following the OMERACT filter 2.1., Methods: A scoping review to identify disease-related manifestations was performed, followed by a special interest group (SIG) session at OMERACT2020 to begin the CNO/SAPHO CDS framework., Results: Candidate items were identified from the scoping review and most fell under Life Impact and Pathophysiology Manifestation core areas. A SIG agreed on the need to develop a CDS for CNO and SAPHO (100%) and for children and adults (91%)., Conclusion: Based on candidate items identified, qualitative research and Delphi surveys will be performed as next steps., Competing Interests: Declaration of Competing Interest None related to this work., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: The purpose of this study was (1) to assess the interreader reliability in detecting and scoring the inflammatory bone lesions in pediatric patients with chronic nonbacterial osteomyelitis (CNO) by using whole-body magnetic resonance imaging (WB-MRI), and (2) to evaluate the responsiveness of the MRI-detected CNO lesions to pamidronate therapy., Methods: Eighty-eight WB-MRI examinations were independently reviewed and scored by 2 radiologists blinded to clinical details in 32 retrospectively enrolled pediatric patients with CNO. Inflammatory bone lesions, soft tissue abnormality, and bony structural changes were scored before and after pamidronate therapy. Lesion responsiveness was calculated by using standardized response mean and interreader reliability was assessed by k statistics., Results: There was good to excellent interreader agreement for the detection and quantification of bone lesions. After the first cycle of pamidronate in all 32 patients, 96 of the 279 lesions (34%; after excluding 108 lesions of hand and feet) resolved, whereas in a subset of 11 patients with 2 or more cycles, 76% of lesions resolved after the second cycle. Twenty-one (7.5%) lesions worsened and 46 (16.4%) new lesions developed after 1 cycle in all 32 patients. In these 11 patients, the number of worsened lesions reduced to 2 (2%) and new lesions to 14 (14.9%) after the second cycle as detected on MRI. Vertebral lesions had the highest response to treatment., Conclusion: WB-MRI is a reliable tool for objective quantification and assessment of response to treatment of pediatric CNO bone lesions and could be used to monitor disease activity for clinical and research purposes., (Copyright © 2021 by the Journal of Rheumatology.)

Background: Chronic nonbacterial osteomyelitis (CNO) is an autoinflammatory disease affecting bone with considerable phenotypic heterogeneity and variable association with other autoinflammatory conditions. Disease pathogenesis is incompletely understood, and treatment protocols vary between physicians with no clinical treatment guidelines available prior to 2017. Although CNO was previously considered benign, it is now clear that long-term sequelae do occur. The aim of this study is to provide a detailed phenotypic description of children and adolescents with CNO who attended tertiary paediatric rheumatology services in Ireland between September 2017 and September 2019, their disease course, treatment and outcomes., Methods: This study involved retrospective review of clinical notes, laboratory, radiology and histology results of Irish children and adolescents with CNO who are currently attending tertiary paediatric rheumatology services. The Bristol diagnostic criteria were applied retrospectively; only patients who met these criteria were included. Criteria for remission and partial response were based on the Childhood Arthritis and Rheumatology Research Alliance (CARRA) criteria for treatment failure., Results: Forty-four children and adolescents were recruited. Demographics in terms of age of onset, gender and number of sites were similar to those previously reported. Overall, 18/44 (40.9%) had extraosseous manifestations associated with CNO; 12/44 (27.2%) had cutaneous involvement. All patients received a regular nonsteroidal anti-inflammatory drug (NSAID) after diagnosis with 27/44 (61.4%) requiring at least 1 second-line medication. Second-line agents used in this cohort were bisphosphonates, methotrexate and TNF-blockers. No patients received systemic corticosteroids., Conclusion: This national cohort showed a high prevalence of extraosseous involvement and a low response rate to NSAID treatment. This may reflect a more inflammatory phenotype and highlights the need to define different subtypes of CNO.

Objective: Acne fulminans (AF) is a rare, explosive systemic form of acne. Chronic nonbacterial osteomyelitis (CNO) or chronic recurrent multifocal osteomyelitis (CRMO) is a primarily pediatric autoinflammatory disorder characterized by sterile osteolytic bone lesions. Concomitant occurrence of CNO/CRMO and AF is very rare, and little is known about the epidemiological and clinical particularities of this association. The aim of this retrospective observational study was to describe the characteristics of pediatric patients with CNO/CRMO associated to AF., Methods: Electronic mailing lists of French medical societies were used to call for patients with CNO/CRMO and AF. A search for published patients with CNO/CRMO and AF was performed by screening PubMed., Results: We identified 5 original patients and 10 patients from the literature. All patients were adolescent boys. Mean age at disease onset was 14.8 years. Nine of 15 patients had received isotretinoin before the sudden onset of AF. Osteoarticular symptoms appeared within < 1-3 months after the onset of AF. The mean numbers of clinical and radiological bone lesions were 3.6 and 5.6, respectively. The percentages of patients with involvement of vertebrae, pelvis, chest, and cranial were 40%, 40%, 33.3%, and 6.6%, respectively. Arthritis was observed in 69.2% of patients and sacroiliac arthritis in 46.2%., Conclusion: CNO/CRMO associated to AF occurs predominantly in male adolescents and is characterized by frequent involvement of the axial skeleton and arthritis. Epidemiological and clinical features of these patients differ from general CNO/CRMO cohorts. Clinical management requires careful handling of isotretinoin doses.

Chronic nonbacterial osteomyelitis (CNO) is an autoinflammatory bone disease in childhood and adolescence with a preference for the female gender. It is manifested with multiple osseous lesions, with a predilection for the metaphyseal end zones of the long bones of the lower extremities. These bone lesions usually occur multifocally, can recur and develop a different appearance depending on the bone structure affected. Patients present with a longer disease history, changing clinical symptoms and unspecific paraclinical signs. Magnetic resonance imaging (MRI) is the imaging of choice and particularly as a whole body examination can speed up the diagnosis and is an important component of follow-up controls. Differential diagnoses include numerous inflammatory, benign and malignant bone diseases. Therefore, it is essential to know the diagnosis of CNO and to take it into consideration in cases of an unclear inflammatory bone process in young patients.

Objective: Serial magnetic resonance imaging (MRI) examinations are often needed in chronic nonbacterial osteomyelitis (CNO) to determine the objective response to treatment. Our objectives in this study were (1) to develop a consensus-based MRI scoring tool for clinical and research use in CNO; and (2) to evaluate interrater reliability and agreement using whole-body (WB)-MRI from children with CNO., Methods: Eleven pediatric radiologists discussed definitions and grading of signal intensity, size of signal abnormality within bone marrow, and associated features on MRI through monthly conference calls and a consensus meeting, using a nominal group technique in July 2017. WB-MRI scans from children with CNO were deidentified for training reading and an interrater reliability study. The reading by each radiologist was conducted in a randomized order. Interrater reliability for abnormal signal and severity were assessed using free-marginal κ statistics., Results: Radiologists reached a consensus on grading CNO-specific MRI findings and on describing bone units based on anatomy. A total of 45 sets of WB-MRI scans, including 4 sets of non-CNO MRI examinations, were selected for the final reading. The mean κ of each category of bones was > 0.7 with majority > 0.9 demonstrating substantial/almost perfect interrater reliability of readings among radiologists. The agreement on signal intensity and the size of signal abnormality within the most commonly affected bones (femur and tibia) were lower than those of other bones., Conclusion: The chronic nonbacterial osteomyelitis magnetic resonance imaging scoring (CROMRIS) tool is a comprehensive standardized scoring tool for MRI in children with CNO. Our interrater study demonstrated good interrater reliability and agreement of readings.

Background: Studies evaluating treatment responses for chronic nonbacterial osteomyelitis (CNO) are lacking. We aimed to measure and compare response rates of medical treatments, time to response of medical treatments among patients with CNO of the mandible, and describe bacterial contamination rates from biopsy., Methods: We conducted a retrospective chart review of all patients diagnosed with CNO of mandible between 2003 and 2017 and extracted demographic, clinical, laboratory, imaging and surgical data. Detailed medication use and response to medications were recorded. The primary outcome was response to medical treatments defined as improvement of presenting symptoms, inflammatory markers, and imaging if available. Medical treatments included nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, disease modifying anti rheumatic drugs (DMARDs), anti-tumor necrosis factor (TNF) therapy, and pamidronate. Descriptive analysis was performed when appropriate. Multivariable logistic regression and Kaplan-Meier curves were applied to compare the responses to medical treatments and time to full response., Results: We identified 22 patients with a median age of 11 and 36% were female. Four patients (18%) had multifocal bone lesions. CT findings (n = 21) showed lytic lesions (62%) and sclerosis (90%). MRI (n = 14) revealed hyperintensity within bone marrow (100%), soft tissue (71%) and bony expansion (71%). Non-antibiotic treatments including NSAIDs (n = 18), glucocorticoids (n = 10), DMARDs (n = 9), anti-TNF therapy (n = 5) and pamidronate (n = 6) were applied. Rates of full responses to anti-TNF therapy (60%) and pamidronate (67%) were higher than that to NSAIDs (11%) (p < 0.05). Patients receiving pamidronate responded more rapidly than those receiving anti-TNF therapy (median two vs 17 months, p = 0.01) when there was a full response. All had bone biopsies. Intraoral biopsy was performed in 12 of 13 operated in our center and the most common contaminants were Neisseria spp and Streptococcus viridians., Conclusion: Both anti-TNF and pamidronate appeared superior to NSAIDs alone in treating mandibular CNO. Patients receiving pamidronate responded faster than those receiving anti-TNF therapy.

Chronic nonbacterial osteomyelitis (CNO) is a primary autoinflammatory bone disease that presents more frequently in children and is characterized by inflammatory bone lesions in the absence of an infectious etiology. There is little information of this disease in Latin America. The objective of the study was to evaluate demographic, clinical, laboratory, imaging, histopathology characteristics, and treatment responses of pediatric CNO patients. The clinical records of 19 patients with CNO diagnosed between 2007 and 2019 at three tertiary centers in Santiago, Chile were reviewed. The median age of onset was 10 years and 47% were female. Median delay in diagnosis was 12 months. All patients had a pattern of recurrent multifocal disease. 37% of patients had positive antinuclear antibodies and 16% HLA-B27 positivity. 21% of patients presented arthritis or other rheumatologic comorbidity, although no association with psoriasis, inflammatory bowel disease (IBD) or palmoplantar pustulosis (PPP) was observed. Eighteen patients received treatment with nonsteroidal anti-inflammatory drugs with partial response. Twelve patients received methotrexate, and half of them received steroids at the same time reaching remission in 50%. Of the five patients who received bisphosphonates, 60% achieved remission. All four patients who received adalimumab had comorbid arthritis and 75% achieved remission. In a series of Chilean children with CNO, all patients presented with multifocal lesions. Comorbid autoimmune diseases including arthritis were frequent, but no association was observed with psoriasis, IBD, or PPP.

Background: Chronic nonbacterial osteomyelitis (CNO) is a rare chronic autoinflammatory syndrome affecting mainly children and young adults. The natural history of the disease is marked by recurrent pain as the mainstay of inflammatory outbreaks. Typical radiographic findings are osteosclerosis and hyperostosis of the medial clavicle, sternum and first rib. Compression of the brachial plexus is exceedingly rare and one of the few surgical indications. Literature on total clavicle reconstruction is scarce. While claviclectomy alone has been associated with fair functional and cosmetic outcomes, several reconstruction techniques with autograft, allograft or even cement ("Oklahoma prosthesis") have been reported with the aim of achieving better pain control, cosmetic outcome and protecting the brachial plexus and subclavian vessels. We herewith report a unique case of complicated CNO of the clavicle treated with total clavicle reconstruction using a free peroneal graft., Case Presentation: A 21-year-old female patient presented with CNO of her left clavicle, associated with recurrent, progressive and debilitating pain as well as limited range of motion. In recent years, she started complaining of paresthesia, weakness and pain radiating to her left arm during arm abduction. The clavicle diameter reached 6 cm on computed tomography, with direct compression of the brachial plexus and subclavian vessels. Following surgical biopsy for diagnosis confirmation, she further developed a chronic cutaneous fistula. Therefore, a two-stage total clavicle reconstruction using a vascularized peroneal graft stabilized by ligamentous reconstruction was performed. At two-year follow-up, complete pain relief and improvement of her left shoulder Constant-Murley score were observed, along with satisfactory cosmetic outcome., Conclusions: This case illustrates a rarely described complication of CNO with direct compression of the brachial plexus and subclavian vessels, and chronic cutaneous fistula. To our knowledge, there is no consensus regarding the optimal management of this rare condition in this context. Advantages and complications of clavicle reconstruction should be carefully discussed with patients due to limited evidence of superior clinical outcome and potential local and donor-site complications. While in our case the outcomes met the patient's satisfaction, it remains an isolated case and further reports are awaited to help surgeons and patients in their decision process.

Chronic nonbacterial osteomyelitis (CNO) is an innate immune system disorder that predominantly affects children. It can present as part of a syndrome or in isolation. It presents as bone pain with or without fever or objective swelling at the site. It is difficult to diagnose. Laboratory studies can be normal, whereas a biopsy reveals sterile osteomyelitis. Osteolytic or sclerotic bone changes may be seen on radiographs. However, MRI is more sensitive for detecting CNO and is considered the gold standard for monitoring the disease. Treatment depends on disease severity and includes nonsteroidal antiinflammatory drugs, bisphosphonates, and cytokine inhibitors., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Chronic nonbacterial osteomyelitis (CNO) is a little known autoinflammatory bone disorder primarily affecting children and sometimes young adults. Diagnosis is often delayed due to its varied and nonspecific initial symptoms. Very few cases are reported from India. The aim of this report is to increase the awareness of this disease among physicians, orthopedic surgeons, and rheumatologists. Four male patients were diagnosed with CNO in the past 3 years. The age at onset varied from 9 to 23 years with a median diagnostic delay of 3.5 years. All patients presented with recurrent bony pain with or without localized swelling over the affected bones. Two patients had previously undergone open surgical procedures with bone biopsies and three patients had received at least one course of antibiotics. Two patients responded well to nonsteroidal anti-inflammatory drugs alone, one patient required a short course of glucocorticoids, and another patient required methotrexate to control disease activity. This case series includes males, onset at a relatively later age in most, and a longer diagnostic delay. Thus, in addition to children and adolescents, CNO should be suspected in young adults presenting with recurrent bony pain with or without localized swelling., Competing Interests: There are no conflicts of interest

Objective: To report efficacy and safety in patients with chronic nonbacterial osteomyelitis (CNO) unresponsive to nonsteroidal antiinflammatory drugs (NSAID) and bisphosphonates and/or glucocorticoids treated with anakinra., Methods: Nine patients (6 females) with refractory CNO were treated with anakinra for at least 6 months. We recorded, at baseline and after 6 months of treatment, clinical and laboratory features, and number and distribution of bone lesions detected by 99mTc-MDP bone scintigraphy. Disease activity was evaluated using a physician's global assessment (PGA)., Results: At baseline, 9/9 patients had mild to severe PGA. After 6 months of treatment, in 5 patients the PGA score was graded from none to minimal. At baseline, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were elevated in 8 out of 9 patients. After 6 months, 5/9 patients had normalized CRP and ESR and in all except 1, CRP and ESR decreased. Before starting anakinra, a total of 77 bone lesions were detected by bone scintigraphy. After 6 months of treatment of the 77 lesions, 42 had resolved and 35 were stable. In 7/9 patients, 20 new lesions appeared during treatment; 2 of these 7 patients were symptomatic. At the last followup visit (median 1.7 yrs, range 0.8-2.8), 6/9 patients maintained a PGA graded as none to minimal., Conclusion: Anakinra is a possible therapeutic alternative in patients with refractory CNO. The practical significance of clinically silent bone lesions detected by bone scintigraphy remains to be established.

Background: Chronic nonbacterial osteomyelitis (CNO) is a multifocal autoinflammatory disease that often impairs daily life in children. This study aimed to investigate the bone metabolic and inflammatory characteristics of patients with CNO, and to assess the differences between responders and nonresponders to conservative treatment., Methods: We investigated the clinical symptoms; laboratory data including inflammatory and bone metabolic biomarkers; and imaging findings from plain radiography, magnetic resonance imaging (MRI), fluorodeoxyglucose-positron emission tomography (FDG-PET), and dual-energy x-ray absorption (DEXA) in 14 patients with CNO. All patients underwent first-line treatment comprising systemic nonsteroidal anti-inflammatory drugs with or without bisphosphonate. According to the response to the first-line treatment, the patients were divided into the clinical remission/partial response group and the no response group. The differences in bone metabolic and inflammatory characteristics between the two groups were assessed., Results: All patients had low bone mineral density assessed with DEXA. The bone metabolic biomarkers (bone-specific alkaline phosphatase and tartrate-resistant acid phosphatase 5b) were increased in boys of all ages and in young girls. Multiple inflammatory regions were detected in all patients by using FDG-PET including asymptomatic regions. The no response group had higher immunoglobulin G (IgG) and a greater number of bone inflammatory lesions detected on MRI than the clinical remission/partial response group., Conclusion: Our data indicate the involvement of abnormal bone turnover, necessity of whole-body scanning, and association of higher serum IgG levels and greater numbers of inflammatory lesions with prolonged disease activity in patients with CNO.

Chronic nonbacterial osteomyelitis (CNO) is an autoinflammatory bone disorder, covering a clinical spectrum with asymptomatic inflammation of single bones at the one end, and chronic recurrent multifocal osteomyelitis (CRMO) at the other end. The exact molecular pathophysiology of CNO remains largely unknown. Provided familial clusters and the association with inflammatory disorders of the skin and intestine suggest a genetic predisposition. Recently, profound dysregulation of cytokine responses was demonstrated in CRMO. Failure to produce antiinflammatory cytokines interleukin (IL)-10 and IL-19 contributes to activation of inflammasomes and subsequent IL-1β release. In IL-10-deficient and in CNO-prone chronic multifocal osteomyelitis mice, IL-1β was linked to bone inflammation. Further, alterations to the gut microbiome were suggested in contributing to IL-1β release from innate immune cells in mice, offering an interesting target in the search for molecular mechanisms in CNO. Here, we summarize clinical presentation and treatment options in CNO/CRMO, current pathophysiological concepts, available mouse models, and promising future scientific directions.

Aim: The aim of this Italian study was to describe the clinical features, treatment options and outcomes of a cohort of patients with chronic nonbacterial osteomyelitis (CNO)., Methods: This was a retrospective cohort study. Laboratory data, diagnostic imaging, histological features and clinical course are reported., Results: We enrolled 47 patients diagnosed with CNO. Bone pain was the leading symptom, and multifocal disease was present in 87% of the patients. The majority of the bone lesions were located in the appendicular skeleton (58%). Extraosseous manifestations were present in 34% of the patients, and renal involvement was detected in four patients. Inflammatory indices were increased in 80%, and bone x-rays were negative in 15% of the patients. Nonsteroidal anti-inflammatory drugs (NSAIDs) were the first therapy for all patients, achieving clinical remission in 27%. A good response to NSAIDs was significantly associated with a better prognosis. Bisphosphonates were used in 26 patients, with remission in 73%. Only six patients (13%), all with spine involvement, developed sequelae., Conclusion: We found a possible association between CNO and renal disease. Bisphosphonates were more likely to lead to clinical remission when NSAIDs and corticosteroids had failed. Vertebral localisation was the only risk factor for potential sequelae., (©2016 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

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.

Introduction: 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., Methods: 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., Results: 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., Conclusions: 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., (© 2015 The Royal Australian and New Zealand College of Radiologists.)

Objective: To retrospectively assess changes in disease activity and skeletal damage in children with chronic nonbacterial osteomyelitis (CNO) after infliximab and methotrexate, with or without zoledronic acid or nonsteroidal antiinflammatory drug (NSAID) monotherapy, using a standardized magnetic resonance imaging (MRI) approach., Methods: Treatment-related changes in clinical and MRI measures from aggressive therapy and NSAID monotherapy groups (n = 9 per group) were evaluated using nonparametric methods., Results: Pain, physical function, physician global assessment, inflammatory markers, nonvertebral inflammatory lesion number, and maximum bone edema score all improved significantly with aggressive therapy (p < 0.03), whereas only the maximum soft tissue inflammation severity decreased (p = 0.02) with NSAID monotherapy. Vertebral deformities and physeal damage did not worsen in the aggressive therapy group but 1 in the NSAID group had worsening of growth plate damage., Conclusion: An aggressive treatment regimen in CNO improved clinical and imaging measures of disease activity without progression of skeletal damage.

Chronic noninfectious osteomyelitis or chronic nonbacterial osteomyelitis (CNO), also known as chronic recurrent multifocal osteomyelitis, is an autoinflammatory bone disorder primarily affecting the pediatric age group. Currently, it is diagnosed on the basis of clinical, laboratory, and imaging features. Imaging plays a crucial role in the diagnosis and follow-up of CNO with whole body magnetic resonance imaging (WBMRI) being the main modality. Radiographs assist in exclusion of common differential diagnoses like infections and malignancy. WBMRI aids in disease detection and exclusion of differential diagnoses, identifies additional lesions, and has a role in ascertaining the pattern of bony involvement which helps with prognostication and grading. Recent recognition of specific morphological and distribution patterns on WBMRI is increasingly allowing an upfront diagnosis of this entity to be made on imaging alone. It is also helpful for assessment of response to therapy during follow-up. This review aims to summarize the role of imaging in the evaluation of CNO, with special emphasis on WBMRI in its assessment. [ABSTRACT FROM AUTHOR]

Bone marrow is a highly cellular tissue undergoing significant developmental and physiologic changes with age. Indeed, with maturation from pediatric to the adult age there is a progressive, centrifugal conversion from red to yellow bone marrow. Histological characteristics of bone marrow are reflected in MR image signal. MR is therefore extremely sensitive in detecting pathological changes which are mostly characterized by increased free water causing high signal intensity on T2. Among the numerous diseases causing bone marrow edema in children chronic nonbacterial osteomyelitis (CNO) certainly has to be mentioned. This idiopathic inflammatory disorder is characterized by nonspecific migrating symptoms like skeletal pain with phases of exacerbations and relapses with alternating acute and chronic MR signs and it is often a diagnosis of exclusion. Hence, with bone marrow edema, various features at imaging should be considered to differentiate malignancies such as osseous lymphoma, osteosarcoma, and Ewing's sarcoma as well as benign lesions like osteomyelitis, post-traumatic, or post-treatment bone marrow edema. The aim of this review is to recall the main characteristics of CNO and provide an overview of its main mimickers highlighting similarities and differences. [ABSTRACT FROM AUTHOR]

Introduction. Chronic recurrent multifocal osteomyelitis (CRMO) is a pediatric autoinflammatory disorder that is characterized by multiple sterile inflammatory bone lesions with a relapsing and remitting course. CRMO belongs to the autoinflammatory family of rheumatologic disorders based on absence of significant titers of autoantibodies and autoreactive T-lymphocytes. In absence of pathognomonic clinical, radiographic or pathological features, diagnosis can be challenging. Case presentation. We report an unusual case of a 3-year-old girl presenting back pain, neurogenic bladder and syringomyelia. A tethered cord was diagnosed and treated, improving urinary function. Despite the surgical treatment, back pain was persistent. A whole body MRI showed multiple lesions compatible with chronic recurrent multifocal osteomyelitis. Conclusion. CRMO shares imaging features with other diseases. It is important for neurosurgeons and radiologists to be able to differentiate other diseases from CRMO because prognosis varies from completely benign to frankly malignant. [ABSTRACT FROM AUTHOR]

Introduction: chronic nonbacterial osteomyelitis (CNO) is an autoinflammatory bone disorder, that most commonly first appears in childhood. Symptoms can be nonspecific at first (fever, night sweats, fatigue), followed by bone pain, bone swelling, nocturnal pain, and impaired function of the affected part of the body. Diagnosis is usually delayed, because there are no widely accepted criteria for CNO, so differentialdiagnoses need to be excluded (malignancy, infection). It can be accompanied by severe complications (vertebral fractures). Case report: this case series presents three female patients who were diagnosed with chronic nonbacterial osteomyelitis. They were referred to a pediatric rheumatologist a minimum of eight months after the first symptoms occurred. The most frequent symptoms were nocturnal bone pain and swelling. None of the patients had a fever. The bones primarily affected were the clavicle, mandible, humerus and vertebra with secondary complications such as compressive vertebral fractures, and scoliosis. One developed paradoxical psoriasis while being treated with TNF inhibitors. Conclusion: this case report highlights the importance of considering chronic nonbacterial osteomyelitis as a potential cause of bone swelling and pain. The key factors for improving the outcome of patients with CNO are early recognition and timely treatment, as well as a multidisciplinary approach due to the complexity of the diagnosis. [ABSTRACT FROM AUTHOR]

Spinal involvement by chronic non-bacterial osteomyelitis (CNO) has been increasingly reported in recent years, often being presented as a diagnostic dilemma requiring differential diagnosis with bacterial spondylodiscitis and/or neoplasia. This study was aimed at identifying the imaging features of CNO facilitating its differentiation from other spinal diseases. Two radiologists assessed the imaging studies of 45 patients (16 male and 29 female, aged from 6 to 75 years, 15 children) with CNO collected from 5 referential centers. Spinal lesions were found in 17 patients (2 children and 15 adults), most often in the thoracic spine. In children, the lesions involved short segments with a destruction of vertebral bodies. In adults, the main findings were prominent bone marrow edema and osteosclerosis, endplate irregularities, and ankylosing lesions extending over long segments; paraspinal inflammation was mild and abscesses were not observed. In both children and adults, the involvement of posterior elements (costovertebral and facet joints) emerged as an important discriminator between CNO and neoplasia/other inflammatory conditions. In conclusion, a careful inspection of imaging studies may help to reduce the number of biopsies performed in the diagnostic process of CNO. [ABSTRACT FROM AUTHOR]

Differential diagnosis of bacterial osteomyelitis (BOM) and chronic nonbacterial osteomyelitis (CNO) is challenging. Pediatric CNO can be diagnosed at around 10 years of age and when CNO cases involve only the jaw, it is difficult to make a diagnosis in a young child. A 3-year-old female developed CNO at the jaw alone. She presented with no fever, right jaw pain, mild trismus, and a preauricular facial swelling around the right mandible. Computed tomography (CT) revealed a hyperostotic right mandible, with osteolytic and sclerotic changes associated with periosteal reaction. At first, we suspected BOM and antibiotics were administered. Subsequently, CNO was diagnosed, and the patient received flurbiprofen (a nonsteroidal anti-inflammatory drug (NSAIDs)). Lack of a sufficient response led to successful treatment with a combination of oral alendronate and flurbiprofen. Physicians should be aware of CNO, a rare autoinflammatory noninfectious bone disease of unknown etiology, even in young children, although the disease mostly affects older children and adolescents. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the clinical and radiological findings of the patients with chronic recurrent multifocal osteomyelitis (CRMO) and to present the benefits of using whole-body magnetic resonance imaging (WBMRI) in these patients and the changes we have made in the technique. Methods: A total of 45 patients who underwent WBMRI between 2017 and 2021 were included in the study. All WBMRI scans included coronal short tau inversion recovery (STIR), coronal T1W, and sagittal spinal STIR sequences. The examination time was 40 min on average. All WBMRIs were evaluated at two different time. At first assessment, only coronal STIR images were evaluated in all patients. In the second assessment, the same patients evaluated with all the sequences. The contribution of coronal T1W and sagittal STIR sequences to the diagnosis was investigated by comparing the first evaluation with the second evaluation. Thirty five patients were diagnosed with CRMO. The remaining 10 patients had other inflammatory, infective, and neoplastic diseases. The diagnosis of 15 patients with CRMO was based on bone marrow biopsy results. Also, biopsy was performed in 10 patients diagnosed as non-CRMO. Results: Most of the patients had multifocal bone lesions, particularly in the metaphyses adjacent to the epiphyseal region. The bones of the lower extremities were the most commonly affected. The mean delay in diagnosis was 17 months (0-96), and the follow-up period was 20 months (1-47) in a total of 35 patients, with a recurrence rate of 28%. In most patients (88%), lesions could be identified from coronal STIR images alone at the initial evaluation. However, in 5 patients whose diagnosis was missed when evaluated only from coronal STIR images, lesion identification and possible preliminary diagnosis were detected only with coronal T1W and sagittal STIR images in the second look. Conclusion: WBMRI is an important examination of systemic diseases such as CRMO that involve multiple sites. In addition to coronal STIR sequences, coronal T1-weighted and sagittal STIR sequences are important in identifying other infective-inflammatory diseases and particularly hematological malignant processes in the differential diagnosis of CRMO. [ABSTRACT FROM AUTHOR]