Autoinflammatory Bone Disease Research Articles

An improved understanding of paediatric chronic nonbacterial osteomyelitis (CNO) pathophysiology informs current and future treatment.

Chronic nonbacterial osteomyelitis (CNO) is an autoinflammatory bone disease that primarily affects children and young people. It can cause significant pain, reduced function, bone swelling and even (vertebral body) fractures. Because of a limited understanding of its pathophysiology, the treatment of CNO remains empiric and is based on relatively small case series, expert opinion and personal experience. Several studies linked pathological NLRP3 inflammasome activation and the resulting imbalance between pro- and anti-inflammatory cytokine expression with CNO. This agrees with elevated pro-inflammatory (mostly) monocyte-derived protein signatures in the blood of CNO patients that may be used as future diagnostic and/or prognostic biomarkers. Recently, rare variants in the P2RX7 gene, encoding for an ATP-dependent trans-membrane channel, were linked with increased NLRP3 inflammasome assembly and prolonged monocyte/macrophage survival in CNO. While the exact molecular mechanisms remain unclear, this will inform future target-directed and individualized treatment. This manuscript reviews most recent developments and their impact on diagnostic and therapeutic strategies in CNO.

Pamidronate for pain in adult chronic nonbacterial osteitis (PAM-CNO): protocol of a randomized, double-blind, placebo-controlled trial

Abstract Chronic nonbacterial osteitis (CNO) is a rare auto-inflammatory bone disease affecting children and adults. Adult CNO is characterized by painful bone lesions, primarily of the anterior chest wall. There is no approved therapy for adult CNO. Current off-label treatments include intravenous bisphosphonates, which have been shown to alleviate pain through decreasing bone turnover. However, no adequately powered randomized controlled trials (RCTs) have been conducted. This double-blind, placebo-controlled RCT investigates the efficacy of intravenous pamidronate to decrease bone pain in adult CNO patients. Recruiting at the Dutch national referral center for CNO, adult patients with persistent bone pain despite non-steroidal anti-inflammatory drugs, or optionally other standard-of-care treatments are randomized to receive two courses of intravenous pamidronate (at 0 and 3 months, 30 mg daily, on 3 consecutive days) or placebo. From 6 months onwards, all patients receive open-label pamidronate for another two courses. The primary outcome is change in score for maximum pain from 0-6 months. Secondary outcomes include change in quantitative intralesional bone turnover as measured on sodium-fluoride positron emission computed tomography ([18F]NaF-PET/CT), inflammation markers, shoulder function, general health, quality of life, fatigue, physical and work activity. The PAM-CNO trial addresses the need for evidence-based treatments in adult CNO. Results will directly impact daily clinical practice, either validating the use of intravenous pamidronate in CNO at the dose used in this trial, or prompting the search for alternative regimens or agents. This trial was registered in EudraCT (reference 2020-001068-27), and the Dutch Trial Register (reference NL68020.058.20).

Chronic non-bacterial osteomyelitis (CNO) and chronic recurrent multifocal osteomyelitis (CRMO) with a focus on pamidronate therapy.

Chronic recurrent multifocal osteomyelitis (CRMO), also called chronic nonbacterial osteomyelitis (CNO) or nonbacterial osteomyelitis (NBO), is a rare autoinflammatory bone disease of unknown etiology. However, the number of patients properly diagnosed would increase with better knowledge of the disease. In this regard, whole-body magnetic resonance imaging (WB MRI) has been found to be a better predictor of active lesions than clinical examination. Importantly, the RINBO index (radiologic index for NBO) quantifies the involvement based on the WB MRI. Further, a chronic nonbacterial osteomyelitis MRI scoring (CROMRIS) has been developed as an online tool for assessing WB MRI. The therapy consists of non-steroidal anti-inflammatory drugs (NSAIDs), bisphosphonates (pamidronate, zoledronate, etc.) and other drugs, including biologics. Pamidronate is an appropriate and safe therapy. The first pilot prospective randomised controlled trial (RCT) on pamidronate vs. placebo was carried out in adults. No RCT has been done in children yet. Besides RCTs, there are a number of issues to be explored in future, i.e. predictors of therapy effect, optimal therapy duration, predictors of therapy discontinuation and evaluation of optimal therapy protocol. Recently, the CNO clinical disease activity score (CDAS) was constructed and validated but the classification criteria are still being developed. As collaboration on this rare disease is essential, a prospective Chronic Nonbacterial Osteomyelitis International Registry (CHOIR) was established to generate future comparative effectiveness research data.

P019 Comparison of newly proposed chronic nonbacterial osteomyelitis classification criteria to previous diagnostic criteria

Abstract Background/Aims Chronic nonbacterial osteomyelitis (CNO) is an aseptic autoinflammatory bone disease of unknown etiology. This diagnosis can be delayed due to the non-specific nature of symptoms and normal imaging studies. New classification criteria were proposed in 2022. This study seeks to validate these new classification criteria by comparing them to previous diagnostic criteria in a cohort of known CNO patients. Methods This is a retrospective case-series of pediatric patients diagnosed with CNO (n = 39) between 2012 and 2023 in Virginia, USA. The newly proposed classification criteria (Table 1) was applied to this cohort. The entry criteria of chronic bone pain, age <18 years, abnormal radiograph and/or MRI were used prior to applying the newly proposed classification criteria. The 2008 Jansson diagnostic criteria and 2016 Bristol diagnostic criteria were also applied to the cohort for comparison and further validation. The clinical manifestations, laboratory results, and imaging studies that lead to a diagnosis of CNO were reviewed. Results The average age of diagnosis was 10 (range 2-17) years-old with the average time between onset of symptoms to confirmed clinical diagnosis being 24 (range 1-120) months. The most common presenting symptoms were bone pain (100%) and arthritis (49%). Evidence of radiographic abnormalities leading to CNO diagnosis was found with regional MRI (64%), bone scan (44%) with some requiring full body MRI (31%). Only one patient did not meet the new classification criteria (1/39; 3%) because of age <3 years, fever and elevated ESR which together gave less than the required 55 points for criteria fulfillment. One different patient (1/39; 3%) did not meet both the Bristol and Jansson criteria because of unifocal disease and lack of bone biopsy. Conclusion This retrospective chart review validates the newly proposed classification criteria for CNO. Older diagnostic criteria (Jansson and Bristol) both require advanced imaging and at times bone biopsy for fulfillment. We conclude that the newly proposed criteria is easy to apply even in the absence of a bone biopsy or advanced imaging studies. The newly proposed criteria will aid in the development of a homogeneous cohort for future studies about CNO. Disclosure A.M. Patel: Member of speakers’ bureau; ABBVIE, AMGEN, SANOFI. K.S. Lee: None. A.J. Kim: None.

Defining the imaging diagnostic criteria for adult chronic non-bacterial osteitis.

Osteitis of the sternocostoclavicular (SCC) region, referred to as sternocostoclavicular hyperostosis (SCCH), is the clinical expression of chronic non-bacterial osteitis (CNO) in adults with this rare chronic auto-inflammatory disorder of the axial skeleton. The diagnosis is based on distinctive computerized tomography (CT) features of sclerosis and hyperostosis of the SCC region, and local increases in osteoid formation visualized by high radiopharmacon uptake on skeletal scintigraphy but clear radiologic diagnostic criteria are lacking. In a cross-sectional study, CT scans and whole-body skeletal scintigraphy images obtained in 169 patients seen at the Center for Bone Quality of the Leiden University Medical Center between 2008 and 2018 with a suspected diagnosis of CNO of the SCC region were re-evaluated by 2 skeletal radiologists and 2 nuclear physicians. The diagnosis was confirmed in 118 (70%) predominantly female patients (n= 103, 89.2%); median age at first symptoms 45years (range 20-73). The diagnosis was excluded in the remaining 51 "non-CNO" patients. Increased radiopharmacon uptake at the SCC region was observed in 82% CNO patients, with the manubrium sterni having the highest predictive ability to discriminate on both imaging modalities. The prevalence of sclerosis of the clavicles, manubrium and first ribs was significantly higher in CNO patients (P< 0.001). Hyperostosis was not observed in non-CNO patients. 46 CNO versus only 2 non-CNO patients had costoclavicular ligament calcification. Our findings identify CT scan features of sclerosis and hyperostosis of manubrium sterni, medial end of clavicles and first ribs, and calcification of costoclavicular ligaments, associated with increased tracer uptake on skeletal scintigraphy at the SCC region, specifically manubrium sterni, as well-defined imaging diagnostic criteria for adult CNO. Pitfalls encountered in the diagnosis of CNO are highlighted. These defined imaging diagnostic criteria for adult CNO should facilitate the diagnosis of this rare auto-inflammatory bone disease across the spectrum of its early to late stages.

P2RX7 gene variants associate with altered inflammasome assembly and reduced pyroptosis in chronic nonbacterial osteomyelitis (CNO)

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.

Update on ocular manifestations of the main monogenic and polygenic autoinflammatory diseases.

Autoinflammatory diseases include disorders with a genetic cause and also complex syndromes associated to polygenic or multifactorial factors. Eye involvement is present in many of them, with different extent and severity. The present review covers ophthalmological lesions in the most prevalent monogenic autoinflammatory diseases, including FMF (familial Mediterranean fever), TRAPS (TNF receptor-associated periodic syndrome), CAPS (cryopyrin-associated periodic syndromes), Blau syndrome, DADA2 (deficiency of adenosine deaminase 2), DITRA (deficiency of the interleukin-36 receptor antagonist), other monogenic disorders, including several ubiquitinopathies, interferonopathies, and the recently described ROSAH (retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and headache) syndrome, and VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. Among polygenic autoinflammatory diseases, ocular manifestations have been reviewed in Behçet's disease, PFAPA (periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis) syndrome, Still's disease and autoinflammatory bone diseases, which encompass CRMO (chronic recurrent multifocal osteomyelitis) and SAPHO (synovitis, acne, pustulosis, hyperostosis and osteitis) syndrome.

Chronic Nonbacterial Osteomyelitis in Inflammatory Bowel Disease.

Chronic nonbacterial osteomyelitis (CNO), also known as chronic recurrent multifocal osteomyelitis (CRMO), is a rare autoinflammatory bone disease primarily affecting children and adolescents. This review presents a comprehensive analysis of the intricate relationship between CNO and inflammatory bowel disease (IBD), shedding light on shared pathophysiological mechanisms and clinical management. A thorough literature review was conducted, encompassing 24 case reports involving 40 patients. The demographic distribution of patients revealed a near-equal gender ratio, with a median age of diagnosis at 12 years. The diagnosis patterns showed a higher proportion of CNO as the initial diagnosis, while Crohn's disease was more prevalent than ulcerative colitis. The time interval between the clinical presentations varied, ranging from simultaneous detection to a substantial 15-year gap. Treatment modalities included nonsteroidal anti-inflammatory drugs (NSAIDs), steroids, aminosalicylates, and biologic agents, such as infliximab, often overlapping in their use and suggesting shared pathophysiological pathways. Both conditions displayed systemic manifestations, and patients often responded well to immunosuppressive medications. The pathophysiology of CNO involves a genetic predisposition, cytokine dysregulation, and osteoclast activation. Dysregulated innate immunity results in immune cell infiltration into bones, causing sterile bone lesions. Notably, emerging evidence hints at a potential link between the microbiome and CNO. In contrast, IBD results from imbalanced mucosal immune responses to the intestinal microbiota. Polymorphisms in the promotor region of IL-10, common cytokines, immune cells, and genetic markers indicate shared immunological and genetic factors between CNO and IBD. Both conditions also involve extraintestinal symptoms. This analysis underscores the need for clinical awareness of the co-occurrence of CNO and IBD, especially among pediatric patients. A deepened understanding of the connections between these seemingly distinct diseases could lead to more effective management and improved patient outcomes.

Long-term follow-up of children with chronic non-bacterial osteomyelitis—assessment of disease activity, risk factors, and outcome

IntroductionChronic 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.ObjectiveTo assess characteristics, courses, and outcomes of CNO with onset in childhood and adolescence and to identify outcome predictors.MethodsFrom 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.ResultsFour 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.ConclusionAn 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.

Inflammatory Diseases of the Eye, Bowel, and Bone in Children.

Pediatric rheumatological diseases present with diverse manifestations affecting various tissues and organs. Though most childhood illnesses with immune dysregulation affect multiple organs or systems simultaneously or gradually, few inflammatory conditions affect certain organs as distinguished primary targets. Pediatric inflammatory diseases of the eye, bowel, and bone represent significant disorders with heterogeneous entities with varying pathophysiological basis like chronic inflammation, vasculitis, autoimmunity, and autoinflammation. Associations or complications of these diseases may remain obscure if their extensions are not explored specifically. Pediatric uveitis, non-uveitic inflammatory diseases, inflammatory bowel diseases, and autoinflammatory bone diseases are the important constituents of this cluster. The author concisely discusses these disorders in this review from pediatric rheumatological perspective. If untreated, these diseases may be organ-threatening. Outcomes are vastly different in undiagnosed patients and in timely diagnosed and treated patients. Lack of awareness and missed exploration of associated illnesses and complications may result in a missed diagnosis or inadequate symptomatic treatment. A multidisciplinary approach to diagnosis and treatment is desirable in these heterogeneous entities. Pediatricians must be aware of the immunological origin of organ-centered symptoms and signs. A proper understanding of molecular details of etiopathogenesis and significant advances in therapy have reduced the morbidity, disability, and mortality of such disorders.

OA02 Validation of newly proposed ACR/EULAR classification criteria for pediatric chronic nonbacterial osteomyelitis

Abstract Background Chronic nonbacterial osteomyelitis (CNO) is an aseptic autoinflammatory bone disease of unknown aetiology. This diagnosis can be delayed due to the non-specific nature of symptoms, referral patterns to non-rheumatology specialists and normal imaging studies. New ACR/EULAR classification criteria have been proposed for CNO and were presented at the American College of Rheumatology scientific meeting in 2022. This study seeks to validate these new classification criteria. Methods This is a retrospective case-series of paediatric patients diagnosed with CNO (n = 34). They were diagnosed and managed between 2012 and 2022 at the University of Virginia in Charlottesville, Virginia and Bon Secours Mercy Health in Richmond, Virginia. The entry criteria of chronic bone pain, age &amp;lt; 18 years, abnormal radiograph and/or MRI were used prior to applying the newly proposed ACR/EULAR classification criteria. Ten domains were evaluated to indicate whether a patient has CNO; those who scored 55 points or higher qualified (see table). The clinical manifestations, laboratory results, and imaging studies that lead to a diagnosis of CNO were reviewed in detail. We applied and validated the newly proposed classification criteria for CNO to this Virginia cohort of previously diagnosed paediatric CNO patients. We also reviewed the characteristics of those that did not fulfill these classification criteria. Result Upon application of the newly proposed ACR/EULAR classification criteria for CNO, 31 out of 34 patients (91%) were found to meet these classification criteria. Of the three patients diagnosed with CNO that did not fulfill the criteria, none had ‘least specific sites’ such as hands or neurocranium, all had elevated ESR and two out of three had an initial response to antibiotics. Their scores were 49, 51 and 53 with classification criteria being met with 55 or higher. The average age at diagnosis was 10 (range 2–17) years-old with the average time between onset of symptoms to confirmed radiographic evidence being 25 (range 1–120) months. The most common presenting symptoms were bone pain (100%) and arthritis (52%) with fever (23%) and rash (3%) being less common. Elevated ESR (39%) and CRP (39%) were found at initial visit with rheumatology. Evidence of commonly seen radiographic abnormalities leading to CNO diagnosis was found with regional MRI (65%), bone scan (42%) with some requiring full body MRI (26%) to confirm other lesions. Some patients did have multiple imaging studies including X-ray, CT, bone scan, MRI and bone biopsy in their workup. Conclusion This retrospective chart review validates the newly proposed ACR/EULAR classification criteria for CNO. We conclude that these criteria are easy to apply even in the absence of a bone biopsy or advanced imaging studies. This will aid in the development of a homogeneous cohort for future studies in CNO. Implication The newly proposed ACR/EULAR classification criteria can be easily applied to a cohort of CNO patients. These criteria have taken into account the lack of advanced imaging availability in certain institutions and lack of availability of a bone biopsy. Our work is ethically approved.

Adult-onset chronic recurrent multifocal osteomyelitis: a case report.

Chronic recurrent multifocal osteomyelitis (CRMO) is an autoinflammatory bone disease predominantly affecting the metaphyses of long bones and is usually seen in children. Although CRMO is generally a pediatric disease, it may also occur in adults. This may result in a delay in the diagnosis of adult-onset CRMO. This report presents an adult-onset female patient who presented with left leg pain followed by swelling in the right knee. The patient was initially started on colchicine treatment, but, due to unresponsiveness in the follow-up the patient, the treatment was switched to a combination of methotrexate and prednisolone. A satisfactory clinical recovery was achieved with these drugs. CRMO could be considered in the differential diagnosis of patients presenting with bone pain and joint complaints. Considering that the disease progresses with clinical flare-ups and remission periods, it should be kept in mind that patients should be followed closely and treatment can be changed.

Diagnostic and therapeutic practices in adult chronic nonbacterial osteomyelitis (CNO)

BackgroundChronic 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.MethodsA 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.Results36 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.ConclusionsFollowing 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.

Update on treatment responses and outcome measure development in chronic nonbacterial osteomyelitis.

To review recent trends in treatment and recent progress in developing outcome measures needed for chronic nonbacterial osteomyelitis (CNO) clinical trials. CNO is an autoinflammatory bone disease. In a minority of patients, the disease is genetically driven, and diagnosis can be made by DNA sequencing. However, for nonsyndromic CNO there is no diagnostic test. The number of children with CNO appears to be increasing and damage is common. Increases in CNO diagnosis is due to raised awareness, increased availability of whole-body magnetic resonance imaging and rising incidence. Treatment remains empiric and it is unclear which second line treatment is superior. Tumor necrosis factor inhibitors (TNFi) and bisphosphonates continue to be used as second line agents for nonsteroidal anti-inflammatory drugs (NSAID) refractory CNO; newer immune modulatory medications are used if this fails. Validated classification criteria, clinical outcome measures and imaging scoring standards are needed for successful clinical trials. Best treatment for NSAID refractory CNO remains unclear. Classification criteria, clinical outcomes measures and standardized imaging scoring have been developed or are near completion. This will facilitate robust clinical trials in CNO with the goal of having approved medications for this painful disease.

Priorities in Chronic nonbacterial osteomyelitis (CNO) – results from an international survey and roundtable discussions

ObjectiveChronic 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.MethodsA 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).ResultsResponses were used to select topics for four moderated roundtable discussions at the “International Conference on CNO and autoinflammatory bone disease” (Liverpool, United Kingdom, May 25-26th, 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.ConclusionsAgreement 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.

Pediatric autoinflammatory bone disorders-a mini review with special focus on pathogenesis and inborn errors of immunity.

Autoinflammatory bone disorders are a group of diseases characterized by sterile osteomyelitis. This includes chronic nonbacterial osteomyelitis and the monogenic forms, Majeed syndrome and deficiency of the interleukin-1 receptor antagonist. These disorders result from innate immune system dysregulation and cytokine imbalance that triggers inflammasome activation causing downstream osteoclastogenesis and excessive bone remodeling. In this review, we will summarize the immunopathogenesis of pediatric autoinflammatory bone diseases with a special focus on the genetics and inborn errors of immunity, while briefly touching on the clinical manifestations and management of each disease as well as areas for future research.

Gathering expert consensus to inform a proposed trial in chronic nonbacterial osteomyelitis (CNO)

Chronic nonbacterial osteomyelitis (CNO) is an autoinflammatory bone disease that primarily affects children and adolescents. CNO is associated with pain, bone swelling, deformity, and fractures. Its pathophysiology is characterized by increased inflammasome assembly and imbalanced expression of cytokines. Treatment is currently based on personal experience, case series and resulting expert recommendations.Randomized controlled trials (RCTs) have not been initiated because of the rarity of CNO, expired patent protection of some medications, and the absence of agreed outcome measures. An international group of fourteen CNO experts and two patient/parent representatives was assembled to generate consensus to inform and conduct future RCTs.The exercise delivered consensus inclusion and exclusion criteria, patent protected (excludes TNF inhibitors) treatments of immediate interest (biological DMARDs targeting IL-1 and IL-17), primary (improvement of pain; physician global assessment) and secondary endpoints (improved MRI; improved PedCNO score which includes physician and patient global scores) for future RCTs in CNO.

Diagnosis and Treatment of Chronic Non-bacterial Osteomyelitis: A Survey on Current Practices Adopted by Pediatric Rheumatologists in Saudi Arabia.

Chronic nonbacterial osteomyelitis (CNO) is an autoinflammatory bone disease usually managed by pediatric rheumatologists (PRs). There is a need for a consensus treatment plan to minimize the diversity in clinical practice in the diagnosis and management of CNO. In this study, we explored the practice of PRs in Saudi Arabia on the diagnosis and treatment of patients with CNO. This is a cross-sectional study that was conducted among PRs in Saudi Arabia (May to September 2020). A survey was performed among PRs registered in the Saudi Commission for Health Specialties using an electronic-based questionnaire. The survey consisted of 35 closed-ended questions about the diagnosis and management of CNO patients. We explored the approaches adopted by PRs in diagnosing and monitoring the disease activity, their awareness of clinical possibilities that necessitate ordering bone biopsy, and the treatment choices they considered for CNO patients. We scrutinized data from a total of 77% (n=41/53) PRs who responded to our survey. Magnetic resonance imaging (MRI) was reported as the most frequently used modality in suspected CNO (82%, n=27/33), followed by plain X-ray (61%) and bone scintigraphy (58%). Magnetic resonance imaging of a symptomatic site is the imaging modality of choice for the diagnosis of CNO (82%), Followed by X-ray (61%) and bone scintigraphy (58%). The reasons for performing bone biopsy were unifocal lesions (82%), unusual sites of presentation (79%), and multifocal lesions (30%). The preferred treatment regimens were bisphosphonates (53%), non-steroidal anti-inflammatory drugs alone (43%), or biologics with bisphosphonates (28%). The reasons to upgrade the treatment in CNO included the development of vertebral lesions (91%), the development of new lesions in MRI (73%), and the elevation of inflammatory markers (55%). The disease activity was assessed by history and physical examination (91%), inflammatory markers (84%), MRI of targeted symptomatic site (66%), and a whole-body MRI (41%). The approach todiagnosis and treatment of CNO varies among PRs in Saudi Arabia. Our findings provide a background for the development of a consensus treatment plan for challenging CNO patients.

Experience of successful treatment of a patient with chronic non-bacterial osteomyelitis (clinical case)

BACKGROUND: Chronic nonbacterial osteomyelitis is a rare autoinflammatory bone disease with periods of relapses and remissions. No etiotropic therapy, diagnostic and treatment standards exist, patients are observed by rheumatologists, immunologists, and orthopedist. They receive symptomatic, anti-inflammatory treatment, broad-spectrum antibiotics, immunosuppressants to control inflammation, which helps to prevent new or to reduce existing pathological foci.&#x0D; CLINICAL CASE DESCRIPTION: This article describes the effect of immune therapy and osteotropic treatment with zoledronic acid combination in a patient with chronic non-bacterial osteomyelitis. In a clinical observation involving comprehensive examination, including radiological (radiography, computed tomography and magnetic resonance imaging) and laboratory methods, a positive outcome was achieved using conservative methods of treatment in a patient with chronic non-bacterial sternum osteomyelitis.&#x0D; CONCLUSION: Thus, a combination of bisphosphonates and immunotherapy may be promising in the treatment of chronic non-bacterial osteomyelitis. However, it is unknown as to how long the remission will last and what treatment program is necessary for the final disease resolution.

Chronic Nonbacterial Osteomyelitis and Inflammatory Bowel Disease: A Literature Review-Based Cohort.

Chronic nonbacterial osteomyelitis (CNO) is a rare autoinflammatory bone disorder that mainly involves children and adolescents. The association with other inflammatory disorders, such as inflammatory bowel disease (IBD), psoriasis, and arthritis, has been reported in the literature. In particular, the relationship between bone and intestinal inflammation is still poorly understood. For this purpose, our review aims to describe the cases reported in the literature concerning this association and to compare them with data from our single-center cohort of patients. We conducted a literature review of published cases of CNO associated with IBD. Eligible articles were identified through a Medline search in the PubMed database until December 2022. We retrospectively reviewed medical records of patients with CNO referred to G. Pini Hospital and compared them with the literature-review-based cohort. Fifty-seven patients with a defined diagnosis of CNO and associated IBD were described in the literature (female 55%). The median age of onset of the disease (CNO or IBD) was 11 years. In 32/53 (60%), a diagnosis of Crohn's disease (CD) was made, while 18 (34%) patients were classified as suffering from ulcerative colitis (UC) and 3 (6%) from undifferentiated IBD. The diagnosis of CNO preceded the diagnosis of IBD in 59% of cases; while in 24%, IBD anticipated CNO; and in 17%, the two conditions appeared simultaneously. The median time between the two events was 24 months. In our Italian cohort (n = 23 patients), no diagnosis of IBD was made. No significant differences were found when comparing clinical and demographical characteristics of the Italian vs. review-based cohort, except for a significant involvement of rachis in the Italian group. The correlation between autoinflammatory bone disease and intestinal inflammation should be further investigated. It is essential to promote awareness among pediatric rheumatologists and gastroenterologists about this possible association to facilitate the diagnosis and better optimize treatment.