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

PURPOSE OF REVIEW: To review recent trends in treatment and recent progress in developing outcome measures needed for chronic nonbacterial osteomyelitis (CNO) clinical trials. RECENT FINDINGS: 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. SUMMARY: 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.

Insurance Status and Tumor Necrosis Factor Inhibitor Initiation Among Children With Juvenile Idiopathic Arthritis in the CARRA Registry.

OBJECTIVE: Prompt escalation to tumor necrosis factor inhibitors (TNFis) is recommended for children with juvenile idiopathic arthritis (JIA) and ongoing disease activity despite treatment with conventional disease-modifying antirheumatic drugs (cDMARDs). It is unknown whether these recommendations are equitably followed for children with different insurance types. We assessed the association of insurance coverage on the odds and timing of TNFi use. METHODS: We conducted a retrospective study of children with newly diagnosed JIA in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry. We compared the odds of starting a TNFi in the first year and time from cDMARD to TNFi initiation between those with public and private insurance. RESULTS: We identified 1086 children with new JIA diagnoses. Publicly insured children had significantly higher active joint counts and parent/patient global assessment scores at the enrollment visit. They were also more likely to have polyarticular arthritis compared to those with private insurance. Odds of any TNFi use in the first year did not differ between publicly and privately insured children. Publicly insured children were escalated from cDMARD to TNFi more quickly than privately insured children. CONCLUSION: Children who were publicly insured had more severe disease and polyarticular involvement at registry enrollment compared to those who were privately insured. Whereas overall TNFi use did not differ between children with different insurance types, publicly insured children were escalated more quickly, consistent with their increased disease severity. Further research is needed to determine why insurance coverage type is associated with disease severity, including how other socioeconomic factors affect presentation to care.

Validating within-limb calibrated algorithm using a smartphone attached infrared thermal camera for detection of arthritis in children.

OBJECTIVES: To determine the impact of physical activity on temperature after within-limb calibration (TAWiC) measures and their reproducibility. To determine if thermal imaging from a smartphone attached thermal camera is comparable to thermal imaging using a handheld thermal camera for detection of arthritis in children. METHODS: Children without symptoms were enrolled to the "asymptomatic exercise cohort", and received infrared imaging, using a standard handheld camera, after initial resting period, after activity, and after second resting period. Children seen in the rheumatology clinic with knee pain were enrolled into the "symptomatic knee pain cohort" and received imaging with both the smartphone-attached and handheld cameras before a routine clinical exam. TAWiC was defined as the temperature differences between joint and ipsilateral mid-tibia as the main readout for arthritis detection. RESULTS: The asymptomatic exercise cohort demonstrated notable changes in absolute and TAWiC temperatures collected by thermal imaging after physical activity, and temperatures did not consistently return to pre-activity levels after a second period of rest. The 95th TAWiC from anterior view were, resting one -0.1 C (0.5), activity -0.7 C (0.5), resting two -0.2 C (0.6) (resting 1 vs resting 2, p-value = 0.13). In the symptomatic knee pain cohort, the smartphone attached and handheld thermal cameras performed similarly in regards to detection of joint inflammation and evaluation of joint temperature using the TAWiC algorithm, with high sensitivity of 80% (55.2-100.0%) and specificity of 84.2% (76.0-92.4%) in the anterior knee view when compared with the gold standard joint exam performed by a pediatric rheumatologist. The mean 95th TAWiC temperature difference between the two cameras was -0.1 C (-0.1 to 0.0) (p = 0.0004). CONCLUSIONS: This study showed continued validity of the TAWiC algorithm across two distinct thermal camera platforms and demonstrates promise for improved accessibility and utility of this technology for arthritis detection.

Psoriasis rate is increased by the exposure to TNF inhibition in children with JIA.

OBJECTIVE: We aimed to investigate the relationship between tumour necrosis factor inhibitors (TNFi) therapy and the onset of new psoriasis in children with juvenile idiopathic arthritis (JIA) using Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry data. METHODS: De-identified data were obtained from the CARRA Registry. Patients with inflammatory bowel disease or psoriasis documented on or prior to JIA diagnosis date or with incomplete data were excluded. Exposure to TNFi was categorised as: (1) ever use; (2) current use or (3) first use only. Adjusted HRs (aHRs) were calculated between exposed and unexposed groups adjusted for methotrexate exposure, sex, race, family history of psoriasis and initial JIA category. RESULTS: A total of 8225 patients were included with a median follow-up of 3.9 years. Over half of the patients were prescribed TNFi (n=4437, 54%). The aHR of new onset of psoriasis after ever exposure to TNFi was 2.93 (2.15 to 3.98). The incidence rate of psoriasis was the highest in children ever receiving and actively receiving adalimumab. Ever concurrent methotrexate use (HR 0.45, 0.29 to 0.69) was associated with lower risk. CONCLUSION: In a large prospective JIA patient registry, we observed a nearly threefold increased risk of psoriasis after TNFi exposureCite Now.

Whole-body MRI at initial presentation of pediatric chronic recurrent multifocal osteomyelitis and correlation with clinical assessment.

BACKGROUND: Chronic recurrent multifocal osteomyelitis (CRMO) is a diagnosis of exclusion, relying heavily on whole-body magnetic resonance imaging (WB-MRI) for diagnosing and evaluating response to therapy. Information with respect to disease distribution and imaging correlation with clinical disease severity at initial presentation is lacking. OBJECTIVE: To retrospectively characterize distribution of disease on WB-MRI and to correlate imaging findings with disease severity at initial rheumatology presentation. MATERIALS AND METHODS: Using a modified version of a recently devised imaging-based scoring system, we evaluated disease distribution and correlation between findings on WB-MRI and clinical disease severity in 54 patients presenting for initial evaluation of CRMO. Symptomatic lesion sites were extracted from chart review and physician global assessment was determined by the consensus of two rheumatologists. RESULTS: Sites of CRMO involvement evident on imaging at initial presentation had a strong predilection for the pelvis and lower extremities. There was significant correlation between the number of lesions detected on WB-MRI and total clinical severity score at initial rheumatology presentation (P<0.01). However, no other imaging parameter correlated with disease severity. CONCLUSION: While the overall number of lesions identified on MRI correlates with clinical severity scores at initial imaging, other MR parameters of CRMO lesions may not be reliable indicators of disease severity at initial presentation. Further research is needed to assess whether these parameters are implicated in longitudinal disease severity or overall response to therapy.

The Many Faces of Pediatric Chronic Recurrent Multifocal Osteomyelitis (CRMO): A Practical Location- and Case-Based Approach to Differentiate CRMO From Its Mimics.

Chronic recurrent multifocal osteomyelitis (CRMO) is an autoinflammatory bone disease of childhood and adolescence characterized by episodic bone pain. Diagnosis relies heavily on whole-body MRI and is made by excluding a wide variety of other disorders with overlapping imaging features, depending on location, marrow distribution, and the presence or absence of multifocality. We present an overview of the clinical and imaging features of CRMO and, through various clinical scenarios, provide tips for tailoring the differential diagnosis based on location and distribution of encountered abnormalities. LEVEL OF EVIDENCE: 4 TECHNICAL EFFICACY STAGE: 3.

Inflammatory manifestations in patients with Shwachman-Diamond syndrome: A novel phenotype.

Shwachman-Diamond syndrome (SDS) is an autosomal recessive multisystem disorder characterized by exocrine pancreatic dysfunction, bone marrow failure, and leukemia predisposition. Approximately 90% of cases are due to biallelic mutations in the Shwachman-Bodian-Diamond (SBDS) gene. Additional phenotypic features variably associated with SDS include skeletal, neurologic, hepatic, cardiac, endocrine, and dental abnormalities. We report five subjects with SDS who developed a range of inflammatory manifestations. Three patients developed inflammatory eye conditions. Single cases of juvenile idiopathic arthritis, chronic recurrent multifocal osteomyelitis, and scleroderma were also noted. Clinical presentation and treatment responses are described. Proteomic analysis revealed increased inflammatory signatures in SDS subjects as compared to controls. Treatment of inflammatory manifestations in patients with SDS may be complicated by potential myelosuppressive toxicities of anti-rheumatic medications. Further research is needed to better understand the potential link between inflammatory disorders and SDS to inform effective treatment strategies.

Chronic Recurrent Multifocal Osteomyelitis and Related Diseases-Update on Pathogenesis.

PURPOSE OF REVIEW: We focus on recent advances in the understanding of the genetic, molecular, immunologic, and environmental factors implicated in the pathogenesis of autoinflammatory bone diseases including the syndromic and non-syndromic forms of chronic recurrent multifocal osteomyelitis (CRMO). RECENT FINDINGS: Evidence implicating the IL-1 pathway in the pathogenesis of the Mendelian forms of CRMO is growing. LIPIN2 can regulate the NLRP3 inflammasome by affecting P2X7 receptor activation, and intracellular cholesterol can modulate P2X7R currents. Work in a mouse model of CRMO demonstrates that dietary manipulation can alter the microbiome and protect these mice from the development of sterile osteomyelitis in vivo. Although the genetic and immunologic basis of non-syndromic CRMO remains only partially understood, the IL-1 pathway is central to the pathogenesis in the syndromic autoinflammatory bone disorders. Recent work implicates lipids and the microbiome in sterile osteomyelitis.

Particulate matter and atherosclerosis: a bibliometric analysis of original research articles published in 1973-2014.

BACKGROUND: Epidemiological and experimental studies have suggested that exposure to particulate air pollution may promote progression of atherosclerosis. METHODS: In the present study, the characteristics and trends of the research field of particulate matter (PM) and atherosclerosis were analyzed using bibliometric indicators. Bibliometric analysis was based on original papers obtained from PubMed/MEDLINE search results (from 1973 to 2014) using Medical Subject Headings (MeSH) terms. A fully-detailed search strategy was employed, and articles were imported into the Thomson Data Analyzer (TDA) software. RESULTS: The visualizing network of the collaborative researchers was analyzed by Ucinet 6 software. Main research topics and future focuses were explored by co-word and cluster analysis. The characteristics of these research articles were summarized. The number of published articles has increased from five for the period 1973-1978 to 89 for the period 2009-2014. Tobacco smoke pollution, smoke and air PM were the most studied targets in this research field. Coronary disease was the top health outcome posed by PM exposure. The aorta and endothelium vascular were the principal locations of atherosclerotic lesions, which were enhanced by PM exposure. Oxidative stress and inflammation were of special concern in the current mechanistic research system. The top high-frequency MeSH terms were clustered, and four popular topics were further presented. CONCLUSION: Based on the quantitative analysis of bibliographic information and MeSH terms, we were able to define the study characteristics and popular topics in the field of PM and atherosclerosis. Our analysis would provide a comprehensive background reference for researchers in this field of study.

Judicious use of biologicals in juvenile idiopathic arthritis.

Juvenile idiopathic arthritis (JIA) is a chronic inflammatory disorder that may cause joint destruction. Biological treatments targeting specific cytokines and cell interactions have transformed the outcomes of JIA. This review focuses on the selection of patients for and the timing and selection of biological treatment in JIA. Tumor necrosis factor (TNF) inhibitors remain the first choice for polyarticular JIA, followed by abatacept and tocilizumab. Monoclonal-antibody TNF inhibitors and abatacept are usually chosen for methotrexate-resistant uveitis. Recent clinical trials of canakinumab, rilonacept, and tocilizumab have obtained great improvement in both systemic and arthritic features in chronic systemic JIA patients. Current guidelines support the early use of a short-acting IL-1 antagonist for macrophage activation syndrome, a life-threatening complication. TREAT and ACUTE studies suggest that a therapeutic window of opportunity during early disease may exist in JIA. Early initiation of biological therapy may be associated with slower progression of joint damage and longer remission.

Golimumab in Children with Chronic Recurrent Multifocal Osteomyelitis: A Case Series and Review of the Literature.

BACKGROUND: Chronic recurrent multifocal osteomyelitis (CRMO) is a rare autoinflammatory bone disease requiring immunosuppressive treatment in half of patients. Monoclonal tumor necrosis factor inhibitors (TNFi) are often used as effective second-line off-label therapies. However, paradoxical psoriasis can occur in a subset of patients exposed to monoclonal TNFi and can prompt conversion to alternate therapy if severe. OBJECTIVE: The aim of this study was to determine the efficacy and safety of golimumab, a fully humanized TNFi, in children with CRMO, including those who develop paradoxical psoriasis after exposure to other monoclonal TNFi. METHODS: A retrospective chart review was conducted of patients with CRMO who received golimumab in a single center between 01 June, 2018 and 31 December, 2020. Patients who were diagnosed before 21 years of age and followed up for CRMO at least once after receiving ≥ 3 months of golimumab were included. Extracted data included patient demographics, whole-body MRI lesion counts, clinically relevant data, laboratory results, patient-reported outcomes, and psoriasis burden. Linear mixed models with log-transformed outcomes were used to assess changes in the outcomes over time. The random effect is included in the model to account for the within-subject correlation of repeated measures. p-values and 95% confidence intervals were reported. RESULTS: Eighteen patients were included. Patients were observed for a median of 9.95 months [interquartile range 3.84-15.64]. The median age at the initiation of golimumab was 10.95 years [9.86-13.77] and the median duration of disease between the disease onset and the initiation of golimumab was 2.60 years [1.66-3.62]. Ten patients received golimumab via intravenous route and eight patients received golimumab via subcutaneous route. The median dose was 1.64 mg/kg/month [1.46, 2]. Fourteen patients were previously treated with disease-modifying antirheumatic drugs and 17 with other TNFi. Patients treated with golimumab showed significant improvement in median physician global assessment for CRMO from 2.00 [1.00-3.00] to 0.00 [0.00-0.25] by the fourth visit (p < 0.001), with median erythrocyte sedimentation rate (ESR) decreasing significantly from 12.00 [6.75-23.75] to 5.00 [3.00-10.00] by the fourth visit (p < 0.05). The median number of lesions on MRI decreased significantly from 3.50 [2.00-5.50] to 0.50 [0.00-4.25] lesions per patient (p < 0.01). Nine out of 12 patients who had previous paradoxical psoriasis associated with adalimumab or infliximab had persistent active psoriasis at study baseline. For patients with psoriasis at study baseline, the prevalence of psoriasis had decreased from 100% to approximately 50-57% at the following visits. Of the 18 patients initiated on golimumab in this study, there was only one new case of mild psoriasis in a patient with previously resolved infliximab-associated paradoxical psoriasis. No serious infections or adverse events were noted during the study. Two patients in the study showed clinical improvement with concomitant golimumab and ustekinumab with no reported adverse side effects or increased effects in these patients over a 16-month interval, showing that this combination can be safe and effective for children with CRMO. CONCLUSION: In our experience, golimumab has been shown to be a safe and effective therapy for CRMO and demonstrated improvement in paradoxical psoriasis in many patients. Longer follow-up periods would be helpful to develop longer term outcomes data for patients with CRMO and overall paradoxical psoriasis risk.

Feasibility of Conducting Comparative Effectiveness Research and Validation of a Clinical Disease Activity Score for Chronic Nonbacterial Osteomyelitis.

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.

Sustained-release oxycodone tablets for moderate to severe painful diabetic peripheral neuropathy: a multicenter, open-labeled, postmarketing clinical observation.

OBJECTIVE: To evaluate the efficacy and safety of sustained-release (SR) oxycodone tablets in the treatment of moderate to severe painful diabetic peripheral neuropathy (DPN). Design. This was a multicenter, randomized, open-labeled study. SETTING: This study was completed in 12 hospitals in China. PATIENTS: A total of 80 Chinese patients undergoing moderate to severe painful DPN. INTERVENTIONS: An initial dose of 10mg is recommended to be taken orally every 12 hours. Dose titration was done appropriately according to pain intensity and adverse reactions. OUTCOME MEASURES: Data record included days, dosage, analgesic efficacy, quality of sleep, adverse events, and combination therapy when patients were treated with SR oxycodone tablets. The continuous observation period was 6 weeks. RESULTS: After medication for 1 week, pain was significantly (P<0.01) relieved from 6.8±1.4 to 2.8±1.6. Onset time was within 45 minutes in nearly 60% of the patients, and within 1 hour in nearly 95% of that ones. More than 90% of the patients achieved stable analgesic dose within 3 days. After using SR oxycodone tablets for 1 week, sleep quality was significantly (P<0.01) improved. In week 1, the average dose of SR oxycodone tablets was 16.63±7.79mg. The average daily dose of most patients was about 20mg after 2 weeks. In all the enrolled patients, 38 (47.5%) had adverse reactions. No serious adverse reactions took place. CONCLUSION: The results of this clinical observation further elaborated the efficacy and safety of SR oxycodone tablets in the treatment of moderate to severe painful diabetic peripheral neuropathy in China.

Increasing Cases of Chronic Nonbacterial Osteomyelitis in Children: A Series of 215 Cases From a Single Tertiary Referral Center.

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.

A Novel Algorithm Using Within-leg Calibration for Enhanced Accuracy of Detection of Arthritis by Infrared Thermal Imaging in Children.

OBJECTIVE: To standardize and improve the accuracy of detection of arthritis by thermal imaging. METHODS: Children with clinically active arthritis in the knee or ankle, as well as healthy controls, were enrolled to the development cohort; another group of children with knee symptoms was enrolled to the validation cohort. Ultrasound was performed in the arthritis subgroup for the development cohort. Joint exam by certified rheumatologists was used as a reference for the validation cohort. Infrared thermal data were analyzed using custom software. Temperature after within-limb calibration (TAWiC) was defined as the temperature differences between joint and ipsilateral mid-tibia. TAWiC of knees and ankles was evaluated using ANOVA across subgroups. Optimal thresholds were determined by receiver-operating characteristic analysis using Youden index. RESULTS: There were significant differences in mean and 95th TAWiC of knee in anterior, medial, lateral views, and of ankles in anterior view, between inflamed and uninflamed counterparts (P < 0.05). The area under the curve was higher by 30% when using TAWiCknee than that when using absolute temperature. Within the validation cohort, the sensitivity of accurate detection of arthritis in the knees using both mean and 95th TAWiC from individual views or all 3 views combined ranged from 0.60 to 0.70, and the specificity was > 0.90 in all views. CONCLUSION: Children with active arthritis or tenosynovitis in knees or ankles exhibited higher TAWiC than healthy joints. Our validation cohort study showed promise for the clinical utility of infrared thermal imaging for arthritis detection.

Chronic Nonbacterial Osteomyelitis: Insights into Pathogenesis, Assessment, and Treatment.

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.

Paradoxical Psoriasis in Children Receiving Anti-TNFα Treatment for Inflammatory/autoimmune Disease.

Tumor necrosis factor alpha inhibitors (TNFi) are widely used in children with autoimmune and autoinflammatory conditions. Although TNFi are approved to treat psoriasis, they have also been shown to paradoxically induce psoriasiform lesions. In this review, we aim to focus on the clinical presentation and management of paradoxical psoriasis after exposure to TNFi in children with juvenile idiopathic arthritis (JIA), inflammatory bowel disease (IBD), or chronic nonbacterial osteomyelitis (CNO). A narrative review of the literature was performed given the limited number of publications on this topic. Children with IBD, CNO, and JIA have a higher risk of developing psoriasis at baseline, which increases after TNFi use in those with JIA and IBD. Risk factors for paradoxical psoriasis remain incompletely defined, and patients with IBD and/or CNO develop paradoxical psoriasis more commonly than those with JIA. Sex, race, and family history were not significantly associated with paradoxical psoriasis. The most commonly implicated TNFi include infliximab and adalimumab. Paradoxical psoriasis occurs in a similar distribution on the body to isolated psoriatic lesions and is morphologically indistinguishable. In many instances, topical therapies are effective in treating psoriasis and children can continue on TNFi for their primary disease. If lesions are severe or unacceptable to patients, TNFi may be switched or discontinued. Further research is needed to better characterize risk factors and understand the mechanism of disease pathogenesis. Pediatric health care providers who prescribe TNFi should counsel families regarding the risk of paradoxical psoriasis prior to starting the medication and monitor for new cutaneous eruptions.