Proteomics based markers of clinical pain severity in juvenile idiopathic arthritis

Introduction Juvenile idiopathic arthritis (JIA) is a cluster of autoimmune rheumatic diseases occurring in children 16 years of age or less. While it is well-known that pain may be experienced during inflammatory and non-inflammatory states, much remains ambiguous regarding the molecular mechanisms that may drive JIA pain. Thus, in this pilot study, we explored the variability of the serum proteomes in relation to pain severity in a cohort of JIA patients. Methods Serum samples from 15 JIA patients (male and female, 12.7 ± 2.8 years of age) were assessed using liquid chromatography/mass spectrometry (LC/MS). Correlation analyses were performed to determine the relationships among protein levels and self-reported clinical pain severity. Additionally, how the expression of pain-associated proteins related to markers of inflammation (Erythrocyte Sedimentation Rate (ESR)) or morphological properties of the central nervous system (subcortical volume and cortical thickness) implicated in JIA were also evaluated. Results 306 proteins were identified in the JIA cohort of which 14 were significantly (p < 0.05) associated with clinical pain severity. Functional properties of the identified pain-associated proteins included but were not limited to humoral immunity (IGLV3.9), inflammatory response (PRG4) and angiogenesis (ANG). Associations among pain-associated proteins and ESR (IGHV3.9, PRG4, CST3, VWF, ALB), as well as caudate nucleus volume (BTD, AGT, IGHV3.74) and insular cortex thickness (BTD, LGALS3BP) were also observed. Conclusions The current proteomic findings suggest both inflammatory- and non-inflammatory mediated mechanisms as potential factors associated with JIA pain. Validation of these preliminary observations using larger patient cohorts and a longitudinal study design may further point to novel serologic markers of pain in JIA.

Clinical characteristics and outcomes of chronic nonbacterial osteomyelitis in children: a multicenter case series

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.

Epidemiology and demographics of juvenile idiopathic arthritis in Africa and Middle East

Juvenile Idiopathic Arthritis (JIA) is a group of chronic heterogenous disorders that manifests as joint inflammation in patients aged <16 years. Globally, approximately 3 million children and young adults are suffering from JIA with prevalence rates consistently higher in girls. The region of Africa and Middle East constitute a diverse group of ethnicities, socioeconomic conditions, and climates which influence the prevalence of JIA. There are only a few studies published on epidemiology of JIA in the region. There is an evident paucity of adequate and latest data from the region. This review summarizes the available data on the prevalence of JIA and its subtypes in Africa and Middle East and discusses unmet needs for patients in this region. A total of 8 journal publications were identified concerning epidemiology and 42 articles describing JIA subtypes from Africa and Middle East were included. The prevalence of JIA in Africa and Middle East was observed to be towards the lower range of the global estimate. We observed that the most prevalent subtype in the region was oligoarticular arthritis. The incidence of uveitis and anti-nuclear antibody (ANA) positivity were found to be lower as compared to the incidence from other regions. There is a huge unmet medical need in the region for reliable epidemiological data, disease awareness, having regional and local treatment guidelines and timely diagnosis. Paucity of the pediatric rheumatologists and economic disparities also contribute to the challenges regarding the management of JIA.

A novel transition clinic structure for adolescent and young adult patients with childhood onset rheumatic disease improves transition outcomes

Background The transition of health care from Pediatric to Adult providers for adolescents and young adults with chronic disease is associated with poor outcomes. Despite the importance of this transition, over 80% of these patients do not receive the services necessary to transition to Adult health care. In 2018, we initiated a transition clinic structure, integrating an Internal Medicine - Pediatrics trained Adult Rheumatologist in a Pediatric Rheumatology clinic to guide this transition. Our goal was to improve transition outcomes. We report the methods of this clinic and its preliminary outcomes. Methods For patients referred to the transition clinic, the Adult Rheumatologist assumed medical management and implemented a six-part modular transition curriculum. This curriculum included a Transition Policy, Transition Readiness Assessment, medication review and education, diagnosis review and education, and counseling on differences between Pediatric and Adult-oriented care. Eligible patients and their families were enrolled in a prospective observational outcomes research registry. Initial data from this transition clinic is reported including adherence with certain aspects of the transition curriculum and clinic utilization. Results The transition clinic Adult Rheumatologist saw 177 patients in 2 years, and 57 patients were eligible for, approached, and successfully enrolled in the registry. From this registry, all patients reviewed the Transition Policy with the Adult Rheumatologist and 45 (78.9%) completed at least one Transition Readiness Assessment. Of the 22 patients for whom transition was indicated, all were successfully transitioned to an Adult Rheumatologist. 17 (77.3%) continued care post-transition with the transition clinic Adult Rheumatologist, and 5 (22.7%) continued care post-transition with a different Adult Rheumatologist. The median time between the last transition clinic visit and first Adult clinic visit was 5.1 months. Conclusions Our experience demonstrated the success of our clinic model regarding participation in the transition curriculum and improved clinic utilization data. Our results are an improvement over transition rates reported elsewhere that did not implement our model. We believe that this structure could be applied to other primary care and subspecialty clinics. Trial registration This research was approved by the University of Utah Institutional Review Board (IRB) in January 2019 (IRB_00115964). Patients were retrospectively registered if involved prior to this date.

Changes over time in inflammatory and structural lesions at the sacroiliac joint in children with spondyloarthritis exposed and unexposed to tumor necrosis factor inhibitor

Background The objective of this work was to describe magnetic resonance imaging (MRI) changes over time in inflammatory and structural lesions at the sacroiliac joint (SIJ) in children with spondyloarthritis (SpA) exposed and unexposed to tumor necrosis factor inhibitor (TNFi). Methods This was a retrospective, multicenter study of SpA patients with suspected or confirmed sacroiliitis who underwent at ≥2 pelvic MRI scans. Images were reviewed independently by 3 radiologists and scored for inflammatory and structural changes using the Spondyloarthritis Research Consortium of Canada (SPARCC) SIJ inflammation score (SIS) and structural score (SSS). Longitudinal, quantitative changes in patient MRI scans were measured using descriptive statistics and stratified by TNFi exposure. We used an average treatment effects (ATE) regression model to explore the average effect of TNFi exposure over time on inflammatory and structural lesions, adjusting for baseline lesion scores. Results Forty-six subjects were evaluated using the SIS (n = 45) and SSS (n = 18). Median age at baseline imaging was 13.6 years, 63% were male and 71% were white. Twenty-three subjects (50%) were TNFi exposed between MRI studies. The median change in SIS in TNFi exposed and unexposed subjects with a baseline SIS ≥0 was − 20.7 and − 14.3, respectively (p = 0.09). Eleven (85%) TNFi exposed and 8 (89%) unexposed subjects with a baseline SIS ≥0 met the SIS minimal clinically important difference (MCID; ≥2.5). Using the ATE model adjusted for baseline SIS, the average effect of TNFi on SIS in patients with a baseline SIS ≥2 was − 14.5 (p < 0.01). Unadjusted erosion change score was significantly worse in TNFi unexposed versus exposed subjects (p = 0.03) but in the ATE model the effect of TNFi was not significant. Conclusion This study quantitatively describes how lesions in the SIJs on MRI change over time in patients exposed to TNFi versus unexposed. Follow-up imaging in TNFi exposed patients showed greater improvement than the unexposed group by most metrics, some of which reached statistical significance. Surprisingly, a majority of TNFi unexposed children with a baseline SIS≥2 met the SIS MCID. Additional studies assessing the short and long-term effects of TNFi on inflammatory and structural changes in juvenile SpA are needed.

Cannabidiol (CBD) Use among children with juvenile idiopathic arthritis

Background Juvenile idiopathic arthritis (JIA) is common and difficult to treat. Cannabidiol (CBD) is now widely available, but no studies to date have investigated the use of CBD for JIA. Methods We performed a chart review to identify patients with JIA at a Midwestern medical institution between 2017 and 2019. We surveyed primary caregivers of JIA patients using an anonymous, online survey with questions on caregiver knowledge and attitudes towards CBD. We compared respondents with no interest in CBD use vs. those contemplating or currently using CBD using descriptive statistics. Results Of 900 reviewed charts, 422 met inclusion criteria. Of these, 236 consented to be sent a survey link, and n=136 (58%) completed surveys. Overall, 34.5% (n=47) of respondents reported no interest in using a CBD product for their child’s JIA, while 54% (n=79) reported contemplating using CBD and 7% (n=10) reported currently giving their child CBD. Only 2% of respondents contemplating or actively using a CBD product learned about CBD from their child’s rheumatologist, compared with television (70%) or a friend (50%). Most respondents had not talked to their child’s rheumatologist about using CBD. Of those currently using CBD, most used oral or topical products, and only 10% of respondents (n=1) knew what dose they were giving their child. Conclusions Our results show infrequent use but a large interest in CBD among caregivers of children with JIA. Given CBD’s unknown safety profile in children with JIA, this study highlights a need for better studies and education around CBD for pediatric rheumatologists.

A descriptive study on multisystem inflammatory syndrome in children in a single center in West Michigan

Background Multisystem Inflammatory Syndrome in Children (MIS-C) is a rare hyperinflammatory condition that occurs following SARS-CoV-2 infection. There is a paucity of research describing risk factors, optimal management, and outcomes of this life-threatening condition. Methods This is a case series of 26 patients diagnosed with MIS-C in a West Michigan pediatric tertiary care center from April 2020 to February 2021. We describe the clinical, imaging, and laboratory characteristics of these patients and detail their treatments and outcomes with comparisons between Pediatric Intensive Care Unit (PICU) and non-PICU patients. Categorical testing utilized Chi-square and Fisher’s Exact tests. Comparison between groups used T-tests or Kruskal-Wallis. Results Fifteen patients (57%) required intensive care. There was no statistically significant difference in demographics between PICU and non-PICU patients, however all Black patients required intensive care. Gastrointestinal symptoms were present in 22 patients (84%). Seventeen patients (65%) had Kawasaki-like features and 12 (46%) developed coronary artery dilation. Patients requiring intensive care were less likely to have a reported history of COVID-19 disease or exposure (p = 0.0362). Statistically significant differences were also noted in peak ferritin (p = 0.0075), procalcitonin, and BNP in those who required intensive care. Conclusions Although overlap exists with other hyperinflammatory conditions, our study provides further evidence that MIS-C is a distinct, albeit heterogenous, disorder with various degrees of cardiac involvement. Anakinra, in conjunction with steroid use, appears to be effective and safe in the treatment of MIS-C. This report identifies procalcitonin, peak ferritin, and BNP as potentially useful biomarkers for severity of disease.

Immunoprofiling of active and inactive systemic juvenile idiopathic arthritis reveals distinct biomarkers: a single-center study

Background This study aimed to perform an immunoprofiling of systemic juvenile idiopathic arthritis (sJIA) in order to define biomarkers of clinical use as well as reveal new immune mechanisms. Methods Immunoprofiling of plasma samples from a clinically well-described cohort consisting of 21 sJIA patients as well as 60 age and sex matched healthy controls, was performed by a highly sensitive proteomic immunoassay. Based on the biomarkers being significantly up- or down-regulated in cross-sectional and paired analysis, related canonical pathways and cellular functions were explored by Ingenuity Pathway Analysis (IPA). Results The well-studied sJIA biomarkers, IL6, IL18 and S100A12, were confirmed to be increased during active sJIA as compared to healthy controls. IL18 was the only factor found to be increased during inactive sJIA as compared to healthy controls. Novel factors, including CASP8, CCL23, CD6, CXCL1, CXCL11, CXCL5, EIF4EBP1, KITLG, MMP1, OSM, SIRT2, SULT1A1 and TNFSF11, were found to be differentially expressed in active and/or inactive sJIA and healthy controls. No significant pathway activation could be predicted based on the limited factor input to the IPA. High Mobility Group Box 1 (HMGB1), a damage associated molecular pattern being involved in a series of inflammatory diseases, was determined to be higher in active sJIA than inactive sJIA. Conclusions We could identify a novel set of biomarkers distinguishing active sJIA from inactive sJIA or healthy controls. Our findings enable a better understanding of the immune mechanisms active in sJIA and aid the development of future diagnostic and therapeutic strategies.