Pediatric Rheumatology Care and Outcomes Improvement Network's Quality Measure Set to Improve Care of Children With Juvenile Idiopathic Arthritis.

OBJECTIVE: To describe the selection, development, and implementation of quality measures (QMs) for juvenile idiopathic arthritis (JIA) by the Pediatric Rheumatology Care and Outcomes Improvement Network (PR-COIN), a multihospital learning health network using quality improvement methods and leveraging QMs to drive improved outcomes across a JIA population since 2011. METHODS: An American College of Rheumatology-endorsed multistakeholder process previously selected initial process QMs. Clinicians in PR-COIN and parents of children with JIA collaboratively selected outcome QMs. A committee of rheumatologists and data analysts developed operational definitions. QMs were programmed and validated using patient data. Measures are populated by registry data, and performance is displayed on automated statistical process control charts. PR-COIN centers use rapid-cycle quality improvement approaches to improve performance metrics. The QMs are revised for usefulness, to reflect best practices, and to support network initiatives. RESULTS: The initial QM set included 13 process measures concerning standardized measurement of disease activity, collection of patient-reported outcome assessments, and clinical performance measures. Initial outcome measures were clinical inactive disease, low pain score, and optimal physical functioning. The revised QM set has 20 measures and includes additional measures of disease activity, data quality, and a balancing measure. CONCLUSION: PR-COIN has developed and tested JIA QMs to assess clinical performance and patient outcomes. The implementation of robust QMs is important to improve quality of care. PR-COIN's set of JIA QMs is the first comprehensive set of QMs used at the point-of-care for a large cohort of JIA patients in a variety of pediatric rheumatology practice settings.

Treatment escalation patterns to start biologics in refractory moderate juvenile dermatomyositis among members of the Childhood Arthritis and Rheumatology Research Alliance.

BACKGROUND: Despite new and better treatments for juvenile dermatomyositis (JDM), not all patients with moderate severity disease respond adequately to first-line therapy. Those with refractory disease remain at higher risk for disease and glucocorticoid-related complications. Biologic disease-modifying antirheumatic drugs (DMARDs) have become part of the arsenal of treatments for JDM. However, prospective comparative studies of commonly used biologics are lacking. METHODS: The Childhood Arthritis and Rheumatology Research Alliance (CARRA) JDM biologics workgroup met in 2019 and produced a survey assessing current treatment escalation practices for JDM, including preferences regarding use of biologic treatments. The cases and questions were developed using a consensus framework, requiring 80% agreement for consensus. The survey was completed online in 2020 by CARRA members interested in JDM. Survey results were analyzed among all respondents and according to years of experience. Chi-square or Fisher's exact test was used to compare the distribution of responses to each survey question. RESULTS: One hundred twenty-one CARRA members responded to the survey (denominators vary for each question). Of the respondents, 88% were pediatric rheumatologists, 85% practiced in the United States, and 43% had over 10 years of experience. For a patient with moderately severe JDM refractory to methotrexate, glucocorticoids, and IVIG, approximately 80% of respondents indicated that they would initiate a biologic after failing 1-2 non-biologic DMARDs. Trials of methotrexate and mycophenolate were considered necessary by 96% and 60% of respondents, respectively, before initiating a biologic. By weighed average, rituximab was the preferred biologic over abatacept, tocilizumab, and infliximab. Over 50% of respondents would start a biologic by 4 months from diagnosis for patients with refractory moderately severe JDM. There were no notable differences in treatment practices between respondents by years of experience. CONCLUSION: Most respondents favored starting a biologic earlier in disease course after trialing up to two conventional DMARDs, specifically including methotrexate. There was a clear preference for rituximab. However, there remains a dearth of prospective data comparing biologics in refractory JDM. These findings underscore the need for biologic consensus treatment plans (CTPs) for refractory JDM, which will ultimately facilitate comparative effectiveness studies and inform treatment practices.

Low copy numbers of complement C4 and C4A deficiency are risk factors for myositis, its subgroups and autoantibodies.

BACKGROUND: Idiopathic inflammatory myopathies (IIM) are a group of autoimmune diseases characterised by myositis-related autoantibodies plus infiltration of leucocytes into muscles and/or the skin, leading to the destruction of blood vessels and muscle fibres, chronic weakness and fatigue. While complement-mediated destruction of capillary endothelia is implicated in paediatric and adult dermatomyositis, the complex diversity of complement C4 in IIM pathology was unknown. METHODS: We elucidated the gene copy number (GCN) variations of total C4, C4A and C4B, long and short genes in 1644 Caucasian patients with IIM, plus 3526 matched healthy controls using real-time PCR or Southern blot analyses. Plasma complement levels were determined by single radial immunodiffusion. RESULTS: The large study populations helped establish the distribution patterns of various C4 GCN groups. Low GCNs of C4T (C4T=2+3) and C4A deficiency (C4A=0+1) were strongly correlated with increased risk of IIM with OR equalled to 2.58 (2.28-2.91), p=5.0×10-53 for C4T, and 2.82 (2.48-3.21), p=7.0×10-57 for C4A deficiency. Contingency and regression analyses showed that among patients with C4A deficiency, the presence of HLA-DR3 became insignificant as a risk factor in IIM except for inclusion body myositis (IBM), by which 98.2% had HLA-DR3 with an OR of 11.02 (1.44-84.4). Intragroup analyses of patients with IIM for C4 protein levels and IIM-related autoantibodies showed that those with anti-Jo-1 or with anti-PM/Scl had significantly lower C4 plasma concentrations than those without these autoantibodies. CONCLUSIONS: C4A deficiency is relevant in dermatomyositis, HLA-DRB1*03 is important in IBM and both C4A deficiency and HLA-DRB1*03 contribute interactively to risk of polymyositis.

Biologics in refractory idiopathic inflammatory myositis (IIM): What experience in juvenile vs adult myositis tells us about the use of biologics in pediatric IIM.

Juvenile dermatomyositis (JDM) is an extremely heterogeneous orphan disease with limited amount of dedicated research on the subject matter. Recent research suggests that JDM may not just be the classic antibody driven complements mediated microangiopathy as was thought to be in the past. The etiopathogenesis of JDM also involves inappropriate stimulation of innate immune system followed by dysregulation of the adaptive immune response through dendritic cells. Many variable immune factors such as genetics, major histocompatibility complex expressions, immunohistochemical variabilities, and diversity in specific and associated autoantibodies may make individual IIM and JDM cases unique. The diversity in IIM and JDM also explains individual variability in response to specific therapies. Classifying and matching the right patients to the right treatment is crucial to the successful treatment of these patients with better outcomes. Sub-type specific biologic therapy may be the best current treatment that can match the patient to the best treatment options. A PubMed search was performed to find all the available cases of refractory myositis patients treated with biologics up to July 2020. Using this search this article reviews all the current biologic treatment options and experiences for both adults and children in the context of recent basic science to assist pediatric rheumatologists in choosing the optimal biologic therapy for a child with recalcitrant JDM.

An unprecedented COPA gene mutation in two patients in the same family: comparative clinical analysis of newly reported patients with other known COPA gene mutations.

INTRODUCTION: The COPA syndrome is a newly recognized monogenic, autosomal dominant autoimmune disease presenting mostly presenting in childhood. Clinical features include inflammation of the lungs, kidneys, and joints. Approximately twenty-six patients with COPA syndrome worldwide have been investigated all originating from eight families. Patients with this syndrome exhibit heterozygous monogenic missense mutations in the WD40 domain. This domain is a functionally-significant area of the alpha subunit of coatomer-associated protein (COPα) which encodes the coat protein complex I (COPI). The COPI dysfunction is also associated with autoantibody expansion. We report two patients with COPA syndrome. METHODS: All testing and molecular genetic analysis were performed after obtaining the informed consent of both the patient and parents. A retrospective chart review was carried out on both the patients. Demographic, clinical and laboratory findings were abstracted from outpatient and inpatient encounters. Pulmonary function tests (PFTs), chest computed tomography (CT) scans, and lung biopsy histopathology reports were also reviewed and summarized. RESULTS: The index case and the father of the child both demonstrated a unique inflammatory pulmonary, arthritis, and renal disease triad starting in early childhood including pulmonary hemorrhage. The two patients had a novel COPA mutation previously undescribed. CONCLUSIONS: To date, only four pathological, genetic mutations have been reported that are compatible with COPA syndrome. We here report two patients with COPA syndrome within the same family with a novel COPA gene mutation different than the heterozygous monogenic missense mutations in the WD40 domain and distinct from the clinical phenotypes reported in the literature so far.

Biologics in refractory myositis: experience in juvenile vs. adult myositis; part II: emerging biologic and other therapies on the horizon.

The idiopathic inflammatory myopathies (IIM) until recently have been considered a heterogeneous broad group of six autoimmune muscle diseases. Initially, autoantibodies in IIM (including JDM) and CD8+ T cell-induced cytotoxicity (PM and IBM) were the predominant recognized etiopathology mechanisms used to classify myopathies. In the early late 1990's to 2000's, evolving understanding of the molecules such as interleukin (IL), tumor necrosis factor (TNF), interferon (IFN), and other cytokines as well as differences in response to therapies, has led IIM researchers to look beyond previous disease mechanisms. For decades the overexpression of Th1- associated cytokines (TNF-α, IFN-γ and IL-12) in the areas of inflammation in skin and muscle in IIM pointed to Th1 as the primary pathway for inflammation in myositis.However, in the last decade overexpression and elevated level of Th17-associated cytokines (IL-17, IL-22, and IL-6) were identified in the blood and the inflamed muscles of myositis patients. We also do not know how Th1 and Th2 cytokines work differently in diverse hosts, in different concentrations, in different inflammatory milieus, and in the presence or absence of each other or other adhesion/co-stimulatory molecules such as NF-κB. Also, several autoantibodies to intracellular organelles have been identified in myositis.In this review, we will discuss the most recent advances in IIM research and how that might bring new biologic therapies to market in the next 5-15 years to assist in the care of our most difficult IIM and JDM patients.

Healthcare Use Patterns and Economic Burden of Chronic Musculoskeletal Pain in Children before Diagnosis.

OBJECTIVES: To evaluate the healthcare use and costs of amplified musculoskeletal pain syndrome (AMPS) in children before diagnosis. STUDY DESIGN: We performed a retrospective study in children with AMPS at a pediatric rheumatology clinic between 2010 and 2014. Data were abstracted on 80 patients after primary rheumatic diseases were excluded. Healthcare visits, medications and diagnostic testing that occurred in the years before diagnosis were collected. The Medical Expenditure Panel Survey was used to estimate visit costs. RESULTS: Patients were adolescent females (89%) and white (86%). The median time to diagnosis was 10.2 months. The median pain score was 6.5 and the median Childhood Health Assessment Questionnaire score was 1.1. In this cohort, 29% had at least 1 ED visit and 5% were hospitalized. All patients saw a rheumatologist and 41% had visited another specialist, typically orthopedics and sports medicine. More than one-half had at least 1 radiographic study and 21% had at least 1 magnetic resonance imaging. The total cost for office, emergency department, and hospital visits for AMPS in all 80 patients was $152 853. The mean cost per patient over the entire study period (2008-2014) was $1911 ± $3808, and 43% of costs were outpatient visits. CONCLUSIONS: Children with AMPS have high levels of disability and take a long time to be diagnosed. As a result, even before diagnosis, they have high levels of healthcare use, diagnostic testing, and medical costs. Early recognition of disability and quicker referral to trained subspecialists may improve the prognosis, reduce unnecessary testing, and reduce the overall costs of healthcare.

Age and fecal microbial strain-specific differences in patients with spondyloarthritis.

BACKGROUND: Prior studies have demonstrated abnormalities in the composition of the gastrointestinal microbiota in pediatric and adult patients with spondyloarthritis (SpA). In particular, diminished fecal abundance of Faecalibacterium prausnitzii and abnormalities in both directions in the abundance of the Bacteroides genus have been identified. METHODS: We obtained fecal specimens from 30 children with treatment-naïve enthesitis-related arthritis (ERA) and 19 healthy controls, as well as specimens from 11 adult patients with longstanding SpA and 10 adult healthy controls. All of the samples underwent sequencing of the 16S ribosomal DNA. A subset of the pediatric fecal samples was subjected to shotgun metagenomics sequencing. RESULTS: ERA patients had decreased abundance of the anti-inflammatory F. prausnitzii A2-165 strain (41 ± 28% versus 54 ± 20% of all sequences matching F. prausnitzii, p = 0.084) and an increased abundance of the control F. prausnitzii L2/6 strain (28 ± 28% versus 15 ± 15%, p = 0.038). Similar trends were observed in adults with longstanding SpA (n = 11) and controls (n = 10). In contrast, the fecal abundance of Bacteroides fragilis was increased in ERA subjects (2.0 ± 4.0% versus 0.45 ± 0.7% of all sequences, p = 0.045), yet was diminished in adult subjects (0.2 ± % versus 1.0 ± % of all sequences, p = 0.106). Shotgun metagenomics sequencing of the fecal DNA in the pediatric subjects revealed diminished coverage of the butanoate pathway (abundance normalized to controls of 1 ± 0.48 versus 0.72 ± 0.33 in ERA, p = 0.037). CONCLUSIONS: The anti-inflammatory F. prausnitzii A2-165 strain appears to be depleted in both pediatric and adult SpA. In contrast, B. fragilis may be depleted in adult disease yet abundant in pediatric SpA, suggesting developmental effects on the immune system.

Assessment of transition readiness in adolescents and young adults with chronic health conditions.

BACKGROUND: Transition from pediatric to adult health care is a vulnerable period for adolescents and young adults. Challenges include paucity of validated measures to assess patients' transition readiness. We evaluated the Transition Readiness Assessment Questionnaire (TRAQ) in adolescents and young adults with rheumatic, gastrointestinal, and endocrine disorders. We examined whether baseline TRAQ scores and other demographic variables predicted transition to adult care over a three year follow up period. METHODS: In this descriptive study at a single institution, eighty-nine adolescents at a single pediatric academic medical center completed demographic and medical history surveys and the TRAQ and were followed over 3 years by telephone interview to determine whether they had transitioned to adult subspecialty care. Transition was defined as attending at least one adult subspecialty appointment. Multivariable logistic regression and Cox proportional hazards regression models were used to determine whether TRAQ scores predicted time to transition. RESULTS: Of the participants, 56% had rheumatic, 21% endocrine, and 23% gastrointestinal conditions. The TRAQ self-management domain score was not significantly associated with age, gender, socioeconomic status, or specialty. The TRAQ self-advocacy score increased with age. Baseline TRAQ scores did not predict transition or time to transition over three years. CONCLUSION: In this cohort of adolescents and young adults who were 16 to 23 years of age at enrollment, 48% transitioned to adult care over three years of follow up. Nearly half reported not discussing transition with provider or seeing provider independently for part of visit. Older age but not other demographic variables nor baseline TRAQ score predicted transition or time to transition to an adult subspecialty provider; however, a there was a trend towards shorter time to transition with the highest quartile TRAQ scores.