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.

Case report and review of the literature: immune dysregulation in a large familial cohort due to a novel pathogenic RELA variant.

OBJECTIVE: To explore and define the molecular cause(s) of a multi-generational kindred affected by Bechet's-like mucocutaneous ulcerations and immune dysregulation. METHODS: Whole genome sequencing and confirmatory Sanger sequencing were performed. Components of the NFκB pathway were quantified by immunoblotting, and function was assessed by cytokine production (IL-6, TNF-α, IL-1ß) after lipopolysaccharide (LPS) stimulation. Detailed immunophenotyping of T-cell and B-cell subsets was performed in four patients from this cohort. RESULTS: A novel variant in the RELA gene, p. Tyr349LeufsTer13, was identified. This variant results in premature truncation of the protein before the serine (S) 536 residue, a key phosphorylation site, resulting in enhanced degradation of the p65 protein. Immunoblotting revealed significantly decreased phosphorylated [p]p65 and pIκBα. The decrease in [p]p65 may suggest reduced heterodimer formation between p50/p65 (NFκB1/RelA). Immunophenotyping revealed decreased naïve T cells, increased memory T cells, and expanded senescent T-cell populations in one patient (P1). P1 also had substantially higher IL-6 and TNF-α levels post-stimulation compared with the other three patients. CONCLUSION: Family members with this novel RELA variant have a clinical phenotype similar to other reported RELA cases with predominant chronic mucocutaneous ulceration; however, the clinical phenotype broadens to include Behçet's syndrome and IBD. Here we describe the clinical, immunological and genetic evaluation of a large kindred to further expand identification of patients with autosomal dominant RELA deficiency, facilitating earlier diagnosis and intervention. The functional impairment of the canonical NFκB pathway suggests that this variant is causal for the clinical phenotype in these patients.

Improving eye screening practice among pediatric rheumatology patients receiving hydroxychloroquine.

OBJECTIVE: Hydroxychloroquine (HCQ) is commonly used in the treatment of various autoimmune diseases related to its many benefits and favorable safety profile. Although HCQ retinopathy was considered to be uncommon, a prevalence of 7.5% was described in a recent study making early detection critical. The most updated screening guidelines by the American Academy of Ophthalmology were published in 2016; however, it lacked pediatric-specific recommendations and the overall compliance with screening guidelines was poor in previous studies. We developed a quality improvement (QI) initiative aiming to create institutional screening recommendations. Additionally, to increase eye screening in pediatric rheumatology clinic for patients receiving HCQ from 65% to 85% in 12 months and to sustain that rate for at least 6 months. METHODS: We formed a multidisciplinary team of pediatric rheumatologists and ophthalmologists, clinical pharmacist, clinic nurses, QI specialist, quality data technician and administrative staff. We included patients receiving HCQ and who were evaluated at Nationwide Children's Hospital rheumatology clinic. A key driver diagram was formulated to identify barriers to compliance and determine possible interventions. Main interventions included summarizing screening guidelines in a step by step algorithm, increasing awareness of these guidelines among patients and providers, improving collaboration and communication with ophthalmologists, and initiating pre-visit planning. RESULTS: Baseline performance data included 164 patients. Fifty-four (33%) of those patients were at high risk for HCQ retinopathy. Of them, 50% were on HCQ dose of >5 mg/kg/day and 31.5% had been taking HCQ for ≥5 years. Two center line shifts were noticed over the course of the project. The target of 85% compliance was reached in February 2019 and was sustained until December 2019. CONCLUSIONS: Our study highlights the importance of interdisciplinary communication to increase awareness of screening guidelines among medical providers and patients. Pre-visit planning played a major role in identifying patients and opportunities for optimizing eye screening in patients at risk for HCQ retinopathy. Collaboration between rheumatologists and ophthalmologists is crucial in managing patients on HCQ. The implementation of same-day eye screening allowed this collaboration to be more efficient. Future efforts are being directed at monitoring and improving utilization of the effective interventions.

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.

Pan-valvulitis in Children With Kawasaki Disease: A Case Report and Review of the Literature.

We present a rare case of pan-valvular involvement in a 5-month-old female with Kawasaki disease shock syndrome despite early treatment with intravenous immunoglobulin and corticosteroids. She experienced a favorable outcome after the addition of infliximab, which was guided based on clinical, laboratory and echocardiogram findings, rather than recrudescence of fever, the most common indicator of intravenous immunoglobulin resistance.

CAR T cell therapy for refractory pediatric systemic lupus erythematosus: a new era of hope?

Systemic lupus erythematosus (SLE) is a chronic autoimmune condition that can affect multiple organ systems and is heterogenous in its presentation and response to therapy. When diagnosed in childhood, SLE is associated with increased morbidity and mortality compared to adult SLE, often requiring substantial immunosuppression with the risk of significant side effects. There remains a significant unmet need for new therapies that can improve disease control and reduce glucocorticoid and other toxic medication exposure for patients with severe or refractory disease. The pathogenesis of SLE involves B cell dysregulation and autoantibody production, which are a hallmark of the disease. Currently approved B cell directed therapies often result in incomplete B cell depletion and may not target long-lived plasma cells responsible for SLE autoantibodies. It is hypothesized that by persistently eliminating both B cells and plasmablasts, CAR T therapy can halt autoimmunity and prevent organ damage in patient's refractory to current B cell-depleting treatments. Herein we summarize the current preclinical and clinical data utilizing CAR T cells for SLE and discuss the future of this treatment modality for lupus.

Improving lupus care index documentation in patients with childhood-onset systemic lupus erythematosus.

Introduction: Childhood-onset systemic lupus erythematosus (c-SLE) presents unique challenges due to increased risk for severe morbidity and mortality compared to adult-onset SLE. Effective disease management relies on accurate disease assessment and documentation. Our project aimed to improve the documentation of the Lupus Care Index (LCI), a disease assessment bundle, by implementing a quality improvement (QI) initiative. Methods: A QI project was conducted at Nationwide Children's Hospital (NCH), targeting patients with c-SLE. The LCI, comprising the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI-2k) Physician Global Assessment (PGA) and patient-reported pain score, was introduced to capture comprehensive disease assessment. Interventions included provider education, standardization of documentation procedures, and electronic health record (EHR) modifications. Automated reports tracked documentation rates, and Pareto charts identified areas for targeted interventions. Results: Baseline analysis revealed incomplete documentation of LCI components in only one-third of c-SLE patients. Following interventions, documentation rates improved from 38% to 90%, with sustained improvement over at least a year. Discussion: Enhancing documentation of LCI in patients with c-SLE is crucial for optimizing disease management. Our quality improvement initiative demonstrated the feasibility of improving documentation practices through targeted interventions and system modifications. Future research should explore the impact of comprehensive documentation on clinical outcomes in pediatric lupus patients. Improving documentation of LCI in patients with c-SLE is essential for optimizing care delivery and clinical outcomes; our QI initiative highlights the effectiveness of systemic interventions in enhancing documentation practices and underscores the importance of continued efforts to improve pediatric lupus care.

Implementation study of the CARRA Uveitis Consensus Treatment Plans: feasibility for clinical practice and applicability for research.

BACKGROUND: Chronic anterior uveitis (CAU) carries a significant risk for eye complications and vision loss. The Childhood Arthritis and Rheumatology Research Alliance (CARRA) introduced consensus treatment plans (CTPs) to standardize treatment for CAU and facilitate future comparative effectiveness studies. Two CTPs were developed to address: 1) initiation of methotrexate (MTX) in patients with CAU naïve to steroid-sparing therapy, and 2) initiation of a TNF inhibitor (TNFi) in patients with severe uveitis or uveitis refractory to MTX. We evaluated implementation of the uveitis CTPs using existing CARRA Registry infrastructure and assessed feasibility of the CTPs for comparative effectiveness research. METHODS: This prospective observational cohort study was conducted at nine pilot sites between February 2020 and August 2022. Patients with JIA-associated CAU (JIA-U) were treated according to either the MTX or TNFi CTP. Uveitis activity and medication use were recorded at 0, 3, and 6 months. We assessed patient enrollment rates, CTP arm selection, uveitis control, and quality of data collection. We also evaluated CTP arm selection in a retrospective cohort of similar JIA-U patients enrolled in the CARRA Registry during the same study period. RESULTS: Seventeen patients were included in the pilot cohort. Eight were treated with the MTX CTP (4 oral MTX, 4 subcutaneous MTX), and 9 with the TNFi CTP (9 received standard-dose adalimumab, none selected high-dose adalimumab or infliximab). Uveitis was controlled in 13 of 17 patients by 6 months. Query of the CARRA-wide Registry identified 42 patients with JIA-U who were treated according to the MTX or TNFi CTPs. Among these, 26 were treated with MTX (8 oral, 18 subcutaneous) and 16 with TNFi (12 standard dose adalimumab, 2 high dose adalimumab, and 2 infliximab). CONCLUSION: Both the MTX and TNFi uveitis CTPs can practically be implemented in clinical settings and are currently being utilized across Registry sites. However, in patients starting TNFi therapy, all pilot study participants and most patients across the CARRA Registry were treated with a standard dose of adalimumab. This consensus on the treatment approach underscores its broad acceptance but also limits the applicability of the uveitis TNFi CTP for comparative effectiveness research.

Multisystem Inflammatory Syndrome in Children and Cardiac Involvement: A Quaternary Center Experience.

We prospectively analyzed clinical and laboratory characteristics associated with cardiac involvement and severe presentation in multisystem inflammatory syndrome in children. Of 146 patients, 66 (45.2%) had cardiac dysfunction and 26 (17.8%) had coronary artery abnormalities. Lower serum albumin levels, absolute lymphocyte and platelet counts, and elevated ferritin, fibrinogen, d-dimer and interleukin-6 levels were associated with cardiac dysfunction. Possible treatment complications were identified.

Interleukin (IL)-1/IL-6-Inhibitor-Associated Drug Reaction With Eosinophilia and Systemic Symptoms (DReSS) in Systemic Inflammatory Illnesses.

BACKGROUND: After introducing IL-1/IL-6 inhibitors, some patients with Still and Still-like disease developed unusual, often fatal, pulmonary disease. This complication was associated with scoring as DReSS (drug reaction with eosinophilia and systemic symptoms) implicating these inhibitors, although DReSS can be difficult to recognize in the setting of systemic inflammatory disease. OBJECTIVE: To facilitate recognition of IL-1/IL-6 inhibitor-DReSS in systemic inflammatory illnesses (Still/Still-like) by looking at timing and reaction-associated features. We evaluated outcomes of stopping or not stopping IL-1/IL-6 inhibitors after DReSS reaction began. METHODS: In an international study collaborating primarily with pediatric specialists, we characterized features of 89 drug-reaction cases versus 773 drug-exposed controls and compared outcomes of 52 cases stopping IL-1/IL-6 inhibitors with 37 cases not stopping these drugs. RESULTS: Before the reaction began, drug-reaction cases and controls were clinically comparable, except for younger disease-onset age for reaction cases with preexisting cardiothoracic comorbidities. After the reaction began, increased rates of pulmonary complications and macrophage activation syndrome differentiated drug-reaction cases from drug-tolerant controls (P = 4.7 × 10-35 and P = 1.1 × 10-24, respectively). The initial DReSS feature was typically reported 2 to 8 weeks after initiating IL-1/IL-6 inhibition. In drug-reaction cases stopping versus not stopping IL-1/IL-6-inhibitor treatment, reaction-related features were indistinguishable, including pulmonary complication rates (75% [39 of 52] vs 76% [28 of 37]). Those stopping subsequently required fewer medications for treatment of systemic inflammation, had decreased rates of macrophage activation syndrome, and improved survival (P = .005, multivariate regression). Resolution of pulmonary complications occurred in 67% (26 of 39) of drug-reaction cases who stopped and in none who continued inhibitors. CONCLUSIONS: In systemic inflammatory illnesses, recognition of IL-1/IL-6-inhibitor-associated reactions followed by avoidance of IL-1/IL-6 inhibitors significantly improved outcomes.

Interferonopathies masquerading as non-Mendelian autoimmune diseases: pattern recognition for early diagnosis.

Type I interferonopathies are a broad category of conditions associated with increased type I interferon gene expression and include monogenic autoinflammatory diseases and non-Mendelian autoimmune diseases such as dermatomyositis and systemic lupus erythematosus. While a wide range of clinical presentations among type I interferonopathies exists, these conditions often share several clinical manifestations and implications for treatment. Presenting symptoms may mimic non-Mendelian autoimmune diseases, including vasculitis and systemic lupus erythematosus, leading to delayed or missed diagnosis. This review aims to raise awareness about the varied presentations of monogenic interferonopathies to provide early recognition and appropriate treatment to prevent irreversible damage and improve quality of life and outcomes in this unique patient population.

Increasing access to psychological services within pediatric rheumatology care.

BACKGROUND: Given the impact of psychological factors on rheumatic disease, pediatric psychologists serve a vital role in promoting quality of life and managing common problems among youth with rheumatic disease. The aim of this project was to increase access to psychological services among youth with rheumatic disease at a children's hospital. METHODS: A quality improvement (QI) team identified key drivers and interventions aimed to increase access to psychological services for youth with rheumatic disease. Data was collected for a 6-month baseline period and 4-year intervention period. We applied the Plan-Do-Study Act method of QI and the American Society for Quality criteria to adjust the center line and control limits. RESULTS: There were two statistically significant center line shifts in the number of patients seen by psychology and one statistically significant shift in referrals to psychology over time with applied stepwise interventions. Patients seen by a psychologist increased by 3,173% from a baseline average of 1.8 to 59.9 patients seen per month (p < 0.03). Psychology referrals increased by 48% from a baseline average of 9.85 to 14.58 referrals per month over the intervention period (p < .01). CONCLUSIONS: Youth with rheumatic disease received increased access to mental health treatment when psychological services were imbedded within rheumatology care. Psychology referrals also increased significantly, suggesting that psychology integration within a medical clinic can increase identification of needs. Results suggest that psychology integration into rheumatology care may increase access to mental health treatment and identification of psychological needs in this at-risk population.

Reintroduction of immunosuppressive medications in pediatric rheumatology patients with histoplasmosis: a case series.

BACKGROUND: Children with rheumatic diseases (cRD) receiving immunosuppressive medications (IM) are at a higher risk for acquiring potentially lethal pathogens, including Histoplasma capsulatum (histoplasmosis), a fungal infection that can lead to prolonged hospitalization, organ damage, and death. Withholding IM during serious infections is recommended yet poses risk of rheumatic disease flares. Conversely, reinitiating IM increases risk for infection recurrence. Tumor necrosis factor alpha inhibitor (TNFai) biologic therapy carries the highest risk for histoplasmosis infection after epidemiological exposure, so other IM are preferred during active histoplasmosis infection. There is limited guidance as to when and how IM can be reinitiated in cRD with histoplasmosis. This case series chronicles resumption of IM, including non-TNFai biologics, disease-modifying anti-rheumatic drugs (DMARDs), and corticosteroids, following histoplasmosis among cRD. CASE PRESENTATION: We examine clinical characteristics and outcomes of 9 patients with disseminated or pulmonary histoplasmosis and underlying rheumatic disease [juvenile idiopathic arthritis (JIA), childhood-onset systemic lupus erythematosus (cSLE), and mixed connective tissue disease (MCTD)] after reintroduction of IM. All DMARDs and biologics were halted at histoplasmosis diagnosis, except hydroxychloroquine (HCQ), and patients began antifungals. Following IM discontinuation, all patients required systemic or intra-articular steroids during histoplasmosis treatment, with 4/9 showing Cushingoid features. Four patients began new IM regimens [2 abatacept (ABA), 1 HCQ, and 1 methotrexate (MTX)] while still positive for histoplasmosis, with 3/4 (ABA, MTX, HCQ) later clearing their histoplasmosis and 1 (ABA) showing decreasing antigenemia. Collectively, 8/9 patients initiated or continued DMARDs and/or non-TNFai biologic use (5 ABA, 1 tocilizumab, 1 ustekinumab, 3 MTX, 4 HCQ, 1 leflunomide). No fatalities, exacerbations, or recurrences of histoplasmosis occurred during follow-up (median 33 months). CONCLUSIONS: In our cohort of cRD, histoplasmosis course following reintroduction of non-TNFai IM was favorable, but additional studies are needed to evaluate optimal IM management during acute histoplasmosis and recovery. In this case series, non-TNFai biologic, DMARD, and steroid treatments did not appear to cause histoplasmosis recurrence. Adverse events from corticosteroid use were common. Further research is needed to implement guidelines for optimal use of non-TNFai (like ABA), DMARDs, and corticosteroids in cRD following histoplasmosis presentation.

Secondary Intracranial Hypertension in Pediatric Patients With Cryopyrin-Associated Periodic Syndrome.

BACKGROUND: Cryopyrin-associated periodic syndrome is characterized by periodic fever, rash, and joint pain. Papilledema rarely occurs. We present our series of patients with cryopyrin-associated periodic syndrome who clinically met the diagnostic criteria for Muckle-Wells syndrome and our experience with secondary intracranial hypertension. METHODS: Retrospective review of all patients with cryopyrin-associated periodic syndrome at Nationwide Children's Hospital from October 2015 to September 2017. RESULTS: Eighteen children met inclusion criteria: 15 females and three males, aged 1.5 to 16.2 years. Fifteen had periodic fever genetic testing; three had a known genetic defect identified, eight had a defect identified not currently known to be associated with cryopyrin-associated periodic syndrome, and four had no defect identified. Six patients (30%) developed headaches and were diagnosed with secondary intracranial hypertension. Lumbar puncture opening pressures ranged from 28 to 45 cm H2O. Only one patient had papilledema. Initial treatment was medical in all cases, by increasing interleukin-1 inhibitor dose and/or acetazolamide. One patient required a ventriculoperitoneal shunt for headache management. No visual acuity loss was detected. All six patients with secondary intracranial hypertension had a known genetic mutation or genetic variant of unknown significance; five involved the NLRP3 gene. CONCLUSIONS: In our series of 18 patients with cryopyrin-associated periodic syndrome, secondary intracranial hypertension occurred at a higher than expected rate. We suspect that genetic defects involving the NLRP3 gene may be a risk factor. Papilledema was present in only one patient. Physicians treating cryopyrin-associated periodic syndrome should be aware of this vision-threatening association and potential therapeutic approach.

Consensus treatment plans for periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome (PFAPA): a framework to evaluate treatment responses from the childhood arthritis and rheumatology research alliance (CARRA) PFAPA work group.

BACKGROUND: Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is the most common periodic fever syndrome in children. There is considerable heterogeneity in management strategies and a lack of evidence-based treatment guidelines. Consensus treatment plans (CTPs) are standardized treatment regimens that are derived based upon best available evidence and current treatment practices that are a way to enable comparative effectiveness studies to identify optimal therapy and are less costly to execute than randomized, double blind placebo controlled trials. The purpose of this project was to develop CTPs and response criteria for PFAPA. METHODS: The CARRA PFAPA Working Group is composed of pediatric rheumatologists, infectious disease specialists, allergists/immunologists and otolaryngologists. An extensive literature review was conducted followed by a survey to assess physician practice patterns. This was followed by virtual and in-person meetings between 2014 and 2018. Nominal group technique (NGT) was employed to develop CTPs, as well as inclusion criteria for entry into future treatment studies, and response criteria. Consensus required 80% agreement. RESULTS: The PFAPA working group developed CTPs resulting in 4 different treatment arms: 1. Antipyretic, 2. Abortive (corticosteroids), 3. Prophylaxis (colchicine or cimetidine) and 4. Surgical (tonsillectomy). Consensus was obtained among CARRA members for those defining patient characteristics who qualify for participation in the CTP PFAPA study. CONCLUSION: The goal is for the CTPs developed by our group to lead to future comparative effectiveness studies that will generate evidence-driven therapeutic guidelines for this periodic inflammatory disease.