Interleukin(IL)-1/IL-6-inhibitor-associated drug reaction with eosinophilia and systemic symptoms (DReSS) in systemic inflammatory illnesses.

BACKGROUND: After introducing interleukin(IL)-1/IL-6 inhibitors, some Still and Still-like patients 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: We sought 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 to 37 cases not-stopping these drugs. RESULTS: Before reaction began, drug-reaction cases and controls were clinically comparable, except for younger disease onset age for reaction cases with pre-existing cardiothoracic comorbidities. After reaction began, increased rates of pulmonary complications and macrophage activation syndrome (MAS), differentiated drug-reaction cases from drug-tolerant controls (p=4.7x10-35; p=1.1x10-24, respectively). Initial DReSS feature was typically reported 2-8 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%(39/52] versus [76%(28/37)]. Those stopping subsequently required fewer medications for treatment of systemic inflammation, had decreased rates of MAS, and improved survival (p=0.005, multivariate regression). Resolution of pulmonary complications occurred in 67%(26/39) 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.

Childhood Arthritis and Rheumatology Research Alliance Biologic DMARD Consensus Treatment Plans for Refractory Moderately Severe Juvenile Dermatomyositis.

OBJECTIVE: The objective was to develop consensus treatment plans (CTPs) for patients with refractory moderately severe juvenile dermatomyositis (JDM) treated with biologic disease-modifying antirheumatic drugs (bDMARDs). METHODS: The Biologics Workgroup of the Childhood Arthritis and Rheumatology Research Alliance (CARRA) JDM Research Committee used case-based surveys, consensus framework, and nominal group technique to produce bDMARD CTPs for patients with refractory moderately severe JDM. RESULTS: Four bDMARD CTPs were proposed: TNF-alpha inhibitor (adalimumab or infliximab), abatacept, rituximab, and tocilizumab. Each CTP has different options for dosing and/or route. Among 76 respondents, consensus was achieved for the proposed CTPs (93% [67/72]) as well as for patient characteristics, assessments, outcome measures, and follow up. By weighted average, respondents indicated that they would most likely use rituximab followed by abatacept, TNF-alpha inhibitor, and tocilizumab. CONCLUSION: CTPs for the use of bDMARDs in refractory moderately severe JDM were developed using consensus methodology. The implementation of the bDMARD CTPs will lay the groundwork for registry-based prospective comparative effectiveness studies.

Improving Outcomes of Pediatric Lupus Care Delivery With Provider Goal-Setting Activities and Multidisciplinary Care Models.

OBJECTIVE: The present study was undertaken to evaluate high-quality care delivery in the context of provider goal-setting activities and a multidisciplinary care model using an electronic health record (EHR)-enabled pediatric lupus registry. We then determined associations between care quality and prednisone use among youth with systemic lupus erythematosus (SLE). METHODS: We implemented standardized EHR documentation tools to autopopulate a SLE registry. We compared pediatric Lupus Care Index (pLCI) performance (range 0.0-1.0; 1.0 representing perfect metric adherence) and timely follow-up 1) before versus during provider goal-setting activities and population management, and 2) in a multidisciplinary lupus nephritis versus rheumatology clinic. We estimated associations between pLCI and subsequent prednisone use adjusted for time, current medication, disease activity, clinical features, and social determinants of health. RESULTS: We analyzed 830 visits by 110 patients (median 7 visits per patient [interquartile range 4-10]) over 3.5 years. The provider-directed activity was associated with improved pLCI performance (adjusted ß 0.05 [95% confidence interval (95% CI) 0.01, 0.09]; mean 0.74 versus 0.69). Patients with nephritis in multidisciplinary clinic had higher pLCI scores (adjusted ß 0.06 [95% CI 0.02, 0.10]) and likelihood of timely follow-up than those in rheumatology (adjusted relative risk [RR] 1.27 [95% CI 1.02, 1.57]). A pLCI score of ≥0.50 was associated with 0.72-fold lower adjusted risk of subsequent prednisone use (95% CI 0.53, 0.93). Minoritized race, public insurance, and living in areas with greater social vulnerability were not associated with reduced care quality or follow-up, but public insurance was associated with higher risk of prednisone use. CONCLUSION: Greater attention to quality metrics is associated with better outcomes in childhood SLE. Multidisciplinary care models with population management may additionally facilitate equitable care delivery.

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.

Anti-Valosin-Containing Protein (VCP/p97) Autoantibodies in Inclusion Body Myositis and Other Inflammatory Myopathies.

OBJECTIVE: The rationale for this study was based on reports that valosin-containing protein (VCP) mutations are found in hereditary inclusion body myositis (IBM) and VCP was detected in rimmed vacuoles of sporadic IBM (sIBM) muscle biopsies. Autoantibodies to VCP have not been reported in sIBM or other inflammatory myopathies (IIMs). The aim of this study was to determine the frequency and clinical significance of anti-VCP antibodies in sIBM and other IIMs. METHODS: Sera were collected from 73 patients with sIBM and 383 comparators or controls, including patients with IIM (n = 69), those with juvenile dermatomyositis (JDM) (n = 67), those with juvenile idiopathic arthritis (JIA) (n = 47), those with primary biliary cholangitis (PBC) (n = 105), controls that were age matched to patients with sIBM (similarly aged controls [SACs]) (n = 63), and healthy controls (HCs) (n = 32). Immunoglobulin G antibodies to VCP were detected by addressable laser bead immunoassay using a full-length recombinant human protein. RESULTS: Among patients with sIBM, 26.0% (19/73) were positive for anti-VCP. The frequency in disease controls was 15.0% (48/320). Among SACs, the frequency was 1.6% (1/63), and in HCs 0% (0/32). Frequencies were 17.5% (11/63) for IIM, 25.7% (27/105) for PBC, 3.0% (2/67) for JDM, and 17.0% (8/47) for JIA. The sensitivity, specificity, positive predictive value, and negative predictive value of anti-VCP for sIBM were 26.0%, 87.2%, 28.4%, and 85.9%, respectively. Of patients with sIBM, 15.1% (11/73) were positive for both anti-VCP and anti-cytosolic 5'-nucleotidase 1A (NT5c1A). Eleven percent of patients (8/73) were positive for anti-VCP, but negative for anti-NT5c1A. CONCLUSION: Anti-VCP has low sensitivity and moderate specificity for sIBM but may help fill the seronegative gap in sIBM. Further studies are needed to determine whether anti-VCP is a biomarker for a clinical phenotype that may have clinical value.

Gene Expression Profiles of Treatment Response and Non-Response in Children With Juvenile Dermatomyositis.

OBJECTIVE: The study objective was to identify differences in gene expression between treatment responders (TRs) and treatment non-responders (TNRs) diagnosed with juvenile dermatomyositis (JDM). METHODS: Gene expression analyses were performed using whole blood messenger RNA sequencing in patients with JDM (n = 17) and healthy controls (HCs; n = 10). Four analyses were performed (A1-4) comparing differential gene expression and pathways analysis exploiting the timing of sample acquisition and the treatments received to perform these comparative analyses. Analyses were done at diagnosis and follow-up, which averaged 7 months later in the cohort. RESULTS: At diagnosis, the expression of 10 genes differed between TRs and TNRs. Hallmark and canonical pathway analysis revealed 11 and 60 pathways enriched in TRs and 3 and 21 pathways enriched in TNRs, respectively. Pathway enrichment at diagnosis in TRs was strongest in pathways involved in metabolism, complement activation, and cell signaling as mediated by IL-8, p38/microtubule associated protein kinases (MAPK)/extracellular signal-regulated kinases (ERK), Phosphatidylinositol 3 Kinase Gamma (PI3Kγ), and the B cell receptor. Follow-up hallmark and canonical pathway analysis showed that 2 and 14 pathways were enriched in TRs, whereas 24 and 123 pathways were enriched in treatment TNRs, respectively. Prior treatment with glucocorticoids significantly altered expression of 13 genes in the analysis of subjects at diagnosis with JDM as compared with HCs. CONCLUSION: Numerous genes and pathways differ between TRs and TNRs at diagnosis and follow-up. Prior treatment with glucocorticoids prior to specimen acquisition had a small effect on the performed analyses.

Pediatric GAD-65 Autoimmune Encephalitis: Assessing Clinical Characteristics and Response to Therapy With a Novel Assessment Scale.

BACKGROUND: Glutamic acid decarboxylase (GAD) encephalitis is a neuroinflammatory disease characterized by a broad range of symptoms including cognitive deficits, behavioral changes, and seizures. Children with this disorder have heterogeneous presentations, and little is known about symptom progression over time and response to immunotherapy. METHODS: This study reports 10 pediatric GAD encephalitis cases and symptoms found at presentation and follow-up. In addition, symptom severity was reported utilizing a novel scale evaluating functional outcomes across the domains affected by autoimmune encephalitis including cognition, language, seizures, psychiatric symptoms, sleep, and movement. Retrospective chart review was conducted for 10 patients aged <18 years, diagnosed with GAD encephalitis, and followed for one year or more. Chart review included clinical, imaging, and laboratory findings at time of diagnosis and at six- and 12-month follow-ups. RESULTS: At presentation, cognitive deficits were found in all patients, seizures in six of 10, and language decline in seven of 10. Psychiatric symptoms were prominent for all but one patient with three of nine patients presenting with psychosis. Fatigue, sleep disruption, and movement disorders were less prominent symptoms, occurring in approximately half of the cohort. Cognition and fatigue improved significantly over time when compared with symptom severity, whereas seizures, psychiatric symptoms, and sleep did not. Language and sleep showed improvement only in early stages. Analysis of seizure frequency and type noted variability mirroring trends noted in adult studies of GAD encephalitis. CONCLUSIONS: This study demonstrated the variability of symptom profiles of pediatric GAD encephalitis and benefits of symptom severity scales. Symptom profiles and progression vary in this population.

An Update on the Treatment of Pediatric Autoimmune Encephalitis.

PURPOSE OF REVIEW: Autoimmune encephalitis (AE) is an increasingly recognized etiology for neuropsychiatric deficits that are highly responsive to immunotherapy. As a result, rheumatologists are often called upon to help with the diagnosis and treatment of these conditions. The purpose of this review is to provide an update on the pharmacologic treatment of AE. RECENT FINDINGS: To date, there are no prospective randomized placebo-controlled trials to guide treatment recommendations for AE. First-line therapies include corticosteroids, intravenous immunoglobulin, and plasma exchange. Second-line therapies include rituximab and cyclophosphamide (CYC), as well as mycophenolate mofetil and azathioprine. For patients refractory to both first- and second-line therapy, there is emerging evidence for the interleukin-6 (IL-6) inhibitor tocilizumab, the proteasome inhibitor bortezomib, and low-dose IL-2. Early treatment initiation and treatment escalation in patients with refractory disease improve outcomes. Given the delayed time between dosing and treatment effects of second-line agents, continuing first-line treatment until the patients shows improvement is recommended. SUMMARY: Although AE can present with dramatic, life-threatening neuropsychiatric deficits, the potential for recovery with prompt treatment is remarkable. First- and second-line therapies for AE lead to clinical improvement in the majority of patients, including full recoveries in many. Early treatment and escalation to second-line therapy in those with refractory disease improves patient outcomes. Novel treatments including IL-6 blockade and proteasome inhibitors have shown promising results in patients with refractory disease.

Cardiac operations for North American children with rheumatic diseases: 1985-2005.

Certain pediatric rheumatic diseases are known to affect the heart, sometimes requiring surgical intervention. The Pediatric Cardiac Care Consortium database was used to characterize cardiac surgical intervention among children with rheumatic diseases from 1985 to 2005. From this large database, the records for patients younger than 21 years who underwent cardiac surgery for any rheumatic disorder were extracted. The data collected included the type of procedure performed, the age at the time of the procedure, and the year the procedure was performed. The 261 pediatric patients identified underwent 361 cardiac surgical procedures for complications of rheumatic heart disease (RHD; 160 patients), neonatal lupus (NLE; 53 patients), Kawasaki disease (KD; 28 patients), systemic lupus erythematosus (SLE; 13 patients), and juvenile rheumatoid arthritis (JRA; 7 patients). Multiple procedures were performed for 23% of the patients. The most common procedures included pacemaker implantations among infants with NLE, coronary artery bypass grafts for KD primarily in 5- to 15-year-olds, and cardiac valve operations among adolescents with RHD, SLE, and JRA. Six perioperative deaths occurred. The proportion of annual pediatric cardiac surgical volume attributable to rheumatic diseases did not change during the period studied. Despite advances in their medical care, children with rheumatic diseases continue to sustain measurable morbidity and mortality due to the cardiovascular manifestations of their disease.