AB1059 A RANDOMIZED, PLACEBO-CONTROLLED STUDY OF ANAKINRA IN PATIENTS WITH STILL´S DISEASE

Background:Adult-onset Still's disease (AOSD) and systemic juvenile idiopathic arthritis (SJIA) are rare autoinflammatory disorders associated with an activated IL-1 pathway, characterized by spiking fever, rash, arthritis, lymphadenopathy, hepatosplenomegaly and serositis. There is a growing understanding that SJIA and AOSD are one disease with different ages of onset, i.e. Still's disease. The anaSTILLs study (anakinra inStill´sdisease) was designed to further evaluate efficacy and safety of anakinra in patients with Still´s disease across all age groups.Objectives:The primary objective was to demonstrate efficacy of anakinra versus placebo as assessed by ACR30 response with absence of fever at Week 2. Secondary objectives included: early onset of efficacy, sustained efficacy, time to study drug discontinuation, safety, pharmacokinetics, clinical signs and biomarkers.Methods:'anaSTILLs' was a randomized, double-blind, placebo-controlled, 12-week study including patients with active and newly diagnosed (6 months) Still´s disease according to adapted ILAR criteria if <16, or Yamaguchi criteria, if ≥16 years of age at disease onset. Patients were randomized to anakinra 2 mg/kg (max 100 mg/day), 4 mg/kg (max 200 mg/day) or placebo.Results:12 patients were randomized and received study drug: 6 anakinra (2 mg/kg n=2, 4 mg/kg n=4) and 6 placebo, the study was terminated early due to slow recruitment. 1 patient on placebo had lymphoma, not Still's disease, and was excluded; thus in total 11 patients were analyzed for efficacy, 8 were children [median (range) age=4.0 (1-11) years] and 3 were adults [median (range) age=32.0 (25-51) years]. 55% were male and the mean symptom duration was 74.2 days. All patients on anakinra but none on placebo achieved ACR30 response with absence of fever at Week 2 (p-value=0.0022). The efficacy of anakinra was further demonstrated by superiority to placebo in ACR50/70/90 responses with absence of fever at Week 2. All placebo patients discontinued the study within 6 weeks, 2 due to progressive disease, 2 due to lack of efficacy and 1 due to withdrawal by patient. There was a numerically higher proportion with early onset of efficacy (Week 1) in the anakinra group compared to placebo. The ACR30/50/70/90 responses in the anakinra group were sustained throughout the study period. Patients in the anakinra group had a prompt and persistent decrease in CRP and ferritin levels at Week 1, which was not observed in the placebo group. There were no unexpected safety findings. All anakinra patients developed anti-drug antibodies (ADAs) at some timepoint during the study. ADAs were persistent throughout the treatment period, except in one patient. Titers were low to moderate. One placebo patient had low ADA titers at one occasion. No neutralizing antibodies were observed and the ADAs did not appear to impact clinical efficacy or safety.Conclusion:Anakinra is superior to placebo in the treatment of Still's disease. ADAs occur frequently but do not appear to adversely impact efficacy or safety. These results confirm the benefits of anakinra treatment in patients with active, newly diagnosed Still´s disease across ages.Disclosure of Interests:Laura Schanberg Grant/research support from: Sobi, BMS, Consultant of: Aurinia, UCB, Sanofi, Peter Nigrovic Grant/research support from: Novartis, BMS, Pfizer, Consultant of: Novartis, BMS, Pfizer, Sobi, Miach Orthopedics, Simcere, XBiotech, Quench Bio, Ashley Cooper: None declared, Winn Chatham Grant/research support from: Sobi, Consultant of: Sobi, Shoghik Akoghlanian: None declared, Namrata Singh: None declared, Egla Rabinovich Grant/research support from: AbbVie, UCB Pharma, Janssen Research & Development, Akaluck Thatayatikom: None declared, Alysha Taxter: None declared, Jonathan Hausmann Consultant of: Novartis, Milan Zdravkovic Shareholder of: Sobi, Employee of: Sobi, Sven Ohlman Shareholder of: Sobi, Employee of: Former employee of Sobi, Henrik Andersson Employee of: Sobi, Susanna Cederholm Shareholder of: Sobi, Employee of: Sobi, Margareta Wikén Shareholder of: Sobi, Employee of: Former employee of Sobi, Rayfel Schneider Grant/research support from: Roche, Novartis, Sobi, Pfizer, Consultant of: Sobi, Novartis, Novimmune, Fabrizio De Benedetti Grant/research support from: AbbVie, Pfizer, Novartis, Novimmune, Sobi, Sanofi, Roche, Speakers bureau: AbbVie, Novartis, Roche, Sob

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

Increase in pediatric recurrent fever evaluations during the first year of the COVID-19 pandemic in North America

The impact of the COVID-19 pandemic on new diagnoses of recurrent fevers and autoinflammatory diseases is largely unknown. The Childhood Arthritis and Rheumatology Research Alliance (CARRA) PFAPA/AID Working Group aimed to investigate the impact of the COVID-19 pandemic on the number of pediatric patients evaluated for recurrent fevers and autoinflammatory diseases in North America. The absolute number of new outpatient visits and the proportion of these visits attributed to recurrent fever diagnoses during the pre-pandemic period (1 March 2019–29 February 2020) and the first year of the COVID-19 pandemic (1 March 2020–28 February 2021) were examined. Data were collected from 27 sites in the United States and Canada. Our results showed an increase in the absolute number of new visits for recurrent fever evaluations in 21 of 27 sites during the COVID-19 pandemic compared to the pre-pandemic period. The increase was observed across different geographic regions in North America. Additionally, the proportion of new visits to these centers for recurrent fever in relation to all new patient evaluations was significantly higher during the first year of the pandemic, increasing from 7.8% before the pandemic to 10.9% during the pandemic year (p &lt; 0.001). Our findings showed that the first year of the COVID-19 pandemic was associated with a higher number of evaluations by pediatric subspecialists for recurrent fevers. Further research is needed to understand the reasons behind these findings and to explore non-infectious triggers for recurrent fevers in children

Assessing the Number of Children Evaluated for Recurrent Fevers During the COVID-19 Pandemic in North America

Background/Purpose: The impact of the COVID-19 pandemic on the number of pediatric patients evaluated in North America for recurrent fevers and autoinflammatory diseases is unknown; however, there have been reports of increased numbers of children presenting with these concerns. The purpose of this project was to determine the number of new patients evaluated for recurrent fevers in temporal relation to the COVID-19 pandemic in North America. Methods: The Childhood Arthritis and Rheumatology Research Alliance (CARRA) Periodic Fever, Aphthous Stomatitis, Pharyngitis, Cervical Adenitis Syndrome (PFAPA)/Autoinflammatory Disease Working Group used previously determined recurrent fever ICD-10 codes, including periodic fever and autoinflammatory syndromes, to quantify monthly numbers of new pediatric patients evaluated for recurrent fever diagnoses by outpatient subspecialists from March 1, 2019 to February 29, 2020 (pre-pandemic) and from March 1, 2020 to February 28, 2021 (during the pandemic). The proportion of new visits evaluated for recurrent fever diagnoses relative to all new visit diagnoses during these two years were compared using a two-sample test of proportions. This study was determined to be IRB exempt by the Cincinnati Children\u27s Hospital IRB. Results: Twenty-four sites reported 1684 new patient visits coded with recurrent fever diagnoses pre-pandemic compared with 2181 during the first year of the pandemic. There was an increase in the total number of recurrent fever evaluations after the onset of the pandemic compared to the year prior in 20 of 24 sites (range-48% to +360%). Of the 20 sites who provided the total number of new visits for all diagnoses, there were 19305 new visits pre-pandemic of which 1318 (6.83%) had a recurrent fever code compared to 17040 new visits during the pandemic with 1690 (9.92%) who received a recurrent fever diagnosis code. The difference between the proportion of new recurrent fever evaluations and total number of new visits pre-pandemic versus during the pandemic was statistically significant (p\u3c 0.0001). Conclusion: Across 24 CARRA-associated North American centers, there was an increase in pediatric patients evaluated for new recurrent fever diagnoses during the first year of the COVID-19 pandemic compared to the year prior, despite a decrease in the total number of new patients. An increase in recurrent fever evaluations merits further investigation given that many daycare centers and schools were closed during a time of increased infection control precautions and attention to fevers. A speculated potential etiology is that unknown, noninfectious triggers precipitate recurrent fever syndromes. The CARRA PFAPA/Autoinflammatory Disease Working Group\u27s project is the first collaborative, multidisciplinary effort to assess the number of children evaluated for recurrent fevers in relation to the COVID-19 pandemic in North America

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

Abstract 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

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 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

International Consensus for the Dosing of Corticosteroids in Childhood-Onset Systemic Lupus Erythematosus With Proliferative Lupus Nephritis

Objective: To develop a standardized steroid dosing regimen (SSR) for physicians treating childhood-onset systemic lupus erythematosus (SLE) complicated by lupus nephritis (LN), using consensus formation methodology. Methods: Parameters influencing corticosteroid (CS) dosing were identified (step 1). Data from children with proliferative LN were used to generate patient profiles (step 2). Physicians rated changes in renal and extrarenal childhood-onset SLE activity between 2 consecutive visits and proposed CS dosing (step 3). The SSR was developed using patient profile ratings (step 4), with refinements achieved in a physician focus group (step 5). A second type of patient profile describing the course of childhood-onset SLE for ≥4 months since kidney biopsy was rated to validate the SSR-recommended oral and intravenous (IV) CS dosages (step 6). Patient profile adjudication was based on majority ratings for both renal and extrarenal disease courses, and consensus level was set at 80%. Results: Degree of proteinuria, estimated glomerular filtration rate, changes in renal and extrarenal disease activity, and time since kidney biopsy influenced CS dosing (steps 1 and 2). Considering these parameters in 5,056 patient profile ratings from 103 raters, and renal and extrarenal course definitions, CS dosing rules of the SSR were developed (steps 3–5). Validation of the SSR for up to 6 months post–kidney biopsy was achieved with 1,838 patient profile ratings from 60 raters who achieved consensus for oral and IV CS dosage in accordance with the SSR (step 6). Conclusion: The SSR represents an international consensus on CS dosing for use in patients with childhood-onset SLE and proliferative LN. The SSR is anticipated to be used for clinical care and to standardize CS dosage during clinical trials. © 2021, American College of Rheumatolog

Delivering clinical trials at home: protocol, design and implementation of a direct-to-family paediatric lupus trial

Introduction Direct-to-family clinical trials efficiently provide data while reducing the participation burden for children and their families. Although these trials can offer significant advantages over traditional clinical trials, the process of designing and implementing direct-to-family studies is poorly defined, especially in children with rheumatic disease. This paper provides lessons learnt from the design and implementation of a self-controlled, direct-to-family pilot trial aimed to evaluate the effects of a medication management device on adherence to hydroxychloroquine in paediatric SLE.Methods Several design features accommodate a direct-to-family approach. Participants meeting eligibility criteria from across the USA were identified a priori through a disease registry, and all outcome data are collected remotely. The primary outcome (medication adherence) is evaluated using electronic medication event-monitoring, plasma drug levels, patient questionnaires and pill counts. Secondary and exploratory endpoints include (1) lupus disease activity measured by a remote SLE Disease Activity Index examination and the Systemic Lupus Activity Questionnaire; and (2) hydroxychloroquine pharmacokinetics and pharmacodynamics. Recruitment of the initial target of 20 participants was achieved within 10 days. Due to initial recruitment success, enrolment was increased to 26 participants. Additional participants who were interested were placed on a waiting list in case of dropouts during the study.Discussion and dissemination Direct-to-family trials offer several advantages but present unique challenges. Lessons learnt from the protocol development, design, and implementation of this trial will inform future direct-to-family trials for children and adults with rheumatic diseases. Additionally, the data collected remotely in this trial will provide critical information regarding the accuracy of teleresearch in lupus, the impact of adherence to hydroxychloroquine on disease activity and a pharmacokinetic analysis to inform paediatric-specific dosing of hydroxychloroquine.Trial registration number ClinicalTrials.gov Registry (NCT04358302)