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BackgroundWe describe the early experiences of adults with systemic rheumatic disease who received the COVID-19 vaccine.MethodsFrom 2 April to 30 April 2021, we conducted an online, international survey of adults with systemic rheumatic disease who received COVID-19 vaccination. We collected patient-reported data on clinician communication, beliefs and intent about discontinuing disease-modifying antirheumatic drugs (DMARDs) around the time of vaccination, and patient-reported adverse events after vaccination.ResultsWe analysed 2860 adults with systemic rheumatic diseases who received COVID-19 vaccination (mean age 55.3 years, 86.7% female, 86.3% white). Types of COVID-19 vaccines were Pfizer-BioNTech (53.2%), Oxford/AstraZeneca (22.6%), Moderna (21.3%), Janssen/Johnson & Johnson (1.7%) and others (1.2%). The most common rheumatic disease was rheumatoid arthritis (42.3%), and 81.2% of respondents were on a DMARD. The majority (81.9%) reported communicating with clinicians about vaccination. Most (66.9%) were willing to temporarily discontinue DMARDs to improve vaccine efficacy, although many (44.3%) were concerned about rheumatic disease flares. After vaccination, the most reported patient-reported adverse events were fatigue/somnolence (33.4%), headache (27.7%), muscle/joint pains (22.8%) and fever/chills (19.9%). Rheumatic disease flares that required medication changes occurred in 4.6%.ConclusionAmong adults with systemic rheumatic disease who received COVID-19 vaccination, patient-reported adverse events were typical of those reported in the general population. Most patients were willing to temporarily discontinue DMARDs to improve vaccine efficacy. The relatively low frequency of rheumatic disease flare requiring medications was reassuring.

BACKGROUNDUndifferentiated systemic autoinflammatory diseases (USAIDs) present diagnostic and therapeutic challenges. Chronic interferon (IFN) signaling and cytokine dysregulation may identify diseases with available targeted treatments.METHODSSixty-six consecutively referred USAID patients underwent underwent screening for the presence of an interferon signature using a standardized type-I IFN-response-gene score (IRG-S), cytokine profiling, and genetic evaluation by next-generation sequencing.RESULTSThirty-six USAID patients (55%) had elevated IRG-S. Neutrophilic panniculitis (40% vs. 0%), basal ganglia calcifications (46% vs. 0%), interstitial lung disease (47% vs. 5%), and myositis (60% vs. 10%) were more prevalent in patients with elevated IRG-S. Moderate IRG-S elevation and highly elevated serum IL-18 distinguished 8 patients with pulmonary alveolar proteinosis (PAP) and recurrent macrophage activation syndrome (MAS). Among patients with panniculitis and progressive cytopenias, 2 patients were compound heterozygous for potentially novel LRBA mutations, 4 patients harbored potentially novel splice variants in IKBKG (which encodes NF-κB essential modulator [NEMO]), and 6 patients had de novo frameshift mutations in SAMD9L. Of additional 12 patients with elevated IRG-S and CANDLE-, SAVI- or Aicardi-Goutières syndrome-like (AGS-like) phenotypes, 5 patients carried mutations in either SAMHD1, TREX1, PSMB8, or PSMG2. Two patients had anti-MDA5 autoantibody-positive juvenile dermatomyositis, and 7 could not be classified. Patients with LRBA, IKBKG, and SAMD9L mutations showed a pattern of IRG elevation that suggests prominent NF-κB activation different from the canonical interferonopathies CANDLE, SAVI, and AGS.CONCLUSIONSIn patients with elevated IRG-S, we identified characteristic clinical features and 3 additional autoinflammatory diseases: IL-18-mediated PAP and recurrent MAS (IL-18PAP-MAS), NEMO deleted exon 5-autoinflammatory syndrome (NEMO-NDAS), and SAMD9L-associated autoinflammatory disease (SAMD9L-SAAD). The IRG-S expands the diagnostic armamentarium in evaluating USAIDs and points to different pathways regulating IRG expression.TRIAL REGISTRATIONClinicalTrials.gov NCT02974595.FUNDINGThe Intramural Research Program of the NIH, NIAID, NIAMS, and the Clinical Center.

Autoantibodies are important for the diagnosis of autoimmune interstitial lung disease (ILD). Standard immunoassays have limitations, including their qualitative nature and/or a narrow dynamic range of detection, hindering the usefulness of autoantibodies as biomarkers of disease activity. Here, the luciferase immunoprecipitation system (LIPS) was evaluated for measuring myositis-specific and other lung-related autoantibodies in 25 subjects with idiopathic inflammatory myopathies (IIM), 26 with Sjögren's disease (SjD), and 10 healthy volunteers. LIPS detected a broad dynamic range of autoantibodies, to MDA5, Jo-1, PL12, KS, U1-70K, and Ro52, and matched seropositivity status with established immunoassays. Robust anti-MDA5 autoantibodies in four IIM-ILD patients had a median value of 1,134,000 LU (IQR 473,000-2,317,000), which was 500 times higher than in 21 seronegative IIM patients. Markedly elevated anti-Jo-1 autoantibodies in five IIM-ILD patients demonstrated a median value of 1,177,000 LU (IQR: 604,000-2,520,000), which was 1000-fold higher than in seronegative patients. Robust anti-Ro52 and other anti-tRNA-synthetase autoantibodies were detected in a subset of IIM-ILD subjects. In SjD, only anti-U1-70K and KS autoantibodies were identified in ILD patients with a prevalence of 30% and 20%, respectively. In longitudinal samples of five IIM-ILD patients, anti-Jo-1 autoantibody levels paralleled clinical improvement of lung function. LIPS can accurately quantify autoantibody levels as biomarkers for treatment response in patients with autoimmune ILD. [ABSTRACT FROM AUTHOR]

Objective: Myositis‐associated autoantibodies (MAAs) have been associated with overlap myositis, certain disease manifestations such as interstitial lung disease (ILD), and worse prognosis in the idiopathic inflammatory myopathies. MAAs overall remain largely uncharacterized in patients with juvenile‐onset myositis. Moreover, it is unknown whether the number of MAAs is associated with disease severity. Methods: Patients with juvenile myositis in cross‐sectional natural history studies who underwent testing for myositis autoantibodies were included. Demographics, myositis autoantibodies, clinical characteristics, medications received, and outcomes of those with and without MAAs were compared. Multivariable logistic regression was performed to determine whether the number of MAAs detected was associated with severe disease features. Results: Among 551 patients, 36% had an MAA and 13% had more than one MAA. Among those who were MAA positive, there was a higher frequency of overlap myositis (18% vs 5.9%, P < 0.001). MAA positivity was associated with certain clinical features, including Raynaud phenomenon (odds ratio [OR] 2.44, 95% confidence interval [CI] 1.41–4.28) and ILD (OR 3.43, 95% CI 1.75–6.96), as well as a chronic disease course (OR 1.72, 95% CI 1.10–2.72) and mortality (OR 3.76, 95% CI 1.72–8.43). The number of MAAs was also associated with mortality (OR 1.83, 95% CI 1.16–2.86). Conclusion: MAAs were prevalent in a large cohort of patients with juvenile myositis. ILD, refractory disease, and mortality were associated with MAA positivity. Prospective studies are needed to determine whether early detection of MAAs may lead to improved outcomes for patients with juvenile myositis. [ABSTRACT FROM AUTHOR]

Objective: Novel autoantibody specificities including anti‐CCAR1 were recently discovered in adult patients with anti‐transcriptional intermediary factor (TIF1)–positive dermatomyositis (DM) and were associated with attenuated cancer emergence. The aims of the present study were to examine whether these autoantibodies occur in patients with juvenile‐onset DM (JDM) and to determine their associated features. Methods: Sera from 150 patients with anti‐TIF1γ autoantibody‐positive JDM in a cross‐sectional cohort and 90 juvenile healthy controls were assayed for anti‐CCAR1, anti‐C1Z1, anti‐IMMT, anti‐TBL1XR1, and anti‐Sp4 autoantibodies. Demographics, myositis autoantibodies, clinical features, medications, outcomes, and HLA‐DRB1 and HLA‐DQA1 alleles were compared between those with and without these autoantibodies. Results: Any one of the anti‐TIF1γ‐associated autoantibodies was present in 44 patients (29%) overall, including 25 (17%) with anti‐Sp4, 22 (15%) with anti‐TBL1XR1, 14 (9%) with anti‐CCAR1, 2 (1%) with anti‐C1Z1, and 2 (1%) with anti‐IMMT autoantibodies. These anti‐TIF1γ‐associated autoantibodies frequently co‐occurred. Patients with any of the anti‐TIF1γ‐associated autoantibodies had less frequent falling (34% [15] vs. 53% [56], P = 0.032) and lower peak muscle enzymes. None of the patients had cancer. Among White patients, HLA‐DRB1*03 was protective against an anti‐TIF1γ‐associated autoantibody (odds ratio 0.20, 95% confidence interval 0.07–0.52). Conclusion: Autoantibodies associated with anti‐TIF1γ were found in isolation and in combination among a subset of patients with JDM. Patients with these autoantibodies had less severe muscle disease and were not enriched for HLA‐DRB1*03. Additional autoantibodies among patients with positive anti‐TIF1γ with JDM likely contribute to the heterogeneity of the anti‐TIF1γ serologic subgroup. [ABSTRACT FROM AUTHOR]

Objectives To utilize whole-body CT imaging and calcium scoring techniques as tools for calcinosis assessment in a prospective cohort of patients with adult and juvenile dermatomyositis (DM and JDM, respectively). Methods Thirty-one patients (14 DM and 17 JDM) who fulfilled Bohan and Peter Classification criteria as probable or definite DM, the EULAR-ACR criteria for definite DM, and with calcinosis identified by physical examination or prior imaging studies were included. Non-contrast whole-body CT scans were obtained using low-dose radiation procedures. Scans were read qualitatively and quantitated. We calculated the sensitivity and specificity of calcinosis detection of physician physical exam against CT. We quantified calcinosis burden using the Agatston scoring technique. Results We identified five distinct calcinosis patterns: Clustered, Disjoint, Interfascial, Confluent and Fluid-filled. Novel locations of calcinosis were observed, including the cardiac tissue, pelvic and shoulder bursa, and the spermatic cord. Quantitative measures using Agatston scoring for calcinosis were used in regional distributions across the body. Physician physical exams had a sensitivity of 59% and a specificity of 90% compared with CT detection. A higher calcium score correlated with higher Physician Global Damage, Calcinosis Severity scores, and disease duration. Conclusion Whole-body CT scans and the Agatston scoring metric define distinct calcinosis patterns and provide novel insights relating to calcinosis in DM and JDM patients. Physicians' physical examinations underrepresented the presence of calcium. Calcium scoring of CT scans correlated with clinical measures, which suggests that this method may be used to assess calcinosis and follow its progression. [ABSTRACT FROM AUTHOR]

Objectives AECAs are detected in multiple forms of vasculitis or vasculopathy, including JDM. High levels of tropomyosin alpha-4 chain (TPM4) gene expression in cutaneous lesions and TPM4 protein expression in some endothelial cells (ECs) have been proven. Furthermore, the presence of autoantibodies to tropomyosin proteins have been discovered in DM. We therefore investigated whether anti-TPM4 autoantibodies are an AECA in JDM and are correlated with clinical features of JDM. Methods The expression of TPM4 protein in cultured normal human dermal microvascular ECs was investigated by Western blotting. Plasma samples from 63 children with JDM, 50 children with polyarticular JIA (pJIA) and 40 healthy children (HC) were tested for the presence of anti-TPM4 autoantibodies using an ELISA. Clinical features were compared between JDM patients with and without anti-TPM4 autoantibodies. Results Autoantibodies to TPM4 were detected in the plasma of 30% of JDM, 2% of pJIA (P  < 0.0001) and 0% of HC (P  < 0.0001). In JDM, anti-TPM4 autoantibodies were associated with the presence of cutaneous ulcers (53%; P  = 0.02), shawl sign rash (47%; P  = 0.03), mucous membrane lesions (84%; P  = 0.04) and subcutaneous edema (42%; P  < 0.05). Anti-TPM4 autoantibodies significantly correlated with the use of intravenous steroids and IVIG therapy in JDM (both P  = 0.01). The total number of medications received was higher in patients with anti-TPM4 autoantibodies (P  = 0.02). Conclusion Anti-TPM4 autoantibodies are detected frequently in children with JDM and are novel myositis-associated autoantibodies. Their presence correlates with vasculopathic and other cutaneous manifestations of JDM that may be indicative of more refractory disease. [ABSTRACT FROM AUTHOR]

Objective The ACR-EULAR Myositis Response Criteria (MRC) were developed as a composite measure using absolute percentage change in six core set measures (CSMs). We aimed to further validate the MRC by assessing the contribution of each CSM, frequency of strength vs extramuscular activity improvement, representation of patient-reported outcome measures (PROM), and frequency of CSM worsening. Methods Data from adult dermatomyositis/polymyositis patients in the rituximab (n  = 147), etanercept (n  = 14), and abatacept (n  = 19) trials, and consensus patient profiles (n  = 232) were evaluated. The Total Improvement Score (TIS), number of improving vs worsening CSMs, frequency of improvement with and without muscle-related CSMs, and contribution of PROM were evaluated by MRC category. Regression analysis was performed to assess contribution of each CSM to the MRC. Results Of 412 adults with dermatomyositis/polymyositis, there were 37%, 24%, 25%, and 14% with no, minimal, moderate, and major MRC improvement, respectively. The number of improving CSMs and absolute percentage change in all CSMs increased by improvement category. In minimal-moderate improvement, only physician-reported disease activity contributed significantly more than expected by MRC. Of patients with at least minimal improvement, 95% had improvement in muscle-related measures and a majority (84%) had improvement in PROM. Patients with minimal improvement had worsening in a median of 1 CSM, and most patients with moderate-major improvement had no worsening CSMs. Physician assessment of change generally agreed with MRC improvement categories. Conclusion The ACR-EULAR MRC performs consistently across multiple studies, further supporting its use as an efficacy end point in future myositis therapeutic trials. [ABSTRACT FROM AUTHOR]

Objective: Stakeholders met to address persistent challenges facing the development of therapeutics for polyarticular juvenile idiopathic arthritis (pJIA), which result in fewer approved therapies for children with pJIA than adults with rheumatoid arthritis (RA) and long lag times from adult RA approval to pediatric labeling. Ensuring that new medications are authorized in a timely manner to meet the needs of JIA patients worldwide is critically important to multiple stakeholders. Methods: The Food and Drug Administration in collaboration with the University of Maryland Center for Regulatory Science and Innovation held a public workshop entitled "Accelerating Drug Development for pJIA" on October 2, 2019, to address challenges surrounding access to new medications for children and adolescents with pJIA. Regulatory, academic, and industry stakeholders, as well as patient representatives, participated in the workshop, which consisted of 4 sessions, including panel discussions. Results: The workshop facilitated broad public discussion of challenges facing the development of pJIA therapeutics, highlighting areas of need and outlining opportunities to expedite development, while underscoring the necessity of close collaboration between all stakeholders, including patients and families. Conclusion: This report summarizes key aspects of the workshop, including the appropriate application of innovative approaches to the development of pJIA therapeutics, including extrapolation, to address current challenges and provide timely access to newer safe and effective treatments. Long‐term safety assessment is of pressing concern to stakeholders and cannot be fully extrapolated from adult studies but requires consistent postmarketing long‐term follow‐up. [ABSTRACT FROM AUTHOR]

Objective: Autoantibodies recognizing specificity protein 4 (Sp4) were recently discovered in adults with idiopathic inflammatory myopathies (IIM). Anti‐Sp4 autoantibodies co‐occurred in patients with anti–transcription intermediary factor 1 (anti‐TIF1) autoantibody‐positive dermatomyositis (DM) and were associated with a reduced risk of cancer. In the present study, the prevalence and clinical features associated with anti‐Sp4 autoantibodies in juvenile‐onset IIM were investigated. Methods: Serum samples from 336 patients with juvenile myositis in a cross‐sectional cohort and 91 healthy controls were screened for anti‐Sp4 autoantibodies using enzyme‐linked immunosorbent assay. Clinical characteristics, outcomes, and HLA alleles of those with and those without anti‐Sp4 autoantibodies were compared. Results: Anti‐Sp4 autoantibodies were present in 23 patients (7%) with juvenile myositis and were not present in any of the controls. Anti‐Sp4 autoantibodies were found among each clinical myositis subgroup. The frequency of TIF1 autoantibody positivity was significantly higher among those with anti‐Sp4 autoantibodies (21 [91%] versus 92 [30%], P < 0.001). In the anti‐TIF1 autoantibody–positive subgroup, Raynaud's phenomenon (8 [38%] versus 2 [2%], P < 0.001) was more common and peak aspartate aminotransferase was significantly lower in those with anti‐Sp4 autoantibodies. None of the patients with anti‐Sp4 autoantibodies required a wheelchair. Among White patients, DQA1*04 and DRB1*08 were associated with anti‐Sp4 autoantibodies. Conclusion: Anti‐Sp4 autoantibodies were found in patients with juvenile‐onset IIM, predominantly those with coexisting anti‐TIF1 autoantibodies. Patients with anti‐Sp4 autoantibodies represent a phenotypic subset of anti‐TIF1 autoantibody–positive myositis characterized by frequent Raynaud's phenomenon and less pronounced muscle involvement, similar to adults with these autoantibodies. Novel immunogenetic risk factors for White patients with IIM were identified among juveniles with anti‐Sp4 autoantibodies. [ABSTRACT FROM AUTHOR]

Objectives The B-cell depleting biologic, rituximab, is used to treat refractory autoimmune myositis. However, the beneficial effects of rituximab appear to outweigh the known contribution of B cells in myositis. We aimed to elucidate how myositis patients respond differently to rituximab and possible alternative mechanisms of action. Methods Here we have: (i) comprehensively investigated concurrent mRNA and microRNA expression in muscle biopsies taken at baseline and 16 weeks post treatment in 10 patients who were part of the rituximab in myositis (RIM) trial; and (ii) investigated the beneficial effect of rituximab on myositis muscle cells. Results Our analyses identified an increased number of changes in gene expression in biopsies from patients who had a clinical response to rituximab (n  =   5) compared with non-responders (n  =   5). The two groups had completely different changes in microRNA and mRNA expression following rituximab therapy, with the exception of one mRNA, BHMT2. Networks of mRNA and microRNA with opposite direction of expression changes highlighted ESR1 as upregulated in responders. We confirmed ESR1 upregulation upon rituximab treatment of immortalized myotubes and primary human dermatomyositis muscle cells in vitro , demonstrating a direct effect of rituximab on muscle cells. Notably, despite showing a response to rituximab, human dermatomyositis primary muscle cells did not express the rituximab target, CD20. However, these cells expressed a possible alternative target of rituximab, sphingomyelinase-like phosphodiesterase 3 b (SMPDL3B). Conclusion In addition to B-cell depletion, rituximab may be beneficial in myositis due to increased ESR1 signalling mediated by rituximab binding to SMPDL3B on skeletal muscle cells. [ABSTRACT FROM AUTHOR]

Objective: This open‐label, 24‐week study was conducted to evaluate the safety and efficacy of abatacept in patients with refractory juvenile dermatomyositis (DM). Methods: Ten patients ≥7 years of age with moderate disease activity were enrolled in a 24‐week study to examine the safety of subcutaneous abatacept and patient responses to the treatment. The primary endpoint was the International Myositis Assessment and Clinical Studies (IMACS) group Definition Of Improvement (DOI). Secondary endpoints included safety, changes in the core set activity measures (CSMs) of the IMACS group and the Pediatric Rheumatology International Trials Organization, and improvements in disease activity based on the American College of Rheumatology (ACR)/EULAR response criteria for juvenile DM. Radiologists blinded with regard to participant data assessed magnetic resonance images (MRIs) of patient thigh muscles. Interferon (IFN)–regulated gene score was performed on whole‐blood RNA samples using a NanoString assay, and cytokines were assessed using a Luminex assay. Results: Five patients achieved DOI at week 12, and 9 patients achieved DOI at week 24, including 2 patients with minimal, 4 patients with moderate, and 3 patients with major improvement by the 2016 ACR/EULAR response criteria for juvenile DM when patients were assessed using the CSMs of the IMACS Group. Improvements from baseline were seen in all CSMs at weeks 12 and 24, except in muscle enzymes. Daily glucocorticoid doses decreased from a mean of 16.7 mg at baseline to 10.2 mg at week 24 (P = 0.002). Average MRI muscle edema scores decreased from a mean baseline score of 5.3 to 2.3 at week 24 (P = 0.01). Six patients had down‐trending IFN‐regulated gene scores and galectin‐9 expression at week 24. Decreases in IFN‐regulated gene scores and in levels of interferon‐γ‐inducible protein 10kDa, galectin‐9, and interleukin‐2 correlated with improvements in disease activity and in muscle edema shown on MRI. Eleven grade 2 or 3 treatment‐emergent adverse events were observed. Conclusion: This open‐label study demonstrated that abatacept may be beneficial for patients with treatment‐refractory juvenile DM. [ABSTRACT FROM AUTHOR]