Safety of baricitinib in Japanese patients with rheumatoid arthritis in clinical use: 3-year data of all-case post-marketing surveillance study.

OBJECTIVE: To assess safety of baricitinib in Japanese patients with rheumatoid arthritis in real-world clinical practice. METHODS: This all-case post-marketing surveillance study included patients initiating baricitinib for rheumatoid arthritis from September 2017 to April 2019. Treatment duration was recorded. Safety data were collected for up to 3 years from baricitinib initiation (up to 4 weeks post discontinuation in discontinuing patients). RESULTS: Safety analyses included 4720 patients; 2580 (54.7%) were ≥65 years old. Baricitinib persistence rate was 45.4% (3 year Kaplan-Meier analysis); the most common discontinuation reason was insufficient effectiveness (n = 1005, 21.3%). Serious adverse events occurred in 600 patients (incidence rate 10.42/100 patient-years; 95% confidence interval, 9.76-11.09). There were 39 deaths (incidence rate 0.43 [0.30-0.57]/100 patient-years). Incidence rate per 100 patient-years for adverse events of special interest were herpes zoster 4.68 (4.22-5.14), serious infection 3.05 (2.68-3.41), malignancy 1.09 (0.87-1.30), major adverse cardiovascular events 0.35 (0.23-0.48) and venous thromboembolism 0.25 (0.15-0.36). Incidence rates did not increase with prolonged exposure. CONCLUSIONS: No new safety concerns were identified during this 3 year post-marketing surveillance study of baricitinib in Japanese patients with rheumatoid arthritis. Patients and clinicians should be cognizant of herpes zoster and other serious infection risks during baricitinib treatment, especially in the first 6 months.

A randomised, parallel-group, double-blind, placebo-controlled phase 3 study to Determine the effectiveness of the type I interferon receptor antibody, Anifrolumab, In SYstemic sclerosis: DAISY study design and rationale.

OBJECTIVES: The type I interferon pathway is a promising target for treatment of patients with systemic sclerosis (SSc). Here, we describe the design of a multinational, randomised phase 3 study to Determine the effectiveness of the type I interferon receptor antibody, Anifrolumab, In SYstemic sclerosis (DAISY). METHODS: DAISY includes a 52-week double-blind, placebo-controlled treatment period, a 52-week open-label active treatment period, and a 12-week safety follow-up period. The patient population includes a planned 306 adults with limited or diffuse cutaneous active SSc who satisfied American College of Rheumatology/European Alliance of Associations for Rheumatology 2013 SSc criteria. Use of standard immunosuppressants, including mycophenolate mofetil, at a stable dose prior to randomisation is permitted in addition to weekly subcutaneous anifrolumab or placebo. Efficacy will be assessed at Week 52 via Revised-Composite Response Index in SSc (CRISS)-25 response (primary endpoint). Lung function and skin thickness will be assessed via change from baseline in forced vital capacity in patients with SSc-associated interstitial lung disease and modified Rodnan Skin Score, respectively (key secondary endpoints). CONCLUSIONS: The DAISY trial will evaluate the efficacy and safety of anifrolumab as a first-in-class treatment option for patients with both limited and diffuse cutaneous SSc and will provide insight into the contributions of type I interferon to SSc pathogenesis. Revised-CRISS-25 can account for improvement and worsening in a broad set of validated clinical measures beyond lung function and skin thickness, including clinician- and patient-reported outcomes, capturing the heterogeneity of SSc.

Systemic sclerosis is a chronic autoimmune disease that leads to inflammation and scarring of the skin and internal organs, especially the lungs. Systemic sclerosis and lupus are both associated with increased interferon signalling, which is usually triggered by viral infections, but is related to damaging inflammation in these diseases. Anifrolumab, a drug that blocks interferon signalling, is already used to treat patients with lupus (also known as SLE), so it could potentially be used to treat patients with systemic sclerosis. This publication details the DAISY study design and explains why it is needed. This study will follow 2 groups of 153 patients with systemic sclerosis over 2 years. During the first year, in addition to any standard immunosuppressant therapy, the groups will receive weekly injections of either anifrolumab or "dummy drug" (placebo). In the second year, all patients will receive anifrolumab with their standard immunosuppressant therapy. Multiple factors will be considered to evaluate the efficacy of anifrolumab treatment, including clinical measurements of skin thickness and lung function, and questionnaires completed by clinicians and patients to report on patient health and their everyday function during treatment. The DAISY study will investigate the efficacy and safety of anifrolumab treatment in a diverse group of patients with systemic sclerosis who currently have limited options for effective treatment. The study will evaluate the impact of anifrolumab treatment on multiple aspects of the disease, and how patients feel about their overall health-related quality of life.

Interstitial lung disease and myositis.

PURPOSE OF REVIEW: In patients with myositis, interstitial lung disease (ILD) is one of the major causes of morbidity and mortality. Given the limited evidence, there is an urgent need to refine the treatment for myositis-ILD. This review aims to highlight recent updates on the management of myositis-associated ILD, focusing on screening, risk stratification, and treatment. RECENT FINDINGS: Asian race and/or residence, dermatomyositis, mechanic's hand, antisynthetase antibodies, and antimelanoma differentiation-associated gene 5 antibodies are risk factors for ILD development. Patients with such risk factors should be screened for ILD using high-resolution computed tomography. Various prediction models for mortality or rapidly progressive ILD (RP-ILD) in patients with myositis-ILD have been proposed, but validation of these models in multiple independent studies is required. Academic societies in Japan, the United Kingdom, and the United States have proposed tentative treatment algorithms for myositis-ILD on the basis of the presence or absence of RP-ILD. SUMMARY: Knowledge on myositis-ILD risk stratification, potentially useful for personalized management approaches in clinical practice, is accumulating. However, further global joint efforts are necessary to build a strong evidence base for consensus algorithms for myositis-ILD.

Identification and management of interstitial lung disease associated with systemic sclerosis (SSc-ILD), rheumatoid arthritis (RA-ILD), and polymyositis/dermatomyositis (PM/DM-ILD): development of expert consensus-based clinical algorithms.

BACKGROUND: Clinical guidance on the identification and management of connective tissue disease-associated interstitial lung disease (CTD-ILD) is needed for optimal clinical practice. We aimed to develop clinical algorithms for identifying and managing three common CTD-ILDs: those associated with systemic sclerosis (SSc-ILD), rheumatoid arthritis (RA-ILD), and polymyositis/dermatomyositis (PM/DM-ILD). RESEARCH DESIGN AND METHODS: Meetings were held October-November 2023 to create consensus-based algorithms for identifying and managing SSc-ILD, RA-ILD, and PM/DM-ILD in clinical practice, based on expert consensus statements for identification and management of CTD-ILD previously derived from a Delphi process. RESULTS: We developed clinical algorithms for SSc-ILD, RA-ILD, and PM/DM-ILD that highlight both commonalities and differences in the identification and management of these CTD-ILDs. Importantly, ILD should be suspected in patients with SSc, RA, or PM/DM who have respiratory symptoms. Chest high-resolution computed tomography has utility for screening, diagnosis and assessment of severity. Furthermore, regular follow-up and multidisciplinary management are important. Disease-specific considerations include unique risk factors such as anti-topoisomerase I antibodies in SSc-ILD, high-titer cyclic citrullinated peptide antibodies in RA, anti-aminoacyl tRNA synthetase antibodies in PM/DM, and anti-melanoma differentiation-associated gene 5 antibody in DM. CONCLUSIONS: These algorithms may help physicians to identify and manage patients with SSc-ILD, RA-ILD, or PM/DM-ILD.

Clinical phenotyping in patients with anti-synthetase antibodies using cluster analysis.

Objectives: To characterize clinically distinct subgroups among unselected patients with anti-synthetase antibodies using cluster analysis. Methods: This study evaluated patients with anti-synthetase antibodies registered to two independent cohorts; 106 consecutive patients from a prospective, single-centre cohort of the Scleroderma/Myositis Centre of Excellence (SMCE) were used as a derivation cohort and 125 patients from the Multicentre Retrospective Cohort of Japanese Patients with Myositis-Associated Interstitial Lung Disease (JAMI) were used as a validation cohort. Anti-synthetase antibodies were identified by RNA immunoprecipitation. A multiple correspondence analysis followed by hierarchical clustering was performed to aggregate the patients into homogeneous subgroups. Subsequently, a simple-to-use classification tree was generated using classification and regression tree analysis. Results: Three clusters were identified in the SMCE cohort: cluster 1 (n = 48), the interstitial pneumonia with autoimmune features/amyopathic dermatomyositis cluster, associated with older age at diagnosis and a higher frequency of malignancy; cluster 2 (n = 46), the DM cluster, corresponded to a younger age at diagnosis with a higher prevalence of myositis, arthritis, DM pathognomonic rashes, mechanic's hands and fever; and cluster 3 (n = 12), the SSc cluster, characterized by chronic interstitial lung disease. There was no significant difference in overall survival or progression-free survival between the clusters. A simple classification tree using myositis and RP was created in the SMCE cohort. Clusters 1 and 2 were successfully reproduced and the classification tree demonstrated favourable performance in the JAMI cohort. Conclusion: Patients with anti-synthetase antibodies were classified into three distinct phenotypes, indicating substantial heterogeneity within this patient group.

Pulmonary Hypertension With Interstitial Pneumonia: Initial Treatment Effectiveness and Severity in a Japan Registry.

Background: Recent guidelines discourage the use of pulmonary arterial hypertension (PAH)-targeted therapies in patients with pulmonary hypertension (PH) associated with respiratory diseases. Therefore, stratifications of the effectiveness of PAH-targeted therapies are important for this group. Objectives: The authors aimed to identify phenotypes that might benefit from initial PAH-targeted therapies in patients with PH associated with interstitial pneumonia and combined pulmonary fibrosis and emphysema. Methods: We categorized 270 patients with precapillary PH (192 interstitial pneumonia, 78 combined pulmonary fibrosis and emphysema) into severe and mild PH using a pulmonary vascular resistance of 5 WU. We investigated the prognostic factors and compared the prognoses of initial (within 2 months after diagnosis) and noninitial treatment groups, as well as responders (improvements in World Health Organization functional class, pulmonary vascular resistance, and 6-minute walk distance) and nonresponders. Results: Among 239 treatment-naive patients, 46.0% had severe PH, 51.8% had mild ventilatory impairment (VI), and 40.6% received initial treatment. In the severe PH with mild VI subgroup, the initial treatment group had a favorable prognosis compared with the noninitial treatment group. The response rate in this group was significantly higher than the others (48.2% vs 21.8%, ratio 2.21 [95% CI: 1.17-4.16]). In multivariate analysis, initial treatment was a better prognostic factor for severe PH but not for mild PH. Within the severe PH subgroup, responders had a favorable prognosis. Conclusions: This study demonstrated an increased number of responders to initial PAH-targeted therapy, with a favorable prognosis in severe PH cases with mild VI. A survival benefit was not observed in mild PH cases. (Multi-institutional Prospective Registry in Pulmonary Hypertension associated with Respiratory Disease; UMIN000011541).

Characteristics of emerging new autoimmune diseases after COVID-19 vaccination: A sub-study by the COVAD group.

BACKGROUND: Despite the overall safety and efficacy of COVID-19 vaccinations, rare cases of systemic autoimmune diseases (SAIDs) have been reported post-vaccination. This study used a global survey to analyze SAIDs in susceptible individuals' post-vaccination. METHODS: A cross-sectional study was conducted among participants with self-reported new-onset SAIDs using the COVID-19 Vaccination in Autoimmune Diseases (COVAD) 2 study dataset-a validated, patient-reported e-survey-to analyze the long-term safety of COVID-19 vaccines. Baseline characteristics of patients with new-onset SAIDs and vaccinated healthy controls (HCs) were compared after propensity score matching based on age and sex in a 1:4 ratio. RESULTS: Of 16 750 individuals, 74 (median age 52 years, 79.9% females, and 76.7% Caucasians) had new-onset SAID post-vaccination, mainly idiopathic inflammatory myopathies (IIMs) (n = 23, 31.51%), arthritis (n = 15; 20.53%), and polymyalgia rheumatica (PMR) (n = 12, 16.40%). Higher odds of new-onset SAIDs were noted among Caucasians (OR = 5.3; 95% CI = 2.9-9.7; p < .001) and Moderna vaccine recipients (OR = 2.7; 95% CI = 1.3-5.3; p = .004). New-onset SAIDs were associated with AID multimorbidity (OR = 1.4; 95% CI = 1.1-1.7; p < .001), mental health disorders (OR = 1.6; 95% CI = 1.3-1.9; p < .001), and mixed race (OR = 2.2; 95% CI = 1.2-4.2; p = .010), where those aged >60 years (OR = 0.6; 95% CI = 0.4-0.8; p = .007) and from high/medium human development index (HDI) countries (compared to very high HDI) reported fewer events than HCs. CONCLUSION: This study reports a low occurrence of new-onset SAIDs following COVID-19 vaccination, primarily IIMs, PMR, and inflammatory arthritis. Identified risk factors included pre-existing AID multimorbidity, mental health diseases, and mixed race. Revaccination was well tolerated by most patients; therefore, we recommend continuing COVID-19 vaccination in the general population. However, long-term studies are needed to understand the autoimmune phenomena arising post-vaccination.

Lung ultrasound in the assessment of interstitial lung disease in patients with connective tissue disease: Performance in comparison with high-resolution computed tomography.

OBJECTIVE: To investigate clinical relevance of performing lung ultrasound (LUS) in patients with connective tissue disease (CTD)-associated interstitial lung disease (ILD) in comparison with high-resolution computed tomography (HRCT). METHODS: This single-centre study enrolled eligible patients with CTD-ILD from the prospective LUS registry. Total B-lines were detected by assessment at 14 sites via LUS. Forced vital capacity, diffusing lung capacity for carbon monoxide (DLCO), DLCO/alveolar volume, 6-minute walking distance, and the ILD-GAP index were used as ILD prognostic parameters. Correlations were examined using single and multiple regression analyses. RESULTS: Sixty-seven patients were enrolled, including 29 with idiopathic inflammatory myopathy or anti-synthetase syndrome, 25 with systemic sclerosis (SSc), 10 with rheumatoid arthritis, and 3 with mixed connective tissue disease. The total number of B-lines correlated with ILD extent on HRCT in patients with CTD-ILD (r = 0.66; P < 0.001), particularly in patients with SSc-ILD (r = 0.78; P < 0.001). Total B-lines and ILD extent on HRCT showed comparable correlations with prognostic parameters, while multiple regression analysis revealed the limited benefit of performing LUS in addition to HRCT in predicting correlations with prognostic factors. CONCLUSIONS: LUS serves as an alternative tool for assessing the severity and prognosis of patients with CTD-ILD.

The effect of nintedanib on health-related quality of life in Japanese patients with progressive fibrosing interstitial lung diseases: A subset analysis of the INBUILD trial.

BACKGROUND: In previous Japanese subgroup/subset analyses of the global INBUILD trial, nintedanib reduced the annual rate of forced vital capacity (FVC) decline and the risk of disease progression in patients with progressive fibrosing interstitial lung diseases (PF-ILDs). This exploratory subset analysis assessed the effect of nintedanib on symptoms and impacts of pulmonary fibrosis in Japanese patients with PF-ILDs, including those with usual interstitial pneumonia (UIP)-like fibrotic pattern on high-resolution computed tomography (HRCT). METHODS: This analysis included Japanese patients who received at least one dose of study treatment in the randomized, double-blind, placebo-controlled INBUILD trial. The Living with Pulmonary Fibrosis (L-PF) questionnaire was used to assess pulmonary fibrosis symptoms and impacts (higher scores indicated greater impairment) at baseline and weeks 12-52. RESULTS: In total, 108 Japanese patients (nintedanib: n = 52; placebo: n = 56) were included; 84 patients had UIP-like fibrotic pattern on HRCT. In the total Japanese subgroup and in those with UIP-like fibrotic pattern, numerically greater increases in L-PF total, symptoms total, symptoms fatigue domain, and impacts scores were observed in the placebo group than in the nintedanib group at all timepoints, starting from week 12. A numerically greater increase in the symptoms dyspnea domain score was observed with placebo versus nintedanib starting from week 36. Throughout the study, the symptoms cough domain score increased in the placebo group but decreased in the nintedanib group. CONCLUSIONS: Our findings demonstrate that nintedanib has the potential to reduce the worsening of symptoms and impacts of pulmonary fibrosis in Japanese patients with PF-ILDs.

Listening to patients, for the patients: The COVAD Study-Vision, organizational structure, and challenges.

BACKGROUND: The pandemic presented unique challenges for individuals with autoimmune and rheumatic diseases (AIRDs) due to their underlying condition, the effects of immunosuppressive treatments, and increased vaccine hesitancy. OBJECTIVES: The COVID-19 vaccination in autoimmune diseases (COVAD) study, a series of ongoing, patient self-reported surveys were conceived with the vision of being a unique tool to gather patient perspectives on AIRDs. It involved a multinational, multicenter collaborative effort amidst a global lockdown. METHODS: Leveraging social media as a research tool, COVAD collected data using validated patient-reported outcomes (PROs). The study, comprising a core team, steering committee, and global collaborators, facilitated data collection and analysis. A pilot-tested, validated survey, featuring questions regarding COVID-19 infection, vaccination and outcomes, patient demographics, and PROs was circulated to patients with AIRDs and healthy controls (HCs). DISCUSSION: We present the challenges encountered during this international collaborative project, including coordination, data management, funding constraints, language barriers, and authorship concerns, while highlighting the measures taken to address them. CONCLUSION: Collaborative virtual models offer a dynamic new frontier in medical research and are vital to studying rare diseases. The COVAD study demonstrates the potential of online platforms for conducting large-scale, patient-focused research and underscores the importance of integrating patient perspective into clinical care. Care of patients is our central motivation, and it is essential to recognize their voices as equal stakeholders and valued partners in the study of the conditions that affect them.

Switching from Beraprost to Selexipag in the Treatment of Pulmonary Arterial Hypertension: Insights from a Phase IV Study of the Japanese Registry (The EXCEL Study: EXChange from bEraprost to seLexipag Study).

Pulmonary arterial hypertension (PAH) remains a significant challenge in cardiology, necessitating advancements in treatment strategies. This study explores the safety and efficacy of transitioning patients from beraprost to selexipag, a novel selective prostacyclin receptor agonist, within a Japanese cohort. Employing a multicenter, open-label, prospective design, 25 PAH patients inadequately managed on beraprost were switched to selexipag. Key inclusion criteria included ongoing beraprost therapy for ≥3 months, a diagnosis of PAH confirmed by mean pulmonary artery pressure (mPAP) ≥ 25 mmHg, and current treatment with endothelin receptor antagonists and/or phosphodiesterase type 5 inhibitors. Outcomes assessed were changes in hemodynamic parameters (mPAP, cardiac index, pulmonary vascular resistance) and the 6 min walk distance (6-MWD) over 3-6 months. The study found no statistically significant changes in these parameters post-switch. However, a subset of patients, defined as responders, demonstrated improvements in all measured hemodynamic parameters, suggesting a potential benefit in carefully selected patients. The transition was generally well-tolerated with no serious adverse events reported. This investigation underscores the importance of personalized treatment strategies in PAH, highlighting that certain patients may benefit from switching to selexipag, particularly those previously on higher doses of beraprost. Further research is needed to elucidate the predictors of positive response to selexipag and optimize treatment regimens for this complex condition.

Development of quality indicators for pregnancy and childbirth in patients with systemic lupus erythematosus.

OBJECTIVES: A quality indicator for the treatment of systemic lupus erythematosus during pregnancy and childbirth that is useful for sharing standard treatment policies has not yet been developed. This study aimed to develop a quality indicator for systemic lupus erythematosus associated with pregnancy and childbirth. METHODS: To identify candidate quality indicators, we conducted a systematic literature review on the development of quality indicators for systemic lupus erythematosus related to pregnancy and childbirth and on clinical practice guidelines. Candidate quality indicator items were extracted from the final selected articles, and a first evaluation, panel meeting, and second evaluation were conducted to determine whether the candidate items were appropriate as quality indicators. Items for which all panel members reached a consensus were designated pregnancy and childbirth-related systemic lupus erythematosus quality indicators. RESULTS: Four articles on systemic lupus erythematosus-quality indicator development and 28 practice guidelines were listed through abstract/text screening. Based on these studies, 52 candidate quality indicators were extracted that were limited to items related to pregnancy and childbirth, and 41 items were selected on which all panel members agreed. CONCLUSION: We developed pregnancy-related systemic lupus erythematosus quality indicators using the RAND/UCLA method and selected 41 items, which could be used clinically.

Collating the voice of people with autoimmune diseases: Methodology for the Third Phase of the COVAD Studies.

INTRODUCTION: The growing recognition of holistic patient care highlights the various factors shaping the quality of life of individuals with autoimmune and rheumatic diseases (AIRDs). Beyond the traditional disease measures, there is an emerging acknowledgment of the less-explored aspects, including subjective well-being, social determinants of health, comorbidities, mental health, and medication adherence. Moreover, digital health services have empowered patients to engage actively in decision-making alongside clinicians. To explore these domains within the context of AIRDs, the "Collating the Voice of People with Autoimmune Diseases" COVAD survey was conceived, a successor of the previous two COVAD surveys. In this document, we present the study protocol in comprehensive detail. METHODS: The COVAD-3 survey is a cross-sectional patient self-reported e-survey incorporating multiple widely accepted scales/scores to assess various aspects of patients' lifestyles objectively. To ensure the survey's accuracy and usability across diverse regions, it will be translated into multiple languages and subjected to rigorous vetting and pilot testing. It will be distributed by collaborators via online platforms and data will be collected from patients with AIRDs, and healthy individuals over eight months. Data analysis will focus on outcome measures related to various social, demographic, economic, and psychological factors. CONCLUSION: With the increasing awareness to adopt a holistic treatment approach encompassing all avenues of life, the COVAD-3 survey aims to gain valuable insights into the impact of social, demographic, economic, and psychological determinants of health on the subjective well-being in patients with AIRDs, which will contribute to a better understanding of their overall health and well-being.

Impaired health-related quality of life in idiopathic inflammatory myopathies: a cross-sectional analysis from the COVAD-2 e-survey.

Objectives: To investigate health-related quality of life in patients with idiopathic inflammatory myopathies (IIMs) compared with those with non-IIM autoimmune rheumatic diseases (AIRDs), non-rheumatic autoimmune diseases (nrAIDs) and without autoimmune diseases (controls) using Patient-Reported Outcome Measurement Information System (PROMIS) instrument data obtained from the second COVID-19 vaccination in autoimmune disease (COVAD-2) e-survey database. Methods: Demographics, diagnosis, comorbidities, disease activity, treatments and PROMIS instrument data were analysed. Primary outcomes were PROMIS Global Physical Health (GPH) and Global Mental Health (GMH) scores. Factors affecting GPH and GMH scores in IIMs were identified using multivariable regression analysis. Results: We analysed responses from 1582 IIM, 4700 non-IIM AIRD and 545 nrAID patients and 3675 controls gathered through 23 May 2022. The median GPH scores were the lowest in IIM and non-IIM AIRD patients {13 [interquartile range (IQR) 10-15] IIMs vs 13 [11-15] non-IIM AIRDs vs 15 [13-17] nrAIDs vs 17 [15-18] controls, P < 0.001}. The median GMH scores in IIM patients were also significantly lower compared with those without autoimmune diseases [13 (IQR 10-15) IIMs vs 15 (13-17) controls, P < 0.001]. Inclusion body myositis, comorbidities, active disease and glucocorticoid use were the determinants of lower GPH scores, whereas overlap myositis, interstitial lung disease, depression, active disease, lower PROMIS Physical Function 10a and higher PROMIS Fatigue 4a scores were associated with lower GMH scores in IIM patients. Conclusion: Both physical and mental health are significantly impaired in IIM patients, particularly in those with comorbidities and increased fatigue, emphasizing the importance of patient-reported experiences and optimized multidisciplinary care to enhance well-being in people with IIMs.

Biomarker analysis from the phase 2b randomized placebo-controlled trial of riociguat in early diffuse cutaneous systemic sclerosis.

OBJECTIVE: To examine disease and target engagement biomarkers in the RISE-SSc trial of riociguat in early diffuse cutaneous systemic sclerosis and their potential to predict the response to treatment. METHODS: Patients were randomized to riociguat (n = 60) or placebo (n = 61) for 52 weeks. Skin biopsies and plasma/serum samples were obtained at baseline and week 14. Plasma cyclic guanosine monophosphate (cGMP) was assessed using radio-immunoassay. Alpha smooth muscle actin (αSMA) and skin thickness were determined by immunohistochemistry, mRNA markers of fibrosis by qRT-PCR in skin biopsies, and serum CXC motif chemokine ligand 4 (CXCL-4) and soluble platelet endothelial cell adhesion molecule-1 (sPECAM-1) by enzyme-linked immunosorbent assay. RESULTS: By week 14, cGMP increased by 94 ± 78% with riociguat and 10 ± 39% with placebo (p < 0.001, riociguat vs placebo). Serum sPECAM-1 and CXCL-4 decreased with riociguat vs placebo (p = 0.004 and p = 0.008, respectively). There were no differences in skin collagen markers between the 2 groups. Higher baseline serum sPECAM-1 or the detection of αSMA-positive cells in baseline skin biopsies were associated with a larger reduction of modified Rodnan skin score from baseline at week 52 with riociguat vs placebo (interaction P-values 0.004 and 0.02, respectively). CONCLUSION: Plasma cGMP increased with riociguat, suggesting engagement with the nitric oxide-soluble guanylate cyclase-cGMP pathway. Riociguat was associated with a significant reduction in sPECAM-1 (an angiogenic biomarker) vs placebo. Elevated sPECAM-1 and the presence of αSMA-positive skin cells may help to identify patients who could benefit from riociguat in terms of skin fibrosis. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02283762.

Agreement between local and central anti-synthetase antibodies detection: results from the Classification Criteria of Anti-Synthetase Syndrome project biobank.

OBJECTIVES: The CLASS (Classification Criteria of Anti-Synthetase Syndrome) project is a large international multicentre study that aims to create the first data-driven anti-synthetase syndrome (ASSD) classification criteria. Identifying anti-aminoacyl tRNA synthetase antibodies (anti-ARS) is crucial for diagnosis, and several commercial immunoassays are now available for this purpose. However, using these assays risks yielding false-positive or false-negative results, potentially leading to misdiagnosis. The established reference standard for detecting anti-ARS is immunoprecipitation (IP), typically employed in research rather than routine autoantibody testing. We gathered samples from participating centers and results from local anti-ARS testing. As an "ad-interim" study within the CLASS project, we aimed to assess how local immunoassays perform in real-world settings compared to our central definition of anti-ARS positivity. METHODS: We collected 787 serum samples from participating centres for the CLASS project and their local anti-ARS test results. These samples underwent initial central testing using RNA-IP. Following this, the specificity of ARS was reconfirmed centrally through ELISA, line-blot assay (LIA), and, in cases of conflicting results, protein-IP. The sensitivity, specificity, positive likelihood ratio and positive and negative predictive values were evaluated. We also calculated the inter-rater agreement between central and local results using a weighted κ co-efficient. RESULTS: Our analysis demonstrates that local, real-world detection of anti-Jo1 is reliable with high sensitivity and specificity with a very good level of agreement with our central definition of anti-Jo1 antibody positivity. However, the agreement between local immunoassay and central determination of anti-non-Jo1 antibodies varied, especially among results obtained using local LIA, ELISA and "other" methods. CONCLUSIONS: Our study evaluates the performance of real-world identification of anti-synthetase antibodies in a large cohort of multi-national patients with ASSD and controls. Our analysis reinforces the reliability of real-world anti-Jo1 detection methods. In contrast, challenges persist for anti-non-Jo1 identification, particularly anti-PL7 and rarer antibodies such as anti-OJ/KS. Clinicians should exercise caution when interpreting anti-synthetase antibodies, especially when commercial immunoassays test positive for non-anti-Jo1 antibodies.

Characteristics and risk factors of COVID-19 breakthrough infections in Idiopathic Inflammatory Myopathies: Results from the COVAD study.

OBJECTIVES: To explore prevalence, characteristics and risk factors of COVID-19 breakthrough infections (BIs) in idiopathic inflammatory myopathies (IIM) using data from the COVID-19 Vaccination in Autoimmune Diseases (COVAD) study. METHODS: A validated patient self-reporting e-survey was circulated by the COVAD study group to collect data on COVID-19 infection and vaccination in 2022. BIs were defined as COVID-19 occurring ≥14 days after 2 vaccine doses. We compared BIs characteristics and severity among IIMs, other autoimmune rheumatic and non-rheumatic diseases (AIRD, nrAID), and healthy controls (HC). Multivariable Cox regression models assessed the risk factors for BI, severe BI and hospitalisations among IIMs. RESULTS: Among 9449 included response, BIs occurred in 1447 (15.3%) respondents, median age 44 years (IQR 21), 77.4% female, and 182 BIs (12.9%) occurred among 1406 IIMs. Multivariable Cox regression among IIMs showed age as a protective factor for BIs [Hazard Ratio (HR)=0.98, 95%CI = 0.97-0.99], hydroxychloroquine and sulfasalazine use were risk factors (HR = 1.81, 95%CI = 1.24-2.64, and HR = 3.79, 95%CI = 1.69-8.42, respectively). Glucocorticoid use was a risk factor for severe BI (HR = 3.61, 95%CI = 1.09-11.8). Non-White ethnicity (HR = 2.61, 95%CI = 1.03-6.59) was a risk factor for hospitalisation. Compared with other groups, patients with IIMs required more supplemental oxygen therapy (IIM = 6.0% vs AIRD = 1.8%, nrAID = 2.2%, and HC = 0.9%), intensive care unit admission (IIM = 2.2% vs AIRD = 0.6%, nrAID, and HC = 0%), advanced treatment with antiviral or monoclonal antibodies (IIM = 34.1% vs AIRD = 25.8%, nrAID = 14.6%, and HC = 12.8%), and had more hospitalisation (IIM = 7.7% vs AIRD = 4.6%, nrAID = 1.1%, and HC = 1.5%). CONCLUSION: Patients with IIMs are susceptible to severe COVID-19 BI. Age and immunosuppressive treatments were related to the risk of BIs.

Breakthrough SARS-CoV-2 infection and disease flares in patients with rheumatoid arthritis: result from COVAD e-survey study.

COVID-19 has been suggested as a possible trigger of disease flares in patients with rheumatoid arthritis (RA). However, factors associated with disease flares remain unknown. This study aimed to identify factors associated with breakthrough infection (BIs) and disease flares in patients with RA following COVID-19. We analysed data from RA patients who participated in the COVID-19 vaccination in autoimmune diseases (COVAD) study. Demographic data, patient-reported outcomes, comorbidities, pharmacologic treatment and details regarding disease flares were extracted from the COVAD database. Factors associated with disease flare-ups were determined by multivariate logistic regression analysis. The analysis comprised 1928 patients with RA who participated in the COVAD study. Younger age, Caucasian ethnicity, comorbidities with obstructive chronic pulmonary disease and asthma were associated with COVID-19 breakthrough infection. Moreover, younger age (odds ratio (OR): 0.98, 95% CI 0.96-0.99, p < 0.001), ethnicity other than Asian, past history of tuberculosis (OR: 3.80, 95% CI 1.12-12.94, p = 0.033), treatment with methotrexate (OR: 2.55, 95% CI: 1.56-4.17, p < 0.001), poor global physical health (OR: 1.07, 95% CI 1.00-1.15, p = 0.044) and mental health (OR: 0.91, 95% CI 0.87-0.95, p < 0.001) were independent factors associated disease flares in patients with RA. Our study highlights the impact of socio-demographic factors, clinical characteristics and mental health on disease flares in patients with RA. These insights may help determine relevant strategies to proactively manage RA patients at risk of flares.