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Objective: We undertook this study to estimate changes in cell‐specific DNA methylation (DNAm) associated with methotrexate (MTX) response using whole blood samples collected from rheumatoid arthritis (RA) patients before and after initiation of MTX treatment. Methods: Patients included in this study were from the Rheumatoid Arthritis Medication Study (n = 66) and the University of California San Francisco Rheumatoid Arthritis study (n = 11). All patients met the American College of Rheumatology RA classification criteria. Blood samples were collected at baseline and following treatment. Disease Activity Scores in 28 joints using the C‐reactive protein level were collected at baseline and after 3–6 months of treatment with MTX. Methylation profiles were generated using the Illumina Infinium HumanMethylation450 and MethylationEPIC v1.0 BeadChip arrays using DNA from whole blood. MTX response was defined using the EULAR response criteria (responders showed good/moderate response; nonresponders showed no response). Differentially methylated positions were identified using the Limma software package and Tensor Composition Analysis, which is a method for identifying cell‐specific differential DNAm at the CpG level from tissue‐level ("bulk") data. Differentially methylated regions were identified using Comb‐p software. Results: We found evidence of differential global methylation between treatment response groups. Further, we found patterns of cell‐specific differential global methylation associated with MTX response. After correction for multiple testing, 1 differentially methylated position was associated with differential DNAm between responders and nonresponders at baseline in CD4+ T cells, CD8+ T cells, and natural killer cells. Thirty‐nine cell‐specific differentially methylated regions associated with MTX treatment response were identified. There were no significant findings in analyses of whole blood samples. Conclusion: We identified cell‐specific changes in DNAm that were associated with MTX treatment response in RA patients. Future studies of DNAm and MTX treatment response should include measurements of DNAm from sorted cells. [ABSTRACT FROM AUTHOR]

Objectives To understand the relationships between deprivation and obesity with self-reported disability and disease activity in people with RA, and to determine whether BMI mediates the relationship between area-level deprivation and these outcomes. Methods Data came from the Rheumatoid Arthritis Medication Study (RAMS), a 1-year multicentre prospective observational cohort of people with RA recruited from rheumatology centres across England commencing MTX for the first time. A total of 1529 and 1626 people were included who had a baseline and at least one follow-up measurement at 6 or 12 months of HAQ—Disability Index (HAQ-DI) and DAS in 28 joints (DAS28), respectively. Linear mixed models estimated the associations of deprivation and obesity with repeated measures HAQ-DI and DAS28. Causal mediation analyses estimated the mediating effect of BMI on the relationship between deprivation and RA outcomes. Results Higher deprivation and obesity were associated with higher disability [adjusted regression coefficients highest vs lowest deprivation fifths 0.32 (95% CI 0.19, 0.45); obesity vs no obesity 0.13 (95% CI 0.06, 0.20)] and higher disease activity [adjusted regression coefficients highest vs lowest deprivation fifths 0.34 (95% CI 0.11, 0.58); obesity vs no obesity 0.17 (95% CI 0.04, 0.31)]. BMI mediated part of the association between higher deprivation and self-reported disability (14.24%) and DAS (17.26%). Conclusions People with RA living in deprived areas have a higher burden of disease, which is partly mediated through obesity. Weight-loss strategies in RA could be better targeted towards those living in deprived areas. [ABSTRACT FROM AUTHOR]

Hepatotoxicity is a serious adverse drug reaction related to methotrexate (MTX). However, the cause of drug‐induced liver injury (DILI) is still unclear and unpredictable. Genetic risk factors may predispose for MTX‐DILI. Therefore, we conducted a nested case‐control genome‐wide association study to explore genetic risk factors associated with MTX‐DILI. Seven international groups contributed blood samples and data of patients with rheumatoid arthritis who used MTX. MTX‐DILI was defined as an alanine aminotransferase (ALT) level of at least three times the upper limit of normal (ULN), to increase contrast controls ALT levels did not raise above two times the ULN. Per study site, control subjects and patients with MTX‐DILI (ratio 3:1) were matched for age, gender, and duration of MTX use. Patients were genotyped using Illumina GSA MD‐24v1‐0 and data were imputed using the 1000 Genomes reference panel. Single‐nucleotide polymorphisms (SNPs) were analyzed using an additive genetic model, corrected for sex, country, and age. A P‐value of ≤ 5 × 10−8 was considered significant, whereas a P‐value of ≤ 5 × 10−6 was considered suggestive. A total of 108 MTX‐DILI cases and 311 controls were included for association analysis. None of the SNPs were significantly associated with MTX‐DILI. However, we found seven suggestive genetic variants associated with MTX‐DILI (P‐values 7.43 × 10−8 to 4.86 × 10−6). Of those, five SNPs were in the intronic protein‐coding regions of FTCDNL1, BCOR, FGF14, RBMS3, and PFDN4/DOK5. Investigation of candidates SPATA9 (rs72783407), PLCG2 (rs60427389), RAVER2 (rs72675408), JAK1 (rs72675451), PTPN2 (rs2476601), MTHFR C677T (rs1801133), and into the HLA region did not show significant findings. No genetic variants associated with MTX‐DILI were found, whereas suggestive SNPs need further investigation. [ABSTRACT FROM AUTHOR]

Objectives To examine associations between PsA and psoriasis vs lifestyle factors and comorbidities by triangulating observational and genetic evidence. Methods We analysed cross-sectional data from the UK Biobank (1836 PsA, 8995 psoriasis, 36 000 controls) to describe the association between psoriatic disease and lifestyle factors (including BMI and smoking) and 15 comorbidities [including diabetes and coronary artery disease (CAD)] using logistic models adjusted for age, sex and lifestyle factors. We applied bidirectional Mendelian randomization (MR) to genome-wide association data (3609 PsA and 7804 psoriasis cases, up to 1.2 million individuals for lifestyle factors and 757 601 for comorbidities) to examine causal direction, using the inverse-variance weighted method. Results BMI was cross-sectionally associated with risk of PsA (OR 1.31 per 5 kg/m2 increase; 95% CI 1.26, 1.37) and psoriasis (OR 1.23; 1.20, 1.26), with consistent MR estimates (PsA OR 1.38; 1.14, 1.67; psoriasis OR 1.36; 1.18, 1.58). In both designs, smoking was more strongly associated with psoriasis than PsA. PsA and psoriasis were cross-sectionally associated with diabetes (OR 1.35 and 1.39, respectively) and CAD (OR 1.56 and 1.38, respective). Genetically predicted glycated haemoglobin (surrogate for diabetes) increased PsA risk (OR 1.18 per 6.7 mmol/mol increase; 1.02, 1.36) but not psoriasis. Genetic liability to PsA (OR 1.05; 1.003, 1.09) and psoriasis (OR 1.03; 1.001, 1.06) were associated with increased risk of CAD. Conclusion Observational and genetic evidence converge to suggest that BMI and glycaemic control are associated with increased psoriatic disease risk, while psoriatic disease is associated with increased CAD risk. Further research is needed to understand the mechanism of these associations. [ABSTRACT FROM AUTHOR]

Objectives The aims were to validate a British English version of the Workplace Activity Limitations Scale (WALS) linguistically, then test this psychometrically in RA, axial spondyloarthritis (axSpA), OA and FM. Methods The WALS was forward translated, reviewed by an expert panel, and cognitive debriefing interviews were conducted. Participants completed a postal questionnaire booklet. Construct (structural) validity was examined by fit to the Rasch measurement model. Concurrent validity included testing between the WALS and the Work Limitations Questionnaire-25 (WLQ-25). Two weeks later, participants were mailed a second questionnaire booklet for test–retest reliability. Results Minor wording changes were made to the WALS, then 831 employed participants completed questionnaires: 267 men and 564 women; 53.5 (s. d. 8.9) years of age; with condition duration 7.7 (s. d. 8.0) years. The WALS satisfied Rasch model requirements, and a WALS Rasch transformation table was created. Concurrent validity was strong with the WLQ-25 (RA r s = 0.78; axSpA r s = 0.83; OA r s = 0.63; FM r s = 0.64). Internal consistency was consistent with group use (α = 0.80–0.87). Test–retest reliability was excellent, with intraclass correlation coefficient (2,1) at ≥0.90. Conclusion A reliable, valid British English version of the WALS is now available for use in the UK. [ABSTRACT FROM AUTHOR]

Objectives Uncertainty regarding the risk of coronavirus disease 2019 (COVID-19), its complications and the safety of immunosuppressive therapies may drive anxiety among adults and parents of children and young people (CYP) with rheumatic diseases. This study explored trajectories of COVID-related anxiety in adults and parents of CYP with rheumatic diseases. Methods Adults and parents of CYP participating in the international COVID-19 European Patient Registry were included in the current study if they had enrolled in the 4 weeks following 24 March 2020. COVID-related anxiety scores (0–10) were collected weekly for up to 28 weeks. Group-based trajectory models explored COVID-related anxiety clusters in adult and parent populations, with optimal models chosen based on model fit, parsimony and clinical plausibility. Demographic, clinical and COVID-19 mitigation behaviours were compared between identified clusters using univariable statistics. Results In 498 parents of CYP and 2640 adults, four common trajectory groups of COVID-related anxiety were identified in each cohort: persistent extreme anxiety (32% and 17%), persistent high anxiety (43% and 41%), improving high anxiety (25% and 32%) and improving moderate anxiety (11% and 10%), respectively. Few characteristics distinguished the clusters in the parent cohort. Higher and more persistent anxiety clusters in the adult cohort were associated with higher levels of respiratory comorbidities, use of immunosuppressive therapies, older age and greater self-isolation. Conclusions COVID-19-related anxiety in the rheumatic disease community was high and persistent during the COVID-19 pandemic, with four common patterns identified. In the adult cohort, higher COVID-related anxiety was related to perceived risk factors for COVID-19 morbidity and mortality. [ABSTRACT FROM AUTHOR]

The article discusses the Myositis Physical Activity Device (MyoPAD) Study which recruited adults with idiopathic inflammatory myopathy (IIM) via the specialist neuromuscular clinic at Salford Royal Hospital in England. Topics include participants of the study, the occurrence of patient-reported IIM flares alongside work absenteeism and reduced work productivity, and importance of adequate medical therapy and disease control to minimising disease flares.