Associated lifestyle factors and comorbidities of difficult-to-treat rheumatoid arthritis: a systematic review and meta-analysis.

Abstract

Factors associated with the risk of difficult-to-treat rheumatoid arthritis remain incompletely understood. We aimed to quantify the associations between key lifestyle factors, comorbidities, and difficult-to-treat rheumatoid arthritis risk. In this systematic review and meta-analysis we systematically searched PubMed, Embase, and Cochrane Library from Jan 1, 2021, to Sept 1, 2025, for observational studies examining predefined lifestyle factors and comorbidities in relation to difficult-to-treat rheumatoid arthritis, as defined by the European Alliance of Associations for Rheumatology. Eligible studies were required to include adult rheumatoid arthritis populations with validated criteria, apply the European Alliance of Associations for Rheumatology definition of difficult-to-treat rheumatoid arthritis, and report adjusted effect estimates or sufficient data for calculation. Pooled odds ratios (ORs) or mean differences with 95% CIs were calculated using inverse-variance methods with random-effects models. Data were extracted independently by two reviewers using a standardised form, with methodological quality assessed using the Newcastle-Ottawa Scale and the Agency for Healthcare Research and Quality checklist. The primary outcome was the association between predefined lifestyle factors and comorbidities and difficult-to-treat rheumatoid arthritis. People with lived experience of rheumatoid arthritis were not involved in the study. The study was registered with PROSPERO (CRD420251148710). 21 studies (22 968 patients with rheumatoid arthritis, of which 2783 had difficult-to-treat rheumatoid arthritis) were included. Significant associations were observed for smoking history (OR 1·16, 95% CI 1·01 to 1·34; I² =23%; 15 [71%] of 21 studies), obesity (1·38, 1·11 to 1·72; I² =0%; eight [38%] studies), fibromyalgia (2·20, 1·64 to 2·96; I² =43%; nine [43%] studies), and depression (1·74, 1·39 to 2·18; I² =0%; nine [43%] studies). No associations were found for current smoking (1·23, 0·98 to 1·55; I² =0%; nine [43%] studies), anxiety (1·45, 0·92 to 2·29; I² =0%; four [19%] studies), and BMI as a continuous measure (mean difference 0·20 kg/m²; 95% CI -0·02 to 0·41; I²=12%; 11 [52%] studies). Analyses of socioeconomic status, osteoarthritis, and alcohol consumption were limited by few available studies. Risk of bias assessment indicated that most studies were of high quality, and no significant publication bias was detected. This systematic review and meta-analysis identified that smoking, obesity, fibromyalgia, and depression are significantly associated with occurrence of difficult-to-treat rheumatoid arthritis. These findings support integrated management approaches that address both inflammatory pathways and risk factors in rheumatoid arthritis treatment strategies. National Natural Science Foundation of China.