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TOPLINE:

A meta-analysis of 21 studies of patients with rheumatoid arthritis (RA) found that a history of smoking, obesity, fibromyalgia, and depression were associated with increased odds of difficult-to-treat RA.

METHODOLOGY:

• Researchers conducted a systematic review and meta-analysis to quantify the association between key lifestyle factors and comorbidities and the risk for difficult‑to‑treat RA.
• They searched three databases and screened conference abstracts for observational studies published between January 2021 and September 2025. Eligible studies applied the 2021 European Alliance of Associations for Rheumatology (EULAR) definition for difficult-to-treat RA.
• Predefined lifestyle factors included smoking, BMI or obesity, use of alcohol, and socioeconomic status, and comorbidities included fibromyalgia, depression, anxiety, and osteoarthritis.
• The primary outcome was the association between predefined lifestyle factors and comorbidities and EULAR-defined difficult-to-treat RA. The follow-up duration ranged from 1.0 to 18.6 years.
• Researchers assessed the quality of studies using the Newcastle-Ottawa Scale or Agency for Healthcare Research and Quality checklist. Heterogeneity across studies was expressed as I².

TAKEAWAY:

• The analysis included 21 studies, of which 81% were judged as high quality. Among 22,968 patients with RA, 2783 had difficult-to-treat RA, giving a crude prevalence of 12.2%.
• A history of smoking was associated with increased odds of difficult-to-treat RA (15 studies; odds ratio [OR], 1.16; 95% CI, 1.01-1.34; I² = 23%), and so was obesity (eight studies; OR, 1.38; 95% CI, 1.11-1.72; I² = 0%).
• Comorbidities associated with increased odds of difficult-to-treat RA included fibromyalgia (nine studies; OR, 2.20; 95% CI, 1.64-2.96; I² = 43%) and depression (nine studies; OR, 1.74; 95% CI, 1.39-2.18; I² = 0%). Osteoarthritis showed a significant association (OR, 1.65; 95% CI, 1.12-2.42; I² = 0%), although this finding came from only two studies.
• Current smoking, anxiety, and continuous BMI showed no statistically significant association with difficult-to-treat RA. Only a small number of studies reported associations with the use of alcohol and low socioeconomic status.

IN PRACTICE:

“The goal should not only be to better define difficult-to-treat rheumatoid arthritis but also to determine whether patients can step out of this state when its dominant drivers are recognized early and managed appropriately,” Lilla Gunkl-Tóth and György Nagy wrote in a comment accompanying the article.

SOURCE:

The study was led by Wenhui Xie, PhD, and Tong Chen, MSc, Peking University First Hospital, Beijing, China. It was published online on April 15, 2026, in The Lancet Rheumatology.

LIMITATIONS:

Most studies were observational, and about half were cross‑sectional, which limited establishing any cause-effect relationships. The application of EULAR definition varied and may have caused misclassification. The analysis did not stratify associations by phenotypes of difficult‑to‑treat RA, and the adjustment of confounders varied across studies.

DISCLOSURES:

The study received funding from the National Natural Science Foundation of China. The authors declared having no competing interests.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.