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Background: Despite recent advancements in the management of rheumatoid arthritis (RA), an estimated 5-34% of patients with RA fail multiple biologic treatments and are considered "difficult-to-treat" (D2T-RA), posing a substantial clinical challenge for rheumatologists. Prior studies evaluating the epidemiology of D2T-RA have applied a range of definitions, partly explaining the broad range in estimated prevalence. In 2021 a European Alliance of Associations for Rheumatology (EULAR) task force proposed a standard definition of D2T-RA that incorporated elements of treatment failure, disease activity, and patient/provider perception.1 Objectives: The objective of the current study was to evaluate the criterion validity of EULAR's D2T-RA definition and estimate prevalence in a cohort of patients diagnosed with RA. Methods: Data from the longitudinal Brigham and Women's Rheumatoid Arthritis Sequential Study (BRASS) registry was used and included participants aged 18 years or older enrolled from 2003-2019. All participants in BRASS had a diagnosis of RA using American College of Rheumatology RA classification criteria or had a diagnosis based on the opinion of their rheumatologist. Participants completed annual visits with their rheumatologist and interim six-month questionnaires. We identified participants with D2T-RA if they met all three EULAR D2T-RA criteria at a study visit. A comparison group of non-D2T-RA participants with biologic and/or targeted synthetic disease-modifying anti-rheumatic drug (b/ts DMARD) experience attending the same visit were identified and matched 2:1 to every D2T-RA participant. Differences in demographic and clinical characteristics and RA medication use between D2T-RA and non-D2T RA comparisons were evaluated using Pearson chi-squared or Fisher Exact tests for categorical variables and Student t-tests or Wilcoxon rank sum tests for continuous variables. Prevalence rates of D2T-RA were estimated using Poisson regression with robust standard errors. Additional analyses explored the prevalence of sub-criteria of EULAR's D2T-RA definition. Results: We observed the prevalence of D2T RA to be 14.4 per 100 persons (95% CI: 12.8 – 16.3) among 1,581 participants with RA, and 22.3 per 100 persons (95% CI: 19.9 – 25.0) among 1,021 RA participants who were b/ts DMARD experienced. Compared to non-D2T-RA participants, D2T-RA participants had: younger age at RA diagnosis; a higher body mass index at the time of becoming D2T; a greater proportion of females; attained less education; more comorbidities; and a greater burden of disease activity that was consistent across multiple measures. Prednisone treatment was more common and methotrexate use was less common among those classified as D2T-RA at the time of becoming classified as D2T compared with non D2T-RA participants. Alternative definitions of EULAR sub criteria resulted in prevalence of D2T RA that ranged from 5.1 – 27.0 per 100 persons, with the greatest prevalence observed using DMARD criteria only, and the lowest prevalence observed when applying DMARD criteria + presence of extra-articular manifestations, glucocorticoid use, or RA symptoms (Table 1). In further explorations of the subcomponents of EULARs definition, we observed that the greatest proportion of participants who were classified as having D2T-RA met persistent disease activity criteria based on DAS28-CRP and/or CDAI criteria only (46%), followed by glucocorticoid use only (13%), and symptoms without evidence of disease activity (8%). Conclusion: EULAR's proposed definition can successfully identify a subset of RA patients who have not achieved low disease activity despite multiple b/ts DMARD treatments and appear to meet criterion validity for 'difficult-to-treat'. Future studies should continue to validate this definition, explore alternative definitions that can be consistently implemented across a broad array of data sources, and evaluate heterogeneity in this important subset of patients with RA. REFERENCES: 1 Nagy G, Roodenrijs NMT, Welsing PM, et al. EULAR definition of difficult-to-treat rheumatoid arthritis. Ann Rheum Dis 2021;80(1): 31-5. Acknowledgements: NIL. Disclosure of Interests: Misti L. Paudel: None declared, Ruogu Li: None declared, Chinmayi Naik: None declared, Nancy A Shadick Dr. Shadick received research grant support from BMS, Amgen, Eli Lilly, Mallinckrodt, Sanofi-Regeneron, and Crescendo Biosciences., Michael E. Weinblatt Dr. Weinblatt has stock options with with Canfite, Scipher and Inmedix, Dr. Weinblatt is a consultant to Abbvie, Amgen, Aclaris, Bristol Myers Squibb, Glaxo Smith Kline, Horizon, Johnson and Johnson, Novartis, Pfizer, Sanofi, Scipher, Set Point, Tremeau, Rani Therapeutics, Revolo, and Sci Rhom., Dr. Weinblatt has received research support from Abbvie, Aqtual, Bristol Myers Squibb, and Janssen, Daniel H. Solomon Dr, Solomon receives salary support from research contracts to Brigham and Women's Hospital from CorEvitas, Janssen, and Novartis
Paudel et al. (Sat,) studied this question.