Identifying Factors Associated With Treatment Response in Rheumatoid Arthritis Clinical Trials

Despite a wealth of studies evaluating rheumatoid arthritis (RA) therapies, it remains difficult to compare efficacies across trials due to heterogeneous study populations. We sought to identify patient/trial characteristics associated with clinical response to enable fairer comparisons.

We reviewed 565 disease-modifying antirheumatic drug studies compiled for American College of Rheumatology (ACR) management guidelines. Seventy-two articles on randomized controlled phase II/III trials from 1995 to 2018 reporting the proportion of patients achieving 20%, 50% or 70% improvement in the ACR's RA disease score (ACR20/50/70) or Disease Activity Score-28 with erythrocyte sedimentation rate or C-reactive protein (DAS28-ESR or DAS28-CRP) with follow-up more than 3 months were included. We explored associations between 34 patient/trial characteristics and ACR responses. We constructed multivariable models using these factors to compute expected response rates and to compare observed with expected response rates across therapies.

Among eligible clinical trials, later publication year, baseline DAS28-CRP score, methotrexate/biologic naivety, baseline ESR, follow-up of 52 weeks or more, number of subjects enrolled, and anticitrullinated peptide antibody seropositivity were associated with greater ACR response. Greater age, longer disease duration, higher baseline Sharp score, and steroid use were associated with lower response rates. Predictive models incorporating these factors explained 29%, 37%, and 53% of variance in ACR20, ACR50, and ACR70, respectively. Overall, comparing observed versus expected rates of response across trials more closely approximated results of head-to-head trials. For example, although observed responses numerically favored adalimumab to tofacitinib, comparison of observed versus expected results across trials more closely approximated the results from a head-to-head trial ("Oral Rheumatoid Arthritis triaL [ORAL] Strategy").

We identified factors associated with ACR response in RA trials. Adjusting for expected outcomes yielded therapy comparisons somewhat more similar to head-to-head trials. These findings could inform other across-trial comparisons, particularly when head-to-head trials are lacking.