Observational data is key in translating knowledge gained from randomized controlled trials (RCTs) to clinical practice in the treatment of patients with rheumatoid arthritis (RA), according to a paper published in Arthritis Care & Research.
Kaleb Michaud, PhD, from the VA Nebraska-Western Iowa Health Care System and the Nebraska Arthritis Outcomes Research Center at the University of Nebraska Medical Center in Omaha, and colleagues, conducted a review of 30 RCTs and 10 US Food and Drug Administration (FDA)-approved biologic agents approved for RA treatment. Two large cohorts of patients with RA were used to determine the eligibility of each RCT in clinical practice: the Veteran’s Affairs Rheumatoid Arthritis (VARA) registry and the Rheumatology and Arthritis Investigational Network Database (RAIN-DB). For additional comparison, biologic agents were grouped into 3 categories: tumor necrosis factor (TNF) inhibitors (etanercept, infliximab, adalimumab, certolizumab pegol, golimumab), non-TNF inhibitors (abatacept, anakinra, rituximab, and tocilizumab), and oral JAK inhibitors (tofacitinib).
All studies focused on patients 18 years of age or older. Disease duration varied between 3 months to more than 1 year. Most studies included a minimum erythrocyte sedimentation rate or C-reactive protein value, and the number of swollen joints varied from 3 to 10.
Mean age of participants was 64 ± 11.3 years in the VARA registry and 58.6 ± 15 years in the RAIN-DB cohort. A majority of patients were white (77% in VARA, 86% in RAIN-DB), and the VARA cohort was primarily male (91%), whereas the RAIN-DB cohort was primarily female (77%). A total of 3.7% of patients in the VARA group and 7.1% of patients in the RAIN-DB group satisfied overall inclusion criteria.
Previous medication use contributed to high percentages of patient exclusion; a mean of 72% of VARA patients and 29% of RAINDB patients were excluded. Specifically, prior methotrexate (MTX) use contributed to the exclusion of 16% of VARA patients and 6.8% RAIN-DB patients, whereas use of other disease modifying antirheumatic drugs (DMARDs) excluded an average of 62% and 27% of patients, respectively.
Generally, eligibility for non-TNF inhibitor biologic agent RCTs was more restrictive than in TNF inhibitor RCTs; mean percentage of excluded patients was 94.7% and 97.7% in the VARA TNF and non-TNF inhibitor groups, and 91.6% and 94% in the RAIN-DB TNF and non-TNF inhibitor groups, respectively. No statistical difference was identified within either the VARA or RAIN-DB groups (VARA TNF vs non-TNF, P =.32; RAIN-DB TNF vs non-TNF, P =.36).
A sensitivity analysis was also conducted to examine the exclusion rate of patients in clinical observation before starting a new biologic. The analysis included 353 VARA and 264 RAIN-DB patients and found that the overall mean of those not eligible decreased to 92.1% in VARA and 90.9% in RAIN-DB.
Summary and Clinical Applicability
“We demonstrated that the vast majority of RA patients in our clinical cohorts did not satisfy criteria for participation in biologic agent RCTs,” wrote Dr Michaud and colleagues. “The disease activity criteria were responsible for the majority of exclusions in these RCTs.”
Dr Michaud and colleagues noted that this is in contrast to standard rheumatology clinical practice, where patients are typically offered biologic treatment as first-line therapy, or “when traditional DMARDs are not sufficient.”
The researchers concluded that the findings of this study emphasize the need for caution when extrapolating trial results to use in the day-to-day management of patients with RA.
- The VARA cohort consists primarily of men, limiting generalizability to typical RA clinic patients.
- The researchers could not systematically apply comorbidities as exclusion criteria.
- DAS28 values ranged from disease remission to high disease activity; further study of RA patients with moderate disease activity would be of interest.
- The RCTs used variable inclusion and exclusion criteria, which was not always clear in the published studies. Well-recognized limitations of randomized controlled trials in rheumatic diseases exist.
Dr Mikuls reports receiving research support from Roche/Genentech.
Vashisht P, Sayles H, Cannella AC, Mikuls TR, Michaud K. Generalizability of patients with rheumatoid arthritis in biologic agent clinical trials. Arthritis Care Res. 2016;68(10):1478-1488. doi: 10.1002/acr.22860