Adverse events related to sulfasalazine played a role in the higher discontinuation rate observed for rheumatoid arthritis (RA) patients on triple therapy when compared with similar patients taking methotrexate and a tumor necrosis factor inhibitor in an observational cohort study of historical data during 2006-2012.
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The findings shed some light on understanding if the noninferior efficacy of triple therapy (TT) with methotrexate (MTX), sulfasalazine (SSZ), and hydroxychloroquine (HCQ) in randomized trials versus combination MTX plus tumor necrosis factor inhibitor (MTX-TNFi) is matched by patients’ persistence and adherence to TT in real-world data.
“With the proven efficacy of these combination therapies, an understanding of the real-world observations outside of clinical trials should be investigated to determine if similar experiences are seen in clinical practice as in clinical trials,” first author Daniel P. Erhardt, MD, MPH, of the George E. Wahlen VA Medical Center, Salt Lake City, and his colleagues wrote in Arthritis Care & Research.
In the current study, the research team identified veterans with RA escalating treatment from MTX to MTX-TNFi (n = 2,125) or to triple therapy (n = 171) from Veterans Affairs (VA) clinical and administrative databases during 2006-2012.
Patients taking MTX-TNFi consistently had significantly higher levels of persistence than did TT patients regardless of the strictness of the definition used. The highest level of persistence as defined in the study – all medications (including MTX) filled without a 90-day or longer gap in treatment over the 12-month study period – was observed in 43.2% of the MTX-TNFi arm, compared with 17.6% in the TT arm. A more liberal definition of persistence that allowed discontinuation of any one disease-modifying antirheumatic drug (DMARD) in TT or MTX in the MTX-TNFi group – provided no new DMARDs were initiated – yielded a persistence rate of 50.3% for MTX-TNFi vs. 32.8% for the TT arm. The persistence rate for MTX-TNFi worsened somewhat to 42.9% when the same discontinuation was allowed and switching was permitted between drugs within the TNFi class for the MTX-TNFi combination group, but it stayed lower for the TT group at 33.9% when single DMARD discontinuation was allowed and switching between nonbiologic DMARDs was permitted (without a 90-day or longer gap prior to the switch).
Adherence as defined by 80% or more of days covered at 1 year was 25.3% in the MTX-TNFi arm, with individual adherence rates of 44.3% for MTX and 46% for TNFi. In comparison, adherence for TT overall was 10.5%, with adherence rates of 48.6% for MTX, 32.8% for HCQ, and 18.7% for SSZ.
TT group patients most commonly discontinued sulfasalazine (20.9%), followed by MTX (8.7%) and HCQ (7.8%), whereas in those treated with MTX-TNFi, many more stopped TNFi alone (53.9%) than MTX alone (19.1%). It also was more common to stop SSZ and HCQ together (37.4%) or all TT drugs (23.5%) than it was to stop MTX plus HCQ together (1.7%).
The most common reason for discontinuation in both groups was an adverse drug event (ADE), cited as the reason in 43.5% of TT patients and 35.7% of combination-therapy patients. Most SSZ discontinuations were reported as an ADE, most often because of concerns of GI toxicity or symptoms, the researchers said. GI toxicity or symptoms was cited as a reason for discontinuing for 18.3% of TT patients who discontinued, compared with only 1.7% of MTX-TNFi patients.
“Findings from our study indicate that ADE play a significant role in influencing drug discontinuation, and further efforts should focus on ways to mitigate ADE when initiating or escalating drug regimens for RA,” they concluded.
They noted that a large percentage of subjects who discontinued their combination therapy for RA were lost to follow-up from the VA system: 34.8% in the TT group and 32.2% in the MTX-TNFi group.
“Research should continue to focus on ascertaining methods to improve real-world treatment retention rates,” they advised.
“More research is also warranted to determine whether patient factors that influence medication adherence independently affect the likelihood of achieving clinical remission, regardless of which therapy is chosen for the treatment of their RA,” they added.
The research was supported by Specialty Care Center of Innovation in the Veterans Health Administration and by the Health Services Research and Development division of the Department of Veterans Affairs. Several of the authors reported receiving research funding and grants from several pharmaceutical companies.
SOURCE: Erhardt DP et al. Arthritis Care Res. 2018 Sep 17. doi: 10.1002/acr.23759