Long-term methotrexate therapy may be discontinued in stable RA patients

More than half of rheumatoid arthritis (RA) patients achieving low disease activity on long-term methotrexate (MTX) remain flare-free following its withdrawal, as shown in a study. The use of a higher MTX dose to preserve low disease activity is predictive of disease flare after discontinuation.

“After achievement of long‐term control of RA, there is a new challenge regarding whether these patients require disease-modifying antirheumatic drugs (DMARDs) for life,” according to the investigators. “Considering the potential side effects of long‐term use of DMARDs as well as cost‐effectiveness, the strategy of tapering or discontinuing DMARDs is important.”

The analysis included 97 RA patients with low disease activity who had weaned off MTX after a median of 19 years of use (median cumulative dose, 11.7 g). The mean Disease Activity Score of 28 joints (DAS28) was 1.96.

Prior to discontinuation, these patients spent a median of 5.7 years on stable medication and 4.8 years on steroid-free condition. MTX was used alone in 25.8 percent of the patients, in combination with conventional synthetic (cs)DMARDs in 56.7 percent, or with biologics or targeted synthetic DMARDs in 17.5 percent.

Within a median of 99 (28–168) days following MTX discontinuation, 43 (44.3 percent) patients experienced a flare (DAS28 >1.2). Thirty-six of them resumed MTX subsequently, six added leflunomide to their therapeutic regimen, and one increased the dose of corticosteroids only. [Int J Rheum Dis 2020;doi:10.1111/1756-185X.13888]

A weekly dose of MTX before discontinuation emerged as a risk factor for disease flare (odds ratio [OR], 1.014, 95 percent confidence interval [CI], 1.014–1.342; p=0.031). Kaplan–Meier curves showed that the risk increase was evident at a weekly MTX dose of ≥12.5 vs <12.5 mg.

There was a tendency toward an increased flare risk seen with elevated C-reactive protein levels at MTX discontinuation (OR, 2.262, 95 percent CI, 0.928–5.511; p=0.072) and average erythrocyte sedimentation rate in the 6 months prior (OR, 1.037, 95 percent CI, 0.996–1.078; p=0.074). Conversely, a longer duration of stable medication before discontinuation showed a tendency toward a lower flare risk (OR, 0.891, 95 percent CI, 0.787–1.009; p=0.069).

“Although we could not evaluate other indices reflecting disease severity such as functional impairment or physical damage, [the findings above] suggest that residual inflammation or disease activity, even if not clinically significant, is associated with a risk of flare after MTX discontinuation,” the investigators pointed out.

A cornerstone drug in RA treatment, MTX is prescribed as either a monotherapy or combination therapy. The European League Against Rheumatism recommendations cite that csDMARDs can be tapered in clinical remission, but due to a higher rate of flare, a shared decision between the patient and physician is needed. [Ann Rheum Dis 2017;76:960‐977]

Indeed, a previous study reported that >50 percent of patients had flare after discontinuation of long-term MTX therapy, the investigators noted. In the present study, on the other hand, more than half of the patients remained with low disease activity following withdrawal of the csDMARD. [Am J Med 1987;82:781‐786]

“Concerning liver toxicity, including hepatic fibrosis, in patients who have used MTX for the long term, this result suggests that MTX can be successfully discontinued in patients with low disease activity,” they said, adding that patients requiring a higher dose of MTX to maintain remission or low disease activity are likely to experience flare if weaned off treatment.