Background/Purpose: The treatment strategy for rheumatoid arthritis (RA) should be divided into remission-induction phase and its maintenance phase. To date, the usefulness of the combination therapy of disease-modifying anti-rheumatic drugs (DMARDs) has been exclusively examined in remission-induction phase. Therefore, we examined whether the addition of another conventional DMARD to methotrexate (MTX) in place of infliximab (IFX) could decrease the rate of disease flare after discontinuing IFX in well-controlled RA patients. The BuSHIDO (Bucillamine Study of Holding remission after Infliximab Dose-Off) trial is a prospective, randomized, controlled study comparing MTX monotherapy with MTX plus bucillamine (Buc), a DMARD structurally related to d-penicillamine, as to flare rate during the following 2 years.   

Methods: RA patients who had been receiving 6 or more infusions of IFX, maintaining DAS28-CRP＜2.6 (or DAS28-ESR<3.2) for more than 6 months, were randomized to either the addition of Buc 200 mg/day to MTX (the group 1) or non-addition of bucillamine (the group 2) upon discontinuing IFX. Primary endpoint was the flare rate (DAS28-ESR>3.2 and DAS28-CRP>2.6) within 2 years. The proportions of patients who met given criteria were compared with Fisher’s exact test.

Results: Finally, 24 and 31 patients, providing a written informed consent, were assigned to the group 1 and 2, respectively. Patients discontinuing MTX during the study period (2 in the group 1, and 4 in the group 2) had been excluded from the subsequent analyses. Seven patients experienced flares in the group 1, while 17 patients did in the group 2. Notably, Buc treatment was discontinued in seven patients because of rash (n=5), reversible proteinuria (n=1) and incompliance (n=1). Three of those seven patients experienced disease flare. The flare rates were 26.7% in Buc-continuing patients and 42.9% in Buc-discontinuing patients, respectively, in the group 1, while it was significantly higher in the group 2 (63.0% versus 31.8% in the whole group 1, p=0.045). Moreover, the flare rates sorted by the achievement of Boolean remission upon IFX discontinuation were significantly different in the group 2 (40.0% in patients achieving remission versus 91.7% in non-remission patients; p=0.014), while the flare rates were similarly reduced in the group 1 (29.4% versus 40.0% in remission and non-remission, respectively).

Conclusion: The combination therapy of non-biological DMARDs, such as bucillamine plus MTX, may be a better treatment strategy rather than MTX monotherapy for maintaining RA remission after the discontinuation of biological agents.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-addition-of-another-disease-modifying-anti-rheumatic-drug-to-methotrexate-in-place-of-infliximab-reduces-the-flare-rate-during-2-years-after-infliximab-discontinuation-in-patients-with-rheumatoid/