Background Anti-tumor necrosis factor (TNF) biological agent, infliximab, (IFX) has been successfully withdrawn in at least a half of patients with rheumatoid arthritis (RA) in sustained remission with IFX plus methotrexate (MTX) .
Objectives We examined whether the addition of another inexpensive disease-modifying anti-rheumatic drug (DMARD) to MTX in place of IFX 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 the prospective, randomized, controlled study comparing MTX monotherapy with MTX plus bucillamine, a DMARD structurally related to D-penicillamine , as to flare rate in the following 2 years.
Methods RA patients who had been receiving 6 or more infusions of IFX, reaching DAS28-ESR <3.2 or DAS28-CRP <2.6 for more than 6 months were randomized to either bucillamine 200 mg/day added to MTX (group 1) or MTX alone (group 2) upon discontinuing IFX. Primary endpoint was the flare rate (DAS28-ESR >3.2 and DAS28-CRP >2.6) within 2 years.
Results The study has been completed at the end of December 2011. Finally, 24 and 31 patients were assigned to group 1 and 2, respectively. Four patients experienced flares in group 1, while 17 patients did in group 2. However, bucillamine treatment was discontinued in seven patients in group 1 because of rash (n=5), proteinuria (n=1) and incompliance (n=1). Among those seven patients, three patients experienced disease flare. MTX treatment was discontinued in four patients because of incompliance. Thus, the flare rates were 26.7% in bucillamine-continuing patients, 42.9% in bucillamine-discontinuing patients, and 63.0% in MTX-alone (group 2) patients, which is significantly higher than MTX plus bucillamine (group 1) patients (p=0.045). The mean radiographic progression assessed by modified Sharp score was 0.2 in group 1, and 0.7 in group 2, respectively (p=0.51). In addition, the multivariate analysis revealed that a stringent control of RA activity upon IFX discontinuation and the addition of bucillamine were the factors independently contributing to the IFX-free disease control.
Conclusions A DMARD-combination therapy, such as bucillamine plus MTX may be useful for maintaining disease remission after the remission induction by anti-TNF biological agents.
Tanaka Y, Takeuchi T, Mimori T, et al. Discontinuation of infliximab after attaining low disease activity in patients with rheumatoid arthritis: RRR (remission induction by Remicade in RA) study. Ann Rheum Dis 2010;69:1286 - 1291.
Ichikawa Y, Saito T, Yamanaka H, et al. Therapeutic effects of the combination of methotrexate and bucillamine in early rheumatoid arthritis: a multicenter, double-blind, randomized controlled study. Mod Rheumatol 2005;15:323 - 328.
Disclosure of Interest T. Kurasawa: None Declared, H. Nagasawa: None Declared, K. Amano: None Declared, T. Takeuchi Grant/Research support from: Mitsubisi Tanabe Pharma, H. Kameda: None Declared