Discontinuing Methotrexate Does Not Worsen RA Symptoms in Patients Receiving Tocilizumab

Tocilizumab (TCZ) monotherapy was noninferior to TCZ and methotrexate (MTX) in patients with rheumatoid arthritis (RA) following initial treatment with tocilizumab and MTX to a low disease activity state, according to a recent study.

RA treatment has consisted of biologics in combination with MTX when MTX monotherapy had been inadequate. Many studies have demonstrated increased efficacy of biologics, such as tumor necrosis factor (TNF) inhibitors, when used together with MTX and decreased benefits of TNF inhibitors, such as etanercept, with decreasing doses of MTX. The Canadian Methotrexate and Etanercept Outcome study did not show noninferiority of placebo versus MTX in patients who achieved low disease activity.

What is interesting is that TCZ, an interleukin-6 receptor antagonist, has not shown decreased efficacy when administered alone versus in combination with MTX, despite being a biologic drug. Previous studies, including the ACT-RAY study, have shown that the efficacy of TCZ with or without MTX was similar. The purpose of the COMP-ACT study was to determine if TCZ monotherapy had a similar response to TCZ plus MTX as initial therapy, and if the response can be maintained in patients with RA who achieved low disease activity after treatment with TCZ plus MTX.

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Disease Activity Score-28 Erythrocyte Sedimentation Rate (DAS28-ESR), proportion of patients achieving improvements according to the American College of Rheumatology (ACR) criteria, and serious adverse events (AEs) were the main outcome measures observed in this study. DAS28-ESR ≤3.2 indicates low disease activity while DAS28-ESR <2.6 indicates disease remission. Efficacy of TCZ versus TCZ plus MTX was observed at week 24. Patients with a DAS28-ESR of ≤3.2 were randomized to receive either TCZ monotherapy or TCZ and MTX and then analyzed for significant change of DAS28-ESR from week 24 to week 40. Noninferiority was defined as a DAS28-ESR change of <0.6.

At week 24, the mean DAS28-ESR score for TCZ monotherapy and TCZ plus MTX groups were 2.11 and 2.13, respectively. Change of DAS28-ESR was 0.46 for TCZ monotherapy versus 0.14 for TCZ plus MTX from week 24 to 40. The adjusted difference was 0.318, thus showing noninferiority (<0.6) between the 2 groups. Forty-two patients in the TCZ and 31 patients in the TCZ and MTX group had worsening in the DAS28-ESR of ≥1.2 between week 24 to 40, a 7.5% difference. The proportion of patients who achieved low disease activity and disease remission at week 40 and 52 were similar between the 2 groups, with the exception that DAS28-ESR ≤3.2 at 40 weeks had a 13.6% difference in favor of TCZ plus MTX.

Response rates determined through the ACR criteria showed lower rates at week 40 and 52 in the TCZ monotherapy group compared with the TCZ plus MTX group. However, these observations were identified as misleading because there were more patients with lower response rates randomized to the TCZ monotherapy group from the start. Safety reports were similar between the 2 groups with no new AEs that were not previously identified prior to this study. There were slightly higher AEs in the TCZ plus MTX group.

Based on this study, patients starting on both TCZ and MTX could be deescalated to TCZ monotherapy after achieving low disease activity. With noninferiority shown in this study, patients can safely decrease drug burden while ensuring disease control.

Reference

Kremer JM, Rigby W, Singer NG, et al. Sustained response following discontinuation of methotrexate in patients with rheumatoid arthritis treated with subcutaneous tocilizumab. Arthritis Rheumatol. 2018;70(8):1200-1208. doi:10.1002/art.40493.