clinical topic updates

Discontinuing Methotrexate in Patients on Biologic-Methotrexate Combination Regimens

by Jeffrey R. Curtis, MD, MS, MPH


While methotrexate (MTX) is considered the foundational drug for the treatment of rheumatoid arthritis (RA) and should be a component of the combination regimens with targeted agents, many people are unable or unwilling to continue MTX indefinitely. The discontinuation of MTX for these patients is usually feasible.

Expert Commentary

Jeffrey R. Curtis, MD, MS, MPH

Marguerite Jones Harbert-Gene V. Ball, MD Professor of Medicine
Co-Director, UAB Pharmacoepidemiology and Pharmacoeconomics Research (PEER) Unit
Division of Clinical Immunology and Rheumatology
University of Alabama at Birmingham
Birmingham, AL

“Some patients may tolerate MTX, but only grudgingly, and, if you wait for them to initiate a discussion about discontinuing MTX due to tolerability issues, that conversation may never happen.”

Jeffrey R. Curtis, MD, MS, MPH

 MTX is the foundation of therapy for patients with RA, and it is associated with at least some incremental benefit when combined with virtually any other biologic or targeted therapy. The evidence suggests that, in those with significant disease activity who are on MTX, a biologic or targeted synthetic agent should be added to the MTX, provided the patient is willing and able to stay on the MTX. Combination therapy with MTX has the advantage of reducing the induction of antidrug antibodies, particularly for monoclonal antibodies and the anti–tumor necrosis factor agents. I might keep these patients on low-dose MTX, even as low as 7.5 mg per week, mainly for the purpose of reducing immunogenicity, for example, with infliximab or adalimumab. This is not an issue with Janus kinase inhibitors and is less of a problem with the anti–interleukin-6 agents.

Many patients do not like being on MTX, and there is a meaningful fraction of individuals who either cannot or will not tolerate it. These patients fall into 2 groups. The first group includes those who have some safety or extreme tolerability issue that makes MTX completely unacceptable (eg, their liver function tests skyrocket, nausea/fatigue are prohibitive), which becomes clear quickly. The other group includes those who just do not feel well on MTX and/or they are uneasy about being on the drug. If their RA is bad enough, they will take the drug, but they are not happy about itSome patients may tolerate MTX, but only grudgingly, and, if you wait for them to initiate a discussion about discontinuing MTX due to tolerability issues, that conversation may never happen.

Once these patients have achieved some improvement in their disease activity, they often want to get off the MTX. Some will bring it up, but others (perhaps those who do not want to be perceived as “bad patients”) will just stop adhering or will discontinue the drug. If you ask your patients, many will tell you that they prefer peeling back MTX if they get to low disease activity. There are data to suggest that this is feasible. For example, in the ORAL Shift study, patients who received tocilizumab plus MTX were able to withdraw MTX without significant worsening of disease activity.

There is no defined protocol for discontinuing MTX, and the drug was just stopped abruptly in some trials. Although this is a clean approach and gives you an answer regarding whether you need MTX, I usually prefer to discontinue the drug over a period of several months. I typically reduce the dose by half and wait 3 to 6 months. If the patient does not feel worse at that point, you can completely stop the drug. This is a less risky method that prevents you from having to reinitiate MTX to recapture the response.


Cohen SB, Pope J, Haraoui B, et al. Methotrexate withdrawal in patients with rheumatoid arthritis who achieve low disease activity with tofacitinib modified-release 11 mg once daily plus methotrexate (ORAL Shift): a randomized, phase 3b/4, non-inferiority trial. The Lancet Rheumatology2019;1(1):E23-E34.

Curtis J, Lin Y, Thangavelu K, et al. Withdrawal of conventional synthetic disease-modifying antirheumatic drugs in the sarilumab open-label EXTEND study: efficacy and safety analysis [abstract 2351]. Arthritis Rheumatol. 2019;71(suppl 10). Accessed March 11, 2020.

Dougados M, Kissel K, Sheeran T, et al. Adding tocilizumab or switching to tocilizumab monotherapy in methotrexate inadequate responders: 24-week symptomatic and structural results of a 2-year randomised controlled strategy trial in rheumatoid arthritis (ACT-RAY). Ann Rheum Dis. 2013;72(1):43-50.

Fleischmann R, Wollenhaupt J, Cohen S, et al. Effect of discontinuation or initiation of methotrexate or glucocorticoids on tofacitinib efficacy in patients with rheumatoid arthritis: a post hoc analysis. Rheumatol Ther. 2018;5(1):203-214.

Kremer JM, Rigby W, Singer NG, et al. Sustained response following discontinuation of methotrexate in patients with rheumatoid arthritis treated with subcutaneous tocilizumab: results from a randomized, controlled trial. Arthritis Rheumatol. 2018;70(8):1200-1208.

Peterfy C, Kremer J, Rigby W, et al. Magnetic resonance imaging (MRI) results following discontinuation of methotrexate in rheumatoid arthritis treated with subcutaneous tocilizumab: the COMP-ACT MRI substudy. J Rheumatol. 2020;47(3):325-332.

Subesinghe S, Scott IC. Key findings from studies of methotrexate tapering and withdrawal in rheumatoid arthritis. Expert Rev Clin Pharmacol. 2015;8(6):751-760.

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