For patients with rheumatoid arthritis (RA) who respond to subcutaneous tocilizumab, discontinuing methotrexate may be an option and offer an alternative to patients who cannot tolerate or prefer not to take methotrexate.
“This is one of the first studies showing that methotrexate may be discontinued in a cohort of patients with a biologic agent without experiencing a significant predefined disease flare,” says Joel Kremer, MD, PFAFF Family Professor of Medicine, Albany Medical College, and director of research, The Center for Rheumatology, Albany, N.Y., and lead author of the first controlled study to examine discontinuing methotrexate in patients receiving subcutaneous tocilizumab for RA.
Treatment of RA commonly includes combination therapy of methotrexate with a biologic agent, with data showing combination therapy is more effective, particularly when methotrexate is combined with tumor necrosis factor (TNF) inhibitors. Data have shown, however, similar efficacy with intravenous tocilizumab either combined with methotrexate or as monotherapy. The study by Kremer et al. builds on this by finding subcutaneous tocilizumab as monotherapy is noninferior to combined therapy with methotrexate.
The study “supports the concept that tocilizumab can be used as a monotherapy,” says Michael Weinblatt, MD, John R and Eileen K. Riedman Professor of Medicine, Harvard Medical School and R. Bruce and Joan M. Mickey Distinguished Chair in Rheumatology, Division of Rheumatology, Immunology and Allergy, Brigham and Women’s Hospital, Boston. “In patients who achieve the targeted goal of low disease activity or remission on the combination of methotrexate and tocilizumab, many patients can maintain low disease activity with abrupt discontinuation of methotrexate.”
A Closer Look at the Study
In the multicenter, double-blind study, 294 patients with RA were randomized at Week 24 to subcutaneous tocilizumab monotherapy (n=147) or methotrexate plus subcutaneous tocilizumab (n=147) for 52 weeks. Patients were among the total 718 patients enrolled in the study who experienced an inadequate response to methotrexate and received combination methotrexate and tocilizumab (162 mg subcutaneously) for 24 weeks. At 24 weeks, all patients (n=294) who had achieved low disease activity per a Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (DAS28-ESR) of <3.2 were randomized to the two treatment groups.
To test the noninferiority (margin of 0.6) of discontinuing methotrexate in this patient cohort, the investigators used a primary outcome measure of the mean change in the DAS28-ESR from Week 24 to Week 40 between the two treatment groups.
The study found the mean changes in DAS28-ESR in the patients treated by tocilizumab monotherapy compared with those treated with combined methotrexate and tocilizumab were 0.46 (95% CI, 0.22, 0.70) and 0.14 (95% CI, -0.11, 0.39), respectively, with an adjusted difference of 0.318 (95% CI, 0.045, 0.592), demonstrating that discontinuing methotrexate was noninferior to the combined therapy.
The study also found similar safety between the two treatment arms, with patients treated with combination methotrexate plus tocilizumab experiencing a slightly higher incidence of adverse events compared with tocilizumab monotherapy. The total number of adverse events per 100 patient-years was 308.07 (95% CI, 272.98, 346.43) and 238.00 (207.58, 271.61), respectively. Of the serious adverse events, infection was the most common, occurring in 2.1% and 2.2% in patients treated with tocilizumab monotherapy and those treated with combined therapy, respectively.
‘This is one of the first studies showing that methotrexate may be discontinued in a cohort of patients with a biologic agent without experiencing a significant predefined disease flare.’ —Joel Kremer, MD
What Does This Mean for Patients?
These results provide a good option for patients who prefer not to stay on methotrexate or are intolerant to it. “If a patient is on the combination of tocilizumab and methotrexate, they may be able to streamline their treatment by discontinuing methotrexate,” says Dr. Kremer. “Most patients would rather take fewer meds.”
However, he cautions that “as with all clinical situations involving changes in treatment, the patient should be followed closely.”
Dr. Weinblatt also says the results offer patients who don’t want to stay on methotrexate the option of stopping the combination therapy and continuing on tocilizumab monotherapy, with many patients able to maintain a good positive response.
However, he also provides several caveats on issues he says were not addressed in the study. Among these were whether a patient can obtain a sustained positive response from discontinuing methotrexate by lowering its dose rather than abruptly stopping it, as was done in the study.
“Another important question is whether you can maintain the positive response of methotrexate plus tocilizumab by stretching out the interval of tocilizumab dosing (e.g., weekly to every other week or every two weeks to every three weeks),” he says. “This had implications on the cost of therapy, which is a critical issue.”
Finally, Dr. Weinblatt points out another study finding: Although DAS28-ESR scores were similar between the two treatment groups at 24 weeks, the response rates of patients randomized to tocilizumab monotherapy who achieved ACR20/50/70 responses from baseline to Week 24 were about 8–11% lower than those randomized to the combination therapy.
“It should be noted that there was still a numeric advantage of the combo compared with stopping methotrexate and maintaining tocilizumab [in these patients],” he says.
Mary Beth Nierengarten is a freelance medical journalist based in Minneapolis.
- 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 Aug; 70(8):1200–1208.