ACR Convergence 2021—Treating patients with rheumatoid arthritis (RA) is something most rheumatologists would consider bread-and-butter medicine. However, despite the frequency with which the condition is encountered in clinical practice, the management of patients with this disease can be far from simple. Bryant England, MD, PhD, an assistant professor of internal medicine in the Division of Rheumatology at the University of Nebraska Medical Center (UNMC) and a rheumatologist for the VA Nebraska-Western Iowa Health Care System, provided an update on the state of RA management in the annual Review Course held during ACR Convergence 2021.
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Optimize Methotrexate Use
Dr. England explained that although methotrexate has been around for decades, its use is often not optimized. Using the 2021 ACR Guideline for the Treatment of Rheumatoid Arthritis as the main point of reference, Dr. England noted that oral methotrexate can reasonably be started at 15 mg weekly—or dosing can be titrated up to that amount four to six weeks after starting the medication.1 Side effects can be managed by split dosing, subcutaneous rather than oral administration and increased intake of folic acid.
If oral methotrexate is tolerated but not optimally effective, clinicians should consider switching to the subcutaneous formulation prior to adding another disease-modifying anti-rheumatic drug (DMARD) or switching to an alternative DMARD.
Dr. England explained that methotrexate remains an extremely important therapeutic for patients with RA because about 30% of patients with RA in clinical trials reach low disease activity on methotrexate monotherapy.
When contemplating tapering DMARD therapy for patients, Dr. England stated that flares will likely occur, & patients must be monitored & restarted on effective therapies in such circumstances.
With respect to methotrexate dose titration, Jain et al. conducted a multicenter, open-label (assessor blinded) randomized clinical trial in which 178 patients with active RA (mean DAS28-CRP of 5.4) were randomized to either usual or fast escalation of methotrexate dose from 15 mg per week to a maximum of 25 mg per week.2 At 16 weeks and 24 weeks of follow-up, essentially no differences in clinical response to treatment were observed, nor were significant differences observed in cytopenias, transaminitis or drug discontinuation/dose reduction between the usual and fast escalation groups.
These results indicate that it is reasonable and safe to guide patients through uptitration of methotrexate doses, even at a quick pace, to reach levels that provide significant clinical benefit.
Dr. Bryant noted the 2021 guideline conditionally recommends not using short-term glucocorticoids (i.e., fewer than three months) at the time of initiation of DMARDs in patients with moderate to high RA disease activity.1 Although glucocorticoids may still play a role in the management of RA, a better appreciation of the potential risks associated even with low-dose therapy has prompted clinicians to avoid using these medications by default.
George et al. sought to evaluate the risk of serious infection associated with low-dose glucocorticoids and did so by identifying more than 120,000 patients with RA who had been on stable immunotherapy for longer than six months and who were receiving no glucocorticoids or less than 5 mg per day. The researchers found that patients treated with glucocorticoids at doses of <5 mg/day had a statistically significantly higher risk of hospitalized infection than those patients who did not receive glucocorticoids.3
These and other study results highlight potential safety concerns with glucocorticoids, while the results of other studies present insights into the potential efficacy of low-dose glucocorticoids. In the SEMIRA trial, 259 patients with RA who were receiving tocilizumab and 5–15 mg/day of glucocorticoids for 24 weeks and who demonstrated stable, low disease activity were randomized to either continue masked prednisone at a dose of 5 mg daily for 24 weeks or to taper masked prednisone, reaching 0 mg per day at week 16.
In this study, Burmester et al. found that continuing glucocorticoids at 5 mg per day for 24 weeks provided better disease control than tapering glucocorticoids, but they also found that 65% of patients in the glucocorticoid-tapering arm remained in low disease activity.4
Thus, Dr. England explained, clinicians must work with patients to weigh the risks and benefits of using and tapering glucocorticoids to treat rheumatoid arthritis.
Dr. England noted that several rules of thumb should be applied when considering treatment modifications. He explained: 1) treat-to-target is an important and evidence-based strategy, 2) numerous alternative treatments to methotrexate monotherapy exist—including triple therapy—and selection of these regimens should be tailored to the patient; 3) continuing methotrexate with most biologics is generally recommended; and 4) Janus kinase inhibitors can be an effective treatment for many patients, but the U.S. Food & Drug Administration’s Boxed Warning regarding major adverse cardiovascular events, malignancy, thrombosis and mortality requires consideration.
When contemplating tapering DMARD therapy for patients, Dr. England stated that flares will likely occur, and patients must be monitored and restarted on effective therapies in such circumstances. In general, a dose-reduction tapering strategy is less likely to cause disease flares than tapering off completely or abruptly discontinuing therapy.
Dr. England’s talk was comprehensive and well researched, and thanks to this lecture, audience members can now feel more comfortable staying up to date on a disease that is seen in the clinic nearly every day.
Jason Liebowitz, MD, completed his fellowship in rheumatology at Johns Hopkins University, Baltimore, where he also earned his medical degree. He is currently in practice with Skylands Medical Group, N.J.
- Fraenkel L, Bathon JM, England BR, et al. 2021 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken). 2021 Jul;73(7):924–939.
- Jain S, Dhir V, Aggarwal A, Gupta R, et al. Comparison of two dose escalation strategies of methotrexate in active rheumatoid arthritis: A multicentre, parallel group, randomised controlled trial. Ann Rheum Dis. 2021 Nov;80(11):1376–1384.
- George MD, Hsu JY, Hennessy S, et al. Risk of serious infection with low-dose glucocorticoids in patients with rheumatoid arthritis: An instrumental variable analysis. 2021 Sep 20.
- Burmester GR, Buttgereit F, Bernasconi C, et al. Continuing versus tapering glucocorticoids after achievement of low disease activity or remission in rheumatoid arthritis (SEMIRA): A double-blind, multicentre, randomised controlled trial. Lancet. 2020 Jul 25;396(10246):267–276.