ACR RA guidelines: 'Maximize' methotrexate use prior to DMARDs, avoid glucocorticoids
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The American College of Rheumatology has released its updated treatment guidelines for rheumatoid arthritis, with a strong emphasis on the use of methotrexate before adding or switching to DMARDs, according to the lead author.
“The key messages are to maximize use of methotrexate prior to adding or switching to disease-modifying antirheumatic drugs,” Liana Fraenkel, MD, MPH, of Berkshire Medical Center, in Pittsfield, Massachusetts, and Yale University School of Medicine, told Healio Rheumatology. “We also include specific recommendations to try to minimize side effects prior to changing DMARDs.”
The ACR updates its clinical practice guidelines every 5 years at minimum. The 2021 guidelines for RA include a total of 44 recommendations, including seven strong and 37 conditional items. Both strong and conditional recommendations require at least a 70% level of agreement by the voting panel.
According to Fraenkel, the ACR continues to strongly recommend targeted treatment for patients without previous exposure to biologic or targeted synthetic DMARDs; the recommendation is conditional for those who have been treated with biologic or targeted synthetic DMARDs. There are also, for the first time, recommendations that address patients with nontuberculous mycobacterial lung disease.
“Another key takeaway is recommendations to try to avoid glucocorticoids whenever possible, including low-dose glucocorticoids,” Fraenkel said.
To develop the new guidelines, the core leadership team drafted a series of clinical population, intervention, comparator and outcomes (PICO) questions, which were then handed to a literature review team that sought answers through the use of systematic literature reviews. In all, the 81 PICO questions led to a literature review that netted 22,971 manuscripts, of which 2,646 were considered by the team for the evidence report. Following a full-text screening, the members mapped a total of 133 studies to at least one of the PICO questions. However, the literature review could not identify any evidence for 33 of the questions.
Later, an in-person panel of 10 patients with RA, moderated by the principal investigator, reviewed the evidence report and provided their perspective. The final voting panel, which included 13 clinicians and two patients, then assessed the evidence reports and patient perspectives before casting their ballots on each recommendation.
The seven strong recommendations are:
- Methotrexate should be used over hydroxychloroquine or sulfasalazine in patients with moderate to high disease activity who are DMARD-naïve;
- Methotrexate monotherapy should be used over biologic or targeted synthetic DMARDs among patients with moderate-to-high disease activity who are DMARD-naïve;
- Methotrexate monotherapy should be used over combination therapy with methotrexate plus a non-TNF-inhibitor biologic or targeted synthetic DMARD among patients with moderate-to-high disease activity who are DMARD-naïve;
- Clinicians should start a conventional synthetic DMARD without longer-term glucocorticoids, rather than initiating such DMARDs with longer-term glucocorticoids, for DMARD-naïve patients with moderate-to-high disease activity;
- Clinicals should use a treat-to-target rather than usual care for patients who have not been previously treated with biologic or targeted synthetic DMARDs;
- Prophylactic antiviral therapy should be used, over frequent monitoring of viral load and liver enzymes alone, among patients starting rituximab (Rituxan, Genentech) who are positive for hepatitis B core antibodies, regardless of hepatitis B surface antigen status; and
- Prophylactic antiviral therapy should also be used, rather than frequent monitoring alone, for patients starting any biologic or targeted synthetic DMARD who are positive for hepatitis B core antibodies and hepatitis B surface antigen.
Addressing patients with nontuberculous mycobacterial lung disease for the first time in an RA treatment guideline, the ACR set a conditional recommendation for using the lowest possible dose of glucocorticoids — and discontinuation if possible — over glucocorticoid continuation in this population. Additionally, the ACR conditionally recommends adding conventional synthetic DMARDs over the addition of a biologic of targeted synthetic DMARD in patients with nontuberculous mycobacterial lung disease who demonstrate moderate to high disease activity despite conventional synthetic DMARD monotherapy.
Lastly, the ACR conditionally recommends abatacept (Orencia, Bristol Myers Squibb) over other biologic and targeted synthetic DMARDs in patients with nontuberculous mycobacterial lung disease who have moderate to high disease activity despite using conventional synthetic DMARDs.
“Recommendations to lead with methotrexate and to add a biologic DMARD or targeted synthetic DMARD for methotrexate non-responders made a lot of sense to me,” Michael Putman, MD, MSci, assistant professor of medicine at the Medical College of Wisconsin, told Healio Rheumatology. “I think patients prefer this approach over triple therapy.”
Putman, who was not involved in the development of the recommendations, added that he was “struck” by how many of the guidelines were rated as “low” or “very low” regarding the certainty of evidence.
“I suspect this reflects the general lack of comparative effectiveness research in rheumatology,” he said. “Most of our trials evaluate novel agents against placebo. That is a commendable first step, but the subsequent step — pitting these agents against each other to learn which is best — rarely happens.”
Overall, Putman rated the guidelines as “very well done.”
“We hope that these guidelines help support best practices across rheumatologists in the right states,” Fraenkel said. “The guidelines also revealed several gaps in the literature for which further research is required to answer key clinical questions, including at what dose methotrexate should be started, and what the best mechanisms to try to decrease side effects to the methotrexate are. Also needed are further data to compare the effectiveness and safety between DMARDs, and information on how best to treat patients with prevalent comorbidities.”
Perspective
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Stanley Cohen, MD
The American College of Rheumatology 2021 recommendations for rheumatoid arthritis treatment continue to reinforce methotrexate as the anchor drug for patients with moderate to high disease activity. They also recommended maximizing methotrexate treatment by switching to subcutaneous from oral or splitting the dose in patients not at low disease activity or remission before progressing therapy.
In contrast to the recent EULAR RA recommendations, the panel strongly recommended avoidance of short-term and long-term glucocorticoids. Although a lofty goal and the preferable approach, in the clinic, short-term use of glucocorticoids is frequently required until DMARDs are effective. Early aggressive therapy utilizing treat-to-target to manage patients continues to be a strong recommendation.
The panel also addressed the conventional synthetic DMARD incomplete responders, conditionally recommending biologic or targeted synthetic DMARDS over triple therapy due to the more rapid and potentially sustained response. They did acknowledge the recent safety concerns with tsDMARDs in patients at high risk for cardiovascular disease, which may limit utilization of this class of medications after csDMARDS.
When switching therapies due to continued disease activity, a switch to a DMARD in a different class was conditionally recommended over the same class. Tapering was addressed in patients in low disease activity or remission for a minimum of 6 months, with the panel suggesting withdrawal of the csDMARD and continuation of the biologic or tsDMARD in contrast to the EULAR 2019 recommendations.
The recommendations also addressed treatment in patients with common comorbidities such as nonalcoholic fatty liver disease, congestive heart failure, pulmonary disease and serious infectious episodes.
The panel should be applauded for making recommendations in these and other comorbid clinical scenarios even though evidence was limited and the recommendations were generally conditional and not strong due to paucity of data. Overall, the recommendations appropriately reflect the newer clinical trial data available since the 2015 recommendations.
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