In early June, the ACR released an updated guideline on the management of rheumatoid arthritis, which includes new recommendations for specific high-risk groups.1 The guideline includes 44 recommendations—seven of which are strong and 37 conditional. It underscores the role of methotrexate as a cornerstone therapy and emphasizes minimizing glucocorticoids, when possible.
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Guideline Development Process
At least every five years, the ACR publishes new guideline updates for specific diagnoses, such as rheumatoid arthritis. The in-depth, rigorous process of guideline development ensures clinicians have the most up-to-date considerations for disease management. Such a process is, perhaps, particularly important for rheumatoid arthritis, which is the subject of an enormous number of publications.
Using the population, intervention, comparator and outcomes (PICO) format, the core group of guideline authors developed updated questions relevant to patient management. Informed by these, a literature review team assessed the medical literature for evidence to address these questions, abstracting and compiling the relevant data into evidence tables. These were reviewed by a patient panel and a separate voting panel (comprising 13 clinicians and two patients from the patient panel).
Like other recent ACR guidelines, these are based on the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. Recommendations are intended not as rigid constraints but as guides for informed, shared decision making. For strong recommendations, evidence usually convincingly shows a given choice will be the best one for almost all patients. In contrast, conditional recommendations have more leeway for implementation, because the evidence may not be as certain and variability in patient preferences may play a larger role.
Because this guideline uses an updated set of PICO questions, specific recommendations are not directly comparable to those in the ACR’s 2015 rheumatoid arthritis guideline.2 The recent guideline contains some new, overarching points of emphasis and some notable differences from earlier guidelines. However, certain themes elucidated in previous guidelines are still strongly emphasized, such as recommendations to employ a treat-to-target strategy to methodically evaluate patients’ disease status and adjust medications when needed.
The guideline’s principal investigator, Liana Fraenkel, MD, MPH, an adjunct professor at Yale University School of Medicine, New Haven, Conn., explains the guideline team thought it was important to give input with respect to medications the patient had previously tried. In addition to disease activity, “we thought a patient’s experience with previous medications was a key factor that determines what a patient and physician will decide in terms of future treatment, as opposed to disease duration,” she says.
Continued Role of Methotrexate as an Anchor Medication
The prominent role of methotrexate stands out in the guideline. The drug has been used for many years, and a wide body of evidence supports its effectiveness and safety in patients, many of whom have been on it for decades.
In the guideline, methotrexate is recommended as monotherapy for most patient populations over other conventional synthetic disease-modifying anti-rheumatic drugs (DMARDs), biologic DMARDs or targeted synthetic DMARDs. Methotrexate should usually be started in patients with moderate to high disease activity as an initial single agent. For almost all patients, the guideline authors recommend maximizing methotrexate to achieve the most possible benefit before adding or switching medications.
The rationale is that most patients will do well on methotrexate alone, Dr. Fraenkel explains. “Given the added toxicity and potential expense of other medications, the panel felt strongly that we should try to treat patients with one drug that we know to be very safe and very effective at both managing symptoms and decreasing long-term complications before adding more medications with added toxicity risk and additional cost,” she adds.
For patients with low disease activity, the guideline writers achieved a different consensus in terms of risk/benefit analysis. Here, they conditionally recommended an initial trial of hydroxychloroquine over other conventional synthetic DMARDs, including methotrexate, due to hydroxychloroquine’s comparatively lower side effect profile. The patient panel, in particular, argued that many patients with low disease activity might prefer this approach.
This is a change from the 2015 guideline, which recommended conventional synthetic DMARD monotherapy, preferably with methotrexate, for patients with low disease activity.2
Dr. Fraenkel puts this recommendation in context, noting that low disease activity is the treatment goal for many patients. In fact, one of the new guideline conditional recommendations is to initially target low disease activity over an initial goal of remission.
“We do have some patients coming to us with low disease activity who need to be treated,” Dr. Fraenkel says. “It made sense to allow for medication that has potentially less toxicity in those patients. And for others with poor prognostic signs or other factors, one would consider methotrexate.”
The guideline also contains new recommendations on the administration of methotrexate, including considerations for initial titration and oral vs. subcutaneous use. For example, it is conditionally recommended that patients who are not at target on oral methotrexate be switched to subcutaneous methotrexate over switching to or adding a different DMARD, consistent with the idea of using methotrexate to its fullest potential before adding other agents.
Treatment Escalation in Patients Not at Target Taking Maximum Methotrexate
The voting panel easily reached consensus recommendations on most topics. However, the panelists vigorously debated what to recommend for patients who have maximized their methotrexate dose but are still not at target.
Ultimately, the panel endorsed a conditional recommendation for adding either a biologic DMARD or a targeted synthetic DMARD to methotrexate over commencing triple therapy (i.e., adding sulfasalazine and hydroxychloroquine). This contrasts with the 2015 guideline, which equally recommended these approaches in patients with high or moderate disease activity taking a DMARD, such as methotrexate. This decision was controversial, given the relatively low certainty of the evidence and the increased societal costs compared with triple therapy.
Dr. Fraenkel explains the delayed efficacy of triple therapy compared with these other choices played a large role in this decision. “Once they have failed methotrexate, patients do not want to wait another three months for something to kick in,” she adds.
Another key reason for this recommendation was the poor long-term tolerance of triple therapy. However, triple therapy may be a better choice in lower resource settings or for patients with specific medical comorbidities.
The guideline contains new recommendations on the administration of methotrexate, including considerations on initial titration & oral vs. subcutaneous use. For example, it is conditionally recommended that patients who are not at target on oral methotrexate be switched to subcutaneous methotrexate over switching to or adding a different DMARD.
Another key difference from the 2015 guideline surrounded recommendations for tapering and potentially discontinuing DMARDs for patients at their disease management target. The 2015 guideline conditionally recommended DMARD tapering for patients who are in remission, although it acknowledged this was based on a low level of evidence.
The new guideline makes clear that drug cessation can be done in different ways. This update provides conditional recommendations favoring continuing a current dose over a dose reduction, favoring dose reduction over gradual discontinuation, and favoring gradual discontinuation over abrupt discontinuation. Essentially, the guideline only recommends considering tapering and eventual discontinuation of a DMARD if that is the patient’s strong preference and if the patient has been in low disease activity or remission for at least six months and will continue to take a therapeutic dose of at least one DMARD.
This issue is important to patients. Dr. Fraenkel notes this was one area in which the patient panel disagreed with the voting panel: Patients strongly preferred discontinuing a DMARD over a dose reduction, when possible, whereas most of the clinicians on the voting panel favored dose reduction over discontinuation. Dr. Fraenkel noted that physicians may worry more about triggering a disease flare, which is more likely to occur with a discontinuation.
Some patients prioritize getting off medications once they are doing well. However, this is not the case for all patients, illustrating the importance of employing a shared decision-making approach.
Many recommendations are aimed at limiting glucocorticoids, when possible and appropriate. This is in line with trends across other rheumatic diseases, as more data have increasingly highlighted the immediate and long-term toxicities of glucocorticoids, even when taken at lower doses. Dr. Fraenkel points out another hazard: It can be extremely difficult to wean patients off glucocorticoids once they have started, so they take them longer than desired or anticipated.
A conditional recommendation is to start a conventional synthetic DMARD without short-term glucocorticoids in patients with moderate to high disease activity who have never previously taken a DMARD. It was recognized that, although short-term glucocorticoids may be needed in some patients (e.g., for temporary symptomatic relief), glucocorticoids should not be routinely prescribed for this purpose. Dr. Fraenkel notes, “It’s a really clear signal to clinicians to not start everybody on them automatically, and if patients need them as bridge therapy, to try to keep tapering them off.”
New Recommendations for Treatment in Special Populations
The guideline also addresses patients with specific comorbidities, updating guidance on such conditions as heart failure. Certain specific patient populations were addressed for the first time, including those with rheumatoid nodules, non-alcoholic fatty liver disease and pulmonary disease. Because of the potential side effects in these specific groups, especially with respect to methotrexate, these recommendations can help inform clinical decisions.
One of these was vigorously debated: the conditional recommendation to start methotrexate in patients with moderate to severe disease activity who also have mild, stable lung disease. Although preexisting lung disease is a risk factor for methotrexate-
related pneumonitis, the voting panel still conditionally recommended its use because of its effectiveness and overall long-term safety and because of the lack of good alternatives without pulmonary risk.
The guideline does not provide updates for certain patient populations. The guideline authors did not re-address hepatitis C because of new, profoundly effective treatments for the disease. In addition, for solid malignancies, treatments have been changing rapidly due to innovations in immunotherapy, making it hard to make recommendations for average patient groups. “Oncology patients are all treated with such a personalized approach, they would have to speak with their oncologist to figure out the best treatment plan,” Dr. Fraenkel notes.
This newest guideline is not a comprehensive compilation of current recommendations on rheumatoid arthritis. For example, the 2008, 2012 and 2015 guidelines still provide helpful information on pre-treatment screening and routine laboratory monitoring, which can be applied to any new agents in a therapeutic class.2-4
Additional helpful recommendations are available regarding perioperative management and reproductive health in separate guidelines devoted to these topics.5-6
Future guidelines currently under development will address non-pharmacologic treatment approaches as well as vaccine use.
One challenge of guideline development is that new literature is always emerging. Just as the authors were about to submit for final journal review, the U.S. Food & Drug Administration released a drug safety alert on a trial of tofacitinib, showing a potential increased risk of cardiovascular events and malignancies in patients taking the JAK inhibitor.7 Peer-reviewed results have not been published, but the authors had to slightly revise these guidelines to acknowledge this status. As this and other medical literature evolves, the guideline will be updated, as needed.
Ruth Jessen Hickman, MD, is a graduate of the Indiana University School of Medicine. She is a freelance medical and science writer living in Bloomington, Ind.
- Fraenkel L, Bathon JM, England BR, et al. 2021 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol. 2021. In peer review.
- Singh JA, Saag KG, Bridges SL Jr, et al. 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol. 2016 Jan;68(1):1–26.
- 3. Singh JA, Furst DE, Bharat A, et al. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken). 2012 May;64(5):625–39.
- Saag KG, Teng GG, Patkar NM, et al; American College of Rheumatology. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum. 2008 Jun 15;59(6):762–784.
- Goodman SM, Springer B, Guyatt G, et al. 2017 American College of Rheumatology/American Association of Hip and Knee Surgeons guideline for the perioperative management of antirheumatic medication in patients with rheumatic diseases undergoing elective total hip or total knee arthroplasty. Arthritis Rheumatol. 2017;69(8):1538–1551.
- Sammaritano LR, Bermas BL, Chakravarty EE, et al. 2020 American College of Rheumatology guideline for the management of reproductive health in rheumatic and musculoskeletal diseases. Arthritis Rheumatol. 2020 Apr;72(4):529–556.
- U.S. Food and Drug Administration. Initial safety trial results find increased risk of serious heart-related problems and cancer with arthritis and ulcerative colitis medicine Xeljanx, Xeljanz XR (tofacitinib). 2021 Feb 4.