Issue: August 2021
Source: Fraenkel L, et al. Arth Care & Res. 2021;doi: 10.1002/acr.24596.
Disclosures: Bathon, England and Fraenkel report no relevant financial disclosures. Cohen reports consulting fees from AbbVie, Eli Lilly & Co., Gilead Sciences, and Pfizer.
August 19, 2021
12 min read

Methotrexate mainstay: ACR guidelines reaffirm old DMARD as ‘anchor drug’ in RA therapy

Issue: August 2021
Source: Fraenkel L, et al. Arth Care & Res. 2021;doi: 10.1002/acr.24596.
Disclosures: Bathon, England and Fraenkel report no relevant financial disclosures. Cohen reports consulting fees from AbbVie, Eli Lilly & Co., Gilead Sciences, and Pfizer.
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Maximizing the disease-modifying benefits of methotrexate is one of the core principles behind the 2021 American College of Rheumatology rheumatoid arthritis guidelines.

There are also strong recommendations for minimizing glucocorticoid use, treating to target and using antiviral medications to prevent infections in certain RA populations. Conditional recommendations cover a wide array of topics, from decisions pertaining to second- and third-line therapy to those for patients with comorbidities like congestive heart failure and pulmonary disease.

Source: Nebraska Medicine/UNMC.
“One of the big new things is that we have recommendations in this guideline for MTX administration,” Bryant R. England, MD, PhD, told Healio Rheumatology. “This was really based on the understanding that our anchor drug has been suboptimally used. When you end up changing therapies or escalating to other medications, you might be leaving some benefit of MTX on the table.”
Source: Nebraska Medicine/UNMC.

There are 44 recommendations included in the document overall. Seven of those are strong recommendations, while the remaining 37 are conditional.

“Strong recommendations were limited to clinical questions or decisions for which data were robust and/or for which clinical practice was already fairly entrenched,” Joan Bathon, MD, director of the Division of Rheumatology at New York-Presbyterian Hospital/Columbia University Medical Center and professor of medicine at Columbia University College of Physicians and Surgeons, said in an interview. “However, many guidelines are ultimately conditional because the evidence is weak around many therapeutic questions and decisions.”

That said, the evidence is considerably stronger now than it was in 2015, when the last ACR RA guideline was published, according to Bryant R. England, MD, PhD, of the Veterans Affairs Nebraska-Western Iowa Health Care System, and the University of Nebraska Medical Center, in Omaha. “For example, in 2015, we did not have any recommendations regarding MTX administration,” he said.

The current document contains much more information on the use of biologics and other targeted synthetic disease modifying anti-rheumatic drugs, as well. Understanding how treatment paradigms have changed since the last iteration is critical to providing patients with the best and most up-to-date care, according to England, who was part of the development team.

Joan Bathon, MD
Joan Bathon

“Treatment guidelines are important to establish best practices based on the evidence available,” Bathon added. “It is critical that practitioners continue to consider each patient’s needs and desires individually, and make a joint decision with each patient, at each therapeutic decision point.”

The differences between the ACR guidelines and those published by EULAR in 2020 also can be instructive about the various therapeutic approaches a clinician may take. It is worth noting, however, that the two organizations mostly align, with the exception of a few minor points of divergence.

If there is one other important message from the authors of the ACR paper, it is that the guidelines were developed using rigorous methodology. This should provide reassurance to rheumatologists around the country that the document will prove a useful, evidence-based resource for clinical decision making.

Guideline Development

The process of developing the guideline followed what have become standard protocols. A core leadership team oversaw the project from start to finish and monitored the progress of a literature review team, a voting panel, a 10-patient panel and a panel of experts with background in various aspects of the process.

At the outset, 81 Population- Intervention- Comparator- Outcomes (PICO) questions were written. The development team then created a project plan that was reviewed by the public. Once this process was completed, a deep dive into the literature began. This resulted in identification of some 23,000 articles that were eventually narrowed down to 133 studies. “These were mapped to at least one clinically relevant question,” England said in a presentation at the ACR 2020 Convergence.

However, as Bathon noted, scant evidence was available for many of the topics the team hoped to address. “There was no evidence found for 41% of the clinically relevant PICO questions,” England said.

Consequently, along with the peer-reviewed evidence, clinical expertise and experience were factored into the recommendations. If there was one area where all of those factors were most robust, it was with regard to evidence surrounding MTX.

‘Anchor Drug’

Stanley Cohen, MD
Stanley Cohen

“The ACR 2021 recommendations for rheumatoid arthritis treatment continue to reinforce MTX as the anchor drug for patients with moderate-to-high disease activity,” Stanley Cohen, MD, clinical professor in the department of internal medicine at the University of Texas Southwestern Medical School, and medical codirector of the Metroplex Clinical Research Center, told Healio Rheumatology.

The 2021 iteration includes three strong recommendations involving MTX. One is that it is recommended over hydroxychloroquine or sulfasalazine for DMARD-naïve patients with moderate-to-high disease activity; the second is that MTX monotherapy is preferred over biologic DMARD or targeted synthetic DMARD monotherapy for DMARD-naïve patients with moderate-to-high disease activity; and the third is that MTX monotherapy is preferable to MTX plus a non-TNF inhibitor biologic or targeted synthetic DMARD for DMARD-naive patients with moderate-to-high disease activity.

Liana Fraenkel, MD, MPH
Liana Fraenkel

“The underlying theme was a strong push to use MTX before going on to other DMARDs,” Liana Fraenkel, MD, MPH, director of Patient Centered Population Health Research at Berkshire Medical Center and adjunct professor of medicine at Yale University, said in an interview. Fraenkel was lead author of the recommendation document.

The development team had good reason to focus on MTX, according to Bathon. “This recommendation largely reflects the extensive amount of clinical trial data with MTX supporting its safety and efficacy, dosing flexibility and relatively low cost, as the first line DMARD in newly-diagnosed RA,” she said.

England addressed the point of MTX dosing. “We wanted providers to be aiming to have patients on at least 15 mg weekly within the first 4 to 6 weeks of treatment,” he said. “We did not want people starting on 7.5 mg per week, and then it takes 3 or 4 or 6 months to get up to 15 mg.”

Looking deeper into the document, the authors also stipulate that oral MTX is conditionally preferable to subcutaneous injection. However, if the patient fails to tolerate the oral version, splitting the dose with a subcutaneous injection or an increase in folic acid is conditionally recommended over a switch to a new DMARD.

“One of the big new things is that we have recommendations in this guideline for MTX administration,” England said. “This was really based on the understanding that our anchor drug has been suboptimally used. When you end up changing therapies or escalating to other medications, you might be leaving some benefit of MTX on the table.”

While patients generally prefer oral formulations over injections, the patient panel was in favor of this recommendation, for one important reason. “They tend to understand the idea of getting the most out of a drug like MTX before making the switch to something else,” England said. In addition, patients understood that if they switched to another drug, they may have to undergo injections anyway.

If there is something else that patients have come to understand, it is that long-term steroid use can lead to a number of undesirable complications.

Sparing Steroids

Evidence was robust enough to recommend that initiation of a conventional synthetic DMARD without longer-term glucocorticoids — defined as a duration of at least 3 months — is now strongly preferred over initiation of a conventional synthetic DMARD with longer-term glucocorticoids for DMARD-naïve patients with moderate-to-high disease activity.

For Fraenkel, “changing the default” from prednisone was top of mind for the guideline development team, with a conditional recommendation made to add or switch to DMARDs for patients to remain at target. “We wanted to push the needle the other way away from glucocorticoids,” she said in a presentation at the 2020 ACR Convergence.

The recommendation was made based on the accumulating evidence of toxicity associated with long-term glucocorticoids. “It is widely recognized that even though generally prescribed as bridge therapy, many RA patients remain on glucocorticoids for much longer than originally anticipated,” Fraenkel said.

Cohen put this recommendation into broader context. “In contrast to the recent EULAR RA recommendations, the panel strongly recommended avoidance of short-term and long-term glucocorticoids,” he said. “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.”

For Bathon, the decision to spare steroid use is a “modest difference” between the approaches espoused by the ACR and EULAR. “The EULAR recommendations advise that short-term glucocorticoids should be considered when initiating or changing conventional synthetic DMARDs but should be tapered as rapidly as clinically feasible,” she said. “In contrast, ACR guidelines recommend switching or adding DMARDs to avoid the addition, or persistent use, of glucocorticoids. Both groups recognize the long-term toxicity of glucocorticoids and advise against long-term use.”

Many clinicians, including England, acknowledge both the utility and the dangers of glucocorticoids. “We know they are effective for reducing RA symptoms and sequelae,” he said. “But, of course, we are also very aware of their long-term toxicities.”

England explained another reason why even short-term steroid use may be perilous. “Steroids are often initiated with the intention of being used only in the short-term, but it is frequently difficult to get patients off of them once they have been initiated,” he said. “This is why the ACR message is that glucocorticoids should not be systematically used for all patients, rather focusing on optimal DMARD treatments.”

Rheumatologists have long relied on steroids to manage flares and bridge the gap until therapies with a different mechanism of action take hold. For that reason, it is possible that some may find it difficult to meet therapeutic targets. With that in mind, the guideline development team took a hard look at the treat-to-target approach.

Prime Time for Treat-to-target

A treat-to-target approach is strongly recommended over usual care for patients who have not been previously treated with biologic or targeted synthetic DMARDs.

“The panel continued to affirm the treat-to-target model,” Cohen said, noting that while the recommendation is strong for DMARDs, it is conditional for biologics, due to paucity of data.

“The treat-to-target approach involves formal quantitation of disease activity at each patient visit and mandates a change in DMARD therapy if a goal of remission or low-disease activity is not attained,” Bathon said. “This recommendation is strong for patients who are DMARD-naïve because early control of disease activity limits joint damage and may reduce other long-term sequelae, such as osteoporosis and cardiovascular disease.”

Treating to target is only conditionally recommended over usual care for patients who have failed one or more DMARDs for a number of reasons, according to Bathon. She suggested that these reasons may include “the lack of data, the fewer remaining DMARD options and the potential contributions of non-inflammatory pain to disease activity scores in this patient population.”

The panel also addressed incomplete responders to a conventional synthetic DMARD. For these patients, there is a conditional recommendation for biologic or targeted synthetic DMARDs over so-called “triple therapy” — delivering MTX, hydroxychloroquine and sulfasalazine simultaneously — due to the more rapid and potentially sustained response.

“They did acknowledge the recent safety concerns with targeted synthetic DMARDs in patients at high risk for cardiovascular disease, which may limit utilization of this class of medications after conventional synthetic DMARDs,” Cohen said.

The move away from the triple therapy approach is a key difference between the 2015 and 2021 documents, according to England. He noted that the reason for this conditional recommendation was largely driven by the patient panel. “Patients wanted a quicker response if they are understanding that they are not getting where they need to be with just MTX,” he said. “While both treatment strategies are highly effective, the biologic/targeted synthetic DMARD may get them there quicker.”

The panel found the decision to move away from the triple therapy approach “difficult” and deliberated it extensively, according to Fraenkel. “In the end, the recognition that the delayed onset of action over weeks to months in patients who had not achieved an acceptable response to MTX compared to the more rapid onset of action of a biologic was a strong influential factor,” she said. “The additional number of studies that have suggested lower tolerance of triple therapy compared to biologics also influenced the panel’s deliberations.”

The preference for a biologic or targeted synthetic DMARD over triple therapy is another difference between the ACR and EULAR recommendations, according to Bathon. “It should be noted, however, that in patients with poor prognostic guidelines, the EULAR guidelines are consistent with the ACR guidelines,” she said.

It is also important to note that the recommendation is conditional because there is evidence that either a biologic-based regimen or triple therapy can ultimately allow a patient to get to the same place over time, England added. “There were also some concerns from the panel about the durability and ability to implement the triple therapy approach,” he said.

As clinicians begin to regularly apply these treatment paradigms in clinical practice, an increasing number of patients will likely find themselves in remission. This will bring about the next decision: when, or if, to taper medications.

Tapering and Dose Reduction

If there is one more broad theme of the document, it pertains to tapering medications. While continuation of all DMARDs at the current dose is conditionally recommended over dose reduction, dose reduction is conditionally recommended over gradual discontinuation. In addition, gradual discontinuation is conditionally recommended over abruptly stopping therapy.

Tapering, it is suggested, should only be considered in patients who have been at target for over 6 months.

“The guidelines recommend continuing medications as opposed to tapering, based on the data to date which suggest a high rate of flares or relapses in patients with taper compared to those who continued their DMARDs,” Fraenkel said. “However, the panel recognizes that it is important for many patients to minimize the use of medications, especially over the long-term.”

It was with this in mind that Fraenkel stressed that, whenever possible, the preference is to continue medications. “Next best will be to decrease the dose or increase the interval between doses of a DMARD, and only when patients strongly prefer to discontinue medication, knowing the increased risk of flare should a DMARD be discontinued,” she said.

“Several studies have now been published that indicate that tapering and/or discontinuing disease-modifying medications for RA is associated with flare,” Bathon said. “This is perhaps not entirely surprising since we recognize RA as a chronic disease for which no cure has been found to date. However, there is a suggestion in the studies that flares may occur less frequently or occur in a more delayed manner if the patient has been in a sustained state of remission or low-disease activity prior to taper, yet flares still occur.”

The subject of tapering is another area of “modest disagreement” between the ACR and EULAR guidelines, according to Bathon. The EULAR guidelines advise tapering and discontinuing glucocorticoids first, followed by the targeted DMARD, followed by MTX, or another conventional synthetic DMARD, she said. “Tapering is contingent upon low-disease activity or remission being sustained at each step.”

In the ACR document, it is suggested that MTX should be tapered first, rather than the targeted DMARD. “The rationale is that the targeted DMARD is usually added after an inadequate response to MTX,” Bathon said. “Therefore, remission is more likely to be sustained if the targeted DMARD is continued as monotherapy.”

Additional Concerns

In addition to addressing issues pertaining to disease activity and remission, the authors also reviewed data concerning comorbidities and other associated factors. The final two strong recommendations reflect this.

One of those points stipulates that prophylactic antiviral therapy is now strongly recommended over frequent monitoring of viral load and liver enzymes alone for patients initiating rituximab (Rituxan, Genentech) who are hepatitis B core antibody positive, regardless of hepatitis B surface antigen status. In the other recommendation, prophylactic antiviral therapy is strongly recommended over frequent monitoring alone for patients initiating any biologic or targeted synthetic DMARD who are hepatitis B core antibody positive and hepatitis B surface antigen positive.

“These guidelines are consistent with other societies who care for patients with liver disease,” Fraenkel said.

Further guidance in special populations, including patients with pulmonary disease, heart failure, lymphoproliferative disorders, non-alcoholic fatty live disease, persistent hypogammaglobulinemia without infection or nontuberculous mycobacterial lung disease can all be found in the recommendations.

“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,” Cohen said.

If there was another consideration for the guideline committee, it pertained to cost, according to England. “The hope would be that patients are getting the medications that they need based on decisions made with their provider, and not by insurance companies,” he said. While cost can certainly be a factor with some medications, the weight of the ACR guidelines should be useful in keeping those medications on insurance provider formularies.

It is for this reason that Cohen believes that uptake of the recommendations could be swift and prevalent. “My sense is that physicians are listening to the literature,” he said.

That said, the literature is still evolving, and the experts already have their work cut out for them for the next iteration of the ACR RA guidelines. “The potential toxicities of the targeted synthetic DMARDs, namely janus kinase (JAK) inhibitors, were alluded to, although not discussed directly, in the 2021 ACR recommendations,” Bathon said. “Data emerging at the time these 2021 guidelines were being developed suggested, but did not definitively prove, that JAK inhibitors are associated with an increased risk of clotting compared to other DMARDs.”

While some data suggest that monotherapy with a JAK inhibitor may be more effective than MTX monotherapy in treating early RA, the concern about clotting precluded a definitive recommendation of one drug class over another, according to Bathon. “Moreover, the FDA has not approved JAK inhibitors as first-line therapy for DMARD-naïve RA patients.”

Certainly, clinicians will make use of these drugs as more data become available. In the meantime, rheumatologists can be certain that the 2021 ACR RA guidelines represent the accumulation of the best available knowledge to date, according to Cohen. “Overall, the recommendations appropriately reflect the newer clinical trial data available since the 2015 recommendations,” he said.