PR: Choosing the initial treatment | MedPage today


“Medical Journeys” is a collection of physician-reviewed clinical resources for the medical team and the patients they serve. Each episode of this 12-part journey through a medical condition contains both a doctor’s guide and a downloadable/printable patient resource. “Medical pathways” chart a path at every stage for doctors and patients and provide ongoing resources and support as the healthcare team navigates the course of an illness.

In 2021, the American College of Rheumatology (ACR) released a new guideline for the treatment of rheumatoid arthritis (RA), highlighting the central role of methotrexate in the management of the disease. The specific recommendations stated that methotrexate was strongly recommended over hydroxychloroquine and sulfasalazine as initial therapy for patients with moderate to high levels of disease activity who had not previously been treated with antirheumatic drugs. disease modifying agents (DMARDs); Methotrexate monotherapy has also been strongly recommended over synthetic biological or targeted agents for DMARD naïve patients starting treatment.

According to the committee that developed the guideline, strong recommendations were those “where the committee is very confident that the recommended option favorably balances the expected benefits and risks for the majority of patients in clinical practice.” Conditional recommendations were those where the panel felt less confident that the potential benefits outweighed the risks.

Methotrexate monotherapy has also been conditionally recommended as initial therapy over dual or triple DMARD therapy in DMARD-naïve patients, as well as combination therapy with a tumor necrosis factor inhibitor ( TNF), and strongly recommended over combination treatment with a non-TNF or targeted biological agent. synthetic agent.

At the time of the guideline’s release, lead author Liana Fraenkel, MD, of Yale University School of Medicine in New Haven, Connecticut, said, “Seventy percent of patients can continue to taking medication and not increasing if methotrexate is used diligently, but it takes some effort. This requires thinking about how to manage side effects and increase the dose.

“We know that many patients, especially in the United States, are on biologics – more than we would expect if methotrexate was used to its full benefit,” she said. MedPage today.

Methotrexate: backtracking

The antimetabolite methotrexate was first used more than 70 years ago for the treatment of childhood leukemia and then in small studies for psoriasis, psoriatic arthritis and rheumatoid arthritis, although concerns have been raised regarding hepatotoxicity. In general, the rheumatology community was hesitant to use an anti-cancer drug for a “mild” non-fatal condition such as rheumatoid arthritis, favoring corticosteroids.

But interest in the drug persisted among some rheumatologists, and in 1983 Michael E. Weinblatt, MD, of Harvard Medical School in Boston, and colleagues initiated a 24-week randomized placebo-controlled crossover study that included 35 patients with refractory RA. The initial dose was 7.5 mg/week, increasing to 15 mg/week after 6 weeks. At week 12, more than 50% of patients had at least a 50% improvement in joint tenderness and 39% had this degree of improvement in joint swelling. The study was published in 1985 in the New England Journal of Medicine.

A second pivotal trial, sponsored by the NIH and published in Arthritis and rheumatism, included 189 patients with active disease who started treatment with methotrexate at 7.5 mg/week, increasing to 15 mg/week. At week 18, 32% of patients had at least a 50% reduction in joint tenderness and 21% had a similar decrease in joint swelling.

Methotrexate was later approved for use in RA in 1988, and subsequent experience included long-term prospective trials and active comparison studies against intramuscular gold (auranofin), which was the standard of care at the time. By the 1990s, methotrexate had become the gold standard DMARD for rheumatoid arthritis, as it remains around the world today.

Getting the most from methotrexate

“In 1988, methotrexate was not expected to alter the course of RA. I had the pleasure of being directly involved in the development of methotrexate in RA and it has been extremely rewarding to see the ‘impact of methotrexate in RA,” Weinblatt wrote in a 2018 op-ed in Arthritis research and therapy. He recently echoed that sentiment, saying, “I think for those of us who have worked on methotrexate for three to four decades, it’s really gratifying to see the role that methotrexate has played in changing the course of rheumatoid arthritis.”

He spoke to MedPage today on his long experience with the drug, offering insight into how to maximize efficacy and minimize associated adverse effects.

“I usually start patients on a dose of 12.5 mg/week, increasing to a therapeutic dose of 20-25 mg/week 4-6 weeks later, using a divided dose morning and evening 1 day per week,” he explained.

The reason for starting with a lower dose is tolerance, with nausea and fatigue being the most common issues. “My European colleagues can actually start at a higher dose than me, but I find that if patients develop nausea they just won’t follow the program. So I’m willing to give up a month or 6 weeks for make sure they tolerate the drug and are comfortable with it before I step it into the therapeutic range,” Weinblatt said.

Regarding the inability of patients to tolerate methotrexate, some rheumatologists have suggested that 30-40% of patients stop taking the drug due to its tolerance. “It’s not my experience,” Weinblatt said. “In my personal experience, it’s probably 10% of patients who quit because of nausea or fatigue. Maybe one of the reasons my adverse event rate is lower is that I use a lot of folinic acid (leucovorin).”

Methotrexate treatment typically involves co-administering folinic acid, but for patients who develop side effects, Weinblatt said he switches to leucovorin rescue, which is what oncologists use when methotrexate is used for cancer chemotherapy.

In addition, he doses leucovorin at least 8 hours after methotrexate, because if folinic acid is administered within 8 hours it interferes with the effectiveness of methotrexate, he explained.

However, “one of the things we have come to appreciate about methotrexate over 30 years is that approximately one-third of patients on methotrexate alone will experience low disease activity and/or remission and will only need monotherapy. This means that two-thirds of patients eventually need another treatment,” he said.

So, for patients who need additional treatment with anti-TNF therapies such as etanercept (Enbrel) or adalimumab (Humira), combination therapy with methotrexate improves efficacy. For example, with adalimumab or infliximab (Remicade), methotrexate increases serum concentrations of these monoclonal antibodies by about 20% to 25% and reduces the development of neutralizing antibodies, he said.

“When I talk to rheumatologists, I really encourage them to address methotrexate issues with patients up front before they go to Dr. Google. I tell them that in high doses it’s a cancer drug , but the doses we use in rheumatoid arthritis are considerably lower so we don’t see the side effects that patients worry about with cancer chemotherapy,” Weinblatt said.

Also, most insurance plans will not cover new therapies unless a trial of methotrexate has failed.

An exception is for patients who have a comorbidity that would preclude the use of methotrexate, such as kidney or liver disease. Methotrexate is 100% eliminated by the kidney, so patients with kidney failure cannot use the drug. Also, if methotrexate is given for unrecognized kidney disease, it can lead to high levels of the drug that can depress the bone marrow and increase the risk of serious infections. Liver function should also be monitored to detect subtle changes that could signal toxicity.

other considerations

The ACR guideline also addressed the use of glucocorticoids, conditionally recommending the use of a DMARD without short-term glucocorticoid use (less than 3 months) rather than the use of a conventional DMARD such as methotrexate plus glucocorticoids. The panel noted that short-term use of glucocorticoids is often necessary to control symptoms before the slower onset of action of DMARDs, but “treatment with glucocorticoids should be limited to the lowest effective dose during shortest possible time”.

The guideline also offered a conditional recommendation regarding the use of subcutaneous methotrexate, suggesting that changing the route of administration is preferable to switching to another DMARD in patients on oral methotrexate who do not reach low disease activity or remission. “The recommendation is conditional because patient preferences and the magnitude of previous response to methotrexate play an important role in this decision,” the group noted.

Finally, the guideline emphasized the increasingly accepted strategy of targeted therapy throughout the course of the disease, stating that “targeted therapy refers to a systematic approach involving frequent monitoring of the disease. disease activity using validated instruments and modifying therapy to minimize disease. activity with the aim of reaching a predefined target (low disease activity or remission).”

Read previous episodes of this series:

Part 1: The beginnings of rheumatoid arthritis: before painful joints

Part 2: RA: another clinical diagnosis

  • Nancy Walsh earned a BA in English Literature from Salve Regina College in Newport, RI


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