乌鸦传媒

"Medical Journeys" is a set of clinical resources reviewed by physicians, meant for the medical team as well as the patients they serve. Each episode of this 12-part journey through a disease state contains both a physician guide and a downloadable/printable patient resource. "Medical Journeys" chart a path each step of the way for physicians and patients and provide continual resources and support, as the caregiver team navigates the course of a disease.

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

Strong recommendations, according to the panel who developed the guideline, were those "for which the panel is highly confident that the recommended option favorably balances the expected benefits and risks for the majority of patients in clinical practice." Conditional recommendations were those for which the panel expressed less confidence that the potential benefits outweighed the risks.

Methotrexate monotherapy also was conditionally recommended as initial treatment over double or triple DMARD therapy in DMARD-naive patients, and also over combination therapy with a tumor necrosis factor (TNF) inhibitor, and strongly recommended over combination therapy with a non-TNF biologic or targeted synthetic agent.

At the time the guideline was published, lead author Liana Fraenkel, MD, of Yale University School of Medicine in New Haven, Connecticut, said: "Seventy percent of patients can stay on one medication and not escalate if methotrexate is used diligently, but that takes some effort. It requires thinking about how to deal with side effects and escalating the dose."

"We know that a lot of patients, especially in the U.S., are on biologics -- more than we would expect if methotrexate was used to its full advantage," she told 乌鸦传媒.

Methotrexate: A Look Back

The antimetabolite methotrexate was first used more than 70 years ago for the treatment of childhood leukemia, and subsequently in small studies for psoriasis, psoriatic arthritis, and RA, although concerns were raised about hepatotoxicity. In general, the rheumatology community was hesitant to use an anticancer drug for a nonlethal, "benign" condition such as RA, 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 randomized, 24-week 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 that degree of improvement in joint swelling. The in 1985 in the New England Journal of Medicine.

A , sponsored by the NIH and published in Arthritis & Rheumatism, included 189 patients with active disease who started treatment with methotrexate at 7.5 mg/week, escalating to 15 mg/week. By 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 then approved for use in RA in 1988, and subsequent experience included long-term prospective trials and active comparator studies versus intramuscular gold (auranofin), which was the standard of care at the time. By the 1990s, methotrexate had become the standard-of-care DMARD for RA, as it remains worldwide today.

Making the Most of Methotrexate

"Little did one anticipate in 1988 that methotrexate would change the course of RA. I had the pleasure of being directly involved in the development of methotrexate in RA and it has been extremely gratifying to see the impact of methotrexate in RA," Weinblatt wrote in a 2018 editorial in Arthritis Research & Therapy. He echoed that sentiment recently, saying, "I think for those of us who have worked on methotrexate for three to four decades now it's really gratifying to see what role methotrexate has made in changing the course of RA."

He spoke to 乌鸦传媒 about his long experience with the drug, offering insights into how to maximize efficacy and minimize the associated adverse effects.

"I generally start patients on a dose of 12.5 mg/week, increasing to a therapeutic dose of 20 to 25 mg/week 4 to 6 weeks later, using a split-dose morning and evening 1 day each week," he explained.

The reason for starting with a lower dose is because of tolerability, with nausea and fatigue being the most common problems. "My European colleagues may actually start at a higher dose than I do, but I find that if patients develop nausea they're just not going to stick with the program. So I'm willing to give up a month or 6 weeks to make sure they tolerate the drug and feel comfortable with it before I escalate it into the therapeutic range," Weinblatt said.

As far as patients' inability to tolerate methotrexate, some rheumatologists have suggested that 30% to 40% of patients stop taking the drug because of tolerability. "That's not been my experience," said Weinblatt. "In my personal experience it's probably 10% of patients who stop because of nausea or fatigue. Perhaps one of the reasons why my adverse event rate is lower is I use a lot of folinic acid (leucovorin)."

Treatment with methotrexate typically involves co-administration of folinic acid, but for patients who develop side effects Weinblatt said he escalates to leucovorin rescue, which is what oncologists use when methotrexate is being used for cancer chemotherapy.

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

However, "one of the things we've come to appreciate about methotrexate over 30 years is that about one-third of patients on methotrexate alone will go into low disease activity and/or remission and only require monotherapy. That 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 enhances the efficacy. For instance, with adalimumab or infliximab (Remicade), methotrexate increases the serum concentrations of those 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 issues of methotrexate with patients upfront before they go to Dr. Google. I tell them that, in high doses, this is an anticancer drug but the doses we use in RA are significantly lower so we don't see the side effects patients are concerned about with cancer chemotherapy," Weinblatt said.

Moreover, most insurance plans will not cover the newer therapies unless a trial of methotrexate has failed.

An exception is for patients who have a comorbidity that would preclude using methotrexate, such as kidney or liver disease. Methotrexate is 100% cleared by the kidney, so patients with renal insufficiency can't use the drug. Also, if methotrexate is given in the setting of unrecognized renal 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 also must be monitored to detect subtle changes that could signal toxicity.

Other Considerations

The ACR guideline also addressed the use of glucocorticoids, conditionally recommending DMARD use without short-term use of glucocorticoids (less than 3 months) over the use of a conventional DMARD such as methotrexate plus glucocorticoids. The panel did note that short-term use of glucocorticoids often is needed for symptom control before the slower onset of action of DMARDs, but "treatment with glucocorticoids should be limited to the lowest effective dose for the shortest duration possible."

The guideline also offered a conditional recommendation regarding the use of subcutaneous methotrexate, suggesting that changing the route of administration is preferred over switching to a different DMARD among 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 panel noted.

Finally, the guideline emphasized the increasingly accepted strategy of treat-to-target through the course of disease, stating, "treat-to-target refers to a systematic approach involving frequent monitoring of disease activity using validated instruments and modification of treatment to minimize disease activity with the goal of reaching a predefined target (low disease activity or remission)."

Read previous installments in this series:

Part 1: RA Beginnings: Before the Painful Joints

Part 2: RA: Still a Clinical Diagnosis