SNOWMASS, COLO. (FRONTLINE MEDICAL NEWS) – “When I started working with methotrexate in 1982, I never would have predicted that methotrexate would become the standard of care in treating rheumatoid arthritis. There’s just no way,” Michael E. Weinblatt, MD, recalled at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

“Even now, 35 years later, we continue to learn more about this fascinating drug,” added Dr. Weinblatt, professor of medicine at Harvard Medical School, Boston.

He highlighted recent developments in this ongoing story and presented some tricks of the trade gained in 35 years of up-close experience with the drug.

“After 30-plus years we’re still learning more about its mechanism of action. Every time there’s a new paper on a different mechanism, I think we all continue to marvel at this drug. I think the reason it works as well as it does is because it’s a dirty molecule. It works across the board on multiple cell lines and multiple pathways,” according to the rheumatologist.

Enhancing effectiveness of biologics

One of the hottest topics in methotrexate research is the drug’s ability to enhance the effectiveness of many, but not all, biologic agents. All of the anti–tumor necrosis factor (anti-TNF) biologics as well as rituximab (Rituxan) are demonstrably more effective when used in combination with methotrexate. Dr. Weinblatt considers the widespread underutilization of this combination strategy scandalous.

“This is an incredibly important point: All of you use biologics and all of you use methotrexate, but I’ve been depressed by the fact that up to 30%-40% of patients – no matter which data set you look at – are on monotherapy biological therapy,” he said.

He cited data from the ongoing BRASS Registry (Brigham and Women’s Hospital Rheumatoid Arthritis Sequential Registry) to underscore his point that good things happen when biologics and methotrexate are used together. Of 1,395 BRASS Registry participants prospectively followed since 2003, the proportion on biologic therapy has climbed steadily from 41% at the outset to 68% in 2016. Remarkably, 82% of patients on biologic therapy remain on their first biologic agent. Fewer than 4% have switched biologics more than twice. That’s very unlike the experiences reported elsewhere.

“I think one of the reasons we have such positive data is that we have a high percentage of patients staying on their background methotrexate,” said Dr. Weinblatt, codirector of clinical rheumatology and associate director of the Center for Arthritis and Joint Diseases at Brigham and Women’s Hospital, Boston.

He noted that Dutch investigators reported at the 2016 annual meeting of the American College of Rheumatology that among 1,230 consecutive rheumatoid arthritis patients started on etanercept (Enbrel) or adalimumab (Humira), 28% in the etanercept group were on concomitant methotrexate, as were 64% of those who started on adalimumab. The patients spent a median of 1.3-1.6 years and a maximum of 9.2-9.3 years on their biologic agent. Patients on adalimumab monotherapy were 2.61-fold more likely to drop out than were those on dual therapy with methotrexate. Patients on etanercept monotherapy were 1.2-fold more likely to drop out, a difference that didn’t achieve statistical significance.

Although the investigators did not study the mechanism of prolonged on-treatment survival, they speculated that it probably involved methotrexate’s documented ability to prevent formation of anti-adalimumab antibodies. In contrast, patients on etanercept don’t develop blocking antibodies, Dr. Weinblatt observed.

The randomized, double-blind CONCERTO trial conducted in 395 methotrexate- and biologic-naive RA patients demonstrated that methotrexate reduces the immunogenicity of adalimumab in dose-dependent fashion. Participants were randomized to open-label adalimumab at 40 mg every 2 weeks plus weekly double-blind methotrexate at 2.5, 5, 10, or 20 mg. Clinical outcomes at 26 weeks as reflected in 28-joint count disease activity score and the Clinical Disease Activity Index were significantly better in patients on 10 or 20 mg/week of methotrexate than in those on 2.5 or 5 mg/week. Serum adalimumab levels were higher in patients on the two higher doses of methotrexate as well ( Ann Rheum Dis. 2015 Jun;74[6]:1037-44 ).

“It ends up that if you don’t use methotrexate or you use a very low dose you increase the risk of developing antibodies against adalimumab and decrease the efficacy of the drug. So in clinical practice, if you’re going to be working with dose titration of methotrexate and your patient is on adalimumab, there’s a threshold below which you probably shouldn’t go. In this study, doses of 10 mg/week or more induced a greater clinical response,” he said.

With infliximab (Remicade), based upon 20-year-old studies, the threshold is 7.5 mg of methotrexate per week.

“With etanercept, we don’t know what the threshold is. You don’t develop blocking anti-drug antibodies with etanercept, but we do know that methotrexate enhances the efficacy of etanercept, and it doesn’t do it by changing the biologic’s pharmacokinetics and there’s no increase in methotrexate blood levels,” the rheumatologist continued.

Unlike the anti-TNF biologics and rituximab, the efficacy of the Janus kinase inhibitors tofacitinib (Xeljanz) and baricitinib is not enhanced when the drugs are used in combination with methotrexate, studies indicate.

The efficacy of certolizumab pegol (Cimzia) wasn’t affected by methotrexate dose category in a prespecified pooled subgroup analysis of the phase III RAPID 1 and RAPID 2 clinical trials. In the 1,273 certolizumab-treated patients, the week-24 treatment response was similar regardless of whether patients were on methotrexate at 10 mg/week or less, 10-15 mg/week, or more than 15 mg/week. The investigators concluded that to minimize treatment-emergent adverse events, physicians can tailor background methotrexate dosing based upon individual patient tolerance without affecting certolizumab’s efficacy ( Arthritis Care Res [Hoboken]. 2016 Mar;68[3]:299-307 ).

An important aspect of this analysis was that among the 325 subjects randomized to placebo rather than certolizumab, the treatment response at week 24 was significantly better in those on more than 15 mg/week of methotrexate than with lower doses of the drug.

“Most patients on methotrexate need more than 15 mg/week. So it astonishes me that such a high percentage of patients enrolled in clinical trials around the world are on, like, 14 mg/week. I mean, most patients need somewhere between 15 and 25 mg/week for a response, although over time you might be able to decrease that dose,” Dr. Weinblatt said.

Side effects of methotrexate

“The biggest issue with methotrexate is the tolerability problem, since serious adverse events are incredibly rare with this molecule,” he said.

Hepatotoxicity is a concern, but Dr. Weinblatt emphasized that elevated liver function tests do not equal cirrhosis.

“Historically, during the first 6 months on methotrexate 20%-25% of patients increase their transaminases in every clinical trial where that’s been looked at. Over time, the liver compensates for the drug. But 5%-6% of patients experience repeated moderate elevations more than 1.5 times the upper limit of normal,” he said.

Key risk factors for methotrexate-related hepatotoxicity were identified in a national observational cohort study of 659 military veterans over age 65 when they started methotrexate for rheumatic diseases. The investigators found a 6% incidence of moderately elevated liver enzymes during a mean follow-up period of 7 months. Obesity was associated with a 1.9-fold increased risk, a serum total cholesterol greater than 240 mg/dL conferred a 5.8-fold elevated risk, and abnormal liver function tests at baseline were associated with a 3.2-fold increased risk ( Arthritis Care Res [Hoboken]. 2014 Aug;66[8]:1159-66 ).

“No surprise: It’s patients who weigh more who are at increased risk for methotrexate-related transaminase increases. I actually think the biggest factor with regard to methotrexate liver disease is the patient’s [body mass index]. Patients in North America aren’t getting any slimmer, so you need to look at this with your patients. If you have a morbidly obese patient on methotrexate whose transaminases suddenly start going up, that’s the patient who’s at greatest risk for methotrexate hepatotoxicity,” he cautioned.

The 3.2-fold increased risk of repeated elevated transaminases associated with abnormal baseline liver function tests in the Veterans Affairs study should be a red flag for rheumatologists.

“I personally think patients shouldn’t start on methotrexate if they have elevated transaminases. They ought to be normal at the start. There are too many other good options now to treat our patients,” Dr. Weinblatt said.

He reported receiving research grants from half a dozen companies and serving as a consultant to more than two dozen.