“This is one of the most exciting areas involving methotrexate,” commented Dr. Weinblatt, a participating investigator in CIRT.
Methotrexate boosts efficacy of selected biologics.
Concomitant methotrexate is known to increase the clinical efficacy of anti–tumor necrosis factor biologics and rituximab. Studies in patients on infliximab or adalimumab have shown that background methotrexate raises serum concentrations of the biologics by 20%-25%, which is presumably the explanation for the increased efficacy. Whether methotrexate enhances or attenuates the efficacy of the oral small-molecule JAK inhibitors is now under study.
One intriguing cohort study has shown that methotrexate reduces the immunogenicity of adalimumab in dose-dependent fashion; the higher the dose of methotrexate, the less ability patients had to develop blocking antibodies against adalimumab (Ann. Rheum. Dis. 2012;71:1914-5).
More recently, the randomized, double-blind CONCERTO trial conducted in 395 methotrexate- and biologic-naive RA patients extended this work. Participants were randomized to open-label adalimumab plus weekly blinded methotrexate at 2.5, 5, 10, or 20 mg. Clinical outcomes at 26 weeks as reflected in 28-joint count disease activity score and other measures were significantly better in patients on 10 or 20 mg/week of methotrexate. Serum adalimumab levels were higher in patients on those doses of methotrexate than in those on 2.5 or 5 mg/week as well (Ann. Rheum. Dis. 2014 Feb. 18 [doi:10.1136/annrheumdis-2013-204769]).
There’s an important lesson here for patient management: “If you’re going to dose-reduce your methotrexate in patients with low disease activity or in remission, there is a threshold at which you should probably stop reducing the methotrexate, at least when your patient is on this biologic,” according to Dr. Weinblatt.
In contrast, no methotrexate dose-threshold effect occurs with etanercept, he added.
Methotrexate and the liver.
A national observational cohort study of 659 military veterans over age 65 when they started methotrexate for RA or other rheumatic diseases found a 6% incidence of moderately elevated liver enzymes during a mean follow-up period of 7 months. The investigators identified a series of independent risk factors for liver function test abnormalities. 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, abnormal liver function tests premethotrexate was associated with a 3.2-fold increased risk, and lack of folic acid supplementation brought a 2.2-fold increase in risk (Arthritis Care Res. 2014;66:1159-66).
“This study confirms what a lot of us have been worried about,” Dr. Weinblatt commented. That is, the risk of methotrexate-related liver toxicity is particularly high in older patients with characteristics consistent with the metabolic syndrome, a condition that has reached epidemic proportions.
A strong take-home message from this study, he added, is that patients should not start on methotrexate if they have abnormal liver function tests. That guidance was included in the original guidelines for methotrexate in RA published back in the mid-1990s.
“I think rheumatologists have kind of lost sight of that. You probably should find out why those tests are elevated. In many cases you’ll find it may be related to NASH [nonalcoholic steatohepatitis],” he said. “I actually think obesity is one of the greatest risk factors for methotrexate toxicity.”
Dr. Weinblatt reported receiving consulting fees or other remuneration from more than two dozen pharmaceutical companies.