SNOWMASS, COLO. – Can an old rheumatoid arthritis drug – like an old dog – learn new tricks?
When that drug is methotrexate, the answer is definitely yes, according to Dr. Michael E. Weinblatt, professor of medicine at Harvard Medical School, Boston.
Clinically important advances and refinements continue to be made in the use of this venerable drug, a treatment mainstay for RA since the mid-1980s.
Dr. Michael E. Weinblatt
“I had the pleasure of participating in a symposium on methotrexate organized by Dr. Joel Kremer at last year’s annual ACR meeting in Boston. This is the second one we’ve done, and I must tell you, the number of people in attendance was extraordinary. We probably filled one of the largest conference rooms for the second time in 2 years. And the questions went on forever. So even though methotrexate is an old drug, there still remains great interest in it,” he observed at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
Here’s what’s new:
Subcutaneous methotrexate for RA is finally legit.
Multiple studies over the past 15 years have established that at methotrexate doses above 15-20 mg/week, subcutaneous therapy achieves superior efficacy, compared with oral therapy. For this reason, rheumatologists have long used once-weekly subcutaneous injections of methotrexate in RA patients with an inadequate clinical response to oral therapy. However, as payers have often informed them, this has been off-label usage. Not any longer. Rheumatoid arthritis is now an FDA-approved indication for subcutaneous methotrexate. Moreover, two easy-to-use, single-dose, once-weekly, autoinjector formulations are now on the market, known as Otrexup and Rasuvo.
In a randomized, crossover study of various doses of oral methotrexate versus Otrexup in 49 RA patients, the systemic bioavailability of oral methotrexate plateaued at doses of 15 mg/week or above. In contrast, the systemic exposure of subcutaneous methotrexate continued to increase linearly out to 25 mg/week, the highest dose studied. And this greater bioavailability wasn’t associated with an increase in adverse events (Ann. Rheum. Dis. 2014;73:1549-51).
Split-dose oral therapy improves bioavailability.
When methotrexate was first prescribed for RA in the mid-1980s, it was given in a pulsed-dose regimen: 8 a.m., 8 p.m., and again at 8 a.m. the next morning. Three doses over a 24-hour period, once weekly.
“Over time, most of us shifted to a once-a-week regimen for convenience, ease-of-administration, and because of some concerns about liver exposure. We’ve come to appreciate, however, that if you dose-escalate methotrexate, a significant percentage of patients do not absorb the drug at doses above 15-20 mg once weekly. But pharmacokinetic studies have demonstrated you get higher drug concentrations with a split dose,” according to the rheumatologist.
For example, a crossover study involving 10 patients on stable doses of oral methotrexate at 25-35 mg/week showed that splitting a dose into two halves given 8 hours apart resulted in 28% greater bioavailability, compared with the standard single dose. Indeed, the bioavailability with the oral split dose was comparable to that achieved with subcutaneous administration (J. Rheumatol. 2006;33:481-5).
“Many of us are now splitting the dose of methotrexate at doses above 17.5-20 mg/week. I would like to caution, however, that this does not mean you should give the drug on Mondays and Thursdays. This was studied 40 years ago at the [National Institutes of Health]. It caused more acute toxicity, including bone marrow suppression, and more chronic toxicity, such as liver disease. So the drug should only be administered over one 24-hour period per week,” Dr. Weinblatt advised.
Methotrexate: the next statin?
Four cohort studies over the past 10 years have reported that methotrexate appears to reduce cardiovascular mortality in RA patients. Registry data are also supportive. The evidence is sufficiently strong that a definitive randomized clinical trial is now well underway. This major study, known as the Cardiovascular Inflammation Reduction Trial (CIRT), is funded by the National Heart, Lung, and Blood Institute and led by renowned cardiologist Dr. Paul Ridker, the Eugene Braunwald Professor of Medicine at Harvard Medical School. It will enroll 7,000 subjects – none with RA – at roughly 350 U.S. and Canadian sites.
Participants are high–cardiovascular risk patients with a history of acute MI within the previous 5 years plus type 2 diabetes or metabolic syndrome. They are being randomized to guideline-directed medical care plus either oral methotrexate at 10-20 mg/week or placebo for 2-4 years. The primary endpoint is cardiovascular death, nonfatal MI, or stroke.
The proposed mechanism of benefit is methotrexate’s anti-inflammatory effect. If the results of CIRT are positive, this low-cost generic drug with a thoroughly understood safety profile could transform preventive cardiology; lowering systemic inflammation would potentially join LDL lowering via statins as a cornerstone of disease prevention.