CHARLOTTE, N.C. – Methotrexate’s role as the mainstay drug of choice to treat rheumatoid arthritis has never been challenged, but questions persist as to why many rheumatologists don’t seem to titrate the dose of the drug up for a long enough period to see significant improvement in disease activity, or don’t instead start with or switch to subcutaneous administration before adding a biologic.
The issue is likely to come to greater prominence soon because of the rise of value-based care, according to Dr. James O’Dell, chief of the division of rheumatology at the University of Nebraska Medical Center, Omaha.
University of Nebraska Medical Center
Dr. James O'Dell
“Rheumatologists will ultimately be held accountable for providing value-based care. We’ll be measured on how well patients are doing, hopefully, and how expensive it is for you to take care of them. When rheumatologists are scored in that way, they will look for ways to provide quality care less expensively. And when they do that, they’ll use more methotrexate, they’ll use higher doses of methotrexate, they’ll use subcutaneous methotrexate, they’ll use more conventional therapy,” he said in an interview.
Dr. O’Dell called for rheumatologists to give methotrexate a longer time to work and to give subcutaneous methotrexate a shot before moving on to biologics, based on analyses of the TEAR (Treatment of Early Aggressive Rheumatoid Arthritis) trial and a U.S. pharmaceutical claims database study of methotrexate-prescribing habits during 2009-2014 that he presented at the annual meeting of the North Carolina Rheumatology Association (NCRA).
Overall, 28% of the early, poor-prognosis RA patients in the TEAR trial who were randomized to receive only oral methotrexate achieved a 28-joint Disease Activity Score (DAS28) of less than 3.2 at 24 weeks. The weekly dose of methotrexate was escalated if there were any tender or swollen joints, rising from 10 mg to 15 mg at 6 weeks and from 15 mg to 20 mg at 24 weeks. Those patients who did well on methotrexate alone showed no clinically meaningful or statistically significant clinical or radiographic differences at week 48 to the end of the study at week 102, compared with patients who initially took methotrexate alone but were randomized to either triple therapy with methotrexate, sulfasalazine, and hydroxychloroquine or combination disease-modifying antirheumatic drug (DMARD) therapy with etanercept and methotrexate after having a DAS28 of 3.2 or higher at 24 weeks, as well as patients who were initially randomized to triple therapy or combination DMARD therapy at the start of the trial (Arthritis Rheum. 2013;65:1985-94).
“The TEAR trial clearly showed that there are many individual patients who do not require anything more than methotrexate alone,” Dr. O’Dell said in an interview. “It also showed that combinations of conventional therapy – methotrexate, sulfasalazine, hydroxychloroquine – are equally efficacious both clinically and radiographically to combinations of methotrexate and etanercept. One of the messages that the TEAR trial clearly showed us is that if you have a patient that needs to step up to a biologic, you can titrate methotrexate up and wait until the 6-month time point to make that decision. And if you wait until 6 months, the patient is not going to be harmed in terms of their ultimate clinical response, and they’re not going to be harmed in terms of radiographic progression.”
However, patients using methotrexate in the TEAR trial only went up to a maximum of 20 mg/week orally, and this itself may be improved on because of evidence for greater bioavailability of oral methotrexate when it is titrated up to even higher doses by 6 months. There also is evidence, although limited, for the superior efficacy and bioavailability of subcutaneous methotrexate, Dr. O’Dell said.
Some data are beginning to indicate the usefulness of going straight to subcutaneous rather than oral methotrexate, he said. Data from the prospective, observational Canadian Early Arthritis Cohort (CATCH) have shown that 55% of patients with early RA who used subcutaneous methotrexate alone as their initial treatment needed it only during the first year of treatment, compared with 23% who were treated initially with oral methotrexate alone. Lack of efficacy was the only statistically significant difference between the two groups that was cited as a reason for failure of the initial treatment, which was the case for 72% of oral users vs. 40% of subcutaneous users.
Another analysis from the CATCH study that was reported at the 2016 Congress of the European League Against Rheumatism (EULAR) suggested that use of subcutaneous methotrexate as an initial treatment for RA could reduce the use of biologics by 53% after adjustment for confounding variables, compared with use of oral methotrexate.