Prior studies have sought to estimate the risk of adverse events with low-dose methotrexate in rheumatologic disorders, but they have been too small to do so with real precision.
At the recent 2019 ACR meeting in Atlanta, , of Brigham and Women's Hospital, discusses his study which investigated the risk of AEs in patients without rheumatic disease using MTX compared with placebo.
Following is a transcript of his remarks:
The question that was asked in the CIRT trial was whether methotrexate at the dosages we give in rheumatology might reduce the risk of subsequent cardiovascular events. At the same time the trial was running, we ran a prospective adverse event trial looking at the safety of methotrexate. Alongside the main trial, we were blindly adjudicating adverse events that were occurring in both the methotrexate and the placebo arms. This took place in 4,700 people; 2,350 approximately took methotrexate at the dosages we take, which represents one of the largest experiences with low-dose methotrexate in adult patients.
Today, what I'll be presenting are some of the findings with respect to adverse events, the incidence, and the relative risk compared to placebo. While we know a lot about methotrexate in rheumatology and across medicine, we've been using the drug for 30 or 40 years. We have mostly observational data where there are no placebos, and we also have data from relatively small randomized trials where there was no blind adjudication of adverse events. This is really a great strength of what we've been able to do.
Some of the findings, I think, are interesting. We did find, as we might have anticipated, that there was an increased risk, about a 20% increased risk of adverse events in the methotrexate arm. Most of them were mild, but there were many, many adverse events. There were adverse events in the hematologic system. 20% to 30% of patients in the methotrexate arm compared to placebo had a risk of anemia. There was leukopenia, reduction of white blood cells were more common in patients on the methotrexate arm. There was also pancytopenia. This is one of the dreaded complications that rheumatologists fear and we often talk about patients. There was an increased risk of pancytopenia. However, there were only 13 cases of pancytopenia in 2,300 patients. Again, it gives us some sense of how common or how uncommon some of these complications in methotrexate therapy are.
We also found an increased risk of infection. We often talk about the infection risk associated with DMARDs, Enbrel, and other biologic DMARDs, but we rarely talk about the risk of infection associated with methotrexate. We found about 15% to 20% risk of infection compared to placebo. Most of those were mild infections, but there was an increase of about 40% of pneumonias. There was some numerical increase in bone and joint infections, as well as shingles. Those did not reach statistical significance, but there was relatively few cases of those types of infections.
Somewhat of a surprising finding was the increased risk of skin cancer. There's been literature on increased risk of skin cancer among patients who are post-transplant, who take immunosuppressors. Here we have patients, just cardiovascular disease patients, who were taking low-dose methotrexate and they had approximately a doubling of the risk of all types of skin cancer: squamous, basal, as well as melanoma. This is something that I think is of importance to rheumatologists, especially when we're treating patients with psoriasis and psoriatic arthritis, because those patients already have an increased risk of skin cancer and we often are considering giving those patients methotrexate.
Those were some of the surprising and interesting results. We also looked at gastrointestinal and liver outcomes. I'll be presenting that in a poster tomorrow, but we did find several cases, about six, of cirrhosis. While rheumatologists have for a long time known that methotrexate can be associated with liver abnormalities, we mostly think about liver test abnormalities and very rare cases of cirrhosis. We found 6 out of 2,300, so relatively rare, but we did find they occurred. Interestingly, the patterns in the patients where cirrhosis occurred was not very elevated liver test abnormalities. As a clinician, I think about the patient who has severe liver test abnormalities, the one I'm most worried about. It turned out the patients with low-level liver test abnormalities, but for long periods, seemed to be the patients that ran into problems with cirrhosis.
I think the results from our studies, while they were not conducted in rheumatology patients, they were conducted in adults with multiple comorbidities very similar to many patients we see in rheumatology clinic. I think these will inform future guidelines about the safe prescribing of methotrexate. I don't want to leave people with the impression that methotrexate is a more dangerous drug than you would realize. I think most rheumatologists recognize it has its toxicities, we know how to monitor it, we do that carefully, but we just have to recognize, just like our other DMARDs, it also has toxicities.