Tuberculosis screening needed for patients receiving methotrexate in endemic areas
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Tuberculosis screening and clinical surveillance are needed for patients prescribed methotrexate — especially alongside corticosteroids or other immunosuppressants — in tuberculosis-endemic areas, according to a speaker at ACR Convergence.
“We know that methotrexate is the foundational DMARD for many rheumatic diseases, in particular rheumatoid arthritis,” Carol Hitchon, MD, MSc, associate professor of medicine at the University of Manitoba, told attendees during a press conference. “It is safe and effective when dosed properly. However, methotrexate does have the potential for significant liver toxicity, as well as infection, particularly for infectious organisms that are targeted by cell-mediated immunity, and tuberculosis is one of those agents. In various areas of the globe, TB is endemic, and it is quite a significant health population for the people in these regions.”
“Historically, there hasn’t been a lot of rheumatology capacity in many of these areas of the globe,” she added. “However, as that increases, there is going to be more and more people who are receiving methotrexate for rheumatic diseases that are high risk for developing tuberculosis or reactivating tuberculosis. Our current guidelines to not really address low-dose methotrexate in the context of TB adequately. There is a lot of information on biologics, but not so much on low-dose methotrexate.”
To analyze the published literature on the rates of tuberculosis among patients receiving less than 30 mg of methotrexate per week, Hitchon and colleagues searched the CINAHL, Embase, Global, MEDLINE and World of Science databases, as well citations from review articles. Focusing on January 1990 to May 2018, the researchers identified 4,707 reports that included the terms “methotrexate” and “tuberculosis.” These were then independently screened by two reviewers to find studies of tuberculosis among patients receiving methotrexate.
The reviewers assessed study quality using the McGill Mixed Methods Appraisal Tool, and withdrew data on tuberculosis incidence and outcomes, as well as the safety of isoniazid. In all, after removing duplicates and ineligible reports, Hitchon and colleagues included 31 studies in their analysis, including eight cohort, seven case-control, 15 case reports or series and one clinical trial. Just 27% of articles reported data from “low to moderate human development index countries,” and studies were of moderate quality, the researchers wrote.
According to the researchers, although the seven case control studies were heterogeneous, most demonstrated that methotrexate was associated with a “modest” increased risk for tuberculosis. Meanwhile, five of the cohort studies reported tuberculosis incidence rates in rheumatic disease — treated with methotrexate with or without biologics — ranging from 102 to 367.9 per 100,000 patient-years. These rates were generally higher than those in the general population, the researchers wrote. Two cohort studies — analyzing methotrexate in RA without biologics — demonstrated a cumulative tuberculosis incidence of 27% in Moldova and 7.9% in China.
Other cohort studies analyzed overt infection rates, including one example, reported in Spain, of 143 per 100,000 patient-years. Rates were higher if methotrexate was co-prescribed with corticosteroids and other immunosuppressants, which was reported in South Africa. Cohort studies also reported latent tuberculosis detection rates, including 1.7%, in Canada.
When reported, the rates of extra-pulmonary tuberculosis were higher than in the general population. One clinical trial in China, two cohort studies in Japan and the United States, and two case series in Belgium and the United States assessed safety of isoniazid and methotrexate. These reports found that isoniazid-related hepatotoxicity and neutropenia were generally more common when taken with methotrexate but were usually reversible.
“The literature we were able to find was actually rather sparse in this area,” Hitchon said. “Also, unfortunately, the majority of cases of reports were not from developing nations, which are more likely to have high rates of endemic TB, and a greater population at risk for TB. We really need to wait for more information from these high TB endemic areas. However, while we are waiting for those data to arrive, I think it is prudent for people who are managing patients who may be at a greater risk for TB, either because of somewhere they liver or where they traveled, that we should have a high suspicion for TB and consider screening for it as part of our workup in the course of initiating treatment like methotrexate.”
“We feel that this does have some practice implications, both globally as well as in some areas in North America in certain populations, and we will wait for more information from other people,” she added. “It is clear, though, that we need more information and recommendations on how to safely prescribe methotrexate in developing nations.”
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Hitchon C. Abstract 0223. Presented at: ACR Convergence 2020; November 5-9, 2020 (virtual meeting).
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