Tuberculosis screening needed for methotrexate users in at-risk locales

November 06, 2020

ATLANTA -- New research presented at ACR Convergence, the American College of Rheumatology's annual meeting, shows that tuberculosis (TB) screening and ongoing clinical care is needed for people on methotrexate who live in areas where the highly infectious illness is common. Methotrexate users who also take corticosteroids or other immunosuppressant therapies are at particular risk and need adequate TB screening.

Methotrexate is one of the most effective and commonly used medications in the treatment of rheumatoid arthritis and other forms of inflammatory arthritis in both adults and children. Methotrexate is part of a group of arthritis treatments called disease-modifying antirheumatic drugs (DMARDs).

Methotrexate effectively control rheumatic diseases and more people around the world are being prescribed this treatment. In many areas, TB is endemic and a serious health risk for local populations. Since methotrexate suppresses a person's immune system, the researchers wanted to know if they are at increased risk of TB infection. Current guidelines for the management of rheumatic diseases do not address TB risk for people who take methotrexate. To learn more, researchers in Canada conducted a systematic review of published literature on TB rates among people who take less than 30 milligrams of methotrexate per week.

"Methotrexate is the foundation medication for treatment of many rheumatic diseases, especially rheumatoid arthritis (RA). Our concern is that methotrexate can affect cell-mediated immunity, which may increase susceptibility to infections, including tuberculosis," says the study's co-author, Carol Hitchon, MD, Associate Professor of Medicine at the University of Manitoba. "TB is endemic across Africa and other parts of the world. Existing guidelines do not address the possible increased risk of TB in these areas. As one step in developing recommendations for the use of methotrexate intended for these areas, we wanted to review the literature on methotrexate use, and the incidence and new diagnosis of TB in people taking methotrexate."

The researchers reviewed published studies from January 1990 to May 2018 that contained the words methotrexate and tuberculosis, as well as citations from review articles. They identified titles, abstracts or full manuscripts from 4,707 different reports, which were then independently screened to pull out studies on TB in patients taking methotrexate. They collected data on TB incidence, or new TB diagnosis versus reactivation of latent TB infection; TB outcomes, such as pulmonary symptoms, dissemination and death; and the safety of isoniazid, the antibiotic used to treat TB. After removing duplicates and studies with insufficient information, 31 moderate-quality studies were used for the review. Only 27% reported data from low to moderate human development index countries.

Based on the case control studies, the review showed that there is a modest increased risk of TB for patients on methotrexate, and that rates of TB in people with rheumatic disease who are treated with either methotrexate or biologic drugs are generally higher than the general population. Two cohort studies reported TB incidence in Moldova and China, where the disease is endemic. They showed 12 TB cases in 44 patients in Moldova and nine cases in 114 patients in China. Based on other studies on TB infection rates in countries like Spain, South Africa and Canada, the researchers found that infection rates were higher if patients were prescribed methotrexate along with corticosteroids or other immunosuppressants. They also found that methotrexate users had higher rates of TB that was extra-pulmonary, or disease that spreads beyond a patient's lungs, compared to the general population.

Five studies from China, the U.S., Japan and Belgium all evaluated the safety of using methotrexate and isoniazid together. Based on this data, the researchers found that isoniazid-related liver toxicity and neutropenia, or low white blood cell count, were more common when people took the antibiotic along with methotrexate, but these effects were usually reversible.

"This work has important implications for physicians using methotrexate in areas of the world with high rates of TB and for travelers returning from regions with high TB rates," says Dr. Hitchon. "TB reactivation should be considered for anyone with possible prior TB exposure. This is especially true for patients who are also on steroids. Overlapping toxicity profiles, such as liver toxicity, for methotrexate with TB treatments indicate a need for close monitoring."
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About ACR Convergence

ACR Convergence, the ACR's annual meeting, is where rheumatology meets to collaborate, celebrate, congregate, and learn. Join ACR for an all-encompassing experience designed for the entire rheumatology community. ACR Convergence is not just another meeting - it's where inspiration and opportunity unite to create an unmatched educational experience. For more information about the meeting, visit https://www.rheumatology.org/Annual-Meeting, or join the conversation on Twitter by following the official hashtag (#ACR20).

About the American College of Rheumatology

The American College of Rheumatology (ACR) is an international medical society representing over 7,700 rheumatologists and rheumatology health professionals with a mission to empower rheumatology professionals to excel in their specialty. In doing so, the ACR offers education, research, advocacy and practice management support to help its members continue their innovative work and provide quality patient care. Rheumatologists are experts in the diagnosis, management and treatment of more than 100 different types of arthritis and rheumatic diseases.

ABSTRACT: Safety of Low Dose Methotrexate (MTX) and Tuberculosis (TB)

Background/Purpose: Increased awareness of the importance of MTX in rheumatic disease is leading to more MTX use in patients from TB-endemic areas. Current management guidelines for rheumatic disease address TB in the context of biologics but not MTX use. We aimed to systematically review the published literature on TB rates with MTX < 30 mg per week.

Methods: We searched CINAHL, Embase, Global, MEDLINE and World of Science databases (Jan 1990 to May 2018) for terms including 'methotrexate' and 'tuberculosis'. We also searched citations from review articles. Titles, abstracts or full manuscripts of the 4707 reports identified were screened independently by 2 reviewers to identify studies reporting TB in patients taking MTX. Study quality was assessed using the McGill Mixed Methods Appraisal Tool (MMAT). Data was extracted on TB incidence (new TB diagnosis vs reactivation of latent TB), and outcomes (pulmonary, dissemination, death) and safety of isoniazid, INH. Descriptive summaries are presented on studies providing outcomes in patients taking MTX < 30 mg per week.

Results: After removing duplicates and studies not meeting criteria or providing sufficient information, 31 studies were included (8 cohort, 7 case-control, 1 clinical trial, 15 case reports/case series). Only 27% of articles reported data from low to moderate human development index countries. Studies were of moderate quality. Seven case control studies were heterogeneous but most demonstrated a modest increased risk of TB with MTX (Table). Five cohort studies reported TB incidence rates in rheumatic disease (treated with MTX +/- biologics) ranging from 102-367.9/100,000 patient-years. These rates were generally higher than comparator general population rates. Two cohort studies of MTX in RA (without biologic) reported cumulative TB incidence in Maldova (12 TB cases in 44 RA patients, 27%) and in China (9/114, 7.9%). Other cohort studies generated rates of overt infection (143/100,000 patient years in Spain, higher if co-prescribed with corticosteroids and other immunosuppressants in South Africa), and latent TB rates detection (16/922 RA screened, 1.7%, in Canada). When reported, rates of extra-pulmonary TB were higher than comparator general population rates. One clinical trial (China), 2 cohorts (Japan, USA) and 2 case series (Belgium, USA) evaluated safety of INH and MTX. Isoniazid-related hepatotoxicity and neutropenia were generally more common when taken with MTX but were usually reversible.

Conclusions: Despite a paucity of high-quality data, this review confirms that TB screening and clinical surveillance are needed in patients from TB-endemic areas who are prescribed MTX, particularly with co-administration of corticosteroids or other immunosuppressants. Isoniazid, if monitored, appears safe and prevents TB reactivation.

American College of Rheumatology

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