Conference Coverage

Methotrexate users need tuberculosis tests in high-TB areas


People taking even low-dose methotrexate need tuberculosis screening and ongoing clinical care if they live in areas where TB is common, results of a study presented at the virtual annual meeting of the American College of Rheumatology suggest.

Coauthor Carol Hitchon, MD, MSc, a rheumatologist with the University of Manitoba in Winnipeg, who presented the findings, warned that methotrexate (MTX) users who also take corticosteroids or other immunosuppressants are at particular risk and need TB screening.

Current management guidelines for rheumatic disease address TB in relation to biologics, but not in relation to methotrexate, Dr. Hitchon said.

“We know that methotrexate is the foundational DMARD [disease-modifying antirheumatic drug] for many rheumatic diseases, especially rheumatoid arthritis,” Dr. Hitchon noted at a press conference. “It’s 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 TB is one of those agents.”

Using multiple databases, researchers conducted a systematic review of the literature published from 1990 to 2018 on TB rates among people who take less than 30 mg of methotrexate a week. Of the 4,700 studies they examined, 31 fit the criteria for this analysis.

They collected data on tuberculosis incidence or new TB diagnoses vs. reactivation of latent TB infection as well as TB outcomes, such as pulmonary symptoms, dissemination, and mortality.

They found a modest increase in the risk of TB infections in the setting of low-dose methotrexate. In addition, rates of TB in people with rheumatic disease who are treated with either methotrexate or biologics are generally higher than in the general population.

They also found that methotrexate users had higher rates of the type of TB that spreads beyond a patient’s lungs, compared with the general population.

Safety of INH with methotrexate

Researchers also looked at the safety of isoniazid (INH), the antibiotic used to treat TB, and found that isoniazid-related liver toxicity and neutropenia were more common when people took the antibiotic along with methotrexate, but those effects were usually reversible.

TB is endemic in various regions around the world. Historically there hasn’t been much rheumatology capacity in many of these areas, but as that capacity increases more people who are at high risk for developing or reactivating TB will be receiving methotrexate for rheumatic diseases, Dr. Hitchon said.

“It’s prudent for people managing patients who may be at higher risk for TB either from where they live or from where they travel that we should have a high suspicion for TB and consider screening as part of our workup in the course of initiating treatment like methotrexate,” she said.

Narender Annapureddy, MD, a rheumatologist at Vanderbilt University, Nashville, Tenn., who was not involved in the research, pointed out that a limitation of the work is that only 27% of the studies are from developing countries, which are more likely to have endemic TB, and those studies had very few cases.

“This finding needs to be studied in larger populations in TB-endemic areas and in high-risk populations,” he said in an interview.

As for practice implications in the United States, Dr. Annapureddy noted that TB is rare in the United States and most of the cases occur in people born in other countries.

“This population may be at risk for TB and should probably be screened for TB before initiating methotrexate,” he said. “Since biologics are usually the next step, especially in RA after patients fail methotrexate, having information on TB status may also help guide management options after MTX failure.

“Since high-dose steroids are another important risk factor for TB activation,” Dr. Annapureddy continued, “rheumatologists should likely consider screening patients who are going to be on moderate to high doses of steroids with MTX.”

A version of this article originally appeared on

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