Q&A: Methotrexate and Tuberculosis

Carol A Hitchon, M.D., FRCP

Tuberculosis screening and ongoing clinical care is needed for patients prescribed methotrexate, particularly if co-administered with corticosteroids or other immunosuppressants, who live in areas where tuberculosis is common, according to researchers recently reporting at the annual meeting of the American College of Rheumatology.

In this Q&A, co-author Carol Hitchon, M.D., associate professor of medicine at the University of Manitoba in Winnipeg, Canada, highlights the findings of this systematic review.

The review included 31 studies published from January 1990 to May 2018. Data from the case control studies included in the review indicated that there was a modest increased risk of tuberculosis for patients on methotrexate. Additionally, tuberculosis rates in people with rheumatic disease who were prescribed either methotrexate or biologic drugs were generally higher than the general population. Two cohort studies showed 12 tuberculosis cases in 44 patients in Moldova and nine cases in 114 patients in China, where the disease is endemic.

Meanwhile, studies from other countries such as Spain, South Africa and Canada showed that infection rates were higher if patients were prescribed methotrexate along with corticosteroids or other immunosuppressants. Additionally, methotrexate users had higher rates of tuberculosis that was extrapulmonary compared with the general population. Meanwhile, studies from China, the United States, Japan and Belgium indicated that isoniazid-related liver toxicity and neutropenia were more common when patients took the antibiotic with methotrexate, but these effects were usually reversible.

Why was the review conducted?

Methotrexate is the cornerstone of treatment for rheumatoid arthritis. Methotrexate is effective and safe when used appropriately but can increase the risk of some infections that are targeted by cell-mediated immune responses which are important for some infections in particular tuberculosis.

Tuberculosis is highly prevalent in many areas of the world including Africa and poses a significant health problem. The World Health Organization states tuberculosis is among the top 10 causes of death and a leading cause of death due to infection.

As more people are recognized to have rheumatic diseases for which methotrexate is the optimal treatment, more people who are at high risk for tuberculosis infection will receive methotrexate. There is still uncertainty regarding the safety of methotrexate use in the setting of tuberculosis and few guidelines address this question. As a first step to developing recommendations for using methotrexate in these areas, we sought to determine the risks of methotrexate in the setting of tuberculosis. We did this by systematically reviewing the published literature.

What were the surprises in the findings?

After searching the literature, we found that there is a modest but increased risk of tuberculosis even with low dose methotrexate. Tuberculosis infection rates in people on low dose methotrexate were generally higher than those on the general population. Tuberculosis risk was highest in setting of other immunosuppression like prednisone(prednisone is known to increase the risk of general infections).

Isoniazid, which is used in the treatment of tuberculosis infection and latent tuberculosis, led to abnormal liver tests, but these were usually transient.

However, there were not many studies, some were relatively small, and very few were from Africa where tuberculosis is highly prevalent.

How significant are the findings?

For people starting low dose methotrexate who are at high risk for tuberculosis, based on where they live or travel, tuberculosis screening is important. The (modest) increase risk indicated by the studies we reviewed translates into a very large number of people potentially at risk.More studies from regions which have high tuberculosis prevalence, like Africa, are needed in order to fully evaluate the effect of methotrexate on tuberculosis and tuberculosis treatment. This is needed to inform guidelines for methotrexate use intended for resource poor regions with high tuberculosis prevalence like many countries in Africa.

What is the current practice and how could the results from your review possibly change this?

The ACR guidelines from 2008 recommend avoiding methotrexate in latent or untreated tuberculosis. This implies a need to screen for tuberculosis. The most commonly used methods available for screening tuberculosis may not be practical in regions with high rates of tuberculosis and/or limited resources. It is not clear how long to wait before starting methotrexate in someone being treated for latent or active tuberculosis.

What are the takeaway points from your findings for clinicians?

The findings are very important for rheumatologists or other clinicians who care for people at high risk of tuberculosis. For people starting low dose methotrexate who are at high risk for tuberculosis, based on where they live or travel, tuberculosis screening is important.

We know tuberculosis screening is important prior to using biologics but this review reminds us that we should not ignore the risk when prescribing methotrexate (particularly when used with prednisone).

While tuberculosis may not be common in some regions of the globe, it remains a significant health risk in many developing countries.

Do you have anything else to add?

More well-designed studies from regions which have high tuberculosis prevalence, like Africa, are needed in order to fully evaluate the effect of methotrexate on tuberculosis and tuberculosis treatment. This is needed to inform guidelines for methotrexate use intended for resource poor regions with high tuberculosis prevalence like many countries in Africa.

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REFERENCE

ABSTRACT: 0223. “Safety of Low Dose Methotrexate (MTX) and Tuberculosis (TB).”The annual meeting of the American College of Rheumatology.11:00 AM, Friday, Nov. 6, 2020.