Leflunomide is a disease-modifying antirheumatic drug (DMARD) that has been widely and successfully used in the treatment of rheumatoid arthritis (RA) for over 20 years. Its positive effect lies in its anti-inflammatory and immunomodulatory properties, through its active metabolite, teriflunomide, which inhibits the de novo synthesis of pyrimidine nucleotides and, at the same time, inhibits tyrosine kinase-type enzymes responsible for intracellular signaling in T and B cells, resulting in a decreased proinflammatory response, predominantly TH1 and TH17, in which tumor necrosis factor (TNF), IFN-γ, IL-12, and IL-15 play key roles in RA.

A regulated activity of these molecules is crucial in the immune response against bacterial pathogens, among which Mycobacterium tuberculosis is one of the most representative, as it is an intracellular microorganism capable of remaining latent and reactivating under treatments that may alter the normal immune response.

The use of leflunomide as monotherapy or in combination with other drugs, such as methotrexate and corticosteroids, has increased in RA patients with moderate to high disease activity as a good alternative before considering biological therapy, offering favorable clinical improvement at a lower cost. In fact, it has been shown that combining synthetic DMARDs can produce a response similar to low-dose rituximab without an increase in serious infections or significant adverse events. Therefore, it is a viable option in regions where access to other disease-modifying therapies is limited. The risk of TB reactivation in patients treated with methotrexate and leflunomide has been reported to be less than 1% in some registries, allowing for the implementation of a relatively safe therapy.

In Colombia, on November 24, 2016, INVIMA (National Institute for the Surveillance of Medications and Food) shared data from its databases, as well as recommendations published by Brazil’s National Health Surveillance Agency (ANVISA), indicating the possibility of TB activation or reactivation in patients under treatment with leflunomide. Other agencies, such as the EMA (European Medicines Agency) and the FDA (Food and Drug Administration), have also suggested an increased risk of TB development; however, they do not provide a clear recommendation regarding active screening for tuberculosis in patients about to start or currently taking leflunomide. According to the American College of Rheumatology (ACR), leflunomide should be discontinued in cases of active bacterial infections, including tuberculosis, unless the TB is latent when treatment begins.

In a Colombian study evaluating adverse effects associated with synthetic DMARD therapy in RA patients, an incidence of 4.9 adverse events per 100 patient-years was reported for leflunomide, with gastrointestinal events and hepatitis being the most common. There was no clear increase in infection risk, either for monotherapy or when combined with methotrexate. However, other reports have shown a significant association, with an odds ratio (OR) of 6.02 (CI 1.47–24.65) for TB reactivation in patients exposed to leflunomide. Additionally, case reports have noted associations between leflunomide and the reactivation of nontuberculous mycobacteria.

The risk of active TB in this population is influenced not only by pharmacological treatment but also by other patient-related risk factors, such as a history of chronic lung disease (regardless of etiology), smoking, or primary or acquired immunodeficiencies. Observational studies indicate that the risk of developing TB while using leflunomide and methotrexate increases up to fourfold in individuals over 65 years of age, especially in countries with a high prevalence of TB. Although leflunomide has been identified and proposed in other reviews as a possible reactivation agent, only one case of active TB was found in the subgroup with latent TB in this patient population. Notably, the patient who developed TB had additional risk factors: ongoing immunosuppressive treatment with anti-TNF biologics, RA duration over 10 years, and a history of smoking.

This may suggest that not all patients about to begin leflunomide treatment require active screening for latent or active TB. However, in higher-risk populations, prior imaging and latent TB testing should be considered, especially in individuals living in endemic regions. Screening is also recommended in individuals with household contacts diagnosed with TB, a history of chronic lung disease, or imaging findings suggestive of active infection. Likewise, studies should be conducted in patients receiving concurrent treatment with moderate to high doses of corticosteroids or other immunomodulatory therapies, both biological and non-biological.

The ACR does not provide a clear recommendation regarding TB screening before initiating methotrexate or leflunomide therapy. However, other rheumatology societies do recommend this practice, particularly for methotrexate. While recommendations for TB screening in patients starting synthetic DMARD therapy vary in different reports, decisions should be individualized. If a patient has clinical symptoms or imaging suggestive of TB, screening is mandatory, due to the potential impact on complications and survival in RA patients.

This study is limited by its observational design and the fact that it focuses on a case series review. However, such studies can play a key role in detecting epidemics by reporting one or more cases or documenting outbreaks of new or previously controlled diseases. They are also useful for describing rare conditions and may serve as the starting point for further investigation.

The findings observed in our case series should be evaluated in an analytical study that allows for control of confounding variables and development of an association and multivariate model. This would help identify the true risk of TB related to leflunomide exposure and enable the development of a solid recommendation regarding TB screening in this patient population.