Screening, prophylaxis, and challenges: Tumor necrosis factor inhibitors and latent tuberculosis infection nexus in rheumatology

In recent years, the application of tumor necrosis factor inhibitors (TNFi) has brought disruptive changes to the treatment of rheumatic diseases (RDs). The application of biological therapy represents a milestone in the tremendous progress of precision medicine. Due to the rapid advances in RD's etiology, it has been wildly reported that TNF-α is involved in the pathogenesis of several inflammatory RDs such as rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis, vasculitis, and inflammatory bowel diseases, and soon TNFi was developed for the treatment of such RDs. Subsequently, in randomized controlled clinical trials (RCTs) and real-world studies (RWS), these agents have been shown to effectively control symptoms and allow return to function in a variety of RDs.1 Nowadays, the application of TNFi takes a significant role in the treat-to-target strategy of RA and the recommendation of AS, especially to patients who are difficult to attain remission through disease-modifying anti-rheumatic drugs (DMARDs).2, 3 However, opportunities often come with challenges, and the clinical application of TNFi also brings a series of new problems, such as infections and carcinomas. The increased risk of tuberculosis (TB) infection caused by Mycobacterium tuberculosis (Mtb) is one of the most crucial issues faced by TNFi applications. Because TNF-α is integral in controlling active TB, as well as in the formation and homeostasis of multinucleated giant cells,4 there is a well-characterized increase in TB risk for patients with RD who are prescribed TNFi, even fatal disseminated tuberculosis.5 Meanwhile, studies have shown that TB infection related to TNFi application meanly resulted by the reactivation of latent tuberculosis infection (LTBI) rather than new infections.5, 6 LTBI refers to the sustained immune response state stimulated by Mtb antigen, without evidence of active TB clinical manifestations, and the reactivation of LTBI is closely related to the immune state of the body. LTBI reactivation is associated with poor prognosis and significant mortality, and additionally come with a substantial cost-burden for healthcare systems largely due to additional treatment and hospitalization needs. Furthermore, the treatment of RDs may also need to be put on hold when TB infections occur.7 Under such conditions, preventing LTBI reactivation becomes an important part of TNFi application, mainly including two aspects: LTBI screening and preventive anti-tuberculosis treatment. However, although recommendations for LTBI screening and prophylaxis in patients planning to be treated with TNFi have been proposed in several countries and regions,7, 8 few patients still experience the reactivation of LTBI and poor prognosis, including both positive and negative LTBI testing.9 Therefore, it is anticipated to address current issues and conduct further research to optimize recommendations. For RD patients who choose to apply TNFi, LTBI screening is an important step to prevent active TB. At present, because there is no gold standard for LTBI diagnosis, the collection of high-risk Mtb exposure history and screening experiments for Mtb are both crucial. Currently, there are two commonly used tests to detect LTBI, tuberculin skin test (TST) and interferon-γ release assay (IGRA). Both these tests detect the presence of immunological memory of T cells exposed to the Mtb and none of them are perfect. The result of TST could be interfered by the previous BCG vaccination, and the use of DMARDs and glucocorticoids with affected sensitivity and specificity. IGRA is more expensive with higher specificity, but TNFi application can also lead to false negative.10 At present, there is few research exploring the specific mechanisms of immunosuppressive therapy's affection toward the results of LTBI screening. Some studies suggest that the effects of immunosuppressive and immunomodulatory therapy on T cells may lead to false-positive and false-negative results of TST and IGRA.11 Further research on how immunosuppressive therapy interacts with LTBI screening may be important for optimizing strategies. Further researches and explorations of optimizing screening strategies for LTBI are also an enlightening direction due to both sensitivity of test remaining about 77%.12 Some studies have begun to explore the above directions: a Spain cohort study showed that a dual screening strategy with TST and IGRA before TNFi treatment is more effective. Compared to one single screening test, dual screening can detect more LTBI patients.13 A British group subsequently endorsed a “triple testing” approach using a combination of risk strategy according to the British Thoracic Society guidelines, TST, and IGRA to achieve maximum sensitivity.14 In addition, the recombinant Mtb fusion protein (EC test) developed in recent years has provided a new detection method with higher accuracy,15 but there have been no reports about its accuracy on application in RD patients. It must be pointed out that LTBI screening before starting TNFi treatment does not always correctly identify patients who are at a risk of reactivation. A study in South Korea showed that 3.1% of the LTBI-negative patients developed active TB after using TNFi.16 Optimizing and layering the screening strategy for LTBI, fully considering the “pyramid” screening model of health economics, and improving the sensitivity and specificity of LTBI screening in the RDs patient may be a more beneficial direction. Moreover, it must also be considered that it could be more appropriate to develop LTBI screening strategies for RD patients based on different countries and regions. Areas with a high TB burden mainly include India, Indonesia, and China, more accurate screening strategy in the aforementioned regions may be further advantageous in preventing TNFi application-associated LTBI reactivation. It is encouraging that in China and India, there has been proposed regionally specific recommendations for LTBI flare screening and treatment.17, 18 For example, in India recommendation, for BCG-non-vaccinated patients TST is recommended, for BCG-vaccinated patients, immunocompromised patients, and patients on immunosuppressive therapy, IGRA is recommended17; while in Chinese recommendation, both TST and IGRA are recommended.18 RD patients with positive LTBI screening should undergo careful testing for active TB. After excluding active TB, both the WHO and the CDC of USA recommend starting the application of TNFi after 3–4 weeks of preventive treatment for TB in advance if the clinical condition allows.19, 20 Some scholars have also proposed that if the condition is urgent, TNFi and preventive treatment can be initiated simultaneously after thorough evaluation.21 There is currently no consensus on the span and plan of preventive treatment for TB. In principle, isoniazid and rifampicin monotherapy or combination therapy can be used, the combination of isoniazid and rifampicin for 3–4 months could be more recommended, especially in patients with exposure to infectious TB patients, or in patients who seroconvert (conversion of TST/IGRA from negative to positive). Compared to isoniazid/rifampicin monotherapy, combination therapy can shorten the treatment time and achieve higher treatment completion rates.21 Although expert comments proposed that after proper LTBI screening, proactive TB therapy has been demonstrated to be effective and well-tolerated to reduce the risk of TB reactivation in RD patients requiring TNFi,22 there are still case reports of TB reactivation and subsequent poor prognosis in patients with preventive treatment.23 In addition, as mentioned earlier, LTBI screening before starting biological therapy may not always accurately identify patients at risk of TB reactivation, and the implementation of LTBI screening in RD patients does not seem to be as well as expected. A longitudinal study in Japan showed that despite the guideline recommendations being widely emphasized, 32% patients received neither TST/IGRA screening nor LTBI treatment before TNFi application.24 On the other hand, the measurement of pretreatment biomarkers, such as inflammatory cytokine levels, is valuable for prediction of treatment efficacy to TNFi.25 Exploration of new biomarkers maybe beneficial for the anticipation of LTBI and prediction of preventive treatment for TB. Therefore, we believe that the conduction of multicenter and large-scale RWS or open-label clinical trials for LTBI screening and TB preventive treatment evaluation to assess LTBI reactivation in RD patients with TNFi applications is of great significance for further optimizing expert recommendations for LTBI diagnosis and treatment in RD patients, at least in countries and regions with high TB burden. Based on current research and data, one cannot predict with certainty which patients will develop active TB during TNFi therapy despite preventive treatment or not. A more in-depth investigation of environmental factors and exploration of biomarkers and pathogenesis may be beneficial for risk stratification and subsequent precise treatment. Taken together, RD with LTBI is an important subgroup in autoimmune disorders, the clinical needs of which have not yet been met (Figure 1). Due to the complexity of RD's clinical process, the high incidence of LTBI in population and the widespread application of TNFi, the reliability of LTBI screening, the effectiveness of preventive treatment for TB, and the possibility of early recognition of TB reactivation are still unresolved issues, and are also promising research directions. More targeted researches on RD with LTBI are expected to provide theoretical supplements, enrich guidelines, and achieve precise treatment and effective disease management. All authors met the authorship criteria; they had a substantial contribution to the conception or design of the work (Kaisheng S, Ximeng L, and Yifang M) or the acquisition (Kaisheng S, Zhenyu J, and Yifang M) or interpretation of data for the work (all authors) and were involved in revising a draft of this work, gave final approval of this version to be published, and are accountable for all aspects of the work in ensuring accuracy and integrity. Our research was financed by Shenzhen Science and Technology Innovation Commission and Shenzhen Clinical Research Center for Tuberculosis. We are also grateful to editors and reviewers of IJRD for their constructive advices. Funding of Shenzhen Science and Technology Innovation Commission (JCYJ2021032413181). None declared. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.