Patients with rheumatoid arthritis (RA) are more susceptible to infection than other people.1 Patients treated with biologic disease-modifying antirheumatic drugs (bDMARDs), especially tumor necrosis factor (TNF) inhibitors, are at increased risk of developing tuberculosis (TB), predominantly via reactivation of latent tuberculosis infection (LTBI).2 LTBI is now recognized as an incipient phase of TB with a potential risk of progressing to active infection; consequently, it is seen as requiring treatment for greatest benefit.3 Accordingly, screening for LTBI is required to prevent TB infection in RA patients undergoing bDMARDs treatment.4

There are two widely used methods for diagnosing LTBI: the tuberculin skin test (TST) and the interferon gamma release assay (IGRA). The TST has long been used in LTBI diagnosis, and while it is very cost effective, it requires two clinic visits to get results. Also, false positivity caused by Bacillus Calmette–Guérin (BCG) vaccination and nontuberculous mycobacteria (NTM) infection and false negativity in immunosuppressed patients are drawbacks.5 On the other hand, the IGRA has relatively high specificity and is not affected by BCG vaccination status.6 Thus, it is more useful in countries with a high rate of BCG vaccination such as Korea though it is more expensive than the TST and requires a well-equipped laboratory and skilled technicians.7

The World Health Organization (WHO) published updated guidelines for LTBI management in 2018, recommending the TST and IGRA equally for LTBI diagnosis.8 In the Korean guidelines, the TST alone, IGRA alone, or a two-step TST/IGRA protocol are recommended for diagnosing LTBI in immunocompetent people.9 However, in immunocompromised patients, TST alone is not recommended; rather, IGRA alone or the two-step TST/IGRA is recommended.9 According to the 2017 Korean guidelines for TB, immunocompromised patients who are recommended to undergo LTBI treatment include patients with human immunodeficiency virus (HIV) and those who are initiating or using immunosuppressive drugs and TNF inhibitors.9 Apart from TNF inhibitors, bDMARDs are not discussed in the Korean guidelines; however, the American College of Rheumatology (ACR) recommends screening all RA patients for LTBI if they are being considered for receiving bDMARDs or tofacitinib10; in addition, IGRA test is recommended for patients with a history of BCG vaccination rather than TST.10

Tofacitinib is the first oral Janus kinase (JAK) inhibitor to be released. Studies have suggested that its administration leads to increased TB reactivation.1112 Thus, as with TNF inhibitor, LTBI screening and treatment are recommended prior to starting tofacitinib.1112 However, there is a lack of information about how LTBI screening and treatment affect the positivity rate and incidence of active TB in patients about to start tofacitinib treatment compared with patients about to start TNF inhibitors or other bDMARDs.

In this study, we examined whether the diagnosis and treatment of latent TB in RA patients are effective in Korea. We also estimated the risk of TB development by calculating the incidence rate of active TB among RA patients receiving targeted therapy.

In this study, we estimated that 26.5% of RA patients initiating bDMARD or JAK inhibitor treatment had LTBI. There was no significant difference in LTBI prevalence among the RA patients starting TNF inhibitors, non-TNF inhibitors, or JAK inhibitors. Most patients were appropriately treated according to the guidelines, and LTBI treatment was mainly with INH. Consequently, the active TB incidence rate during the first targeted therapy was low (63.6/100,000 PYs).

There have been 6 previous studies of LTBI prevalence and TB incidence in RA patients using bDMARDs in Korea,161718192021 and we conducted a literature review of those studies (Table 4). LTBI prevalence in RA patients ranged from 19.4% to 47.7% in those studies, compared with our 26.5% prevalence among all patients. TB incidence rates in previous studies (313.8–1,317.0 per 100,000 PYs) were higher than in our study in point estimates (63.6 per 100,000 PYs). It is possible that this low incidence, even with the relatively large numbers of patients, was because the study population was limited to first users of targeted therapy or because our institution screened and treated LTBI rigorously in accordance with clinical practice guidelines. It is important to note that the TB incidence rate has not increased recently, even though only IGRA has been used since the Korean guidelines for TB were released in 2017.

There was one case of active TB development in the TNF inhibitor group; this can be explained in two ways.

First, using a TNF inhibitor might create a higher risk of TB activation than using a non-TNF inhibitor or a JAK inhibitor, because there were no instances of active TB development in the latter groups. TNF inhibitors are known to facilitate LTBI progression to active TB by inhibiting phagosome maturation and inducing T-cell apoptosis, complement-dependent cytotoxicity, and antibody-dependent cell-mediated cytotoxicity, all increasing susceptibility to TB reactivation.22 On the other hand, it is not yet clear how JAK inhibitors increase the incidence of TB or other infections.23 However, non-TNF inhibitors or JAK inhibitors cannot be considered safer than TNF inhibitors based on our study because of the differences in LTBI positivity and follow-up duration between the groups. The positivity rates for IGRA test on its own were 21.7% (TNF inhibitor group), 31.6% (non-TNF inhibitor group), and 13.6% (JAK inhibitor group), indicating that RA patients who had been IGRA positive were more likely to have been treated with non-TNF inhibitors and least likely to have been treated with JAK inhibitors. Moreover, the follow-up duration for JAK inhibitor use was only 53.3 PYs, while that for bDMARDs was 1,519.9 PYs. Therefore, further long-term study of treatment safety is required to elucidate the risk of active TB development in JAK inhibitor users.

Second, the diagnostic performance of each LTBI screening test should be considered. One patient who developed active TB was negative on the IGRA and equivocal on the TST with an induration of 10 mm. This raises the question of whether it is appropriate to not treat LTBI in patients who are shown to be negative by IGRA alone. According to the current Korean guidelines for TB published in 2017, patients initiating TNF inhibitors can be diagnosed with LTBI by the TST/IGRA two-step test or IGRA alone, which is the same as for immunocompromised patients.9 As many studies continue to confirm the efficiency of the IGRA, an increasing number of patients undergo IGRA alone for LTBI screening.1619 Although the agreement between TST and IGRA results is moderate or low,24252627 LTBI screening based on IGRA can sufficiently lower TB incidence, as this study demonstrates. Further research is needed regarding screening for LTBI with the TST/IGRA two-step test versus IGRA alone. There should also be renewed debate regarding the need to repeat LTBI screening to identify newly developed TB infection in patients using TNF inhibitors, non-TNF inhibitors, and JAK inhibitors for long durations.28

Of the 197 patients who received LTBI treatment, 196 received INH monotherapy. INH is a major drug in LTBI treatment, but the long regimen duration (6–9 months) reduces compliance.2930 Although INH treatment is associated with liver-function test abnormalities, our previous work showed that it does not lead to discontinuation of bDMARDs.31 In the present study, none of the patients who received INH monotherapy developed active TB. This means that INH monotherapy is effective as an LTBI treatment, but further research is needed on the long-term effects in patients receiving targeted therapy, especially patients who received sequential treatment with bDMARDs and JAK inhibitors.

Our study has several limitations. First, the observation period was limited to the period when the first bDMARD or JAK inhibitor was used. A short observation period, especially for JAK inhibitors, might have resulted in measuring a low active TB incidence. However, in previous studies, the median times between TB infection and treatment with bDMARDs and JAK inhibitors in RA patients were 7.9 months (95% CI, 4.0–36.1) and 64 weeks (range, 15–161), respectively.1129 Thus, the results from this study are still valuable. The safety of JAK inhibitors should be evaluated in a future study where long-term data are collected. Second, patients often receive more than one bDMARD or JAK inhibitor, but that was not reflected in this study. Further research is needed on how sequential treatment with bDMARDs and JAK inhibitors and continuous exposure to these substance affects TB activation. Third, it is difficult to generalize from our results because data were collected from a single institution, which may have introduced a selection bias that influenced active TB incidence.

In conclusion, TB incidence in RA patients receiving TNF inhibitor, non-TNF inhibitor, or JAK inhibitor treatment was low. LTBI screening and treatment with INH according to the Korean guidelines are appropriate. However, further study is needed to evaluate the efficacy of IGRA on its own for screening LTBI, and to evaluate the long-term risk of TB development in patients who use JAK inhibitors.