Incidence of Tuberculosis Among Korean Patients with Ankylosing Spondylitis Who Are Taking Tumor Necrosis Factor Blockers

MATERIALS AND METHODS

RESULTS

DISCUSSION

Per our results, the TNF blocker-naive AS cohort between 2002 and 2009 had a 4.3-fold higher risk of TB compared with that of the general population. Patients with rheumatic diseases are vulnerable to infections because of the intrinsic immune dysregulation associated with the disease processes, the immunosuppressive therapies used, and other associated comorbidities^10,11. After the introduction of TNF blockers, the incidence of TB increased significantly among patients with autoimmune diseases³. TNF-α is critical for the host immune response against intracellular bacteria, particularly TB^12,13, as this cytokine plays a central role in macrophage activation, cell recruitment to the sites of infection, granuloma formation, and the maintenance of granuloma integrity^14,15,16. Moreover, the release of TNF-α in response to TB infection is believed to have several beneficial effects. In vitro studies suggest that TNF-α promotes macrophage phagocytosis, thereby increasing mycobacteria destruction¹⁷ and inducing granuloma formation, all of which ultimately serve to sequester the invading mycobacteria and inhibit further dissemination¹³. Further, TNF-α-induced granuloma formation is important for survival after primary infection^18,19,20. In patients with latent tuberculosis infections (LTBI), iatrogenic TNF-α neutralization by monoclonal antibodies may result in the dissolution of intact granulomas, the release of viable mycobacteria, and disease reactivation²¹.

While the increased risk of TB in patients treated with TNF blockers has already been well established in reports from multiple countries^{4,5,22,23,24,25}, most data derive from studies of patients with RA who were treated with infliximab or etanercept. Our study, which focuses on patients with AS treated with TNF blockers, also reveals similar patterns to those seen in previous RA cohorts⁴. Compared with a TNF blocker-naive RA cohort in Korea⁴, the mean age (4th decade vs 6th decade), total percentage of patients with DM (1.3% vs 4.9%), and the percentage of patients treated with methotrexate (23.5% vs 93.6%) were all lower in our TNF blocker-naive AS cohort. These differences provide a possible explanation for why fewer TB cases occurred in our cohort than in the RA cohort.

Nonetheless, the risk of TB in the TNF blocker-naive AS cohort was found to be 4.3-fold higher than that in the general Korean population, especially among young individuals. While the exact cause for this discrepancy remains unclear, data from 1 prospective study²⁶ indicate that nonspecific sub-clinical pulmonary involvement (manifested as apical fibrosis, interstitial lung disease, bronchiectasis, or emphysema) occurs frequently in AS, particularly in early AS. Another recent retrospective analysis²⁷ also suggests that TB is the most frequent pulmonary infection in patients with AS and commonly presents with apical lung fibrosis. Still, the exact causal mechanism resulting in increased risk of TB among patients with AS remains unknown.

To identify specific risk factors of TB in patients with AS receiving TNF blockers, clinical characteristics from 919 TNF blocker-naive and 354 TNF blocker-exposed subjects were compared using a logistic regression analysis. However, no significant association (except HLA-B27 positivity) was identified between the 2 cohorts. We contend that this occurred because of the relatively small sample size and followup period, and strict TST surveillance for LTBI as well as appropriate anti-TB chemoprophylaxis, which likely further reduced the TB incidence rate in the TNF blocker-exposed AS cohort. Additionally, the most common TNF blocker prescribed was etanercept, accounting for 59% of all cases, and study participants taking etanercept had a TB incidence rate of zero.

In the infliximab-treated AS cohort, 1 of 2 TB cases showed positive TST conversion, progressing from an initial negative result to a strong reactive result (> 15 mm). This particular individual was treated with infliximab for 16 months, then miliary TB was diagnosed. Notably, the median time from the first infliximab dose to TB diagnosis was 21.5 months (range 16 to 27 mo), longer than the interval in other studies. In patients with RA, the median interval from initiation of infliximab treatment to LTBI reactivation was 3 months²⁸. We contend that the TB cases in our cohort may not have resulted from the reactivation of LTBI but instead represent the progression of new infections that occurred throughout treatment¹. In the adalimumab-treated AS cohort, 1 TB case had a history of pulmonary TB, which was later diagnosed as being in complete remission after a 6-month course of anti-TB medication. At the time of adalimumab initiation, this subject had undergone neither TST nor additional prophylactic TB treatment, as he had already finished a full course of anti-TB therapy. In this case, the median time from first adalimumab dose to TB diagnosis was 12 months. No cases of TB occurred in the etanercept-treated AS cohort. Our finding that etanercept is associated with a lower risk of TB compared to those of monoclonal antibodies supports most data from other RA cohort studies in Korea and other countries^4,5,23,25,29.

The different pharmacologic mechanisms of action among TNF blockers may account for the varying rates of LTBI, particularly between the 2 monoclonal antibodies and etanercept. Specifically, etanercept binds only trimeric soluble TNF (sTNF) and releases sTNF faster than do monoclonal antibodies. Conversely, both infliximab and adalimumab bind trimeric as well as monomeric sTNF, forming significantly more stable complexes. Moreover, etanercept binds sTNF and transmembrane TNF-α (tmTNF-α) at equal ratios, while monoclonal antibodies are able to bind both forms of TNF molecules at once^1,30. In particular, infliximab can bind tmTNF-α much more tightly than can the other agents, and facilitates macrophage and monocyte lysis through antibody- and complement-mediated cytotoxicity^13,16. Further, the effect of bolus dosing and high peak levels of infliximab may additionally increase the risk of infection^12,31. Accordingly, infliximab likely disturbs the host’s ability to suppress TB infection significantly more than do either of the other 2 agents¹².

According to the South Korean guidelines published in 2004³², all patients must be screened for LTBI by TST, chest radiography, physical examination, and interview prior to receiving TNF blocker therapy. Under these guidelines, patients exhibiting positive TST (defined as an area of induration with a diameter ≥ 10 mm) are recommended to receive isoniazid at a dose of 4 to 6 mg/kg/day for 9 months. Additionally, all patients with intermediate TST (defined as an area of induration between 5 mm and 10 mm) with a history of incompletely treated TB, untreated exposure to TB, or a documented episode of TB are also recommended to receive anti-TB chemoprophylaxis 1 month prior to starting TNF blocker therapy. Due to anergy to cutaneous delayed hypersensitivity resulting from deficient cell-mediated immunity (either from the underlying disease itself or because of immunosuppressive treatments)³³, patients with RA undergoing treatment with immunosuppressive agents often exhibited false-negative TST results³⁴. As such, a reactivation of LTBI has been increased in patients with RA treated with TNF blocker¹². In a recent study by Inanc, et al³⁵, patients with AS who were treated with immunosuppressive agents, as well as untreated patients, rarely showed false-negative TST results, compared with the results of similar populations of patients with RA. However, we previously reported that, even after starting TNF blocker therapy, the positive TST conversion rate was significantly higher in patients with AS than it was in patients with RA, which could represent either new TB infection or reactivation of LTBI³⁶. The TST has a low specificity as the PPD used for TST shares antigens with Bacillus Calmette-Guérin (BCG) and several nontuberculous mycobacteria (NTM)³⁷. Interferon-γ (IFN-γ) assays use antigens that are highly specific for M. tuberculosis and that are not present in NTM³⁸. As a result, IFN-γ assays are now suggested as supplementary tests for the diagnostic exclusion of LTBI in Korea, where BCG vaccination for newborn babies and children is still recommended^13,34,39,40.

Our study has several notable limitations. The study design was retrospective, without case control, and the patient data regarding smoking were incomplete. The rate of TB in the general population may not be accurate. It was reported by KNTA, which is dependent on the quality of the information and case reporting activities of the private sector. Additionally, the sample sizes were small and a longer followup period was needed. Nonetheless, our study represents some of the first research to specifically focus on the relative risk of TB among patients with AS treated with TNF blockers.

The risk of TB in Korean patients with AS was relatively lower than in Korean patients with RA, and higher than in the general Korean population. However, when the risk for TB was compared between the TNF blocker-exposed AS cohort and the TNF blocker-naive AS cohort, no significant difference was identified. These results were obtained partially through strict surveillance for LTBI with TST, chest radiography, and medical history, and through low usage of immunosuppressive drugs and a low rate of concomitant diseases with AS. Additionally, our data strongly suggest that, among patients with AS, etanercept is associated with a lower risk of TB infection compared with monoclonal antibodies. Given these data, TNF blockers seem relatively safe options for the treatment of AS if proper surveillance remains an essential prerequisite prior to starting TNF blocker therapy. Serial TST with adjuvant IFN-γ assays and proper anti-TB chemoprophylaxis would likely further reduce future reactivation of LTBI or new TB infections in Korean patients with AS.