With the clinical use of anti-TNF agents, significant progress has been made in the treatment of many autoinflammatory diseases, especially rheumatologic diseases. It has been reported that the widespread use of anti-TNF drugs increases the risk of mycobacterial infections, especially tuberculosis (TB), and bacterial, viral and fungal infections. Especially in countries with a high prevalence of tuberculosis, reactivation of latent tuberculosis infection poses an important problem for anti-TNF therapy. In the report of the World Health Organization (WHO), the incidence of TB in Turkey was reported to be 16/100.000, and the risk of TB development was reported to be 10-20 times higher in the use of Anti-TNF biological agents (5,10). Currently, a Guideline for Tuberculosis in Patients Using Anti-TNF Therapy was published by the Public Health Agency of the Ministry of Health, Turkey in 2016(9). According to this; all patients for whom TNF-alpha inhibitor treatment is decided are screened for LTBI with TST or IGRA before receiving Anti TNF-alpha treatment. In our study, LTBI was found in 17 (14.8%) of 115 cases. Similarly, in a study conducted by Kılıç et al. with 144 children receiving anti-TNF in our country, they reported the rate of LTBI as 4.8%(13). Girit et al. reported the rate of LTBI before treatment as 28.1% in their study with 57 cases(14).
There are different recommendations in different guidelines regarding the method of screening for LTBI in patients receiving anti-TNF therapy, and what should be the cut-off value taken, especially for TST. While the cut-off value for TST was ≥5 mm in the American Thoracic Society guideline published in 2017, the cut-off value was recommended as ≥10 mm in the consensus report of The Tuberculosis Network European Trials Group(15,16). In our country, the Rheumatism Research and Education Association (RAED) recommended the TST cut-off value as 5 mm for adults and children(17). In the Tuberculosis Guidelines for Patients Using Anti-TNF Therapy, which was recently updated by the Ministry of Health, Public Health Agency of Turkey, the cut-off value is recommended as ≥10 mm for pediatric patients with BCG vaccine and ≥5 mm for those who have not been vaccinated(9). It has been stated that concomitant rheumatic and autoimmune diseases and other immunosuppressive drugs used concurrently may affect the results of TST and IGRA used for detection of tuberculosis development and LTBI(9). In our study, all cases were screened primarily with TST, and the cut-off value was ≥10 mm for those vaccinated with BCG and ≥5 mm for those who were not vaccinated. TST value was ≥10 mm in 15 of 17 patients with LTBI diagnosis and INH prophylaxis was started, while TST was ≥5 mm in 1 patient (patient 13) and TST was 1 mm in 1 patient (patient 16). Since the TST=5 mm case had no BCG scar and the TST=1 mm case had positive IGRA test, which was studied simultaneously, INH prophylaxis was given to 2 cases for 9 months.
Different rates have been reported in studies conducted in many different countries and centers in terms of the risk of developing active tuberculosis in patients receiving anti-TNF therapy. Kilic et al. reported that tuberculosis developed in 1 (0.69%) of 144 pediatric patients receiving anti-TNF therapy(13). Similarly, the rate of tuberculosis development was reported as 0.85% by Çağatay et al., and 1.5% by Hanta et al(18,19). Contrary to these studies, Girit et al. and Kurt et al. reported that tuberculosis did not develop in any of the patients receiving anti-TNF(14,20). Conflicting results have been reported in studies examining the benefit of prophylaxis for LTBI. In the study of Börekçi et al., the development of TB in cases receiving anti-TNF treatment did not differ significantly between the groups that received and did not receive INH prophylaxis (12). In the study of Kaptan et al., active tuberculosis developed in 7 of 389 cases who received anti-TNF treatment, and they reported that all cases received INH prophylaxis (21). In a multicenter study which is conducted by Noguera-Julian et al., they reported that out of 19 cases who developed tuberculosis, 15 were previously screened for LTBI and 1 case was under INH prophylaxis(22). In our study, although 17 cases received INH prophylaxis for LTBI, none of our patients developed active tuberculosis. The absence of a case of TB in our study was attributed to the fact that all cases were screened appropriately for LTBI and the administration of INH prophylaxis with patients’ compliance in necessary cases reduced the risk of TB.
In previous studies, it has been shown that the risk of tuberculosis development is different depending on the primary disease and the type and duration of use of the Anti-TNF agent. In a study evaluating the incidence of TB in 10,000 patients who received anti-TNF therapy in the UK, it was shown that TB development was higher on adalimumab (144/100,000) and infliximab (136/100,000) treatments compared to etanercept (39/100,000) (23). Active TB can be seen in an average of 13.6 months after etanercept treatment is started, and 5.5 months and 18.5 months after infliximab and adalimumab treatment, respectively (23). This is also due to the effect of infliximab on the elimination of granulysin-expressing CD45RA+ subgroups of effector memory CD8+ T cells, which are involved in the intracellular killing of M. tuberculosis (24,25). In another study evaluating chronic disease and TST response, the lowest response was observed in RA patients, while the highest response was observed in Ankylosing spondylitis (AS) patients(26). In our study, we did not have any patient who developed active tuberculosis. Acid-Fast-Stain (AFS), tuberculosis culture and radiological findings were found to be normal in the active tuberculosis screening performed in 4 patients who received INH prophylaxis for LTBI and had suspicious symptoms for tuberculosis.
The main limitations of our study are the limited number of cases, the limited information availability on patient follow-up due to the retrospective nature of the study, and the lack of Quantiferon test for most of the cases.
As a result, all patients who are planned to receive anti-TNF therapy should be definitely screened for tuberculosis. Although it is not detected at the beginning of the treatment, regular tuberculosis screening should be continued during the treatment with contact history, symptoms, physical examination, chest X-ray and TST/IGRA in the light of current guidelines.