We were able to show that TST positivity rate was significantly higher in SpA patients compared to that of RA patients prior to initiation of biological and targeted synthetic DMARDs, although BCG scar rates were similar and QFT-GIT positivity rates were only slightly different. Although the smoking rate was higher, and systemic steroid and conventional DMARD use were less frequent in SpA compared to RA, a higher rate of TST positivity was not attributable to those (Table 3).
Treatment with immunosuppressive medications has been known to block the immune response against tuberculin and Mycobacterium tuberculosis-specific antigens to some degree and may be responsible for false-negative TST and QFT-GIT results [11, 33]. A higher rate of complete cutaneous anergy and slightly lower QFT-GIT positivity in RA compared to the SpA group in the present study may be caused by more frequent use of systemic steroids and conventional DMARDs in RA. The potential impact of intrinsic immune dysregulation in rheumatic diseases on LTBI and screening tests was not evaluated before. But diminished immune response against microbes and vaccines was attributed not only to immunosuppressive medications but the disease itself in patients with RA [34–36].
Conflicting results on the performance of IGRAs compared to TST in terms of sensitivity and specificity to detect LTBI have been reported in immunocompromised adults without HIV infection [20–24]. The principal reason for that is the lack of a gold standard test for LTBI, which is, by definition, the presence of an immune response - assumed to be caused by a previous sensitization - against Mycobacterium tuberculosis antigens with no evidence of active tuberculosis [1]. It is not a direct microbiological diagnosis, and false-positive and -negative results are of great concern both by TST and IGRAs [1, 11, 12]. It is also difficult to evaluate the progression to active tuberculosis in immunocompromised patients tested by TST and IGRAs comparatively since patients with positive results of either test are usually given treatment due to a high risk of reactivation. According to the present and two previous studies [20, 24], increasing the TST cut-off value slightly improved the agreement between the two tests but to a moderate level at most. So, TST - QFT-GIT disagreement in the immunocompromised adult population without HIV infection does not seem to be caused primarily by a cut-off issue. BCG vaccination is a well-known factor for false-positive TST results and a potential reason to use IGRAs to detect LTBI [3, 5–7, 12] but cannot explain the discrepant study results conducted in BCG-vaccinated patient groups [20–24]. A possible reason why studies report different TST - QFT-GIT agreement rates in BCG-vaccinated patients may be the difference in the patient groups (i.e. patient groups with different diseases) and the degree of immunosuppression of the study groups. According to a meta-analysis of long-term extension studies, not only TST - QFT-GIT agreement but the actual tuberculosis risk was also different in different rheumatic diseases including RA and SpA independent of the treatment with biologics [37]. Treatment with TNF-α inhibitors increased the risk of tuberculosis in both RA and SpA but to a higher level in RA [37]. Not so unexpectedly, studies conducted in different patient groups, such as inflammatory bowel disease patients under treatment with various immunosuppressive agents, TNF-α inhibitor-scheduled patients with rheumatic diseases under DMARDs, and solid organ transplantation candidates with no immunosuppressive medication use reported different agreement rates between TST and QFT-GIT [20, 24]. Different TST results were reported even in psoriasis and psoriatic arthritis patients despite similar QFT-GIT results [38]. Different agreement rates between TST and QFT-GIT in RA and SpA in the present study may represent an example of this situation. To overcome the effect of conventional DMARD and steroid treatment on screening tests, the Australian Rheumatology Association suggests screening LTBI at the initial diagnosis of inflammatory arthritis [5]. Anyway, candidates for biological and targeted synthetic DMARDs have traditionally been screened in the same way regardless of their underlying rheumatic disease, although both the tuberculosis progression (reactivation) rates and the screening test results may differ. It should additionally be stated that TST procedures with different types and units of tuberculin products in different countries may also contribute to discrepant study results [11, 20–24].
In correlation with TST positivity rates for a 5 mm cut-off as suggested by the Turkish Society for Rheumatology, Turkish Thoracic Society, and Ministry of Health [8], LTBI treatment rates were higher in SpA compared to RA group (Table 1). There lies a paradox here. RA patients, who are more immunosuppressed and more prone to tuberculosis reactivation, were given less LTBI treatment since they had lower TST positivity compared to SpA patients. The opposite seems true for SpA patients. This particular point implies the necessity of studies in separate disease groups rather than pre-biologic patient pools.
IGRA-only and combined test approaches were proved effective and safe particularly to reduce overtreatment with antituberculosis drugs in immunocompromised and BCG-vaccinated patients [21, 39–42] but debate exists on this topic [15, 22, 23, 33]. In a longitudinal study of inflammatory arthritis patients comparing different baseline LTBI screening strategies before TNF-α inhibitors in a high tuberculosis burden BCG-vaccinated population, incidence rates of active tuberculosis, after a mean exposure of 4 ± 2.4 years to TNF-α inhibitors, were 1348.0, 862.1, and 540.2 cases/100000 patient-years in TST (cut-off ≥ 10 mm), TST (cut-off ≥ 5 mm), and QFT groups, respectively, although the difference was not found statistically significant [43]. Cost-effectiveness and antituberculosis drug-related toxicity are also important concerns regarding LTBI screening and treatment strategies but beyond the scope of this study.
There are several limitations of this study. This was a cross-sectional study and tuberculosis progression (reactivation) rates were not available. TST and QFT-GIT were performed in different centers and it was not known which test was performed first. Test intervals were also not known. Since BCG vaccination is routine in Turkey, the missing data on BCG scar and vaccination history do not seem to cause confusion to interpret the study results. There were some differences in age, education status, pre-biologic systemic steroid and conventional DMARD use, and TST results between the study groups and the entire RA and SpA populations (Additional file 1). But these were not thought to have a major impact on the main results. Overall, this study adds valuable information to the relevant field regarding the difference in the performance of LTBI screening tests in RA and SpA.