## 2 Medical Framework
Patients with positive TST results (IDR > 5 mm) or positive QuantiFERON results will be recommended chemoprophylaxis with isoniazid at 5 mg/kg/day, with a maximum of 300 mg/day for 9 months. The biological therapy may be initiated after at least one month of chemoprophylaxis. In patients who have had negative initial tests, periodic screening for the reactivation of tuberculosis is recommended at least once every 12 months by using the QuantiFERON-TB Gold test or the tuberculin skin test (TST). The QuantiFERON-TB Gold In-Tube assay seems to be a more accurate test for the detection of LTBI in RA patients compared with the TST [14,20,21]. The QuantiFERON-TB Gold Test (QFT) is a simple blood test that aids in the diagnosis of _Mycobacterium tuberculosis_ infections, both for the latent and for the active forms. The test measures the intensity of the cellular immune responses to antigens that mimic ESAT-6 and CFP-10 proteins, produced by the mycobacterium. The recognition process includes the generation and release of cytokines, especially interferon (IFN)-\(\gamma\), which can be detected and quantified by an enzyme-linked immunosorbent assay [22]. The results of the QuantiFERON-TB Gold test are based on the proportion of interferon-\(\gamma\) released in response to tuberculin as compared with the mitogen. Unlike the tuberculin skin test, QFT results are not influenced by the baulic Calmette-Guerin (BCG) vaccination, and a history of infections with nontuberculous mycobacteria also have a lesser influence. Adverse hypersensitivity reactions that may occur with the tuberculin skin test are also eliminated. Also, the results of the QuantiFERON-TB test are much more objective, without errors in reading and interpretation [22]. The mitogen tube is used as an IFN-\(\gamma\) positive control for each specimen tested and serves as a control for correct blood handling and incubation. The mitogen used is phytohaemagglutinin-P (PHA), which is a nonspecific stimulator of T-cells [22]. A low IFN-\(\gamma\) response to mitogen (<0.5 IU/mL) indicates an indeterminate result when a blood sample also has a negative response to the TB antigens. This pattern may occur with insufficient lymphocytes, reduced lymphocyte activity due to improper specimen handling, or an inability of the patient's lymphocytes to generate IFN-\(\gamma\)[23]. The diagnosis of a latent tuberculosis infection (LTBI) in patients with immunmediated inflammatory diseases raises a number of issues due to the characteristics of these patients. Although the QFT test has a 99% specificity and an overall sensitivity for active TB of 92%, some patients remain with an \"indeterminate result\" due to the inability of lymphocytes to secrete interferon (IFN)-\(\gamma\) after 24 h of stimulation to phytohaemagglutinin(PHA), causing the failure of the appropriate positive control. The reported prevalence of indeterminate results is higher in patients with chronic inflammatory conditions compared to healthy people. Also, patients who receive at least one immunosuppressive drug (especially steroids) are more likely to have an indeterminate result [23; 24]. Regarding the risk of latent tuberculosis reactivation, numerous studies have concluded that biological therapy is associated with an increased risk of tuberculosis. A latent tuberculosis infection is the body's immune response to contact with _Mycobacterium tuberculosis_. Infected people have no clinical manifestations nor radiological or bacteriological evidence, and they are not contagious, but some of them risk reactivating the disease [25]. A retrospective study conducted in 11 medical centers in Romania on patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriatic arthropathy treated with biological anti-TNF alpha therapy between January 1999 and June 2011 investigated the incidence of tuberculosis. The observational research included 693 patients, of whom 492 had RA.