Rationale Anti-tumour necrosis factor (TNF) agents and other anti-rheumatic medications increase the risk of TB in rheumatoid arthritis (RA). Whether they increase the risk of infections with nontuberculous mycobacteria (NTM) is uncertain. Objectives To determine the effect of anti-TNF therapy and other anti-rheumatic drugs on the risk of NTM disease and TB in older patients with RA. Methods Population-based nested case–control study among Ontario seniors aged ≥67 years with RA who were prescribed at least one anti-rheumatic medication between 2001 and 2011. We identified cases of TB and NTM disease microbiologically and identified drug exposures using linked prescription drug claims. We estimated ORs using conditional logistic regression, controlling for several potential confounders. Measurements and main results Among 56 269 older adults with RA, we identified 37 cases of TB and 211 cases of NTM disease; each case was matched to up to 10 controls. Individuals with TB or NTM disease were both more likely to be using anti-TNF therapy (compared with non-use); adjusted ORs (95% CIs) were 5.04 (1.27 to 20.0) and 2.19 (1.10 to 4.37), respectively. Exposure to leflunomide and other anti-rheumatic drugs with high immunosuppressing potential also were associated with both TB and NTM disease, while oral corticosteroids and hydroxychloroquine were associated with NTM disease. Conclusions Anti-TNF use is associated with increased risk of both TB and NTM disease, but appears to be a relatively greater risk for TB. Several other anti-rheumatic drugs were also associated with mycobacterial infections.

https://thorax.bmj.com/content/thoraxjnl/70/7/677.full.pdf

Increased risk of mycobacterial infections associated with anti-rheumatic medications

Immunocompromised persons with latent tuberculosis infection (LTBI) are at increased risk for tuberculosis reactivation compared with the general population. The tuberculin skin test, the traditional assay for diagnosing LTBI, has reduced accuracy in immunocompromised patients. IFN-γ release assays (IGRAs) are in vitro blood tests that measure T-cell release of IFN-γ after stimulation with antigens unique to Mycobacterium tuberculosis. Here we review the data for the use of QuantiFERON-TB Gold In-Tube and T-SPOT.TB, the two currently available IGRAs, in immunocompromised adults, including persons infected with HIV, patients with immune-mediated inflammatory disorders, candidates for treatment with tumor necrosis factor-α inhibitors, patients receiving hemodialysis, solid-organ transplant recipients, and patients with cancer. On the basis of the available data, IGRAs have advantages over the tuberculin skin test in specific patient populations and in certain situations. Further studies are needed to more accurately define the usefulness of IGRAs in immunocompromised patients.

IFN-γ Release Assays in the Diagnosis of Latent Tuberculosis Infection among Immunocompromised Adults

OBJECTIVE: To estimate the risk of tuberculosis (TB) in patients with rheumatoid arthritis (RA) both with and without exposure to biological therapy and to directly compare the risks between therap ...

https://ard.bmj.com/content/annrheumdis/74/6/1212.full.pdf?with-ds=yes

Are patients with rheumatoid arthritis still at an increased risk of tuberculosis and what is the role of biological treatments

There is little disagreement that screening for latent tuberculosis (TB) infection (LTBI) prior to biologic therapy is necessary. Unfortunately, there is much less agreement with regard to how best to accomplish this task. A decade ago, we had just one screening tool, the tuberculin skin test (TST), and screening algorithms for such patients were presumably straightforward. With the recent introduction and fairly widespread adoption of interferon γ release assays (IGRAs), clinicians have a new tool that theoretically improves their ability to screen. However, since the introduction of IGRAs, the studies conducted within the biologic therapy setting that compare IGRAs and TST have been fraught with a lack of statistical power and heterogeneity (eg, differing underlying inflammatory disease states, variable immunosuppressive therapies or underlying BCG status),1 ,2 and firm conclusions regarding the relative sensitivity of these two screening tests (Quantiferon-Gold TB In-tube (QFT-IT) or the T-SPOT. TB assay) is only now becoming more clear. Kleinert et al and Mariette et al have published two studies to overcome some of these limitations,3 ,4 and along with other data, we believe the time has arrived to offer a screening algorithm that is practical in its approach. While we believe IGRAs have become the preferred screening tool in this setting, unfortunately these recent data argue that an IGRA alone is insufficient to identify all patients at risk.

TB is rumoured to infect nearly a third of the world's population. The risk of LTBI progression to active TB is clearly heightened by antitumour necrosis factor α (anti-TNF) therapy, and the absolute risk of this complication is driven by the background prevalence of LTBI in a particular region and the probability of infection in an individual. Within low prevalence countries, rates of anti-TNF-associated TB are typically 5–10-fold higher than background general populations, …

https://ard.bmj.com/content/annrheumdis/71/11/1757.full.pdf

You can't always get what you want, but if you try sometimes (with two tests—TST and IGRA—for tuberculosis) you get what you need

Treatment with biologic agents, in particular tumor necrosis factor alpha (TNF-α) inhibitors, is associated with an increased risk of tuberculosis (TB), and screening and treatment for latent TB infection (LTBI) in patients undergoing such treatment is therefore indicated. The risk of TB associated with different biologics varies significantly, with the highest relative risks, 29.3 and 18.6, associated with adalimumab and infliximab, respectively. The risk of TB with newer TNF-α inhibitors and other biologics appears to be lower. Performance of LTBI screening tests is affected by immune-mediated inflammatory diseases and immunosuppressive therapy in patients due to commence TNF-α inhibitor treatment. Interferon gamma release assays (IGRAs) have a higher specificity than the tuberculin skin test (TST) in patients with Bacillus Calmette-Guerin (BCG) vaccination and have probably a better sensitivity than TST in immunosuppressed patients. LTBI screening programs prior to commencement of anti-TNF-α treatment significantly reduce the incidence of TB, but the optimal screening algorithm, in particular the question of whether a combination of IGRA and TST or a single test only should be used, is a matter of ongoing debate. Use of TST in combination with IGRA is justified to increase sensitivity. Repeat testing for LTBI should be limited to patients at increased risk of TB. If TB develops during anti-TNF-α treatment, it is more likely to be disseminated and extrapulmonary than are other TB cases. Discontinuation of anti-TNF-α treatment in patients diagnosed with TB is associated with an increased risk of immune reconstitution inflammatory syndrome, which is probably best managed by reintroduction of anti-TNF-α treatment.

Biologic agents and tuberculosis

Objectives To characterise optimal screening strategies for latent tuberculosis infection (LTBI) prior to the initiation of anti-tumour necrosis factor therapy. Methods Patients in 62 German rheumatology centres were evaluated for LTBI. Each patient was screened with a tuberculin skin test (TST) and one form of an interferon-γ release assay (IGRA), either TSPOT.TB (TSPOT) or Quantiferon TB Gold (QFT). Results A total of 1529 patients with rheumatological disease were tested with a TST, 844 with TSPOT and 685 with QFT. TST was positive in 11.3% (n=173). The prevalence of LTBI was 8.0% when defined as a positive TST and no previous Bacille Calmette-Guerin (BCG) vaccination and 7.9% when based on a positive IGRA. Combining both estimates increased the prevalence of LTBI to 11.1%. Clinical risk factors for LTBI were found in 122 patients (34 with a history of prior TB, 81 close contacts and 27 with suggestive chest x-ray lesions). A compound risk factor (CRF) was defined as the presence of at least one of these three risk factors. Statistical analyses were conducted to examine the association between CRF and LTBI test outcomes. In multivariate analysis, TST was influenced by CRF (OR 6.2; CI 4.08 to 9.44, p Conclusion LTBI test results in an individual patient need to be considered in the context of prior BCG vaccination and clinical risk factors. In patient populations with low rates of TB incidence and BCG vaccination, the use of both TST and IGRA may maximise sensitivity in detecting LTBI but may also reduce specificity.

https://ard.bmj.com/content/annrheumdis/71/11/1791.full.pdf

Diel R

Papers

Screening for latent tuberculosis infection: performance of tuberculin skin test and interferon-γ release assays under real-life conditions