Tuberculosis (TB) and nontuberculous mycobacterial infection (NTM) remain a major challenge in rheumatology practice. There is often significant immune dysregulation in patients with autoimmune rheumatic diseases (AIRD). Moreover, various immunosuppressive agents and immunomodulators used to manage these AIRDs further complicate this, leading to a potential risk of acquiring various infections, including TB. In the Indian subcontinent, where TB risk is very high, an active search for TB infection is almost always mandatory before starting any biological or targeted synthetic DMARDs (b/tsDMARDs). Recently, there has been a change in terminology too. The term ‘latent tuberculosis infection (LTBI)’ has been replaced by ‘tuberculosis infection (TBI)’ [1]. This change highlights that infection exists on a dynamic spectrum, not as a fully dormant condition, as the ‘latent’ terminology suggests. Moreover, there is a recent change in TBI diagnostics and preventive therapies too.

Cy-TB for screening of tuberculosis infection

Screening for TBI is important before starting b/ts-DMARDS in patients with AIRD, especially in countries with high TB burden like India. The traditional screening options were tuberculin skin test (TST) and interferon-γ release assays (IGRAs). Both have certain merits and demerits. TST was the preferred screening modality for a long time due to its low cost and ready availability across all health set-ups. However, it can be less accurate after BCG vaccination or exposure to environmental mycobacteria. On the other hand, IGRA is a blood-based test against the specific antigenic targets ESAT-6 and CFP-10, and offers higher specificity compared to TST in BCG-vaccinated groups. But it is more costly and requires laboratory facilities. To circumvent these problems, the Serum Institute of India in Pune developed Cy-TB (SIILTIBCY). It uses similar M. tuberculosis-specific antigens, ESAT-6 and CFP-10, the same as IGRA. However, unlike IGRA, which is an in vitro test, Cy-TB is conducted intradermally in vivo in the suspected patient, and results are read after 48- 72 hours, with a 5 mm induration cut-off recommended by NTEP. It presents a promising alternative by combining the ease of skin testing with antigen specificity similar to IGRA. 

Recent Indian studies highlighted Cy-TB’s potential. A 2026 multicentre study involving 2,651 participants and 647 household contacts compared Cy-TB with IGRA as the standard. Cy-TB showed a sensitivity of 82.6%, a specificity of 71.1%, an overall agreement of 74.8%, and a kappa coefficient of 0.50 in comparison to IGRA as the standard; its performance was comparable to PPD [2]. In another systematic review, Cy-TB demonstrated substantially higher specificity of 98-99% and a strong agreement with IGRA [3]. These variations imply Cy-TB shouldn’t replace clinical assessment, chest radiography, or IGRA in high-risk patients. Besides, there is a lack of adequate data regarding its effectiveness across different rheumatic diseases or levels of immunosuppression [1]. Still, in India, Cy-TB is a valuable practical alternative where access to IGRA is often limited by cost.

Newer treatment of tuberculosis infection

Replacing ‘LTBI’ with ‘TBI’ provides a clearer description of the treatment. The preferred terms include “TB preventive treatment” (TPT), which captures the principal aim of TPT, which is to reduce the risk of TBI progressing to TB disease after active TB has been excluded.

There is significant change in TPT regimens in recent years. The focus has shifted from isoniazid-based monotherapy towards more comprehensive rifamycin-based regimens. Indian national guideline recommends 6 months of daily Isoniazid (6H) or three months of weekly Isoniazid and Rifapentine (3HP) for at-risk groups, such as patients to be started on b/ts-DMARDs. WHO additionally recommends four months of daily rifampicin (4R), three months of daily Isoniazid and Rifampicin (3HR) or one month of daily Isoniazid and Rifapentine (1HP) for certain groups of populations as a choice of TPT. Amongst these regimens, shorter rifamycin-based regimens like 3HP provide comparative efficacy and higher compliance and completion rates in various studies, thus making it the preferred choice of TPT nowadays.

However, it is important to keep certain points in mind. Since rifampicin and rifapentine are strong enzyme inducers, there is a potential risk of drug interactions. Additionally, although some guidelines suggest starting TPT about four weeks before planned initiation of b/tsDMARDs, practical considerations may require starting both treatments simultaneously, particularly when delaying immunosuppression isn’t feasible due to severity of AIRDs. Isoniazid-based regimens should also include pyridoxine, especially for patients with a higher risk of neuropathy.

Importance of NTM infection in rheumatology

Nontuberculous mycobacteria (NTM) are increasingly being recognised as important opportunistic pathogens in rheumatology practice. Systemic AIRDs like rheumatoid arthritis, Sjögren syndrome, or inflammatory myositis, when associated with predisposing lung conditions like bronchiectasis or interstitial lung disease, can develop NTM pulmonary infections. Furthermore, use of various immunosuppressants such as corticosteroids and b/tsDMARDs can further escalate this risk. A recent cohort study conducted in South Korea in 2025 found that RA patients have three times higher risk of developing NTM pulmonary disease compared with matched controls [5]. Moreover, NTM infections may cause many musculoskeletal symptoms like arthritis, tenosynovitis, or spondylodiscitis, which can sometimes mimic the presentation of various AIRDs. 

It is pertinent to remember that differentiating NTM from TBI or TB disease is crucial, as their treatments differ greatly. In case of persistent respiratory symptoms or suspicious imaging, sputum culture for identification of NTM should be ordered. Nevertheless, a positive NTM culture from respiratory samples must be interpreted with clinical and radiological context, as it could indicate a mere colonisation rather than active infection. 

Conclusion:

Mycobacterial risk management in rheumatology has moved from traditional LTBI screening to a more comprehensive TBI-focused approach. Cy-TB offers a highly specific and cheaper diagnostic alternative, and shorter rifamycin-based treatment courses improve treatment compliance and consequent treatment efficacy. Additionally, raising awareness of NTM disease is vital for safer, personalised immunosuppressive therapies in patients with AIRDs.

References:

1. Malaviya AN, Kedia N, Patel M, Kapoor S, Garg S, Mohan A, et al. Screening for Tuberculosis Infection in Rheumatology Practice: An Update. Indian Journal of Rheumatology. 2026;0(0). doi:10.1177/09733698251406356

2. Singh M, Hussain T, Modi B, Nair S, Kumar S, Alvi Y, et al. Diagnostic accuracy and safety of Cy-Tb for detection of tuberculosis infection: A multicentric study from India. Indian J Med Res. 2026;163(3):309-318. doi:10.25259/IJMR_1794_2025

3. Choudhary S, Saurabh S, Gupta MK, Lenka R, Sidholi P, Jaiswal S. Latent Tuberculosis Infection Diagnostics: Comparative Performance of TST, IGRAs, and Cy-Tb: Reg No: 302. J. Epidemiol. Found. India [Internet]. 2025 Dec. 31;3((2Supp):72. Available from: https://efi.org.in/journal/index.php/JEFI/article/view/488

4. Guidelines for Programmatic Management of Tuberculosis Preventive Treatment in India. https://tbcindia.mohfw.gov.in/wp-content/uploads/2023/05/Guidelines-for-Programmatic-Management-of-Tuberculosis-Preventive-Treatment-in-India.pdf

5. Yang B, Han K, Jung JH, et al. Rheumatoid arthritis and risk of non-tuberculous mycobacterial pulmonary disease: a nationwide longitudinal cohort study. BMJ Open Respir Res. 2025;12(1):e003397. doi:10.1136/bmjresp-2025-003397