Evaluation of Latent and Active Tuberculosis Development in Patients Receiving Biologic Agent Therapy: A Retrospective Analysis

Abstract

Objective To determine the incidence of active TB in patients re- ceiving biological/tsDMARD therapy and to examine the effects of LTBI prophylaxis and the level of immu- nosuppression on risk. Material and Method Patients aged ≥18 years who started biological treat- ment between 2019 and 2024 were reviewed retro- spectively. Inclusion criteria: ≥3 months of biological/ tsDMARD use, at least one LTBI test (PPD or IGRA) performed before the treatment, and ≥6 months of fol- low-up records. Exclusions: previous active TB, miss- ing baseline data, or follow-up at an external center. Demographics, diagnosis, agent type/duration, addi- tional immunosuppression, BCG scar, LTBI screening results, prophylaxis regimen, and adverse events were recorded. The primary endpoint was defined as active TB. The relationship between LTBI treatment, level of immunosuppression, LTBI positivity, and active TB was examined using Bayesian logistic regression. Results A total of 101 patients were reviewed. PPD was per- formed in 69.1% and IGRA in 51.5% of patients; BCG scar was observed in 93.8%. Two cases of active TB (2.0%) were observed: one developed under barici- tinib and the other under bevacizumab. The LTBI pro- phylaxis completion rate was 71.2%, and hepatotox- icity was 11.9%. Bayesian analysis revealed a high but uncertain risk association with LTBI treatment (OR 57.65; 95% CrI 0.93-3303.16), which was consistent with indication confounding. The likelihood of higher risk was 78% in the low-moderate immunosuppres- sion group. No independent effect of LTBI positivity was observed. Conclusion Active TB under biological/tsDMARD therapy is rare but important. The high risk seen in those receiving LTBI prophylaxis may be a result of clinicians select- ing high-risk patients rather than the treatment itself. The findings achieved in this study suggest that cau- tion is necessary with JAK inhibitors and anti-angio- genic agents and should be confirmed by larger pro- spective studies.

Keywords

• Tuberculosis
• Tuberculosis
• Latent
• Antirheumatic Agents
• Biological Products
• Janus Kinase Inhibitors

Supporting Institution

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for- profit sectors.

Ethical Statement

This study was approved by the Non-Interventional Clinical Research Ethics Committee of Çanakkale Onsekiz Mart University (Decision date: 18.06.2025, Number: 2025-09/09-38).

References

1. 1. McInnes IB, Schett G. Pathogenetic insights from the treatment of rheumatoid arthritis. Lancet 2017;389(10086):2328-2337. ht- tps://doi.org/10.1016/S0140-6736(17)31472-1
2. 2. Singh JA, Saag KG, Bridges SL, et al. 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis & Rheumatology 2016;68(1):1-26. https://doi. org/10.1002/art.39480
3. 3. Dobler CC. Biologic Agents and Tuberculosis. Microbiol Spectr. 2016;4(6):TNMI7-0026-2016. https://doi.org/10.1128/microbi- olspec.TNMI7-0026-2016
4. 4. Solovic I, Sester M, Gomez-Reino JJ, et al. The risk of tubercu- losis related to tumour necrosis factor antagonist therapies: a TBNET consensus statement. Eur Respir J. 2010;36(5):1185- 206. https://doi.org/10.1183/09031936.00028510
5. 5. Flynn JL, Chan J, Lin PL. Macrophages and control of granu- lomatous inflammation in tuberculosis. Mucosal Immunology. 2011;4(3):271-8. https://doi.org/10.1038/mi.2011.14
6. 6. Keane J, Gershon S, Wise R, et al. Tuberculosis associated with infliximab, a tumour necrosis factor alpha-neutralising agent. N Engl J Med. 2001;345(15):1098-1104. https://doi. org/10.1056/NEJMoa011110
7. 7. Cantini F, Nannini C, Niccoli L, et al. Risk of Tuberculosis Re- activation in Patients with Rheumatoid Arthritis, Ankylosing Spondylitis, and Psoriatic Arthritis Receiving Non-Anti-TN- F-Targeted Biologics. Mediators Inflamm. 2017;2017:8909834. https://doi.org/10.1155/2017/8909834
8. 8. Goletti D, Petrone L, Ippolito G, et al. Preventive therapy for tuberculosis in rheumatological patients undergoing therapy with biological drugs. Expert Review of Anti-Infective Therapy 2018;16(6):501-512. https://doi.org/10.1080/14787210.2018.1 483238

9. 9. Cooper AM, Khader SA. The role of cytokines in the initiation, expansion, and control of cellular immunity to tuberculosis. Im- munol Rev. 2008;226:191-204. https://doi.org/10.1111/j.1600- 065X.2008.00702.x
10. 10. Ji DX, Yamashiro LH, Chen KJ, et al. Type I interferon-dri- ven susceptibility to Mycobacterium tuberculosis is mediated by IL-1Ra. Nat Microbiol. 2019;4(12):2128-2135. https://doi. org/10.1038/s41564-019-0578-3
11. 11. Ministry of Health of the Republic of Türkiye, General Directora- te of Public Health. Tuberculosis Control in Türkiye 2023 Report. Ankara: Ministry of Health of the Republic of Türkiye; 2024.
12. 12. Pai M, Zwerling A, Menzies D. Systematic review: T-cell-based assays for the diagnosis of latent tuberculosis infection: an up- date. Annals of Internal Medicine 2008;149(3):177-84. https:// doi.org/10.7326/0003-4819-149-3-200808050-00241
13. 13. Aguado JM, Manuel O. Editorial for ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Do- cument on the safety of targeted and biological therapies: an infectious diseases perspective. Clin Microbiol Infect. 2018;24 Suppl 2(Suppl 2):S1. https://doi.org/10.1016/j.cmi.2018.04.029
14. 14. Singh JA, Cameron C, Noorbaloochi S, et al. Risk of seri- ous infection in biological treatment of patients with rheu- matoid arthritis: a systematic review and meta-analysis. Lancet 2015;386(9990):258-65. https://doi.org/10.1016/S0140- 6736(14)61704-9
15. 15. Von Elm E, Altman DG, Egger M, et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement: guidelines for reporting observational studies. In- ternational journal of surgery 2014 12(12):1495-9. https://doi. org/10.1016/j.ijsu.2014.07.013
16. 16. Saukkonen JJ, Cohn DL, Jasmer RM, et al. An official ATS statement: hepatotoxicity of antituberculosis therapy. Ameri- can Journal of Respiratory and Critical Care Medicine 2006 174(8):935-52. https://doi.org/10.1164/rccm.200510-1666ST
17. 17. Listing J, Gerhold K, Zink A. The risk of infections associated with rheumatoid arthritis, with its comorbidity and treatment. Rheumatology 2013;52(1):53-61. https://doi.org/10.1093/rheu- matology/kes305
18. 18. Ministry of Health of the Republic of Turkey. Tuberculosis Diag- nosis and Treatment Guide. 2019.
19. 19. Lorenzetti R, Zullo A, Ridola L, et al. Higher risk of tuberculosis reactivation when anti-TNF is combined with immunosuppres- sive agents: a systematic review of randomised controlled tri- als. Ann Med. 2014;46(7):547-54. https://doi.org/10.3109/0785 3890.2014.941919
20. 20. Sterling TR, Njie G, Zenner D, Cohn DL, et al. Guidelines for the Treatment of Latent Tuberculosis Infection: Recommendati- ons from the National Tuberculosis Controllers Association and CDC, 2020. MMWR Recomm Rep. 2020;69(1):1-11. https:// doi.org/10.15585/mmwr.rr6901a1