TB Risk and Targeted Immunotherapy/Biologics Recommendations

SFDPH TB Clinic/UCSF TB-Targeted Immunotherapy Group (TB-TIG)*

Recommendations for TB Screening  in Persons taking Targeted Immunotherapies (including Tumor Necrosis Factor Inhibitors)

The use of new targeted immunotherapies (or biologics) has radically transformed the available treatment options for many chronic diseases. These targeted immunotherapies work by blocking specific molecules that mediate certain immune responses or by depleting the cells that express them. Some can also increase the risk of progression to active TB disease by downregulating the immunologic functions that contain TB organisms. This risk varies by drug class and mechanism of action¹.

The use of tumor necrosis factor (TNF)-alpha inhibitors has been associated with high risk of progression of TB; active TB infection occurring in the setting of TNF-inhibitor use has a greater  likelihood of involving extra-pulmonary sites and of being disseminated at presentation compared with other TB cases². The risk has been reported to be greater with infliximab and adalimumab than with etanercept². Latent TB infection (LTBI) screening and treatment appears to significantly reduce the incidence of progression to active TB in these patients³.

There is growing evidence that other targeted immunotherapies (e.g., PD-1/PDL-1 inhibitors, CTLA-4 inhibitors, JAK kinase inhibitors, and IL-6 and IL-23 inhibitors to name a few) are also associated with increased risk of TB reactivation. These targeted immunotherapies should be treated similarly as for a TNF-inhibitor. Data is rapidly emerging in this area as more targeted immunotherapies are approved.  Based mostly on expert opinion, SFDPH recommends that patients with a diagnosis of LTBI should be initiated on treatment for at least 1 month, if possible, prior to starting those targeted immunotherapies where a risk for TB progression has been identified.

The Table lists targeted immunotherapies as of July 2023 where the manufacturer’s package insert recommends TB testing⁴. This list may not include all available targeted immunotherapies; check the manufacturer’s package insert for details.

References 

1. Guidelines for the Treatment of Latent Tuberculosis Infection: Recommendations from the National Tuberculosis Controllers Association and CDC, 2022. Available at URL: https://www.tbcontrollers.org/resources/tb-infection/clinical-recommendations/
2. Dixon WG, Hyrich KL, Watson KD, Lunt M, et al. Drug-specific risk of tuberculosis in patients with rheumatoid arthritis treated with anti-TNF therapy: results from the British Society for Rheumatology Biologics Register (BSRBR). Ann Rheum Dis. 2010;69(3):522.
3. Carmona L, Gómez-Reino JJ, Rodríguez-Valverde V, et al. Effectiveness of recommendations to prevent reactivation of latent tuberculosis infection in patients treated with tumor necrosis factor antagonists. Arthritis Rheum. 2005;52(6):1766.
4. List of targeted immunotherapies: Murrill MT, Velásquez GE, Louie J, Tahir P, Kim A, D. Szumowski JD, Salazar J, Minter D, Casalegno ML, Phillips A, Ernst J. Latent tuberculosis screening recommendations for targeted immunotherapies. Presented at the 2023 National Tuberculosis Conference. June 12, 2023, Atlanta, United States

*University of California San Francisco TB-Targeted Immunotherapy Group (TB-TIG)

• Joel Ernst, MD, UCSF Division of Experimental Medicine
• Annie Kim, Clinical Pharmacist, UCSF-San Francisco General Hospital
• Janice Louie, MD, MPH, SFDPH TB Clinic/ UCSF Division of Infectious Diseases
• Daniel Minter, MD, UCSF Division of Infectious Diseases
• Matthew Murrill, MD, PhD, UCSF Department of Medicine
• Allison Phillips, PhD, SFDPH TB Clinic
• Haiyan Ramirez-Batlle, SFDPH TB Clinic
• Jorge Salazar, MD, UCSF Division of Infectious Diseases
• John Szumowski, MD, MPH, UCSF Division of HIV, ID & Global Medicine
• Gustavo Velasquez, MD, MPH, UCSF Division of HIV, ID & Global Medicine

Targeted Immunotherapies and TB Risk, 2023

University of California San Francisco TB Targeted Immunotherapy Group (TB-TIG)

TB testing with interferon-gamma release assay or tuberculin skin test is recommended for the following targeted immunotherapies (per the manufacturers drug insert)

Abbreviations: CTLA-4, Cytotoxic T-lymphocyte associated protein 4; mAb, monoclonal antibody; TNF, tumor-necrosis factor;  IL, interleukin; IFN, interferon

Note:  While the manufacturers’ package insert does not mentioned risk of active TB for the PD-1 (programmed cell death-1) and PDL-1 (programmed cell death ligand-1) inhibitor class of drugs, use in animal models has demonstrated increased severity of TB infections and enhanced inflammatory response. TB infected PD-1 knockout mice exhibit markedly decreased survival compared to wild-type controls, which correlated with increased bacterial proliferation and inflammatory responses in these animals.  PD-1 blockage using a primate anti-PD-1 antibody was also shown to exacerbate TB infection in rhesus macaques. Pending further data, the SFDPH TB Clinic recommends TB testing prior to use of these classes of drugs (including atezolizumab, avelumab, cemiplimab, dostarlimab, durvalumab, nivolumab, nivolumab/relatlimab and pembrolizumab).

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