Risk of mycobacterial infection associated with biologic agents and JAK inhibitors

INTRODUCTION — Biologic agents and Janus kinase (JAK) inhibitors represent important treatment advances for a number of immune-mediated inflammatory conditions (including rheumatoid arthritis, the seronegative spondyloarthropathies, psoriasis, and inflammatory bowel disease) [1,2]. (See "Overview of biologic agents in the rheumatic diseases" and "Overview of the Janus kinase inhibitors for rheumatologic and other inflammatory disorders".)

Use of these agents is associated with increased risk of tuberculosis (TB); all patients should be screened for TB infection prior to their use.

The approach to use of these agents in the context of risk for mycobacterial infections will be reviewed here. Other infectious complications of tumor necrosis factor-alpha inhibitors are discussed separately. (See "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects" and "Tumor necrosis factor-alpha inhibitors: Bacterial, viral, and fungal infections".)

GENERAL PRINCIPLES

Biologic agents

TNF-alpha inhibitors

●Agents – Several tumor necrosis factor (TNF)-alpha inhibitors have been approved for the treatment of a variety of inflammatory illnesses (eg, rheumatoid arthritis, Crohn disease) by the US Food and Drug Administration:

•Infliximab – A chimeric (mouse/human) anti-TNF-alpha monoclonal antibody

•Adalimumab – A fully human monoclonal anti-TNF-alpha antibody

•Etanercept – A soluble TNF-alpha receptor fusion protein

•Certolizumab pegol – A pegylated Fab fragment of a humanized monoclonal antibody

•Golimumab – A human monoclonal anti-TNF-alpha antibody

Among the available biologics, these agents have the greatest impact on ability of the host to contain TB infection. They are discussed in further detail separately. (See "Overview of biologic agents in the rheumatic diseases", section on 'TNF inhibition'.)

●Effect on host defenses – Host defense against mycobacteria relies on the granulomatous response; this consists of sequestration of bacilli within granulomas, which are comprised of a central core of macrophages, multinucleated giant cells, and necrotic debris, surrounded by macrophages and lymphocytes [3].

TNF-alpha is required for orderly recruitment of these cells and for continued function of the granuloma [4-6]. The ability of macrophages to contain intracellular tuberculosis bacillary growth is also dependent on TNF-alpha [7,8]. (See "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects".)

Other biologic agents — Non-TNF biologic agents include abatacept, tocilizumab, rituximab, anifrolumab, ustekinumab, sarilumab, interleukin (IL)-17 blockers, and IL-23 blockers. (See "Overview of biologic agents in the rheumatic diseases".)

JAK inhibitors — JAK inhibitors include tofacitinib, baricitinib, upadacitinib, deucravacitinib, and others. (See "Overview of the Janus kinase inhibitors for rheumatologic and other inflammatory disorders".)

Quantifying risk for TB — The risk of tuberculosis (TB) and its timing varies depending on the agent.

●Risk for TB varies depending on the immunosuppressive agent

•TNF-alpha inhibitors – All TNF-alpha inhibitors are associated with increased risk of TB disease (active TB); the risk is greater for the anti-TNF monoclonal antibodies (infliximab and adalimumab) than for the soluble receptor fusion protein etanercept [1]. The risk associated with the newer monoclonal agents (certolizumab and golimumab) is presumed to be similar to the other anti-TNF monoclonal antibodies; however, for these agents the risk has not been established in population-based studies or compared with the other agents [9,10].

The risk of TB among more than 13,000 patients receiving TNF-alpha inhibitors was evaluated in a national prospective observational study using data from the British Society for Rheumatology Biologics Register [11]. Among patients with rheumatoid arthritis receiving infliximab, adalimumab, or etanercept (10,712 patients) or traditional disease-modifying antirheumatic drugs (DMARDs; 3232 patients), 40 episodes of TB occurred among those receiving TNF-alpha inhibitors; case rates for infliximab, adalimumab, and etanercept were 144, 136, and 39 cases per 100,000 person-years, respectively. No cases were reported in the DMARD cohort.

In a Swedish study including more than 30,000 patients (of whom 4930 had rheumatoid arthritis, of whom 2500 received TNF-alpha inhibitors), the relative risk of TB among patients not treated with TNF-alpha inhibitors compared with the general population was 2.0 (95% CI 1.2-3.4); by contrast, the relative risk of TB among patients treated with TNF-alpha inhibitors compared with those not treated with TNF-alpha inhibitors was 4.0 (95% CI 1.3-12) [12].

Potential explanations for differences in risk between TNF-alpha inhibitors include varying degrees of granuloma penetration, differential downregulation of TB antigen-stimulated interferon-gamma production, and varying effects upon antimicrobial-producing CD8 effector cells [13-15].

Many of the TB cases associated with TNF-alpha inhibitors likely represent reactivation of TB infection (latent TB). The risk of TB correlates with background regional TB risk.

•Other non-TNF-alpha inhibitor biologics – Data on TB risk are limited for many of the non-TNF-alpha inhibitor biologics.

-Abatacept – The risk with abatacept is lower than observed for TNF blockers; in a study including eight trials of abatacept and more than 4100 patients, the TB incidence was 0.07 per 100 patient-years [16].

-Tocilizumab, sarilumab (monoclonal antibodies blocking IL-6 signaling) – In a postmarketing surveillance study including more than 3800 patients with rheumatoid arthritis treated with tocilizumab, four patients developed TB (incidence 0.22 per 100 patient-years); all had been screened appropriately before starting therapy [17].

-Rituximab (a chimeric monoclonal antibody targeted against the pan-B-cell marker CD20 to inhibit several B cell activities) – Rituximab is thought to carry lower risk than TNF blockers, although cases have been reported. In one study including more than 980 patients who received at least one dose of rituximab, with 3844 patient-years of follow-up, no cases of TB disease were observed [18]. (See "Rituximab: Principles of use and adverse effects in rheumatoid arthritis".)

-Anifrolumab (a fusion protein that binds to the costimulatory molecules CD80 and CD86 on antigen-presenting cells [APCs] to prevent T cell activation) – Anifrolumab inhibits type-1 interferon signaling. This could theoretically increase risk, but the actual risk is unknown. Within clinical trials, patients were screened for TB infection. Several patients converted to a positive interferon-gamma release assay (IGRA) during the trials, but no TB disease occurred.

-Ustekinumab – Ustekinumab blocks IL-12/23 and has not been observed to increase the risk of TB, although its label suggests screening for TB prior to its use.

-IL-17 blockers – IL-17 blockers carry no or very little risk of TB. No increased risk was observed in clinical trials, although rare cases have been reported in real world data. The labels for these therapeutics recommend screening for TB prior to starting them, based upon how pivotal clinical trials were conducted in which such screening was employed.

-IL-23 blockers – IL-23 blockers would not be expected to increase risk, and no increased risk has been observed with the use of these agents.

•JAK inhibitors – JAK inhibitors include tofacitinib, baricitinib, upadacitinib, deucravacitinib, and others.

In one study of tofacitinib including data from phase 2, phase 3, and long-term extension clinical trial data from more than 5600 patients, in patients with rheumatoid arthritis treated with tofacitinib, 26 cases of TB disease were identified. The median time between start of tofacitinib and TB diagnosis was 64 weeks, and extrapulmonary disease was observed in 58 percent of cases [19].

Cases were also reported above background population rates in the baricitinib program in rheumatoid arthritis, and cases have also been observed with upadacitinib in randomized controlled trials for rheumatoid arthritis and other conditions [20,21].

The development program for deucravacitinib did not report any TB cases, although patients were screened prior to trial entry [22,23].

●Variable timing of TB disease onset – Treatment with infliximab is associated with a shorter time to development of TB disease compared with etanercept and adalimumab:

•In a British study including more than 13,000 patients receiving TNF-alpha inhibitors, the median time to development of TB disease was shortest for infliximab (5.5 months) compared with etanercept (13.4 months) and adalimumab (18.5 months) (figure 1) [11].

•Similarly, in a study including 233,000 patients treated with infliximab and 113,000 patients treated with etanercept, 43 percent of infliximab-associated cases of TB disease occurred during the first 90 days of treatment, a pattern consistent with reactivation of TB infection; by contrast, etanercept-associated TB cases were distributed evenly throughout during the reporting period, with only 10 percent occurring during the first 90 days of treatment [24].

The basis for variable times of onset is uncertain; the observations may reflect differential drug effects on reactivation risk, occurrence of new infection, or the waning effects of prior isoniazid therapy for prevention of reactivation.

●Influence of underlying rheumatoid arthritis – Rheumatoid arthritis has been associated with increased risk for the development of TB in some studies [12,25,26], but not others [27]. TNF-alpha inhibitors appear to increase the risk of TB beyond that which may be associated with rheumatoid arthritis itself.

TUBERCULOSIS

TB infection

Screening — All patients who are planning to undergo treatment with a biologic agent or JAK inhibitor should be screened for tuberculosis (TB) infection prior to initiation of immunosuppressive therapy [2,28].

Prior to immunosuppression — In patients who screen positive and are treated for TB infection prior to initiation of a biologic agent or JAK inhibitor, the risk for subsequent development of TB disease is low, although not eliminated [9,19,29]. As an example, in a registry study including more than 7800 patients with rheumatic conditions in Spain treated with tumor necrosis factor (TNF)-alpha inhibitors , implementation of recommendations for TB screening were associated with a decline in TB disease rates by 78 percent (incidence risk ratio [IRR] 0.22, 95% CI 0.03-0.88) [30].

●Components of screening – Screening should include:

•Clinical history, including:

-Epidemiologic risk factors for TB exposure (See "Epidemiology of tuberculosis", section on 'Risk factors'.)

-Clinical manifestations of TB disease (cough >2 weeks, fevers, night sweats, weight loss)

•Physical examination

•Interferon-gamma release assay (IGRA), or if not available, a tuberculin skin test (TST) [31,32]

●Approach to screening – Our approach to screening for TB infection varies depending upon whether the patient has risk factors for TB infection:

•Presence of risk factors for TB infection – Using a single screening test does not identify all patients at risk for TB infection; false-negative results are more likely in immunocompromised individuals [9,33-35]. Accordingly, in immunosuppressed patients with risk factors for prior TB exposure, we favor a dual testing strategy, which consists of checking a second test if the first test is negative (algorithm 1) [28].

For the initial screening test, we prefer an IGRA over TST; IGRA is likely more sensitive in the setting of immunosuppression, it can be accomplished in one visit, and it eliminates uncertainty regarding history of Bacille Calmette-Guérin (BCG) vaccination.

For previously exposed and anergic individuals, beginning with TST (followed by IGRA) may improve sensitivity.

For repeat testing, either the same IGRA or another assay may be used. Available IGRAs include the QuantiFERON-TB Gold and the T-SPOT.TB assay.

Issues related to IGRAs are discussed further separately. (See "Use of interferon-gamma release assays for diagnosis of tuberculosis infection (tuberculosis screening) in adults".)

•Absence of risk factors for TB infection – For patients without risk factors for TB infection, we screen with a single test (preferably IGRA) (algorithm 2).

●Patients with positive screening test – For patients with positive IGRA or TST and no clinical manifestations of TB, a chest radiograph should be obtained (algorithm 3) [2].

•Normal chest radiograph – For patients with normal chest radiograph, treatment for TB infection should be administered.

•Abnormal chest radiograph – For patients with abnormal chest radiograph, three sputum specimens should be obtained for acid-fast bacilli smear, mycobacterial culture, and nucleic acid amplification testing [28]:

-For patients with negative sputum microbiologic evaluation, treatment for TB infection should be administered. The immunosuppressive agent may be administered after the patient has completed at least one month of treatment. (See "Treatment of tuberculosis infection (latent tuberculosis) in nonpregnant adults without HIV infection".)

-For patients with positive sputum microbiologic evaluation, treatment for TB disease should be administered. The immunosuppressive agent may be administered after the patient has completed antituberculous therapy. (See "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults without HIV infection".)

For patients with clinical manifestations of TB, the diagnostic approach is outlined separately. (See "Diagnosis of pulmonary tuberculosis in adults".)

Surveillance screening — For patients on a biologic agent or JAK inhibitor who have ongoing risk of TB exposure, repeat screening for TB infection should be performed annually [2,36]. TST may be preferred for repeat screening since IGRA test conversions and reversions may be difficult to interpret [37]. (See "Tuberculosis infection (latent tuberculosis) in adults: Approach to diagnosis (screening)", section on 'Diagnostic approach'.)

For patients on a biologic agent or JAK inhibitor with no ongoing risk of TB exposure in the setting of negative initial screening or successful completion of treatment for TB infection, repeat screening is not necessary.

Management

Indications for treatment — For patients planning to undergo treatment with a biologic agent or JAK inhibitor, indications for treatment of TB infection include:

●Patients with positive IGRA or positive TST (≥5 mm induration) and no evidence of TB disease

●Patients with prior diagnosis of TB infection who did not complete treatment, even in the setting of negative IGRA or TST (<5 mm)

For patients with negative or indeterminate screening test results for TB infection, treatment decisions should be individualized based on the risk of TB exposure and the likelihood that a negative test may represent a false-negative result. Treatment may be warranted for patients with a strong likelihood of prior TB exposure (eg, evidence of remote TB disease on chest radiography [regional fibrosis with or without hilar lymphadenopathy], history of close contact with a TB case, or residence in a country with high TB incidence (table 1)). We have a lower threshold for treating patients who were immunosuppressed at the time of testing for TB infection since immunosuppression reduces the sensitivity of the screening tests.

Clinical approach

●Antimycobacterial therapy – Patients who warrant treatment for TB infection may be treated with any approved regimen (table 2); while rifampin-based regimens are preferred, drug-drug interactions should be considered carefully. As an example, for patients on tofacitinib who warrant treatment for TB infection, isoniazid monotherapy is preferred given the drug interaction between tofacitinib and rifampin (concurrent use can decrease tofacitinib bioavailability by 80 percent) [1].

Issues related to treatment of TB infection are discussed further separately. (See "Treatment of tuberculosis infection (latent tuberculosis) in nonpregnant adults without HIV infection", section on 'Clinical approach'.)

●Administration of the immunosuppressive agent – Patients can start the biologic or JAK inhibitor at any time after starting preventive therapy for TB infection. We prefer to administer the immunosuppressive agent once the patient has completed at least several weeks of antituberculous treatment [9,38]; this approach is in agreement with the American College of Rheumatology and gives the clinician time to verify the patient is tolerating antituberculous treatment [2].

TB disease

Clinical manifestations

●General principles – General issues related to clinical manifestations of TB disease are discussed separately. (See "Pulmonary tuberculosis: Clinical manifestations and complications" and "Diagnosis of pulmonary tuberculosis in adults".)

●Atypical manifestations – For patients who develop TB disease in association with use of a biologic agent or JAK inhibitor, the likelihood of extrapulmonary involvement, smear-negative disease, and disseminated disease is higher compared with patients who develop TB disease in the absence of these agents [14,39-42]. In one report including 70 patients with TB associated with infliximab, 57 percent had extrapulmonary disease [43]. Patients with disseminated TB may lack pulmonary symptoms and have normal chest radiographs, leading to diagnostic delay. (See "Clinical manifestations, diagnosis, and treatment of miliary tuberculosis".)

●Paradoxical worsening – A paradoxical worsening of TB symptoms can occur after starting TB treatment in patients who discontinue immunosuppressive therapy; this is known as immune reconstitution inflammatory syndrome (IRIS) [44-46]. In one study IRIS developed in 7 percent of patients developed TB disease after TNF-alpha inhibitor withdrawal; IRIS occurred a median of 45 days after starting TB treatment and 110 days after the last TNF-alpha inhibitor dose [47,48]. (See "Immune reconstitution inflammatory syndrome", section on 'Tuberculosis'.)

Management

●Antimycobacterial therapy – Treatment of TB disease is discussed separately. (See "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults without HIV infection" and "Clinical manifestations, diagnosis, and treatment of miliary tuberculosis", section on 'Treatment'.)

●Approach to immunosuppression – Patients on a biologic agent or JAK inhibitor at the time of TB diagnosis should discontinue it; it may be resumed following completion of treatment for TB disease. Decisions regarding resumption of immunosuppression prior to completion of TB treatment should be guided by clinical circumstances; this may be feasible for certain patients in the setting of drug-susceptible TB, sputum culture conversion to negative, and clinical improvement.

●Immune reconstitution inflammatory syndrome – Issues related to management of IRIS are discussed separately. (See "Treatment of pulmonary tuberculosis in adults with HIV infection: Follow-up after initiation of therapy", section on 'Immune reconstitution inflammatory syndrome'.)

NONTUBERCULOUS MYCOBACTERIAL DISEASE

Epidemiology — In areas of low tuberculosis (TB) incidence, nontuberculous mycobacterial (NTM) disease occurs more commonly than TB among patients on biologic agents or JAK inhibitors. NTM disease in the setting of these agents is most often attributed to use of tumor necrosis factor (TNF)-alpha inhibitors. In one study including more than 8400 patients with rheumatoid arthritis on TNF-alpha inhibitors, the incidence of NTM disease was 106 per 100,000; this was approximately double the rate among patients with rheumatoid arthritis and no TNF-alpha inhibitor exposure (figure 2) [49]. In addition, rheumatoid arthritis is an independent risk factor for NTM disease (irrespective of risk associated with use of immunosuppressive agents) [50,51].

In a review including 105 patients receiving TNF-alpha inhibitors with NTM disease, the median age was 62 years, females predominated (65 percent), and most had rheumatoid arthritis (70 percent) [52]. Most patients were also taking prednisone (65 percent) or methotrexate (55 percent). M. avium was the most common NTM species, occurring in 50 percent of patients. Extrapulmonary disease was observed in 44 percent of cases, including involvement of skin and soft tissues (26 percent), bones or joints (9 percent), disseminated disease (8 percent), or the eye (1 percent).

Clinical manifestations and diagnosis

●Clinical manifestations – NTM infection of the lungs often occurs in the context of preexisting lung disease, especially bronchiectasis, chronic obstructive pulmonary disease (COPD), pneumoconiosis, cystic fibrosis, or previous tuberculosis. Clinical manifestations include cough, fatigue, malaise, fever, weight loss, dyspnea, hemoptysis, and chest discomfort. (See "Overview of nontuberculous mycobacterial infections".)

●Diagnosis – There is no established screening test for NTM infection. Diagnostic evaluation includes chest computed tomography (CT) and culture of respiratory specimens; this is discussed further separately. (See "Diagnosis of nontuberculous mycobacterial infections of the lungs".)

Management

●Antimycobacterial therapy – Issues related to treatment of NTM infections are discussed separately. (See "Overview of nontuberculous mycobacterial infections" and "Treatment of Mycobacterium avium complex pulmonary infection in adults" and "Treatment of osteomyelitis due to nontuberculous mycobacteria in adults" and "Rapidly growing mycobacterial infections: Mycobacteria abscessus, chelonae, and fortuitum".)

●Administration of the immunosuppressive agent – Biologic agents and JAK inhibitors should be discontinued in patients with NTM disease. The optimal approach to timing for resumption is uncertain given lack of data; the approach should be individualized based on clinical factors including the pathogen, disease burden, and severity of the underlying inflammatory condition.

SUMMARY AND RECOMMENDATIONS

●Risk of tuberculosis (TB) – Use of biologic agents and Janus kinase (JAK) inhibitors is associated with increased risk of TB disease. The risk of TB and its timing are variable depending on the agent. (See 'Quantifying risk for TB' above.)

●TB infection

•Screening prior to immunosuppression – All patients who are planning to undergo treatment with a biologic agent or JAK inhibitor should be screened for TB infection prior to initiation of immunosuppressive therapy. (See 'Screening' above.)

-Screening should include clinical history, physical examination, and a screening test (preferably interferon-gamma release assay [IGRA]) (algorithm 1 and algorithm 2).

-For patients with positive IGRA or tuberculin skin test (TST) and no clinical manifestations of TB, a chest radiograph should be obtained (algorithm 3). For patients with abnormal chest radiograph, three sputum specimens should be obtained.

•Surveillance screening – For patients on a biologic agent or JAK inhibitor who have ongoing risk of TB exposure, repeat screening for TB infection should be performed annually. (See 'Surveillance screening' above.)

•Management

-Patients with TB infection – For patients who are planning to undergo treatment with a biologic agent or JAK inhibitor, we recommend treatment for those who are diagnosed with TB infection or have a history of inadequately treated TB infection (Grade 1B). (See 'Indications for treatment' above.)

-Patients with negative or indeterminate results – For patients with negative or indeterminate screening test results for TB infection, treatment decisions should be individualized based on the risk of TB exposure and the likelihood that a negative test may represent a false-negative result. (See 'Indications for treatment' above.)

-Regimen selection – Patients who warrant treatment for TB infection may be treated with any approved regimen (table 2); while rifampin-based regimens are preferred, drug-drug interactions should be considered carefully. (See 'Clinical approach' above.)

-Initiating immunosuppression – Patients can start the biologic or JAK inhibitor at any time after starting preventive therapy for TB infection. We prefer to administer the immunosuppressive agent once the patient has completed at least several weeks of antituberculous treatment. (See 'Clinical approach' above.)

●TB disease

•Clinical manifestations – The likelihood of extrapulmonary TB, smear-negative disease, and disseminated disease may be higher among patients on biologic agents or JAK inhibitors. In addition, a paradoxical worsening of TB symptoms can occur after starting TB treatment in patients who discontinue immunosuppressive therapy. (See 'Clinical manifestations' above.)

•Management – Patients on a biologic agent or JAK inhibitor at the time of TB diagnosis should discontinue it; it may be resumed following completion of treatment for TB disease. Decisions regarding resumption of immunosuppression prior to completion of TB treatment should be guided by clinical circumstances. (See 'Management' above.)

●Nontuberculous mycobacterial (NTM) disease – In areas of low TB incidence, NTM disease occurs more commonly than TB among patients on biologic agents or JAK inhibitors. Immunosuppressive agents should be discontinued in patients with NTM disease. The optimal approach to timing for resumption is uncertain; it should be individualized based on clinical factors. (See 'Nontuberculous mycobacterial disease' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Robert S Wallis, MD, who contributed to an earlier version of this topic review.