INTRODUCTION — Inhibitors of tumor necrosis factor (TNF)-alpha represent important treatment advances in a number of inflammatory conditions, including rheumatoid arthritis, the seronegative spondyloarthropathies, psoriasis, and inflammatory bowel disease. TNF-alpha inhibitors offer a targeted strategy that contrasts with the nonspecific immunosuppressive agents traditionally used to treat most inflammatory diseases.
However, multiple potential complications and adverse effects of targeted TNF-alpha inhibition have been identified. These include:
●Mycobacterial infections including those due to Mycobacterium tuberculosis (tuberculosis [TB]) and nontuberculous mycobacteria (NTM)
●Other infections (bacterial, viral, and fungal)
●Injection site reactions
●Infusion reactions
●Induction of autoimmunity
●Demyelinating disease
●Nonmelanomatous skin cancer
The association between TNF-alpha inhibitor use and TB mycobacterial infections will be reviewed here. Other major complications of TNF-alpha therapy 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" and "Tumor necrosis factor-alpha inhibitors: Risk of malignancy" and "Tumor necrosis factor-alpha inhibitors: Induction of antibodies, autoantibodies, and autoimmune diseases".)
TNF-ALPHA INHIBITORS — Several inhibitors of TNF-alpha have been approved for the treatment of a variety of inflammatory illnesses (eg, rheumatoid arthritis, Crohn disease) by the US Food and Drug Administration. These medications are:
●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
These agents are discussed in detail elsewhere. (See "Overview of biologic agents and kinase inhibitors in the rheumatic diseases", section on 'TNF inhibition'.)
TNF-ALPHA AND HOST DEFENSES — The importance of TNF-alpha in protection against several mycobacterial infections, including M. tuberculosis, Mycobacterium avium, Mycobacterium bovis, and Bacillus Calmette-Guérin (BCG), has been studied in animal models [1-5]. Host defense against mycobacteria rely on the granulomatous response in which bacilli are sequestered within granulomas, which are comprised of a central core of macrophages, multinucleated giant cells, and necrotic debris surrounded by macrophages and lymphocytes [6]. TNF-alpha is required for the orderly recruitment of these cells and for continued function of the granuloma [1,7,8]. In addition, the ability of macrophages to contain intracellular tuberculosis bacillary growth is dependent on TNF-alpha [9,10]. (See "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects", section on 'TNF-alpha and host defenses'.)
TUBERCULOSIS
Risk of tuberculosis — All TNF-alpha inhibitors increase the risk of tuberculosis (TB) [11-20], although the risk elevation is greater for the anti-TNF monoclonal antibodies infliximab and adalimumab than for the soluble receptor fusion protein etanercept [11-14,19,21]. The risk associated with the newer monoclonal agents certolizumab and golimumab has not been established in population-based studies or compared with the other agents. However, TB cases have been reported with the use of these agents, and their risk is presumed to be similar to the other monoclonal anti-TNF agents [22,23]. Many of the TB cases associated with TNF-alpha inhibitors likely represent reactivation of latent tuberculosis infection (LTBI), hence the rationale for screening for LTBI before initiating therapy. In areas of low TB prevalence, a minority of TNF-alpha inhibitor-associated cases represent newly acquired infection.
Elevated TB rates were first noted in randomized clinical trials of these compounds. For the older compounds (ie, infliximab, etanercept, adalimumab), which have been available for some time, risk has since been studied in a population-based fashion. Such studies clearly show that the risk of TB with these agents varies strongly according to background regional TB risk. Older studies conducted before TB screening prior to the initiation of a TNF-alpha inhibitor was widespread report higher risk estimates than more recent studies. A systematic review of TB incidence in patients receiving biologic agents supports these ideas as well as the effectiveness of screening for LTBI prior to the use of these agents (figure 1) [24].
The first population-based study to compare the incidence of TB among individual TNF-alpha inhibitors was conducted within the British Society for Rheumatology Biologics Register, a national prospective observational study (figure 2) [21]. This registry was used to compare rates of TB in >10,000 patients treated with a TNF-alpha inhibitor (3295 receiving infliximab, 3913 receiving etanercept, 3504 receiving adalimumab) and 3232 patients with active rheumatoid arthritis (RA) receiving traditional disease-modifying antirheumatic agents. The following findings were noted:
●There were 40 cases of TB, all in the TNF-alpha cohort.
●The rate of TB was higher among patients receiving adalimumab (144 events per 100,000 person-years) or infliximab (136 events per 100,000 person-years) compared with etanercept (39 events per 100,000 person-years).
●After adjustment, the incidence-rate ratio compared with patients who were receiving etanercept was 3.1 (95% CI 1.0-9.5) for infliximab and 4.2 (95% CI 1.4-12.4) for adalimumab.
●Twenty-five of 40 cases of TB (62 percent) were extrapulmonary; 11 cases involved disseminated disease.
●Patients of non-White race had a sixfold increased risk of TB than White patients.
●The median time to onset of disease was shortest for infliximab compared with the other TNF-alpha inhibitors. (See 'Time to onset' below.)
Influence of underlying RA — Some of the studies cited above compared the incidence of TB in patients on TNF-alpha inhibitors with the baseline population risk. However, this may overestimate the absolute increase in risk since the majority of patients on these drugs have rheumatoid arthritis (RA), and RA itself has been associated with the development of TB in some [17,25,26], but not all [27], studies.
Nevertheless, TNF-alpha inhibitors appear to increase the risk of TB beyond that which may be associated with RA itself. This was illustrated by hospitalization data from Sweden between 1999 and 2001 that assessed the relative risk of TB in RA patients compared with the general population, as well as the risk of TB in RA patients receiving TNF-alpha inhibitors compared with RA patients not treated with these agents [17]. The relative risk of TB among RA patients who were not treated with TNF-alpha inhibitors compared with the general population was 2.0 (95% CI 1.2-3.4). In contrast, the relative risk of RA patients treated with TNF-alpha inhibitors compared with RA patients not treated with TNF-alpha inhibitors was 4.0 (95% CI 1.3-12).
Biological basis of differential risks — Animal and in vitro studies support the biologic plausibility of the observations from population-based studies that etanercept increases the risk of TB to a lesser extent than adalimumab or infliximab. Potential explanations include varying degrees of granuloma penetration, differential downregulation of TB antigen-stimulated interferon-gamma production, and varying effects upon antimicrobial-producing CD8 effector cells [28-30].
●In a murine model of acute tuberculosis infection, no difference was observed in survival or bacillary load between mice treated with etanercept, adalimumab, and infliximab [30]. However, in a chronic infection model (meant to simulate latent TB), bacillary load was lower and survival was greater in the mice treated with etanercept. The authors noted differences in the degree of granuloma penetration among these animals on autopsy, in that etanercept was found to a lesser extent within granulomas. The authors hypothesized that the greater penetration of granulomas with the monoclonal antibodies could lead to greater interruption of cell-cell signaling and greater granuloma dysfunction as potential explanation for the differential survival observed between the etanercept- and monoclonal antibody-treated animals. However, this hypothesis was not directly tested.
●T cell dysfunction without cell death was observed in a study in which whole-blood cultures were exposed to TNF-alpha inhibitors [29]. Infliximab and adalimumab reduced the proportion of TB-responsive CD4 cells by 70 and 50 percent in vitro, respectively, and suppressed antigen-induced interferon-gamma production by 65 to 70 percent. In contrast, etanercept had significantly less effect on these parameters. Thus, the increased TB risk with infliximab and adalimumab may reflect their combined effects on TNF-alpha and interferon-gamma.
●An in vitro study evaluated the effect of infliximab upon granulysin and perforin, two antimicrobial peptides with direct bactericidal effects against tuberculosis bacilli [28]. Investigators observed that the M. tuberculosis-reactive CD8+CCR7-CD45RA+ effector memory T cells (TEMRA cells) that express both granulysin and perforin are significantly downregulated by complement-mediated lysis induced by infliximab's inhibition of membrane-bound TNF. Since etanercept is well-known to have less membrane TNF-binding capacity and avidity than the monoclonal antibodies, the authors hypothesized that a greater downregulation of these antimicrobial peptides would be seen in monoclonal-treated patients, resulting in less robust human defenses against TB. However, it should be noted that the authors did not directly explore this hypothesis in their study nor did they compare downregulation of these peptides between etanercept and the monoclonal antibodies.
Data from these and other studies evaluating potential differential effects of these drugs on host immune responses to TB suggest there is biologic plausibility to the observed risk difference in population-based studies. However, which potential biologic explanations are of highest relevance remain unclear.
Time to onset — Cases of TB that occur soon after the initiation of a TNF-alpha inhibitor are likely to represent reactivation of LTBI, whereas those that occur later may represent either delayed reactivation or newly acquired TB infection progressing directly to active disease. Several studies have indicated shorter times to TB onset for infliximab (range of median values 12 to 32 weeks) compared with etanercept (18 to 79 weeks) [11,12,14-17,21,27]. In the study cited above from the United Kingdom evaluating all three drugs, the median time to event was lowest for infliximab (5.5 months) compared with etanercept (13.4 months) and adalimumab (18.5 months) (figure 2) [21]. Thirteen of 40 cases occurred after discontinuing treatment. The basis for different times of onset is unknown, but delayed onset may reflect differential drug effects on reactivation risk, occurrence of new infection, or the waning effects of prior isoniazid therapy for prevention of reactivation.
In another study, 43 percent of infliximab-associated cases of TB occurred during the first 90 days of treatment, a pattern consistent with reactivation of latent infection. In 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 [15]. (See 'Risk of tuberculosis' above.)
Clinical features of TB in the anti-TNF setting — Similar to tuberculosis (TB) that occurs with other types of immunosuppression, TB occurring in association with TNF-alpha inhibitors has a higher likelihood of involving extrapulmonary sites and of being disseminated at presentation compared with TB cases in the absence of immunosuppression [29,31-34]. Patients with disseminated TB may lack pulmonary symptoms and have normal chest radiographs, leading to delays in diagnosis. Patients should be educated on the pulmonary and extrapulmonary signs and symptoms of TB, including cough, fever, malaise, weight loss, night sweats, and enlarged lymph nodes. Patients with clinical findings suggestive of TB should undergo diagnostic testing without delay. (See 'Risk of tuberculosis' above and "Clinical manifestations, diagnosis, and treatment of miliary tuberculosis" and "Clinical manifestations and complications of pulmonary tuberculosis" and "Diagnosis of pulmonary tuberculosis in adults".)
A paradoxical worsening of symptoms (immune reconstitution inflammatory syndrome [IRIS]) occurs in a small percentage of patients after starting TB therapy and discontinuing the TNF-alpha inhibitor. (See 'Disease worsening during TB treatment' below.)
Screening and prevention — Given the risk of reactivation of LTBI in patients receiving a TNF-alpha inhibitor, it is crucial to screen all patients for LTBI prior to starting a TNF-alpha inhibitor. Most recent recommendations suggest that screening include a careful history focused on identifying potential epidemiologic risk factors for prior TB exposure, a physical examination, a tuberculin skin test (TST) and/or interferon-gamma release assay (IGRA), and a chest radiograph in those with a positive TST or IGRA or a history or physical examination suggestive of TB [7,32,35-39]. Patients with evidence of LTBI should initiate LTBI therapy prior to starting a TNF-alpha inhibitor. (See 'Latent tuberculosis infection' below.)
Our approach to screening for LTBI varies depending upon whether the patient has any risk factors for LTBI:
●Patients with risk factors for LTBI – Data suggest that using only one screening test does not identify all patients at risk for TB, as false-negative results are more likely in immunocompromised individuals [22,40,41]. A dual testing strategy is consistent with recommendations from the American College of Rheumatology as well as some public health agencies [35-37,39,42,43].
Accordingly, in patients with risk factors for prior TB exposure, we favor a dual testing strategy in which we check a second test if the first test is negative. Specific recommendations are provided in the following algorithm (algorithm 1). We generally use the IGRA as the initial screening test. We prefer the IGRA over the TST as it is likely more sensitive under conditions of immunosuppression, it can be accomplished in one visit, and it eliminates the need to know a patient's Bacille Calmette-Guérin (BCG) history (which is not always clear). However, in patients who have not received the BCG vaccine, the TST is a reasonable alternative.
●Patients without risk factors for LTBI – For patients without risk factors for LTBI, screening with one test should be performed. In such patients, it is unlikely that a dual testing strategy would sufficiently increase screening sensitivity in order to justify a second test in those whose initial test is negative. As noted above, we prefer the IGRA but, in those who have not received the BCG vaccine, the TST is a reasonable alternative. Specific recommendations are provided in the following algorithm (algorithm 2).
When the IGRA result is indeterminate with either test, repeat testing is indicated in patients with risk factors for LTBI (algorithm 1) and patients without risk factors (algorithm 2). Available IGRAs include the QuantiFERON-TB Gold Plus and the T-SPOT.TB assay. When retesting, it is acceptable to use either the same IGRA or another assay.
Given the improved specificity of IGRAs in patients who have received BCG, they are preferentially recommended over the TST in patients with prior BCG use [35,39]. The evaluation for LTBI in patients who have received BCG is discussed in more detail separately. (See "Use of interferon-gamma release assays for diagnosis of latent tuberculosis infection (tuberculosis screening) in adults".)
At least one population-based study attests to the effectiveness of screening and treating LTBI prior to initiating TNF-alpha inhibitor therapy. After widespread institution of TB screening in patients planning to start a TNF-alpha inhibitor in Spain in 2002, investigators measured TB incidence and found a 74 percent reduction in TB among patients treated with infliximab. Data from randomized clinical trials further attest to the effectiveness of screening [44]. Most notably, in early adalimumab trials, the incidence of TB dropped after the introduction of mandatory screening prior to therapy start [45]. Other more recent trials also indirectly suggest that screening is effective, in that patients who screen positive and are treated for LTBI have a very low risk for subsequent TB in the setting of TNF-alpha inhibitor use [22,46,47].
Screening for LTBI in patients preparing to receive a TNF-alpha inhibitor is recommended by the United States Centers for Disease Control and Prevention (CDC), the American College of Rheumatology, and a variety of other agencies and specialist societies [32,35-37,39,48].
The management of LTBI is discussed below. (See 'Latent tuberculosis infection' below.)
Rescreening — The need to rescreen patients during ongoing or subsequent TNF-alpha antagonist use is debated [49]. Clearly, patients at risk of ongoing TB exposure should be rescreened [36,37]. However, for patients who have screened negative or who have successfully completed LTBI therapy who lack the potential for subsequent TB exposure, rescreening is probably unnecessary. This is consistent with recommendations for other immunocompromised hosts, such as patients with human immunodeficiency virus (HIV) infection, for whom guidelines recommend annual screening only in patients at high risk for TB exposure [50].
Management — As noted above, the CDC recommends starting treatment for LTBI prior to starting a TNF-alpha inhibitor [32]. We agree with this recommendation. (See 'Screening and prevention' above.)
In addition, when active TB infection is diagnosed in a patient receiving a TNF-alpha inhibitor, the TNF-alpha inhibitor should be discontinued and treatment for active TB should be initiated. (See 'Active tuberculosis' below.)
Latent tuberculosis infection
Indications for treatment — The indications for treatment of LTBI include the following:
●In accordance with the CDC, we recommend treatment of LTBI for all patients planning to take a TNF-alpha inhibitor who have a positive TST (≥5 mm induration) or IGRA and no evidence of active tuberculosis [32,35].
●TNF-alpha inhibitor candidates with a negative TST (<5 mm) or IGRA should also be treated if they have previously been diagnosed with LTBI but did not complete LTBI therapy.
●The treatment of patients with a negative LTBI screening test should be made on a case-by-case basis, depending on the risk of TB exposure and the likelihood that a negative test represents a false-negative result [35-37,43]. The same concept applies to patients with indeterminate IGRA results. Although the risk of LTBI is lower in such patients than in patients with a positive screening test, treatment for LTBI should be considered if there is 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 having resided in a country with high TB prevalence). We have a lower threshold for treating patients who were immunocompromised at the time of testing for LTBI, given that immunocompromisation lowers the sensitivity of these tests.
The approach to screening and management of LTBI is summarized in algorithms for patients with risk factors for LTBI (algorithm 1) and for patients without risk factors for LTBI (algorithm 2).
Clinical approach — Patients who warrant LTBI treatment may be treated with any approved regimen; these are summarized in the table and discussed separately (table 1) [51]. (See "Treatment of tuberculosis infection in nonpregnant adults without HIV infection", section on 'Clinical approach'.)
We prefer a delay of one to two weeks between starting LTBI therapy and starting a TNF-alpha inhibitor, to ensure the patient is tolerating LTBI treatment prior to initiation of TNF-alpha inhibition. However, the optimal time interval is uncertain; some data suggest that no delay is necessary and that treatment for LTBI may start any time prior to initiation of the TNF-alpha inhibitor (including the same day) [22].
Active tuberculosis — When active TB disease is diagnosed in a patient receiving a TNF-alpha inhibitor, treatment for active TB should be initiated without delay. Most authorities recommend that anti-TNF-alpha therapy be discontinued, at least temporarily. The optimal timing of reinitiation of a TNF-alpha inhibitor in patients with active TB remains to be determined. Some authorities suggest that TNF-alpha inhibitor treatment may be resumed after drug susceptibility results are known and clinical improvement is evident [32,52].
A small phase I trial of 16 patients with HIV infection with pulmonary TB who were started on adjunctive etanercept on day 4 of antituberculous therapy suggests that it is safe to use etanercept in this setting [53]. However, these reports involved a different patient population than those who typically require TNF-alpha inhibitor therapy. Further prospective studies are required before TNF-alpha inhibitors can be recommended routinely during the early phase of antituberculous therapy.
The treatment of active TB is discussed elsewhere. (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'.)
Disease worsening during TB treatment — Discontinuation of a TNF-alpha inhibitor in the setting of active tuberculosis (TB) may be associated with a paradoxical worsening of TB [54-56]. The basis for this is hypothesized to be an immune reconstitution inflammatory syndrome. A retrospective analysis of the French RATIO biologics registry identified disseminated TB as a risk factor for IRIS due to TNF-alpha inhibitor withdrawal (odds ratio 11.4) [57]. In such cases, the use of glucocorticoids may be beneficial. In rare cases, a TNF-alpha inhibitor has been reintroduced to treat severe paradoxical reactions unresponsive to glucocorticoids [58]. (See "Immune reconstitution inflammatory syndrome".)
NONTUBERCULOUS MYCOBACTERIAL DISEASE — Several years after the recognition of TNF-alpha inhibitor-associated tuberculosis (TB), reports of nontuberculous mycobacterial (NTM) disease were published. A 2007 survey of Infectious Diseases Society of America members of the Emerging Infections Network suggested that, in the United States, NTM infections were more likely than TB in patients receiving these agents [59]. Respondents were asked to report mycobacterial infections in their patients over the previous six months. In patients receiving biologic therapies, NTM infections were reported nearly twice as often as TB (32 versus 17 cases, respectively). M. avium complex was the most frequently reported NTM species (in 16 patients), followed by M. chelonae (in 5 patients), M. abscessus (in 3 patients), M. marinum (in 3 patients), and others (in 5 patients).
The epidemiology and clinical presentations of NTM infections in patients receiving TNF-alpha inhibitors was evaluated in a later review of the US MedWatch surveillance system, which included all cases reported through January 1, 2007 [60]. Of 239 cases reported, 105 (44 percent) met NTM disease criteria. Among those with NTM infections, the median age was 62 years, women predominated (65 percent), and most (70 percent) had rheumatoid arthritis (RA). Most patients were taking prednisone (65 percent) or methotrexate (55 percent) in combination with a TNF-alpha inhibitor. M. avium was the most common species implicated, occurring in 50 percent of patients. Similar to TB in the TNF antagonist setting, a high rate of extrapulmonary disease was reported (44 percent), which included the skin and soft tissues (26 percent), bones or joints (9 percent), disseminated disease (8 percent), and the eye (1 percent).
More recently, several population-based studies have been published documenting that TNF-alpha inhibitors increase the risk of NTM disease. In the United States, an area of low background TB prevalence, the incidence of NTM exceeds that of TB in the setting of TNF-alpha inhibition. A study conducted within the northern California Kaiser Permanente population of over 3 million individuals identified incidence of NTM disease of 106/100,000 among patients with RA using these drugs, a rate approximately double that of RA patients without TNF-alpha inhibitor exposure (figure 3) [48]. Other studies have documented that NTM disease is associated with RA irrespective of therapy, with disease rates several-fold higher in RA patients than in those without RA [61].
Screening and diagnosis — Screening for pulmonary NTM disease prior to biologic therapy remains largely theoretical, although presumably some infected patients are identified during screening for LTBI. Clinical suspicion of chronic pulmonary NTM should be raised in any older adult patient with underlying bronchiectasis or chronic unexplained cough. Bronchiectasis is not uncommon in RA and is strong risk factor for NTM disease, although chest radiographs frequently lack sensitivity to identify the condition. For patients with chronic unexplained cough, further evaluation should include chest computerized tomography and culture of respiratory specimens [48,62]. (See "Diagnosis of nontuberculous mycobacterial infections of the lungs".)
Management — Similar to the approach with TB and other active infections, TNF-alpha inhibitors should be stopped in any patient diagnosed with NTM disease. Whether these agents can be reintroduced during therapy for NTM disease is controversial. In some case series of patients with pulmonary M. avium-intracellulare infection, TNF-alpha inhibitors have been associated with poor outcomes despite antimycobacterial therapy, but, in other case reports, this strategy has appeared to be safe in some patients [20,63,64]. It is likely that the outcomes of such patients largely hinge upon NTM disease burden, the pathogen involved, and other unknown host factors that promote either NTM disease stability or progression.
Antimycobacterial management for NTM infections is discussed in detail 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".)
SUMMARY AND RECOMMENDATIONS
●Tumor necrosis factor (TNF)-alpha inhibitors increase the risk of tuberculosis (TB). This risk is greater with infliximab and adalimumab than with etanercept. The comparative risk of other TNF-alpha inhibitors has not been studied, but the risk is thought to be similar to the other monoclonal antibodies (ie, infliximab, adalimumab). (See 'Risk of tuberculosis' above.)
●Cases of TB occurring in association with TNF-alpha inhibitors have a higher likelihood of involving extrapulmonary sites and of being disseminated at presentation compared with TB in the absence of immunosuppression. (See 'Clinical features of TB in the anti-TNF setting' above.)
●Patients treated with a TNF-alpha inhibitor should be educated on the pulmonary and extrapulmonary symptoms of TB. Patients with symptoms of potential TB should undergo diagnostic testing without delay. (See 'Clinical features of TB in the anti-TNF setting' above.)
●All patients being considered for TNF-alpha inhibitor therapy should be screened for latent tuberculosis infection (LTBI). Appropriate screening includes a careful history focused on epidemiologic risk factors for prior TB exposure, physical examination, the use of screening tests such as the tuberculin skin test (TST) or interferon-gamma release assay (IGRA), and a chest radiograph in those with a positive TST or IGRA or a history or physical exam suggestive of TB. The approach to screening and management of LTBI is summarized in algorithms for patients with risk factors for LTBI (algorithm 1) and for patients without risk factors for LTBI (algorithm 2). (See 'Screening and prevention' above.)
●We recommend that all patients planning to start a TNF-alpha inhibitor who are either diagnosed with LTBI or have a history of inadequately treated LTBI begin a regimen for LTBI prior to initiating anti-TNF-alpha therapy (Grade 1B). Treatment for LTBI treatment should be considered in patients planning to start a TNF-alpha inhibitor who have a negative screening test (or an indeterminate test, for the IGRA) but who have evidence of remote TB disease on chest radiography (eg, regional fibrosis with or without hilar lymphadenopathy) or a high likelihood of prior TB exposure (eg, history of close contact with a TB case or having resided in a country with high TB prevalence), especially in those who were immunocompromised at the time of testing for LTBI. (See 'Indications for treatment' above.)
●Patients diagnosed with LTBI who are planning to take TNF-alpha inhibitors should be treated with four months of rifampin, nine months of isoniazid (INH), or three months of once-weekly INH plus rifapentine (table 1). We prefer some delay between starting LTBI treatment and starting the TNF-alpha inhibitor (eg, one to two weeks) in order to make sure that the patient is taking and tolerating LTBI treatment. Patients should be monitored monthly with liver function tests during therapy for LTBI. (See 'Clinical approach' above.)
●We suggest that anti-TNF-alpha therapy be discontinued in patients who develop active TB at least until drug susceptibility results can be obtained and clinical improvement has been achieved during therapy for TB (Grade 2C). For patients who require continued TNF-alpha inhibitor therapy, we suggest resuming it once the TB has improved on antituberculous therapy (Grade 2C). (See 'Active tuberculosis' above.)
●Discontinuation of a TNF-alpha inhibitor in the setting of TB may be associated with a paradoxical worsening of TB, which is likely due to an immune reconstitution inflammatory syndrome. Patients with this reaction may benefit from glucocorticoids. Some have suggested that the resumption of TNF-alpha inhibitors may be indicated, but this remains controversial. (See 'Disease worsening during TB treatment' above.)
●TNF-alpha inhibitors increase the risk of nontuberculous mycobacterial infections (figure 3). Similar to TB, patients who develop NTM disease while using a TNF-alpha inhibitor should discontinue the anti-TNF therapy while being treated for NTM. (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.
