HomeTNF-alpha inhibitors (TNFi), including infliximab, adalimumab, etanercept, golimumab and certrolizumab, are associated with an elevated risk of reactivation of TB disease. Multiple registry analyses estimate the risk of TB to be more than twice that of patients with inflammatory disease not taking TNFi and up to 20 times higher than the general population.76–79
TB reactivation rates appear higher when TNFi therapy is given along with methotrexate or azathioprine.80 Furthermore, within the TNFi class, infliximab and adalimumab appear to convey a higher risk of TB reactivation than etanercept.81,82 The introduction of systematic screening for TB infection prior to initiation of treatment with TNFi appears to have reduced, but not eliminated, TB in people receiving these agents.79,83,84
TNF-a is a cytokine essential for the activation of macrophages and the formation and maintenance of granulomas.85 The inhibition of TNF-a function leads to reduced immunologic containment of TB infection and can alter the clinical presentation of disease.
Indeed, people with TNFi-associated TB are more likely to have disseminated, meningeal and extra-pulmonary disease and less likely to have cavitary chest disease or sputum smear positivity.86,87 This atypical presentation may delay TB recognition.87,88 TB in patients treated with TNFi usually occurs within a median of 3 months after starting TNFi therapy.87,89
Sometimes, use of TNFi is delayed in patients who are under evaluation for possible TB before the diagnosis is confirmed, out of concern that the immune suppression may hasten disease progression or lead to dissemination before effective anti-TB therapy can be established.90–92 However, it should be noted that abrupt TNFi withdrawal may be associated with exacerbation of TB disease despite anti-TB treatment, somewhat analogous to IRIS seen in HIV-coinfected patients.93,94 Vigilance for this effect is prudent and re-introduction of TNFi has been reportedly effective in its management.86,92,95,96 Small cohort studies and clinical experience suggest that TNFi can be safely administered once patient is established on effective TB therapy and provided that drug-resistance is not suspected.95,97–100
Despite lack of experimental data, many experts recommend longer treatment courses in patients receiving TNFi, reasoning that, as for people with untreated HIV infection, and thus persistent immune dysfunction, treatment extension may reduce relapse risk.16 Relapse in people re-started on TNFi therapy and completing standard TB treatment durations has been reported.21,95
Recommendations
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We conditionally recommend that, where TNF-alpha inhibitors are stopped following the development of TB disease, it can be re-introduced once the patient is established on effective TB therapy (poor evidence).
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We conditionally recommend extending TB treatment to nine months in patients receiving TNF-alpha inhibitors (poor evidence).
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