Managing risks of TNF inhibitors: An update for the internist
ABSTRACTTumor necrosis factor (TNF) inhibitors have many beneficial effects, but they also pose infrequent but significant risks, including serious infection and malignancy. These risks can be minimized by judicious patient selection, appropriate screening, careful monitoring during treatment, and close communication between primary care physicians and subspecialists.
KEY POINTS
- Over the past 10 years, TNF inhibitors have substantially altered the management of autoimmune diseases such as rheumatoid arthritis and inflammatory bowel disease.
- Safety concerns include risks of infection, reactivation of latent infection (eg, fungal infection, granulomatous infection), malignancy, and autoimmune and neurologic effects.
- Before treating, take a complete history, including exposure to latent infections and geographic considerations, and bring patients’ immunizations up to date.
- Regular clinical and laboratory monitoring during treatment helps optimize therapy and minimize the risk of adverse effects.
- Physicians must be aware of atypical presentations of infection and understand how their treatment may differ in patients on biologic therapy.
Granulomatous infections such as tuberculosis
Anti-TNF agents increase the risk of de novo granulomatous infections and of reactivating such infections. Granuloma formation and intracellular destruction of mycobacteria depend on TNF. TNF is important in maintaining the anatomic integrity of granulomas where these organisms have been sequestered, and blocking TNF leads to breakdown of granulomas and release of virulent organisms.69,70
TNF inhibitors increase the risk of reactivation of latent tuberculosis infection. The risk is greater with infliximab and adalimumab than with etanercept,71,72 and it has been described with certolizumab.74 Study results are varied thus far but show a risk of tuberculosis reactivation five to 30 times higher than in the general population, with tremendous variability in risk depending on background rates of previous exposure.
The absence of typical tuberculosis symptoms further complicates care in these cases. Fever, weight loss, and night sweats tend to be TNF-mediated and are therefore masked by anti-TNF agents, leading to atypical presentations. In addition, active tuberculosis infection associated with TNF inhibitors is more likely to involve extrapulmonary sites such as the skin and musculoskeletal system and to be disseminated at presentation.
A paradoxical worsening of tuberculosis symptoms may also be seen in patients with latent tuberculosis reactivation, especially after discontinuing anti-TNF therapy. This is thought to result from an immune reconstitution inflammatory syndrome.
The pretreatment evaluation should include a history of risk factors, a physical examination, and either a tuberculin skin test or an interferon-gamma-release assay. Interferon-gamma-release assays are particularly helpful in patients who have received bacille Calmette-Guérin vaccination. In patients who test positive or have been exposed, tuberculosis treatment should begin 4 weeks before starting anti-TNF therapy, though the optimal timing of antituberculosis agents is still controversial.74–77
If tuberculosis develops in a patient on anti-TNF therapy, he or she should receive antituberculosis drugs. Anti-TNF therapy should be stopped and should be resumed after 2 months only if no other treatment option is available.75
Invasive opportunistic fungal infections
Invasive opportunistic fungal infections have been reported with anti-TNF therapy, including histoplasmosis and coccidioidomycosis.78–80 Most patients who had histoplasmosis were treated with other immunosuppressive therapies and resided in or were raised near the Ohio or Mississippi River valleys, where this disease is endemic. Similarly, most cases of coccidioidomycosis were in endemic areas of Arizona, California, and Nevada, and patients on concomitant immunosuppressive therapy.78
Currently, there is no evidence to recommend obtaining Histoplasma capsulatum or Coccidioides immitis serologies before initiating anti-TNF therapy in patients in endemic areas.81 However, patients must be instructed to seek medical attention quickly for pulmonary or febrile illnesses.
Viral hepatitis infections
The data on hepatitis B and hepatitis C in patients on biologic therapies are mostly limited to case reports.
Hepatitis B. A small prospective study from Spain followed the liver biochemistry tests and hepatitis B status of 80 patients with Crohn disease treated with infliximab. Of three patients who were chronic hepatitis B carriers before starting infliximab, two experienced reactivation of hepatitis B after discontinuing infliximab, and one ultimately died. The third patient was treated with lamivudine concurrently with infliximab without clinical or biochemical changes during or after therapy.82
Similar findings were observed in two patients with rheumatoid arthritis on treatment with infliximab. One of the patients required liver transplantation, and both were treated with lamivudine, resulting in normalization of liver function test results.83,84
Recent reviews indicate that despite these findings, hepatitis B reactivation after anti-TNF withdrawal may not be common.85 There are limited data on hepatitis B reactivation and associated liver dysfunction in patients with inflammatory bowel disease treated with immunosuppressants. In a retrospective multicenter trial by Loras et al86 in patients with inflammatory bowel disease who had viral hepatitis, 36% of patients positive for hepatitis B surface antigen developed liver dysfunction, and six patients developed liver failure. In that study, treatment with more than two immunosuppressants was an independent predictor of hepatitis B reactivation.
Prolonged immunosuppression (longer than 3 months) has also been identified as an independent predictor of liver dysfunction (OR 3.06; 95% 95% CI 1.02–9.16).87
The European Association for the Study of the Liver and the American Association for the Study of Liver Diseases recommend starting lamivudine before chemotherapy or immunomodulator or immunosuppressive therapy in hepatitis B virus carriers and continuing preventive treatment for at least 6 months after stopping immunomodulating drugs. Lamivudine at a dose of 100 mg/day may reduce the risk of reactivation of hepatitis B.88–90 Tenofovir and entecavir may be useful alternatives in patients with hepatitis B who have never received nucleoside analogues. Hepatitis B reactivation did not occur in any of the 16 patients who received preventive entecavir treatment while receiving immunosuppressive treatments.89,91
In patients receiving immunosuppressive therapy, hepatitis B reactivation is associated with significant morbidity and mortality. Although risk factors for reactivation of hepatitis B virus infection have been identified, we recommend preventive treatment for all carriers positive for hepatitis B surface antigen. This should be done regardless of the number, type, and dosage of immunosuppressants and regardless of hepatitis B virus DNA levels.90
The frequency of hepatitis B and hepatitis C infection in patients with Crohn disease has been reported to be as high as 24%. The high incidence is thought to be secondary to multiple blood transfusions and surgeries.92 The use of biologic agents, including anti-TNF agents, in chronic hepatitis B virus- or hepatitis C virus-infected patients can lead to enhanced viral replication and hepatitis exacerbation.
Although active viral replication can occur during treatment with biologic agents, reactivation or exacerbation can also occur after the anti-TNF agent is stopped.82 This finding has prompted the recommendation that all candidates for biologic therapy be tested for hepatitis B immunization status, followed by immunization in nonimmune patients before starting anti-TNF therapy.93,94
Hepatitis C. There are no guidelines that adequately address the use of anti-TNF agents in patients with chronic hepatitis C infection.
Several small retrospective studies in rheumatoid arthritis patients with hepatitis C have shown that TNF inhibitors can be safely used without worsening liver function tests or changing the viral load.95–98 This is reassuring and provides the subspecialist with another treatment option, as other therapies such as disease-modifying antirheumatic drugs and steroids are known to aggravate viral hepatitis and increase the risk of viremia.96
Although small retrospective studies and one large randomized double-blind placebo-controlled trial have shown TNF inhibitors to be relatively safe in rheumatoid arthritis patients with hepatitis C, their use in these patients should be considered only with caution if they have evidence of hepatic synthetic dysfunction (eg, hypoalbuminemia, thrombocytopenia, increased international normalized ratio). The American College of Rheumatology recommends avoiding TNF inhibitors in Child-Pugh classes B and C.99
