Infectious Complications of Biologic Agents
Section snippets
Infections associated with tumor necrosis factor antagonists
Most of the pivotal RCTs did not report an increase rate of infections.6, 7, 8 Short-term follow-up, selection bias, and low statistical power for detecting infrequent adverse events may explain the results. Nonetheless, this finding has not been consistent, with some investigators describing an increased rate of infections. Keystone and colleagues,9 in a 52-week trial of adalimumab, found that the proportion of patients who had a serious infection was 3.8% versus 0.5% in the placebo group (P
Infections associated with non–tumor necrosis factor antagonists
Besides the three TNF antagonists, other biologic DMARDs targeting different molecules or sites, such as ABA and RTX, have been developed and approved to treat RA.
TCZ is a humanized monoclonal antibody targeting the interleukin 6 receptor that was licensed in Japan to treat RA and juvenile idiopathic arthritis; it also has been approved in the European Union and in other countries for treatment of RA. Most of the safety data obtained for these agents come from RCTs. Overall, an increased risk
Opportunistic and rare infections
In recent years, various unusual infections that usually occur in immunocompromised patients have been reported to be associated with the use of TNF blockers. Case reports published include infections by toxoplasma,47 listeria,48, 49 histoplasma,50 leishmania,51 coccidioidomycosis,52 and legionella infections,53, 54 among others. In France, a registry of patients who had opportunistic or severe infections registered over a 1-year reported 10 consecutive cases of pneumonia due to legionella. Of
Tuberculosis and other mycobacterial infections with tumor necrosis factor antagonists
TB is a major cause of illness and death worldwide, especially in Asia and Africa. An estimated 1.5 million people died from TB in 2006. In addition, another 200,000 people who had HIV died from HIV-associated TB.57
As discussed previously, a study conducted in Spain demonstrated a fourfold increase (RR 3.68; 95% CI, 2.36–5.92) in TB among patients who had RA in the prebiologics era when compared with the general population, with a mean annual incidence of 124 per 100,000 patients. In Spain, the
Tuberculosis with non–tumor necrosis factor antagonists
As discussed previously, TNF is a relevant cytokine that promotes granuloma formation, which prevents active TB development. Therefore, it is not surprising that blocking other cytokines or sites has not been associated with similar increases in TB infections. Another circumstance that might have contributed to this situation is the increased awareness of the need to prevent this infection. Nonetheless, a few cases of TB associated with the administration of ABA and TCZ36, 70 have been
Nontuberculous mycobacterial infections
Nontuberculous mycobacterial (NTM) infections usually are acquired from environmental sources. Most species are less aggressive than M tuberculosis; therefore, symptomatic infections usually are associated with immunocompromised patients. The most frequent clinical locations of NTM infections are the skin and lungs; however, patients who have HIV infection, patients who are immunosuppressed due to transplants, and patients receiving anti-TNF therapy are susceptible to developing disseminated
Summary
Infection is a frequent complication in RA and other autoimmune diseases. Since 2000 the spectrum of therapeutic possibilities (ie, biologic agents) for treating RA has expanded rapidly. Most of the reports have described an increase of infections with the use of TNF antagonists that also may apply to severe infections, especially when TNF blockers are administered at higher doses than recommended. TB is associated with the use of TNF blockers. In most cases, TB is the result of latent TB
Acknowledgments
We are indebted to the Spanish Society of Rheumatology, especially to Loreto Carmona, for providing unpublished data for the BIOBADASER database. We also thank her for reviewing and providing invaluable suggestions for improving the quality of this manuscript.
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EM-M and AB have received honoraria, less than 10,000 Euros, for educational programs and as advisors for Wyeth, Abbott, Roche, and Schering-Plough.