Patients taking monoclonal anti–tumor necrosis factor antibody therapy were more likely than those on soluble anti-TNF receptor therapy to develop opportunistic infections, other than tuberculosis, in a study of a French national registry.
Of the three anti-TNF agents used in France in 2004-2007, infliximab was associated with an 18-fold increased risk and adalimumab was associated with a 10-fold increased risk for nontuberculosis opportunistic infection, compared with etanercept, Dr. Dominique Salmon-Ceron and her associates reported. The findings were published online on Dec. 21, 2010. A higher incidence of opportunistic infection with infliximab or adalimumab, compared with etanercept, did not reach statistical significance because of the rarity of the infections. But the findings are supported by previous reports from the Food and Drug Administration, a Spanish registry, a study of 21 Japanese patients, and other accounts of a greater risk for opportunistic infection with infliximab, compared with etanercept, the investigators noted (Ann. Rheum. Dis. 2010 Dec. 21 [doi:10.1136/ard.2010.137422]).
The study also identified a third risk factor: treatment with more than 10 mg/day of oral steroids or IV steroid boluses during the year before a diagnosis of non-TB opportunistic infection. Previous studies also identified this risk factor in patients with rheumatoid arthritis or systemic lupus erythematosus, so the current analysis “strengthens the need to avoid high doses of steroids for patients receiving anti-TNF agents,” reported Dr. Salmon-Ceron, who is professor of infectious diseases at Université René Descartes, Paris, as well as a member of the staff at of Hôpital Cochin in that city.
The data in the study come from the 3-year French RATIO (Research Axed on Tolerance of Biotherapies) registry and involved all cases in France of opportunistic infections in patients receiving anti-TNF agents for any reason. The case-control analysis matched each of the 43 case patients (with a total of 45 opportunistic infections) with 3 control patients who took anti-TNF agents without developing opportunistic infections.
Patients had been treated with anti-TNF agents for RA (26), spondyloarthritides (3), inflammatory colitis (8), psoriasis (1), or other problems (5). Four were on etanercept, 10 received adalimumab, and 39 were on infliximab.
Using reports from pharmaceutical companies, the investigators estimated a total of 57,711 patient-years of use of anti-TNF therapy during the study period. They calculated an annual incidence of opportunistic infection in patients receiving anti-TNF agents as 152 per 100,000 patient-years, after adjusting for age and sex.
Differences in the incidence of opportunistic infection differed by anti-TNF agent, but the differences were not statistically significant (7 per 100,000 patient-years with etanercept, 62 per 100,000 patient-years with adalimumab, and 291 per 100,000 patient-years with infliximab). Because the opportunistic infections were rare, the confidence intervals were large and prevented statistical significance in comparisons.
Dr. Salmon-Ceron and her associates previously reported analyses of the same database showing that TB is the most common opportunistic infection in patients on anti-TNF agents, and that these therapies increased the risk for Legionella pneumophila pneumonia. They excluded those two infections from the current study to look at the risk for other infections.
The non-TB opportunistic infections were diverse and severe. Ten of the 43 patients required treatment in the intensive care unit, and 4 died. RATIO followed patients for 3 years from the diagnosis of opportunistic infection. An expert committee of three infectious disease specialists validated the diagnoses of opportunistic infection.
Bacterial infections accounted for a third of the opportunistic infections, including four with listeriosis, four with nocardiosis, four with atypical mycobacteriosis, and three with non-typhoid salmonellosis.
Of the 43 cases, 18 were viral infections, including 8 with severe herpes zoster, 3 with varicella, 3 with extensive herpes simplex, and 4 with disseminated cytomegalovirus infections.
In all, 10 cases were fungal infections, including 5 with pneumocystosis, 3 with invasive aspergillosis, and 2 with cryptococcosis.
Two cases were parasitic infections, both with leishmaniasis.
The anti-TNF therapy was stopped when opportunistic infection developed in all but one patient with pneumocystosis who remained on infliximab and recovered. Seventeen patients resumed anti-TNF therapy (usually the same one) after treating the opportunistic infection for a median of 1.7 months. Three relapses of opportunistic infections occurred, two among the 17 patients who resumed anti-TNF therapy and one among the 26 patients who did not restart anti-TNF agents.
Some of Dr. Salmon-Ceron’s coauthors have been consultants or speakers for Abbott, Schering Plough, UCB, or Wyeth. The study was funded by Abbott, Schering Plough, Wyeth, and INSERM (Institut National de la Santé et de la Recherche Médicale).