No Increased Risk for Serious Infection With Biologics

Debra Gordon

November 06, 2011

November 6, 2011 (Chicago, Illinois) — Patients with autoimmune diseases have no greater risk overall of being hospitalized with serious infections after initiating therapy with tumor necrosis factor (TNF)-alpha antagonists than patients receiving nonbiologic treatments, according to research reported here at the American College of Rheumatology 2011 Annual Meeting.

The data were published online in JAMA, the Journal of the American Medical Association to coincide with the presentation.

The Safety Assessment of Biologic Therapy (SABER) project is a federally funded study analyzing data from 4 large American databases that comprise 407,319 patients with autoimmune diseases.

Researchers compared infection rates in 3 groups. In the first, 10,484 patients with rheumatoid arthritis (RA) were analyzed in matched pairs — those receiving infliximab, adalimumab, or etanercept; and those receiving leflunomide, sulfasalazine, or hydroxychloroquine after methotrexate. A second group consisted of 2323 patients with inflammatory bowel disease (IBD). Those initiating infliximab or adalimumab treatment were compared with those receiving the nonbiologics azathioprine or mercaptopurine. The third group consisted of 3215 patients with psoriasis, psoriatic arthritis, or ankylosing spondylitis (psoriasis and spondyloarthropathies). Those receiving 1 of the 3 biologics were compared with those receiving methotrexate, hydroxychloroquine, sulfasalazine, or leflunomide.

The researchers evaluated the effects of glucocorticosteroid use separately.

"We think there is a lot of controversy about whether these drugs increase the risk of infection," said lead author Carlos G. Grijalva, MD, MPH, from Vanderbilt University in Nashville, Tennessee. "Data from clinical trials suggest that they can increase the risk, compared with placebo, but you know that these patients have other alternatives and can receive other nonbiologics." The real question, he pointed out, should be whether the biologics increase the risk for infection relative to nonbiologic options. "That is exactly the question we tried to answer."

Overall, the researchers found that patients were hospitalized with 1172 serious infections, about half of which were pneumonia and skin and soft tissue infections, with a 3.6% fatality rate for patients with RA, a 2.1% rate for those with IBD, and a 7.1% rate for those with psoriasis and spondyloarthropathies.

Although there was no difference overall in serious infection rates between patients initiating biologic treatments and those initiating nonbiologic treatments, RA patients with baseline glucocorticosteroid use had a significantly increased risk for hospitalization, compared with those with no baseline use (adjusted hazard ratio [aHR], 1.32, 1.78, and 2.95 for low, medium, and high doses of glucocorticoids, respectively).

In addition, the rate of serious infection in patients with RA receiving infliximab was about 25% greater than in those receiving nonbiologics (aHR, 1.25; 95% confidence interval [CI], 1.07 to 1.48), compared with patients using either etanercept (aHR, 1.26; 95% CI, 1.07 to 1.47) or adalimumab (aHR, 1.23; 95% CI, 1.02 to 1.48).

Although patients with psoriasis and spondyloarthropathy had infection rates similar to those initiating nonbiologics (aHR, 1.05; 95% CI, 0.76 to 1.45), those with baseline use of glucocorticoids exhibited a significantly increased risk for serious infections, compared with no baseline low use (aHR, 1.15; 95% CI, 0.75 to 1.77), medium use (aHR, 2.01; 95% CI, 1.08 to 3.73), or high use (aHR, 2.77; 95% CI, 1.44 to 5.32). There were no significant differences in infection rates between the 2 IBD groups, regardless of TNF-alpha use or baseline glucocorticoid use (aHR, 1.10; 95% CI, 0.83 to 1.46).

Dr. Grijalva had no explanation for the increased infection rate with steroid use. "It is interesting that it is consistent for the other disease groups but not for IBD," he said, adding that "we need to explore that further."

The increased infection rate with infliximab could be due to the loading dose required with the drug or the method of administration, he said. Infliximab is administered with intravenous infusion, whereas abatacept and etanercept are administered with subcutaneous injection.

The study results "should be reassuring for patients and providers," said Dr. Grijalva, "because we observed that the use of these medications is not associated with an increased risk of infection — except for infliximab in the RA population."

He and his colleagues will be mining the datasets to investigate other issues related to the use of biologic drugs in patients with autoimmune disease, including the risk for other tuberculosis and opportunistic infections.

"It is always a challenge when using databases like these to make sure you have accurate data," said Eric Ruderman, MD, professor of medicine in the division of rheumatology at Northwestern University Feinberg School of Medicine in Chicago, Illinois. "However, this group has perfected the process and has a track record, so I'm reassured that the data are accurate."

"This is the first large-scale look at infections across disease categories, which is very helpful," Dr. Ruderman said. The differences in infection rates between disease states provide additional confidence in the data, he added, given that this also occurs in clinical practice. "The takeaway is that while the biologics are not without risk, it is further reassurance that what risk there is is reasonable and appropriate, given the benefit of the drugs," he explained.

Dr. Grijalva has disclosed no relevant financial relationships. Dr. Ruderman reports being a consultant for Amgen, Abbott, Genentech, Eli Lilly, Pfizer, and UCB; and receiving research funding from Abbott, Genentech, and Pfizer.

JAMA. Published online November 6, 2011. Abstract

American College of Rheumatology (ACR) 2011 Annual Meeting: Abstract 801. Presented November 6, 2011.

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