Infection risk from biologics deserves careful scrutiny

Denver - Although relatively healthy patients taking biologic drugs for psoriasis generally face a low risk of infection, an expert says, patients with additional risk factors should proceed cautiously.

Because biologic drugs impact the immune system, says Kenneth B. Gordon, M.D., the most important safety question physicians and patients usually ask is whether these drugs increase infection risks. However, he adds, discussing safety and risks outside the context of biologic benefits may needlessly alarm patients. Dr. Gordon is a professor of dermatology at Northwestern University Feinberg School of Medicine, Chicago.

Physicians cannot assess the safety of a treatment for a particular patient in a vacuum, Dr. Gordon says. The way a physician interprets data strongly impacts what he or she tells patients about biologic drugs’ safety.

“We try to generalize. But the most important thing is to think about the patient in front of you,” he says.

With any therapy, Dr. Gordon says, “We’re trying to improve the patient’s general health. And highlighting one little area - such as infection, malignancy or cardiovascular disease - as a single entity loses the big picture.”

Next: Risk factors

Risk factors

Key factors that impact the safety discussion include infection risk over time, Dr. Gordon says.

“The risk may be different on day one versus day 144. We must consider that when looking at patients’ infection risk,” he says.

Other important factors include study designs - observational versus randomized, controlled trials (RCTs), for example - and how registries express safety data.

More importantly, “Inclusion and exclusion criteria have a major impact on how we think about infection risk. RCTs use these criteria, which might impact the risks we see. Therefore, we might have to consult other sources of data” in other indications.

Regarding infection risk, particularly in anti-tumor necrosis factor (TNF) therapies, “There’s a slew of data that is not based on psoriasis trials,” Dr. Gordon says.

Evaluating these data requires great care. For starters, Dr. Gordon says that the more patients one sees or studies, the greater the chance of seeing rare events. To “tease out” these data most effectively, dermatologists must look at higher-risk populations.

“Patients with psoriasis, much to our luck, are a relatively low-risk group. To find high-risk groups of patients, often we must go to other indications. They might provide an indication of what happens when you have a high-risk patient, versus the 25-year-old, otherwise well patient,” he says.

Next: Assessing infection risks

Assessing infection risks

In a study that assessed infection risks in patients with rheumatoid arthritis (RA) taking disease-modifying antirheumatic drugs, use of 7.5 mg to 14 mg of corticosteroids daily conferred an adjusted incidence rate ratio of serious infection of 2.1; use of 15 or more milligrams daily: adjusted incidence rate ratio 4.7 (Strangfeld A, Eveslage M, Schneider M, et al. Ann Rheum Dis. 2011;70(11):1914-1920).

“Prednisone is probably the worst player in terms of infection risk among any of the medications we use, yet we use it all the time without thinking twice,” Dr. Gordon says.

Other risk factors associated with increased infection in the study included age, chronic lung or renal disease and a history of serious infections.

“The key is, the presence of these multiple risk factors, and other medicines, even within the same disease, drive the risk of infection,” he says.

By the same token, a meta-analysis has shown that when one adjusts for exposure, patients with psoriasis taking TNF inhibitors face no more risk of serious infection than placebo-treated patients in short-term clinical trials (Dommasch ED, Abuabara K, Shin DB, et al. J Am Acad Dermatol. 2011;64(6):1035-1050).

Next: Long-term impact

Long-term impact

Subsequent studies also show an odds ratio of around one for serious infections in patients taking TNF inhibitors long-term (Pariser DM, Leonardi CL, Gordon K, et al. J Am Acad Dermatol. 2012;67(2):245-256; Kimball AB, Pariser D, Yamauchi PS, et al. J Am Acad Dermatol. 2013;68(5):756-764).

“To me, that means that the risk of infection might always be there, though it does not increase with longer-term exposure,” Dr. Gordon says.

More importantly, he says, a Cochrane review showed that studies performed in different countries report slightly different rates of serious infections in patients with RA taking TNF inhibitors (Singh JA, Wells GA, Christensen R, et al. Cochrane Database Syst Rev. 2011;(2):CD008794).

“Along with the idea that other risk factors increase the patient’s risk for infection quite significantly, the one thing I find very important is what happens with prolonged exposure to biologic therapies in RA,” he says.

Specifically, the comorbidity-adjusted rate of serious infections decreases over time.

“There’s a slight increase for the first few months after the initial exposure, then it drifts down (Askling J, Fored CM, Brandt L, et al. Ann Rheum Dis. 2007;66(10):1339-1344). Is it because the medicines are becoming safer?” Dr. Gordon says. “I don’t believe so. I believe it’s because many of the patients who are at risk already have been selected out - they’ve had an infection, and stopped the treatment.”

A French registry showed a fairly significant increased risk in patients on TNF inhibitors who took more than 10 mg daily of prednisone (Salmon-Ceron D, Tubach F, Lortholary O, et al. Ann Rheum Dis. 2011;70(4):616-623).

“But when you add on a biologic, there seems to be an increased risk of opportunistic infections as well,” he says. “Again, these are almost always found in high-risk individuals - that’s what we need to think about when we are discussing infection risk.”

Next: Seeking more data

Seeking more data

As with TNF inhibitors in psoriasis trials, Dr. Gordon says, long-term use of ustekinumab in clinical trials does not appear to increase patients’ risk of serious infections. But ustekinumab differs from TNF inhibitors, he says, because little ustekinumab data exists outside of psoriasis populations.

“With ustekinumab, I can’t talk about infection risk in other indications and in those high-risk individuals. We don’t have that data today, but hopefully we will get it over time,” he says.

“The clinical trials in psoriasis don’t indicate a significant increased risk of infection. Is that what I tell a patient? No. I tell patients that there is an increased risk of infection with these medicines,” Dr. Gordon says. “In patients with psoriasis who are young and healthy, that risk is relatively low. The biggest recommendation I make to patients is to check the things we can check,” such as screening for hepatitis and TB, when considering biologic therapy.

Once on a biologic drug for psoriasis, Dr. Gordon says, “The most important message for every patient is, no heroics.”

Dr. Gordon tells every patient using a biologic drug for psoriasis that if they get a low-level fever, chronic cough or illness that lasts longer than seven to 10 days, they should see him or their primary care physician and perhaps undergo a chest X-ray.

“When I see a patient who is at higher risk,” he says, “such as an uncontrolled diabetic, an elderly patient or a patient with chronic renal disease, I tell them it’s even more important to watch for signs of infection than it is for otherwise healthy patients.”

Dr. Gordon has received research support and/or honoraria from Abbvie, Amgen, Celgene, Eli Lilly, Merck, Novartis and Pfizer.