Therapeutic, management considerations with biologics

July 24, 2020

Studies offer further insight into risks associated with biologic therapy. One study suggests it’s not necessary to stop biologic therapy preoperatively to limit post-operative infections. Another systematic review does not rule out melanoma risk.

A recent study suggests that stopping biologic therapy preoperatively to limit postoperative infections may be unnecessary, while a systematic review does not rule out the possibility that biologic therapies may increase melanoma risk. Both studies, however, are hampered by a lack of quality data.

Infection risk

In the first study, investigators led by Daniela Kroshinsky, M.D., MPH, of Massachusetts General Hospital and MassGeneral Hospital for Children, analyzed records of 827 patients who were given adalimumab (Humira, Abbvie), infliximab (Remicade, Janssent CarePath), etanercept (Enbrel, Amgen) or ustekinumab (Stelara, Janssen CarePath) for any inflammatory indication. The study appeared online May 5 in the Journal of the American Academy of Dermatology.

Investigators found no changes in risk of skin and soft tissue infections (SSTIs) with biologic therapy non-perioperatively (P=0.49) or in those who stopped biologic therapy preoperatively versus those who did not. Among 180 patients who underwent 218 surgical procedures, 14.5% of patients who stopped biologics perioperatively developed postoperative SSTIs, versus 6.3% of patients who continued therapy preoperatively (P=0.08).1

However, biologic therapy with concomitant corticosteroids increased postoperative SSTI risk (60.0% versus 34.3%, P=0.029) and overall SSTI risk (P=0.0049).

"Treatment with systemic corticosteroids led to an increased postoperative SSTI (rate) in this analysis, implying that corticosteroid use maybe the significant factor in predisposing patients to SSTIs while on biologics, not the biologic agent itself," investigators write.

Investigators furthermore found no significant difference in incidence of postoperative SSTIs relative to when patients stopped biologic therapy preoperatively (<3 half-lives, 6.7%; 3 to 5 half-lives, 14.9%; or >5 half-lives, 21.4%; P= 0.52). However, disease flares occurred in one patient, three patients and one patient, respectively, in the foregoing groups. As disease severity has been shown to be associated with increased infection risk in patients with rheumatoid arthritis (RA), investigators write, stopping a biologic and developing a subsequent flare may actually increase SSTI risk more so than continuing the biologic.

Accordingly, study authors suggest reevaluating current guidelines recommending that biologic agents be stopped preoperatively. It may be more efficacious, they say, to focus on minimizing corticosteroid use and other concomitant risk factors.

George Han, M.D., PhD, who was not involved with the study, says that due to a dearth of quality data, there currently are no clear guidelines for using biologics in the context of surgeries. He is system medical director and chief of teledermatology for Mount Sinai Health System and assistant professor of dermatology at the Icahn School of Medicine at Mount Sinai.

Current guidelines guesstimate to the best of experts' ability, says Dr. Han.

"I've seen guidelines with certain time frames or half-lives,” he says. “But not all biologics are governed by the same pharmacodynamic principles, so half-lives might not be the most relevant indicator of the functional level of the drug."

Interleukin (IL)-23 inhibitors' half-lives are in the range of 20 to 25 days, he says. But if patients stop taking such drugs, psoriasis can take six or more months to return.

"So there is some biological function that is going beyond the half-life," he says. Nevertheless, dermatologists have not seen significantly elevated infection risks with IL-23 inhibitors, or other biologics.

Dr. Han says it's helpful to have more literature supporting the fact that biologics exert no substantial impact on skin infection rates.

"It's reassuring, and it supports our general view nowadays that these are by and large very safe medications that don't have a significant impact on infections that we might concerned about in regular practice," Dr. Han says.

With shorter-acting medications such as TNF inhibitors (which pose the greatest mechanistic concern for infection), Dr. Han adds, perhaps it is reasonable to consider skipping a dose pre-surgically. "But the other medicines we have in the market are more targeted and persist longer. I don't believe it's that reasonable to tell people to wait a whole dose or skip many months of treatment before doing elective procedures."

Melanoma data

In a separate study, Esse et al. found that compared to conventional systemic treatments, biologic use was positively associated with melanoma in patients with psoriasis (hazard ratio 1.57; 95% confidence interval 0.61-4.09), inflammatory bowel disease (IBD) and rheumatoid arthritis (RA). Pooled relative risk (pRR) for both IBD and RA was 1.20.2 However, none of these differences were statistically significant. The study appeared online May 20 in JAMA Dermatology.

"There are concerns that long-term treatment with biologic therapies, such as those targeting tumor necrosis factor, could increase the long-term risk of cancer relative to people treated with conventional systemic therapy due to biologics' impact on the immune system," says first author Shamarke Esse, MRes, a doctoral research student in the Division of Musculoskeletal and Dermatological Sciences, University of Manchester, United Kingdom.

As melanoma is an aggressive, highly immunogenic skin cancer, he says, it should be of concern to people treated with biologics because melanoma risk increases with immunosuppression. "The evidence to date, as laid out by our study, is limited. Therefore, it is important to clarify if patients with these common inflammatory conditions who are increasingly prescribed biologic therapy are at increased risk of developing melanoma," Mr. Esse says.

Following Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines, investigators searched Embase, MEDLINE and the Cochrane Central Register of Controlled Trials between January 1, 1995 and February 7, 2019. Ultimately, seven cohort studies met inclusion criteria. These studies included 34,029 biologic-treated patients and 135,370 biologic-naïve patients treated with conventional systemic agents.

Esse et al. write that to the best of their knowledge, theirs is the first systematic review and meta-analysis of melanoma risk associated with biologic use in IBD and psoriasis that incorporates biologic-naïve patients for comparison purposes. However, investigators found only one psoriasis study (2,285 patients, versus 3,604 controls) and two IBD studies that met inclusion criteria. "The small number of studies eligible for inclusion meant that the pooled risk estimates were likely to be disproportionately affected by single studies," write Esse et al.

"Based on the limited evidence to date," Mr. Esse adds, "a clinically meaningful increase in risk cannot be ruled out. Population-based cohort studies, adjusting for key risk factors, are urgently required to clarify this risk before any recommendations can be made."

DISCLOSURES:

Dr. Han is or has been an investigator, consultant/advisor, or speaker for AbbVie, Athenex, Boehringer Ingelheim, Bond Avillion, Bristol Myers Squibb, Celgene, Eli Lilly, Novartis, Janssen, LEO Pharma, MC2, Ortho Dermatologics, PellePharm, Pfizer, Regeron, Sanofi Genzyme, SUN Pharmaceuticals and UCB. Mr. Esse reports no relevant financial interests.

REFERENCES:

1. Nguyen ED, Gabel CK, Kroshinsky D. Assessing the incidence of skin and soft tissue interaction in patients on biologics. [Published online ahead of print May 5, 2020]. J Am Acad Dermatol. 2020;S0190-9622(20)30794-5. doi:10.1016/j.jaad.2020.03.128

2. Esse S, Mason KJ, Green AC, Warren RB. Melanoma risk in patients treated with biologic therapy for common inflammatory diseases: A systematic review and meta-analysis. [Published online ahead of print May 20, 2020]. JAMA Dermatol. 2020;e201300. doi:10.1001/jamadermatol.2020.130

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