Clinical Context

Immune checkpoint inhibitors (ICIs) have revolutionized treatment of late-stage and metastatic cancers but are often complicated by various heterogeneous immune-related adverse events (irAEs). These occur in the skin in 30% to 50% of treated patients.

Bullous pemphigoid, an immune-mediated condition characterized by large, fluid-filled blisters on the skin, is a rare but serious complication of cancer therapy with ICIs that may result in treatment interruption or cessation. To identify risk factors for bullous pemphigoid in patients receiving ICIs, the investigators performed a case control study nested within a retrospective cohort study.^[1]

Study Synopsis and Perspective

Investigators in Boston, Massachusetts reported that among patients receiving ICIs, being aged 70 years or older and having skin cancer are both significant risk factors for bullous pemphigoid. On the plus side, ICI-induced bullous pemphigoid also appears to be a marker for improved tumor responses to therapy.

In a nested case control study of 5636 patients with cancer who received either a programmed cell death protein 1 (PD-1) inhibitor such as pembrolizumab or nivolumab or a cytotoxic T-lymphocyte--associated protein 4 inhibitor such as ipilimumab, 35 patients (0.6%) developed bullous pemphigoid. The study by Nicole R. LeBoeuf, MD, MPH, from Brigham and Women's Hospital in Boston, Massachusetts, and colleagues was published online April 13 in JAMA Dermatology.^[1]

"What is interesting is that 0.6 is a small number, but we're seeing bullous pemphigoid at considerably higher frequency than is expected in the general population," LeBoeuf said in an interview with Medscape Medical News.

Although bullous pemphigoid has the potential to disrupt ICI therapy, it also appears to be a marker for a favorable tumor response, the investigators found.

Their findings suggest that management of bullous pemphigoid for patients receiving ICIs should focus on early identification and management with therapies directed at the specific toxicity, LeBoeuf said.

"When you make a specific diagnosis like bullous pemphigoid, then you can treat that specific disease with very targeted therapies, such as omalizumab or dupilumab or rituximab -- things that are not globally immune suppressing like steroid or other T-cell depleting agents. Studies have shown that depleting B cells with anti-CD20 agents is not detrimental to [ICI] therapy," she said.

Dermatologic Adverse Events Common

As previously reported by Medscape Medical News, about 40% of patients with cancer treated with ICIs experience dermatologic irAEs that can range from mild rashes and hair and nail changes to uncommon but life-threatening complications, such as Stevens-Johnson syndrome, a form of toxic epidermal necrolysis, according to members of a European Academy of Dermatology and Venereology task force.

"The desirable, immune-mediated oncologic response is often achieved at the cost of [irAEs] that may potentially affect any organ system," they wrote in a position statement on the management of ICI-derived AEs.^[2]

LeBoeuf and colleagues noted that although reported risk factors for idiopathic bullous pemphigoid include advanced age, type 2 diabetes, use of dipeptidyl peptidase-4 inhibitors, cerebrovascular disease, and neurocognitive disease, risk factors for bullous pemphigoid and other dermatologic AEs associated with ICIs are less well-known.

Study Details

The study investigators evaluated records for all patients in the 3 Harvard-affiliated hospitals to identify patients with ICI-associated bullous pemphigoid from October 2014 through December 2020. Control persons were all patients in the Dana-Farber cancer registry who received ICIs during the study period.

The investigators chose age at ICI initiation (< 70 years or ≥ 70 years), sex, ICI agents, and cancer type as potential risk factors.

They used propensity score matching based on age, cancer type, ICI agent, and number of ICI cycles to match 2 control persons with each case patient.

Of the 5636 patients treated with ICIs during the study period, 35 (0.6%) developed bullous pemphigoid. The median age was 72.8 years, and 71.4% were men.

In a multivariate logistic regression model that included 2955 patients with complete data in the cancer registry, factors significantly associated with developing bullous pemphigoid included age 70 years or older (odds ratio [OR] 2.32; P = .01), having melanoma (OR 3.21; P < .001), and having nonmelanoma skin cancer (NMSC) (OR 8.32; P < .001).

In comparing the 35 case patients with their matched control patients, a complete or partial response at first restaging imaging was significantly associated with developing bullous pemphigoid (OR 3.37; P = .01). In addition, there was a higher likelihood of tumor responses to ICIs among patients with bullous pemphigoid compared with matched control patients (objective response rate 82.9% vs 61.4%; P = .03).

Prudent Toxicity Management

Ryan Sullivan, MD, who treats patients with skin cancer at Massachusetts General Hospital Cancer Center but was not involved in the study, commented that the findings raise questions about the relationship between skin cancers and irAEs.

"It is compelling that bullous pemphigoid is a skin toxicity and is more common to happen in skin cancer patients," he noted. "That's a very interesting finding, and the reason that it's interesting is that it's harder to understand why a presumably antibody-mediated side effect would be more likely to have that cross-reactivity where the tumor started and where the toxicity happened," he said in an interview with Medscape Medical News.

He noted that the benefits of ICIs for patients with skin cancers far outweigh the risks for dermatologic AEs such as bullous pemphigoid and that ICI-associated events require judicious management.

"This is true across the spectrum of toxicities: There are clear manifestations of toxicity that we should be more thoughtful about what's driving them, more thoughtful about what it is, and more thoughtful about treating them, other than just pouring steroids into patients in industrial doses and hoping that everything's going to be OK," he said.

No funding source for the study was reported. LeBoeuf reported receiving grants from the National Institutes of Health National Cancer Institute during the conduct of the study and personal fees for serving as a consultant for several companies outside the study. Co-author Arash Mostaghimi, MD, MPA, MPH, is associate editor of JAMA Dermatology but was not involved in study selection or evaluation for publication. Sullivan disclosed consulting for ICI makers Bristol-Myers Squibb Company and Merck & Co., Inc.

Clinical Implications

• Age ≥ 70 years and skin cancer were associated with increased risk of developing ICI-associated bullous pemphigoid; patients who develop ICI-induced bullous pemphigoid have relatively improved tumor responses.
• Early identification and toxic effect-directed treatment should therefore be prioritized, especially in patients at risk of developing de novo bullous pemphigoid.
• Implications for the Healthcare Team: Patients at risk for bullous pemphigoid development should be counseled and monitored throughout ICI treatment.

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