Reports Describe ICI-Related Cutaneous Adverse Events

A recent case report explains how epitope spread may cause immune checkpoint inhibitor (ICI)–associated bullous pemphigoid (BP). A separate research letter spotlights cases of partial lipodystrophy (LD) and reminds dermatologists to consider immune checkpoint inhibition in cases of acquired LD. Both reports appeared online on April 9 in JAMA Dermatology.

Seven-Year Itch

Authors led by Hiroshi Koga, MD, PhD, of the Department of Dermatology, Kurume University School of Medicine, Fukuoka, Japan, noted that although the number of ICI-associated BP reportsis growing, how these drugs break immune tolerance to BP-related proteins and spur BP development remains unclear.

Their case report featured an 80-year-old female receiving nivolumab for primary lung cancer who developed bullae on her lower legs and elsewhere after 10 months of treatment. After oral prednisolone 15 mg/day failed to halt the BP, methylprednisolone pulse therapy followed by prednisolone, doxycycline, mycophenolate mofetil, and plasmapheresis succeeded.

Pre-ICI serum testing revealed anti-BP180-C-terminus antibodies, which, along with the patient’s 7-year history of itching, may have signaled non-BP, the authors wrote. The patient initially had no anti-BP180NC16A antibodies — until reactivity spread to NC16A and BP230 during ICI treatment. Hence, the non-BP may have become BP, they surmised, when the targeted epitope spread to NC16A.

To help predict patients at higher risk for cutaneous immune-related adverse events and BP, authors suggested that “screening patients for the presence of anti-BP180 antibodies at initiation” of ICI treatment.

“We know that checkpoint inhibitor–associated bullous pemphigoid is not rare,” said Mary M. Tomayko, MD, PhD, associate professor of dermatology and pathology at Yale University School of Medicine, New Haven, Connecticut, who was asked to comment on the case. A study published in JAMA Dermatology in 2022 showed a prevalence of 0.6%. A previous study in the Journal of the American Academy of Dermatology, co-authored by Tomayko, showed a rate of around 1%.

“My estimate, after looking at the numbers carefully,” she said, “is that the chance of developing BP while on programmed cell death protein 1 (PD-1) or programmed cell death ligand 1 (PD-L1) inhibitors is about 50 times higher than if you weren’t.” One potential explanation for the high likelihood, she said, is that patients who develop BP while on ICIs were “brewing bullous pemphigoid all along,” with low-level autoimmunity insufficient to manifest clinical symptoms.

“Another hypothesis is that the autoimmunity develops de novo after initiation of the checkpoint inhibitors,” she said. “There is good rationale for either hypothesis. And this patient shows evidence of both.”

The patient had preexisting autoimmunity against a BP180 epitope that manifested as itch, Tomayko explained. “But with the PD-1 inhibition, which takes the brakes off the immune system and allows for a robust immunity to evolve within the tumor, she then developed pathological autoimmunity.”

ICI-Induced LD

In a separate study, authors led by Julia Riganti, MD, of the Department of Dermatology, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina, retrospectively identified 13 cases of rapid fat loss, including five involving primary melanomas, among patients who received anti-PD-1, anti-PD-L1, or anticytotoxic T-lymphocyte–associated protein 4 therapy between 2015 and 2023. 

Nine of the affected patients received pembrolizumab. The average onset time was 9.4 doses. The most common LD presentation was localized (n = 7), usually at injection sites, followed by generalized (n = 4). Unlike the partial idiopathic variant, which usually affects the face and upper trunk, study patients with partial LD (n = 2) showed no specific fat loss distribution, which the authors said is a novel observation. Additionally, only one patient experienced diffuse erythema and edema before LD onset. 

Four patients discontinued oncology treatment because of LD. As with other LD syndromes, the authors wrote, the treatment landscape for ICI-LD remains uncharted. Steroids typically fail, they added, and optimal management remains unclear.

LD is a very rare immune-related adverse event of immune checkpoint inhibition, said Tomayko, who was not involved with the study. The authors reported that, to their knowledge, only 21 ICI-associated cases, including those in their review, have been reported.

Nevertheless, Tomayko told Medscape Medical News that the study thoroughly classifies ICI-LD and reminds dermatologists that if they see acquired LD, immune checkpoint inhibition should be on their radar.

“It’s a sizable case series for an uncommon condition, and it adds to our understanding of how autoreactivity can lead to the pathogenesis of lipodystrophies,” she added. 

The study authors reported no funding sources. Riganti reported receiving personal fees from Janssen, RAFFO Laboratories, La Roche-Posay, CeraVe (L’Oreal), and Unilever. Tomayko reported no relevant financial relationships.

John Jesitus is a Denver-based freelance medical writer and editor.