Cutaneous complications of immune checkpoint inhibitors

By Heidi Splete, Contributing Writer, March 1, 2024

Immune checkpoint inhibitors (ICIs) are a mainstay of immunotherapy for many cancer types — including breast, colon, liver, lung, skin, stomach, and rectal — but cancer care often brings challenging skin side effects that patients (and even physicians) may not expect.

ICIs work by keeping immune checkpoint proteins in check. When checkpoint proteins are doing their job, they prevent an immune response from becoming strong enough to destroy healthy cells, but they also can prevent the immune system from tackling tumor cells, according to the National Cancer Institute.

ICIs are designed to keep the checkpoint proteins from binding with their partner proteins that would inhibit an immune response, thereby allowing T cells to take on tumor cells.

However, the activity of ICIs can spark immune-related adverse events (irAEs), including a range of skin conditions. These cutaneous irAEs (cirAEs) may prompt patients and physicians to discontinue potentially lifesaving therapies, so identification is essential to develop management strategies and minimize interruptions to cancer care.

“Dermatologists remain integral members of cancer care teams in which they provide expectant management, enhance preventative skin care practices, and support patients through treatment to facilitate optimized anti-cancer management while limiting cutaneous toxicities and maximizing quality of life,” according to the authors of the United States Cutaneous Oncodermatology Management (USCOM) algorithm, developed to provide tools for the prevention and management of cirAEs.

The USCOM consortium has published two previous algorithms related to cancer and the skin: one on the use of general measures and over-the-counter agents to treat cirAEs and one to prevent and treat acute radiation dermatitis.

The current algorithm, published in the Journal of Drugs in Dermatology, uses the Common Terminology Criteria for Adverse Events (CTCAE) grading system, and the authors focused on six types of cirAEs associated with ICIs: maculopapular eruption, pruritus, eczematous eruption, bullous eruption, lichenoid eruption, and psoriasiform eruption (2023;22:11(Suppl 1):s3-10).

Assess severity

“Immune checkpoint inhibitors are widely used by oncologists in a variety of cancers and commonly result in cutaneous immune-related adverse events,” said Jonathan Leventhal, MD, FAAD, director of the Oncodermatology Clinic at Yale School of Medicine.

“It is important for dermatologists to recognize the scope of these eruptions and have an algorithmic approach toward diagnosis and management,” said Dr. Leventhal, who also served as corresponding author of the USCOM algorithm. “Timely treatment may improve patients’ quality of life and allow continuation of cancer therapy whenever possible,” he said.

A 2022 review published in Current Oncology identified additional severe cutaneous adverse reactions (SCARs), that are rare but potentially life-threatening, including Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), drug rash with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) (2022, 29(4), 2871-2886). “Other less-frequent manifestations include ICI-induced dermatomyositis, Sweet syndrome, interstitial granulomatous dermatitis, pityriasis rubra pilaris-like erythroderma, and lupus-like cutaneous reaction,” wrote Chieh-Hsun Chen, MD, of Kaosiung Medical University in Taiwan, and colleagues.

The ICIs currently approved by the FDA are CTLA-4 inhibitors (ipilimumab, tremelimumab), LAG-3 inhibitors (relatimab), PD-1 inhibitors (pembrolizumab, nivolumab, cemiplimab, dostarlimab), and PD-L1 inhibitors (atezolizumab, avelumab, durvalumab).

More than skin deep

Skin events often strike sooner than other toxicities in cancer patients, and cutaneous cirAEs occur in more than 30% of patients who use them, making them the most common category of ICI side effects, according to the authors of a 2020 review in the Journal of Cutaneous Medicine and Surgery. In the article, the authors noted that the most frequent culprits behind cirAEs are CTLA-4 inhibitors, which account for 43% to 45% of issues, followed by PD-1/PD-L1 inhibitors (18% to 34%). However, both CTLA-4 and PD-1/PD-L1 inhibitors are similarly responsible for toxicity of Grade 3 or higher, which occurs in approximately 1% to 3% of cases.

Although cirAEs generally occur early in treatment, they can happen at any time, and the type of skin reaction may determine the time of onset. “As such, granulomatous, lichenoid, psoriasiform, eczematous, and immunobullous reactions have been observed to have a longer time of onset than maculopapular and SJS-like reactions,” they said. Mucosal involvement in the eye, nose, mouth, and genitalia, palmoplantar involvement, and vesiculobullous lesions are among the hallmarks that could indicate more severe conditions, they added.

Skin toxicities have not shown a dose-dependent relationship with ICI treatments, and data indicate that any cirAEs may occur in any type of cancer, the authors emphasized.

Rash reactions

A maculopapular or morbilliform rash is usually the first skin reaction to appear in patients treated with ICIs, and is the most common cutaneous side effect. The rash risk rises with CTLA-4 inhibitors and combination therapies, and occurs less frequently with use of anti-PD-1 and anti-PD-L1.

Clinical features of maculopapular eruptions include pruritic erythematous macules and papules; these may form thin plaques, and occur mainly on the trunk and extremities, according to Chen and colleagues.

Most maculopapular eruptions in response to ICIs are mild and self-limiting, and may be managed with emollients, topical steroids, or oral antihistamines. However, Chen and colleagues advised physicians to be vigilant, as a maculopapular eruption may be the initial presentation of bullous pemphigoid (BP), SJS/TEN, or DRESS. For patients with SJS/TEN, for example, permanent cessation of ICIs is needed, they said.

Aggressive treatment and interruption of immunotherapy is often necessary in cases of severe rash, such as CTCAE of Grade 2 or higher, that negatively impact patients’ quality of life, Dr. Leventhal told DermWorld. “Examples include bullous pemphigoid or severe cutaneous adverse reactions,” he noted.

“However, Grade 4 reactions which are life-threatening, such as toxic epidermal necrolysis, require immediate urgent care and discontinuation of immunotherapy,” he emphasized.

“While most mild rashes respond to topical therapy, higher-grade rashes often require systemic steroids,” said Dr. Leventhal. Other alternative therapies are available for recalcitrant cases, including targeted options such as acitretin for lichenoid reactions, interleukin-4/-13 blockers for dermatitis or bullous pemphigoid, and apremilast or interleukin-12/-23 blockers for psoriasiform reactions, and rituximab for bullous pemphigoid, he added. “Close communication with the oncology team is crucial to provide multidisciplinary care and coordination of dermatologic as well as oncologic treatment.”

As for additional research, prospective studies are needed to examine the long-term safety and efficacy of targeted agents in the management of cutaneous immune-related adverse events, Dr. Leventhal said.

Itching and eczema

Pruritus occurs in approximately half of patients treated with ICIs; it may occur in conjunction with maculopapular rash, or develop on normal-appearing skin, according to the authors of the USCOM algorithm. Oral antihistamines and topical emollients are the foundations of treatment for itching of any severity, and systemic therapies such as gabapentin/pregabalin, naloxone/naltrexone, or aprepitant may be needed, they said. Don’t discount the impact of itching on patients’ well-being. “Notably, ICI-related pruritus has been demonstrated to be independently associated with lower patient quality of life,” they said.

Eczematous eruptions in patients treated with ICIs often present pruritic erythematous papules accompanied by scaly plaques, according to the USCOM algorithm. Topical corticosteroids can help in moderate cases, and dupilumab or narrowband ultraviolet B (UVB) phototherapy can be added in more severe cases. Reserve oral steroids for persistent or severe cases, the authors wrote.

Psoriasis problems

Cases of psoriasis associated with ICI treatment may be new or a flare-up of pre-existing psoriasis, most often in response to anti-PD-1/anti-PD-L1, according to the review by Chen and colleagues. They cited a study of 21 patients in whom the average time between starting anti-PD-1 and a psoriasis flare was approximately 50 days.

However, psoriasis might not be a bad sign, and instead might signal a more robust treatment response. A 2021 study in the Journal for ImmunoTherapy of Cancer including 76 adults with pre-existing psoriasis showed that 57% experienced a psoriasis flare after a median of 44 days of ICI therapy (2021;9:e003066. doi:10.1136/jitc-2021-003066). The researchers examined safety and efficacy outcomes in these patients. Of the patients who experienced psoriasis flares, approximately half (53%) were managed with topical therapy alone, and only five needed to discontinue immunotherapy because of their flares. Notably, progression-free survival was significantly longer in patients with psoriasis flares compared to those without (39 months vs. 9.7 months, p = 0.049).

Lessons for lichenoids

Cancer patients treated with anti-PD-1/anti-PD-L1 may also develop lichenoid dermatitis, with a presentation described by Chen and colleagues as scaly plaques ranging from erythematous to violaceous, mostly on the trunk and extremities, that may be localized or generalized. Mucosal involvement is rare in these patients, wrote Chen and colleagues. Management may include potent topical steroids, but corticosteroids are a consideration, they said.

Management matters

Management of cutaneous adverse events in cancer patients is a balancing act of considering how to bring patients relief without compromising their cancer care. The most common strategies involve topical or systemic corticosteroids, as well as vitamin D analogs and moisturizers/topical emollients. Data also support the use of narrow-band ultraviolet B (NB-UVB) therapy for patients with psoriasis or vitiligo.

The presentation of skin reactions in people using ICIs covers a broad range, from mild to very severe, said Beth McLellan, MD, FAAD, chief of dermatology at Albert Einstein College of Medicine and Montefiore Health System.

“Some of the most exuberant lichen planus I have seen has been due to ICIs,” said Dr. McLellan, an oncodermatology expert and one of the coauthors of the USCOM algorithm. Skin reactions in patients undergoing cancer treatment can also begin with a relatively mild presentation and evolve quickly to more severe involvement, she noted.

“Physicians should recognize the significant impact cutaneous toxicity can play on a patient’s quality of life, and also the possibility for it to disrupt their cancer care,” Dr. McLellan said. “Dermatologists can often reassure patients that they will be able to manage the skin problem without impacting the patient’s ability to receive their cancer therapy.”

The decision to discontinue an ICI in cases of extreme skin reactions should be made in consultation with the full oncology team, and not taken lightly, Dr. McLellan emphasized.

“Using CTCAE grading can be helpful to communicate the severity of the condition to the oncology team,” said Dr. McLellan. “Discontinuation of any ICI should be discussed with the oncology team, taking into account any possible options for managing the skin condition that might allow continuation of the ICI.”

Alopecia and vitiligo are conditions that can be very challenging to treat, said Dr. McLellan. “Unfortunately, the newer treatment option, JAK inhibitors, are not usually used, since we still don’t know what impact these medications will have on the active malignancy and response to immunotherapy,” she said.

Alopecia answers (and questions)

“The data are too limited to identify any risk factors for alopecia as a side effect of ICIs at this time,” said Carolyn Goh, MD, FAAD, associate clinical professor in dermatology at the University of California, Los Angeles, David Geffen School of Medicine. “One might consider the similar risk factors for alopecia areata in the general population which includes a history of atopy, family or personal history of autoimmune disease or alopecia areata,” said Dr. Goh, an expert in alopecia and coauthor of a review of alopecia areata as a side effect of ICI treatment.

“Dermatologists can support cancer patients with alopecia by recognizing the connection and working with the patient and their oncologist to discuss the best course of action,” Dr. Goh said. “One of the cases we reviewed did discontinue treatment and had [hair] regrowth. This is not typically recommended, however, as patients experiencing hair loss due to ICI therapy appear to have a robust anti-cancer response,” she said.

“I recommend a team-based, patient-centered approach to managing the patient’s alopecia,” said Dr. Goh. “First, making an appropriate diagnosis and determining that it is related to the ICI therapy, then targeting the type of alopecia with safe treatments that will not interfere with their cancer therapy,” she said. “Treatments such as topical, intralesional, or systemic corticosteroids, topical or oral minoxidil would be a mainstay, but in some situations, oral JAK inhibitors may be appropriate,” she added.

Are cutaneous complications a good sign?

Some research suggests that skin reactions to cancer treatments may predict a more positive outcome for the patients. A 2018 case-control study in the Journal of the American Academy of Dermatology examined oncologic outcomes in patients who experienced dermatitis after PD-1/PD-L1 inhibitor therapy.

In the study, the researchers compared outcomes for 20 patients treated with PD-1/PD-L1 inhibitors with no previous history of dermatitis who developed cirAEs and 94 control patients who did not develop dermatitis during treatment. Of the patients with dermatitis, 50% had lichenoid dermatitis, 40% had spongiotic dermatitis, 5% had lymphoid infiltrate, and one patient had a vacuolar interface dermatitis.

The best overall response (determined by complete response, partial response, stable disease, or progressive disease) was significantly improved in the patients with dermatitis compared to the controls (p < .0001); both progression-free survival and overall survival were also significantly longer in dermatitis patients vs. controls.

“When a patient gets a rash from their ICI treatment, it typically portends a better cancer prognosis. However, some rash types suggest better prognosis than others,” said Lisa Zaba, MD, FAAD, associate professor of dermatology at Stanford University.

“For example, developing a ‘lichenoid interface’ rash demonstrates better cancer prognosis than developing a blistering rash,” she said.

Although rashes are common in patients treated with ICIs, itching might catch physicians by surprise, said Dr. Zaba, who also serves as director of the Merkel cell carcinoma multi-disciplinary clinic and as a member of the supportive oncodermatology group at the Stanford Cancer Center.

“Itch occurs in about half of patients on ICIs, but despite the high prevalence, many physicians are not aware of this side effect,” Dr. Zaba said. “The itch can be debilitating, and therefore it is important to recognize this and treat it.”

Although skin side effects are unpleasant, don’t hesitate to tell patients that such reactions may signal a stronger response to treatment, Dr. Zaba said. “It is always helpful to tell patients that despite having a bad rash, this likely means that the ICI is helping with their cancer. Hope is a powerful medicine, and not to be underestimated as a management strategy,” she said.

“Secondly, while topical steroids and antihistamines are a mainstay for treating most of the rash types, the choice of oral medication we choose differs by rash subtype,” said Dr. Zaba. “When choosing oral medications to treat the rash, it is critical for dermatologists to choose medications that are minimally immunosuppressive in order to give the ICI a chance to work. One example of this is using dupilumab to treat ICI bullous pemphigoid instead of using oral steroids,” she explained.

Looking ahead, Dr. Zaba and colleagues are researching additional strategies to manage ICI-induced rashes. “Currently, we are doing single cell analysis of the immune infiltrate contained within ICI rashes to uncover additional pathways that may be targeted to treat the rashes while maintaining cancer immunity,” she said.

The review in the Journal of Cutaneous Medicine and Surgery also noted that improved progression-free survival has been associated with all cirAEs, and that studies focused specifically on maculopapular rash and vitiligo-like lesions have shown associations between these reactions and improved survival in cancer patients.

Diagnostic challenges and treatment strategies

“Cutaneous reactions to ICI occur across a spectrum of phenotypes, and the diversity of these reactions means that a simple answer is likely to miss important nuance,” said Noah Hornick, MD, PhD, FAAD, assistant professor of dermatology at Oregon Health & Science University. “Collectively, skin irAE have been shown to be predictive of both the development of irAE in other organ systems and of tumor response to ICI,” he said. “While this generalization is encouraging, it should be kept in mind that certain, and generally more morbid, skin reactions have also been shown to be negative prognostic indicators. Considering both the subtype and context of an eruption is essential in knowing what conclusions to draw from its occurrence,” he noted.

Pathophysiologic understanding of many skin reactions to ICIs is still fairly limited, so in general, any inflammatory skin condition occurring after the introduction of ICI could be classified as an irAE, Dr. Hornick said. “While this means that a lot of rarer dermatoses can be termed irAEs simply because they occur in the right patient, there is enough evidence that many of these reactions differ from ‘naturally occurring’ skin disease to the extent that they should be considered distinct entities.”

“In my opinion, examples of these conditions would include things like progressive immunotherapy-related mucocutaneous eruption (PIRME), which is a name given to an SJS/TEN-like eruption that occurs in the context of ICI and a second potentially triggering medication,” he explained. “PIRME, when considered as its own entity, has a more benign course than true SJS/TEN, and may not preclude additional ICI therapy.”

Other less-common reactions that may arise in patients treated with ICIs include acneiform or papulopustular reactions, which are more commonly associated with various non-ICI classes of targeted therapies, granulomatous reactions, and the cutaneous manifestations of autoimmune connective tissue diseases, Dr. Hornick said.

As an oncodermatologist, Dr. Hornick’s role is to maximize the potential efficacy of patients’ cancer therapies. “Primarily, I do that by managing cutaneous reactions in order to eliminate them as an obstacle to continued treatment, but just as important is ensuring that my interventions don’t negatively impact their antineoplastics,” he said. “The correlation between irAEs and tumor response emphasizes the importance of selecting therapeutics that are as specific to the reaction being treated as possible, either by favoring topical therapies, or by choosing treatments with the narrowest immunologic impact available to achieve control of the reaction,” he noted.

“While some mechanistic insight can be gleaned from comparing cutaneous irAEs to the naturally occurring dermatoses they resemble, translating therapies from traditional inflammatory dermatology is not uniformly successful or appropriate,” Dr. Hornick said. “It is essential that we develop an understanding of the immunologic mechanisms of these eruptions, their similarities to one another, and their differences from their namesake naturally occurring dermatoses in order to select or design therapies that have the precision necessary to alleviate cutaneous irAEs without impact to anti-tumor efficacy,” he emphasized.

Dr. Leventhal disclosed serving on advisory boards for Sanofi, Regeneron, and La Roche Posay and as a primary investigator on clinical trials funded by OnQuality, Inc. Dr. Hornick had no financial conflicts to disclose. Dr. Zaba had no financial conflicts to disclose. Dr. McLellan disclosed serving as a consultant for Paula’s Choice and Laroche Posay. Dr. Goh disclosed serving as a speaker for Pfizer.

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