Dermatologic Toxicities of Immunotherapy

Cancer immunoediting is the process by which malignant cells evade the immune system—first by incomplete elimination of tumor cells during immunosurveillance, followed by an equilibrium phase, and finally by an immune escape phase. The immune escape phenomenon is mediated by a variety of interactions within the tumor microenvironment, among which immune checkpoint pathways play a prominent role. Immune checkpoint axes such as cytotoxic T-lymphocyte–associated protein 4 (CTLA-4)–B7-1/B7-2 and programmed cell death 1 transmembrane protein (PD-1)–PD-L1/PD-L2 are physiological negative regulators of activated T cells that lead to immune tolerance of normal tissues and therefore prevent autoimmunity. Because tumor cells upregulate these pathways to dampen immunosurveillance, inhibiting these axes by utilizing monoclonal antibodies has proved to be a successful therapeutic strategy for a wide range of malignancies.

The downside to the unbridled immune activation with immune checkpoint inhibitors (ICIs) is that it can also lead to loss of immune homeostasis and result in a broad spectrum of immune-related adverse effects (irAEs). These irAEs can affect a variety of organ systems and bear a resemblance to autoimmune diseases in their clinical presentation. Dermatological irAEs are the most common irAEs reported and can be seen in 37% to 70% (all-grade) of patients treated with ipilimumab and in 17% to 37% of those receiving PD-1 inhibitors. Grade 3 or higher toxicity is seen only in 1% to 3% of these patients. The incidence of cutaneous toxicities also varies according to the underlying malignancy—it appears to be more common in patients with melanoma or renal cell carcinoma in comparison to patients with non–small-cell lung cancer.

There are emerging data to suggest that the development of irAEs is associated with objective tumor responses and improved survival outcomes. ^, Objective response rates as high as 69% to 75% in patients who developed cutaneous irAEs with ICIs have been reported in the literature. In a meta-analysis of 27 studies of patients with advanced melanoma treated with immunotherapy, the development of vitiligo as an irAE was associated with improved progression-free survival (hazard ratio [HR] 0.51; 95% confidence interval [CI] 0.32–0.82, P < .005) and overall survival (HR 0.25; 95% CI 0.10–0.61; P < .003). It is therefore imperative to treat cutaneous irAEs effectively while minimizing interruption of therapy with ICIs because patients who develop irAEs appear to be more likely to derive benefit from continued treatment.

In this chapter we describe the various clinical manifestations of cutaneous toxicities of ICIs, their pathophysiology, and approaches for their management and treatment.

Clinical manifestations: The time to onset of dermatological toxicities with immunotherapeutic agents is quite variable. Whereas some patients may develop cutaneous adverse events within 2 weeks of initiating therapy, others may manifest toxicities several months into their treatment. Despite the broad spectrum of dermatological reactions noted with immunotherapeutic agents, these can be classified into broad categories based on common clinicopathological features. The most commonly observed rashes are usually inflammatory in nature. This category includes maculopapular rashes along with a variety of other less frequent rashes such as lichenoid, acneiform, exfoliative, dermal hypersensitivity-like, psoriasiform, or photosensitivity rashes. The common cutaneous toxicity noted with ICIs is a pruritic maculopapular rash. Maculopapular rashes tend to have an early onset into the treatment course and occur earlier with a combination of CTLA-4/PD-1 blockade than with either agent alone. On examination, characteristic erythematous macules or papules are usually noted on the trunk but usually spare the hands, feet and face. Occasionally, the rash may be more prominent in sun-exposed areas. Rarely, maculopapular rashes may precede more severe cutaneous toxicities, which are described later. Lichenoid rashes are characteristically noted with PD-1/PD-L1 inhibitors rather than with CTLA-4 blockers and tend to present later. Physical examination in such cases shows flat-topped papules with visible striae which may involve the palms and soles and rarely present with mucosal lesions in the oral or genital regions. Psoriasiform dermatological reactions resemble psoriasis in their manifestations and include the typical erythematous plaques covered by silvery white scales, which are preferentially located over the knees, elbows, scalp, or the intertriginous areas. Other less common forms of psoriasis, such as pustular or guttate psoriasis, or even the development of de-novo psoriatic arthritis with immunotherapy have been described. ^,

Inflammatory rashes: Inflammatory rashes also include the potentially life threatening severe cutaneous adverse reactions (SCARs) such as drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN), and acute generalized exanthematous pustulosis (AGEP).

• ■

  DRESS: DRESS is a clinical syndrome in which patients develop a skin eruption accompanied by significant eosinophilia and organ involvement after exposure to a culprit drug. Patients often present with a morbilliform rash which progresses to a confluent erythematous rash with follicular accentuation, typically involving greater than 50% of the body surface area (BSA) and often with facial involvement. Patients have other systemic symptoms such as fever, malaise, lymphadenopathy, and other symptoms related to underlying organ dysfunction. Laboratory workup usually reveals significant eosinophilia, atypical lymphocytosis, and abnormal liver or renal function tests. Some patients may also have pulmonary involvement in the form of interstitial pneumonitis with or without pleural effusions.

• ■

  AGEP: AGEP is a drug reaction characterized by the development of diffuse sterile pustules usually on top of an erythematous rash and is accompanied by systemic symptoms such as fever. The rash usually starts in the face or intertriginous areas and spreads to the trunk or limbs. Mucosal surfaces are usually spared. Patients may have facial edema and fever at presentations. Laboratory evaluations are remarkable for leukocytosis with a neutrophilic predominance.

• ■

  SJS and TEN: SJS and TEN are severe cutaneous adverse effects which are a consequence of extensive keratinocyte necrosis in reaction to immunotherapy, leading to detachment of the epidermis. Based on the percentage of BSA involved, the reaction is either categorized as SJS (<10% of BSA) or TEN (>30% BSA). Patients with 10% to 30% BSA involvement have an SJS/TEN-overlap syndrome. Patients may present with a prodrome consisting of fever, flu-like symptoms, photophobia, conjunctival itching, erythematous rash, myalgias, or arthralgias. On examination, patients usually have a painful erythematous rash in the involved areas which may evolve into vesicles or bullae with time. The palms and soles tend to be spared in this condition. A positive Nikolsky sign, in which superficial sloughing of the skin can be provoked by applying lateral pressure to the surface of apparently uninvolved skin, is classically positive. Mucosal involvement is also typical, manifesting as painful erosions in the buccal mucosa and, occasionally, with severe conjunctivitis, odynophagia, or genital erosions. Due to massive fluid and electrolyte losses and the catabolic state associated with this disorder, electrolyte imbalances as well as hypoalbuminemia are commonly noted upon laboratory evaluation. These patients are at risk of bacterial superinfection of their skin lesions and must be carefully monitored and treated for the same.

Rashes resembling autoimmune conditions: Another broad category of cutaneous reactions includes rashes that resemble autoimmune dermatological conditions. Bullous pemphigoid-like reactions have been reported with PD-1/PD-L1 inhibitors but have not been reported with CTLA-4 inhibitors. The onset of blistering may be heralded by pruritis or a mild erythematous rash. On physical examination, patients often have a variable number of tense bullae which can rupture leading to moist erosions. These blisters are more commonly noted on the trunk or intertriginous areas and rarely involve mucosal surfaces. These lesions may also persist even after discontinuation of the offending immunotherapeutic agent. Other reactions that resemble autoimmune conditions include dermatomyositis (serological workup may be negative for anti-Jo1 antibodies), vasculitis, and Sjogren’s or sicca syndrome.

Vitiligo: Other rare cutaneous toxicities as a result of alteration of melanocytes include vitiligo, regression of melanocytic nevi, and tumoral melanosis. The higher incidence of vitiligo in patients with melanoma is likely a consequence of shared antigens among melanoma cells and melanocytes. Vitiligo associated with immunotherapeutic agents is usually symmetric in distribution and tends to be irreversible.

Other dermatological toxicities: Other infrequently observed toxicities include alopecia, re-pigmentation of hair, and dystrophic nails. ^,