Cutaneous immune-related adverse events associated with immune checkpoint inhibitors

INTRODUCTION — 

Immune checkpoint inhibitors (ICIs) are increasingly used for the treatment of various malignancies (table 1) (see "Principles of cancer immunotherapy", section on 'Immune checkpoint inhibitors'). ICIs target the T cell deactivation system via the cytotoxic T lymphocyte-associated protein 4 (CTLA-4) receptor, programmed cell death protein 1 (PD-1) receptor, programmed cell death ligand 1 (PD-L1), and lymphocyte-activation gene 3 (LAG3). The resulting T cell activation enhances the host antitumor response and can result in generalized or tissue-specific inflammatory responses, collectively called immune-related adverse events (irAEs) [1]. Cutaneous immune-related adverse events (cirAEs) have the highest incidence and are the earliest occurring [2-6].

This topic will discuss the diagnosis and management of cirAEs. Other irAEs are discussed separately. The cutaneous adverse events associated with other cancer therapies are also discussed separately.

●(See "Overview of toxicities associated with immune checkpoint inhibitors".)

●(See "Cutaneous adverse events of molecularly targeted therapy and other biologic agents used for cancer therapy".)

●(See "Cutaneous adverse effects of conventional chemotherapy agents".)

●(See "Toxic erythema of chemotherapy (hand-foot syndrome)".)

●(See "Acneiform eruption secondary to epidermal growth factor receptor (EGFR) and MEK inhibitors".)

●(See "Hand-foot skin reaction induced by multitargeted tyrosine kinase inhibitors".)

●(See "Radiation dermatitis".)

EPIDEMIOLOGY — 

Overall, immune-related adverse events (irAEs) occur in approximately 90 percent of patients treated with cytotoxic T lymphocyte-associated protein 4 (CTLA-4) inhibitors, 70 percent of patients treated with anti-programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1), and nearly all patients treated with combined therapy, with most adverse events being grade 1 to 2 in severity (table 2) [7-15]. (See "Overview of toxicities associated with immune checkpoint inhibitors".)

Cutaneous immune-related adverse events (cirAEs) are among the most common irAEs. They occur in approximately 40 percent of patients treated with anti-CTLA-4 or anti-PD-1 monotherapy and 60 percent of those treated with combination therapy with both classes of agents [14,16-19]. Most cirAEs are low grade, with approximately 2 to 9 percent being grade 3 or greater. There is variability in time to onset that may be affected by patient factors as well as the checkpoint inhibitor regimen.

●An analysis of surveillance data from VigiBase, the World Health Organization (WHO) global database of individual case safety reports, found 11,000 distinct cases of cirAEs, including vitiligo-like depigmentation, immunobullous diseases, lichenoid dermatitis, erythema multiforme-like eruption, Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), maculopapular eruption, psoriasiform dermatitis, and eczematous dermatitis [20]. The median time to onset after treatment initiation was widely variable: one month for erythema multiforme and SJS/TEN, two months for eczematous dermatitis and maculopapular eruption, four months for lichenoid dermatitis, and five to six months for vitiligo and bullous pemphigoid.

●A Delphi consensus document additionally identified Grover disease, eruptive atypical squamous proliferation, pruritus without rash, and erosive mucocutaneous disease as common cirAEs [21].

RISK FACTORS — 

Factors that may increase the risk of developing cutaneous immune-related adverse events (cirAEs) include:

●Pre-existing inflammatory cutaneous diseases – Patients with pre-existing inflammatory cutaneous disease (eg, atopic dermatitis, psoriasis, lichen planus, or vitiligo) are likely to experience cutaneous flares with immune checkpoint inhibitors (ICIs) [22].

●Increased cytokine levels prior to immune checkpoint inhibitor initiation – Research is underway to explore the possibility that increased cytokine levels prior to ICI initiation, specifically interleukin (IL) 17, or certain human leukocyte antigen (HLA) haplotypes are associated with an increased incidence or severity of immune-related adverse events (irAEs) [23].

•In a study of 427 consecutive patients seen in a referral dermatology clinic for cirAEs, increased levels of eosinophils, IL-6, IL-10, and immunoglobulin E (IgE) at the time of presentation were associated with grade 3 and above cirAEs [24].

•In a study comparing histologic and ribonucleic acid (RNA) expression profiles in affected skin from five patients with Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and five patients with cirAEs from anti-programmed cell death protein 1 (PD-1) treatment, both SJS/TEN and cirAEs were associated with expression of PI3 (elafin), GZMB (granzyme B), and CXCL 9 to 11 (a group of chemokines involved in T cell activation) [25]. Unlike SJS/TEN, however, cirAEs showed increased expression of CCL27, granulysin, FAS ligand, and perforin.

●Human leukocyte antigen types – A study of 102 patients on ICI therapy did not find specific HLA types associated with all irAEs [26]. However, a strong association between HLA-DRB1*11:01 and ICI-induced pruritus was found in 32 patients.

●Previous drug hypersensitivity reactions – A retrospective study of 378 patients who developed a cirAE found that patients with a previous history of drug reaction had an increased risk of nonspecific rash with ICI treatment [27]. No association was found with other subtypes of cirAEs.

●Specific immune checkpoint inhibitor therapy and type of cancer – In a retrospective cohort study that included 8637 patients treated with an ICI in a national insurance claims database, patients treated with ipilimumab monotherapy were less likely to experience cirAEs compared with patients treated with pembrolizumab monotherapy [28]. In contrast, the risk was increased for patients treated with combination therapy. Melanoma and renal cell carcinoma were also independent risk factors for developing cirAEs compared with lung cancer.

●Tumor stage/burden – In patients with melanoma, elevated levels of lactate dehydrogenase (LDH; a surrogate marker of high tumor burden) at baseline or >3 months after initiation of ICIs are associated with a lower risk of cirAEs [29,30].

PATHOGENESIS — 

Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) pathways play a central role in regulating cellular immune responses. The intended effect of immune checkpoint inhibitors (ICIs) is to upregulate the host T cell immune response to the tumor. However, the blockade of this control mechanism can result in generalized or tissue-specific inflammatory responses, collectively called immune-related adverse events (irAEs), which represent upregulation of T cell response to nontumor targets.

The spectrum of irAEs includes autoinflammatory (aberrant upregulation of the innate immune system) and autoimmune (aberrant upregulation of the adaptive immune system) responses, with the latter being more frequent [2,31-34].

The exploration of the relationship of ICI-induced autoimmune reactions with conventional autoimmune mechanisms shows many similarities in terms of T and B cell-activating autoantigens, but the precise mechanisms have not been determined. It has been shown that anti-CTLA-4 therapy induces increased CD4⁺ T cells in the lymph nodes, and anti-PD-1 therapy induces increased CD8⁺ T cells in the tissues [35].

Studies on autoimmunity induced by tumor necrosis factor (TNF) inhibitors and recombinant interferon (IFN)-alpha showed T helper type 2 (Th2) mediation via interleukin (IL) 4 and IL-6 [35]. Similar mechanisms might explain the presence of both adaptive immunity-driven and ICI-mediated irAEs.

CLINICAL MANIFESTATIONS — 

Cutaneous immune-related adverse events (cirAEs) include pruritus, inflammatory skin reactions (eg, "maculopapular," lichenoid, psoriasiform, eczematous eruptions), immunobullous diseases, vitiligo-like depigmentation, alopecia areata, and rarely, severe cutaneous adverse reactions (including Stevens-Johnson syndrome/toxic epidermal necrolysis [SJS/TEN] and drug reaction with eosinophilia and systemic symptoms [DRESS]) [2,31-34,36].

These reactions mimic, but are not identical to, the primary inflammatory or autoimmune diseases and should be more correctly labeled as "disease-like reactions." However, for simplicity, they are often called by the primary disease name. The clinical and histopathologic features of cirAEs are summarized in the table (table 3).

Pruritus — In patients receiving immune checkpoint inhibitors (ICIs), pruritus can occur in association with cutaneous xerosis (picture 1) or inflammatory skin reactions, sometimes disproportionate to the visible dermatitis. In approximately 20 percent of patients treated with ICIs, pruritus occurs in the absence of a concurrent skin eruption. Pruritus with or without rash occurs after a median of 6 to 12 weeks, usually presents with nonfocal involvement of the trunk and lower extremities, and can be associated with excoriations and prurigo nodularis-like lesions from repeated scratching [32,36].

Inflammatory dermatoses — Inflammatory eruptions are the most common cutaneous reactions to ICIs. They include nonspecific "maculopapular" or morbilliform eruptions and psoriasiform, eczematous, and lichenoid dermatoses (table 3). Of note, in clinical trials, these eruptions are often reported under the umbrella terms "rash" or "maculopapular rash."

Maculopapular (morbilliform) eruption — "Maculopapular" (morbilliform) eruption is the most common cirAE associated with ICIs [2,31]. It typically appears three to six weeks after treatment initiation, involves the trunk and the extensor aspect of the extremities in most cases, and can be accompanied by pruritus (table 3 and picture 2 and picture 3). Unlike the maculopapular eruptions associated with other medications, the maculopapular eruption of immunotherapy tends to be self-limited and resolves even with continued administration of the drug. (See "Exanthematous (maculopapular) drug eruption".)

Lichenoid eruption — Lichenoid eruptions have been reported in up to 25 percent of patients with cirAEs [3,37,38]. The eruption typically presents 6 to 12 weeks following treatment initiation and consists of flat-topped, pink to violaceous papules resembling primary lichen planus in a localized or generalized distribution, often associated with pruritus. Bullous lichenoid eruptions, mucosal involvement with oral or genital ulcers, and nail dystrophy have also been reported [37,39]. (See "Lichen planus" and "Lichenoid drug eruption (drug-induced lichen planus)".)

Eczematous eruption — Eczematous eruption presents with rough, pruritic, erythematous macules and papules, diffuse or coalescing in large or nummular patches (picture 4 and table 3). The trunk and extremities are predominantly involved. Some patients have a history of atopic disease. (See "Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis".)

Psoriasiform eruption — ICI-related psoriasiform eruptions are relatively uncommon. In the EudraVigilance (European Union Drug Regulating Authorities Pharmacovigilance) system, new-onset psoriasis or exacerbation of pre-existing psoriasis have been reported in approximately 4 percent of patients treated with ICIs [40]. In most cases (71 percent), patients had pre-existing disease. Indeed, patients with pre-existing psoriasis are likely to flare with initiation of immunotherapy. One multi-institutional study observed that 57 percent of patients with psoriasis treated with immunotherapy experienced worsening psoriasis, with 23 percent requiring systemic therapy to treat their flares, and 7 percent discontinuing immunotherapy due to their skin disease [22].

Plaque psoriasis (picture 5) is the most common clinical type, followed by palmoplantar, pustular, and guttate psoriasis, but in many cases, patients present with more than one clinical subtype of psoriasis [22,41,42].

Uncommon inflammatory reactions — Uncommon cutaneous reactions to ICIs include:

●Granulomatous dermatitis – Sarcoid-like cutaneous reactions have been described in patients treated with ICIs, most frequently with pembrolizumab [43,44]. Patients may develop classic red-brown papules or nodules on the head, trunk, or extremities (picture 6). Bone and lung involvement, the latter presenting as mediastinal/hilar lymphadenopathy, have also been reported with or without skin lesions [45]. Sarcoid-like lymphadenopathy is especially relevant to this population, as it can be mistaken for nodal cancer involvement on surveillance imaging [45,46].

●Acneiform eruptions – Acneiform eruptions similar to the papulopustular eruption associated with epidermal growth factor receptor (EGFR) inhibitors have been reported with both cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) inhibition [47].

Immunobullous diseases and other autoimmune diseases — Patients with underlying autoimmune diseases may experience exacerbation of the pre-existing disease, new development of a different autoimmune disease, or both [48].

Bullous pemphigoid — Bullous pemphigoid and other autoimmune bullous disorders have been reported in patients on ICI therapy [49-54].

●Clinical presentation – Bullous pemphigoid usually appears 13 to 16 weeks after drug initiation but can present later and even after treatment completion [51,55]. It may present with a prodromal phase of pruritus, followed by the development of generalized or localized, tense blisters filled with serous or hemorrhagic fluid (picture 7) [50,55-57]. Urticarial plaques without bullae and mucosal involvement have been reported in some patients [51]. Bullous pemphigoid may also present with intractable pruritus [58]. Compared with idiopathic bullous pemphigoid, ICI-induced bullous pemphigoid may have a milder phenotype [51,59].

●Diagnosis – The diagnostic work-up includes a biopsy of normal-appearing perilesional skin for routine histopathologic examination and direct immunofluorescence (DIF) as well as serologic testing by enzyme-linked immunosorbent assay (ELISA) for circulating antibodies against bullous pemphigoid antigen 180 (BP180) and bullous pemphigoid antigen 230 (BP230). In cases of suspected urticarial bullous pemphigoid without bullae, a biopsy for DIF can be obtained from an urticarial plaque instead of perilesional skin.

It should be noted that patients with ICI-induced bullous pemphigoid may lack some or all histopathologic, immunofluorescence, and serologic diagnostic features of idiopathic bullous pemphigoid, making it difficult to obtain an accurate diagnosis (table 3) [49]. (See "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid".)

Other bullous disorders — Other bullous disorders that have been reported in patients receiving ICI therapy include lichen planus pemphigoides and suprabasal acantholytic dermatoses resembling Grover disease [52,54,60,61]. (See "Grover disease (transient and persistent acantholytic dermatosis)" and "Paraneoplastic pemphigus" and "Lichen planus", section on 'Overlap syndromes'.)

Vitiligo-like depigmentation — Vitiligo-like depigmentation has been reported in 11 and 25 percent of patients with advanced melanoma receiving anti-CTLA-4 and anti-PD-1 therapy, respectively [2]. The clinical phenotype of vitiligo associated with ICI therapy is distinctive, characterized by multiple flecked macules that evolve to large patches located on sun-exposed areas (picture 8) [62]. There can be preceding erythema, although this is not often reported. Patients typically do not have a personal or family history of vitiligo or other autoimmune diseases. (See "Vitiligo: Pathogenesis, clinical features, and diagnosis".)

Connective tissue diseases — Autoimmune connective tissue diseases are uncommon, but potentially severe, immune-related adverse events (irAEs) [63-65].

●Lupus erythematosus – Systemic lupus erythematosus, subacute cutaneous lupus, and bullous lupus have all been reported with anti-PD-1 monotherapy and ICI combination therapy [66-71]. (See "Drug-induced lupus".)

●Dermatomyositis – Dermatomyositis (picture 9A-B) has been reported with all classes of ICIs [72-74]. Most of the reported cases were associated with increased titers of anti-transcription intermediary factor (TIF) 1-gamma antibodies, which are strongly associated with paraneoplastic dermatomyositis [75]. (See "Clinical manifestations of dermatomyositis and polymyositis in adults".)

●Scleroderma – Systemic sclerosis, eosinophilic fasciitis, and scleroderma-like cutaneous changes have been reported in patients treated with anti-PD-1 agents [76,77]. (See "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults" and "Eosinophilic fasciitis".)

Oral mucosal toxicities — Oral mucosal toxicities from ICIs include oral lichenoid reactions, sicca syndrome, and rarely, Sjögren's disease and mucous membrane pemphigoid [78-84]. In general, these reactions are low grade and likely underreported.

●Sicca syndrome – Sicca syndrome (mouth dryness with or without eye dryness), clinically indistinguishable from that associated with Sjögren's disease, has been reported in 6 to 24 percent of patients receiving ICIs [85]. In rare cases, sicca syndrome may occur in the setting of ICI-induced flare of a pre-existing Sjögren's disease [86]. (See "Clinical manifestations of Sjögren's disease: Exocrine gland disease".)

●Oral lichenoid reactions – Oral lichenoid reactions present with reticulate, white streaks (Wickham striae) or erosive lesions that can involve any area of the mouth [87]. They occur months after treatment initiation.

On histology, there is a patchy or diffuse interface dermatitis with a band-like infiltrate predominantly composed of CD4 and CD8 lymphocytes [37]. (See "Oral lichen planus: Pathogenesis, clinical features, and diagnosis" and "Lichenoid drug eruption (drug-induced lichen planus)".)

Hair and nail toxicities

●Hair toxicities

•Alopecia areata and alopecia universalis have been reported in approximately 1 to 2 percent of patients treated with ICIs (picture 10) [2,88-90]. It is usually a late adverse effect (table 3) and may occur several months after the initiation of treatment [91]. Concurrent nail dystrophy may be seen in some patients. Histopathology shows a perifollicular lymphocytic infiltrate. (See "Alopecia areata: Clinical manifestations and diagnosis".)

•Hair depigmentation, repigmentation, or darkening are unusual irAEs associated with ICI treatment [92-94]. Poliosis, a depigmentation of the scalp hair, eyebrows, and eyelashes, can be seen in isolation or in the setting of vitiligo-like depigmentation in patients with melanoma [95,96].

•Diffuse darkening of the hair was reported in a series of 14 patients receiving anti-PD-1 or anti-programmed cell death ligand 1 (PD-L1) therapy for non-small cell lung cancer [92].

●Nail toxicities – Nail toxicities are not well documented in clinical trials, and their incidence is unknown. Onycholysis (picture 11), onychoschizia (picture 12), and inflammatory nail changes may occur in the course of ICI therapy as isolated manifestations or may be associated with inflammatory dermatoses, such as psoriasiform or lichenoid eruptions [3,16,88,90,97-99]. Onychodystrophy has been reported in patients who developed alopecia areata or dermatomyositis [72,88,100].

Rare cutaneous adverse events

Severe cutaneous adverse reactions — Severe cutaneous adverse reactions, including SJS/TEN [101], acute generalized exanthematous pustulosis (AGEP) [102], and DRESS, have been described in isolated case reports [101,103,104]. These reactions are rare, and their frequency is not known, although it is estimated to be <1 percent of all cirAEs. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis" and "Acute generalized exanthematous pustulosis (AGEP)" and "Drug reaction with eosinophilia and systemic symptoms (DRESS)".)

Some reactions reported as SJS/TEN are actually SJS/TEN-like reactions that mimic SJS/TEN clinically and/or histologically [105]. Unlike true SJS/TEN, ICI-induced SJS/TEN-like reactions are believed to be severe, immune-mediated bullous eruptions due to enhanced ICI cytotoxicity [39].

There is evidence that some ICI-related severe eruptions that clinically resemble SJS/TEN may represent an immunotherapy-potentiated reaction to another concurrently administered medication, even if that medication had been previously well tolerated [106,107].

The term "progressive immunotherapy-related mucocutaneous eruption" has been proposed for such eruptions, which are likely to represent a distinct clinical entity from ICI-induced SJS/TEN [106]. In one case report, the ICI administration was successfully resumed following the identification and withdrawal of the potential "co-conspirator" medication [107].

Keratoacanthoma-like squamous proliferations and cutaneous squamous cell carcinoma — Keratoacanthoma-like squamous proliferations and cutaneous squamous cell carcinoma have been reported in patients receiving immunotherapy. An analysis of data from the US Food and Drug Administration's (FDA) Adverse Event Reporting System from 2004 to 2023 that included 158,000 reports of PD-1/PD-L1 inhibitor use found 43 reports of patients who developed keratoacanthoma-like squamous proliferations and 83 who developed cutaneous squamous cell carcinoma [108].

The pathophysiology and malignant potential of keratoacanthoma-like squamous proliferations are incompletely understood. These lesions may present without other skin diseases or as part of a broader hypertrophic lichenoid dermatitis. Histologically, they are very similar to hypertrophic lichen planus, and clinicopathologic correlation is often necessary for a precise diagnosis [109].

In many cases, keratoacanthoma-like squamous proliferations can be managed conservatively with modalities such as topical or intralesional steroids, intralesional chemotherapy, or cryotherapy, though some are treated with electrodesiccation and curettage or surgical excision [110-114]. Surgical excision is the treatment of choice for cutaneous squamous cell carcinoma.

Other rare reactions

●Vasculitis – Vasculitis most commonly presents as large-vessel vasculitis and, less commonly, leukocytoclastic vasculitis or granulomatous polyangiitis [115-118].

●Purpura fulminans – There is one report of purpura fulminans and multiorgan involvement developing in a patient treated with pembrolizumab for clear renal cell carcinoma [119].

●Neutrophilic dermatoses – Neutrophilic dermatoses, including Sweet syndrome, pustular eruptions, and pyoderma gangrenosum (picture 13), have been rarely reported [120]. Additionally, a case of pyoderma gangrenosum exacerbated by anti-PD-1 therapy was reported [121].

●Erythema nodosum – Erythema nodosum-like panniculitis (picture 14) has been reported in a few patients [122,123].

CORRELATION WITH TUMOR RESPONSE AND SURVIVAL — 

The relationship between immune-related adverse events (irAEs), including cutaneous immune-related adverse events (cirAEs), and tumor response to treatment has been examined in several studies but remains incompletely defined due to multiple factors, including [124]:

●Late onset and long duration of irAEs.

●Tumor type and tumor burden.

●Potential effect of treatments for irAEs, including systemic corticosteroids and other immunosuppressive treatments, on tumor outcome.

●A positive association with irAEs and improved tumor response in patients with metastatic melanoma has been demonstrated for vitiligo and cutaneous toxicities in general. Similar findings have not been replicated in other cancer types [6,125-128].

The late onset of irAEs is of special relevance. In cohort studies, patients who progress earlier are less likely to develop toxicity because they may die or discontinue treatment because of disease progression, whereas people who stay on treatment for a longer period have more time to experience toxicity. This may result in an overestimate of the survival advantage associated with the development of irAEs due to the so-called "immortal time bias" [129].

●In a series of 577 patients treated with anti-programmed cell death ligand 1 (PD-L1) for melanoma or non-small cell lung cancer, the occurrence of an irAE was significantly associated with improved overall survival (hazard ratio [HR] 0.56, 95% CI 0.41-0.75) and progression-free survival (HR 0.63, 95% CI 0.47-0.83) [130].

●Another retrospective study that included 628 patients with cirAEs found a survival benefit only for patients who had also developed a non-cirAE [131].

●In a multicenter cohort of 3731 patients treated with an immune checkpoint inhibitor (ICI), patients who developed a cirAE had a better survival compared with patients without a cirAE (HR 0.87, 95% CI 0.79-0.98) [132]. Patients with melanoma and cirAEs had a better prognosis (HR 0.44, 95% CI 0.38-0.51). Among the cirAE morphologies, vitiligo was associated with a more favorable prognosis (HR 0.29, 95% CI 0.12-0.71).

●The occurrence of vitiligo-like depigmentation in patients with advanced melanoma treated with ICIs appears to correlate with a more favorable prognosis. In a systematic review of 137 studies with nearly 6000 patients with stage III to IV melanoma treated with immunotherapy, the development of vitiligo-like depigmentation was associated with both improved progression-free survival and overall survival (HR 0.51, 95% CI 0.32-0.82 and HR 0.25, 95% CI 0.10-0.61, respectively) [133].

EVALUATION AND DIAGNOSIS — 

The diagnosis of cutaneous immune-related adverse events (cirAEs) is based on patient history and clinical examination in most cases. A skin biopsy and laboratory tests may be needed for an accurate diagnosis [4,21].

Patient history

●Medical history – A complete medical history, including history of chronic dermatologic disorders, should be obtained from all patients with suspected cirAE.

●Medication history – All current and recent medications should be assessed as well as the temporal relationship between drug administration and onset of pruritus and/or skin eruption. The potential role of other medications in the occurrence of skin symptoms should be carefully evaluated.

●Time of onset – The time to onset of specific cirAEs may provide a clue to the correct diagnosis [2]. Many inflammatory eruptions induced by immune checkpoint inhibitors (ICIs) present within one to two cycles of therapy initiation (ie, after two to six weeks), and most appear within three to six months. However, some cirAEs, such as immunobullous eruptions, alopecia, and vitiligo-like depigmentation, can appear late during the treatment course and up to 12 months after the last administration.

●Concurrent nondermatologic irAE – History of a concurrent nondermatologic immune-related adverse event (irAE) may support the diagnosis of cirAE.

Clinical examination

●Perform a careful total body skin examination, including the mucosal surfaces, to assess the lesion morphology, location, and severity.

●Assess the general status of the patient.

●In patients with widespread eruption, consider the possibility of life-threatening reactions, such as Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) or drug reaction with eosinophilia and systemic symptoms (DRESS).

●Assess the severity of the skin eruption using the National Institutes of Health/National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.5 (table 4A-D) [134].

Dermatology consultation — In patients manifesting cirAEs (and particularly in those with grade 2+ cirAEs), accurate dermatologic diagnosis is of key importance for appropriate management and for limiting disruption of anticancer treatment. Clinical examination by a dermatologist, combined with clinicopathologic correlation with skin biopsy if indicated, increases the likelihood of obtaining specific and actionable diagnoses.

There is evidence both in the outpatient and inpatient settings that dermatology consultation results in decreased ICI therapy interruption [135], targeted inhibitor interruption [136], and increased overall survival [137,138].

Skin biopsy and histopathology — In select patients, a biopsy of lesional skin (or perilesional in bullous reactions) may be needed for routine histopathologic examination and direct immunofluorescence (DIF). The histopathologic findings are cirAE specific (table 3).

●Maculopapular (morbilliform) eruption – Vacuolar degeneration at the dermal-epidermal junction and a superficial perivascular infiltrate predominantly composed of CD4 T cells with a variable amount of eosinophils [139]. (See "Exanthematous (maculopapular) drug eruption".)

●Eczematous eruption – Epidermal spongiosis and a perivascular lymphocytic infiltrate with or without eosinophils. (See "Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis".)

●Lichenoid eruption – Vacuolar interface dermatitis with a band-like lymphohistiocytic infiltrate at the dermal-epidermal junction predominantly composed of CD4 lymphocytes, CD1631 histiocytes, variable eosinophils, and melanophages [139]. (See "Lichenoid drug eruption (drug-induced lichen planus)".)

●Psoriasiform eruption – Regular acanthosis, parakeratosis, hypogranulosis, and variable spongiosis. (See "Psoriasis: Epidemiology, clinical manifestations, and diagnosis".)

●Bullous pemphigoid-like eruption – Subepidermal blister, dermal inflammatory infiltrate with lymphocytes, eosinophils, and variable neutrophils; DIF of perilesional skin shows linear deposits of immunoglobulin G (IgG) and complement component 3 (C3) at the dermal-epidermal junction. (See "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid", section on 'Routine histopathologic examination'.)

Laboratory tests — Laboratory results can be helpful in diagnosing specific rashes.

●Cultures for bacteria, viruses, or fungi may be required to rule out infection.

●If there is suspicion of nutritional deficiency, which can mimic or exacerbate cirAEs, a nutritional work-up should be undertaken, including zinc, B12, and vitamin D levels.

●Complete blood count (CBC) with differential. Peripheral eosinophilia may indicate DRESS in the appropriate clinical scenario.

●Specific laboratory testing is needed for the diagnosis of immunobullous disease, including serologic testing by enzyme-linked immunosorbent assay (ELISA) for circulating antibodies against bullous pemphigoid antigen 180 (BP180) and bullous pemphigoid antigen 230 (BP230). (See 'Bullous pemphigoid' above and "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid", section on 'Diagnosis'.)

●The laboratory work-up for other autoimmune diseases is discussed in detail elsewhere. (See "Systemic lupus erythematosus in adults: Clinical manifestations and diagnosis", section on 'Diagnosis' and "Diagnosis and classification of Sjögren's disease" and "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults".)

DIFFERENTIAL DIAGNOSIS — 

The differential diagnosis of cutaneous reactions to immune checkpoint inhibitors (ICIs) includes:

●Drug reaction to other medications – Patients with cancer are often on combination cancer therapy. It is important to consider reactions due to other drugs and latency time since starting treatment and to assess drug causality carefully. (See "Drug eruptions", section on 'Approach to the diagnosis'.)

In the case of a Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN)-like eruption, synergistic toxicity between immunotherapy and other medications may produce an epidermolytic skin reaction.

●Disseminated zoster – The presence of vesicles on an erythematous base suggests herpes zoster. A skin biopsy and viral culture can clarify the diagnosis. (See "Epidemiology, clinical manifestations, and diagnosis of herpes zoster".)

●Atypical infections – Infections with atypical mycobacteria, deep fungal infections, or angiotropic fungal infections may present with erythematous to skin-colored nodules. A skin biopsy and tissue culture are necessary for accurate diagnosis.

●Cutaneous metastases – Cutaneous metastases may present as eruptive, erythematous to skin-colored, possibly ulcerated papules or nodules. A skin biopsy is usually necessary to establish the diagnosis.

MANAGEMENT

Our approach — Mucocutaneous immune-related adverse events (irAEs) not only impact patient quality of life but can also affect the patient's ability to remain on cancer therapy. When promptly recognized and treated, patients on immune checkpoint inhibitor (ICI) monotherapy may not need treatment interruption or discontinuation. However, the ICI-related cutaneous immune-related adverse events (cirAEs) can be prolonged and difficult to manage [140].

Our approach to the management of mucocutaneous toxicities of cirAEs is consistent with published guidelines (algorithm 1) [4,141-151].

●Most cutaneous eruptions are of low grade (grade 1 or 2) and can be managed with topical corticosteroids and oral antihistamines for symptomatic treatment of pruritus.

●More severe eruptions (grade 3 or 4 or intolerable grade 2) usually require systemic treatments and interruption or even discontinuation of ICI therapy.

●The decision to continue, interrupt, or stop ICI treatment is made in the individual patient based on the consideration of the severity of cutaneous involvement, impact on the general status of the patient, and efficacy of ICI therapy for the patient.

Evidence from high-quality studies on the efficacy of topical and systemic treatments for cirAEs is limited and mainly based on case series, indirect evidence of efficacy for similar cutaneous diseases unrelated to ICI therapy, and clinical experience [142].

Impact of systemic immunosuppressants and immunomodulators on tumor response — The effect of systemic immunosuppressants and immunomodulators administered to treat cirAEs on tumor response to ICIs is not fully understood. A few retrospective studies in patients with melanoma and other malignancies do not indicate a change in tumor response [152-154]. However, other studies have reported reduced progression-free and overall survival for patients treated with high-dose systemic corticosteroids for noncutaneous toxicities associated with ICIs [155,156].

High-quality studies are needed to understand the full effect of immunomodulators on tumor response. Until that time, topical treatments and targeted immunomodulators are preferred.

Treatment of specific cirAEs

Pruritus — The management of pruritus is based on its severity (table 4B and algorithm 1). First-line symptomatic treatments include oral antihistamines and topical agents (eg, medium- to high-potency topical steroids, camphor-menthol lotions, bland emollients, capsaicin lotion).

Second-line therapies include gamma-aminobutyric acid analogs (eg, gabapentin, pregabalin), doxepin, selective serotonin reuptake inhibitors, aprepitant, naloxone, dronabinol, oral corticosteroids, dupilumab, and omalizumab (table 5). (See "Pruritus: Therapies for generalized pruritus".)

Laboratory work-up to exclude a prodromal phase of bullous pemphigoid should be considered in patients with severe, refractory pruritus [58]. (See 'Bullous pemphigoid' above.)

Maculopapular (morbilliform) eruption — The Common Terminology Criteria for Adverse Events (CTCAE) for grading maculopapular rash (table 4C) can be used for maculopapular (morbilliform) eruption as well as for all inflammatory dermatoses. Immunotherapy-induced maculopapular eruptions are typically self-limited and will resolve even with continued immunotherapy administration.

The approach to treatment is outlined below (algorithm 1) [24,157]:

●Grade 1 – ICI therapy is continued. Medium- to high-potency topical corticosteroids (table 6) are applied to the involved areas twice daily. Emollients can be used liberally.

●Grade 2 – ICI therapy is continued. High-potency topical corticosteroids are applied to the involved areas twice daily. For rash unresponsive to topical therapy alone, a short course of systemic corticosteroids (eg, prednisone 0.5 to 1 mg/kg/day) tapered over two weeks is a second-line option.

●Grade 3 or intolerable grade 2 – Interrupt ICI therapy. Systemic corticosteroids (eg, prednisone 0.5 to 1 mg/kg/day, typically 40 to 80 mg per day) are administered until improvement is noted and then tapered over two to four weeks. Infliximab and tocilizumab (an anti-interleukin [IL] 6R monoclonal antibody) have been proposed as treatment options for patients with severe rash unresponsive to systemic corticosteroids [24,158].

Eczematous eruption — The treatment of eczematous eruption is based on severity (table 4C).

●Grade 1 – Continue ICI therapy. For grade 1 rash (table 4C), we suggest medium- to high-potency topical corticosteroids (table 6) and emollients. Topical corticosteroids are applied to the involved areas twice daily.

●Grade 2 – Continue ICI therapy. For grade 2 rash, we suggest high-potency topical corticosteroids as first-line therapy. Topical corticosteroids are applied to the involved areas twice daily. For rash unresponsive to topical therapy alone, treatment options include systemic corticosteroids (eg, prednisone 0.5 to 1 mg/kg/day) and narrowband ultraviolet B (NBUVB) phototherapy, if available and feasible.

●Grade 3 or intolerable grade 2 – Interrupt ICI therapy. For grade 3 eruptions, we suggest systemic corticosteroids (eg, prednisone 0.5 to 1 mg/kg/day) tapered over two to four weeks as first-line therapy. Alternative therapies include NBUVB phototherapy, if available and feasible, and dupilumab. (See "Treatment of atopic dermatitis (eczema)" and "Treatment of atopic dermatitis (eczema)", section on 'Phototherapy' and "Treatment of atopic dermatitis (eczema)", section on 'Dupilumab'.)

Lichenoid eruption — The treatment of lichenoid eruption is based on severity (table 4C) and similar to that of idiopathic lichen planus.

●Grade 1 – Continue ICI therapy. For grade 1 eruption (table 4C), we suggest medium- to high-potency topical corticosteroids (table 6). Topical corticosteroids are applied to the involved areas twice daily until improvement.

●Grade 2 – Continue ICI therapy. For grade 2 eruption, we suggest high-potency topical corticosteroids as first-line treatment (table 6). Topical corticosteroids are applied to the involved areas twice daily until improvement to grade 1 or less is noted. For rash unresponsive to topical therapy alone, second-line therapies include systemic corticosteroids (eg, prednisone 0.5 to 1 mg/kg/day), NBUVB phototherapy, if available and feasible, and methotrexate.

●Grade 3 or intolerable grade 2 – Interrupt ICI therapy. For grade 3 lichenoid eruption, we suggest systemic corticosteroids (eg, prednisone 0.5 to 1 mg/kg/day) tapered over two to four weeks as first-line therapy. Second-line therapies include acitretin (at a dose of 10 to 25 mg per day) and methotrexate.

Psoriasiform eruption — The treatment of psoriasiform eruption is based on severity (table 4C).

●Grade 1 – Continue ICI therapy. For grade 1 eruption, we suggest medium- to high-potency topical corticosteroids (table 6) as first-line therapy (algorithm 1). Topical corticosteroids are applied twice daily until improvement is noted.

●Grade 2 – Continue ICI therapy. For grade 2 eruption, we suggest high-potency topical corticosteroids as first-line treatment (table 6). Second-line therapies for rash unresponsive to topical therapy alone include NBUVB phototherapy, if available and feasible, or apremilast. (See "Chronic plaque psoriasis in adults: Treatment of disease requiring phototherapy or systemic therapy", section on 'Systemic therapies' and "Chronic plaque psoriasis in adults: Treatment of disease requiring phototherapy or systemic therapy", section on 'Phototherapy'.)

●Grade 3 or intolerable grade 2 – Interrupt ICI therapy. For grade 3 eruption, we suggest high-potency topical corticosteroids in combination with NBUVB phototherapy, if available and feasible, or systemic therapies, including nonbiologic agents (ie, acitretin, methotrexate, cyclosporine, apremilast) or biologic immunomodulators. The latter, including anti-IL-23 therapies (eg, ustekinumab, guselkumab, risankizumab), are preferred.

Ustekinumab, an inhibitor of IL-12 and IL-23, can be particularly helpful for pustular psoriasis. Anti-IL-17 agents (eg, secukinumab, ixekizumab), although they potentially improve tumor response, may increase the patient's risk of colitis [159]. Anti-tumor necrosis factor (TNF) therapies, although not first line, could have utility in patients where a biosimilar therapy may be the most financially feasible option. As with treatment of primary psoriasis, the management of immunotherapy-induced psoriasiform eruptions hinges on the presence or absence of symptoms of concurrent inflammatory arthritis, as available therapies for skin psoriasis are differentially effective against inflammatory arthritis. (See "Chronic plaque psoriasis in adults: Overview of management" and "Treatment of psoriatic arthritis".)

Bullous pemphigoid-like eruption — The management of bullous pemphigoid in patients treated with ICIs is based on severity (table 4D) and is similar to that of idiopathic bullous pemphigoid (algorithm 1) . (See "Management and prognosis of bullous pemphigoid".)

●Grade 1 – Continue ICI therapy [160]. For grade 1 eruption, high-potency topical corticosteroids (table 6) are the treatment of choice. Topical corticosteroids are applied twice daily to the involved areas.

●Grade 2 or 3 – Interrupt ICI therapy. For grade 2 or 3 bullous pemphigoid, we suggest moderate- to high-dose oral corticosteroids (eg, prednisone 0.5 to 1 mg/kg per day) as first-line, short-term therapy. The use of doxycycline, which is a treatment option for primary pemphigoid, is not recommended in patients receiving immunotherapy. Antibiotics can cause long-term changes in the gut microbiome that can potentially diminish the efficacy of immunotherapy [161].

For disease not responding to systemic corticosteroids or recurring after tapering steroids, second-line therapies include conventional immunosuppressants (eg, methotrexate, mycophenolate mofetil) and biologic agents (eg, dupilumab, rituximab, omalizumab), with dupilumab being the preferred long-term therapy option.

A single-institution study demonstrated that IL-4 and IL-13 messenger ribonucleic acids (mRNAs) are overexpressed in lesional skin of both ICI-induced and idiopathic bullous pemphigoid [162]. This finding may explain the efficacy of dupilumab, a human monoclonal antibody that binds to the alpha subunit of the IL-4 receptor and inhibits downstream signaling of IL-4 and IL-13, in the management of severe bullous pemphigoid [163,164].

Severe cutaneous adverse reactions — Severe cutaneous adverse reactions, such as Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS), are all considered grade 3 or 4 in severity (table 7A-B). Management involves [145] (see "Stevens-Johnson syndrome and toxic epidermal necrolysis: Management, prognosis, and long-term sequelae" and "Drug reaction with eosinophilia and systemic symptoms (DRESS)"):

●Grade 3 – Interrupt ICI and consider permanent discontinuation. Evaluate for other potentially contributory medications. Consider admission to a hospital for urgent dermatologic consultation, supportive therapy, and wound care. Intravenous methylprednisolone (at a dose of 1 to 2 mg/kg daily) should be initiated and maintained until improvement is achieved. Potential adjunctive therapies including oral cyclosporine and TNF-alpha inhibitors should be considered depending on the clinical scenario. Wound management involves gentle skin care and assessment and treatment of secondary bacterial infection. Early consultation with ophthalmology, otolaryngology, urology, and gynecology is required for evaluation and treatment of mucosal involvement.

●Grade 4 – Discontinue ICI. Patients with grade 4 SJS/TEN should be urgently admitted to an intensive care unit or burn unit for supportive care and wound care. Urgent consultation with ophthalmology, otolaryngology, urology, and gynecology for treatment of mucosal involvement and prevention of sequelae is required.

Vitiligo — Photoprotection to avoid sunburn is recommended for all patients who have depigmented areas in sun-exposed areas. For patients who desire treatment, therapeutic options are based on the extent of depigmentation (table 8) and include high-potency topical corticosteroids and NBUVB phototherapy [165]. (See "Vitiligo: Management and prognosis".)

However, the decision to treat vitiligo-like depigmentation should be discussed with the oncology team, as there are reports of spontaneous repigmentation associated with melanoma recurrence [166,167]. Thus, it may be prudent to avoid any attempt to reduce autoimmunity to melanocytic antigens in patients with melanoma.

Alopecia areata — Treatments for alopecia areata associated with ICI therapy include high-potency topical steroids in a lotion or foam formulation (table 6) and intralesional corticosteroids (triamcinolone 0.1%, 2.5 to 5 mg/mL). Janus kinase (JAK) inhibitors (eg, oral tofacitinib, oral ruxolitinib) may be an option for refractory cases. However, the safety of JAK inhibitors has not been studied in patients with active metastatic cancer nor in the setting of ICI therapy. (See "Alopecia areata: Management".)

Oral mucosal toxicity — The treatment of ICI-related oral mucosal toxicity is based on severity (table 9). Maintaining good oral hygiene is indicated for all patients. For severe mucosal involvement, interruption of ICI therapy may be considered [87].

●Grade 1 or 2 – High-potency topical corticosteroids (table 6) (eg, dexamethasone 0.5 mg/5 mL swish and spit, clobetasol propionate 0.05% gel).

●Grade 3 or intolerable grade 2 – Oral corticosteroids (eg, prednisone 0.5 to 1 mg/kg per day for two to four weeks). Interrupt ICI treatment until improvement to grade 1 or tolerable grade 2. For erosive or bullous lesions not responding to oral corticosteroids or recurring after tapering corticosteroids, second-line therapies include conventional immunosuppressants (eg, methotrexate, mycophenolate mofetil) or biologic agents (eg, rituximab, dupilumab). (See "Management of mucous membrane pemphigoid".)

Nail toxicity — General recommendations for patients who experience dystrophic nail alterations associated with ICI therapy include nail care (eg, nail clipping, avoiding cuticle manipulation) and the use of nail strengtheners. Concurrent fungal infections should be treated with topical or systemic antifungal agents. (See "Onychomycosis: Management".)

FOLLOW-UP — 

We typically see patients with acute cutaneous immune-related adverse events (cirAEs) every one to two weeks until the eruption is well controlled. Thereafter, patients are seen every three months by dermatology if on stable anticancer treatment.

PROGNOSIS — 

Most cutaneous immune-related adverse events (cirAEs) are low grade, self-limiting, and usually controlled with topical therapies and oral antihistamines, although complete resolution may not occur until cessation of immune checkpoint inhibitor (ICI) therapy. The small subset of patients who have high-grade cirAEs (6 percent or less) may experience a prolonged course, requiring interruption or even discontinuation of cancer therapy. The majority of severe cirAEs resolve after ICI discontinuation.

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Management of toxicities due to checkpoint inhibitor immunotherapy".)

SUMMARY AND RECOMMENDATIONS

●Epidemiology – Cutaneous immune-related adverse events (cirAEs) result from the effects of T cell activation induced by immune checkpoint inhibitors (ICIs). They occur in approximately 90 percent of patients treated with cytotoxic T lymphocyte-associated protein 4 (CTLA-4) inhibitors, 70 percent of patients treated with programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors, and nearly all patients treated with combined therapy. Risk factors include pre-existing inflammatory skin diseases and history of drug hypersensitivity reactions. (See 'Introduction' above and 'Epidemiology' above and 'Risk factors' above.)

●Clinical presentation – Most commonly, cirAEs present as inflammatory skin reactions (eg, maculopapular [morbilliform] eruption (picture 2); lichenoid, psoriasiform (picture 5), or eczematous reactions (picture 4)). Less common presentations include immunobullous diseases (eg, bullous pemphigoid (picture 7)), autoimmune rheumatic diseases (eg, lupus erythematosus, dermatomyositis (picture 9A)), vasculitis, and neutrophilic dermatoses (eg, Sweet syndrome, pyoderma gangrenosum (picture 13)). Rarely, ICIs may cause severe cutaneous adverse reactions (including Stevens-Johnson syndrome/toxic epidermal necrolysis [SJS/TEN] and drug reaction with eosinophilia and systemic symptoms [DRESS]). (See 'Clinical manifestations' above.)

●Evaluation and diagnosis – The diagnosis of cirAEs is based on patient history and clinical examination in most cases. The time to onset of specific cirAEs is highly variable compared with reactions to other medications but may nonetheless provide a clue to the correct diagnosis (table 3). A skin biopsy and laboratory work-up may be needed for the diagnosis of indeterminate inflammatory dermatoses, bullous pemphigoid, and other autoimmune diseases. (See 'Evaluation and diagnosis' above.)

●Management – The management of cirAEs is based on their severity (table 4C-D). The decision to continue, interrupt, or stop ICI treatment is made in the individual patient based on the severity of cutaneous involvement and impact on the patient's functional status (algorithm 1). In general, for grade 1 reactions, ICI treatment is continued at the usual dose. For grade 2, treatment is continued at the usual dose or held until improvement to grade 0 or 1. For grade 3 or intolerable grade 2 reactions, ICI treatment is interrupted until improvement to grade 0 or 1 and then resumed at a lower dose as per protocol. (See 'Management' above.)

•Pruritus – We suggest oral antihistamines as initial symptomatic treatment for pruritus (Grade 2C). Adjunctive symptomatic therapies include medium- to high-potency topical steroids, camphor-menthol lotions, bland emollients, and capsaicin lotion. For pruritus uncontrolled with oral antihistamines, alternatives include gamma-aminobutyric acid analogs (eg, gabapentin, pregabalin), doxepin, selective serotonin reuptake inhibitors, aprepitant, naloxone, dronabinol, oral corticosteroids, dupilumab, and omalizumab (table 5). (See "Pruritus: Therapies for generalized pruritus".)

•Maculopapular (morbilliform), eczematous, lichenoid, or psoriasiform eruption

-Grade 1 to 2 eruption – For most patients with grade 1 or 2 inflammatory cirAEs, we suggest topical corticosteroids rather than systemic corticosteroids (Grade 2C). Medium- to high-potency topical corticosteroids (table 6) are applied twice daily until improvement is noted. ICI therapy is usually continued. Narrowband ultraviolet B (NBUVB) phototherapy, if available or feasible, may be a treatment option for grade 2 eruptions unresponsive to topical corticosteroids. Oral antihistamines may be used for symptomatic control of pruritus.

-Grade ≥3 or intolerable grade 2 eruption – For patients with more severe inflammatory cirAEs that do not respond to topical corticosteroids, we suggest systemic corticosteroids rather than other immunosuppressants or immunomodulators as initial treatment (algorithm 1) (Grade 2C). We typically use prednisone 0.5 to 1 mg/kg/day tapered over two to four weeks. These patients may require interruption of ICI therapy.

Alternative therapies for eruptions uncontrolled by systemic corticosteroids include NBUVB phototherapy, if available and feasible, immunosuppressants (eg, methotrexate, mycophenolate mofetil, apremilast), or biologic immunomodulators (eg, dupilumab [for eczematous eruptions], ustekinumab, guselkumab, infliximab [for psoriasiform eruptions]). (See 'Maculopapular (morbilliform) eruption' above and 'Eczematous eruption' above and 'Lichenoid eruption' above and 'Psoriasiform eruption' above.)

•Bullous pemphigoid-like eruption

-Grade 1 – For grade 1 bullous pemphigoid, we suggest high- to super high-potency topical corticosteroids (table 6) rather than systemic therapies as initial treatment (Grade 2C). Topical corticosteroids are applied twice daily to the involved areas until improvement. ICI therapy is usually continued.

-Grade 2 or 3 – For grade 2 or 3 bullous pemphigoid, we suggest moderate- to high-dose oral corticosteroids (eg, prednisone 0.5 to 1 mg/kg per day) rather than other immunosuppressants or immunomodulators as initial therapy (Grade 2C). These patients may require interruption of ICI therapy. For disease not responding to systemic corticosteroids, second-line therapies include conventional immunosuppressants (eg, methotrexate, mycophenolate mofetil) or biologic agents (eg, dupilumab, rituximab, omalizumab). (See 'Bullous pemphigoid-like eruption' above.)

●Prognosis – Most cirAEs are low grade, self-limiting, and usually controlled with topical therapies. Patients who have high-grade cirAEs may experience a prolonged course, requiring management with systemic immunomodulators to avoid interruption or even discontinuation of cancer immunotherapy. (See 'Prognosis' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Mario E Lacouture, MD, who contributed to earlier versions of this topic review.