INTRODUCTION — Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that are increasingly used for the treatment of various solid and hematologic malignancies (table 1A). 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, and programmed cell death ligand 1 (PD-L1).
The resulting T cell activation enhances the host tumor response. Off-target effects of this T cell response comprise immune-related adverse events (irAEs), of which cutaneous irAEs have the highest incidence and are the earliest occurring [1-5]. They include inflammatory skin reactions (eg, maculopapular, lichenoid, eczematous eruptions), immunobullous diseases, vitiligo, alopecia areata, and, rarely, severe cutaneous drug reactions (eg, Stevens-Johnson syndrome/toxic epidermal necrolysis [SJS/TEN], drug reaction with eosinophilia and systemic symptoms [DRESS]) [1,6-9].
The cutaneous 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 ICI monotherapy may not need treatment interruption or discontinuation. However, the ICI-related, cutaneous irAEs can be prolonged and difficult to manage [10].
As ICIs can be used in combination with conventional cytotoxic chemotherapy and targeted molecular therapy, cutaneous adverse events may include those induced by or exacerbated by the ICIs.
This topic will discuss the diagnosis and management of cutaneous irAEs. Other irAEs are discussed separately. The cutaneous adverse events associated with other cancer therapies are also discussed separately.
●(See "Toxicities associated with checkpoint inhibitor immunotherapy".)
●(See "Rheumatologic complications of checkpoint inhibitor immunotherapy".)
●(See "Cutaneous adverse effects of conventional chemotherapy agents".)
●(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 — 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 1B) [11-18].
Any-grade and high-grade cutaneous irAEs occur in approximately 50 and 2 percent of patients treated with ipilimumab monotherapy, respectively, and 40 and 2 percent of patients treated with anti-PD-1 monotherapy, respectively [18,19]. Severe irAEs are also more frequent with combination therapy of anti-CTLA-4 plus anti-PD-1 than with monotherapy with either class of agents [20-22].
RISK FACTORS — 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). 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 cutaneous irAEs, increased levels of eosinophils, IL-6, IL-10, and immunoglobulin E (IgE) at the time of presentation were associated with grade 3 and above cutaneous irAEs [24].
●In a study comparing histologic and RNA expression profiles in affected skin from five patients with Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and five patients with cutaneous irAEs from anti-programmed cell death protein 1 (PD-1) treatment, both SJS/TEN and cutaneous irAEs 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, cutaneous irAEs showed increased expression of CCL27, granulysin, FAS ligand, and perforin.
●A study of 102 Swiss patients on ICI therapy did not find specific HLA types associated with all irAEs. However, a strong association between HLA-DRB1*11:01 and ICI-induced pruritus was found in 32 patients [26].
Tumor-associated B cells, specifically tumor-induced plasmablast-like-enriched B cells (TIPB; CD27+/CD38+/PAX5), play an essential role in sustaining tumor inflammation and recruiting CD8+ T cells in human melanoma. High expression of TIPB before ICI therapy predicts response to therapy and overall survival [27]. As most cutaneous irAEs are T cell mediated, increased TIPBs may also be a predictor of cutaneous irAEs.
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, blockade of this control mechanism can result in generalized or tissue-specific, inflammatory responses, collectively called immune-related adverse events (irAEs). Cutaneous irAEs are thought to be off-target or on-target but off-tumor effects of the ICIs [25].
The spectrum of irAEs can be divided into autoinflammatory and autoimmune responses. The former are nonspecific upregulations of the innate immune system. Most of the cutaneous irAEs, however, fall into the category of autoimmune responses, which represent a more specific activation of adaptive immunity. Cutaneous, autoimmune diseases occur more frequently with anti-PD-1/programmed cell death ligand 1 (PD-L1) than with anti-CTLA-4 therapy.
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 tissue [28].
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 [28]. Similar mechanisms might explain the presence of both adaptive, immunity-driven and antibody-mediated irAEs.
CLINICAL MANIFESTATIONS — The clinical and histopathologic features of cutaneous immune-related adverse events (irAEs) are summarized in the table (table 2).
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, or may present in the absence of a concurrent skin eruption. Pruritus without rash occurs in approximately 20 percent of patients treated with ICIs after a median of three treatment cycles. It usually involves the trunk and lower extremities, where excoriations and prurigo nodularis-like lesions can be noted [7].
Inflammatory dermatoses — Inflammatory eruptions are the most common cutaneous reactions to ICIs. They include nonspecific, maculopapular eruption and psoriasiform, eczematous, and lichenoid dermatoses (table 2). Of note, in clinical trials, these eruptions are often reported under the umbrella terms "rash" or "maculopapular rash."
Maculopapular eruption — Maculopapular eruption is the most common cutaneous irAE associated with ICIs, occurring more frequently with anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) therapy than with anti-programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) therapy [1,6]. It typically appears three to six weeks after treatment initiation, involves the trunk and the extensor aspect of the extremities in most cases, and is often accompanied by pruritus (picture 2A-B and table 2).
Histology shows vacuolar degeneration at the dermal-epidermal junction and a superficial, perivascular infiltrate predominantly composed of CD4 T cells, with variable amount of eosinophils [29].
Eczematous eruption — Eczematous eruption presents with pruritic, erythematous macules and papules, diffuse or coalescing in large or nummular patches (picture 3 and table 2). The trunk and extremities are predominantly involved. Some patients have a history of atopic disease.
Histology shows epidermal spongiosis and a perivascular, inflammatory infiltrate.
Lichenoid eruption — Lichenoid eruptions have been reported in up to 25 percent of patients with cutaneous irAEs [2,30,31]. The eruption typically presents 6 to 12 weeks following treatment initiation, with flat-topped, violaceous papules resembling idiopathic lichen planus in a localized or generalized distribution, often associated with pruritus. Bullous, lichenoid eruptions and mucosal involvement with oral or genital ulcers and nail dystrophy have also been reported [30,32].
Histologically, there is a vacuolar interface dermatitis with a band-like, lymphohistiocytic infiltrate at the dermoepidermal junction predominantly composed of CD4 lymphocytes, CD1631 histiocytes, variable eosinophils, and melanophages (table 2) [29]. (See "Lichenoid drug eruption (drug-induced lichen planus)".)
Psoriasiform eruption — In the European 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. In most cases (71 percent), patients had pre-existing disease [33]. Plaque psoriasis is the most common clinical type (picture 4), followed by palmoplantar, pustular, and guttate psoriasis, but in many cases, patients present with more than one clinical subtype of psoriasis [34,35].
On histology, spongiosis may be noted along with the typical features of psoriasis (table 2).
Other — Uncommon cutaneous reactions to ICIs include:
●Granulomatous dermatitis – Sarcoid-like, cutaneous reactions have been described in patients treated with ICIs, most frequently with pembrolizumab [36,37]. Patients may develop classic, red-brown papules or nodules on the head, trunk, or extremities (picture 5). Bone and lung involvement, the latter presenting as mediastinal/hilar lymphadenopathy, have also been reported with or without skin lesions [38].
●Acneiform eruptions – Acneiform eruptions similar to the papulopustular eruption associated with epidermal growth factor receptor (EGFR) inhibitors have been reported with both CTLA-4 and PD-1 inhibition [39].
Immunobullous diseases — Bullous pemphigoid and other bullous disorders have been reported in patients on ICI therapy [40-45].
Bullous pemphigoid — Bullous pemphigoid usually appears 13 to 16 weeks after drug initiation but can present later and even after treatment completion [42,46]. 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 6) [41,46-48]. Urticarial plaques without bullae and mucosal involvement have been reported in some patients [42]. Bullous pemphigoid may also present with intractable pruritus [49]. Compared with idiopathic bullous pemphigoid, ICI-induced bullous pemphigoid appears to have a milder phenotype [42].
The diagnostic work-up includes a biopsy of normal-appearing, perilesional skin for routine histopathologic examination and direct immunofluorescence, as well as serologic testing by enzyme-linked immunosorbent assay for circulating antibodies against bullous pemphigoid antigen 180 (BP180) and bullous pemphigoid antigen 230 (BP230). It should be noted, however, that patients with ICI-induced bullous pemphigoid may lack some or all histopathologic, immunofluorescence, and serologic diagnostic features of bullous pemphigoid, making it difficult to obtain an accurate diagnosis (table 2) [40]. (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 suprabasal, acantholytic dermatoses resembling Grover's disease, paraneoplastic pemphigus, and lichen planus pemphigoides [43,45,50]. (See "Grover's disease (transient and persistent acantholytic dermatosis)" and "Paraneoplastic pemphigus" and "Lichen planus", section on 'Overlap syndromes'.)
Vitiligo-like depigmentation — Vitiligo has been reported in 11 and 25 percent of patients with advanced melanoma receiving anti-CTLA-4 and anti-PD-1 therapy, respectively [1]. 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 7) [51]. 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".)
Mucosal toxicities — Mucosal toxicities include aphthous ulcers, periodontal disease, and stomatitis, as well as oral and genital lichen planus, xerostomia, and, rarely, Sjögren syndrome and mucous membrane pemphigoid. In general, these reactions are low grade and likely underreported in patients receiving ICIs [52-55].
Oral lichenoid reactions typically present with reticulate, white streaks (Wickham striae) or erosive lesions. On histology, there is a patchy or diffuse interface dermatitis with a band-like infiltrate predominantly composed of CD4 and CD8 lymphocytes [30]. (See "Oral lichen planus: Pathogenesis, clinical features, and diagnosis" and "Lichenoid drug eruption (drug-induced lichen planus)".)
Hair and nail toxicities — Alopecia areata and alopecia universalis have been reported in approximately 1 to 2 percent of patients treated with ICIs (picture 8) [1,56,57]. It is usually a late adverse effect (table 2) and may occur several months after the initiation of treatment [58]. 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 [59-61]. Diffuse darkening of the hair was reported in a series of 14 Spanish patients receiving anti-PD-1 or anti-PD-L1 therapy for non-small cell lung cancer [59].
Nail toxicities are not well documented in clinical trials, and their incidence is unknown. Onycholysis (picture 9), onychoschizia (picture 10), and inflammatory nail changes may occur in the course of ICI therapy as isolated manifestations or may be associated with inflammatory dermatoses, such as psoriasis, or lichen planus [2,19,56,62-64]. Onychodystrophy has been reported in patients who developed alopecia areata or dermatomyositis [56,65,66].
Rare cutaneous adverse events — Rarely reported cutaneous irAEs include:
●Severe cutaneous adverse reactions – Severe cutaneous adverse reactions, including Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) [67], acute generalized exanthematous pustulosis (AGEP) [68], and drug reaction with eosinophilia and systemic symptoms (DRESS), have been described in isolated case reports [67,69,70]. These reactions are rare, and their frequency is not yet available, although it is estimated to be less than 1 percent of all cutaneous irAEs. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis" and "Drug reaction with eosinophilia and systemic symptoms (DRESS)".)
●Keratoacanthoma – Keratoacanthoma-type squamous cell carcinoma has been reported in at least six patients with eruptive or reactive morphologies all on anti-PD-1 monotherapy (picture 11). They were treated conservatively with cryotherapy, intralesional steroids, electrodessication and curettage, and excision [71-75].
●Autoimmune rheumatic disease [76,77]:
•Systemic lupus erythematosus, subacute cutaneous lupus, and bullous lupus have all been reported with anti-PD-1 monotherapy and ICI combination therapy [78-83]. (See "Drug-induced lupus".)
•Dermatomyositis (picture 12A-B), Sjögren syndrome, systemic sclerosis, and scleroderma-like cutaneous changes have also been reported [66,84-87]. Differentiating drug-induced dermatomyositis from paraneoplastic dermatomyositis can be difficult [72,88]. (See "Malignancy in dermatomyositis and polymyositis".)
●Vasculitis – Vasculitis most commonly presents as large-vessel vasculitis and, less commonly, leukocytoclastic vasculitis or granulomatous polyangiitis [89-92].
●Neutrophilic dermatoses – Neutrophilic dermatoses, including Sweet syndrome, pustular eruptions, and pyoderma gangrenosum (picture 13), have been rarely reported [93]. Additionally, a case of pyoderma gangrenosum exacerbated by anti-PD-1 therapy was reported [94].
●Erythema nodosum – Erythema nodosum-like panniculitis (picture 14) has been reported in a few patients [95,96].
ASSOCIATION WITH TUMOR RESPONSE — The occurrence of vitiligo in patients with advanced melanoma treated with immune checkpoint inhibitors (ICIs) appears to be associated 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 was associated with both improved progression-free survival and overall survival (hazard ratio [HR] 0.51, 95% CI 0.32-0.82 and HR 0.25, 95% CI 0.10-0.61, respectively) [97].
Pruritus, rash, and thyroid disease were the most common immune-related adverse events (irAEs) associated with improved response to ICI in patients with urothelial cancer [98].
EVALUATION AND DIAGNOSIS — The diagnosis of cutaneous immune-related adverse events (irAEs) is based, in most cases, on patient history and clinical examination. A skin biopsy and laboratory tests may be needed for an accurate diagnosis [3]:
●Patient history – All current and recent medications should be assessed, as well as the temporal relationship between drug administration and onset of pruritus or skin eruption. The potential role of other medications in the occurrence of skin symptoms should be carefully evaluated.
Most inflammatory eruptions induced by immune checkpoint inhibitors (ICIs) present within one to two cycles of therapy initiation (ie, after two to six weeks). However, some cutaneous irAEs, such as bullous pemphigoid, alopecia, and vitiligo, can appear late during the treatment course. The time to onset of specific cutaneous irAEs may provide a clue to the correct diagnosis (table 2) [1]:
•0 to 3 weeks – Eczematous and psoriasiform dermatitis
•3 to 6 weeks – Maculopapular rash and pruritus
•6 to 12 weeks – Lichenoid drug eruption
•7 to ≥16 weeks – Vitiligo
•13 to 15 weeks – Bullous pemphigoid
•13 to ≥16 weeks – Alopecia areata
•Any time – Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP)
●Clinical examination – A careful total body skin examination, including the mucosal surfaces, should be performed to assess the lesion morphology, location, and severity. The general status of the patient should be assessed as well. The possibility of life-threatening reactions, such as SJS/TEN or DRESS, should be considered in patients with widespread eruption.
Severity is usually assessed using the National Institutes of Health/National Cancer Institute common terminology criteria version 5.5 (table 3) [99].
●Biopsy – In select patients, a biopsy of lesional skin (or perilesional in bullous reactions) may be needed for routine histopathologic examination and direct immunofluorescence. The histopathologic findings are cutaneous irAE specific and are summarized in the table (table 2).
●Laboratory tests – Cultures for bacteria, viruses, of fungi may be required to rule out infection. Specific laboratory testing is needed for the diagnosis of bullous pemphigoid and other autoimmune diseases. The laboratory work-up for these conditions is discussed elsewhere. (See 'Bullous pemphigoid' above and "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid", section on 'Diagnosis' and "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'Diagnosis'.)
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, latency time since starting treatment, and assess drug causality carefully. (See "Drug eruptions".)
●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 necessary for the correct diagnosis.
MANAGEMENT
General considerations — Our approach to the management of mucocutaneous toxicities of immune checkpoint inhibitors (ICIs) is consistent with published guidelines (algorithm 1) [3,100-105]. Most cutaneous eruptions are of low grade and can be managed with topical corticosteroids and antihistamines. More severe eruptions (grade ≥3 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 upon consideration of the severity of cutaneous involvement and impact on the general status of the patient.
Evidence from high-quality studies on the efficacy of topical and systemic treatments for cutaneous immune-related adverse events (irAEs) is limited and mainly based on case series, indirect evidence of efficacy for similar cutaneous diseases unrelated to ICI therapy, and clinical experience. As an example, the efficacy and adverse effects of immunomodulators (eg, systemic corticosteroids, tumor necrosis factor [TNF] inhibitors, and other biologics) have not been prospectively studied in ICI-induced toxicities. Their effect on tumor response to ICI is not fully understood. A few retrospective studies in patients with melanoma do not indicate a change in tumor response with the use of immunomodulators [106,107]. However, further studies are needed to evaluate the benefits and potential harms of immunomodulators for the treatment of cutaneous irAEs.
Pruritus/urticaria — The management of pruritus is based on its severity (table 4 and algorithm 1). First-line, symptomatic treatments include oral antihistamines and topical agents (eg, medium-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. (See "Pruritus: Therapies for generalized pruritus" and "New-onset urticaria", section on 'Treatment'.)
Inflammatory dermatoses — The Common Terminology Criteria for Adverse Events (CTCAE) for grading maculopapular rash (table 5A) can be used for all inflammatory dermatoses. The approach to treatment is outlined below (algorithm 1) [24,108]:
●Grade 1 – Continue ICI. Twice-daily medium- to high-potency topical corticosteroids (table 6).
●Grade 2 – Continue ICI. High-potency topical corticosteroids are the first-line treatment (table 6). Second-line therapies for patients unresponsive to topical therapy alone include systemic corticosteroids (eg, prednisone 0.5 to 1 mg/kg/day) and narrowband ultraviolet B (NBUVB) phototherapy, if available. Third-line options include apremilast for psoriasiform eruption, acitretin (10 to 25 mg per day) for lichenoid eruption, and hydroxychloroquine 200 mg twice daily for granulomatous eruption.
●Grade 3 or intolerable grade 2 – Interrupt ICI. Systemic corticosteroids (eg, prednisone 0.5 to 1 mg/kg/day) tapered over two to four weeks are the first-line therapy for grade 3 eruptions. Second-line therapies include dupilumab for eczematous dermatitis; methotrexate, acitretin, ustekinumab, guselkumab, infliximab, or adalimumab for lichenoid and psoriasiform eruptions; and doxycycline (100 mg orally twice daily), hydroxychloroquine (200 mg orally twice daily), or TNF inhibitors for granulomatous eruptions. (See "Treatment of atopic dermatitis (eczema)", section on 'Dupilumab' and "Treatment of psoriasis in adults", section on 'Biologic agents' and "Cutaneous sarcoidosis: Management".)
Bullous pemphigoid — The management of bullous pemphigoid in patients treated with ICIs is based on severity (table 5B) and similar to that of idiopathic bullous pemphigoid (algorithm 1) (see "Management and prognosis of bullous pemphigoid"):
●Grade 1 – Continue ICI. High-potency topical steroids twice daily.
●Grade 2 or 3 − Interrupt ICI. Moderate to high-dose oral corticosteroids (eg, prednisone 0.5 to 1 mg/kg per day) or oral doxycycline (100 mg twice daily) are first-line therapies. Second-line therapies include dupilumab, omalizumab, rituximab, intravenous immune globulin, methotrexate, and mycophenolate mofetil.
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 severity (table 7A-B). Management involves [102]:
●Grade 3 – Interrupt ICI. Consider admission to a hospital for urgent dermatologic consultation, supportive therapy, and wound care. Intravenous methylprednisolone (1 to 2 mg/kg daily) should be initiated and maintained until improvement is achieved. 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 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 and wound care. Urgent consultation with ophthalmology, otolaryngology, urology, and gynecology for treatment of mucosal involvement and prevention of sequelae is required.
The management of SJS/TEN and DRESS are discussed in greater detail separately. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Management, prognosis, and long-term sequelae" and "Drug reaction with eosinophilia and systemic symptoms (DRESS)".)
Vitiligo — Photoprotection to avoid sunburn is recommended for all patients who have depigmented areas in photoexposed 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 [109].
The management of vitiligo is discussed in detail separately. (See "Vitiligo: Management and prognosis".)
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.
The management of alopecia areata is discussed in detail elsewhere. (See "Alopecia areata: Management".)
Mucosal toxicity — Topical corticosteroids (eg, dexamethasone 0.5 mg/5 mL swish and spit) are the first-line therapy for mucosal lesions associated with ICI therapy. For severe mucosal involvement, interruption of ICI therapy may be considered.
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 use of nail strengtheners. Concurrent fungal infections should be treated with topical or systemic antifungal agents. (See "Onychomycosis: Management".)
PROGNOSIS AND FOLLOW-UP — Most cutaneous immune-related adverse events (irAEs) 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 cutaneous irAEs (6 percent or less) may experience a prolonged course, requiring interruption or even discontinuation of cancer therapy. The majority of severe cutaneous irAEs resolve after ICI discontinuation.
We typically see patients with acute cutaneous irAEs every one to two weeks until the eruption is well controlled. Thereafter, patients are seen every three months if on stable anticancer treatment.
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 (irAEs) are the most common adverse events associated with immune checkpoint inhibitor (ICI) therapy, occurring in up to 50 percent of patients treated with monotherapy and in up to 70 percent of patients treated with combination therapy (table 1A-B). Patients with pre-existing, inflammatory skin diseases are likely to experience cutaneous flare-ups with ICIs. (See 'Epidemiology' above and 'Risk factors' above.)
●Clinical presentation − Cutaneous irAEs result from off-target effects of T cell activation induced by ICIs and present most commonly as inflammatory skin reactions (eg, maculopapular (picture 2A), lichenoid, psoriasiform (picture 4), eczematous reactions (picture 3)). Less common presentations include immunobullous diseases (eg, bullous pemphigoid (picture 6)), autoimmune rheumatic diseases (eg, lupus erythematosus, dermatomyositis (picture 12A)), vasculitis, and neutrophilic dermatoses (eg, Sweet syndrome, pyoderma gangrenosum (picture 13)). Rarely, ICIs may cause severe cutaneous drug reactions (eg, Stevens-Johnson syndrome/toxic epidermal necrolysis [SJS/TEN], drug reaction with eosinophilia and systemic symptoms [DRESS]). (See 'Clinical manifestations' above.)
●Evaluation and diagnosis − The diagnosis of cutaneous irAEs is based, in most cases, on patient history and clinical examination. The time to onset of specific cutaneous irAEs may provide a clue to the correct diagnosis (table 2). A skin biopsy and laboratory work-up may be needed for the diagnosis of bullous pemphigoid and other autoimmune diseases. (See 'Evaluation and diagnosis' above and "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid", section on 'Diagnosis' and "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'Diagnosis'.)
●Management – The management of cutaneous irAEs is based on their severity (table 5A-B). 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) (see 'Management' above):
•Grade 1 to 2 cutaneous immune-related adverse events – Most patients with grade 1 or 2 cutaneous irAEs can be treated with topical corticosteroids, emollients, and oral antihistamines while continuing ICI therapy. Medium- to high-potency topical corticosteroids (table 6) are applied twice daily until improvement is noted.
•Grade ≥3 or intolerable grade 2 cutaneous immune-related adverse events – Patients with more severe cutaneous irAEs that do not respond to topical therapies should be treated with systemic corticosteroids (eg, prednisone 0.5 to 1 mg/kg/day tapered over two to four weeks) and may require interruption or even discontinuation of ICI therapy. For patients with irAEs uncontrolled by systemic corticosteroids, alternative therapies include immunosuppressor agents (eg, methotrexate, mycophenolate mofetil) and biologic immunomodulators (eg, dupilumab, ustekinumab, guselkumab, infliximab, adalimumab, rituximab).
