ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Cutaneous immune-related adverse events associated with immune checkpoint inhibitors

Cutaneous immune-related adverse events associated with immune checkpoint inhibitors
Author:
Anisha B Patel, MD
Section Editors:
Maja Mockenhaupt, MD, PhD
Michael B Atkins, MD
Deputy Editor:
Rosamaria Corona, MD, DSc
Literature review current through: Jan 2024.
This topic last updated: Jan 22, 2024.

INTRODUCTION — Immune checkpoint inhibitors (ICIs) are increasingly used for the treatment of various malignancies (table 1). (See "Principles of cancer immunotherapy", section on 'Checkpoint inhibitor immunotherapy'.)

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 antitumor response and can result in generalized or tissue-specific inflammatory responses, collectively called immune-related adverse events (irAEs). Cutaneous immune-related adverse events (cirAEs) have the highest incidence and are the earliest occurring [1-5].

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 "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) [6-13]. (See "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 [13-17]. Most cirAEs are low grade, with approximately 2 to 9 percent being grade 3 or greater.

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, the most common of which were, in order of frequency, vitiligo, bullous pemphigoid, lichenoid dermatitis, erythema multiforme, toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), drug eruption, and eczematous dermatitis [18]. However, this list may be skewed toward more severe toxicities, as the higher-incidence, low-grade toxicities are likely to be underreported, while rarer severe toxicities (eg, SJS/TEN and bullous pemphigoid) are likely to be overreported. The median time to onset after treatment initiation was widely variable: one month for erythema multiforme, TEN, and SJS; two months for eczematous dermatitis and drug eruption; four months for lichenoid dermatitis; and five to six months for vitiligo and bullous pemphigoid.

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).

●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) [19].

•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 [20].

•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) [21]. 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. However, a strong association between HLA-DRB1*11:01 and ICI-induced pruritus was found in 32 patients [22].

●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 [23]. 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 [24]. 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 patients with lung cancer.

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 off-target (or at least off-tumor) effects of T cell response upregulation. In the case of metastatic melanoma, vitiligo may represent an on-target, off-tumor effect as the tumoral melanocytes and epidermal melanocytes may share a common antigen.

The spectrum of irAEs includes autoinflammatory (ie, nonspecific upregulations of the innate immune system) and autoimmune responses [1,25-28]. Most cutaneous immune-related adverse events (cirAEs), however, fall in the latter category, which represents a more specific activation of adaptive immunity and occurs 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 tissues [29].

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 [29]. Similar mechanisms might explain the presence of both adaptive immunity-driven and antibody-mediated irAEs.

CLINICAL MANIFESTATIONS — Cutaneous immune-related adverse events (cirAEs) include pruritus, 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]) [1,25-28,30].

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 three treatment cycles and usually involves the trunk and lower extremities, where excoriations and prurigo nodularis-like lesions can be noted [26,30].

Inflammatory dermatoses — Inflammatory eruptions are the most common cutaneous reactions to ICIs. They include nonspecific maculopapular 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 eruption — Maculopapular (morbilliform) eruption is the most common cirAE associated with ICIs [1,25]. It typically appears three to six weeks after treatment initiation, in most cases involves the trunk and the extensor aspect of the extremities, and is often accompanied by pruritus (picture 2A-B and table 3). (See "Exanthematous (maculopapular) drug eruption".)

Lichenoid eruption — Lichenoid eruptions have been reported in up to 25 percent of patients with cirAEs [2,31,32]. 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, mucosal involvement with oral or genital ulcers, and nail dystrophy have also been reported [31,33]. (See "Lichen planus" and "Lichenoid drug eruption (drug-induced lichen planus)".)

Eczematous eruption — Eczematous eruption presents with pruritic, erythematous macules and papules, diffuse or coalescing in large or nummular patches (picture 3 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 [34]. In most cases (71 percent), patients had pre-existing disease.

Plaque psoriasis (picture 4) 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 [35-37].

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 [38,39]. 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 [40].

●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 [41].

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 [42].

Bullous pemphigoid — Bullous pemphigoid and other bullous disorders have been reported in patients on ICI therapy [43-48]. Bullous pemphigoid usually appears 13 to 16 weeks after drug initiation but can present later and even after treatment completion [45,49]. 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) [44,49-51]. Urticarial plaques without bullae and mucosal involvement have been reported in some patients [45]. Bullous pemphigoid may also present with intractable pruritus [52]. Compared with idiopathic bullous pemphigoid, ICI-induced bullous pemphigoid appears to have a milder phenotype [45,53].

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). It should be noted, however, 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) [43]. (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 paraneoplastic pemphigus, lichen planus pemphigoides, and suprabasal acantholytic dermatoses resembling Grover's disease [46,48,54,55]. (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) [56]. 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) [57,58].

●Systemic lupus erythematosus, subacute cutaneous lupus, and bullous lupus have all been reported with anti-PD-1 monotherapy and ICI combination therapy [59-64]. (See "Drug-induced lupus".)

●Dermatomyositis (picture 8A-B) has been reported with all classes of ICIs [65-67]. 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 [68]. (See "Clinical manifestations of dermatomyositis and polymyositis in adults".)

●Sjögren's disease, systemic sclerosis, and scleroderma-like cutaneous changes have also been reported [69-72]. (See "Clinical manifestations of Sjögren's disease: Exocrine gland disease" and "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults".)

Mucosal toxicities — Mucosal toxicities include aphthous ulcers, periodontal disease, and stomatitis, as well as oral and genital lichen planus, xerostomia, and rarely, Sjögren's disease and mucous membrane pemphigoid. In general, these reactions are low grade and likely underreported in patients receiving ICIs [73-76].

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 [31]. (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 9) [1,77-79]. It is usually a late adverse effect (table 3) and may occur several months after the initiation of treatment [80]. 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 [81-83]. 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 [81].

Nail toxicities are not well documented in clinical trials, and their incidence is unknown. Onycholysis (picture 10), onychoschizia (picture 11), 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 eruption [2,14,77,79,84-86]. Onychodystrophy has been reported in patients who developed alopecia areata or dermatomyositis [65,77,87].

Rare cutaneous adverse events

Severe cutaneous adverse reactions — Severe cutaneous adverse reactions, including SJS/TEN [88], acute generalized exanthematous pustulosis (AGEP) [89], and DRESS, have been described in isolated case reports [88,90,91]. These reactions are rare, and their frequency is not yet available, although it is estimated to be less than 1 percent of all cirAEs. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis" 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 [92]. Unlike true SJS/TEN, ICI-induced SJS/TEN-like reactions are believed to be severe, immune-mediated bullous eruptions due to enhanced ICI cytotoxicity [33].

Other rare reactions

●Keratoacanthoma – Keratoacanthoma-type squamous cell carcinomas have been reported in at least six patients with eruptive or reactive morphologies, all on anti-PD-1 monotherapy (picture 12). They were treated conservatively with cryotherapy, intralesional steroids, electrodessication and curettage, and excision [93-97].

●Vasculitis – Vasculitis most commonly presents as large-vessel vasculitis and, less commonly, leukocytoclastic vasculitis or granulomatous polyangiitis [98-101].

●Neutrophilic dermatoses – Neutrophilic dermatoses, including Sweet syndrome, pustular eruptions, and pyoderma gangrenosum (picture 13), have been rarely reported [102]. Additionally, a case of pyoderma gangrenosum exacerbated by anti-PD-1 therapy was reported [103].

●Erythema nodosum – Erythema nodosum-like panniculitis (picture 14) has been reported in a few patients [104,105].

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 [106]:

●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 [5,107-110].

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 in the study 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" [111].

●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) [112].

●Another retrospective study that included 628 patients with cirAEs found a survival benefit only for patients who had also developed a non-cirAE [113].

●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) [114]. 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 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 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) [115].

EVALUATION AND DIAGNOSIS — The diagnosis of cutaneous immune-related adverse events (cirAEs) 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 cirAEs, such as bullous pemphigoid, alopecia, and vitiligo, can appear late during the treatment course. The time to onset of specific cirAEs may provide a clue to the correct diagnosis (table 3) [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 4A-D) [116].

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 eruption – Vacuolar degeneration at the dermal-epidermal junction and a superficial perivascular infiltrate predominantly composed of CD4 T cells, with variable amount of eosinophils [117]. (See "Exanthematous (maculopapular) drug eruption".)

●Eczematous eruption – Epidermal spongiosis and a perivascular lymphocytic infiltrate with 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 [117]. (See "Lichenoid drug eruption (drug-induced lichen planus)".)

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

●Bullous pemphigoid – Subepidermal blister, dermal inflammatory infiltrate with lymphocytes, eosinophils, and 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 for 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.

●Specific laboratory testing is needed for the diagnosis of bullous pemphigoid, 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 "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 and latency time since starting treatment and to assess drug causality carefully. (See "Drug eruptions", section on 'Approach to the diagnosis'.)

●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 — 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 [118].

Our approach to the management of mucocutaneous toxicities of cirAEs is consistent with published guidelines (algorithm 1) [3,119-128].

●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 upon 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 [120].

The effect of systemic immunosuppressants and immunomodulators on tumor response to ICIs is not fully understood. A few retrospective studies in patients with melanoma do not indicate a change in tumor response [129,130]. However, further studies are needed to evaluate the benefits and potential harms of immunomodulators for the treatment of cirAEs.

Pruritus/urticaria — 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. (See "Pruritus: Therapies for generalized pruritus" and "New-onset urticaria", section on 'Treatment'.)

Maculopapular eruption — The Common Terminology Criteria for Adverse Events (CTCAE) for grading maculopapular rash (table 4C) can be used for maculopapular eruption as well as for all inflammatory dermatoses.

The approach to treatment is outlined below (algorithm 1) [20,131]:

●Grade 1 – ICI therapy is continued. Medium- to high-potency topical corticosteroids (table 5) are applied to the involved areas twice daily. Emollients can be used liberally.

●Grade 2 – ICI therapy is continued. High-potency topical corticosteroids (table 5) 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 [20,132].

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 5) 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 5). 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 5). 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 5) 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 are first-line treatment (table 5). Second-line therapies for rash unresponsive to topical therapy alone include NBUVB phototherapy, if available and feasible, or apremilast.

●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 acitretin, methotrexate, cyclosporine, apremilast, or biologic agents. Newer, more specific immunomodulators, 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 [133]. 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. (See "Treatment of psoriasis in adults".)

Bullous pemphigoid — 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. For grade 1 eruption, high-potency topical corticosteroids (table 5) 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) or oral doxycycline (at a dose of 100 mg twice daily) as first-line therapy. For disease not responding to systemic corticosteroids, second-line therapies include conventional immunosuppressants (eg, methotrexate, mycophenolate mofetil) and biologic agents (eg, dupilumab, rituximab, omalizumab).

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 [134]. 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 [135,136].

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 6A-B). Management involves [123]:

●Grade 3 – Interrupt ICI. 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. 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.

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 sun-exposed areas. For patients who desire treatment, therapeutic options are based on the extent of depigmentation (table 7) and include high-potency topical corticosteroids and NBUVB phototherapy [137].

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 5) 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 (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.

We typically see patients with acute cirAEs 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 (cirAEs) result from off-target 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 in 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 (picture 2A), lichenoid, psoriasiform (picture 4), or eczematous reactions (picture 3)). Less common presentations include immunobullous diseases (eg, bullous pemphigoid (picture 6)), autoimmune rheumatic diseases (eg, lupus erythematosus, dermatomyositis (picture 8A)), 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 cirAEs is based, in most cases, on patient history and clinical examination. The time to onset of specific cirAEs may provide a clue to the correct diagnosis (table 3). 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.)

●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). (See 'Management' above.)

•Maculopapular, 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 5) 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 as initial therapy (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), and biologic immunomodulators (eg, dupilumab [for eczematous eruptions], ustekinumab, guselkumab, infliximab [for psoriasiform eruptions]). (See 'Maculopapular eruption' above and 'Eczematous eruption' above and 'Lichenoid eruption' above and 'Psoriasiform eruption' above.)

•Bullous pemphigoid

-Grade 1 – For grade 1 bullous pemphigoid, we suggest high- to super high-potency topical corticosteroids (table 5) 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) or oral doxycycline (at a dose of 100 mg twice daily) rather than other immunosuppressants and immunomodulators as first-line 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' above.)

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

  1. Geisler AN, Phillips GS, Barrios DM, et al. Immune checkpoint inhibitor-related dermatologic adverse events. J Am Acad Dermatol 2020; 83:1255.
  2. Coleman E, Ko C, Dai F, et al. Inflammatory eruptions associated with immune checkpoint inhibitor therapy: A single-institution retrospective analysis with stratification of reactions by toxicity and implications for management. J Am Acad Dermatol 2019; 80:990.
  3. Haanen JBAG, Carbonnel F, Robert C, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2017; 28:iv119.
  4. Gault A, Anderson AE, Plummer R, et al. Cutaneous immune-related adverse events in patients with melanoma treated with checkpoint inhibitors. Br J Dermatol 2021; 185:263.
  5. Patel AB, Farooq S, Welborn M, et al. Cutaneous adverse events in 155 patients with metastatic melanoma consecutively treated with anti-CTLA4 and anti-PD1 combination immunotherapy: Incidence, management, and clinical benefit. Cancer 2022; 128:975.
  6. Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363:711.
  7. Weber JS, D'Angelo SP, Minor D, et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol 2015; 16:375.
  8. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 2015; 372:320.
  9. Weber J, Mandala M, Del Vecchio M, et al. Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma. N Engl J Med 2017; 377:1824.
  10. Robert C, Ribas A, Wolchok JD, et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet 2014; 384:1109.
  11. Robert C, Schachter J, Long GV, et al. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med 2015; 372:2521.
  12. Eggermont AMM, Blank CU, Mandala M, et al. Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma. N Engl J Med 2018; 378:1789.
  13. Villadolid J, Amin A. Immune checkpoint inhibitors in clinical practice: update on management of immune-related toxicities. Transl Lung Cancer Res 2015; 4:560.
  14. Sibaud V. Dermatologic Reactions to Immune Checkpoint Inhibitors : Skin Toxicities and Immunotherapy. Am J Clin Dermatol 2018; 19:345.
  15. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med 2019; 381:1535.
  16. Long GV, Atkinson V, Cebon JS, et al. Standard-dose pembrolizumab in combination with reduced-dose ipilimumab for patients with advanced melanoma (KEYNOTE-029): an open-label, phase 1b trial. Lancet Oncol 2017; 18:1202.
  17. Robert C, Ribas A, Schachter J, et al. Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study. Lancet Oncol 2019; 20:1239.
  18. Le TK, Brown I, Goldberg R, et al. Cutaneous Toxicities Associated with Immune Checkpoint Inhibitors: An Observational, Pharmacovigilance Study. J Invest Dermatol 2022; 142:2896.
  19. Young A, Quandt Z, Bluestone JA. The Balancing Act between Cancer Immunity and Autoimmunity in Response to Immunotherapy. Cancer Immunol Res 2018; 6:1445.
  20. Phillips GS, Wu J, Hellmann MD, et al. Treatment Outcomes of Immune-Related Cutaneous Adverse Events. J Clin Oncol 2019; 37:2746.
  21. Goldinger SM, Stieger P, Meier B, et al. Cytotoxic Cutaneous Adverse Drug Reactions during Anti-PD-1 Therapy. Clin Cancer Res 2016; 22:4023.
  22. Hasan Ali O, Berner F, Bomze D, et al. Human leukocyte antigen variation is associated with adverse events of checkpoint inhibitors. Eur J Cancer 2019; 107:8.
  23. Jacoby TV, Otto TS, Asdourian MS, et al. Association of pre-existing drug allergies with cutaneous immune-related adverse events among patients on immune checkpoint inhibitor therapy. Br J Dermatol 2022; 187:424.
  24. Wongvibulsin S, Pahalyants V, Kalinich M, et al. Epidemiology and risk factors for the development of cutaneous toxicities in patients treated with immune-checkpoint inhibitors: A United States population-level analysis. J Am Acad Dermatol 2022; 86:563.
  25. Patel AB, Pacha O. Skin Reactions to Immune Checkpoint Inhibitors. Adv Exp Med Biol 2020; 1244:235.
  26. Malviya N, Tattersall IW, Leventhal J, Alloo A. Cutaneous immune-related adverse events to checkpoint inhibitors. Clin Dermatol 2020; 38:660.
  27. Lacouture M, Sibaud V. Toxic Side Effects of Targeted Therapies and Immunotherapies Affecting the Skin, Oral Mucosa, Hair, and Nails. Am J Clin Dermatol 2018; 19:31.
  28. Quach HT, Johnson DB, LeBoeuf NR, et al. Cutaneous adverse events caused by immune checkpoint inhibitors. J Am Acad Dermatol 2021; 85:956.
  29. Masson MJ, Collins LA, Pohl LR. The role of cytokines in the mechanism of adverse drug reactions. Handb Exp Pharmacol 2010; :195.
  30. Muhaj F, Karri PV, Moody W, et al. Mucocutaneous adverse events to immune checkpoint inhibitors. Front Allergy 2023; 4:1147513.
  31. Shi VJ, Rodic N, Gettinger S, et al. Clinical and Histologic Features of Lichenoid Mucocutaneous Eruptions Due to Anti-Programmed Cell Death 1 and Anti-Programmed Cell Death Ligand 1 Immunotherapy. JAMA Dermatol 2016; 152:1128.
  32. Kratzsch D, Simon JC, Ziemer M. Lichen planus-like drug eruption on anti-PD-1 therapy. J Dtsch Dermatol Ges 2017; 15:1238.
  33. Reschke R, Mockenhaupt M, Simon JC, Ziemer M. Severe bullous skin eruptions on checkpoint inhibitor therapy - in most cases severe bullous lichenoid drug eruptions. J Dtsch Dermatol Ges 2019; 17:942.
  34. Cutroneo P, Ingrasciotta Y, Isgrò V, et al. Psoriasis and psoriasiform reactions secondary to immune checkpoint inhibitors. Dermatol Ther 2021; 34:e14830.
  35. Nikolaou V, Sibaud V, Fattore D, et al. Immune checkpoint-mediated psoriasis: A multicenter European study of 115 patients from the European Network for Cutaneous Adverse Event to Oncologic Drugs (ENCADO) group. J Am Acad Dermatol 2021; 84:1310.
  36. Halle BR, Betof Warner A, Zaman FY, et al. Immune checkpoint inhibitors in patients with pre-existing psoriasis: safety and efficacy. J Immunother Cancer 2021; 9.
  37. Tarafdar N, Sachdeva M, Savinova I, et al. Onset of psoriasis with immune checkpoint inhibitor therapy: A systematic review. J Am Acad Dermatol 2024; 90:392.
  38. Trilleras-Gomez AP, Hull KJ, Drew DZ. Case Report and Review of 7 Similar Cases in the Literature: Cutaneous Sarcoidosis as Side Effect of Pembrolizumab Plus Chemotherapy in Stage IV Squamous Cell Carcinoma of Lung. J Immunother 2021; 44:90.
  39. Apalla Z, Kemanetzi C, Papageorgiou C, et al. Challenges in sarcoidosis and sarcoid-like reactions associated to immune checkpoint inhibitors: A narrative review apropos of a case. Dermatol Ther 2021; 34:e14618.
  40. Chorti E, Kanaki T, Zimmer L, et al. Drug-induced sarcoidosis-like reaction in adjuvant immunotherapy: Increased rate and mimicker of metastasis. Eur J Cancer 2020; 131:18.
  41. Welborn M, Kubicki SL, Garg N, Patel AB. Twelve cases of acneiform eruptions while on anti-CTLA4 therapy. Support Care Cancer 2020; 28:2499.
  42. Abdel-Wahab N, Shah M, Lopez-Olivo MA, Suarez-Almazor ME. Use of Immune Checkpoint Inhibitors in the Treatment of Patients With Cancer and Preexisting Autoimmune Disease: A Systematic Review. Ann Intern Med 2018; 168:121.
  43. Siegel J, Totonchy M, Damsky W, et al. Bullous disorders associated with anti-PD-1 and anti-PD-L1 therapy: A retrospective analysis evaluating the clinical and histopathologic features, frequency, and impact on cancer therapy. J Am Acad Dermatol 2018; 79:1081.
  44. Tsiogka A, Bauer JW, Patsatsi A. Bullous Pemphigoid Associated with Anti-programmed Cell Death Protein 1 and Anti-programmed Cell Death Ligand 1 Therapy: A Review of the Literature. Acta Derm Venereol 2021; 101:adv00377.
  45. Sadik CD, Langan EA, Gutzmer R, et al. Retrospective Analysis of Checkpoint Inhibitor Therapy-Associated Cases of Bullous Pemphigoid From Six German Dermatology Centers. Front Immunol 2020; 11:588582.
  46. Kwon CW, Murthy RK, Kudchadkar R, Stoff BK. Pembrolizumab-induced lichen planus pemphigoides in a patient with metastatic Merkel cell carcinoma. JAAD Case Rep 2020; 6:1045.
  47. Schwartzman G, Simpson MM, Jones R, et al. Anti-PD1 immune checkpoint inhibitor-induced bullous pemphigoid in metastatic melanoma and non-small cell lung cancer. Cutis 2020; 105:E9.
  48. Chen WS, Tetzlaff MT, Diwan H, et al. Suprabasal acantholytic dermatologic toxicities associated checkpoint inhibitor therapy: A spectrum of immune reactions from paraneoplastic pemphigus-like to Grover-like lesions. J Cutan Pathol 2018; 45:764.
  49. Jour G, Glitza IC, Ellis RM, et al. Autoimmune dermatologic toxicities from immune checkpoint blockade with anti-PD-1 antibody therapy: a report on bullous skin eruptions. J Cutan Pathol 2016; 43:688.
  50. Carlos G, Anforth R, Chou S, et al. A case of bullous pemphigoid in a patient with metastatic melanoma treated with pembrolizumab. Melanoma Res 2015; 25:265.
  51. Naidoo J, Schindler K, Querfeld C, et al. Autoimmune Bullous Skin Disorders with Immune Checkpoint Inhibitors Targeting PD-1 and PD-L1. Cancer Immunol Res 2016; 4:383.
  52. Molina GE, Reynolds KL, Chen ST. Diagnostic and therapeutic differences between immune checkpoint inhibitor-induced and idiopathic bullous pemphigoid: a cross-sectional study. Br J Dermatol 2020; 183:1126.
  53. Bur D, Patel AB, Nelson K, et al. A retrospective case series of 20 patients with immunotherapy-induced bullous pemphigoid with emphasis on management outcomes. J Am Acad Dermatol 2022; 87:1394.
  54. Kawsar A, Edwards C, Patel P, et al. Checkpoint inhibitor-associated bullous cutaneous immune-related adverse events: a multicentre observational study. Br J Dermatol 2022; 187:981.
  55. McNally MA, Vangipuram R, Campbell MT, et al. Paraneoplastic pemphigus manifesting in a patient treated with pembrolizumab for urothelial carcinoma. JAAD Case Rep 2021; 10:82.
  56. Larsabal M, Marti A, Jacquemin C, et al. Vitiligo-like lesions occurring in patients receiving anti-programmed cell death-1 therapies are clinically and biologically distinct from vitiligo. J Am Acad Dermatol 2017; 76:863.
  57. Allenbach Y, Anquetil C, Manouchehri A, et al. Immune checkpoint inhibitor-induced myositis, the earliest and most lethal complication among rheumatic and musculoskeletal toxicities. Autoimmun Rev 2020; 19:102586.
  58. Kostine M, Truchetet ME, Schaeverbeke T. Clinical characteristics of rheumatic syndromes associated with checkpoint inhibitors therapy. Rheumatology (Oxford) 2019; 58:vii68.
  59. Michot JM, Fusellier M, Champiat S, et al. Drug-induced lupus erythematosus following immunotherapy with anti-programmed death-(ligand) 1. Ann Rheum Dis 2019; 78:e67.
  60. Shao K, McGettigan S, Elenitsas R, Chu EY. Lupus-like cutaneous reaction following pembrolizumab: An immune-related adverse event associated with anti-PD-1 therapy. J Cutan Pathol 2018; 45:74.
  61. Blakeway EA, Elshimy N, Muinonen-Martin A, et al. Cutaneous lupus associated with pembrolizumab therapy for advanced melanoma: a report of three cases. Melanoma Res 2019; 29:338.
  62. Zitouni NB, Arnault JP, Dadban A, et al. Subacute cutaneous lupus erythematosus induced by nivolumab: two case reports and a literature review. Melanoma Res 2019; 29:212.
  63. Wouters A, Durieux V, Kolivras A, et al. Bullous Lupus Under Nivolumab Treatment for Lung Cancer: A Case Report With Systematic Literature Review. Anticancer Res 2019; 39:3003.
  64. Kosche C, Owen JL, Choi JN. Widespread subacute cutaneous lupus erythematosus in a patient receiving checkpoint inhibitor immunotherapy with ipilimumab and nivolumab. Dermatol Online J 2019; 25.
  65. Messer A, Drozd B, Glitza IC, et al. Dermatomyositis associated with nivolumab therapy for melanoma: a case report and review of the literature. Dermatol Online J 2020; 26.
  66. Guerra NL, Matas-García A, Serra-García L, et al. Dermatomyositis unleashed by immune checkpoint inhibitors. Three additional cases and a review of the literature. Autoimmun Rev 2023; 22:103375.
  67. Sakurai T, Takahashi J, Komatsu T, et al. Anti-TIF1γ antibody-positive dermatomyositis associated with nivolumab administration in a patient with advanced oesophageal squamous cell carcinoma: A case report and literature review. Mod Rheumatol Case Rep 2023; 7:416.
  68. Fiorentino DF, Chung LS, Christopher-Stine L, et al. Most patients with cancer-associated dermatomyositis have antibodies to nuclear matrix protein NXP-2 or transcription intermediary factor 1γ. Arthritis Rheum 2013; 65:2954.
  69. Terrier B, Humbert S, Preta LH, et al. Risk of scleroderma according to the type of immune checkpoint inhibitors. Autoimmun Rev 2020; 19:102596.
  70. Higashi T, Miyamoto H, Yoshida R, et al. Sjögren's Syndrome as an Immune-related Adverse Event of Nivolumab Treatment for Gastric Cancer. Intern Med 2020; 59:2499.
  71. Mavragani CP, Moutsopoulos HM. Sicca syndrome following immune checkpoint inhibition. Clin Immunol 2020; 217:108497.
  72. Warner BM, Baer AN, Lipson EJ, et al. Sicca Syndrome Associated with Immune Checkpoint Inhibitor Therapy. Oncologist 2019; 24:1259.
  73. Vigarios E, Epstein JB, Sibaud V. Oral mucosal changes induced by anticancer targeted therapies and immune checkpoint inhibitors. Support Care Cancer 2017; 25:1713.
  74. Obara K, Masuzawa M, Amoh Y. Oral lichenoid reaction showing multiple ulcers associated with anti-programmed death cell receptor-1 treatment: A report of two cases and published work review. J Dermatol 2018; 45:587.
  75. Fässler M, Rammlmair A, Feldmeyer L, et al. Mucous membrane pemphigoid and lichenoid reactions after immune checkpoint inhibitors: common pathomechanisms. J Eur Acad Dermatol Venereol 2020; 34:e112.
  76. Zumelzu C, Alexandre M, Le Roux C, et al. Mucous Membrane Pemphigoid, Bullous Pemphigoid, and Anti-programmed Death-1/ Programmed Death-Ligand 1: A Case Report of an Elderly Woman With Mucous Membrane Pemphigoid Developing After Pembrolizumab Therapy for Metastatic Melanoma and Review of the Literature. Front Med (Lausanne) 2018; 5:268.
  77. Zarbo A, Belum VR, Sibaud V, et al. Immune-related alopecia (areata and universalis) in cancer patients receiving immune checkpoint inhibitors. Br J Dermatol 2017; 176:1649.
  78. Antoury L, Maloney NJ, Bach DQ, et al. Alopecia areata as an immune-related adverse event of immune checkpoint inhibitors: A review. Dermatol Ther 2020; 33:e14171.
  79. Emvalomati A, Oflidou V, Papageorgiou C, et al. Narrative Review of Drug-Associated Nail Toxicities in Oncologic Patients. Dermatol Pract Concept 2023; 13.
  80. Galli G, Proto C, Cossa M, et al. Unusual skin toxicity associated with sustained disease response induced by nivolumab in a patient with non-small cell lung cancer. Tumori 2019; 105:NP57.
  81. Rivera N, Boada A, Bielsa MI, et al. Hair Repigmentation During Immunotherapy Treatment With an Anti-Programmed Cell Death 1 and Anti-Programmed Cell Death Ligand 1 Agent for Lung Cancer. JAMA Dermatol 2017; 153:1162.
  82. Wolner ZJ, Marghoob AA, Pulitzer MP, et al. A case report of disappearing pigmented skin lesions associated with pembrolizumab treatment for metastatic melanoma. Br J Dermatol 2018; 178:265.
  83. Manson G, Marabelle A, Houot R. Hair Repigmentation With Anti-PD-1 and Anti-PD-L1 Immunotherapy: A Novel Hypothesis. JAMA Dermatol 2018; 154:113.
  84. Sibaud V, Eid C, Belum VR, et al. Oral lichenoid reactions associated with anti-PD-1/PD-L1 therapies: clinicopathological findings. J Eur Acad Dermatol Venereol 2017; 31:e464.
  85. Ruiz-Bañobre J, Pérez-Pampín E, García-González J, et al. Development of psoriatic arthritis during nivolumab therapy for metastatic non-small cell lung cancer, clinical outcome analysis and review of the literature. Lung Cancer 2017; 108:217.
  86. Law-Ping-Man S, Martin A, Briens E, et al. Psoriasis and psoriatic arthritis induced by nivolumab in a patient with advanced lung cancer. Rheumatology (Oxford) 2016; 55:2087.
  87. Sheik Ali S, Goddard AL, Luke JJ, et al. Drug-associated dermatomyositis following ipilimumab therapy: a novel immune-mediated adverse event associated with cytotoxic T-lymphocyte antigen 4 blockade. JAMA Dermatol 2015; 151:195.
  88. Coleman EL, Olamiju B, Leventhal JS. The life-threatening eruptions of immune checkpoint inhibitor therapy. Clin Dermatol 2020; 38:94.
  89. Hwang SJ, Carlos G, Wakade D, et al. Ipilimumab-induced acute generalized exanthematous pustulosis in a patient with metastatic melanoma. Melanoma Res 2016; 26:417.
  90. Lu J, Thuraisingam T, Chergui M, Nguyen K. Nivolumab-associated DRESS syndrome: A case report. JAAD Case Rep 2019; 5:216.
  91. Mirza S, Hill E, Ludlow SP, Nanjappa S. Checkpoint inhibitor-associated drug reaction with eosinophilia and systemic symptom syndrome. Melanoma Res 2017; 27:271.
  92. Maloney NJ, Ravi V, Cheng K, et al. Stevens-Johnson syndrome and toxic epidermal necrolysis-like reactions to checkpoint inhibitors: a systematic review. Int J Dermatol 2020; 59:e183.
  93. Freites-Martinez A, Kwong BY, Rieger KE, et al. Eruptive Keratoacanthomas Associated With Pembrolizumab Therapy. JAMA Dermatol 2017; 153:694.
  94. Haraszti S, Polly S, Ezaldein HH, et al. Eruptive squamous cell carcinomas in metastatic melanoma: An unintended consequence of immunotherapy. JAAD Case Rep 2019; 5:514.
  95. Antonov NK, Nair KG, Halasz CL. Transient eruptive keratoacanthomas associated with nivolumab. JAAD Case Rep 2019; 5:342.
  96. Marsh RL, Kolodney JA, Iyengar S, et al. Formation of eruptive cutaneous squamous cell carcinomas after programmed cell death protein-1 blockade. JAAD Case Rep 2020; 6:390.
  97. Fradet M, Sibaud V, Tournier E, et al. Multiple Keratoacanthoma-like Lesions in a Patient Treated with Pembrolizumab. Acta Derm Venereol 2019; 99:1301.
  98. Tomelleri A, Campochiaro C, De Luca G, et al. Anti-PD1 therapy-associated cutaneous leucocytoclastic vasculitis: A case series. Eur J Intern Med 2018; 57:e11.
  99. Daxini A, Cronin K, Sreih AG. Vasculitis associated with immune checkpoint inhibitors-a systematic review. Clin Rheumatol 2018; 37:2579.
  100. Castillo B, Gibbs J, Brohl AS, Seminario-Vidal L. Checkpoint inhibitor-associated cutaneous small vessel vasculitis. JAAD Case Rep 2018; 4:675.
  101. Belkaid S, Berger M, Nouvier M, et al. A case of Schönlein-Henoch purpura induced by immune checkpoint inhibitor in a patient with metastatic melanoma. Eur J Cancer 2020; 139:169.
  102. Ravi V, Maloney NJ, Worswick S. Neutrophilic dermatoses as adverse effects of checkpoint inhibitors: A review. Dermatol Ther 2019; 32:e13074.
  103. Welborn ME, Kubicki SL, Patel AB. Pyoderma Gangrenosum Following Initiation of Immune Checkpoint Inhibitor Therapy. J Immunother Precis Oncol 2018; 1:82.
  104. Pach J, Moody K, Ring N, et al. Erythema nodosum-like panniculitis associated with immune checkpoint inhibitor therapy: Two cases reporting a rare cutaneous adverse event. JAAD Case Rep 2021; 13:118.
  105. Tetzlaff MT, Jazaeri AA, Torres-Cabala CA, et al. Erythema nodosum-like panniculitis mimicking disease recurrence: A novel toxicity from immune checkpoint blockade therapy-Report of 2 patients. J Cutan Pathol 2017; 44:1080.
  106. Blum SM, Rouhani SJ, Sullivan RJ. Effects of immune-related adverse events (irAEs) and their treatment on antitumor immune responses. Immunol Rev 2023; 318:167.
  107. Freeman-Keller M, Kim Y, Cronin H, et al. Nivolumab in Resected and Unresectable Metastatic Melanoma: Characteristics of Immune-Related Adverse Events and Association with Outcomes. Clin Cancer Res 2016; 22:886.
  108. Sanlorenzo M, Vujic I, Daud A, et al. Pembrolizumab Cutaneous Adverse Events and Their Association With Disease Progression. JAMA Dermatol 2015; 151:1206.
  109. Hua C, Boussemart L, Mateus C, et al. Association of Vitiligo With Tumor Response in Patients With Metastatic Melanoma Treated With Pembrolizumab. JAMA Dermatol 2016; 152:45.
  110. Nakamura Y, Tanaka R, Asami Y, et al. Correlation between vitiligo occurrence and clinical benefit in advanced melanoma patients treated with nivolumab: A multi-institutional retrospective study. J Dermatol 2017; 44:117.
  111. Dall'Olio FG, Rizzo A, Mollica V, et al. Immortal time bias in the association between toxicity and response for immune checkpoint inhibitors: a meta-analysis. Immunotherapy 2021; 13:257.
  112. Kfoury M, Najean M, Lappara A, et al. Analysis of the association between prospectively collected immune-related adverse events and survival in patients with solid tumor treated with immune-checkpoint blockers, taking into account immortal-time bias. Cancer Treat Rev 2022; 110:102452.
  113. Asdourian MS, Jacoby TV, Shah N, et al. Noncutaneous immune-related adverse events predict overall and progression-free survival in patients with cutaneous toxicities after immune checkpoint inhibitor therapy. J Am Acad Dermatol 2023; 88:1368.
  114. Zhang S, Tang K, Wan G, et al. Cutaneous immune-related adverse events are associated with longer overall survival in advanced cancer patients on immune checkpoint inhibitors: A multi-institutional cohort study. J Am Acad Dermatol 2023; 88:1024.
  115. Teulings HE, Limpens J, Jansen SN, et al. Vitiligo-like depigmentation in patients with stage III-IV melanoma receiving immunotherapy and its association with survival: a systematic review and meta-analysis. J Clin Oncol 2015; 33:773.
  116. Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. 2017. United States Department of Health and Human Services. Available at: https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcae_v5_quick_reference_5x7.pdf (Accessed on January 22, 2021).
  117. Ellis SR, Vierra AT, Millsop JW, et al. Dermatologic toxicities to immune checkpoint inhibitor therapy: A review of histopathologic features. J Am Acad Dermatol 2020; 83:1130.
  118. Sibaud V, Meyer N, Lamant L, et al. Dermatologic complications of anti-PD-1/PD-L1 immune checkpoint antibodies. Curr Opin Oncol 2016; 28:254.
  119. Apalla Z, Nikolaou V, Fattore D, et al. European recommendations for management of immune checkpoint inhibitors-derived dermatologic adverse events. The EADV task force 'Dermatology for cancer patients' position statement. J Eur Acad Dermatol Venereol 2022; 36:332.
  120. Nadelmann ER, Yeh JE, Chen ST. Management of Cutaneous Immune-Related Adverse Events in Patients With Cancer Treated With Immune Checkpoint Inhibitors: A Systematic Review. JAMA Oncol 2022; 8:130.
  121. Brahmer JR, Lacchetti C, Thompson JA. Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline Summary. J Oncol Pract 2018; 14:247.
  122. Thompson JA. New NCCN Guidelines: Recognition and Management of Immunotherapy-Related Toxicity. J Natl Compr Canc Netw 2018; 16:594.
  123. Choi J, Anderson R, Blidner A, et al. Multinational Association of Supportive Care in Cancer (MASCC) 2020 clinical practice recommendations for the management of severe dermatological toxicities from checkpoint inhibitors. Support Care Cancer 2020; 28:6119.
  124. Puzanov I, Diab A, Abdallah K, et al. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. J Immunother Cancer 2017; 5:95.
  125. Thompson JA, Schneider BJ, Brahmer J, et al. Management of Immunotherapy-Related Toxicities, Version 1.2019. J Natl Compr Canc Netw 2019; 17:255.
  126. Thompson JA, Schneider BJ, Brahmer J, et al. NCCN Guidelines Insights: Management of Immunotherapy-Related Toxicities, Version 1.2020. J Natl Compr Canc Netw 2020; 18:230.
  127. Schneider BJ, Naidoo J, Santomasso BD, et al. Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update. J Clin Oncol 2021; 39:4073.
  128. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Management of Immunotherapy-Related Toxicities, Version 2.2023. https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf (Accessed on November 02, 2023).
  129. Fujii T, Colen RR, Bilen MA, et al. Incidence of immune-related adverse events and its association with treatment outcomes: the MD Anderson Cancer Center experience. Invest New Drugs 2018; 36:638.
  130. Horvat TZ, Adel NG, Dang TO, et al. Immune-Related Adverse Events, Need for Systemic Immunosuppression, and Effects on Survival and Time to Treatment Failure in Patients With Melanoma Treated With Ipilimumab at Memorial Sloan Kettering Cancer Center. J Clin Oncol 2015; 33:3193.
  131. Brown AM, Masterson W, Lo J, Patel AB. Systemic Treatment of Cutaneous Adverse Events After Immune Checkpoint Inhibitor Therapy: A Review. Dermatitis 2023; 34:201.
  132. Hibler BP, Markova A. Treatment of severe cutaneous adverse reaction with tocilizumab. Br J Dermatol 2020; 183:785.
  133. Deng Z, Wang S, Wu C, Wang C. IL-17 inhibitor-associated inflammatory bowel disease: A study based on literature and database analysis. Front Pharmacol 2023; 14:1124628.
  134. Shipman WD, Singh K, Cohen JM, et al. Immune checkpoint inhibitor-induced bullous pemphigoid is characterized by interleukin (IL)-4 and IL-13 expression and responds to dupilumab treatment. Br J Dermatol 2023; 189:339.
  135. Fournier C, Hirsch I, Spreafico A, et al. Dupilumab as a treatment for cutaneous immune-related adverse events induced by immune checkpoint inhibitors: A case series and review of the literature. SAGE Open Med Case Rep 2023; 11:2050313X231195462.
  136. Moghadam P, Tancrede E, Bouaziz JD, et al. Efficacy and safety of dupilumab in bullous pemphigoid: a retrospective multicentric study of 36 patients. Br J Dermatol 2023; 189:244.
  137. Belum VR, Benhuri B, Postow MA, et al. Characterisation and management of dermatologic adverse events to agents targeting the PD-1 receptor. Eur J Cancer 2016; 60:12.
Topic 128565 Version 10.0

References

1 : Immune checkpoint inhibitor-related dermatologic adverse events.

2 : Inflammatory eruptions associated with immune checkpoint inhibitor therapy: A single-institution retrospective analysis with stratification of reactions by toxicity and implications for management.

3 : Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.

4 : Cutaneous immune-related adverse events in patients with melanoma treated with checkpoint inhibitors.

5 : Cutaneous adverse events in 155 patients with metastatic melanoma consecutively treated with anti-CTLA4 and anti-PD1 combination immunotherapy: Incidence, management, and clinical benefit.

6 : Improved survival with ipilimumab in patients with metastatic melanoma.

7 : Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial.

8 : Nivolumab in previously untreated melanoma without BRAF mutation.

9 : Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma.

10 : Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial.

11 : Pembrolizumab versus Ipilimumab in Advanced Melanoma.

12 : Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma.

13 : Immune checkpoint inhibitors in clinical practice: update on management of immune-related toxicities.

14 : Dermatologic Reactions to Immune Checkpoint Inhibitors : Skin Toxicities and Immunotherapy.

15 : Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma.

16 : Standard-dose pembrolizumab in combination with reduced-dose ipilimumab for patients with advanced melanoma (KEYNOTE-029): an open-label, phase 1b trial.

17 : Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study.

18 : Cutaneous Toxicities Associated with Immune Checkpoint Inhibitors: An Observational, Pharmacovigilance Study.

19 : The Balancing Act between Cancer Immunity and Autoimmunity in Response to Immunotherapy.

20 : Treatment Outcomes of Immune-Related Cutaneous Adverse Events.

21 : Cytotoxic Cutaneous Adverse Drug Reactions during Anti-PD-1 Therapy.

22 : Human leukocyte antigen variation is associated with adverse events of checkpoint inhibitors.

23 : Association of pre-existing drug allergies with cutaneous immune-related adverse events among patients on immune checkpoint inhibitor therapy.

24 : Epidemiology and risk factors for the development of cutaneous toxicities in patients treated with immune-checkpoint inhibitors: A United States population-level analysis.

25 : Skin Reactions to Immune Checkpoint Inhibitors.

26 : Cutaneous immune-related adverse events to checkpoint inhibitors.

27 : Toxic Side Effects of Targeted Therapies and Immunotherapies Affecting the Skin, Oral Mucosa, Hair, and Nails.

28 : Cutaneous adverse events caused by immune checkpoint inhibitors.

29 : The role of cytokines in the mechanism of adverse drug reactions.

30 : Mucocutaneous adverse events to immune checkpoint inhibitors.

31 : Clinical and Histologic Features of Lichenoid Mucocutaneous Eruptions Due to Anti-Programmed Cell Death 1 and Anti-Programmed Cell Death Ligand 1 Immunotherapy.

32 : Lichen planus-like drug eruption on anti-PD-1 therapy.

33 : Severe bullous skin eruptions on checkpoint inhibitor therapy - in most cases severe bullous lichenoid drug eruptions.

34 : Psoriasis and psoriasiform reactions secondary to immune checkpoint inhibitors.

35 : Immune checkpoint-mediated psoriasis: A multicenter European study of 115 patients from the European Network for Cutaneous Adverse Event to Oncologic Drugs (ENCADO) group.

36 : Immune checkpoint inhibitors in patients with pre-existing psoriasis: safety and efficacy.

37 : Onset of psoriasis with immune checkpoint inhibitor therapy: A systematic review.

38 : Case Report and Review of 7 Similar Cases in the Literature: Cutaneous Sarcoidosis as Side Effect of Pembrolizumab Plus Chemotherapy in Stage IV Squamous Cell Carcinoma of Lung.

39 : Challenges in sarcoidosis and sarcoid-like reactions associated to immune checkpoint inhibitors: A narrative review apropos of a case.

40 : Drug-induced sarcoidosis-like reaction in adjuvant immunotherapy: Increased rate and mimicker of metastasis.

41 : Twelve cases of acneiform eruptions while on anti-CTLA4 therapy.

42 : Use of Immune Checkpoint Inhibitors in the Treatment of Patients With Cancer and Preexisting Autoimmune Disease: A Systematic Review.

43 : Bullous disorders associated with anti-PD-1 and anti-PD-L1 therapy: A retrospective analysis evaluating the clinical and histopathologic features, frequency, and impact on cancer therapy.

44 : Bullous Pemphigoid Associated with Anti-programmed Cell Death Protein 1 and Anti-programmed Cell Death Ligand 1 Therapy: A Review of the Literature.

45 : Retrospective Analysis of Checkpoint Inhibitor Therapy-Associated Cases of Bullous Pemphigoid From Six German Dermatology Centers.

46 : Pembrolizumab-induced lichen planus pemphigoides in a patient with metastatic Merkel cell carcinoma.

47 : Anti-PD1 immune checkpoint inhibitor-induced bullous pemphigoid in metastatic melanoma and non-small cell lung cancer.

48 : Suprabasal acantholytic dermatologic toxicities associated checkpoint inhibitor therapy: A spectrum of immune reactions from paraneoplastic pemphigus-like to Grover-like lesions.

49 : Autoimmune dermatologic toxicities from immune checkpoint blockade with anti-PD-1 antibody therapy: a report on bullous skin eruptions.

50 : A case of bullous pemphigoid in a patient with metastatic melanoma treated with pembrolizumab.

51 : Autoimmune Bullous Skin Disorders with Immune Checkpoint Inhibitors Targeting PD-1 and PD-L1.

52 : Diagnostic and therapeutic differences between immune checkpoint inhibitor-induced and idiopathic bullous pemphigoid: a cross-sectional study.

53 : A retrospective case series of 20 patients with immunotherapy-induced bullous pemphigoid with emphasis on management outcomes.

54 : Checkpoint inhibitor-associated bullous cutaneous immune-related adverse events: a multicentre observational study.

55 : Paraneoplastic pemphigus manifesting in a patient treated with pembrolizumab for urothelial carcinoma.

56 : Vitiligo-like lesions occurring in patients receiving anti-programmed cell death-1 therapies are clinically and biologically distinct from vitiligo.

57 : Immune checkpoint inhibitor-induced myositis, the earliest and most lethal complication among rheumatic and musculoskeletal toxicities.

58 : Clinical characteristics of rheumatic syndromes associated with checkpoint inhibitors therapy.

59 : Drug-induced lupus erythematosus following immunotherapy with anti-programmed death-(ligand) 1.

60 : Lupus-like cutaneous reaction following pembrolizumab: An immune-related adverse event associated with anti-PD-1 therapy.

61 : Cutaneous lupus associated with pembrolizumab therapy for advanced melanoma: a report of three cases.

62 : Subacute cutaneous lupus erythematosus induced by nivolumab: two case reports and a literature review.

63 : Bullous Lupus Under Nivolumab Treatment for Lung Cancer: A Case Report With Systematic Literature Review.

64 : Widespread subacute cutaneous lupus erythematosus in a patient receiving checkpoint inhibitor immunotherapy with ipilimumab and nivolumab.

65 : Dermatomyositis associated with nivolumab therapy for melanoma: a case report and review of the literature.

66 : Dermatomyositis unleashed by immune checkpoint inhibitors. Three additional cases and a review of the literature.

67 : Anti-TIF1γantibody-positive dermatomyositis associated with nivolumab administration in a patient with advanced oesophageal squamous cell carcinoma: A case report and literature review.

68 : Most patients with cancer-associated dermatomyositis have antibodies to nuclear matrix protein NXP-2 or transcription intermediary factor 1γ.

69 : Risk of scleroderma according to the type of immune checkpoint inhibitors.

70 : Sjögren's Syndrome as an Immune-related Adverse Event of Nivolumab Treatment for Gastric Cancer.

71 : Sicca syndrome following immune checkpoint inhibition.

72 : Sicca Syndrome Associated with Immune Checkpoint Inhibitor Therapy.

73 : Oral mucosal changes induced by anticancer targeted therapies and immune checkpoint inhibitors.

74 : Oral lichenoid reaction showing multiple ulcers associated with anti-programmed death cell receptor-1 treatment: A report of two cases and published work review.

75 : Mucous membrane pemphigoid and lichenoid reactions after immune checkpoint inhibitors: common pathomechanisms.

76 : Mucous Membrane Pemphigoid, Bullous Pemphigoid, and Anti-programmed Death-1/ Programmed Death-Ligand 1: A Case Report of an Elderly Woman With Mucous Membrane Pemphigoid Developing After Pembrolizumab Therapy for Metastatic Melanoma and Review of the Literature.

77 : Immune-related alopecia (areata and universalis) in cancer patients receiving immune checkpoint inhibitors.

78 : Alopecia areata as an immune-related adverse event of immune checkpoint inhibitors: A review.

79 : Narrative Review of Drug-Associated Nail Toxicities in Oncologic Patients.

80 : Unusual skin toxicity associated with sustained disease response induced by nivolumab in a patient with non-small cell lung cancer.

81 : Hair Repigmentation During Immunotherapy Treatment With an Anti-Programmed Cell Death 1 and Anti-Programmed Cell Death Ligand 1 Agent for Lung Cancer.

82 : A case report of disappearing pigmented skin lesions associated with pembrolizumab treatment for metastatic melanoma.

83 : Hair Repigmentation With Anti-PD-1 and Anti-PD-L1 Immunotherapy: A Novel Hypothesis.

84 : Oral lichenoid reactions associated with anti-PD-1/PD-L1 therapies: clinicopathological findings.

85 : Development of psoriatic arthritis during nivolumab therapy for metastatic non-small cell lung cancer, clinical outcome analysis and review of the literature.

86 : Psoriasis and psoriatic arthritis induced by nivolumab in a patient with advanced lung cancer.

87 : Drug-associated dermatomyositis following ipilimumab therapy: a novel immune-mediated adverse event associated with cytotoxic T-lymphocyte antigen 4 blockade.

88 : The life-threatening eruptions of immune checkpoint inhibitor therapy.

89 : Ipilimumab-induced acute generalized exanthematous pustulosis in a patient with metastatic melanoma.

90 : Nivolumab-associated DRESS syndrome: A case report.

91 : Checkpoint inhibitor-associated drug reaction with eosinophilia and systemic symptom syndrome.

92 : Stevens-Johnson syndrome and toxic epidermal necrolysis-like reactions to checkpoint inhibitors: a systematic review.

93 : Eruptive Keratoacanthomas Associated With Pembrolizumab Therapy.

94 : Eruptive squamous cell carcinomas in metastatic melanoma: An unintended consequence of immunotherapy.

95 : Transient eruptive keratoacanthomas associated with nivolumab.

96 : Formation of eruptive cutaneous squamous cell carcinomas after programmed cell death protein-1 blockade.

97 : Multiple Keratoacanthoma-like Lesions in a Patient Treated with Pembrolizumab.

98 : Anti-PD1 therapy-associated cutaneous leucocytoclastic vasculitis: A case series.

99 : Vasculitis associated with immune checkpoint inhibitors-a systematic review.

100 : Checkpoint inhibitor-associated cutaneous small vessel vasculitis.

101 : A case of Schönlein-Henoch purpura induced by immune checkpoint inhibitor in a patient with metastatic melanoma.

102 : Neutrophilic dermatoses as adverse effects of checkpoint inhibitors: A review.

103 : Pyoderma Gangrenosum Following Initiation of Immune Checkpoint Inhibitor Therapy

104 : Erythema nodosum-like panniculitis associated with immune checkpoint inhibitor therapy: Two cases reporting a rare cutaneous adverse event.

105 : Erythema nodosum-like panniculitis mimicking disease recurrence: A novel toxicity from immune checkpoint blockade therapy-Report of 2 patients.

106 : Effects of immune-related adverse events (irAEs) and their treatment on antitumor immune responses.

107 : Nivolumab in Resected and Unresectable Metastatic Melanoma: Characteristics of Immune-Related Adverse Events and Association with Outcomes.

108 : Pembrolizumab Cutaneous Adverse Events and Their Association With Disease Progression.

109 : Association of Vitiligo With Tumor Response in Patients With Metastatic Melanoma Treated With Pembrolizumab.

110 : Correlation between vitiligo occurrence and clinical benefit in advanced melanoma patients treated with nivolumab: A multi-institutional retrospective study.

111 : Immortal time bias in the association between toxicity and response for immune checkpoint inhibitors: a meta-analysis.

112 : Analysis of the association between prospectively collected immune-related adverse events and survival in patients with solid tumor treated with immune-checkpoint blockers, taking into account immortal-time bias.

113 : Noncutaneous immune-related adverse events predict overall and progression-free survival in patients with cutaneous toxicities after immune checkpoint inhibitor therapy.

114 : Cutaneous immune-related adverse events are associated with longer overall survival in advanced cancer patients on immune checkpoint inhibitors: A multi-institutional cohort study.

115 : Vitiligo-like depigmentation in patients with stage III-IV melanoma receiving immunotherapy and its association with survival: a systematic review and meta-analysis.

116 : Vitiligo-like depigmentation in patients with stage III-IV melanoma receiving immunotherapy and its association with survival: a systematic review and meta-analysis.

117 : Dermatologic toxicities to immune checkpoint inhibitor therapy: A review of histopathologic features.

118 : Dermatologic complications of anti-PD-1/PD-L1 immune checkpoint antibodies.

119 : European recommendations for management of immune checkpoint inhibitors-derived dermatologic adverse events. The EADV task force 'Dermatology for cancer patients' position statement.

120 : Management of Cutaneous Immune-Related Adverse Events in Patients With Cancer Treated With Immune Checkpoint Inhibitors: A Systematic Review.

121 : Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline Summary.

122 : New NCCN Guidelines: Recognition and Management of Immunotherapy-Related Toxicity.

123 : Multinational Association of Supportive Care in Cancer (MASCC) 2020 clinical practice recommendations for the management of severe dermatological toxicities from checkpoint inhibitors.

124 : Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.

125 : Management of Immunotherapy-Related Toxicities, Version 1.2019.

126 : NCCN Guidelines Insights: Management of Immunotherapy-Related Toxicities, Version 1.2020.

127 : Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update.

128 : Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update.

129 : Incidence of immune-related adverse events and its association with treatment outcomes: the MD Anderson Cancer Center experience.

130 : Immune-Related Adverse Events, Need for Systemic Immunosuppression, and Effects on Survival and Time to Treatment Failure in Patients With Melanoma Treated With Ipilimumab at Memorial Sloan Kettering Cancer Center.

131 : Systemic Treatment of Cutaneous Adverse Events After Immune Checkpoint Inhibitor Therapy: A Review.

132 : Treatment of severe cutaneous adverse reaction with tocilizumab.

133 : IL-17 inhibitor-associated inflammatory bowel disease: A study based on literature and database analysis.

134 : Immune checkpoint inhibitor-induced bullous pemphigoid is characterized by interleukin (IL)-4 and IL-13 expression and responds to dupilumab treatment.

135 : Dupilumab as a treatment for cutaneous immune-related adverse events induced by immune checkpoint inhibitors: A case series and review of the literature.

136 : Efficacy and safety of dupilumab in bullous pemphigoid: a retrospective multicentric study of 36 patients.

137 : Characterisation and management of dermatologic adverse events to agents targeting the PD-1 receptor.

آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟