Mechanisms of Cutaneous irAEs Induced by ICIs: Comparison
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Immune checkpoint inhibitors (ICIs) have emerged as promising therapeutic options for the treatment of various cancers. These novel treatments effectively target key mediators of immune checkpoint pathways. ICIs primarily consist of monoclonal antibodies that specifically block cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death 1 (PD-1), programmed cell death-ligand 1 (PD-L1), and lymphocyte activation gene 3 protein (LAG-3). Despite the notable efficacy of ICIs in cancer treatment, they can also trigger immune-related adverse events (irAEs), which present as autoimmune-like or inflammatory conditions.

  • immune checkpoint inhibitor
  • immune-related adverse event
  • cutaneous immune-related adverse event
  • anti-CTLA-4 inhibitor
  • anti-PD-1 inhibitor
  • anti-PD-L1 inhibitor
  • anti-LAG-3 inhibitor

1. Introduction

Immune-checkpoint inhibitors (ICIs) have revolutionized the management of advanced malignancies over the past decade by offering groundbreaking therapeutic options [1,2][1][2]. Current biologic agents target natural immune checkpoint molecules, including cytotoxic T-lymphocyte antigen 4 (CTLA-4) [3[3][4],4], programmed cell death 1 (PD-1), programmed cell death-ligand 1 (PD-L1) [5[5][6],6], and lymphocyte activation gene 3 protein (LAG-3) [7], to enhance their antitumoral activity. While immune-checkpoint inhibitors hold great promise, their non-specific immunologic activations can give rise to various autoimmune-like or inflammatory diseases known as immune-related adverse events (irAEs) [8,9][8][9]. These adverse events predominantly affect the skin, gastrointestinal tract, liver, and endocrine glands, but they have the potential to involve any organ system [10,11][10][11].
Cutaneous immune-related adverse events (irAEs) are the most common complications associated with ICIs and often present as the initial manifestation. These events usually develop within the first few weeks to months after initiating immunotherapy, but they can occur at any time, even after treatment discontinuation [12]. A wide range of clinical presentations, including morbilliform eruptions, pruritus, lichenoid eruptions, psoriasiform dermatitis, vitiligo, bullous disorders, alopecia, and severe cutaneous adverse reactions (SCARs), have been reported [8,10,11,13,14][8][10][11][13][14]. These adverse events can significantly impact patients’ quality of life and may require the discontinuation of treatment. Therefore, early recognition and prompt management of cutaneous irAEs is important to minimize the immunotherapy-related morbidity and to achieve favorable outcomes in cancer patients.

2. Cutaneous Immune-Related Adverse Events

Despite the remarkable therapeutic efficacy of immune checkpoint inhibitors, their usage can give rise to a wide array of autoimmune and autoinflammatory reactions referred to as irAEs, due to their non-specific activation of the immune system. Among these irAEs, cutaneous irAEs are the most prevalent and often present as the earliest symptoms in patients undergoing immunotherapy. Generally, cutaneous irAEs emerge within weeks to months after initiating treatment with immune checkpoint inhibitors, although they can occur at any time, even after discontinuation of treatment [12]. Most cutaneous toxicities are mild to moderate in severity (CTCAE grades 1–2) and typically resolve spontaneously. In rare cases, severe cutaneous adverse reactions (SCARs) can occur, including conditions like Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) [41,42,43][15][16][17]. The occurrence of cutaneous irAEs has been reported in 30% to 60% of patients receiving treatment. Among various ICIs, anti-CTLA-4 monotherapy has a significantly higher rate of cutaneous irAEs (44–59%) compared to anti-PD-1 (34–42%) and anti-PD-L1 monotherapy (20%). Furthermore, the combination of CTLA-4 and PD-1 inhibition generally leads to an increased incidence (59–72%) and severity of skin toxicities [43,44,45][17][18][19]. It is believed that cutaneous irAEs are not dependent on the dosage of ICIs and can occur regardless of the underlying malignancy. However, recent research suggests that melanoma and renal cell carcinoma may carry a higher risk compared to other types of cancer [45][19]. Additionally, patients with pre-existing autoimmune diseases or pre-existing skin damage are more prone to experiencing cutaneous irAEs [11,46][11][20]

3. Subtypes and Possible Mechanisms of Cutaneous Immune-Related Adverse Events

The precise mechanisms responsible for ICI-induced cutaneous irAEs are not fully understood. However, several potential pathogeneses have been proposed. These include the involvement of type IV hypersensitivity reactions, genetic variations in certain human leukocyte antigen (HLA) variants, activation of self-reactive T cells and B cells that target shared antigens found in both tumor cells and normal tissues, stimulation of B cells and the humoral immune response, increased production of proinflammatory cytokines with immune-related consequences, potential exposure of host antigens from tumor cells due to cytotoxic attacks, and potential exacerbation of drug eruptions due to concurrent medication usage. The possible mechanisms of cutaneous irAEs are summarized in Table 21.
Table 21.
Possible pathogenesis, onset time, and frequency of cutaneous irAEs.
Cutaneous irAEs Onset Time Mainly Associated ICIs Frequency Possible Mechanisms
Morbilliform eruption 3–6 weeks Anti-CTLA-4 >

Anti-PD-1/PD-L1		 Anti-CTLA-4: 49–68%

Anti-PD-1/PD-L1: 20%		 Type IV hypersensitivity reaction
Pruritus 1–27 weeks Anti-CTLA-4 >

Anti-PD-1/PD-L1		 Anti-CTLA-4: 25–36%

Combination: 33–47%		 Genetic difference in HLA variants

Increased proinflammatory cytokines
Lichenoid eruption 6–12 weeks Anti-PD-1/PD-L1 Anti-PD-1/PD-L1: <17% Autoreactive T cells against common antigen

Increased proinflammatory cytokines

Innate immunity
Psoriasiform eruption 3–12 weeks Anti-PD-1/PD-L1 Anti-PD-1/PD-L1: 3–12% Th17 pathway activation

Increased proinflammatory cytokines
Vitiligo like depigmentation 7–65 weeks Anti-PD-1/PD-L1 >

Anti-CTLA-4		 Anti-PD-1/PD-L1: 7–11%

Anti-CTLA-4: 2–9%		 Autoreactive T cells against common antigen
Bullous pemphigoid 13–80 weeks Anti-PD-1/PD-L1 Anti-PD-1/PD-L1: 1% T cell dependent humoral immunity

T cell independent humoral immunity
SJS/TEN 1–20 weeks Anti-CTLA-4 >

Anti-PD-1/PD-L1		 Rare Autoreactive T cells against common antigen

Type IV hypersensitivity reaction
Abbreviations: irAEs, immune-related adverse events; SJS/TEN, Stevens–Johnson syndrome/toxic epidermal necrolysis; ICIs, immune checkpoint inhibitors; anti-CTLA-4, anti-cytotoxic T-lymphocyte antigen 4; anti-PD-1, anti-programmed cell death 1; anti-PD-L1, anti-programmed cell death-ligand 1; HLA, human leukocyte antigen.

3.1. Morbilliform (Maculopapular) Eruption

The morbilliform eruption is the most commonly observed cutaneous irAE. It affects approximately 49–68% of patients undergoing anti-CTLA-4 therapy and 20% of patients receiving PD-1/PD-L1 inhibitors [13,47][13][21]. Typically, the morbilliform rash occurs within the first three to six weeks after initiating ICIs treatment [10,12,48,49][10][12][22][23]. Clinical presentations include pruritic faint erythematous macules and papules that coalesce into plaques. It primarily affects the trunk and the extensor side of the extremities, while the head, palms, and soles are usually unaffected [13,14][13][14]. Histopathological examinations reveal interface changes and perivascular or periadnexal lymphocytic infiltration, with or without eosinophils. Although maculopapular rashes are usually mild and resolve on their own, they can occasionally serve as an initial presentation of severe cutaneous adverse reactions like SSJS/TEN or DRESS. The detailed mechanisms of ICI-induced morbilliform eruption remains unclear, but there is a hypothesis suggesting an association with type IVc hypersensitivity reactions [12[12][24],50], in which cytotoxic T cells act as effector cells. Under immunotherapy, activated cytotoxic T lymphocytes can directly harm target cells by releasing cytotoxic cytokines, including perforin, granulysin, either granzymes or granzymes B, and through physical interaction via the FasL/FasR pathway. Moreover, type IVc hypersensitivity is also predominantly implicated in SJS/TEN [50,51][24][25].

3.2. Pruritus

Pruritus is another common cutaneous irAE associated with ICIs. It can occur in conjunction with other skin manifestations or as an isolated symptom. Studies have indicated that pruritus affects approximately 14% to 47% of patients receiving ICIs, with higher incidence rates seen in those receiving anti-CTLA-4 monotherapy (25–36%) and combination therapy (33–47%) [12,43][12][17]. Typically, pruritus manifests within one to twenty-seven weeks after starting therapy and is commonly observed on the scalp and trunk, while the face, anterior neck, genitalia, and soles are usually unaffected [11,52,53][11][26][27]. In most cases, pruritus induced by ICIs is of low severity, and less than 2% of patients develop refractory high-grade pruritus [54,55][28][29]. The most extensively studied cytokines in the pathogenesis of itch are Th2 cytokines, including IL-4, IL-13, and IL-31. Certain Th1 cytokines, such as IL-17, may also be involved in psoriasis-related itch. Therefore, pruritus induced by ICIs may result in Th1/Th2 dysregulation, leading to the production of cytokines that promote skin inflammation [56,57][30][31]. However, the precise mechanism of ICI-related pruritus is not yet fully understood. Genetic differences in human leukocyte antigen (HLA) haplotypes have been implicated in predisposing patients to develop irAEs. As a result, it is believed that genetic factors play a role in the pathogenesis of irAEs. Some irAEs closely resemble established autoimmune disorders that are associated with specific HLA risk alleles. For example, ICI-related colitis has been linked to HLA-DQB1*03:01 [58,59][32][33], ICI-induced hypothyroidism to HLA-DR8 [60][34], and ICI-related arthritis to HLA-DRB1*04:05 [61][35]. Similarly, specific HLA alleles have been found to be associated with ICI-induced pruritus, such as HLA-DRB1*11:01, as reported in several studies [59,62][33][36]. Despite extensive investigations, the exact mechanism linking HLA variants to irAEs remains elusive.

3.3. Lichenoid Eruptions

Lichenoid eruptions are more prevalent in patients receiving PD-1/PD-L1 inhibitors compared to those receiving CTLA-4 inhibitors [13,47,63,64,65,66][13][21][37][38][39][40]. These eruptions usually occurs between six to twelve weeks after initiation of ICI therapy [11[11][12],12], affecting less than 17% of patients using anti-PD-1 agents [67][41]. Clinical manifestations of lichen planus (LP) are characterized by shiny, flat-topped, polygonal, erythematous to violaceous papules and plaques with a thin, white lacelike pattern (Wickham striae) on the surface of the lesions, and it often exhibits symmetrical distribution on the flexural areas of the extremities. In contrast, ICI-associated lichenoid eruptions are pruritic, multiple, often grouped and confluent, purple-colored, flat-topped, slightly keratotic papules, or plaques mostly on the extensor surfaces of extremities and the trunk. Moreover, unlike lichen planus, ICI-induced LP-like eruptions are less frequently involved in the genital or oral mucosa, and Wickham striae are usually absent [13,68,69,70,71,72,73,74,75][13][42][43][44][45][46][47][48][49]. Both lichen planus (LP) and lichenoid eruptions share common histopathological findings, such as interface changes characterized by a dense band-like superficial infiltration of lymphocytes, a saw-tooth rete ridge pattern, hyperkeratosis, hypergranulosis, and the presence of apoptotic cells in the basal layer of the epidermis. However, in ICI-induced LP-like eruptions, there are additional distinctive features, including focal spongiosis, parakeratosis, focal interruption of the granular layer, and the presence of eosinophils or necrotic keratinocytes [13,68,69][13][42][43]. Furthermore, rare variants of LP, including ulcerative LP [70][44], hyperkeratotic LP [71][45], inverse LP [72][46], bullous LP [73[47][48],74], and lichen nitidus [75][49], have also been reported in association with ICIs. The detailed pathogenesis of ICI-induced lichenoid eruption remains unclear. However, it is believed that blocking the PD-1/PD-L1 pathway may enhance inflammatory reactions by activating the immune system, such as cytotoxic T cells and APCs. Prominent interferon-γ (IFN-γ) production in patients with oral LP receiving PD-1 inhibitors was found in a previous report [76][50]. Another study revealed increased mRNA expression of IFN-γ and granzyme B after anti-PD-1 agent treatment [77][51]. In addition, the expression of PD-L1 in keratinocytes has been speculated to play a protective role against cytotoxic T cells in a murine model. Furthermore, MHC-class-II molecule expression on keratinocytes induced by IFN-γ was also noted in a previous paper [78][52]. Based on these findings, it is hypothesized that inhibition of immune checkpoints may facilitate antigen presentation and lead to damage of basal epidermal keratinocytes through the activation of autoreactive cytotoxic T cells, which are mediated by IFN-γ and other molecules [79][53]. Gene expression profiles and immune compositions of ICI-related lichenoid eruption have also been analyzed previously. One study reported increased CD14+ and CD16+ monocytes and upregulation of toll-like receptor 2 (TLR 2) and TLR4 in patients with ICI-induced lichenoid dermatitis. Additionally, study also found higher numbers of T-Bet+ (Th1) cells and lower numbers of Gata-3+ (Th2) cells and FoxP3 (T regulatory) cells in the immune profiles of lichenoid eruptions. These findings suggest that the innate immune response may also be involved in the initiation of lichenoid eruptions through the CD14/TLR signaling pathway [80][54].

3.4. Psoriasiform Eruptions

Psoriasiform eruptions are more frequently observed in patients receiving PD-1/PD-L1 inhibitors than in patients receiving CTLA-4 inhibitors. Approximately 3–12% of patients treated with PD-1 inhibitors may be affected [13,14,81,82][13][14][55][56]. These eruptions can be categorized into two types, including newly onset psoriasis (de novo psoriasis) and a flare-up of pre-existing psoriasis (reactivated psoriasis). A previous report revealed that out of 115 cases of ICI-induced psoriasis, 70% of patients developed de novo psoriasis, while 30% had a history of psoriasis [83][57]. The lesions commonly appear after three to twelve weeks of treatment [10[10][12],12], with an average onset time of about fifty days for psoriasis flare-ups and about ninety-one days for newly developed psoriasis [81][55]. The most common type of ICI-induced psoriasiform eruption is plaque psoriasis, characterized by erythematous silvery scaly plaques with well-defined borders localized on the extensor surfaces of extremities and the trunk. Less frequent variants, including palmoplantar, pustular, guttate, and inverse psoriasis, have also been reported previously [83][57]. Histopathological findings resemble typical psoriasis vulgaris, with features such as parakeratosis, hypogranulosis, acanthosis with elongated rete ridges, and a perivascular lymphocytic infiltration [10,13,63][10][13][37]. Moreover, compared to typical psoriasis, variable spongiosis, infiltration of eosinophils, and lichenoid change can also be found in ICI-related psoriasis [84,85][58][59]. In the general population, psoriasis is mainly driven by the activation of the Th17 pathway, and several cytokines, including tumor necrosis factor alpha (TNF-α), IL-23, IL-17, and IL22, play important roles in its pathogenesis [86][60]. The detailed mechanisms underlying ICI-induced psoriasiform eruptions are still unclear. However, studies in animal models have shown that blocking immune checkpoint molecules can result in enhanced production of IL-17A and IL-22 via activated T cells, either through gene silencing or monoclonal antibody treatment. Based on these findings, it is hypothesized that ICIs may lead to the overproduction of proinflammatory cytokines, mediated by activated Th17 cells, which in turn promote neutrophil recruitment and keratinocyte hyperproliferation, ultimately exacerbating or inducing psoriasis. In patients, psoriasis is frequently associated with obesity and imbalanced dietary habits [87][61]. In a murine model system, it has been observed that the consumption of a Western diet (WD) high in fat and simple sugars dramatically increases the expression of PD-1 on γδ low (GDL) T cells, which are the main producers of IL-17A, thereby exacerbating the psoriasiform dermatitis induced by imiquimod (IMQ). Additionally, mice fed a WD and exhibiting obesity demonstrate a greater severity of IMQ-induced psoriasiform dermatitis compared to control mice when administered anti-PD1 treatment. Based on these findings, it is hypothesized that WD-induced obesity may be involved in the development of de novo psoriasis-like skin lesions or the worsening of pre-existing psoriasis in patients undergoing anti-PD-1 therapy, although the exact mechanism remains unknown [88,89][62][63].

3.5. Vitiligo-like Depigmentation

Vitiligo is an autoimmune disease characterized by the presence of well-defined, depigmented macules or patches resulting from the loss of functional melanocytes in the epidermis [90,91,92][64][65][66]. Among the various types of cutaneous irAEs, vitiligo-like depigmentation (VLD) is a subtype that occurs as a result of reactive autoimmunity targeting melanocytes in normal tissues during immunotherapy. VLD is more frequently observed in patients with advanced melanoma, while its occurrence in other malignancies is relatively rare [91,93,94,95][65][67][68][69]. Compared to anti-CTLA-4 therapy, VLD is more often induced during anti-PD-1 therapy, with incidence rates ranging from 7–11% and 2–9%, respectively. Moreover, the lesions commonly develop between seven and sixty-five weeks after starting ICI therapy, with a median onset time of approximately twenty-six weeks, and these lesions often persist even after discontinuation of immunotherapy [11,12,96][11][12][70]. Despite the significant psychosocial impact, the occurrence of VLD during ICI therapy is significantly associated with a favorable prognosis in patients with melanoma, including prolonged progression-free survival and overall survival rates [97][71]. This correlation highlights the strong relationship between irAEs and enhanced antitumor activity [10,90,91,97][10][64][65][71]. The clinical manifestations of ICI-induced VLD differ from those of idiopathic vitiligo, which tends to occur more commonly in periorificial areas and acral surfaces. VLD is characterized by the presence of multiple flecked macules that evolve into larger patches, predominantly affecting sun-exposed areas in a symmetrical pattern. Unlike idiopathic vitiligo, VLD is not associated with the Koebner phenomenon [98][72]. Moreover, an inflammatory phase may precede the development of depigmented lesions in VLD [53[27][65],91], and depigmentation of the skin may coincide with poliosis of the eyelashes and scalp hair [43,53][17][27]. Histologically, VLD shows an inflammatory infiltrate in the dermis primarily composed of T cells and a lack of melanocytes. The exact pathogenesis of immunotherapy-induced VLD remains uncertain, but several studies have proposed that its development is related to cross-reactivity against shared antigens present on both melanocytes and tumor cells. Upon treatment with anti-PD-1 agents, skin depigmentation occurs as a result of cytotoxic T cell activation against these shared antigens, which include Melanoma antigen recognized by T cells 1 (MART-1, also called Melan-A), GP100, tyrosinase-related proteins 1 and 2 (TRP1 and TRP2), and tyrosinase [97,99][71][73]. Immunohistochemical staining analysis has further revealed the presence of CD4 and MART-1/Melan-A specific CD8 T cells in close proximity to apoptotic melanocytes, indicating that anti-CTLA-4 antibodies may also contribute to stimulating an immune reaction against melanocytes [100][74].

3.6. Autoimmune Bullous Disease

Compared to other cutaneous irAEs, autoimmune bullous disorders are relatively less frequently observed. The incidence of ICI-induced bullous diseases is approximately 1% in patients treated with PD-1/PD-L1 inhibitors [12,13,101][12][13][75], and the onset time is typically between thirteen and eighty weeks after initiating immunotherapy, which is longer than other cutaneous irAEs [12,102,103][12][76][77]. Among the bullous diseases associated with immunotherapy, bullous pemphigoid (BP) is the most common presentation, followed by bullous lichenoid dermatitis and linear IgA bullous dermatosis [101][75]. The clinical presentations of ICI-induced BP resemble classic BP, characterized by a pruritic prodromal non-bullous phase followed by the development of tense bullae filled with serous or hemorrhagic fluid mainly localized on the trunk and extremities. Other variants, such as urticarial-predominant, eczematous rash, Grover disease–like, and dyshidrosiform, have also been reported previously [53,104][27][78]. However, unlike idiopathic BP, mucous membrane involvement is more common, with a frequency of up to 40% [64,105][38][79]. Histopathological findings are similar to those of spontaneous BP, which show subepidermal blisters with numerous eosinophils, and direct immunofluorescence reveals linear deposition of complement component 3 (C3) and immunoglobulin G (IgG) along the basement membrane zone [10,13,106][10][13][80]. It is believed that autoimmune bullous disorders induced by PD-1/PD-L1 inhibitors involve both T cell and B cell dysregulation. In T cell-independent humoral immunity, PD-1/PD-L1 blockades can enhance B-cell activation, leading to the production of disease-specific autoantibodies. These autoantibodies are responsible for cross-reactive immunogenicity against basement membrane proteins BP180 and BP230, which are expressed on certain cancer cells (such as melanoma and non-small cell lung carcinoma) as well as normal skin, thereby inducing BP [68,106,107,108][42][80][81][82]. In T cell-dependent humoral immunity, PD-1 acts as an activator for B cells interacting with either follicular helper T cells (Tfh) or follicular regulatory T cells (Tfr) within the germinal centers. Tfh cells play a role in the selection and survival of B cells, enabling their differentiation into memory B cells or high-affinity antibody-producing plasma cells. On the other hand, Tfr cells maintain immune balance by suppressing both Tfh cells and B cells. Inhibition of PD-1 may reduce the suppressive ability of Tfr cells and lead to potentially mutated B cells selected by Tfh cells. This can result in an aberrant production of low-affinity plasma cells, which contribute to the development of numerous antibody-mediated autoimmune disorders, including BP [107][81]. In addition to cross-reactivity, the production of autoantibodies against different epitopes, which is termed epitope-spreading phenomena, has also been observed in anti-PD-1/PD-L1-associated BP [107][81]. It has been reported that host genetic background may also be important in their susceptibility to irAEs, and several genetic variants associated with irAEs have been identified recently [109][83]. One SNP associated with an increased risk of autoimmune bullous pemphigoid has been linked to the DSC2 gene [110][84].

3.7. Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis-like Reaction

ICI-related SCARs, such as SJS/TEN-like reactions, are rare dermatologic toxicities, but they can be potentially life-threatening [111,112,113,114][85][86][87][88]. The onset time of SCARs varies from one to twenty weeks after initiation of immunotherapy [12[12][89],115], and the mortality rates are approximately 10% for SJS, 30% for SJS-TEN overlap syndrome, and 50% for TEN, respectively [105,115,116][79][89][90]. The clinical presentations are similar to classical SJS/TEN, including fever, conjunctival injection, and malaise, followed by diffuse erythema, with or without targetoid lesions on the trunk and extremities, progressing to flaccid bullae with a positive Nikolsky sign. In addition, mucosal involvement of the conjunctivae, oral cavity, gastrointestinal tract, respiratory tract, and genitalia may be observed [46,117][20][91]. However, unlike classical SJS/TEN, the SJS/TEN-like eruption has a longer onset time and the symptoms are usually milder than typical SJS/TEN, with less ocular involvement and less denuded skin. It has also been found that a morbilliform eruption may precede the ICI-induced SJS/TEN-like reactions. Therefore, it is important to closely monitor patients with a morbilliform rash for red-flag signs, such as blister formation, a positive Nikolsky sign, development of targetoid lesions, skin pain or mucosal involvement [118][92]. Histopathological findings show full-thickness epidermal necrolysis with extensive keratinocyte necrosis, subepidermal bullae, and a varied degree of inflammation in the superficial dermis with a sparse dermal infiltrate. Some studies speculate that the inhibition of checkpoint molecules interferes with the balance between the peripheral tolerance and the function of keratinocytes in protecting against damages, which eventually explains the frequent ICI-induced cutaneous eruptions. It has been found that PD-L1 is usually undetectable in normal skin, but ICI treatment can stimulate PD-L1 expression, triggering apoptosis of PD-L1 expressing keratinocytes induced by activated cytotoxic T cells [12,119][12][93]. Moreover, ICI-induced SJS/TEN-like eruptions exhibit a similar gene expression profile to classical SJS/TEN, both of which show increased expression of inflammatory chemokines, cytotoxic mediators (such as perforin and granzyme B), and apoptosis-promoting molecules (such as Fas Ligand). It is believed that, similar to morbilliform rash, type IVc hypersensitivity may also be involved in SJS/TEN-like reactions [12,115,120][12][89][94]. Furthermore, the enhancement of co-stimulatory factors and dysfunction of Treg cells are also associated with SJS/TEN pathogenesis [12].

References

  1. Abdel-Wahab, N.; Shah, M.; Lopez-Olivo, M.A.; Suarez-Almazor, M.E. Use of Immune Checkpoint Inhibitors in the Treatment of Patients with Cancer and Preexisting Autoimmune Disease: A Systematic Review. Ann. Intern. Med. 2018, 168, 121–130.
  2. Barrios, D.M.; Do, M.H.; Phillips, G.S.; Postow, M.A.; Akaike, T.; Nghiem, P.; Lacouture, M.E. Immune checkpoint inhibitors to treat cutaneous malignancies. J. Am. Acad. Dermatol. 2020, 83, 1239–1253.
  3. Tivol, E.A.; Borriello, F.; Schweitzer, A.N.; Lynch, W.P.; Bluestone, J.A.; Sharpe, A.H. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 1995, 3, 541–547.
  4. Huang, C.; Zhu, H.X.; Yao, Y.; Bian, Z.H.; Zheng, Y.J.; Li, L.; Moutsopoulos, H.M.; Gershwin, M.E.; Lian, Z.X. Immune checkpoint molecules. Possible future therapeutic implications in autoimmune diseases. J. Autoimmun. 2019, 104, 102333.
  5. Alsaab, H.O.; Sau, S.; Alzhrani, R.; Tatiparti, K.; Bhise, K.; Kashaw, S.K.; Iyer, A.K. PD-1 and PD-L1 Checkpoint Signaling Inhibition for Cancer Immunotherapy: Mechanism, Combinations, and Clinical Outcome. Front. Pharmacol. 2017, 8, 561.
  6. Chinai, J.M.; Janakiram, M.; Chen, F.; Chen, W.; Kaplan, M.; Zang, X. New immunotherapies targeting the PD-1 pathway. Trends Pharmacol. Sci. 2015, 36, 587–595.
  7. Tawbi, H.A.; Schadendorf, D.; Lipson, E.J.; Ascierto, P.A.; Matamala, L.; Castillo Gutierrez, E.; Rutkowski, P.; Gogas, H.J.; Lao, C.D.; De Menezes, J.J.; et al. Relatlimab and Nivolumab versus Nivolumab in Untreated Advanced Melanoma. N. Engl. J. Med. 2022, 386, 24–34.
  8. Postow, M.A.; Sidlow, R.; Hellmann, M.D. Immune-Related Adverse Events Associated with Immune Checkpoint Blockade. N. Engl. J. Med. 2018, 378, 158–168.
  9. Johnson, D.B.; Chandra, S.; Sosman, J.A. Immune Checkpoint Inhibitor Toxicity in 2018. JAMA 2018, 320, 1702–1703.
  10. Geisler, A.N.; Phillips, G.S.; Barrios, D.M.; Wu, J.; Leung, D.Y.M.; Moy, A.P.; Kern, J.A.; Lacouture, M.E. Immune checkpoint inhibitor-related dermatologic adverse events. J. Am. Acad. Dermatol. 2020, 83, 1255–1268.
  11. Quach, H.T.; Johnson, D.B.; LeBoeuf, N.R.; Zwerner, J.P.; Dewan, A.K. Cutaneous adverse events caused by immune checkpoint inhibitors. J. Am. Acad. Dermatol. 2021, 85, 956–966.
  12. Watanabe, T.; Yamaguchi, Y. Cutaneous manifestations associated with immune checkpoint inhibitors. Front. Immunol. 2023, 14, 1071983.
  13. Chen, C.H.; Yu, H.S.; Yu, S. Cutaneous Adverse Events Associated with Immune Checkpoint Inhibitors: A Review Article. Curr. Oncol. 2022, 29, 2871–2886.
  14. Muhaj, F.; Karri, P.V.; Moody, W.; Brown, A.; Patel, A.B. Mucocutaneous adverse events to immune checkpoint inhibitors. Front. Allergy. 2023, 4, 1147513.
  15. Inno, A.; Metro, G.; Bironzo, P.; Grimaldi, A.M.; Grego, E.; Di Nunno, V.; Picasso, V.; Massari, F.; Gori, S. Pathogenesis, clinical manifestations and management of immune checkpoint inhibitors toxicity. Tumori 2017, 103, 405–421.
  16. Wang, D.Y.; Salem, J.E.; Cohen, J.V.; Chandra, S.; Menzer, C.; Ye, F.; Zhao, S.; Das, S.; Beckermann, K.E.; Ha, L.; et al. Fatal Toxic Effects Associated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-analysis. JAMA Oncol. 2018, 4, 1721–1728.
  17. Sibaud, V. Dermatologic Reactions to Immune Checkpoint Inhibitors: Skin Toxicities and Immunotherapy. Am. J. Clin. Dermatol. 2018, 19, 345–361.
  18. Collins, L.K.; Chapman, M.S.; Carter, J.B.; Samie, F.H. Cutaneous adverse effects of the immune checkpoint inhibitors. Curr. Probl. Cancer. 2017, 41, 125–128.
  19. Wongvibulsin, S.; Pahalyants, V.; Kalinich, M.; Murphy, W.; Yu, K.H.; Wang, F.; Chen, S.T.; Reynolds, K.; Kwatra, S.G.; Semenov, Y.R. 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, 563–572.
  20. Brahmer, J.R.; Lacchetti, C.; Schneider, B.J.; Atkins, M.B.; Brassil, K.J.; Caterino, J.M.; Chau, I.; Ernstoff, M.S.; Gardner, J.M.; Ginex, P.; et al. Management of Immune-Related Adverse Events in Patients Treated with Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline. J. Clin. Oncol. 2018, 36, 1714–1768.
  21. Muntyanu, A.; Netchiporouk, E.; Gerstein, W.; Gniadecki, R.; Litvinov, I.V. Cutaneous Immune-Related Adverse Events (irAEs) to Immune Checkpoint Inhibitors: A Dermatology Perspective on Management . J. Cutan. Med. Surg. 2021, 25, 59–76.
  22. Curry, J.L.; Tetzlaff, M.T.; Nagarajan, P.; Drucker, C.; Diab, A.; Hymes, S.R.; Duvic, M.; Hwu, W.J.; Wargo, J.A.; Torres-Cabala, C.A.; et al. Diverse types of dermatologic toxicities from immune checkpoint blockade therapy. J. Cutan. Pathol. 2017, 44, 158–176.
  23. Bottlaender, L.; Amini-Adle, M.; Maucort-Boulch, D.; Robinson, P.; Thomas, L.; Dalle, S. Cutaneous adverse events: A predictor of tumour response under anti-PD-1 therapy for metastatic melanoma, a cohort analysis of 189 patients. J. Eur. Acad. Dermatol. Venereol. 2020, 34, 2096–2105.
  24. Chu, M.T.; Chang, W.C.; Pao, S.C.; Hung, S.I. Delayed Drug Hypersensitivity Reactions: Molecular Recognition, Genetic Susceptibility, and Immune Mediators. Biomedicines 2023, 11, 177.
  25. Pichler, W.J.; Adam, J.; Daubner, B.; Gentinetta, T.; Keller, M.; Yerly, D. Drug hypersensitivity reactions: Pathomechanism and clinical symptoms. Med. Clin. N. Am. 2010, 94, 645–664.
  26. Phillips, G.S.; Freites-Martinez, A.; Wu, J.; Chan, D.; Fabbrocini, G.; Hellmann, M.D.; Lacouture, M.E. Clinical Characterization of Immunotherapy-Related Pruritus Among Patients Seen in 2 Oncodermatology Clinics. JAMA Dermatol. 2019, 155, 249–251.
  27. Malviya, N.; Tattersall, I.W.; Leventhal, J.; Alloo, A. Cutaneous immune-related adverse events to checkpoint inhibitors. Clin. Dermatol. 2020, 38, 660–678.
  28. Sibaud, V.; Meyer, N.; Lamant, L.; Vigarios, E.; Mazieres, J.; Delord, J.P. Dermatologic complications of anti-PD-1/PD-L1 immune checkpoint antibodies. Curr. Opin. Oncol. 2016, 28, 254–263.
  29. Apalla, Z.; Papageorgiou, C.; Lallas, A.; Delli, F.; Fotiadou, C.; Kemanetzi, C.; Lazaridou, E. Cutaneous Adverse Events of Immune Checkpoint Inhibitors: A Literature Review. Dermatol. Pract. Concept. 2021, 11, e2021155.
  30. Sutaria, N.; Adawi, W.; Goldberg, R.; Roh, Y.S.; Choi, J.; Kwatra, S.G. Itch: Pathogenesis and treatment. J. Am. Acad. Dermatol. 2022, 86, 17–34.
  31. Yu, S.; Li, Y.; Zhou, Y.; Follansbee, T.; Hwang, S.T. Immune mediators and therapies for pruritus in atopic dermatitis and psoriasis. J. Cutan. Immunol. Allergy 2019, 2, 4–14.
  32. Goyette, P.; Boucher, G.; Mallon, D.; Ellinghaus, E.; Jostins, L.; Huang, H.; Ripke, S.; Gusareva, E.S.; Annese, V.; Hauser, S.L.; et al. High-density mapping of the MHC identifies a shared role for HLA-DRB1*01:03 in inflammatory bowel diseases and heterozygous advantage in ulcerative colitis. Nat. Genet. 2015, 47, 172–179.
  33. Hasan Ali, O.; Berner, F.; Bomze, D.; Fassler, M.; Diem, S.; Cozzio, A.; Jorger, M.; Fruh, M.; Driessen, C.; Lenz, T.L.; et al. Human leukocyte antigen variation is associated with adverse events of checkpoint inhibitors. Eur. J. Cancer 2019, 107, 8–14.
  34. Akturk, H.K.; Couts, K.L.; Baschal, E.E.; Karakus, K.E.; Van Gulick, R.J.; Turner, J.A.; Pyle, L.; Robinson, W.A.; Michels, A.W. Analysis of Human Leukocyte Antigen DR Alleles, Immune-Related Adverse Events, and Survival Associated with Immune Checkpoint Inhibitor Use Among Patients With Advanced Malignant Melanoma. JAMA Netw. Open 2022, 5, e2246400.
  35. Tison, A.; Garaud, S.; Chiche, L.; Cornec, D.; Kostine, M. Immune-checkpoint inhibitor use in patients with cancer and pre-existing autoimmune diseases. Nat. Rev. Rheumatol. 2022, 18, 641–656.
  36. Paternoster, L.; Standl, M.; Waage, J.; Baurecht, H.; Hotze, M.; Strachan, D.P.; Curtin, J.A.; Bonnelykke, K.; Tian, C.; Takahashi, A.; et al. Multi-ancestry genome-wide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis. Nat. Genet. 2015, 47, 1449–1456.
  37. Ellis, S.R.; Vierra, A.T.; Millsop, J.W.; Lacouture, M.E.; Kiuru, M. Dermatologic toxicities to immune checkpoint inhibitor therapy: A review of histopathologic features. J. Am. Acad. Dermatol. 2020, 83, 1130–1143.
  38. Apalla, Z.; Rapoport, B.; Sibaud, V. Dermatologic immune-related adverse events: The toxicity spectrum and recommendations for management. Int. J. Womens Dermatol. 2021, 7, 625–635.
  39. Tetzlaff, M.T.; Nagarajan, P.; Chon, S.; Huen, A.; Diab, A.; Omar, P.; Aung, P.P.; Torres-Cabala, C.A.; Mays, S.R.; Prieto, V.G.; et al. Lichenoid Dermatologic Toxicity from Immune Checkpoint Blockade Therapy: A Detailed Examination of the Clinicopathologic Features. Am. J. Dermatopathol. 2017, 39, 121–129.
  40. Schaberg, K.B.; Novoa, R.A.; Wakelee, H.A.; Kim, J.; Cheung, C.; Srinivas, S.; Kwong, B.Y. Immunohistochemical analysis of lichenoid reactions in patients treated with anti-PD-L1 and anti-PD-1 therapy. J. Cutan. Pathol. 2016, 43, 339–346.
  41. Shi, V.J.; Rodic, N.; Gettinger, S.; Leventhal, J.S.; Neckman, J.P.; Girardi, M.; Bosenberg, M.; Choi, J.N. 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, 1128–1136.
  42. Yamamoto, T. Skin Manifestation Induced by Immune Checkpoint Inhibitors. Clin. Cosmet. Investig. Dermatol. 2022, 15, 829–841.
  43. Lage, D.; Juliano, P.B.; Metze, K.; de Souza, E.M.; Cintra, M.L. Lichen planus and lichenoid drug-induced eruption: A histological and immunohistochemical study. Int. J. Dermatol. 2012, 51, 1199–1205.
  44. Niesert, A.; Guertler, A.; Schutti, O.; Engels, L.; Flaig, M.; French, L.; Schlaak, M.; Reinholz, M. Ulcerated Lichen Planus after Adjuvant Use of Programmed Cell Death-1-Inhibitor: A Case Report and Systematic Review of the Literature. Acta Derm. Venereol. 2021, 101, adv00472.
  45. Maarouf, M.; Alexander, C.; Shi, V.Y. Nivolumab reactivation of hypertrophic lichen planus, a case report and review of published literature. Dermatol. Online J. 2018, 24, 9.
  46. Guggina, L.M.; Yanes, D.A.; Choi, J.N. Inverse lichenoid drug eruption associated with nivolumab. JAAD Case Rep. 2017, 3, 7–9.
  47. Wakade, D.V.; Carlos, G.; Hwang, S.J.; Chou, S.; Hui, R.; Fernandez-Penas, P. PD-1 inhibitors induced bullous lichen planus-like reactions: A rare presentation and report of three cases. Melanoma Res. 2016, 26, 421–424.
  48. Biolo, G.; Caroppo, F.; Salmaso, R.; Alaibac, M. Linear bullous lichen planus associated with nivolumab. Clin. Exp. Dermatol. 2019, 44, 67–68.
  49. Komatsu-Fujii, T.; Nakajima, S.; Iwata, M.; Kataoka, T.; Hirata, M.; Nomura, T.; Kabashima, K. Upregulated programmed death ligand 1 expression in nivolumab-induced lichen nitidus: A follow-up report with an immunohistochemical analysis. J. Dermatol. 2020, 47, e319–e320.
  50. Zhou, G.; Zhang, J.; Ren, X.W.; Hu, J.Y.; Du, G.F.; Xu, X.Y. Increased B7-H1 expression on peripheral blood T cells in oral lichen planus correlated with disease severity. J. Clin. Immunol. 2012, 32, 794–801.
  51. Anegawa, H.; Otsuka, A.; Kaku, Y.; Nonomura, Y.; Fujisawa, A.; Endo, Y.; Kabashima, K. Upregulation of granzyme B and interferon-gamma mRNA in responding lesions by treatment with nivolumab for metastatic melanoma: A case report. J. Eur. Acad. Dermatol. Venereol. 2016, 30, e231–e232.
  52. Yawalkar, N.; Pichler, W.J. Mechanisms of cutaneous drug reactions. J. Dtsch. Dermatol. Ges. 2004, 2, 1013–1023.
  53. Yawalkar, N.; Pichler, W.J. Immunohistology of drug-induced exanthema: Clues to pathogenesis. Curr. Opin. Allergy Clin. Immunol. 2001, 1, 299–303.
  54. Curry, J.L.; Reuben, A.; Szczepaniak-Sloane, R.; Ning, J.; Milton, D.R.; Lee, C.H.; Hudgens, C.; George, S.; Torres-Cabala, C.; Johnson, D.; et al. Gene expression profiling of lichenoid dermatitis immune-related adverse event from immune checkpoint inhibitors reveals increased CD14(+) and CD16(+) monocytes driving an innate immune response. J. Cutan. Pathol. 2019, 46, 627–636.
  55. Bonigen, J.; Raynaud-Donzel, C.; Hureaux, J.; Kramkimel, N.; Blom, A.; Jeudy, G.; Breton, A.L.; Hubiche, T.; Bedane, C.; Legoupil, D.; et al. Anti-PD1-induced psoriasis: A study of 21 patients. J. Eur. Acad. Dermatol. Venereol. 2017, 31, e254–e257.
  56. De Bock, M.; Hulstaert, E.; Kruse, V.; Brochez, L. Psoriasis Vulgaris Exacerbation during Treatment with a PD-1 Checkpoint Inhibitor: Case Report and Literature Review. Case Rep. Dermatol. 2018, 10, 190–197.
  57. Nikolaou, V.; Sibaud, V.; Fattore, D.; Sollena, P.; Ortiz-Brugues, A.; Giacchero, D.; Romano, M.C.; Riganti, J.; Lallas, K.; Peris, K.; 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, 1310–1320.
  58. Ruiz-Banobre, J.; Abdulkader, I.; Anido, U.; Leon, L.; Lopez-Lopez, R.; Garcia-Gonzalez, J. Development of de novo psoriasis during nivolumab therapy for metastatic renal cell carcinoma: Immunohistochemical analyses and clinical outcome. APMIS 2017, 125, 259–263.
  59. Balak, D.M.; Hajdarbegovic, E. Drug-induced psoriasis: Clinical perspectives. Psoriasis 2017, 7, 87–94.
  60. Lowes, M.A.; Russell, C.B.; Martin, D.A.; Towne, J.E.; Krueger, J.G. The IL-23/T17 pathogenic axis in psoriasis is amplified by keratinocyte responses. Trends Immunol. 2013, 34, 174–181.
  61. Barrea, L.; Macchia, P.E.; Tarantino, G.; Di Somma, C.; Pane, E.; Balato, N.; Napolitano, M.; Colao, A.; Savastano, S. Nutrition: A key environmental dietary factor in clinical severity and cardio-metabolic risk in psoriatic male patients evaluated by 7-day food-frequency questionnaire. J. Transl. Med. 2015, 13, 303.
  62. Yu, S.; Wu, X.; Zhou, Y.; Sheng, L.; Jena, P.K.; Han, D.; Wan, Y.J.Y.; Hwang, S.T. A Western Diet, but Not a High-Fat and Low-Sugar Diet, Predisposes Mice to Enhanced Susceptibility to Imiquimod-Induced Psoriasiform Dermatitis. J. Investig. Dermatol. 2019, 139, 1404–1407.
  63. Yu, S.; Wu, X.; Shi, Z.; Huynh, M.; Jena, P.K.; Sheng, L.; Zhou, Y.; Han, D.; Wan, Y.Y.; Hwang, S.T. Diet-induced obesity exacerbates imiquimod-mediated psoriasiform dermatitis in anti-PD-1 antibody-treated mice: Implications for patients being treated with checkpoint inhibitors for cancer. J. Dermatol. Sci. 2020, 97, 194–200.
  64. de Golian, E.; Kwong, B.Y.; Swetter, S.M.; Pugliese, S.B. Cutaneous Complications of Targeted Melanoma Therapy. Curr. Treat. Options Oncol. 2016, 17, 57.
  65. Hua, C.; Boussemart, L.; Mateus, C.; Routier, E.; Boutros, C.; Cazenave, H.; Viollet, R.; Thomas, M.; Roy, S.; Benannoune, N.; et al. Association of Vitiligo with Tumor Response in Patients With Metastatic Melanoma Treated with Pembrolizumab. JAMA Dermatol. 2016, 152, 45–51.
  66. Teulings, H.E.; Limpens, J.; Jansen, S.N.; Zwinderman, A.H.; Reitsma, J.B.; Spuls, P.I.; Luiten, R.M. 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, 773–781.
  67. Yun, S.J.; Oh, I.J.; Park, C.K.; Kim, Y.C.; Kim, H.B.; Kim, H.K.; Hong, A.R.; Kim, I.Y.; Ahn, S.J.; Na, K.J.; et al. Vitiligo-like depigmentation after pembrolizumab treatment in patients with non-small cell lung cancer: A case report. Transl. Lung Cancer Res. 2020, 9, 1585–1590.
  68. Yin, E.S.; Totonchy, M.B.; Leventhal, J.S. Nivolumab-associated vitiligo-like depigmentation in a patient with acute myeloid leukemia: A novel finding. JAAD Case Rep. 2017, 3, 90–92.
  69. Liu, R.C.; Consuegra, G.; Chou, S.; Fernandez Penas, P. Vitiligo-like depigmentation in oncology patients treated with immunotherapies for nonmelanoma metastatic cancers. Clin. Exp. Dermatol. 2019, 44, 643–646.
  70. Guida, M.; Strippoli, S.; Maule, M.; Quaglino, P.; Ramondetta, A.; Chiaron Sileni, V.; Antonini Cappellini, G.; Queirolo, P.; Ridolfi, L.; Del Vecchio, M.; et al. Immune checkpoint inhibitor associated vitiligo and its impact on survival in patients with metastatic melanoma: An Italian Melanoma Intergroup study. ESMO Open 2021, 6, 100064.
  71. Lommerts, J.E.; Bekkenk, M.W.; Luiten, R.M. Vitiligo induced by immune checkpoint inhibitors in melanoma patients: An expert opinion. Expert Opin. Drug Saf. 2021, 20, 883–888.
  72. Larsabal, M.; Marti, A.; Jacquemin, C.; Rambert, J.; Thiolat, D.; Dousset, L.; Taieb, A.; Dutriaux, C.; Prey, S.; Boniface, K.; 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, 863–870.
  73. Gault, A.; Anderson, A.E.; Plummer, R.; Stewart, C.; Pratt, A.G.; Rajan, N. Cutaneous immune-related adverse events in patients with melanoma treated with checkpoint inhibitors. Br. J. Dermatol. 2021, 185, 263–271.
  74. Weber, J.S.; Kahler, K.C.; Hauschild, A. Management of immune-related adverse events and kinetics of response with ipilimumab. J. Clin. Oncol. 2012, 30, 2691–2697.
  75. Siegel, J.; Totonchy, M.; Damsky, W.; Berk-Krauss, J.; Castiglione, F., Jr.; Sznol, M.; Petrylak, D.P.; Fischbach, N.; Goldberg, S.B.; Decker, R.H.; 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, 1081–1088.
  76. Hanley, T.; Papa, S.; Saha, M. Bullous pemphigoid associated with ipilimumab therapy for advanced metastatic melanoma. JRSM Open 2018, 9, 2054270418793029.
  77. Kuwatsuka, Y.; Iwanaga, A.; Kuwatsuka, S.; Okubo, Y.; Murayama, N.; Ishii, N.; Hashimoto, T.; Utani, A. Bullous pemphigoid induced by ipilimumab in a patient with metastatic malignant melanoma after unsuccessful treatment with nivolumab. J. Dermatol. 2018, 45, e21–e22.
  78. Singer, S.; Nelson, C.A.; Lian, C.G.; Dewan, A.K.; LeBoeuf, N.R. Nonbullous pemphigoid secondary to PD-1 inhibition. JAAD Case Rep. 2019, 5, 898–903.
  79. Kuo, A.M.; Markova, A. High Grade Dermatologic Adverse Events Associated with Immune Checkpoint Blockade for Cancer. Front. Med. 2022, 9, 898790.
  80. Naidoo, J.; Schindler, K.; Querfeld, C.; Busam, K.; Cunningham, J.; Page, D.B.; Postow, M.A.; Weinstein, A.; Lucas, A.S.; Ciccolini, K.T.; et al. Autoimmune Bullous Skin Disorders with Immune Checkpoint Inhibitors Targeting PD-1 and PD-L1. Cancer Immunol. Res. 2016, 4, 383–389.
  81. Tsiogka, A.; Bauer, J.W.; 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.
  82. Hammers, C.M.; Stanley, J.R. Mechanisms of Disease: Pemphigus and Bullous Pemphigoid. Annu. Rev. Pathol. 2016, 11, 175–197.
  83. Abdel-Wahab, N.; Diab, A.; Yu, R.K.; Futreal, A.; Criswell, L.A.; Tayar, J.H.; Dadu, R.; Shannon, V.; Shete, S.S.; Suarez-Almazor, M.E. Genetic determinants of immune-related adverse events in patients with melanoma receiving immune checkpoint inhibitors. Cancer Immunol. Immunother. 2021, 70, 1939–1949.
  84. Muller, R.; Heber, B.; Hashimoto, T.; Messer, G.; Mullegger, R.; Niedermeier, A.; Hertl, M. Autoantibodies against desmocollins in European patients with pemphigus. Clin. Exp. Dermatol. 2009, 34, 898–903.
  85. Keerty, D.; Koverzhenko, V.; Belinc, D.; LaPorta, K.; Haynes, E. Immune-Mediated Toxic Epidermal Necrolysis. Cureus 2020, 12, e9587.
  86. Maloney, N.J.; Ravi, V.; Cheng, K.; Bach, D.Q.; Worswick, S. Stevens-Johnson syndrome and toxic epidermal necrolysis-like reactions to checkpoint inhibitors: A systematic review. Int. J. Dermatol. 2020, 59, e183–e188.
  87. Chirasuthat, P.; Chayavichitsilp, P. Atezolizumab-Induced Stevens-Johnson Syndrome in a Patient with Non-Small Cell Lung Carcinoma. Case Rep. Dermatol. 2018, 10, 198–202.
  88. Raschi, E.; Antonazzo, I.C.; La Placa, M.; Ardizzoni, A.; Poluzzi, E.; De Ponti, F. Serious Cutaneous Toxicities with Immune Checkpoint Inhibitors in the U.S. Food and Drug Administration Adverse Event Reporting System. Oncologist 2019, 24, e1228–e1231.
  89. Chen, C.B.; Wu, M.Y.; Ng, C.Y.; Lu, C.W.; Wu, J.; Kao, P.H.; Yang, C.K.; Peng, M.T.; Huang, C.Y.; Chang, W.C.; et al. Severe cutaneous adverse reactions induced by targeted anticancer therapies and immunotherapies. Cancer Manag. Res. 2018, 10, 1259–1273.
  90. Bhardwaj, M.; Chiu, M.N.; Pilkhwal Sah, S. Adverse cutaneous toxicities by PD-1/PD-L1 immune checkpoint inhibitors: Pathogenesis, treatment, and surveillance. Cutan. Ocul. Toxicol. 2022, 41, 73–90.
  91. Salati, M.; Pifferi, M.; Baldessari, C.; Bertolini, F.; Tomasello, C.; Cascinu, S.; Barbieri, F. Stevens-Johnson syndrome during nivolumab treatment of NSCLC. Ann. Oncol. 2018, 29, 283–284.
  92. Saw, S.; Lee, H.Y.; Ng, Q.S. Pembrolizumab-induced Stevens-Johnson syndrome in non-melanoma patients. Eur. J. Cancer 2017, 81, 237–239.
  93. Vivar, K.L.; Deschaine, M.; Messina, J.; Divine, J.M.; Rabionet, A.; Patel, N.; Harrington, M.A.; Seminario-Vidal, L. Epidermal programmed cell death-ligand 1 expression in TEN associated with nivolumab therapy. J. Cutan. Pathol. 2017, 44, 381–384.
  94. Goldinger, S.M.; Stieger, P.; Meier, B.; Micaletto, S.; Contassot, E.; French, L.E.; Dummer, R. Cytotoxic Cutaneous Adverse Drug Reactions during Anti-PD-1 Therapy. Clin. Cancer Res. 2016, 22, 4023–4029.
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