2025+EADV专案组声明：皮肤免疫相关不良事件的预防和处理

其他综合与多学科· 未分类与其他 · 2025

Correspondence

Davide Fattore, Section of Dermatology,Department of Clinical Medicine and Surgery,University of Naples Federico II, Via S.Pansini 5, Naples, Italy.Email:dott.davidefattore@gmail.com

Abstract

Cancer immunotherapy, particularly immune checkpoint inhibitors(ICI), has revo-lutionized oncology treatment by leveraging the immune system to recognize and eliminate cancer cells. However, despite its efficacy, immunotherapy may induce immune-related adverse events(irAEs), including dermatological events, that can range from mild rashes to severe life-threatening conditions such as toxic epidermal necrolysis. This paper aims to explore and analyse the preventive measures for cuta-neous irAEs(cirAEs). By identifying risk factors, recognizing early signs and imple-menting preventive strategies, healthcare professionals can significantly mitigate the severity of irAEs, thereby improving patient outcomes and quality of life.

KEYWORDS

immune checkpoint inhibitors,immune-related adverse events,immunotherapy,ipilimumab,nivolumab,onoddermatology,pembrolizumab,preventative strategies

INTRODUCTION

The emergence of immune checkpoint inhibitors(ICI) has opened new horizons in cancer treatment, significantly im-proving survival rates for patients with advanced cancers.While it is considered a game-changer in oncology, it also leads to immune-related adverse events(irAEs),including der-matological toxicities.2 Dermatologic AEs are frequently one of the most common manifestations of irAEs and can precede more serious systemic complications.3,4 With this review, we aimed to capture the landscape of cutaneous irAEs(cirAEs),to describe the risk factors related to them, and recommend evidence-based preventive strategies that can be employed to reduce their occurrence and mitigate their impact.

# Risk factors for dermatologic adverse events

# Genetic predisposition

Patients with a history of autoimmune diseases or a family history of autoimmune conditions may be more susceptible to developing irAEs, including skin toxicities. Risk factors include personal or family history of the disease, personal or family history of thyroid disease or other autoimmune disease, or multiple halo nevi for vitiligo. 6 Studies have linked certain HLA alleles to a higher incidence of derma-tologic irAEs. Hasan Ali et al. described an increased risk of pruritus in melanoma patients with HLA-DRB1*11:01 during ICI therapy.

$$\text{ PREVENTATIVE STRATEGIES OF AER}$$

# Pre-existing skin conditions

Patients with pre-existing dermatologic conditions such as psoriasis, eczema or alopecia are at increased risk of exacerba-tion during immunotherapy.8 The development of ICI-related oral toxicities is multifactorial and unpredictable. However, it is important to emphasize that poor oral hygiene, periodon-titis, tobacco consumption, pre-existing autoimmune disease with oral involvement, history of head and neck radiation therapy, may contribute to the development or reinforcement of oral toxicity. However, not all such patients experience ex-cerabations and they should not prevent patients from starting ICI. There is a clear need for stratification based on disease activity, concurrent therapies and immune profiles.9,10

# Specific cancer types

Melanoma patients are notably prone to developing vitiligo-like depigmentation, possibly due to shared antigens be-tween melanocytes and melanoma cells.

Combination therapy

Patients receiving combination therapy, such as anti-PD-1 and anti-CTLA-4 agents, often experience more severe and frequent dermatologic AEs due to heightened immune acti-vation." Recent translational studies suggest these are not merely due to heightened systemic immune activation but involve specific immunopathogenic mechanisms. For ex-ample, lichenoid dermatitis-commonly observed in these patients-has been linked to the expansion and activation of skin-resident memory T cells, particularly CD8+ CD103+populations, which may be reactivated in the context of checkpoint inhibition.12

# Influence of age, sex and ethnicity

The role of non-modifiable factors on the occurrence of cirAEs remains unclear. McCormack et al.13 conducted a ret-rospective study of patients aged 0-21 years. They found the occurrence of cirAEs in 32% of patients, maculopapular reac-tion in 50% of cases, followed by pruritus and vitiligo in 8% of patients. Instead, Thompson et al.14 studied the population of patients with sarcoma and treated with ICI from 2010 to 2019 in the same hospital. They found no statistically significant differences between adult and paediatric patients in terms of incidence and characterization of cirAEs. Regarding gender,Regarding gender, women generally experience a higher rate and distinct patterns of irAEs compared to men, primarily due to variations in immune regulatory pathways and hor-monal influences.15 Bui et al. observed in a population of 235 adults with melanoma and treated with ICI a higher risk of occurrence of cirAEs among female patients compared with the male group, with odds ratio(OR) 2.1.15 While this finding

Why was the study undertaken?

● Immunotherapy has transformed cancer treat-ment.Checkpoint inhibitors can trigger immune-related skin reactions. These reactions range from mild rashes to life-threatening events. The study examines how to prevent cutaneous irAEs(cirAEs) to improve outcomes and quality of life.

What does this study add?

● The manuscript reviews the epidemiological characteristics and risk factors of cirAEs. It then describes for each of them the most recent up-dates in their management.

What are the implications of this study for disease understanding and/or clinical care?

● Dermatologists must recognize and manage cirAEs effectively. Proper care may prevent can-cer treatment discontinuation. Management strategies can improve cancer patients' quality of life. In this regard, the manuscript also aims to portray preventive strategies for cirAEs.

raises important questions about sex-based immunological differences, several limitations must be considered before drawing causal inferences. First, the retrospective nature of the study raises the possibility of reporting bias, as women may be more likely to report mild dermatologic symptoms or seek dermatologic consultation than men. Additionally,the study did not control for hormonal status(e.g., meno-pausal vs. premenopausal),body surface area or concomitant medications, all of which could confound the observed sex differences. Finally, it remains unclear whether ethnicity may influence the incidence of cirAEs. Thompson et al. observed that among patients receiving ICI, non-Whites were half as likely to be diagnosed with cirAEs(OR=0.501) but were re-ferred to the dermatologist about six times more often than Whites.16 This is probably due to the lesser characterization of dermatologic diseases in this population, thus more studies on the topic are needed.

Family history

Rather than broadly noting a family history of autoimmune disease, a more refined stratification-based on the degree of relatedness, specific autoimmune conditions(e.g.,vitiligo,lupus, psoriasis) and early disease onset in relatives-could improve risk modelling. While these parameters have been individually associated with increased autoimmune suscep-tibility, their predictive value for cirAEs specifically remains to be formally validated.17-19

FATTORE ET AL.

Preventive strategies for irAEs

Prevention of irAEs requires a multifaceted approach that includes risk assessment, patient education, skin monitoring and early intervention.

Pre-treatment counselling and risk assessment

Before initiating immunotherapy, patients should undergo a thorough dermatologic evaluation, particularly if they have a history of autoimmune diseases or pre-existing skin condi-tions. A detailed explanation of potential dermatologic AEs and their warning signs should be provided to the patient.Patients should also be encouraged to report any new or worsening skin symptoms early.20

Prophylactic skincare regimens

Regular use of emolients and moisturizers can help main-tain skin barrier integrity and prevent xerosis, which is com-monly associated with pruritus. Gentle skin rare routines,such as using mild, fragrance-free cleansers and avoiding excessive sun exposure, should also be advised. Emolliers such as petrolatum or ceramide-based creams help to re-store the skin barrier and prevent xerosis, which can exac-erbate itching. Using lukewarm water for baths or showers instead of hot water may be beneficial 21-23 Additionally, sun protection measures, including broad-spectrum sunscreen and protective clothing, are essential to reduce the risk of photosensitivity reactions, which are sometimes triggered by ICI.24 These precautions are also useful in preventing maculopapular rash, although its mechanisms are not fully elucidated.

Topical corticosteroids and immunosuppressive agents

Patients with pre-existing dermatosis may benefit from the use of mid- and high-potency corticosteroids to prevent their worsening that may be related to irAEs. Calcineurin inhibitors, such as tacrolimus, can also be considered for these patients, providing localized immunosuppres-sion without the systemic effects associated with oral corticosteroids.

Management of pre-existing skin conditions

Patients with chronic skin conditions should work closely with their dermatologists before starting immunotherapy to optimize control of their disease. The decision regarding the continuation of a systemic treatment, including biologic agents, should be made on an individual basis, case by case,in collaboration with the oncologist. Close monitoring and

early intervention at the first sign of exacerbation can pre-vent more severe manifestations.25 As psoriasis, lichenoid reactions and vitiligo may be exacerbated by the Koebner phenomenon, patients should also avoid scratching and minor trauma on the skin.

Regular dermatologic monitoring

For patients with pre-existing skin conditions, routine skin examinations should be conducted throughout the course of immunotherapy, with increased vigilance in the first 12 weeks when most AEs occur.26 For those with no relevant medical history, they should be regularly and actively re-ferred to the oncologist for the development of any type of dermatologic AE.

Interdisciplinary collaboration

A team-based approach is essential in managing and prevent-ing cirAEs. Oncologists, dermatologists and nursing staff should work together to promptly recognize and treat any skin-related toxicities. Collaboration ensures that treatment changes, such as dose adjustments or temporary discontinua-tion of ICI, are made in a timely manner, preventing irrevers-ible damage or severe systemic complications.27 For example,increasing patients' awareness of potential hair disorders re-lated to ICI may facilitate early detection and prompt interven-tion. This proactive approach, involving collaboration with the oncology team, is essential for achieving optimal outcomes and minimizing the impact on patients' quality of life.

METHODS

This Position Statement was developed by the EADV Task Force through a comprehensive literature review and ex-pert consensus. Relevant studies published in peer-reviewed journals up to 2025 were reviewed using databases such as PubMed and Embase. In addition, expert opinions and clinical experience were incorporated to formulate practical recommendations for the prevention of cirAEs in patients undergoing immunotherapy. The draft was reviewed and revised through collaborative discussions and consensus meetings among task force members.

COMMON DERMATOLOGICAL ADVERSE EVENTS IN CANCER IMMUNOTHERAPY

Pruritus

Pruritus is a common AE during immunotherapy, often oc-curring even without visible skin lesions and significantly impairing quality of life.28

PREVENTATIVE STRATEGIES OF AER

Epidemiology

Pruritus is the most frequently reported cirAE, affecting about one-third of patients.29 A meta-analysis found that 13% of patients treated with nivolumab and 20% with pem-brolizumab experienced pruritus of any grade.30 The inci-dence rises to 47% with ipilimumab-based combination therapies.31

Prognosis of skin toxicity

Most cases are mild and manageable with appropriate treat-ment. However, severe pruritus can require treatment modi-fications or discontinuation, potentially affecting oncologic outcomes.32,33 Interestingly, recent studies suggest that developing cirAEs, including pruritus, correlates with im-proved overall survival(OS) and progression-free survival(PFS) in patients receiving ICI.34 A meta-analysis showed reduced mortality risk in patients with cirAEs(hazard ratio[HR]=0.61 for OS, HR=0.52 for PFS), across various cancer types and treatments, suggesting a potential positive prog-nostic role.34

Updates in management

ICI can be continued in most patients, and it is rarely nec-essary to interrupt or discontinue ICI. Furthermore, to re-duce the decline in quality of life, proper management and counselling are essential(Table 1). Topical medications that can be accompanied by oral antihistamines are rec-ommended for mild pruritus, whereas GABA analogs can be added in moderate pruritus.35 For refractory grade 2 or severe pruritus, additional immune-modulating treatments such as dupilumab,36 a monoclonal antibody targeting IL-4 and IL-13, should be considered as steroid-sparing agents to minimize the negative impact of broad immunosuppression as observed with oral corticosteroids. Omalizumab, an anti-IgE approved for chronic spontaneous urticaria, also showed positive results against cirAEs-related pruritus.37

Maculopapular rash

Maculopapular rash(MR) is among the most common cu-taneous irAEs, typically presenting within the first weeks of treatment and often accompanied by pruritus.38

Epidemiology

MR affects up to 68% of patients treated with anti-CTLA-4 agents and up to 20% of those on anti-PD-1/PD-L1 thera-pies.39 It usually appears within 3-6 weeks of treatment ini-tiation but can also develop later.11,40 The rash commonly

involves the trunk and proximal limbs, sparing the face in most cases.11,30,40 Pruritus is frequently reported.

Prognosis of skin toxicity

MR is generally mild and self-limited. Grades 1-2 forms,affecting less than 30% of body surface area(BSA), are most common. Severe forms(grade≥3) are rare, occur-ring in less than 4% of cases.41 Dermatologic assessment is advised in severe or atypical cases or if refractory to initial treatment.6 The prognostic significance of MR remains uncertain.

Updates in management

Grade 1 treatment is symptomatic and relies on the use of topical moisturizers and topical potent or super-potent cor-ticosteroids applied to the affected areas.6,42 In Grade 2 reac-tions, the addition of oral antihistamines is recommended.G.42 Patients can continue immunotherapy up to Grade 3.6,42 In Grades 1-2 reactions, patients should be re-evaluated 2-4 weeks after the start of dermatological therapy, and in the event of worsening or persistence of the eruption, it is necessary to switch to therapies of the next degree of sever-ity.6 Systemic corticosteroids(0.5-1 mg/kg/day of prednisone equivalent) are recommended for Grade 3 rashes and only after ruling out other cirAEs requiring specific management(e.g.,psoriasis).6,42,43 Finally,in Grade 4 rash,immunotherapy should be discontinued and methylprednisolone 2 mg/kg/day should be administered together with urgent supportive measures.6,42,43 Preventative recommendations and man-agement algorithms with levels of evidence are provided in Table 2. Practical management algorithms for pruritus and maculopapular rash are provided in Figures 1 and 2.

Psoriasis

Psoriasis is a well-recognized irAE, mainly associated with PD-1 and PD-L1 blockade.44 It may worsen pre-existing disease or trigger de novo cases, typically present-ing as plaque psoriasis, with less frequent scalp and nail involvement.

Epidemiology

ICI-induced psoriasis has an estimated incidence of around 3%45,46 and has a twofold increase in risk.4 Both flares of pre-existing psoriasis and new-onset cases occur with similar fre-quency.47 A meta-analysis reported psoriasis flares in 45% of patients with pre-existing disease on ICI, with 18.5% requiring treatment discontinuation.48 Notably, patients with prior pso-riasis tend to flare earlier than those with de novo psoriasis.

FATTORE ET AL.

TABLE 1 Pruritus: preventative recommendations and management algorithm.

|Severity (CTCAE v5.0)|Intervention|LoE|GoR| |---|---|---|---| |Prevention|If history of pruritus or pruritus skin disorder $$\begin{array}[]{l}\text{Consider dermatology referral}\\ \text{ around treatment start}\\ \end{array}$$ Fragrance-free moisturizers and soap free cleansers Start ICI|V|B| |Grade 1 Mild or localized; topical intervention|Skin-directed therapy|V|B| |indicated|Euse of potent topical steroids (e.g.triaminolone 0.1% or mometasone fuorate 0.1% cream odin pruritic areas) Systemic therapy|IV|B| ||Consider non-sedating antihistamines such as cetirizine 10mg,loratodine 10mg or bilastine 20mg(once a day), withdraw if no effect after 1 week|V|B| ||Continue ICI at current dose||| |Grade 2 Widespread and intermittent; skin soap free cleansers|Skin-directed therapy||Multidisciplinary decision to hold or discontinue to lCI(at least| |scratching (e.g., edema, papula- tion, excoriations, lichenification, oozing/crusts); oral intervention|Use of potent operant steroids (e.g.traincinolone 0.1% or cobatolus 0.05% cream od-bidin pruritic areas)|IV|B|

oral intervention indicated; limiting instrumental ADL

Systemic therapy

Non-sedating antihistamines such as cetrizine 10mg,loratadine 10mg or bilastine 20mg(once a day)

Consider replacing antihistamines with GABA analogs, e.g. gabapentin 100-300mg tid or pregabalin, 50-100mg tid (itrate)

Continue ICI at current dose

Persistent Grade 2 Additional systemic anti-itch

Consider neurokinine 1 receptor antagonists e.g. aprepitant 1256 day 1,80mg day 3,80mg day 5

and

Consider dupilumab(600mg s.c.followed by 300mg s.c.q.2 weeks)

Consider omalizumab 300 mg s.c. every 4 weeks*

Reassess after 2-4 weeks, if worsening or no improvement,proceed to next step

|Severity (CTCAE v5.0)|Intervention|Intervention|LoE|GoR| |---|---|---|---|---| |Grade 3|Skin-directed therapy|Skin-directed therapy||| |Widespread and constant; limiting self care ADL or sleep; systemic corticosteroid or immunosuppressive therapy indicated|Use of potent or superpotent topical steroids(e.g. traincinolone 0.1% or clobetasol 0.05% cream bid per day in pruritic areas) Systemic therapy|IV 0.05% cream bid per day in pruritic areas) Systemic therapy|B 0.05% cream bid per day in pruritic areas) Systemic therapy|A 0.05% cream bid per day in pruritic areas) Systemic therapy| ||Consider course of systemic corticosteroids(e.g. prednisone 0.5-1mg/kg body weight/day, 14-day taper)a|IV 0.5-1mg/kg body weight/day, 14-day taper)a||| ||GABA analogs, e.g.gabapentin 100-300mg tid or pregabalin, 50-100mg tid(titrate)|IV 100-300mg tid or pregabalin, 50-100mg tid(titrate)|B|B| ||and|||| ||Consider dupilumab(600mg s.c. followed by 300mg s.. q 2 weeks)a|IV 0|IV 0|A| ||or|||| ||Consider omalizumab 300 mg s.c. every 4 weeks°|IV 0|IV 0|B| ||Multidisciplinary decision to hold or discontinue ICI(at least improvement to G1/G2)||||

Skin-directed treatment can be maintained with systemic treatment,as needed.

*Prior to initiation of systemic immune-modulators(including predni-sone and omalizumab),a skin biopsy with direct immunofluorescence is recommended.

Levels of evidence and grades of recommendation(Adapted from the

Infectious Diseases Society of America-United States Public Health Service Grading System).

Levels of evidence

1 Evidence from at least one large randomized, controlled trial of good methodological quality(low potential for bias) or meta-analyses of well conducted randomized trials without heterogeneity

II Small randomized trials or large randomized trials with a suspicion of bias(lower methodological quality) or meta-analyses of such trials or of trials demonstrated heterogeneity

Ⅲ Prospective cohort studies

IV| Retrospective cohort studies or case-control studies

V Studies without control group, case reports, expert opinions

Grades of recommendation

A Strong evidence for efficacy with a substantial clinical benefit,strongly recommended

B Strong or moderate evidence for efficacy but with a limited clinical benefit, generally recommended

C Insufficient evidence for efficacy or benefit does not outweigh the risk or the disadvantages(adverse events, costs),optional

D Moderate evidence against efficacy or for adverse outcome,generally not recommended

PREVENTATIVE STRATEGIES OF AER

TABLE 2 Maculopapular rash: preventative recommendations and management algorithm.

|Severity(CTAE v5.0)|Preventative measures|Management|LoE|GoR| |---|---|---|---|---| |Grade 1|Use of cleansing oil,|Skin-directed therapy|IV|A| |macules/papules covering<10% BSA with or without symptoms(e.g., pruritus, burning)|moisturising and emolient creams|Potent or superpotent topical corticosteroids (e.g.,betamethasone dipropionate 0.05%, triamcinolone0.1% or clobetasol 0.05% cream, over the skinlesions)||| ||Protect skin from any kind of physical and/or chemical damage|Oral antihistamines- fragrance-free moisturizers(applied to full body surface) Continue ICI at current dose||| |||Reassess after 2-4 weeks; if reactions worsen or donot improve, proceed to next step||| |Grade 2'|Use of cleansing oil, maculisering and emolient|Skin-directed therapy|IV|A| |macules/papules covering 10-30% BSA with or without symptoms(e.g., pruritus, burning);limiting instrumental ADL; rash covering>30% BSAwith or without mild symptoms|protect skin from any kind of physical and/or chemical damage|Potent or superpotent topical corticosteroids(e.g. betamethasone dipropionate 0.05%, triamcinolone0.1% or clobetasol 0.05% cream, over the skin lesions) Oral antihistamines- fragrance-free moisturizers(applied to full body surface)||| |||Continue ICI at current dose||| |||Reassess after 2-4 weeks; if reactions worsen or donot improve, proceed to next step||| |Persistent or intolerable grade 2t|Use of cleansing oil, moisturising and emolient creams|Reinforce grade 2 management|IV|B| |Or|moisturising and emolient|Consider oral corticosteroids(0.5-1 mg/kg/day orequivalent with dose increase up to 2 mg/kg/day ifno improvement1t)||| |Grade 3t|Protect skin from any kind of physical and/or chemical damage|Withhold ICI||| |macules/papules covering>30% BSA withmoderate or severe symptoms(e.g., pruritus,||Reassess after 2-4 weeks: If avoid erivalent|4|A| |burning); limiting self-care ADL|burning); limiting self-care ADL|if reactions worsen or do not next step. if reactions improve, start oral corticosteroids tapering. Rechallenge ICI when Grade 1, and after tapering oral corticosteroids at a dose ≤10 mg/day|5|B| |Grade 4t|Use of cleansing oil,|Methylprednisolone 2 mg/kg/day or equivalent|IV|B| |Life-threatening consequences, urgent intervention needed.|moisturising and emolient creams|Permanently discontinue and urgent supportive measures||| ||Protect skin from any kind of physical and/or chemical damage|||| |ADL,activities of daily life;BSA,body|cture area;CTCAE,Common Terminology Criteria for Adverse Events; ICI, immune checkpoint inhibitors. 1vCheck for rash-associated dermatosis and other skin disorders induced by immune checkpoint inhibitors, and bullous pemphigoid, or life-threatening cutaneous drug reactions).|1Check for rash-associated dermatosis and other skin disorders induced by immune checkpoint inhibitors, bullous pemphigoid, or life-threatening cutous drug reactions).|32|CI, immune checkpoint inhibitors. E;ICI, immune checkpoint inhibitors, E;ICI, immune checkpoint inhibitors, E;ICI, immune checkpoint inhibitors, E;ICI, immune checkpoint inhibitors, E;ICI, immune checkpoint inhibitors, E;ICI, immune checkpoint, E;ICI, immune checkpoint, E;ICI| |||Reassess after 2-4 weeks:|49,50||

ADL,activities of daily life;BSA,body area;CTCAE,Common Terminology Criteria for Adverse Events;ICI,immune checkpoint inhibitors,'Check for rash-associated dermatosis and other skin disorders induced by immune checkpoint inhibitors(including lichenoid reactions, psoriasis,Grover's disease, bullous pemphigoid, or life-threatening cutaneous drug reactions).

§A shared-decision process is recommended, involving a careful consideration of patient's preferences, psychologic impact, tumour stage(advuant vs.metastatic setting), response to ICI and treatments risks and benefits.

Prognosis of skin toxicity

Pre-existing psoriasis is not a contraindication to ICI ther-apy.10 However, patients with psoriasisform and bullous irAEs often need systemic immunomodulators. ${}^{29}$ Psoriasis leads to permanent ICI discontinuation in a minority of cases. A systematic review reported permanent discontinuation in 13.6% of cases and temporary interruption in 15.5%. ${}^{46}$ About 30% of patients require systemic treatment. ${}^{49,50}$

Updates in management

When topical agents fail to provide adequate symptomatic control for psoriasis, systemic treatments should be consid-ered(Table 3). Acitretin and methotrexate are preferred due

to their favourable safety profiles and minimal interference with immunotherapy. Apremilast has demonstrated safety in patients with prior or current malignancies, though its impact on cancer progression in the context of ICI treat-ment is not well-studied.51,52 Fumaric acid ester analogues can also be considered for cancer patients, but their potential interactions with ICI remain a concern due to their action of inducing apoptosis in activated T cells and associated lym-phocyte depletion.53

Evidence regarding the use of biologics for treating cuta-neous irAEs is limited. Preclinical models suggest combin-ing ICI with anti-TNFa agents may enhance the anti-tumour efficacy of ICI.54 However, long-term use of TNFa inhibitors might deplete the pool of cytotoxic T lymphocytes(CTL)that target tumour antigens, potentially reducing tumour antigen-specific CTLs.55,56 In the clinical setting, some

FATTORE ET AL.

![Grade 1(mild)\nTopical treatments $\pm$ Oral anthistamines\nRe-evaluate\nin 2-4 weeks\nGrade 2 (moderate)\nAdd GABA analogs\nRefractory or severe\nConsider dupilum or amolizumab\n](2/aj0YEe4oUhYkBdfpda0fYP/figure6b00a29dc6094db4b0355bf233436c1c_0_2.png) FIGURE 1 Algorithm for the management of pruritus in patients receiving immune checkpoint inhibitors.

![Grade 1(<10% BSA)\nTopical corticosteroids + emolients\nRe-evaluate\nin 2-4 weeks\nGrade 2(10-30% BSA)\nAdd Oral antihistamines\nSystemic corticosteroids (0,5-1 mg/kg/day); continue ICI\nGrade 3(>30% BSA)\nDiscontinue ICI + high dose corticosteroids + urgent care\n](2/aj0YEe4oUhYkBdfpda0fYP/figureec8c99b024b1476db116d8680e41f934_0_4.png) FIGURE 2 Algorithm for the management of maculopapular rash induced by immune checkpoint inhibitors.

studies report lower survival rates for patients with high-grade irAEs treated with TNFa inhibitors compared to those treated with corticosteroids, although other studies show no decrease in survival. ${ }^{57}$ Short courses of anti-TNFa inhibitors are generally safe and effective in managing irAEs in cancer patients on ICI, with treatment tapered once symptoms are managed.

The safety of newer classes of biologic agents for psoriasis,such as anti-IL-23, anti-IL-17 and anti-IL-12/23 monoclonal antibodies, in cancer patients is also under investigation although preclinical data suggest that they may benefit pa-tients with previous or concomitant cancer. 58,59 Conflicting data exist regarding the safety of anti-IL-12/23, as IL-12 plays a protective role against skin inflammation 60 and suppresses tumour growth and metastasis through IFN synthesis stimulation. 61,62

In clinical settings, all categories of biologic therapies have been used in small case studies. 44,63 Both favourable outcomes and loss of ICI-anti-tumor efficacy have been re-ported across all classes, suggesting these treatments should be reserved for severe, treatment-resistant cases. ${}^{44,64,65}$ Once

symptoms are managed, biological treatment can be tapered.Concurrent use of biologics with immunotherapy to prevent recurrences during ICI rechallenge has yet to be studied in prospective clinical trials.

Lichen planus-like rash

Lichen planus-like rash (LPLR) during ICI looks like clas-sic lichen planus. Less frequently, hypertrophic and bullous forms may appear. ${ }^{4}$

Epidemiology

Reported incidence of LPLR ranges from 17% to almost 100%.40,66,67 Nevertheless, in our and other authors' ex-perience, incidence is lower, accounting for<10% of all cirAEs. 6,11,42,68,69

Prognosis of skin toxicity

LPLR is often difficult to treat and may severely impact quality of life due to intense pruritus. 40,66,67 Early diagnosis and prompt management are essential to maintain immu-notherapy. Some studies suggest LPLR may correlate with improved progression-free survival. ${ }^{68}$

Updates in management

In Grade 1 and Grade 2, first-line treatment involves con-servative management with potent and very potent topical corticosteroids and immunotherapy can be maintained in most cases(Table 4).11,40,42,67,69 Oral antihistamines may be proposed to control pruritus. In localized or hypertrophic lesions, intralesional triamcinolone acetonide injections could be used.70

Patients should be reassessed after 2-4 weeks. If reac-tions worsen or do not improve, or in Grade 3, systemic treatments, including oral corticosteroids and/or oral reti-noids, should be considered. ${}^{11,40,42,67,71-75}$ Withholding im-munotherapy may be discussed on a case-by-case basis and shared-decision process.

Again, patients should be reassessed after 2-4 weeks. If reactions improve, oral corticosteroids should be tapered progressively. Rechallenge with immunotherapy may be conducted when LPLR is grade $\leq$ 1, and after tapering oral corticosteroids at a dose $\leq$ 10mg/day.

If reactions worsen or do not improve, or in recalci-trant lesions, oral corticosteroids at 1 mg/kg/day should be maintained. Immunosuppressive drugs (methotrexate, aza-thioprine) have been sporadically proposed. Narrowband UVB is considered an additional treatment option.40,66,76 Withholding or discontinuing immunotherapy may be

PREVENTATIVE STRATEGIES OF AER

TABLE 3 Management recommendations for psoriasis-like rash.

|History of Preexisting Psoriasis|Preventative measures • Referral to dermatologist Specialist|Management|LoE|GoR| |---|---|---|---|---| |History of Preexisting Psoriasis|Preventative measures • Referral to dermatologist Specialist|• Acitretin, Apremilast, Methotrexate, Fumaric Acid Esters analogs: Can be maintained when starting ICI ● Cyclosporine: Adjust treatment before initiating ICI ● Biologic Therapies: Should be discussed case by case with cancer specialists|IV|B| |Grade 1||||| |Psoriatic plaques covering<10% BSA; no psychosocial impact|• Consider to quit smoking|Continue ICI at current dose Reassess after 2-4 weeks and monitor for change in severity ● Use topical agents# If reactions worsen or do not improve, proceed to next|IV|B| |Grade 2||Continue ICI at current dose||| |Psoriatic plaques covering 10-30% BSA with or without symptoms||Continue ICI at current dose|IV|B| |Intolerable Grade 1||• Reinforce Grade 1 management||| |||● Consider narrowband ultraviolet B||| |||or||| |||● Start systematic treatment': Acitretin 10-30 mg d, Methotrexate 10-25 mg/week Apremilast 30 mg bid||| |||● Reassess before each ICI treatment and monitor for change in severity||| |||If reactions worsen or do not improve, proceed to next||| |Grade 3||● Reinforce Grade 2 management||| |Psoriatic plaques covering>30% BSA with or without symptoms||● Consider biologics#: anti-TNFa anti-IL-23 anti-IL-17||B| |||If reactions worsen or do not improveDiscontinue ICI|||

BSA, body surface area; ICI, immune checkpoint inhibitors.

*Potent Topical Corticosteroids; Vitamin D analogues; Tazarotene 0.05%; Coal Tar; Salicylic Acid$^{\text{Narrowband UVB should be limited to patients with solid cancers other than melanoma. A shared-decision process is recommended for melanoma patients.

A shared-decision process is recommended, involving a careful consideration of patient's preferences, psychological impact, tumor stage(adjuvant vs.metastatic setting), response to ICI and treatments risks and benefits.

s Once symptoms are well-controlled, biologic treatment can be discontinued.

discuss on a case-by-case basis and shared-decision pro-cess. Hospitalization should be considered until control of disease activity.

Finally, biologic agents have been successfully used in the management of cirAEs, including LPLR. Dupilumab was used in patients with steroid-refractory or steroid-dependentcirAEs.36 Thirty-four of 39 patients(87%) re-sponded. Among these 34 responders, 15(44.1%) were complete responders with total cirAEs resolution and 19(55.9%) were partial responders. Omalizumab37,77 was pro-posed to oncologic patients developing Grade 2/3 pruri-tus with either anti-HER2 or ICI, who were resistant to topical steroids and at least one additional systemic treat-ment. Results showed 82% of responders, including 43%of complete response.77 JAK inhibitors, which target the JAK-STAT signalling pathway, have gained attention for their potential in treating various immune-mediated dis-eases. Several studies have highlighted the role of Type I interferons(such as IFNy), involved in the JAK-STAT pathway,in the pathogenesis of lichenoid diseases. Given the involvement of the JAK pathway in the development

of LPLR, current understanding makes JAK inhibitors a promising therapeutic option.

Vitiligo

Vitiligo-like reaction(VLR)usually occurs with bilateral symmetrical distribution in sun-exposed areas with subse-quent gradual enlargement of the patches.79 Depigmentation can also involve hair; in fact, a study by Dousset et al.79 found leukotricria in 34.1% of patients with melanoma and treated with anti-PD-1.

Epidemiology

VLR is most frequently reported in melanoma patients treated with ICI. Its incidence reaches up to 11% with anti-CTLA-4 therapies and up to 25% with anti-PD-1 agents.Meta-analyses estimate incidences of 8.3% with pembroli-zumab and 7.5% with nivolumab in melanoma.6,28,80

FATTORE ET AL.

TABLE 4 Management recommendations for lichen planus-like rash.

|Severity(CTCAE v5.0)|Preventive measures|Management|LoE|GoR| |---|---|---|---|---| |Grade 1|Fragrance-free moisturizers|Skin-directed therapy|IV|A| |macules/papules covering<10% BSA with or|Avoid scratching and minor skin trauma|Potent or superpotent topical corticosteroids(e.g., betathemasone dipropionate 0.05%, triamcinolone 0.1%|IV|A| |without symptoms(e.g.,pruritus, burning) with or|Referral to dermatologist Examine skin, hair, nail, oral and genital mucosa|or clobetasol 0.05% cream, over the skin lesions)||| |Macules/papules covering 10-30% BSA with or||Oral antihistamines||| |without symptoms(e.g.,pruritus, burning); limiting instrumental Activities of daily life; rash covering>30% BSA with or without mild symptoms||Continue immune checkpoint inhibitors(ICL) at current dose||| |||||| |||Reassess after 2-4 weeks; if reactions worsen or do not improve, proceed to next step||| |Persistent or intolerable Grade 2||Reinforce grade 2 management||IV| |or||consider oral corticosteroids(0.5-1 mg/kg/day for 4/6 weeks) and high-potency or very high-potency topical||B| |Grade 2 with severe mucosal lesions||corticosteroids||| |or||+- oral retinoids(alitretinoin, acitretinoin 20-30 mg/day)||| |Grade 3||Withhold ICI*||| |macules/papules covering>30% BSA with moderate or severe symptoms||||| |(e.g.,pruritus, burning); limiting self-care activities of daily life||||| |||Reassess after 2-4 weeks: ● If reactions worsen or do not improve, proceed to next step||| |||. If reactions improve, start oral corticosteroids||| |||tapering||| |||Rechallenge ICI when G≤1, and after tapering oral corticosteroids at a dose≤10 mg/d||| |Recalcitrant lesions||Reinforce grade 3 management||V| |||Mainain oral corticosteroids(1 mg/kg/day) withhold or discontinue ICI* Consider other steroid-sparing agents: harrowband ultraviolet B phototherapy**, immunosuppressive drugs (e.g. methotrexate)* biologic therapies(dupilumab, malizumab) consider hospitalization until control of disease activity|||

*A shared-decision process is recommended, involving a careful consideration of patient's preferences, psychological impact, tumor stage(advjuvant vs.metastatic setting), response to ICI and treatments risks and benefits

**Narrowband UVB should be limited to patients with solid cancers other than melanoma. A shared-decision process is recommended for melanoma patient

VLR usually begins with an inflammatory phase, appear-ing after a median of 8 months, though onset can range from 1 to 44 months. Combination therapies are linked to earlier onset.80,81

Prognosis of skin toxicity

VLR may persist despite cancer treatment discontinuation and,indeed, repigmentation after discontinuation was associated in several cases with disease progression or tumour recurrence.11 Disease extent and progression significantly affect patients'well-being, with rapid progression having a particularly nega-tive influence, with a possible impact on treatment compliance.The observation that VLR progressed in a subset of patients following discontinuation of ICI therapy hints at the irrevers-ible nature of most irAEs.82 VLR is a favourable prognostic fac-tor in patients with melanoma. This may be due to melanocyte

destruction by autoreactive CD8+ T cells; moreover, T-cell in-filtration,also involved in microenvironment of tumour, could explain a better response to immunotherapy.83,84

Updates in management

Management strategies, including cosmetics, sun pro-tection, topical anti-inflammatory treatment and photo-therapy, are associated with a positive impact on quality of life.85 Different treatment approaches reflect the lack of standardized guidelines for VLR management.6,28,80 Topical treatments are preferred in literature guidelines and expert recommendations(Table 5); patients usually received topical corticosteroids or calcineurin inhibitors.A promising therapeutic approach for treating general-ized VLR involves Janus kinase(JAK) inhibitors, either topical or systemic.

PREVENTATIVE STRATEGIES OF AER

TABLE 5 Vitiligo-like reactions. Preventative recommendations and management algorithm.

|Severity(CTCAE v5.0)|Preventative measures|Management|LoE|GoR| |---|---|---|---|---| |Grade 1|UVA/UVB high photoprotection|No treatmentt|III-IV|B| |Hypopigmentation or depigmentation covering<10% BSA; no psychosocial impact||or potentual corticosteroids topical calcineurin inhibitors Continue ICI at current dose Reassess after several weeks and monitor for change in severity, clinical improvement, patient satisfaction and psychologic impact; consider camouflage if needed If reactions worsen or do not improve, proceed to next step||| |Grade 2||0 No treatmentt|III-IV|B| |Hypopigmentation or depigmentation covering>10% BSA; associated psychosocial impact||or potent topical corticosteroids and/or topical calcineurin inhibitors l atic current octare severe also after several weeks and monitor for change in severity, clinical improvement, patient satisfaction and psychologic impact;||| |||Continue ICI at current dose Reassess after several weeks and monitor for change in severity, clinical improvement, patient satisfaction and psychologic impact;||| |||consider camouflage if needed If reactions worsen or do not improve, proceed to next step||| |Grade 2||||III-IV B| |Hypopigmentation or depigmentation covering>10% BSA; associated psychosocial impact|UVA/UVB high photoprotection|No treatmentt or||| |||or potent topical corticosteroids and/or topical calcineurin inhibitors and/or narrowband ultraviolet B phototherapyi+ Continue ICI at current dose Reassess after several weeks and monitor for change in severity, clinical improvement, patient satisfaction and psychologic impact; consider camouflage if needed|||

BSA, body surface area; CTCAE, Common Terminology Criteria for Adverse Events; ICI, immune checkpoint inhibitors.

1A shared-decision process is recommended, involving a careful consideration of patient's preferences, psychological impact, tumour stage(adjuvant vs. metastatic setting), response to ICI and treatments risks and benefits.

Narrowband UVB should be limited to patients with solid cancers other than melanoma.A shared-decision process is recommended for melanoma patients.

Bullous pemphigoid and bullous reactions

Bullous pemphigoid (BP) is the most frequent bullous irAE. Other rare conditions include lichen planus pem-phigoides, pemphigus, dermatitis herpetiformis, epider-molysis bullosa acquisita, linear IgA disease and mucous membrane pemphigoid. These conditions can severely impair quality of life, requiring prompt dermatologic intervention. 6

Epidemiology

The incidence of bullous reactions with the use of ICI is about 1%.4 ICI-associated BP appears from weeks to sev-eral months after ICI initiation and usually manifests with tense bullae and urticarial plaques over the trunk and ex-tremities. Elderly patients are at higher risk of ICI-related BP occurrence.86,87 In immunofluorescence studies, BP230 autoantibodies are less frequently identified as compared to spontaneous BP, but histopathologic findings are identical in both entities.88

Prognosis of skin toxicity

ICI-induced BP often requires complex management. Severe cases may necessitate hospitalization and can lead to ICI dis-continuation, especially in grade≥3 events. However, lim-ited evidence links BP to cancer outcomes.4

Updates in management

Management of ICI- associated BP is challenging, as phy-sicians should consider control of BP, without jeopard-izing the immunotherapeutic effect of ICI with the use of systemic corticosteroids. Super-potent topical steroids and steroid sparing agents are of high therapeutic value in this specific context.6,88,89 Tetracyclines are also recommended in ICI-induced BP.90 Newly developed biologics, such as dupilumab, have shown promising results in management of itching cirAE,including BP.37,91

Table 6 summarizes the recommendations of manage-ment of ICI-associated BP.

Hair irAEs

Hair disorders induced by ICI are recognized side effects of cancer immunotherapy.

Epidemiology

The overall incidence of alopecia due to ICI is relatively low,ranging from 1% to 5% in patients receiving these treat-ments.°Alopecia area(AA) is the most common form,although scarring types such as frontal fibrosing alopecia(FFA), lichen plano-pilaris(LPP)92 and telogen effluvium have also been reported.93 Hair disorders can appear sev-eral months after the initiation of therapy, and these effects

FATTORE ET AL.

TABLE 6 Recommendations of management of ICI-associated BP.

|Severity(CTCAE|5.0)|Intervention|LoE|GoR| |---|---|---|---|---| |Grade 1 (<10% BSA)|Superpotent topical corticosteroids(30-40 g/day of cobetolasol propionate applied, bid, over Continue ICI at current dose|IV|A|| |Grade 1 (<10% BSA)|Reassess after 2-4 weeks; if reactions do not improve, consider the addition of oral prednis- alone at a doses10mg/day If reactions worsen, proceed to next step|IV|A|| |Grade 2 (10%-30% BSA)|Consorl corticosteroids(0.5 mg/kg/day, prednisolone) and superpotent topical cortico- steroids Wound care with petrolatum-based emolients and non-stick dressings are recommended withhold ICI|IV|A|| |Reassess after 2-4 weeks: If reactions worsen or do not improve, increase the dose of oral prednisolone or proceed to next step ● If reactions improve, start oral corticosteroids tapering ● Rechallenge ICI when G≤1 and after tapering oral corticosteroids at a dose≤ 10mg/d||||| |Reassess after 2-4 weeks: If reactions worsen or do not improve, increase the dose of oral prednisolone or proceed to next step ● If reactions improve, start oral corticosteroids tapering ● Rechallenge ICI when G≤1 and after tapering oral corticosteroids at a dose≤ 10mg/d|Oral corticosteroids(0.5-1.0 mg/kg/day, l prednisolone) Consider a steroid-sparing agent a b Withhold or discontinue ICI° Consider hospitalization until control of disease activity||IV|A| ||Reassess after 2 weeks: ● If reactions worsen proceed to next step|||| |Grade 4 (>30% BSA)|For reactions improve start oral corticosteroids tapering; ● Re-challenge ICI when G≤1 and after tapering oral corticosteroids at a dose≤ 10mg/d|||| |Grade 4 (>30% BSA)||||| |Grade 3b (>30% BSA)|Oral corticosteroids(0.5-1.0 mg/kg/day, l prednisolone) Consider a steroid-sparing agent a b Withhold or discontinue ICI° Consider hospitalization until control of disease activity|||IV| ||Reassess after 2 weeks: ● If reactions worsen proceed to next step ● If reactions improve start oral corticosteroids tapering; ● Re-challenge ICI when G≤1 and after tapering oral corticosteroids at a dose≤ 10mg/d|||| |Grade 4 (>30% BSA; with fluid and/or electrolyte abnormalities)|Hospitalize(intensive care or burn unit) the patient and use IV methylprednisolone 1-2 mg/ kg/day until control of disease activity, then switch to prednisolone 0.5-1 mg/kg/day and start tapering discontinue ICI|||V|

A shared-decision process is recommended, involving a careful consideration of patient's preferences, psychologic impact, tumour stage(adjuvant versus metastatic setting), response to ICI and treatments risks and benefits

b tetracycline, dupilumab, niacinamide, dapsone, methotrexate, IVIG, omalizumab, rituximab;

cultures of skin and/or blood samples are mandatory if there are signs of infection

CTCAE: Common terminology criteria for adverse event, BSA: body surface area, ICI: immune checkpoint inhibitor

are generally more frequently seen in patients treated with combination immunotherapy, such as PD-1 inhibitors with CTLA-4 inhibitors.6

Prognosis of hair toxicity

Different forms of alopecia, such as AA or FFA, as well as hair repigmentation, had been reported to have a positive prog-nostic value for remission of the underlying neoplasm, 92,94 even if the toxicity started several months after treatment initiation.11,95 In addition, young age and male sex have been reported as positive prognostic factors for persistent alope-cia, which may occur in a third of patients.94 For scarring alopecia, such as LPP and FFA, the toxicity still evolves even after stopping immunotherapy.92,96

Updates in management

Management of immunotherapy-induced hair disorders is quite different, and most publications on this topic focus on the management of AA.20,84,97 Generally, recommenda-tions are the same as for the idiopathic form, including in-tralesional and topical high-potency corticosteroids, topical minoxidil and topical diphenylcyclopropenone. Systemic immunomodulators, both classic ones(methotrexate,cyclo-sporine,mycophenolate mofetil) and JAK inhibitors, namely

with baricitib or ritlecitinib, are possible therapeutic op-tions.20,94,98-100 Finally, in severe cases or due to patient preferences, camouflaging techniques may be considered.97 Due to the immune-related pathogen-esis of ICI alopecia and the lack of consensus or evidence,5-alpha-reductase inhibitors are actually not recommended for these patients, despite their use in other alopecias and selected oncologic cases.

Regarding scarring alopecia, the aim of treatment is to stop the inflammatory process leading to permanent hair loss.101 The most used drugs are topical or intralesional cor-ticosteroids and topical tacrolimus.92,102 One of the most useful and safe systemic therapies is hydroxychloroquine,which has also been proved to be successful in treating immunotherapy-induced arthritis.101-103 Some patients may experience changes in hair colour(hair repigmentation or poliosis) or hair texture. Currently, no specific treatment is recommended for these changes, as they do not generally af-fect quality of life or require medical intervention. However,cosmetic recommendations are possible.11,104 Table 7 pro-vides preventative recommendations and a management algorithm.

Nail irAEs

Unlike the numerous nail-related adverse events com-monly associated with traditional chemotherapy or targeted

PREVENTATIVE STRATEGIES OF AER-

therapy, cancer immunotherapy has reported relatively few nail changes or toxicities.105

Epidemiology

ICI, such as anti-CTLA-4 and anti-PD1, can cause nail involvement in conjunction with immune-related skin conditions like lichenoid or psoriatic rashes and alopecia area.105 Furthermore, a few case reports describe nail changes associated with nivolumab, such as bluish-grey fingernail discoloration,an onycholysis,107 two cases of nail lichenoid changes,108 and dystrophy of the nail plate associated with periungal and nail bed inflammation after 43 cycles of the drug, with improvement of mani-festations upon discontinuation of therapy, except for the dystrophy.109

Prognosis of nail toxicity

The prognosis of nail toxicity is generally favourable, as most nail changes are reversible. In many cases, nail abnormali-ties such as discoloration, thinning or brittleness improve gradually over time after treatment ends. In some instances,permanent nail damage can occur.

Updates in management

Nail pigmentation necessitates photoprotection, minimiz-ing excessive exposure to sunlight, but generally diminishes once the medication is stopped. For onchyolysis, it is advised to use topical emollients daily on the nail apparatus, apply protective nail lacquers to reduce water loss from the nail plate and wear cotton gloves.110 Patients should steer clear of any harmful or irritating practices, such as manipulating the cuticles, onychophagia, prolonged water immersion, ex-posure to solvents or harsh chemicals and applying artificial nails.108 In severe cases, onycholysis requires timely inter-vention to encourage nail reattachment, as delays can lead to permanent oncholysis.110

Oral mucosa irAEs

OM-irAEs are not infrequent among patients treated with ICI and are probably underestimated due to the lack of sys-tematic oral examination.

Epidemiology

In a recent meta-analysis of 95 clinical trials,"11 the over-all weighted prevalence was 5% for dry mouth, 3% for stomatitis and 3% for dysgeusia. Only 3.8% of patients

experienced severe grade.111,112 Lichenoid reactions and autoimmune bullous disorders with oral involvement have been well described to date.6,11,113,114 The mean onset is 3 months from the initiation of treatment, and most AEs occur within the first 12 months.25,112,114-116 However, late onset has been reported more than a year after therapy.Immune-mediated sialadenitis presenting with oral sicca syndrome is the most common oral irAE reported in asso-ciation with ICI.117,118 Oral lichenoid reactions(OLR) rep-resent the second most frequent oral toxicity. Other reported mucosal manifestations include oral bul-lous disorders such as mucous membrane pemphigoid,lichen planus pemphigoid or more frequently, bullous pemphigoid. Oral ulcerations associated with ICI-related life-threatening reactions(e.g.,toxic epidermal necrolysis and Stevens Johnson syndrome) can also exceptionally occur.6,116,119,120 Moreover, a recent multi-centre cohort study reports an increased risk of developing periodontitis in patients under ICI.121

Prognosis of oral mucosa toxicity

Reduced saliva production may impact oral health with demineralization of teeth and decay leading to loss of dentition, dentine hypersensitivity, increased risk of peri-odontal disease, secondary mucosal infection, increased risk of mucosal trauma, reduced capacity for mucosal re-pair, and impact on speech and taste.113 OLR may persist even after the inducing drug has been discontinued. Oral examination with long-term monitoring remains key due to the low risk of malignant transformation, which re-mains theoretical.6,122

Finally, patients with oral irAEs appear at higher risk of having a non-oral irAE. Patients who have non-oral irAEs should be monitored for the development of oral irAEs for prompt management.123

Updates in management

Pretherapeutic oral examination by an oral specialist in order to detect pre-existing mucosal abnormalities, screen and treat dental and periodontal infections and eliminate sources of trauma or xerostomia.119 Patient education in the implementation of basic oral care on a multi-daily basis is essential to limit oral toxicities.

Management recommendations are based on expert opinion.6,116 OM-irAEs are generally mild, self-limited and manageable with mucosa-directed therapy and supportive measures. If not, the introduction of a short course of oral cor-ticosteroids, a dose reduction or interruption of treatment may be discussed. Interruption, discontinuation, or reintroduction of ICI therapy should be discussed on a case-by-case basis by a multidisciplinary team.6,11,112 Table 8 provides preventative recommendations and management algorithm.

FATTORE ET AL.

TABLE 7 Alopecia area and scarring aloappa: management algorithm and recommendations.

|Severity(CTCAE v.50)|Preventative measures|Intervention|LoE|GoR| |---|---|---|---|---| |Grade 1|Risk Assessment: Screen for|Alopeia Aureta|V|A| |Hair loss of less than 50% of normal for|personal history of AA or LPP|No treatment*||| |that individual that is not obvious from|before initiating ICLs.|||| |a distance but only on close inspection;|Early Referral: if hair loss is|or||| |over the hair loss, but it does not require|observed.|Intralesional corticosteroids(triaminolone)+/-potent or||| |a wig or hairpiece to camouflage|Counsel patients on possible hair loss, emphasize early symptom reporting. Non pharmacological strategies are recommended to prevent AA or LPP|superpotent topical corticosteroids(e.g., betathesone dipropionate 0.05%, triamcinol 0.1% or cobetasol 0.05% lotion)+ topical minoxidl 5% solution or foam or low dose oral minoxidl 5.5mg/day. continue ICI at current dose Reassess after 4 weeks and monitor for change in severity,improvement, patient satisfaction and psycholog- ical impact; continue dermatologic therapy as needed if successful response||| |||if reactions worsen or do not improve, proceed to next step Scarring alopraia||| |||No treatment*||| |||or||| |||Potent or super potent topical corticosteroids+/-topical tacrolimus+/- intralesional corticosteroids+/- hydroxyclo- roquine 200mg 12/24 daily+ topical minoxid 5%||| |||If scaling, consider combination of calcipotriol/betameth- asone gel||| |||Consider systemic corticosteroids for inflammatory phase of LPP||| |||continue ICI at current dose||| |||continue ICI at current dose||| |||Reassess after 4 weeks and monitor for change in severity,improvement, patient satisfaction and psycho- logic impact; continue dermatologic therapy as needed if successful response||| |||If reactions worsen or do not improve, proceed to next step||| |Grade 2|Hair loss more than 50% normal for that|Alopeia Aureta|V|A| |individual that is readily apparent to oth- ers; a wig or hair piece is necessary if the||||| |layer loss more than 50% normal for that||Notreatment*||| |irans to desire can'to oth- ers; a wig or hair piece is necessary if the||Or||| |patient desires to completely camouflage||Same management as Grade 1||| |the hair loss; associated with psychoso- cial impact||Other therapies could be considered* including topical||| |||immunotherapy with diphenylycproponeen. Continue||| |||dermatologic therapy as needed if successful response||| |||continue ICI at current dose||| |||continue ICI at current dose||| |||Reassess after 4 weeks and monitor for change in severity, clinical improvement, patient satisfaction and||| |||perthability impact; consider scalp prothesis or camou- flag if needed||| |||flage if needed||| |||If reactions worsen or do not improve, proceed to next step||| |||costricial alopeia||| |||Notreatment*||| |||or||| |||Same management as Grade 1||| |||Other therapies could be considered* including acitretin 25||| |||mg daily,mycophenolate mofetil 500-1500mg twice daily, cyclosporine 3 to 5 mg/kg/day, pioglitazone 15-30 mg daily,thalidomide 100-200 mg daily,doxycycline 100mg twice daily,naltrexone 3mg daily.Continue dermatologic therapy as needed if successful response||| |||therapy as needed if successful response||| |||Continue ICI at current dose||| |||Reassess after 4 weeks and monitor for change in severity, clinical improvement, patient satisfaction and psychological therapy as needed||| |||psychologic impact; consider scalp prothesis or camou- flag if needed||| |||flag if needed||| |||||| |||Alopeia Aureta and Scarring alopeia|V|C| |||(to intralesional corticosteroids and topical|No treatment*|| |||or||| ||||Consider other steroid-sparing agents/immunosuppressive|| |||drugs(e.g. methotrexate)||| |||Monitor for change in severity, clinical improvement, patient satisfaction and psychological impact; or scalp||| |||Continue ICI at current dose if positive cancer outcome,||| |||with psychological support if needed||| |||*A shared-decision process is recommended, involving a careful consideration of patient's preferences, psychological impact, tumor stage(advu||| ||versus metastatic setting),response to ICI and treatments risks and benefits.|||| ||JAK inhibitors could be used with caution in cancer patients. Personalized risk assessment and vigilant monitoring is recommended when considering|JAK inhibitors could be used with caution in cancer patients. Personalized risk assessment and vigilant monitoring is recommended when considering|||

*A shared-decision process is recommended, involving a careful consideration of patient's preferences, psychological impact, tumor stage(adjuvant versus metastatic setting), response to ICI and treatments risks and benefits.

JAK inhibitors could be used with caution in cancer patients. Personalized risk assessment and vigilant monitoring is recommended when considering prescribing JAK inhibitors for alopecia areata in cancer patients.

$$\text{ PREVENTATIVE STRATEGIES}$$$$\text{ OF AER}$$

TABLE 8 Management recommendations for OM-irAEs.

|Clinical grade|Dry mouth|Reticulated lesions|Erosive/bullous lesions| |---|---|---|---| ||Serum screening for anti-SSA/SSB antibodies|Screening for other oral lesions compatible with a lichenoid reaction (atrophy, plaques, erosive/ulcerous lesions)|Consider immunofluorescence, ELISA assay, histology to exclude/ confirm autoimmune bullous diseas or lichen planus pemphigoid, proceed as follows| ||Treat associated oral burns(screening for deficiencies of iron and vitamins B9 and B12, stomatodynia)|Consider biopsy for refractory/ severe cases to confirm oral lichenoid reaction|In the case of an isolated lichenoid reaction, proceed as in the previous column("reticulated lesions")| |Grade 1-2 Grade 1: asymptomatic or mild symptoms|Rule out candidal superinfection|Maintain good oral hygiene (LoE V/GoR B)|Maintain good oral hygiene| |Grade 2: oral mucosal lesions with moderate pain, modified diet may be necessary|Stimulation of saliva, hydration LoE V/GoR B|Topical corticosteroids (dexamethasone solution 0.1 mg/ml,prednisolone mouthwash, clobasetal topical cream 0.05%, flucinideon topical gel 0.05%); tacrolimus ointment|Oral cavity coating, lubricating and moistening agents Topical corticosteroids (dexamethasone solution 0.1 mg/ ml,prednisolone mouthwash, clobetasol topical cream 0.05%, flucinideon topical gel 0.05%); tacrolimus ointment|

|Continue immunotherapy treatment at the same dose and monitor for change in severity|||| |---|---|---|---| |Intolerable grade 2 or more|||| |Intolerable grade 2 or oral symptoms|Maintain good oral hygiene|Maintain good oral hygiene|Maintain good oral hygiene| |associated with severe pain interfering with oral intake|Supportive care/dietary recommendations|Supportive care/dietary recommendations|Supportive care/dietary recommendations| |Grade 3 or more: recalcitrant oral symptoms|Oral corticosteroids 0.5 mg/kg/ day for 2-4 weeks and reduce if improvement|Oral corticosteroids 0.5 mg/kg/day for 2-4+/- oral retinoids(acitretinin 20-30 mg/day) and suspend immunotherapy|Consider systemic management of autoimmune bullous disease:oral corticosteroids(0.5-1 mg/ kg/day) for 2-4 weeks; consider steroid-sparing agents(dapsone, rituximab, methotrexate,omalizumab, dupilumab); suspend immunotherapy until grade 0 or tolerable grade 2| ||If no improvement, oral corticosteroids 1 mg/kg/day and suspend or discontinue immunotherapy until grade 0 or tolerable grade 2|Reduce oral corticosteroids and resume immunotherapy after a return to tolerable grade 0 or tolerable grade 2|omalizumab, dupilumab); suspend immunotherapy until grade 0 or tolerable grade 2 Multidisciplinary decision to reintroduce immunotherapy(taking into account the stage of the tumor and the response, risks and benefits of treatment).| ||If no improvement, oral corticosteroids(1 mg/kg/day) and consider steroid-sparing agents (methotrexate, thalidomide, hydroxychloroquine, etc.); suspend immunotherapy until grade 0 or tolerable grade 2|If no improvement, oral corticosteroids(1 mg/kg/day) and consider steroid-sparing agents (methotrexate, thalidomide, hydroxychloroquine, etc.); suspend immunotherapy until grade 0 or tolerable grade 2|into account the stage of the tumor and the response, risks and benefits of treatment).| ||LoE V/GoR A|LoE V/GoR A||

Autoimmune skin diseases: Lupus erythematosus, Sicica syndrome/Sjogren's syndrome, Dermatomyositis, scleroderma/Morphea

ICI, including PD-1 and CTLA-4 inhibitors, can disrupt immune tolerance, leading to autoimmunity and poten-tially to lupus-like syndromes, including systemic lupus erythematosus(SLE) and subacute cutaneous lupus ery-thematosus(SCLE).124-128 PD-1 blockade has also been linked to chilblain lupus-like reactions in patients with pre-existing SLE, while SCLE-like eruptions have been reported with durvalumab. ${}^{129,130}$ Furthermore, several pa-tients have developed de novo SCLE-like eruptions, and ICI-induced SCLE is a distinct entity, which can result in a delayed and/or prolonged skin reaction despite treatment

discontinuation.125,131,132 Interestingly, lupus-like reac-tions in ICI-treated patients can co-occur with notable anti-tumour responses, as illustrated by a case in which a patient with pancreatic adenocarcinoma developed SLE after pembrolizumab therapy yet experienced significant tumour regression.133

Moreover, ICI can exacerbate pre-existing autoimmune conditions, raising safety concerns for patients with a his-tory of autoimmune diseases undergoing immunotherapy.134 Reactivation of SLE has been observed in some patients re-ceiving chemo-immunotherapy, emphasizing the need for careful risk assessment in these populations.

Sicca syndrome(SS) is an irAE associated with ICI that targets exocrine glands, leading to symptoms such as dry eyes(xerophthalmia) and mouth(xerostomia).136,137 It has been linkedth to all subtypes of ICI.117 Symptoms typically

FATTORE ET AL.

emerge within the first 3 months of therapy, ranging from mild to severe, and are often accompanied by saliadenitis and glandular injury.

PD-1 blockade appears to play a role in triggering SS,with studies indicating increased PD-L1 expression in the glandular epithelium of SS patients.117,139-141 Management of ICI-induced sicca syndrome/SS includes hydration, topical symptomatic treatment, ocular glucocorticoid/cyclosporine,oral cholinergic agonists, discontinuation of ICI treatment and oral glucocorticoids, though responses to these ther-apies can vary.141,142 Early intervention can help mitigate the effects, although profound deficits in saliva flow can be long-term.

Dermatomyositis is a rare but serious irAEs.143,144 The presence of specific autoantibodies, such as anti-TIF-1y,complicates the distinction between paraneoplastic and treatment-related cases.144,145

Case reports have described dermatomyositis after the initiation of ICIs, particularly with nivolumab and tori-palimab, supporting a direct association between immuno-therapy and autoimmune myopathies.146,147

Scleroderma-like syndromes, including morphea, have been reported with ICI therapy. These conditions may cause irreversible skin fibrosis, affecting quality of life and compli-cating cancer treatment decisions.148 Intravenous immuno-globulin has shown benefit in some cases, though the fibrotic process often limits treatment efficacy.149 Generalized mor-phea, especially with combination ICI therapy, suggests a potential for severe immune dysregulation requiring aggres-sive management.150,151

EMERGING THERAPIES AND FUTURE DIRECTIONS

Newer strategies, such as personalized immunother-apy regimens, based on genetic and immune profiling,may reduce the incidence and severity of adverse events.Furthermore, ongoing research into biomarkers that pre-dict dermatologic toxicities could lead to more individu-alized preventive strategies, improving overall treatment tolerability. The use of biologics and small-molecule inhib-itors targeting specific inflammatory pathways involved in skin toxicity is also under investigation. It is obvious that handling cirAEs with the use of skin-directed medications cannot be made by oncologists, and the role of dermatolo-gists becomes essential towards holistic management of cancer patients today.2

CONCLUSION

Dermatological adverse events are common but manage-able complications of cancer immunotherapy. Through early identification, patient education, and the implemen-tation of evidence-based preventive strategies, healthcare

professionals can significantly reduce the impact of these events on the patient's quality of life and cancer treatment outcomes. As the use of immunotherapy expands, continued research and interdisciplinary collaboration will be critical in refining preventive measures and developing novel thera-peutic options for managing dermatologic toxicities.

AUTHOR CONTRIBUTIONS

Conceptualization: Davide Fattore, Zoe Apalla, Azael Freites-Martinez, Nello Tommasino, Vincent Sibaud.Methodology: Davide Fattore, Michela Starace, Maddalena Napolitano, Vincent Sibaud. Formal analysis and investiga-tion: Davide Fattore, Vasiliki Nikolaou, Giuseppe Lauletta,Ariadna Ortiz-Brugues, Pietro Sollena, Michela Starace,Nuno Miguel Preto Gomes, Dimitra Koumaki,Emmanuelle Vigarios, Kraehuenbell Nello, Katerina Grafanaki,Warioa Ortiz-Brugues, Pietro Sollena, Michela Starace,Nuno Miguel Preto Gomes, Dimitra Koumaki,Emmanuelle Vigarios, Kraehuenbell Nuko, Katerina Grafanaki, Vincent Sibaud. Supervision: Davide Fattore,Zoe Apalla, Maddalena Napolitano, Vincent Sibaud. All authors read and approved the final version of the manuscript.

AFFILIATIONS

1Section of Dermatology,Department of Clinical Medicine and Surgery,University of Naples Federico II, Naples, Italy

Second Dermatology Department,School of Medicine,Faculty of Health Sciences,Aristotle University of Tessaloniki,Thessaloniki,Greece

3Department of Dermatology,Hospital Ruber de Juan Bravo, Universidad Europea,Madrid,Spain

4Department of Dermatology-Venereology,Faculty of Medicine,National and Kapodistrian University of Athens,“A. Sygros” Hospital for Skin and Venereal Diseases,Athens,Greece

Department of Oncodermatology, Institut Universitaire du Cancer-Oncopole,Toulouse,France

Dermatology Unit,Department of Surgical and Medical Sciences,Fondazione Pollicinico Universitario Agostino Gemelli IRCCS, Rome,Italy

Dermatology Unit,IRCCS Azienda Ospedaliero-Universitaria di Bologna,Bologna,Italy

8Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy

9Department of Dermatovereology,Unidade Local de Saude Alto Minho, Viana do Castelo, Portugal

10Department of Dermatology,University Hospital of Heraklion, Heraklion,Greece

1"Oral Medicine Department, Institut Claudius Regaud, Institut Universitaire du Cancer Toulouse-Oncopole, Toulouse, France

12Department of Dermatology and Allergology,Kantonsspinal Aarau,Aarau,Switzerland

13Department of Dermatology,University Hospital Zurich(USZ), University of Zurich(UZH), Zurich, Switzerland

14Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology,Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine,New York City,New York,USA

15Department of Dermatology-Venereology,School of Medicine, University of Patras,Patras, Patras, Greece

16Department of Biochemistry,School of Medicine, University of Patras, Patras,Greece

17Oncology Department, Institut Universitaire du Cancer,Toulouse,France

ACKNOWLEDGEMENTS

The authors have nothing to report.

PREVENTATIVE STRATEGIES OF AER

FUNDING INFORMATION

None.

CONFLICT OF INTEREST STATEMENT

The article has not been previously published and is not cur-rently submitted elsewhere. Davide Fabftore acted as speaker,consultant and advisory board member for Pierre Fabre and L'Oreal. Azael Freites-Martinez acted as speaker, consultant and advisory board member for SHB law firm-Sanofi, J and J Spain, Isdin Spain and Galderma Spain. Ariadna Ortiz-Brugues acted as speaker, consultant and advisory board member for Berula Nature, Janssen, Almirall, Galderma, Pierre Fabre, Novartis, BMS and Merck. Michela Starace acted as speaker,consultant and advisory board member for Pierre Fabre and L'Oreal. Lukas Kraehuenbehl acted as speaker,consultant and supporting for attending meetings for Janssen, Astra Zeneca, Sanofi, Regeneron, Almirall, Kyowa Kirin, Johnson& Johnson. Vincent Sibaud acted as a speaker and supporting for attending meetings for Pierre Fabre,Novartis, BMS, SDB, Bayer, Janssen, L'Oreal, Regeneron,Immunocure, Astellas, Astra Zeneca. Zoe Apalla, Nello Tommasino, Vasiliiki Nikolaou, Giuseppe Lauletta, Pietro Sollena, Nuno Miguel Preto Gomes, Dimitra Koumaki,Emmanuel Vigarios, Katerina Grafanaki and Maddalena Napolitano have no conflict of interest to declare.

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author upon reasonable request.

ETHICAL APPROVAL

All procedures performed in studies involving human par-ticipants were in accordance with the ethical standards of the institutional and/or nationalsearch committee and with the 1964 Helsinki Declaration and its later amend-ments or comparable ethical standards.

ETHICS STATEMENT

No individual patient case details are reported in this study;therefore, written informed consent for publication was not required.

ORCID

Davide Fatore https://orcid.org/0000-0002-1925-1243 Zoe Apalla https://orcid.org/0000-0002-9255-8196 Azael Freites-Martinez https://orcid.org.org/0000-0002-3121-5667 Nello Tommasino https://orcid.org/0009-0002-7997-1784 Vasiliki Nikolaou https://orcid.org/0001-9340-9152 Giuseppe Lauletta https://orcid.org/0009-0009-5607-8877 Ariadna Ortiz-Brugues https://orcid.org/0000-0001-6205-0941 Michela Starace https://orcid.org/0000-0002-3981-1527 Nuno Miguel Preto Gomes https://orcid.org.org/0000-0003-4278-3106 Dimitra Koumaki https://orcid.org/0000-0001-7074-2374

Katerina Grafanaki https://orcid.

org/0000-0002-6569-1928

Maddalena Napolitano https://orcid.

org/0000-0003-3309-8190

Vincent Sibaud https://orcid.org/0000.org/0000-0003-2585-6633

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How to cite this article: Fattore D, Apalla Z, Freites-Martinez A,Tommasino N,Nikolaou V,Lauletta G,et al. Prevention and management of cutaneous immune-related adverse events: EADV Task Force statement.J Eur Acad Dermatol Venereol.2025;00:1-21.https://doi.org/10.1111/jdv.70149

2025;00:1-21.https://doi.org/10.1111/jdv.70149

表 1
Severity (CTCAE v5.0)	Intervention	LoE	GoR
Prevention	If history of pruritus or pruritus skin disorder $$\begin{array}[]{l}\text{Consider dermatology referral}\\ \text{ around treatment start}\\ \end{array}$$ Fragrance-free moisturizers and soap free cleansers Start ICI	V	B
Grade 1 Mild or localized; topical intervention	Skin-directed therapy	V	B
indicated	Euse of potent topical steroids (e.g.triaminolone 0.1% or mometasone fuorate 0.1% cream odin pruritic areas) Systemic therapy	IV	B
	Consider non-sedating antihistamines such as cetirizine 10mg,loratodine 10mg or bilastine 20mg(once a day), withdraw if no effect after 1 week	V	B
	Continue ICI at current dose
Grade 2 Widespread and intermittent; skin soap free cleansers	Skin-directed therapy		Multidisciplinary decision to hold or discontinue to lCI(at least
scratching (e.g., edema, papula- tion, excoriations, lichenification, oozing/crusts); oral intervention	Use of potent operant steroids (e.g.traincinolone 0.1% or cobatolus 0.05% cream od-bidin pruritic areas)	IV	B

表 2
Severity (CTCAE v5.0)	Intervention	Intervention	LoE	GoR
Grade 3	Skin-directed therapy	Skin-directed therapy
Widespread and constant; limiting self care ADL or sleep; systemic corticosteroid or immunosuppressive therapy indicated	Use of potent or superpotent topical steroids(e.g. traincinolone 0.1% or clobetasol 0.05% cream bid per day in pruritic areas) Systemic therapy	IV 0.05% cream bid per day in pruritic areas) Systemic therapy	B 0.05% cream bid per day in pruritic areas) Systemic therapy	A 0.05% cream bid per day in pruritic areas) Systemic therapy
	Consider course of systemic corticosteroids(e.g. prednisone 0.5-1mg/kg body weight/day, 14-day taper)a	IV 0.5-1mg/kg body weight/day, 14-day taper)a
	GABA analogs, e.g.gabapentin 100-300mg tid or pregabalin, 50-100mg tid(titrate)	IV 100-300mg tid or pregabalin, 50-100mg tid(titrate)	B	B
	and
	Consider dupilumab(600mg s.c. followed by 300mg s.. q 2 weeks)a	IV 0	IV 0	A
	or
	Consider omalizumab 300 mg s.c. every 4 weeks°	IV 0	IV 0	B
	Multidisciplinary decision to hold or discontinue ICI(at least improvement to G1/G2)

表 3
Severity(CTAE v5.0)	Preventative measures	Management	LoE	GoR
Grade 1	Use of cleansing oil,	Skin-directed therapy	IV	A
macules/papules covering<10% BSA with or without symptoms(e.g., pruritus, burning)	moisturising and emolient creams	Potent or superpotent topical corticosteroids (e.g.,betamethasone dipropionate 0.05%, triamcinolone0.1% or clobetasol 0.05% cream, over the skinlesions)
	Protect skin from any kind of physical and/or chemical damage	Oral antihistamines- fragrance-free moisturizers(applied to full body surface) Continue ICI at current dose
		Reassess after 2-4 weeks; if reactions worsen or donot improve, proceed to next step
Grade 2'	Use of cleansing oil, maculisering and emolient	Skin-directed therapy	IV	A
macules/papules covering 10-30% BSA with or without symptoms(e.g., pruritus, burning);limiting instrumental ADL; rash covering>30% BSAwith or without mild symptoms	protect skin from any kind of physical and/or chemical damage	Potent or superpotent topical corticosteroids(e.g. betamethasone dipropionate 0.05%, triamcinolone0.1% or clobetasol 0.05% cream, over the skin lesions) Oral antihistamines- fragrance-free moisturizers(applied to full body surface)
		Continue ICI at current dose
		Reassess after 2-4 weeks; if reactions worsen or donot improve, proceed to next step
Persistent or intolerable grade 2t	Use of cleansing oil, moisturising and emolient creams	Reinforce grade 2 management	IV	B
Or	moisturising and emolient	Consider oral corticosteroids(0.5-1 mg/kg/day orequivalent with dose increase up to 2 mg/kg/day ifno improvement1t)
Grade 3t	Protect skin from any kind of physical and/or chemical damage	Withhold ICI
macules/papules covering>30% BSA withmoderate or severe symptoms(e.g., pruritus,		Reassess after 2-4 weeks: If avoid erivalent	4	A
burning); limiting self-care ADL	burning); limiting self-care ADL	if reactions worsen or do not next step. if reactions improve, start oral corticosteroids tapering. Rechallenge ICI when Grade 1, and after tapering oral corticosteroids at a dose ≤10 mg/day	5	B
Grade 4t	Use of cleansing oil,	Methylprednisolone 2 mg/kg/day or equivalent	IV	B
Life-threatening consequences, urgent intervention needed.	moisturising and emolient creams	Permanently discontinue and urgent supportive measures
	Protect skin from any kind of physical and/or chemical damage
ADL,activities of daily life;BSA,body	cture area;CTCAE,Common Terminology Criteria for Adverse Events; ICI, immune checkpoint inhibitors. 1vCheck for rash-associated dermatosis and other skin disorders induced by immune checkpoint inhibitors, and bullous pemphigoid, or life-threatening cutaneous drug reactions).	1Check for rash-associated dermatosis and other skin disorders induced by immune checkpoint inhibitors, bullous pemphigoid, or life-threatening cutous drug reactions).	32	CI, immune checkpoint inhibitors. E;ICI, immune checkpoint inhibitors, E;ICI, immune checkpoint inhibitors, E;ICI, immune checkpoint inhibitors, E;ICI, immune checkpoint inhibitors, E;ICI, immune checkpoint inhibitors, E;ICI, immune checkpoint, E;ICI, immune checkpoint, E;ICI
		Reassess after 2-4 weeks:	49,50

表 4
History of Preexisting Psoriasis	Preventative measures • Referral to dermatologist Specialist	Management	LoE	GoR
History of Preexisting Psoriasis	Preventative measures • Referral to dermatologist Specialist	• Acitretin, Apremilast, Methotrexate, Fumaric Acid Esters analogs: Can be maintained when starting ICI ● Cyclosporine: Adjust treatment before initiating ICI ● Biologic Therapies: Should be discussed case by case with cancer specialists	IV	B
Grade 1
Psoriatic plaques covering<10% BSA; no psychosocial impact	• Consider to quit smoking	Continue ICI at current dose Reassess after 2-4 weeks and monitor for change in severity ● Use topical agents# If reactions worsen or do not improve, proceed to next	IV	B
Grade 2		Continue ICI at current dose
Psoriatic plaques covering 10-30% BSA with or without symptoms		Continue ICI at current dose	IV	B
Intolerable Grade 1		• Reinforce Grade 1 management
		● Consider narrowband ultraviolet B
		or
		● Start systematic treatment': Acitretin 10-30 mg d, Methotrexate 10-25 mg/week Apremilast 30 mg bid
		● Reassess before each ICI treatment and monitor for change in severity
		If reactions worsen or do not improve, proceed to next
Grade 3		● Reinforce Grade 2 management
Psoriatic plaques covering>30% BSA with or without symptoms		● Consider biologics#: anti-TNFa anti-IL-23 anti-IL-17		B
		If reactions worsen or do not improveDiscontinue ICI

表 5
Severity(CTCAE v5.0)	Preventive measures	Management	LoE	GoR
Grade 1	Fragrance-free moisturizers	Skin-directed therapy	IV	A
macules/papules covering<10% BSA with or	Avoid scratching and minor skin trauma	Potent or superpotent topical corticosteroids(e.g., betathemasone dipropionate 0.05%, triamcinolone 0.1%	IV	A
without symptoms(e.g.,pruritus, burning) with or	Referral to dermatologist Examine skin, hair, nail, oral and genital mucosa	or clobetasol 0.05% cream, over the skin lesions)
Macules/papules covering 10-30% BSA with or		Oral antihistamines
without symptoms(e.g.,pruritus, burning); limiting instrumental Activities of daily life; rash covering>30% BSA with or without mild symptoms		Continue immune checkpoint inhibitors(ICL) at current dose

		Reassess after 2-4 weeks; if reactions worsen or do not improve, proceed to next step
Persistent or intolerable Grade 2		Reinforce grade 2 management		IV
or		consider oral corticosteroids(0.5-1 mg/kg/day for 4/6 weeks) and high-potency or very high-potency topical		B
Grade 2 with severe mucosal lesions		corticosteroids
or		+- oral retinoids(alitretinoin, acitretinoin 20-30 mg/day)
Grade 3		Withhold ICI*
macules/papules covering>30% BSA with moderate or severe symptoms
(e.g.,pruritus, burning); limiting self-care activities of daily life
		Reassess after 2-4 weeks: ● If reactions worsen or do not improve, proceed to next step
		. If reactions improve, start oral corticosteroids
		tapering
		Rechallenge ICI when G≤1, and after tapering oral corticosteroids at a dose≤10 mg/d
Recalcitrant lesions		Reinforce grade 3 management		V
		Mainain oral corticosteroids(1 mg/kg/day) withhold or discontinue ICI* Consider other steroid-sparing agents: harrowband ultraviolet B phototherapy*, immunosuppressive drugs (e.g. methotrexate) biologic therapies(dupilumab, malizumab) consider hospitalization until control of disease activity

表 6
Severity(CTCAE v5.0)	Preventative measures	Management	LoE	GoR
Grade 1	UVA/UVB high photoprotection	No treatmentt	III-IV	B
Hypopigmentation or depigmentation covering<10% BSA; no psychosocial impact		or potentual corticosteroids topical calcineurin inhibitors Continue ICI at current dose Reassess after several weeks and monitor for change in severity, clinical improvement, patient satisfaction and psychologic impact; consider camouflage if needed If reactions worsen or do not improve, proceed to next step
Grade 2		0 No treatmentt	III-IV	B
Hypopigmentation or depigmentation covering>10% BSA; associated psychosocial impact		or potent topical corticosteroids and/or topical calcineurin inhibitors l atic current octare severe also after several weeks and monitor for change in severity, clinical improvement, patient satisfaction and psychologic impact;
		Continue ICI at current dose Reassess after several weeks and monitor for change in severity, clinical improvement, patient satisfaction and psychologic impact;
		consider camouflage if needed If reactions worsen or do not improve, proceed to next step
Grade 2				III-IV B
Hypopigmentation or depigmentation covering>10% BSA; associated psychosocial impact	UVA/UVB high photoprotection	No treatmentt or
		or potent topical corticosteroids and/or topical calcineurin inhibitors and/or narrowband ultraviolet B phototherapyi+ Continue ICI at current dose Reassess after several weeks and monitor for change in severity, clinical improvement, patient satisfaction and psychologic impact; consider camouflage if needed

表 7
Severity(CTCAE	5.0)	Intervention	LoE	GoR
Grade 1 (<10% BSA)	Superpotent topical corticosteroids(30-40 g/day of cobetolasol propionate applied, bid, over Continue ICI at current dose	IV	A
Grade 1 (<10% BSA)	Reassess after 2-4 weeks; if reactions do not improve, consider the addition of oral prednis- alone at a doses10mg/day If reactions worsen, proceed to next step	IV	A
Grade 2 (10%-30% BSA)	Consorl corticosteroids(0.5 mg/kg/day, prednisolone) and superpotent topical cortico- steroids Wound care with petrolatum-based emolients and non-stick dressings are recommended withhold ICI	IV	A
Reassess after 2-4 weeks: If reactions worsen or do not improve, increase the dose of oral prednisolone or proceed to next step ● If reactions improve, start oral corticosteroids tapering ● Rechallenge ICI when G≤1 and after tapering oral corticosteroids at a dose≤ 10mg/d
Reassess after 2-4 weeks: If reactions worsen or do not improve, increase the dose of oral prednisolone or proceed to next step ● If reactions improve, start oral corticosteroids tapering ● Rechallenge ICI when G≤1 and after tapering oral corticosteroids at a dose≤ 10mg/d	Oral corticosteroids(0.5-1.0 mg/kg/day, l prednisolone) Consider a steroid-sparing agent a b Withhold or discontinue ICI° Consider hospitalization until control of disease activity		IV	A
	Reassess after 2 weeks: ● If reactions worsen proceed to next step
Grade 4 (>30% BSA)	For reactions improve start oral corticosteroids tapering; ● Re-challenge ICI when G≤1 and after tapering oral corticosteroids at a dose≤ 10mg/d
Grade 4 (>30% BSA)
Grade 3b (>30% BSA)	Oral corticosteroids(0.5-1.0 mg/kg/day, l prednisolone) Consider a steroid-sparing agent a b Withhold or discontinue ICI° Consider hospitalization until control of disease activity			IV
	Reassess after 2 weeks: ● If reactions worsen proceed to next step ● If reactions improve start oral corticosteroids tapering; ● Re-challenge ICI when G≤1 and after tapering oral corticosteroids at a dose≤ 10mg/d
Grade 4 (>30% BSA; with fluid and/or electrolyte abnormalities)	Hospitalize(intensive care or burn unit) the patient and use IV methylprednisolone 1-2 mg/ kg/day until control of disease activity, then switch to prednisolone 0.5-1 mg/kg/day and start tapering discontinue ICI			V

表 8
Severity(CTCAE v.50)	Preventative measures	Intervention	LoE	GoR
Grade 1	Risk Assessment: Screen for	Alopeia Aureta	V	A
Hair loss of less than 50% of normal for	personal history of AA or LPP	No treatment*
that individual that is not obvious from	before initiating ICLs.
a distance but only on close inspection;	Early Referral: if hair loss is	or
over the hair loss, but it does not require	observed.	Intralesional corticosteroids(triaminolone)+/-potent or
a wig or hairpiece to camouflage	Counsel patients on possible hair loss, emphasize early symptom reporting. Non pharmacological strategies are recommended to prevent AA or LPP	superpotent topical corticosteroids(e.g., betathesone dipropionate 0.05%, triamcinol 0.1% or cobetasol 0.05% lotion)+ topical minoxidl 5% solution or foam or low dose oral minoxidl 5.5mg/day. continue ICI at current dose Reassess after 4 weeks and monitor for change in severity,improvement, patient satisfaction and psycholog- ical impact; continue dermatologic therapy as needed if successful response
		if reactions worsen or do not improve, proceed to next step Scarring alopraia
		No treatment*
		or
		Potent or super potent topical corticosteroids+/-topical tacrolimus+/- intralesional corticosteroids+/- hydroxyclo- roquine 200mg 12/24 daily+ topical minoxid 5%
		If scaling, consider combination of calcipotriol/betameth- asone gel
		Consider systemic corticosteroids for inflammatory phase of LPP
		continue ICI at current dose
		continue ICI at current dose
		Reassess after 4 weeks and monitor for change in severity,improvement, patient satisfaction and psycho- logic impact; continue dermatologic therapy as needed if successful response
		If reactions worsen or do not improve, proceed to next step
Grade 2	Hair loss more than 50% normal for that	Alopeia Aureta	V	A
individual that is readily apparent to oth- ers; a wig or hair piece is necessary if the
layer loss more than 50% normal for that		Notreatment*
irans to desire can'to oth- ers; a wig or hair piece is necessary if the		Or
patient desires to completely camouflage		Same management as Grade 1
the hair loss; associated with psychoso- cial impact		Other therapies could be considered* including topical
		immunotherapy with diphenylycproponeen. Continue
		dermatologic therapy as needed if successful response
		continue ICI at current dose
		continue ICI at current dose
		Reassess after 4 weeks and monitor for change in severity, clinical improvement, patient satisfaction and
		perthability impact; consider scalp prothesis or camou- flag if needed
		flage if needed
		If reactions worsen or do not improve, proceed to next step
		costricial alopeia
		Notreatment*
		or
		Same management as Grade 1
		Other therapies could be considered* including acitretin 25
		mg daily,mycophenolate mofetil 500-1500mg twice daily, cyclosporine 3 to 5 mg/kg/day, pioglitazone 15-30 mg daily,thalidomide 100-200 mg daily,doxycycline 100mg twice daily,naltrexone 3mg daily.Continue dermatologic therapy as needed if successful response
		therapy as needed if successful response
		Continue ICI at current dose
		Reassess after 4 weeks and monitor for change in severity, clinical improvement, patient satisfaction and psychological therapy as needed
		psychologic impact; consider scalp prothesis or camou- flag if needed
		flag if needed

		Alopeia Aureta and Scarring alopeia	V	C
		(to intralesional corticosteroids and topical	No treatment*
		or
			Consider other steroid-sparing agents/immunosuppressive
		drugs(e.g. methotrexate)
		Monitor for change in severity, clinical improvement, patient satisfaction and psychological impact; or scalp
		Continue ICI at current dose if positive cancer outcome,
		with psychological support if needed
		*A shared-decision process is recommended, involving a careful consideration of patient's preferences, psychological impact, tumor stage(advu
	versus metastatic setting),response to ICI and treatments risks and benefits.
	JAK inhibitors could be used with caution in cancer patients. Personalized risk assessment and vigilant monitoring is recommended when considering	JAK inhibitors could be used with caution in cancer patients. Personalized risk assessment and vigilant monitoring is recommended when considering

表 9
Clinical grade	Dry mouth	Reticulated lesions	Erosive/bullous lesions
	Serum screening for anti-SSA/SSB antibodies	Screening for other oral lesions compatible with a lichenoid reaction (atrophy, plaques, erosive/ulcerous lesions)	Consider immunofluorescence, ELISA assay, histology to exclude/ confirm autoimmune bullous diseas or lichen planus pemphigoid, proceed as follows
	Treat associated oral burns(screening for deficiencies of iron and vitamins B9 and B12, stomatodynia)	Consider biopsy for refractory/ severe cases to confirm oral lichenoid reaction	In the case of an isolated lichenoid reaction, proceed as in the previous column("reticulated lesions")
Grade 1-2 Grade 1: asymptomatic or mild symptoms	Rule out candidal superinfection	Maintain good oral hygiene (LoE V/GoR B)	Maintain good oral hygiene
Grade 2: oral mucosal lesions with moderate pain, modified diet may be necessary	Stimulation of saliva, hydration LoE V/GoR B	Topical corticosteroids (dexamethasone solution 0.1 mg/ml,prednisolone mouthwash, clobasetal topical cream 0.05%, flucinideon topical gel 0.05%); tacrolimus ointment	Oral cavity coating, lubricating and moistening agents Topical corticosteroids (dexamethasone solution 0.1 mg/ ml,prednisolone mouthwash, clobetasol topical cream 0.05%, flucinideon topical gel 0.05%); tacrolimus ointment

表 10
Continue immunotherapy treatment at the same dose and monitor for change in severity
Intolerable grade 2 or more
Intolerable grade 2 or oral symptoms	Maintain good oral hygiene	Maintain good oral hygiene	Maintain good oral hygiene
associated with severe pain interfering with oral intake	Supportive care/dietary recommendations	Supportive care/dietary recommendations	Supportive care/dietary recommendations
Grade 3 or more: recalcitrant oral symptoms	Oral corticosteroids 0.5 mg/kg/ day for 2-4 weeks and reduce if improvement	Oral corticosteroids 0.5 mg/kg/day for 2-4+/- oral retinoids(acitretinin 20-30 mg/day) and suspend immunotherapy	Consider systemic management of autoimmune bullous disease:oral corticosteroids(0.5-1 mg/ kg/day) for 2-4 weeks; consider steroid-sparing agents(dapsone, rituximab, methotrexate,omalizumab, dupilumab); suspend immunotherapy until grade 0 or tolerable grade 2
	If no improvement, oral corticosteroids 1 mg/kg/day and suspend or discontinue immunotherapy until grade 0 or tolerable grade 2	Reduce oral corticosteroids and resume immunotherapy after a return to tolerable grade 0 or tolerable grade 2	omalizumab, dupilumab); suspend immunotherapy until grade 0 or tolerable grade 2 Multidisciplinary decision to reintroduce immunotherapy(taking into account the stage of the tumor and the response, risks and benefits of treatment).
	If no improvement, oral corticosteroids(1 mg/kg/day) and consider steroid-sparing agents (methotrexate, thalidomide, hydroxychloroquine, etc.); suspend immunotherapy until grade 0 or tolerable grade 2	If no improvement, oral corticosteroids(1 mg/kg/day) and consider steroid-sparing agents (methotrexate, thalidomide, hydroxychloroquine, etc.); suspend immunotherapy until grade 0 or tolerable grade 2	into account the stage of the tumor and the response, risks and benefits of treatment).
	LoE V/GoR A	LoE V/GoR A

图示：Grade 1(mild) Topical treatments $\pm$ Oral anthistamines Re-evaluate in 2-4 weeks Grade 2 (moderate) Add GABA analogs Refractory or severe Consider dupilum or amolizumab

图示：Grade 1(<10% BSA) Topical corticosteroids + emolients Re-evaluate in 2-4 weeks Grade 2(10-30% BSA) Add Oral antihistamines Systemic corticosteroids (0,5-1 mg/kg/day); continue ICI Grade 3(>30% BSA) Discontinue ICI + high dose corticosteroids + urgent care

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2025+EADV专案组声明：皮肤免疫相关不良事件的预防和处理. 2025.