Advanced Management Solutions for High-Grade Cutaneous Toxicities to Cancer Therapy

The emergence of immune checkpoint inhibitors (ICIs) has fundamentally altered the prognosis for patients with advanced skin malignancies, yet the high incidence of cutaneous immune-related adverse events (irAEs) remains a significant barrier to treatment continuity. Here, we review the clinical manifestations and histopathologic features of high-grade dermatologic toxicities, with a specific focus on the management of eruptions including bullous pemphigoid, atopic, psoriasiform, and lichenoid dermatitis. 

This review synthesizes existing research to highlight the multifaceted nature of ICI-induced cutaneous irAEs, which pose both a clinical challenge and a potential biomarker for assessing the effectiveness of cancer therapy. Moreover, we provide therapeutic strategies aimed at treating cutaneous immune-related adverse events while improving patient quality of life and enabling the continuation of life-saving cancer therapy.

INTRODUCTION TO IMMUNOTHERAPY AND CUTANEOUS TOXICITY

The landscape of skin cancer treatment has undergone a significant transformation with the introduction of immune checkpoint inhibitors (ICIs), especially those targeting programmed cell death 1 (PD-1) and its ligand (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). These therapies have become essential in the management of metastatic melanoma and are increasingly being used to treat nonmelanoma skin cancers, including cutaneous squamous cell carcinoma and Merkel cell carcinoma.^1-3

Although ICI therapy enhances the immune system’s capacity to identify and eliminate malignant cells, it frequently induces immune-related adverse events (irAEs) due to a breakdown in self-tolerance.⁴

MECHANISMS OF CUTANEOUS TOXICITY

The immunopathogenesis of cutaneous irAEs is driven by distinct mechanisms depending on the checkpoint pathway involved. PD-1/PD-L1 inhibitors (eg, nivolumab, pembrolizumab, atezolizumab) remove inhibitory signals on cytotoxic T-cells, enabling them to attack both tumor cells and skin keratinocytes via cross-reactive antigens. This mechanism predominantly underlies bullous pemphigoid, lichenoid reactions, and vitiligo-like depigmentation.^5,6 CTLA-4 inhibitors (eg, ipilimumab) act earlier in T-cell activation, blocking a coinhibitory signal and producing a broader, more systemic immune activation that frequently manifests as maculopapular or psoriasiform eruptions.⁶ Combination ICI therapy amplifies immune activation across both pathways and is associated with higher grades and greater diversity of cutaneous toxicity.^7,8

At the tissue level, the underlying mechanisms involve activation of T-cells that cross-react with antigens shared by the tumor and the skin, upregulation of inflammatory cytokines (including IL-17, IL-4, IL-13, and IL-31), B cell-mediated autoantibody production (as in bullous pemphigoid), and loss of regulatory T-cell suppression.^6,9 The specific morphologic pattern of an eruption, therefore, reflects the immunologic pathway activated and should guide targeted therapeutic decisions.

EPIDEMIOLOGY AND SURVIVAL ASSOCIATIONS

Cutaneous toxicities rank among the most prevalent irAEs, affecting as many as 30% to 50% of patients treated with ICIs.^5,7,8 While most reactions are mild, high-grade (Grade 3–4) toxicities such as severe exfoliative dermatitis or bullous disorders present a significant clinical challenge, often requiring the cessation of life-saving cancer therapy.^10,11

Notably, the development of certain cutaneous irAEs has been associated with improved overall survival in melanoma patients. Numerous studies have indicated that the onset of skin toxicity such as vitiligo or lichenoid eruptions may act as a clinical biomarker for a robust anti-tumor immune response.^9,12,13 Specifically, patients who experience these events have demonstrated longer progression-free survival compared to those who have not.^12,13 This association underscores the importance of managing cutaneous irAEs proactively rather than reflexively halting therapy.

CLINICAL CONSIDERATIONS WHEN FACING HIGH-GRADE CUTANEOUS TOXICITY

High-grade cutaneous toxicity requires a careful multidisciplinary approach. When evaluating a patient with severe cutaneous irAE, clinicians must simultaneously address several interconnected questions: Can the patient be safely rechallenged with ICI after the reaction resolves? What is the patient’s current cancer status and response to therapy? Are other organ systems involved? And what alternative oncologic treatment options exist?^10,14,15

RECHALLENGE AFTER HIGH-GRADE TOXICITY

The decision to rechallenge immunotherapy after a severe cutaneous reaction is particularly complex and must be individualized. Favorable factors include a Grade 2–3 initial toxicity, a brisk response to corticosteroids or targeted agents, and an absence of mucosal involvement. In contrast, Grade 4 dermatitis, extensive bullous disease, or Stevens–Johnson-like features argue strongly against rechallenge.^10,11,16 Oncologic context is equally critical when effective alternative systemic therapies are available and the risk of rechallenge may outweigh its benefit; conversely, when ICI therapy represents the only viable option, cautious rechallenge under close dermatologic supervision may be warranted.^1,2,14 Rechallenge decisions should always be made through close multidisciplinary evaluation. For a summary of the key clinical factors that inform this decision, see the Table 1.¹⁴

DOSE REDUCTION AND MODIFICATION

Unlike cytotoxic chemotherapy, dose reduction of ICI agents is not a standard strategy for managing cutaneous irAEs, as the adverse events are immunologically rather than pharmacokinetically driven. However, switching from a combination ICI regimen to a single-agent approach or transitioning between agents within the same drug class may reduce toxicity burden while preserving antitumor efficacy in selected patients.^10,14 In practice, temporary ICI withholding rather than permanent discontinuation is the preferred initial step for Grade 3 toxicities, allowing time for the skin reaction to resolve to Grade 1 or less before reconsideration of therapy.

MULTISYSTEM ASSESSMENT, CANCER STATUS, AND ONCOLOGY COLLABORATION

A thorough systems review is essential when a patient presents with high-grade cutaneous toxicity. The simultaneous presence of irAEs in other organ systems including colitis, pneumonitis, myocarditis, or hepatitis significantly shifts the risk-benefit calculus and may preclude rechallenge.^4,10 Conversely, isolated cutaneous involvement without systemic irAEs carries a more favorable prognosis for continued or resumed ICI therapy.

The patient’s cancer status must be weighed equally. Patients with objective tumor response or stable disease on ICI therapy, for whom immunotherapy represents the most effective available option, are more likely to benefit from aggressive management of cutaneous toxicity and cautious rechallenge. For patients with progressive disease despite ICI therapy, or for whom multiple effective alternatives exist, the threshold for permanent discontinuation should be lower.^1,2,9,12

Ongoing communication between the dermatologist and the oncology team is essential to ensure that cutaneous irAEs are managed effectively enough to support continuation or safe resumption of cancer therapy. Multidisciplinary tumor board discussion is recommended for Grade 3–4 toxicities, and dermatology should be formally integrated into the oncology care pathway for patients receiving ICI therapy.^10,15

MANAGEMENT STRATEGIES FOR ADVANCES CUTANEOUS ERUPTIONS

Care teams managing cancer patients with cutaneous irAEs have a broad therapeutic toolbox that allows treatment to be tailored to the patient’s clinical presentation, preferences, and tolerability profile. Management of high-grade toxicities includes modalities such as phototherapy and corticosteroids, as well as targeted biologic therapies and other systemic immunomodulators selected according to the specific morphologic pattern.^16,17 Table 2 provides a comprehensive overview of eruption types, associated drug classes, histopathologic features, and preferred management strategies.

THE ROLE OF PHOTOTHERAPY ACROSS ERUPTION TYPES

Narrowband ultraviolet B (NB-UVB) phototherapy is a valuable, nonimmunosuppressive treatment modality for several ICI-induced cutaneous eruptions. Its mechanism of action involves the induction of T-cell apoptosis in the skin, suppression of local cytokine production, and restoration of regulatory T-cell activity, all without systemic immunosuppression that could compromise the anti-tumor effects of ICI therapy.^5,16 These properties make NB-UVB particularly attractive in the oncologic setting, where systemic corticosteroids carry the risk of blunting anti-tumor responses.

NB-UVB is most effective for psoriasiform and atopic dermatitis–like eruptions and can be considered for select cases of diffuse maculopapular rash.^5,6 However, phototherapy is avoided in lichenoid dermatitis, as UV exposure may theoretically trigger or exacerbate interface reactions. Practical limitations include the need for repeated clinic visits and patient availability, which may be challenging in the setting of active cancer treatment.

PSORIASIFORM ERUPTIONS

Psoriasiform eruptions induced by ICIs often appear within 4 to 8 weeks of treatment initiation and mimic classic psoriasis clinically and histologically, demonstrating regular acanthosis, parakeratosis, and Munro microabscesses driven by Th1/Th17 immune skewing.^5,6,16 Management for mild-to-moderate disease typically involves topical corticosteroids and NB-UVB phototherapy. For high-grade or refractory cases, systemic agents targeting the dysregulated Th17 axis are increasingly utilized. IL-17 inhibitors (secukinumab, ixekizumab) directly neutralize the primary effector cytokine, while IL-23 inhibitors (guselkumab, risankizumab) suppress the upstream driver of Th17 differentiation.^5,16,17 These biologics are particularly appealing in the oncologic context, as they do not produce broad immunosuppression, and emerging data suggest they do not compromise ICI anti-tumor efficacy. Acitretin, an oral retinoid, remains an option in patients for whom biologic therapy is not feasible.¹⁶

ATOPIC DERMATITIS-LIKE ERUPTIONS AND SEVERE PRURITIS

Atopic dermatitis–like eruptions and severe pruritus are among the most burdensome cutaneous irAEs encountered in clinical practice, typically presenting within 2 to 12 weeks of ICI initiation. Histopathologically, these reactions demonstrate spongiotic dermatitis with dermal eosinophilia and a perivascular lymphocytic infiltrate, reflecting a Th2-skewed inflammatory state driven by IL-4, IL-13, and IL-31 upregulation.^5,6,18 Dupilumab, a monoclonal antibody targeting the IL-4 receptor alpha shared by IL-4 and IL-13 signaling, has demonstrated significant efficacy in resolving ICI-associated atopic-like eruptions and pruritus without compromising the anti-tumor effects of ICI therapy.^18,19 By specifically blocking the Th2 inflammatory pathway in the skin, dupilumab addresses the pathogenic driver without broadly suppressing anti-tumor T-cell responses. For patients with refractory pruritus who do not respond adequately to dupilumab, nemolizumab, a monoclonal antibody targeting the IL-31 receptor alpha, a key mediator of itch, represents an emerging therapeutic option.¹⁹

LICHENOID ERUPTIONS

Lichenoid reactions are among the more common cutaneous irAEs, occurring in 9% to 24% of patients treated with PD-1 inhibitors and up to 14% of those receiving CTLA-4 inhibitors.^5,8,17 They characteristically present with pruritic, violaceous, flat-topped papules in a distribution resembling idiopathic lichen planus, and can be particularly persistent, sometimes appearing or worsening even after discontinuation of the offending ICI agent, a pattern that distinguishes them clinically from drug reactions driven by direct toxicity.^8,17,20 Histopathologically, lichenoid irAEs demonstrate a dense, band-like lymphocytic infiltrate at the dermal-epidermal junction (DEJ), basal vacuolar change, and Civatte (colloid) bodies, consistent with interface dermatitis mediated by cytotoxic T-cells targeting basal keratinocytes.^16,17 Management for high-grade lichenoid dermatitis typically begins with high-potency topical corticosteroids, escalating to systemic corticosteroids for Grade 3–4 disease. Acitretin has demonstrated utility in refractory cases. IL-17 or IL-23 biologics may be considered for persistent, steroid-refractory lichenoid disease, although evidence is less robust than for psoriasiform eruptions. 

BULLOUS PEMPHIGOID

Bullous pemphigoid (BP) is the most clinically distinct and potentially severe cutaneous irAE, with a median onset of approximately 4 months after ICI initiation. It is most strongly associated with PD-1/PD-L1 inhibitors and is thought to arise when ICI-induced immune activation generates pathogenic autoantibodies targeting BP180 (type XVII collagen) and BP230 at the cutaneous basement membrane zone.^21-23 Clinically, BP presents with tense subepidermal bullae on an erythematous base; direct immunofluorescence (DIF) demonstrates linear IgG and C3 deposition at the basement membrane, confirming the diagnosis.

The management of ICI-associated BP involves a prolonged systemic steroid taper, often supplemented by steroid-sparing agents such as doxycycline and nicotinamide for milder disease. For severe or refractory cases, rituximab, a monoclonal antibody targeting CD20 on B cells, has emerged as a pivotal option.^21,23 Rituximab directly addresses the underlying pathogenesis of BP by depleting the B cell populations responsible for producing the pathogenic anti-BP180 and anti-BP230 autoantibodies.^16,22 Clinical evidence suggests that rituximab can be particularly effective in ICI-induced BP, often enabling a more rapid steroid taper and reducing the cumulative corticosteroid burden.²¹ In cases of Grade 4 dermatitis or extensive bullous disease, a combination of targeted biologics and intravenous immunoglobulin (IVIG) may be necessary to achieve skin clearance.^11,23 Dupilumab, which targets the IL-4 receptor alpha shared by IL-4 and IL-13 signaling, has received US Food and Drug Administration (FDA) approval for bullous pemphigoid, reflecting its established role in addressing the Th2 component of ICI-associated BP pathogenesis. Similarly, nemolizumab, targeting the IL-31 receptor alpha, received FDA approval for atopic dermatitis, further expanding the targeted biologic toolkit for Th2-mediated cutaneous irAEs, including severe pruritus.^24,25

RECHALLENGE DECISION FRAMEWORK

Given the survival benefit associated with ICI therapy and the potentially reversible nature of many cutaneous irAEs, discontinuation should not be the reflexive response to high-grade toxicity. Rather, rechallenge decisions should be guided by a structured framework incorporating the severity and type of the initial reaction, the patient’s oncologic status, the time course of the irAE, involvement of other organ systems, and the patient’s response to prior immunosuppression.^10,14 Shared decision-making, explicitly documenting the risks, benefits, and alternatives with the patient, is both an ethical imperative and a medicolegal best practice.^10,15 Table 1 outlines the key clinical factors that favor or disfavor rechallenge.

CONCLUSION AND FUTURE DIRECTIONS

The integration of immunotherapy into the standard of care for skin cancers has created a new frontier in oncodermatology. The appearance of cutaneous toxicities demands a shift in clinical mindset. These events should be viewed not merely as complications to be suppressed, but as visible manifestations of a re-engaged immune system that, in many cases, portends improved oncologic outcomes.^1,2,9,12,13

Moving forward, dermatologists have more nonsteroidal options that are safe for long-term use, including  targeted interventions such as rituximab for B cell-mediated bullous disease, dupilumab and nemolizumab for Th2-driven pruritus, and IL-17/IL-23 biologics for Th17-mediated psoriasiform eruptions.^18,21,23 Novel nonsteroidal topicals are also emerging as important steroid-sparing options in this setting, including topical ruxolitinib, a JAK1/JAK2 inhibitor approved for atopic dermatitis,²⁶ and tapinarof, an aryl hydrocarbon receptor agonist approved for plaque psoriasis and atopic dermatitis.²⁷ These agents may be particularly useful for facial, intertriginous, or other sensitive-site eruptions where long-term corticosteroid use carries risk of atrophy. Management of these toxicities is further guided by institutional algorithms, such as the MD Anderson ICI dermatitis algorithm, which provides a practical, grade-based framework for the full spectrum of immune-mediated dermatologic toxicities.²⁸ Nonimmunosuppressive modalities such as NB-UVB phototherapy offer additional tools that address the cutaneous irAE without compromising the systemic anti-tumor response. As we refine the safety profiles of ICI rechallenge and neoadjuvant applications, the formal collaboration between dermatology and oncology through co-management, multidisciplinary tumor boards, and integrated care pathways will remain the cornerstone of successful treatment.^2,10,14

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2. Spadafora M, Paganelli A, Raucci M, et al. Neoadjuvant immunotherapy in cutaneous squamous cell carcinoma: systematic literature review and state of the art. Cancers (Basel). 2025;17(4):637. doi:10.3390/cancers17040637 

3. Lin C, Ballah T, Nottage M, et al. A prospective study investigating the efficacy and toxicity of definitive chemoradiation and immunotherapy in locally and/or regionally advanced unresectable cutaneous squamous cell carcinoma. Radiat Oncol. 2021;16(1):69. doi:10.1186/s13014-021-01795-5 

4. Yin Q, Wu L, Han L, et al. Immune-related adverse events of immune checkpoint inhibitors: a review. Front Immunol. 2023;14:1167975. doi:10.3389/fimmu.2023.1167975 

5. Sibaud V. Dermatologic reactions to immune checkpoint inhibitors. Am J Clin Dermatol. 2018;19(3):345-361. doi:10.1007/s40257-017-0336-3 

6. Bhardwaj M, Chiu MN, Pilkhwal Sah S. Adverse cutaneous toxicities by PD-1/PD-L1 immune checkpoint inhibitors: pathogenesis, treatment, and surveillance. Cutan Ocul Toxicol. 2022;41(1):73-90. doi:10.1080/15569527.2022.2034842 

7. Patel AB, Farooq S, Welborn M, et al. Cutaneous adverse events in 155 patients with metastatic melanoma consecutively treated with anti-CTLA-4 and anti-PD-1 combination immunotherapy: incidence, management, and clinical benefit. Cancer. 2022;128(5):975-983. doi:10.1002/cncr.34004 

8. Edwards CL, Comito F, Agraso Busto S, et al. Cutaneous toxicities in patients with melanoma receiving checkpoint inhibitor therapy: a retrospective review. Clin Exp Dermatol. 2021;46(2):338-341. doi:10.1111/ced.14469 

9. Chan L, Hwang SJE, Byth K, et al. Survival and prognosis of individuals receiving programmed cell death 1 inhibitor with and without immunologic cutaneous adverse events. J Am Acad Dermatol. 2020;82(2):311-316. doi:10.1016/j.jaad.2019.06.035 

10. Schneider BJ, Naidoo J, Santomasso BD, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO guideline update. J Clin Oncol. 2021;39(36):4073-4126. doi:10.1200/JCO.21.01440 

11. Randhawa M, Archer C, Gaughran G, et al. Combined immune therapy grade IV dermatitis in metastatic melanoma. Asia Pac J Clin Oncol. 2019;15(4):262-265. doi:10.1111/ajco.13136 

12. Zhang S, Tang K, Wan G, et al. Cutaneous immune-related adverse events are associated with longer overall survival in advanced cancer patients on immune checkpoint inhibitors: a multi-institutional cohort study. J Am Acad Dermatol. 2023;88(5):1024-1032. doi:10.1016/j.jaad.2022.12.048 

13. Hua C, Boussemart L, Mateus C, et al. Association of vitiligo with tumor response in patients with metastatic melanoma treated with pembrolizumab. JAMA Dermatol. 2016;152(1):45-51. doi:10.1001/jamadermatol.2015.2707 

14. Mizuno K, Maeda O, Ando Y. Efficacy and safety of immune checkpoint inhibitor rechallenge following immune-related adverse events: a review. Jpn J Clin Oncol. 2026;56(2):117-129. doi:10.1093/jjco/hyaf200 [Verify publication year, volume, issue, pages, and DOI because this appears to be a future-dated citation.] 

15. Phillips GS, Wu J, Hellmann MD, et al. Treatment outcomes of immune-related cutaneous adverse events. J Clin Oncol. 2019;37(30):2746-2758. doi:10.1200/JCO.18.02141 

16. Martel J, Hanania HL, Patel AB. Immune checkpoint inhibitor-induced cutaneous toxicities: a review of histopathologic and clinical features. Hum Pathol. 2023;140:144-172. doi:10.1016/j.humpath.2023.04.016 

17. Coleman E, Ko C, Dai F, Tomayko MM, Kluger H, Leventhal JS. Inflammatory eruptions associated with immune checkpoint inhibitor therapy: a single-institution retrospective analysis with stratification of reactions by toxicity and implications for management. J Am Acad Dermatol. 2019;80(4):990-997. doi:10.1016/j.jaad.2018.10.062 

18. Singh N, Conner A, Nahmias Z. Dupilumab as an innovative therapy for symptomatic management of chemotherapy-induced pruritus: a case series. Skin Health Dis. 2024;4(2):e365. doi:10.1002/ski2.365 

19. Venturi F, Veronesi G, Scotti B, Dika E. Cutaneous toxicities of advanced treatment for cutaneous melanoma: a prospective study from a single-center institution. Cancers (Basel). 2024;16(21):3679. doi:10.3390/cancers16213679 

20. Mandalà M, Massi D, De Giorgi V. Cutaneous toxicities of BRAF inhibitors: clinical and pathological challenges and call to action. Crit Rev Oncol Hematol. 2013;88(2):318-337. doi:10.1016/j.critrevonc.2013.06.002 

21. Lopez AT, Geskin L. A case of nivolumab-induced bullous pemphigoid: review of dermatologic toxicity associated with programmed cell death protein 1/programmed death ligand 1 inhibitors and recommendations for diagnosis and management. Oncologist. 2018;23(10):1119-1126. doi:10.1634/theoncologist.2018-0128 

22. Lopez AT, Khanna T, Antonov N, Audrey-Bayan C, Geskin L. A review of bullous pemphigoid associated with PD-1 and PD-L1 inhibitors. Int J Dermatol. 2018;57(6):664-669. doi:10.1111/ijd.13984 

23. Siegel J, Totonchy M, Damsky W, et al. Bullous disorders associated with anti-PD-1 and anti-PD-L1 therapy: a retrospective analysis evaluating the clinical and histopathologic features, frequency, and impact on cancer therapy. J Am Acad Dermatol. 2018;79(6):1081-1088. doi:10.1016/j.jaad.2018.07.008 

24. Silk AW, Barker CA, Bhatt DL, et al. Dupilumab for bullous pemphigoid. N Engl J Med. 2024;391(6):502-511. doi:10.1056/NEJMoa2314492 

25. Silverberg JI, Guttman-Yassky E, Toth D, et al. Two phase 3 trials of nemolizumab in atopic dermatitis. N Engl J Med. 2023;389(18):1685-1696. doi:10.1056/NEJMoa2301366 

26. Papp K, Szepietowski JC, Kircik L, et al. Efficacy and safety of ruxolitinib cream for the treatment of atopic dermatitis: results from 2 phase 3, randomized, double-blind studies. J Am Acad Dermatol. 2021;85(4):863-872. doi:10.1016/j.jaad.2021.04.085 

27. Lebwohl MG, Stein Gold L, Strober B, et al. Phase 3 trials of tapinarof cream for plaque psoriasis. N Engl J Med. 2021;385(24):2219-2229. doi:10.1056/NEJMoa2103629 

28. Patel AB, George S, Huen A, et al. Evaluation and management of suspected immune-mediated dermatologic toxicities. MD Anderson Cancer Center Clinical Effectiveness Algorithm. Published 2024. Accessed May 2, 2026. https://www.mdanderson.org/content/dam/mdanderson/documents/for-physicians/algorithms/clinical-management/clin-management-dermatologic-toxicities-web-algorithm.pdf

Preetha Muralidharan, MBBS

• Department of Dermatology, The University of Texas MD Anderson Cancer Center
• Department of Epidemiology, UTHealth Houston School of Public Health

Houston, TX

Rebeca Martinez, MD

• Department of Dermatology, Division of Internal Medicine
• The University of Texas MD Anderson Cancer Center

Houston, TX

Anisha B. Patel, MD

• Department of Dermatology, Division of Internal Medicine
• The University of Texas MD Anderson Cancer Center

Houston, TX