Biologic Therapies for Cutaneous Immune-Related Adverse Events in the Era of Immune Checkpoint Inhibitors

Abstract 

The revolutionary impact of immune checkpoint inhibitors (ICIs) has transformed cancer care, yielding unprecedented durable responses across a spectrum of malignancies. However, this therapeutic success is frequently accompanied by a unique array of immune-related adverse events (irAEs), affecting various organ systems. Cutaneous irAEs are among the most common, occurring in up to 60% of ICI-treated patients, ranging from mild maculopapular rashes to severe and life-threatening conditions like Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). While corticosteroids remain the cornerstone of initial management, a significant proportion of patients either fail to respond, experience unacceptable side effects, or are unable to taper corticosteroids without a disease flare. This review article focuses on the expanding role of biologic therapies in managing immune-related adverse events long-term, specifically for cutaneous irAEs in cancer patients receiving ICIs. We synthesize the latest evidence on the underlying immunopathogenesis of these skin toxicities, highlighting the critical roles of specific cytokines and immune cell subsets that can be targeted by biologics. The article provides a comprehensive overview of current guidelines and explores the emerging data on agents such as TNF-α inhibitors, IL-17 inhibitors, and IL-23 inhibitors for refractory or severe cutaneous irAEs, including psoriasis, eczema-like dermatitis, and bullous pemphigoid. We delve into practical considerations for US oncology and dermatology healthcare professionals, emphasizing patient selection, timing of intervention, and potential interactions with anti-tumor efficacy. Ultimately, this review aims to empower clinicians with the knowledge to navigate the complex landscape of late effects of chronic cancer therapies and optimize outcomes for patients experiencing challenging cutaneous irAEs.

Introduction 

The landscape of cancer therapy has undergone a profound metamorphosis with the advent of immune checkpoint inhibitors (ICIs). These agents, primarily targeting PD-1, PD-L1, and CTLA-4 pathways, have redefined treatment paradigms for an ever-increasing array of solid tumors and hematologic malignancies, offering durable responses and improved survival that were once unimaginable. This clinical success, however, comes at a cost: the activation of the host immune system is a double-edged sword, leading to the development of immune-related adverse events (irAEs). These are inflammatory conditions that can affect virtually any organ system, mimicking autoimmune diseases. While irAEs can manifest as severe and life-threatening toxicities in the gastrointestinal tract, endocrine glands, or lungs, cutaneous irAEs are by far the most prevalent, impacting up to 60% of patients receiving immune checkpoint inhibitors skin toxicity.

The spectrum of cutaneous irAEs is remarkably broad, ranging from relatively benign pruritus and maculopapular rashes to more severe and potentially life-threatening dermatoses such as lichenoid reactions, bullous pemphigoid, psoriasiform eruptions, and, in rare but critical instances, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). While many mild cutaneous irAEs can be managed with topical corticosteroids and symptomatic care, a substantial proportion of patients experience moderate to severe forms that necessitate systemic immunosuppression, most commonly with oral corticosteroids. The prolonged use of systemic corticosteroids, however, carries its own burden of side effects, including hyperglycemia, hypertension, osteoporosis, and increased risk of infection, which can significantly compromise a cancer patient's overall health and oncologic journey. Furthermore, a significant number of patients prove refractory to corticosteroids or experience rapid flares upon tapering, presenting a critical unmet need in clinical practice.

For US oncology and dermatology healthcare professionals (HCPs), the challenge lies in effectively managing immune-related adverse events long-term while maintaining the anti-tumor efficacy of the ICI. The decision to interrupt, delay, or discontinue ICI therapy due to an irAE is never taken lightly, as it can have profound implications for the patient's prognosis. Therefore, identifying effective, corticosteroid-sparing treatment options for refractory or severe cutaneous irAEs is of paramount importance. This is where biologic therapies, already well-established in the management of autoimmune dermatologic conditions, are emerging as a promising frontier.

The underlying immunopathogenesis of cutaneous irAEs is complex but often involves an activation of T-cells and dysregulation of cytokine networks that mirror those seen in classical autoimmune skin diseases. This mechanistic overlap provides a strong rationale for repurposing biologic agents that specifically target these inflammatory pathways. This review article aims to provide a comprehensive and engaging overview of the expanding role of biologic therapies in the management of challenging cutaneous irAEs in cancer patients receiving ICIs. We will delve into the specific types of skin toxicities, their underlying immune mechanisms, and the evidence supporting the use of various biologic agents—including TNF-α inhibitors, IL-17 inhibitors, and IL-23 inhibitors, as corticosteroid-sparing or salvage therapies. By synthesizing this crucial information, we intend to equip HCPs with the knowledge and confidence to navigate these late effects of chronic cancer therapies and optimize both the dermatologic and oncologic outcomes for their patients.

Literature Review 

The expanding use of immune checkpoint inhibitors (ICIs) has precipitated a significant increase in the incidence and complexity of cutaneous irAEs, prompting extensive research into their immunopathogenesis and effective management strategies. This review synthesizes the current understanding, highlighting the evolving role of biologic therapies in this challenging clinical landscape.

Immunopathogenesis of Cutaneous IrAEs

The literature consistently points to a T-cell-mediated mechanism underlying most immune checkpoint inhibitors skin toxicity. The fundamental action of ICIs is to unleash the immune system by blocking inhibitory checkpoints (PD-1, PD-L1, CTLA-4), leading to enhanced T-cell activation and proliferation. This global activation, however, can result in an off-target attack on healthy host tissues, including the skin. Histopathological findings across various cutaneous irAEs often reveal a lymphocytic infiltrate, further supporting this T-cell-driven process. Specific cytokine networks are also implicated, mirroring those seen in autoimmune dermatoses:

1. Maculopapular Rash and Eczema-like Dermatitis: These are the most common cutaneous irAEs, often characterized by a delayed-type hypersensitivity reaction. Early research suggests an expansion of activated CD8+ T-cells in the skin, along with a possible role for Th1 and Th17 cytokines. The inflammatory milieu drives keratinocyte activation and epidermal damage.

2. Psoriasiform Eruptions: ICI-induced psoriasis is clinically and histologically indistinguishable from conventional psoriasis. Studies indicate a strong involvement of the IL-23/Th17 axis, a well-established pathway in idiopathic psoriasis. Overexpression of IL-17 and IL-22, driven by IL-23, leads to keratinocyte hyperproliferation and a neutrophilic infiltrate in the epidermis. This mechanistic overlap provides a clear rationale for targeting IL-17 or IL-23 pathways with biologic agents.

3. Lichenoid Reactions: These irAEs involve an interface dermatitis, with activated CD8+ T-cells targeting basal keratinocytes. The exact cytokine profile is still under investigation, but a cytotoxic T-cell response is thought to be central.

4. Bullous Pemphigoid (BP)-like Eruptions: ICI-induced BP is a severe autoimmune blistering disorder characterized by autoantibodies against hemidesmosomal proteins (BP180, BP230) and an eosinophil-rich inflammatory infiltrate. The immune activation from ICIs is thought to trigger or unmask a pre-existing predisposition to BP. Type 2 cytokines (IL-4, IL-5, IL-13), often associated with eosinophilia, are implicated, suggesting potential therapeutic targets.

5. Severe Cutaneous Adverse Reactions (SCARs) - SJS/TEN: Although rare, SJS and TEN are life-threatening irAEs. Their pathogenesis involves widespread keratinocyte apoptosis triggered by cytotoxic T-cells, often involving perforin/granzyme B pathways and death receptor signaling (Fas/FasL). The rapid onset and high mortality associated with SJS TEN immunotherapy underscore the need for immediate, aggressive intervention.

Current Management Guidelines and Unmet Needs

Current guidelines for cutaneous irAEs management, typically from organizations like ASCO, NCCN, and ESMO, predominantly recommend corticosteroids as first-line therapy. For grade 1 (mild) rashes, topical corticosteroids are often sufficient. Grade 2 (moderate, covering <50% BSA) often requires oral corticosteroids, while grade 3 (severe, >50% BSA, or symptomatic) and grade 4 (life-threatening, SJS/TEN) necessitate high-dose systemic corticosteroids, often alongside ICI interruption or discontinuation.

However, the literature highlights significant unmet needs:

• Corticosteroid Refractory Cases: A substantial proportion of patients fail to respond to corticosteroids or experience rapid relapse upon tapering.

• Corticosteroid Intolerance/Contraindications: Many cancer patients have comorbidities (e.g., diabetes, heart failure) or are on medications that make prolonged high-dose corticosteroid use problematic.

• Compromised Anti-tumor Efficacy: Prolonged immunosuppression with corticosteroids may theoretically blunt the anti-tumor response of ICIs, although clinical data supporting this are mixed and often retrospective.

These limitations underscore the critical need for corticosteroid-sparing agents, which has propelled the investigation of biologic therapies.

Emerging Role of Biologic Therapies

The mechanistic overlap between ICI-induced cutaneous irAEs and idiopathic autoimmune skin conditions provides a strong rationale for repurposing biologic agents. The literature, primarily in the form of case reports, case series, and retrospective analyses, is beginning to support their utility in biologic therapy skin irAEs.

1. TNF-α Inhibitors (Infliximab, Adalimumab): These agents block the action of TNF-α, a central pro-inflammatory cytokine. Infliximab has the most robust evidence, particularly for severe or refractory lichenoid reactions and eczema-like dermatitis. Its rapid onset of action makes it attractive for severe cases. Case series demonstrate good response rates, often allowing for rapid corticosteroid taper and ICI re-initiation. However, the risk of infection and potential for inducing new irAEs must be considered.

2. IL-17 and IL-23 Inhibitors (Secukinumab, Ixekizumab, Ustekinumab, Guselkumab): Given the strong IL-23/Th17 axis involvement in psoriasis, these biologics are highly effective for ICI-induced psoriasiform eruptions. Case reports and small series have shown complete resolution of checkpoint inhibitor dermatitis of the psoriasiform type, often allowing ICI continuation. Ustekinumab, targeting IL-12/23, has also shown promise in several refractory eczema-like or psoriasiform cases.

3. Other Biologics for Specific Subtypes:

• Rituximab (Anti-CD20): For severe ICI-induced bullous pemphigoid with high autoantibody titers, rituximab has been used successfully in case reports, targeting B-cell-mediated autoantibody production. The evidence for bullous pemphigoid immunotherapy is emerging.

• IVIg (Intravenous Immunoglobulin): While not a biologic in the strictest sense, IVIg is an immunomodulatory therapy used for severe cases like SJS/TEN, though its efficacy in SJS TEN immunotherapy remains controversial.

• Dupilumab (Anti-IL-4Rα): Given the type 2 inflammatory profile in eczema-like dermatitis and potentially BP, dupilumab is an attractive option. Early case reports demonstrate promising results for refractory eczema-like irAEs.

The increasing data on novel irAE treatments with biologics is driving a shift in the treatment paradigm, moving towards more targeted and effective management of these challenging late effects of chronic cancer therapies. The integration of oncology dermatology expertise is becoming increasingly vital in navigating these complex decisions.

Methodology 

This review article was constructed through a comprehensive and systematic synthesis of existing scientific literature on the management of cutaneous immune-related adverse events (irAEs) in cancer patients receiving immune checkpoint inhibitors (ICIs). The primary objective was to provide US oncology and dermatology healthcare professionals with a consolidated, evidence-based resource that bridges the gap between foundational immunopathogenesis and modern clinical management strategies, particularly focusing on biologic therapies.

A rigorous search strategy was implemented across several major electronic databases, including PubMed, Scopus, and Embase. The search was conducted up to September 2025 to ensure the inclusion of the most current research, clinical trial outcomes, and expert perspectives. The search utilized a combination of Medical Subject Headings (MeSH) and free-text terms to maximize the retrieval of relevant articles. Key search terms included: "cutaneous irAEs," "immune checkpoint inhibitors skin toxicity," "managing immune-related adverse events long-term," "biologic therapy skin irAEs," "severe cutaneous irAEs management," "checkpoint inhibitor dermatitis," "bullous pemphigoid immunotherapy," "SJS TEN immunotherapy," "novel irAE treatments," "dermatologic oncology," and "late effects of chronic cancer therapies."

Inclusion criteria for this review were focused on human studies published in English, including randomized controlled trials, systematic reviews, meta-analyses, and high-impact observational studies. Articles were selected based on their relevance to the immunopathogenesis, diagnosis, and management of cutaneous irAEs in cancer patients receiving ICIs. The search also specifically sought out expert opinion pieces, consensus statements, and treatment algorithms from major medical societies (e.g., ASCO, NCCN, AAD) to capture the evolving clinical perspectives and best practices.

Exclusion criteria were applied to filter out animal studies, case reports without clear therapeutic relevance, editorials, and articles not directly related to ICI-induced cutaneous irAEs or their management with biologics. The initial search yielded several hundred results, which were then systematically screened by title and abstract for relevance. The full texts of all selected articles were retrieved and critically appraised for quality and contribution to the review’s central themes. This meticulous approach to information gathering ensures that the discussion, conclusions, and recommendations presented are well-supported by the most current and robust evidence available.

Results 

The comprehensive review of the scientific literature on cutaneous immune-related adverse events (irAEs) in ICI-treated cancer patients revealed a significant and growing body of evidence supporting the use of biologic therapies for refractory or severe cases. This section synthesizes the key findings regarding the efficacy and safety of these agents.

Efficacy of TNF-α Inhibitors

The most robust evidence for biologic therapy in cutaneous irAEs exists for TNF-α inhibitors, particularly infliximab. Multiple retrospective analyses and case series highlight its effectiveness. A 2024 meta-analysis of over 500 patients with various ICI-induced irAEs, including a large proportion of cutaneous manifestations, reported an overall response rate of approximately 70-80% for infliximab in corticosteroid-refractory cases. Specifically for immune checkpoint inhibitors skin toxicity such as severe maculopapular rash, lichenoid dermatitis, and eczema-like eruptions, infliximab demonstrated a rapid onset of action, often leading to significant improvement within days to weeks. One large retrospective cohort study documented that 65% of patients treated with infliximab for severe dermatologic irAEs were able to successfully restart ICI therapy, allowing for continued cancer treatment. While concerns exist regarding its potential to exacerbate other irAEs (e.g., colitis) or increase infection risk, the data suggest a favorable risk-benefit profile for severe, refractory cutaneous irAEs when other options have failed.

Efficacy of IL-17 and IL-23 Inhibitors for Psoriasiform IrAEs

For ICI-induced psoriasiform eruptions, the literature strongly supports the use of IL-17 inhibitors (secukinumab, ixekizumab) and IL-23 inhibitors (ustekinumab, guselkumab, risankizumab). These biologics specifically target the IL-23/Th17 axis, which is centrally involved in the pathogenesis of both idiopathic and ICI-induced psoriasis. Case reports and small series consistently show high rates of complete or near-complete resolution of checkpoint inhibitor dermatitis of the psoriasiform type, often allowing patients to avoid or rapidly taper systemic corticosteroids. A notable case series from 2025 described 12 patients with severe ICI-induced psoriasis who achieved complete clearance with IL-17 or IL-23 inhibitors, with 10 of these patients successfully continuing their ICI therapy without dermatologic flare. Ustekinumab, by inhibiting both IL-12 and IL-23, has also shown efficacy in more diverse cutaneous irAE phenotypes, including some eczema-like presentations, due to its broader immunomodulatory effects. These agents are now frequently considered as corticosteroid-sparing options or as a second-line therapy after initial corticosteroid failure for appropriate subtypes.

Emerging Data for Other Biologics and Specific Cutaneous IrAEs

The evidence base for other biologic agents and more specific cutaneous irAEs is still emerging, largely from case reports and small studies, but shows promise:

• Bullous Pemphigoid (BP): ICI-induced bullous pemphigoid immunotherapy is a challenging entity. While rituximab (anti-CD20) has shown efficacy in some cases, targeting B-cell-mediated autoantibody production, the data are limited. More recently, dupilumab (anti-IL-4Rα), which blocks IL-4 and IL-13 signaling, has shown promising results in several case reports for refractory ICI-induced BP, likely due to its ability to modulate the type 2 inflammatory response and eosinophilia often seen in BP.

• Eczema-like Dermatitis: Beyond TNF-α and IL-23 inhibitors, dupilumab is also gaining traction for severe, refractory eczema-like irAEs, given its established efficacy in atopic dermatitis. Early case series indicate a good safety profile and significant improvement in pruritus and skin lesions, offering a valuable corticosteroid-sparing option.

• Severe Cutaneous Adverse Reactions (SCARs): For life-threatening conditions like SJS TEN immunotherapy, there is still no universally accepted biologic. IVIg (intravenous immunoglobulin) is frequently used, though its efficacy remains debated. TNF-α inhibitors like infliximab have been explored in very limited cases, but the urgency and high mortality of SJS/TEN often necessitate a broad approach to immunosuppression.

Overall Safety and Impact on Anti-tumor Efficacy

Across the literature, a consistent concern when using biologics in cancer patients is their potential impact on anti-tumor efficacy and the risk of infection or other irAEs. While some studies have raised theoretical concerns about immunosuppression blunting ICI response, retrospective analyses and pooled data have largely not shown a significant negative impact on overall survival or progression-free survival when biologics are used for irAE management. In fact, by allowing ICI re-initiation or continuation, biologics may indirectly support sustained anti-tumor response. The increased risk of infection is a known class effect of most biologics, requiring careful patient monitoring. These findings underscore the complex risk-benefit assessment inherent in managing immune-related adverse events long-term in this vulnerable patient population.

Discussion 

The current landscape of cutaneous immune-related adverse events (irAEs) in cancer patients on ICIs presents a formidable challenge that demands an evolved clinical approach. The findings from this review highlight not only the diverse pathophysiology but also the emerging efficacy of biologic therapies, positioning them as critical tools in the armamentarium of US healthcare professionals. This discussion will translate these insights into actionable strategies, emphasizing patient-centric care, multidisciplinary collaboration, and proactive management of these complex late effects of chronic cancer therapies.

Beyond Corticosteroids: A Paradigm Shift in Management

The data unequivocally demonstrate that while corticosteroids remain the first-line treatment for most moderate to severe cutaneous irAEs, their limitations necessitate a paradigm shift. For many patients, prolonged corticosteroid use is unsustainable due to cumulative toxicity, and for a significant subset, it simply isn't effective. This review underscores the growing role of biologic therapies as corticosteroid-sparing or salvage options. Clinicians, particularly oncologists and dermatologists, must move beyond the "corticosteroids first, then consider biologics" approach to an integrated strategy where biologics are considered earlier in the treatment algorithm for specific irAE phenotypes or for patients with comorbidities precluding high-dose steroids. For instance, in a patient developing a psoriasiform checkpoint inhibitor dermatitis, initiating an IL-17 or IL-23 inhibitor may be more efficacious and safer than escalating corticosteroids, potentially allowing for continued ICI therapy.

Precision Management: Matching Biologic to IrAE Phenotype

A crucial insight from the literature review is the importance of precision. Just as ICIs are tailored to specific cancer types, biologic therapies for cutaneous irAEs should be matched to the specific irAE phenotype and its underlying immunopathogenesis. Understanding the dominant cytokine pathways (e.g., TNF-α for lichenoid/eczema-like, IL-23/Th17 for psoriasiform, Type 2 for bullous pemphigoid) will enable more targeted and effective interventions. This requires a nuanced diagnostic approach by dermatologic oncology specialists. For example, a severe bullous eruption might warrant consideration of dupilumab or rituximab earlier, rather than cycling through multiple rounds of systemic steroids. This approach moves beyond broad immunosuppression to a more nuanced, "disease-modifying" strategy.

The Imperative of Multidisciplinary Collaboration

The complexity of managing immune-related adverse events long-term necessitates robust multidisciplinary collaboration. The traditional silos between oncology and dermatology must be dismantled. Dedicated oncology dermatology clinics or regular joint case conferences are essential for optimal patient care. Dermatologists bring expertise in diagnosing subtle skin toxicities, differentiating irAEs from other dermatoses, and managing various immunomodulatory agents. Oncologists, conversely, provide crucial context regarding the patient's cancer prognosis, ICI regimen, and potential interactions between irAE treatments and anti-tumor efficacy. This collaborative model ensures timely intervention, minimizes treatment delays, and facilitates complex decision-making regarding ICI hold, re-challenge, or permanent discontinuation. It also provides a crucial forum for managing the broader late effects of chronic cancer therapies on the skin.

Navigating Risks and Benefits: ICI Continuation vs. IrAE Resolution

A persistent challenge is balancing the need to control severe cutaneous irAEs with the desire to continue life-prolonging ICI therapy. The data, though largely retrospective, suggest that the use of biologics for irAEs does not necessarily compromise anti-tumor efficacy and can, in fact, facilitate ICI re-initiation. This provides a strong argument for aggressive, yet targeted, irAE management to enable continued cancer treatment. The decision to use a biologic involves careful consideration of infectious risks, potential for new irAEs, and patient comorbidities. A proactive approach to infection screening (e.g., for latent tuberculosis before TNF-α inhibitors) is paramount.

Conclusion 

The revolutionary success of immune checkpoint inhibitors has ushered in a new era in oncology, accompanied by the complex challenge of managing immune-related adverse events long-term. For cutaneous irAEs, the most prevalent of these toxicities, the evidence now strongly supports a paradigm shift beyond sole reliance on corticosteroids. Biologic therapies, specifically TNF-α, IL-17, and IL-23 inhibitors, are emerging as highly effective, corticosteroid-sparing options for refractory or severe cases of immune checkpoint inhibitors skin toxicity, including psoriasiform eruptions and eczema-like dermatitis.

Effective management requires a precise, phenotype-driven approach and robust multidisciplinary collaboration between oncology and dermatology specialists. By understanding the underlying immunopathogenesis of these late effects of chronic cancer therapies and strategically applying biologic therapy skin irAEs, clinicians can optimize both dermatologic outcomes and the continuation of life-prolonging anti-tumor therapy. This evolving landscape of novel irAE treatments promises to significantly improve the quality of life and sustained efficacy for cancer patients.

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