Defining D-irAEs: consensus-based disease definitions for the diagnosis of dermatologic adverse events from immune checkpoint inhibitor therapy.

With an increasing number of patients eligible for immune checkpoint inhibitors, the incidence of immune-related adverse events (irAEs) is on the rise. Dermatologic immune-related adverse events (D-irAEs) are the most common and earliest to manifest, often with important downstream consequences for the patient. Current guidelines lack clarity in terms of diagnostic criteria for D-irAEs. The goal of this project is to better define D-irAE for the purposes of identification, diagnosis, and future study of this important group of diseases.The objectives of this project were to develop consensus guidance for an approach to D-irAEs including disease definitions and severity grading. Knowing that consensus among oncologists, dermatologists, and irAE subspecialists would be critical for usability, we formed a Dermatologic irAE Disease Definition Panel. The panel was composed of 34 experts, including oncologists, dermatologists, a rheumatologist, and an allergist/immunologist from 22 institutions across the USA and internationally. A modified Delphi consensus process was used, with two rounds of anonymous ratings by panelists and two virtual meetings to discuss areas of controversy. Panelists rated content for usability, appropriateness, and accuracy on 9-point scales in electronic surveys and provided free text comments. A working group aggregated survey responses and incorporated them into revised definitions. Consensus was based on numeric ratings using the RAND/UCLA Appropriateness Method with prespecified definitions.Following revisions based on panelist feedback, all items received consensus in the second round of ratings. Consensus definitions were achieved for 10 core D-irAE diagnoses: ICI-vitiligo, ICI-lichen planus, ICI-psoriasis, ICI-exanthem, ICI-bullous pemphigoid, ICI-Grover's, ICI-eczematous, ICI-eruptive atypical squamous proliferation, ICI-pruritus without rash, and ICI-erosive mucocutaneous. A standard evaluation for D-irAE was also found to reach consensus, with disease-specific exceptions detailed when necessary. Each disorder's description includes further details on disease subtypes, symptoms, supportive exam findings, and three levels of diagnostic certainty (definite, probable, and possible).These consensus-driven disease definitions standardize D-irAE classification in a useable framework for multiple disciplines and will be the foundation for future work. Given consensus on their accuracy and usability from a representative panel group, we anticipate that they can be used broadly across clinical and research settings.

Updates in SJS/TEN: collaboration, innovation, and community.

Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) is a predominantly drug-induced disease, with a mortality rate of 15-20%, that engages the expertise of multiple disciplines: dermatology, allergy, immunology, clinical pharmacology, burn surgery, ophthalmology, urogynecology, and psychiatry. SJS/TEN has an incidence of 1-5/million persons per year in the United States, with even higher rates globally. One of the challenges of SJS/TEN has been developing the research infrastructure and coordination to answer questions capable of transforming clinical care and leading to improved patient outcomes. SJS/TEN 2021, the third research meeting of its kind, was held as a virtual meeting on August 28-29, 2021. The meeting brought together 428 international scientists, in addition to a community of 140 SJS/TEN survivors and family members. The goal of the meeting was to brainstorm strategies to support the continued growth of an international SJS/TEN research network, bridging science and the community. The community workshop section of the meeting focused on eight primary themes: mental health, eye care, SJS/TEN in children, non-drug induced SJS/TEN, long-term health complications, new advances in mechanisms and basic science, managing long-term scarring, considerations for skin of color, and COVID-19 vaccines. The meeting featured several important updates and identified areas of unmet research and clinical need that will be highlighted in this white paper.

Diffuse Cutaneous Aphthosis After Combined Targeted Cancer Therapies and Responsive to Pentoxifylline.

This case series describes 3 patients who developed cutaneous aphthosis while taking an epidermal growth factor receptor inhibitor in combination with an MEK inhibitor.

Immune Profiling of Dermatologic Adverse Events from Checkpoint Blockade using Tissue Cyclic Immunofluorescence.

In this study, we demonstrate the utility of whole-slide CyCIF (tissue-based cyclic immunofluorescence) imaging for characterizing immune cell infiltrates in immune checkpoint inhibitor (ICI)-induced dermatologic adverse events (dAEs). We analyzed six cases of ICI-induced dAEs, including lichenoid, bullous pemphigoid, psoriasis, and eczematous eruptions, comparing immune profiling results obtained using both standard immunohistochemistry (IHC) and CyCIF. Our findings indicate that CyCIF provides more detailed and precise single-cell characterization of immune cell infiltrates than IHC, which relies on semi-quantitative scoring by pathologists. This pilot study highlights the potential of CyCIF to advance our understanding of the immune environment in dAEs by revealing tissue-level spatial patterns of immune cell infiltrates, allowing for more precise phenotypic distinctions and deeper exploration of disease mechanisms. By demonstrating that CyCIF can be performed on friable tissues, such as bullous pemphigoid, we provide a foundation for future studies to examine the drivers of specific dAEs using larger cohorts of phenotyped toxicity and suggest a broader role for highly multiplexed tissue imaging in phenotyping the immune mediated disease that they resemble.

Cutaneous eruptions from ibrutinib resembling epidermal growth factor receptor inhibitor-induced dermatologic adverse events.

BACKGROUND: Ibrutinib is an oral inhibitor of Bruton tyrosine kinase that is approved by the United States Food and Drug Administration for several lymphoproliferative disorders and chronic graft-versus-host disease. OBJECTIVE: To characterize cutaneous eruptions arising from ibrutinib and highlight overlap with epidermal growth factor receptor (EGFR) inhibitor-induced dermatologic adverse events. METHODS: Single-center retrospective cohort of patients referred to the Skin Toxicities Program for treatment of cutaneous eruptions while taking ibrutinib. RESULTS: Among 19 patients, cutaneous eruptions manifested as facial-predominant papulopustular eruptions, petechiae, or ecchymoses, photosensitivity, panniculitis, xerosis, and clinical staphylococcal overgrowth. Most patients were able to continue ibrutinib therapy with focused treatment of their cutaneous toxicities. LIMITATIONS: This study represents cases at a single tertiary care center and is limited to patients referred for toxicity. CONCLUSIONS: With the exception of petechiae, the cutaneous toxicities of ibrutinib overlap with those associated with selective EGFR inhibitors. We observed that these reactions can be successfully managed using approaches for EGFR inhibitor-induced cutaneous adverse events.

Challenging Dermatologic Considerations Associated with Immune Checkpoint Inhibitors.

Immune checkpoint inhibitors have emerged as a new paradigm in oncologic care for many malignancies. However, nonspecific immune activation has led to "collateral damage" in the form of immune-related adverse events, with skin being a commonly affected organ. Cutaneous immune-related adverse events include a wide spectrum of clinical presentations and challenging considerations, often necessitating dermatology referral to support diagnosis and management, particularly for atypical presentations or more severe, cutaneous immune-related adverse events that may require specialized dermatologic evaluations including biopsy and histopathology. Close collaborations between oncologists and dermatologists may optimize clinical decision making in the following challenging management settings: non-steroidal therapies for corticosteroid-refractory, cutaneous immune-related adverse events, immune checkpoint inhibitor rechallenge, balancing cutaneous immune-related adverse events and treatments, and immune checkpoint inhibitors in patients with pre-existing autoimmune disease, skin conditions, and organ transplants. These complex clinical decisions that often lack rigorous data should be made in close collaboration with dermatologists to minimize unnecessary morbidity and mortality. This article provides a review of approaches to challenging dermatologic considerations associated with immune checkpoint inhibitor therapies.

Hypersensitivity Reactions and Immune-Related Adverse Events to Immune Checkpoint Inhibitors: Approaches, Mechanisms, and Models.

Immune checkpoint inhibitors (ICI) are a major class of cancer therapeutics that may cause durable responses in a growing proportion of patients with metastatic cancer. These agents remove negative regulators on T cells and may cause autoimmunelike toxicities that affect all organ systems. Monoclonal antibodies are much less commonly associated with traditional hypersensitivity reactions. Herein, we discuss the pathophysiology, clinical presentation, and management of toxicities of ICI and discuss their broader context within drug hypersensitivity.

Clinical Characteristics, Disease Course, and Outcomes of Patients With Acute Generalized Exanthematous Pustulosis in the US.

Importance: Acute generalized exanthematous pustulosis (AGEP) is a rare, severe cutaneous adverse reaction associated with systemic complications. Currently available data are largely limited to small retrospective case series. Objective: To describe the clinical characteristics, disease course, and outcomes of a heterogeneous group of patients with AGEP across the US. Design, Setting, and Participants: A retrospective review of a case series of patients was conducted from January 1, 2000, through July 31, 2020. All 340 included cases throughout 10 academic health systems in the US were scored retrospectively using the EuroSCAR scoring system, and patients with a score corresponding to probable or definite AGEP and aged 18 years or older were included. Main Outcomes and Measures: Patient demographic characteristics, clinical course, suspected causative agent, treatment, and short- and long-term outcomes. Results: Most of the 340 included patients were women (214 [62.9%]), White (206 [60.6%]), and non-Hispanic (239 [70.3%]); mean (SD) age was 57.8 (17.4) years. A total of 154 of 310 patients (49.7%) had a temperature greater than or equal to 38.0 °C that lasted for a median of 2 (IQR, 1-4) days. Of 309 patients, 263 (85.1%) developed absolute neutrophilia and 161 patients (52.1%) developed either absolute or relative eosinophilia. Suspected causes of AGEP were medications (291 [85.6%]), intravenous contrast agents (7 [2.1%]), infection (3 [0.9%]), or unknown (39 [11.5%]). In 151 cases in which a single medication was identified, 63 (41.7%) were ß-lactam antimicrobials, 51 (33.8%) were non-ß-lactam antimicrobials, 9 (6.0%) were anticonvulsants, and 5 (3.3%) were calcium channel blockers. The median time from medication initiation to AGEP start date was 3 (IQR, 1-9) days. Twenty-five of 298 patients (8.4%) had an acute elevation of aspartate aminotransferase and alanine aminotransferase levels, with a peak at 6 (IQR, 3-9) days. Twenty-five of 319 patients (7.8%) experienced acute kidney insufficiency, with the median time to peak creatinine level being 4 (IQR, 2-5) days after the AGEP start date. Treatments included topical corticosteroids (277 [81.5%], either alone or in combination), systemic corticosteroids (109 [32.1%]), cyclosporine (10 [2.9%]), or supportive care only (36 [10.6%]). All-cause mortality within 30 days was 3.5% (n = 12), none of which was suspected to be due to AGEP. Conclusions and Relevance: This retrospective case series evaluation of 340 patients, the largest known study cohort to date, suggests that AGEP onset is acute, is usually triggered by recent exposure to an antimicrobial, may be associated with liver or kidney complications in a minority of patients, and that discontinuation of the triggering treatment may lead to improvement or resolution.

Intralesional corticosteroid injections are less painful without local anesthetic: a double-blind, randomized controlled trial.

BACKGROUND: Corticosteroid injections are a commonly used treatment for dermatologic pathologies. Although the injectable is often prepared with a local anesthetic, we hypothesize that patients receiving an injection with anesthetic will experience no decrease in pain at the time of injection. METHODS: Patients requiring a corticosteroid injection were prospectively randomized into two cohorts to receive a corticosteroid (triamcinolone acetonide) combined with either lidocaine with epinephrine 1:100 000 (anesthetic) or bacteriostatic normal saline. Both patient and clinician were blinded to the treatment arm. The primary outcome was pain associated with the injection measured using a Visual Analog Scale (VAS) immediately following the injection. RESULTS: Thirty-one patients were enrolled with 18 in the saline group and 13 in the lidocaine with epinephrine group. Pain scores were significantly higher for injections containing lidocaine with epinephrine versus saline (VAS 5.0 vs 2.0, p = .0056). CONCLUSIONS: For various dermatologic pathologies, corticosteroid injections are effective and have relatively little associated pain. Counterintuitively, we found that there is more injection-associated pain when lidocaine with epinephrine is included with the corticosteroid. Therefore, clinicians should omit this anesthetic or dilute corticosteroids with normal saline, rather than with lidocaine and epinephrine. This will minimize injection pain as well as decrease the risk of pharmacologic adverse reactions from an unnecessary additional medication. Due to the small sample size, additional research may be necessary for generalization to other indications. Clinicaltrials.gov listing: NCT03630198.

Case Report: Infantile Urticaria as a Herald of Neonatal Onset Multisystem Inflammatory Disease With a Novel Mutation in NLRP3.

Neonatal multisystem onset inflammatory disorder (NOMID) is a severe autoinflammatory syndrome that can have an initial presentation as infantile urticaria. Thus, an immediate recognition of the clinical symptoms is essential for obtaining a genetic diagnosis and initiation of early therapies to prevent morbidity and mortality. Herein, we describe a neonate presenting with urticaria and systemic inflammation within hours after birth who developed arthropathy and neurologic findings. Pathologic evaluation of the skin revealed an infiltration of lymphocytes, eosinophils, and scattered neutrophils. Genetic analysis identified a novel heterozygous germline variant of unknown significance in the NLRP3 gene, causing the missense mutation M408T. Variants of unknown significance are common in genetic sequencing studies and are diagnostically challenging. Functional studies of the M408T variant demonstrated enhanced formation and activity of the NLRP3 inflammasome, with increased cleavage of the inflammatory cytokine IL-1ß. Upon initiation of IL-1 pathway blockade, the infant had a robust response and improvement in clinical and laboratory findings. Our experimental data support that this novel variant in NLRP3 is causal for this infant's diagnosis of NOMID. Rapid assessment of infantile urticaria with biopsy and genetic diagnosis led to early recognition and targeted anti-cytokine therapy. This observation expands the NOMID-causing variants in NLRP3 and underscores the role of genetic sequencing in rapidly identifying and treating autoinflammatory disease in infants. In addition, these findings highlight the importance of establishing the functional impact of variants of unknown significance, and the impact this knowledge may have on therapeutic decision making.

Business Education in Dermatology Residency: A Survey of Program Directors.

With the rising cost of health care in the United States and an increasingly competitive market, dermatology residents would benefit from business training. We constructed an 8-part questionnaire for dermatology program directors (PDs) to determine the current perceptions of and resources available for business education. Of the 139 surveys distributed, 35 were completed (25.2%). Approximately one half of the respondents said their programs offered business training, primarily through seminars or lectures. Most PDs felt business education during residency was important and that programs should implement more training. The most important topics identified for inclusion in a business curriculum were economics or finance, management, and health care policy or government. Our survey identified a gap between the perceived importance and current supply of business education during dermatology residency training. Future efforts should aim to develop a standardized, dermatology-specific curriculum that is readily available to all programs and residents.

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

BACKGROUND: Immune checkpoint inhibitors (ICIs) are approved to treat multiple cancers. Retrospective analyses demonstrate acceptable safety of ICIs in most patients with autoimmune disease, although disease exacerbation may occur. Psoriasis vulgaris is a common, immune-mediated disease, and outcomes of ICI treatment in patients with psoriasis are not well described. Thus we sought to define the safety profile and effectiveness of ICIs in patients with pre-existing psoriasis. METHODS: In this retrospective cohort study, patients from eight academic centers with pre-existing psoriasis who received ICI treatment for cancer were evaluated. Main safety outcomes were psoriasis exacerbation and immune-related adverse events (irAEs). We also assessed progression-free survival (PFS) and overall survival. RESULTS: Of 76 patients studied (50 (66%) male; median age 67 years; 62 (82%) with melanoma, 5 (7%) with lung cancer, 2 (3%) with head and neck cancer, and 7 (9%) with other cancers; median follow-up 25.1 months (range=0.2-99 months)), 51 (67%) received anti-PD-1 antibodies, 8 (11%) anti-CTLA-4, and 17 (22%) combination of anti-PD-1/CTLA-4. All patients had pre-existing psoriasis, most frequently plaque psoriasis (46 patients (61%)) and 15 (20%) with psoriatic arthritis. Forty-one patients (54%) had received any prior therapy for psoriasis although only two (3%) were on systemic immunosuppression at ICI initiation. With ICI treatment, 43 patients (57%) experienced a psoriasis flare of cutaneous and/or extracutaneous disease after a median of 44 days of receiving ICI. Of those who experienced a flare, 23 patients (53%) were managed with topical therapy only; 16 (21%) needed systemic therapy. Only five patients (7%) required immunotherapy discontinuation for psoriasis flare. Forty-five patients (59%) experienced other irAEs, 17 (22%) of which were grade 3/4. PFS with landmark analysis was significantly longer in patients with a psoriasis flare versus those without (39 vs 8.7 months, p=0.049). CONCLUSIONS: In this multicenter study, ICI therapy was associated with frequent psoriasis exacerbation, although flares were manageable with standard psoriasis treatments and few required ICI discontinuation. Patients who experienced disease exacerbation performed at least as well as those who did not. Thus, pre-existing psoriasis should not prevent patients from receiving ICIs for treatment of malignancy.

Cutaneous adverse events caused by immune checkpoint inhibitors.

IMPORTANCE: Immune checkpoint inhibitors (ICIs) have emerged as active therapies for a variety of cancers. Cutaneous toxicities are common immune-related adverse events and patients will often be referred to dermatologists for evaluation. OBSERVATIONS: Cutaneous adverse events to ICIs can have a variety of clinical presentations. Among the more common are eczematous, morbilliform, and lichenoid dermatoses, as well as vitiligo and pruritus. Less common adverse events include psoriasiform dermatoses, bullous disorders, and severe cutaneous adverse reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms. Because of the immunologic mechanism of ICIs, there are also a variety of rheumatologic adverse reactions with cutaneous manifestations, such as scleroderma, dermatomyositis, cutaneous lupus erythematosus, and various vasculitides. These cutaneous reactions often respond to topical or systemic steroids, although specific toxicities may have alternative treatments available. CONCLUSIONS AND RELEVANCE: As they become more widely prescribed, dermatologists will see an increasing number of patients with cutaneous adverse events caused by ICI therapies. Accurately diagnosing and treating these toxicities is paramount to achieving the most favorable outcomes for patients.