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.

The Impact of Dermatologic Adverse Events on the Quality of Life of Oncology Patients: A Review of the Literature.

Dermatologic adverse events resulting from oncologic therapy are common and negatively impact patients' quality of life. Dermatologic adverse events include toxicity of the skin, oral mucosa, nails, and hair and are seen with cytotoxic chemotherapy, targeted therapy, immunotherapy, and radiation therapy, with distinct patterns of dermatologic adverse events by drug class. Here, we review the literature on the impact of dermatologic adverse events on quality of life. Studies on quality of life in patients with cancer have relied on scales such as the Dermatologic Life Quality Index and Skindex to demonstrate the association between dermatologic adverse events and declining quality of life. This relationship is likely due to a variety of factors, including physical discomfort, changes to body image, decreased self-esteem, and an effect on social interactions. Addressing such quality-of-life concerns for patients with cancer is critical, not only for patients' well-being but also because decreased satisfaction with treatment can lead to discontinuation of treatment or dose reduction. Prophylactic treatment and early management of dermatologic adverse events by experienced dermatologists can alleviate the negative effects on quality of life and allow continuation of life-prolonging treatment.

Multi-center retrospective review of vitiligo-like lesions in breast cancer patients treated with cyclin-dependent kinase 4 and 6 inhibitors.

PURPOSE: Cutaneous adverse effects from cyclin-dependent 4 and 6 kinase inhibitors (CDK4/6i) used in metastatic breast cancer are prevalent and well described. Vitiligo-like lesions have been reported and are rare. They can negatively impact patients' quality of life and may be associated with survival benefits. We describe the clinical characteristics of vitiligo-like lesions in an international cohort of patients treated with CDK4/6i to help improve recognition and management. METHODS: Retrospective review of patients diagnosed with vitiligo-like lesions from CDK4/6i from five academic institutions in the USA and Europe was performed. Ten patients were included in the study. RESULTS: Median age of our patients was 55 (range 37-86). Median progression-free survival was 24 months in 5 patients. The median time to rash was 10 months. Sun-exposed areas such as the arms and face were the most affected areas. Multiple skin-directed therapies such as topicals, laser, and phototherapy were trialed with minor success. Mild repigmentation was seen in one patient treated with ruxolitinib cream. CDK4/6 treatment was discontinued due to the vitiligo-like lesions in one patient. CONCLUSION: Clinical characteristics are similar to previously reported findings in case reports and series. We add topical ruxolitinib as a potential treatment option for these patients and include data regarding progression-free survival that should continue to be collected. No definitive conclusions can be made regarding survival benefits from our cohort. Clinicians should refer these patients to dermatologists to aid with management.

INDIVIDUAL ARTICLE: USCOM Algorithm for the Prevention and Management of Cutaneous Immunotherapy-Related Adverse Events.

BACKGROUND: In 2023, nearly 2 million patients will be diagnosed with cancer in the United States and at least 40% will be eligible for treatment with an immune checkpoint inhibitor (ICI). Cutaneous immune related adverse events (cirAEs) from ICIs are common and include pruritus as well as maculopapular, eczematous, bullous, lichenoid, and psoriasiform reactions. All clinicians interfacing with cancer patients must expedite proper evaluation and diagnosis, treatment, and/or consultation that supports the need for evidence-directed guidelines. MATERIALS AND METHODS: A panel of advisors was selected, and a systematic literature review generated foundational evidence to develop a treatment algorithm for cirAEs via a modified Delphi process. Iterations of the algorithm were performed until the group met consensus. RESULTS: An algorithm that tailors the management of cirAEs was developed based on the CTCAE v.5 grading of skin disorders. Representative clinical images and suggested diagnostic measures, supplement the algorithm. CONCLUSION: Recognition and treatment of cirAEs guided through a multidisciplinary, physician-developed algorithm will limit disruption of immunotherapy, optimize quality of life, and enhance overall outcomes in patients treated with ICIs. J Drugs Dermatol. 2023;22:11(Suppl 1):s3-10.

Recognition and Treatment of Wounds in Persons Using Xylazine: A Case Report From New Haven, Connecticut.

BACKGROUND: Xylazine is an α 2 -adrenergic agonist that is commonly used as a veterinary tranquilizer and is increasingly present in the unregulated US drug supply since at least 2019. There are many suspected clinical complications of xylazine use, including unusual skin wounds, atypical overdose presentations, and possible dependence and withdrawal syndromes. However, there are few reports of cutaneous manifestations of xylazine in patients who inject drugs that can guide diagnosis and management in patients with confirmed xylazine toxicology. CASE SUMMARY: We present the cases of 3 stably housed patients in Connecticut with opioid use disorder and intravenous use of fentanyl who presented with atypical, chronic wounds at the site of injection drug use. Xylazine toxicology sent on all 3 patients was positive. All patients were seen by wound care and dermatology, and 1 patient was followed by infectious diseases. Wound care management strategies are discussed as well as harm reduction strategies. For all patients, the dose of their medication for opioid use disorder was increased to decrease frequency of drug use given concern that patients were exposed to a drug supply containing xylazine. CLINICAL SIGNIFICANCE: This case report presents wound characteristics that raise the index of suspicion for xylazine-involved injection wounds and might assist in their diagnosis and management. There is urgent need for more reporting of such cases as well as rigorous research to understand the potential impact of xylazine on people who use drugs. Multidisciplinary best practices should be established.

Crusted Scabies Presenting as Erythroderma in a Patient With Iatrogenic Immunosuppression for Treatment of Granulomatosis With Polyangiitis.

The diagnosis of scabies can be difficult when the infection presents as erythroderma. Crusted scabies is a severe form of scabies caused by cutaneous ectoparasitic infection by the mite Sarcoptes scabiei var hominis. Crusted scabies most commonly occurs in patients with underlying immunosuppression from acquired infection or subsequent to solid organ or bone marrow transplantation. We present a rare case of a patient with granulomatosis with polyangiitis (GPA) who developed azathioprine-induced myelosuppression and subsequent erythrodermic crusted scabies. It is critical to maintain a broad differential when patients present with erythroderma, especially in the setting of medication-induced immunosuppression for the treatment of autoimmune disease.

PD-1 maintains CD8 T cell tolerance towards cutaneous neoantigens.

The peripheral T cell repertoire of healthy individuals contains self-reactive T cells1,2. Checkpoint receptors such as PD-1 are thought to enable the induction of peripheral tolerance by deletion or anergy of self-reactive CD8 T cells3-10. However, this model is challenged by the high frequency of immune-related adverse events in patients with cancer who have been treated with checkpoint inhibitors11. Here we developed a mouse model in which skin-specific expression of T cell antigens in the epidermis caused local infiltration of antigen-specific CD8 T cells with an effector gene-expression profile. In this setting, PD-1 enabled the maintenance of skin tolerance by preventing tissue-infiltrating antigen-specific effector CD8 T cells from (1) acquiring a fully functional, pathogenic differentiation state, (2) secreting significant amounts of effector molecules, and (3) gaining access to epidermal antigen-expressing cells. In the absence of PD-1, epidermal antigen-expressing cells were eliminated by antigen-specific CD8 T cells, resulting in local pathology. Transcriptomic analysis of skin biopsies from two patients with cutaneous lichenoid immune-related adverse events showed the presence of clonally expanded effector CD8 T cells in both lesional and non-lesional skin. Thus, our data support a model of peripheral T cell tolerance in which PD-1 allows antigen-specific effector CD8 T cells to co-exist with antigen-expressing cells in tissues without immunopathology.

Factors associated with the use of adjuvant radiation therapy in stage III melanoma.

Objective: The role of radiation therapy (RT) in melanoma has historically been limited to palliative care, with surgery as the primary treatment modality. However, adjuvant RT can be a powerful tool in certain cases and its application in melanoma has been increasingly explored in recent years. The aim of this study is to explore national patterns of care and associations surrounding the use of adjuvant RT for stage III melanoma. Methods: The National Cancer Data Base (NCDB) was used to identify patients who were diagnosed with stage III melanoma between 2004 and 2014. Exclusion criteria included those with distant metastatic disease, in-situ histology, no confirmed positive nodes, palliative intent therapy, and dosing regimens inconsistent with National Comprehensive Cancer Network (NCCN) guidelines for adjuvant RT in melanoma. Patients treated with and without adjuvant RT were compared and factors associated with use of adjuvant RT were identified using multivariable logistic regression analyses. Results: A total of 7,758 cases of stage III melanoma were analyzed, of which 11.7% received adjuvant RT. The mean age of the overall cohort was 58.5 years, and the majority of patients were male (64.7%), white (96.6%), on private insurance (51.3%), and presented to a non-high-volume facility (90.3%). Multivariable regression analyses revealed that patients who present to the hospital in 2009-2014 as compared to 2004-2008 (odds ratio [OR] 1.61, 95% confidence interval [CI] 1.36-1.92), had 4 or more positive nodes (OR 4.30, 95% CI 3.67-5.04), and had microscopic residual tumor (OR 2.11, 95% CI 1.46-3.04) were more likely to receive adjuvant RT. Factors that were negatively associated with receiving adjuvant RT included female gender (OR 0.72, 95% CI 0.61-0.85) and median income of at least $63,000 (OR 0.66, 95% CI 0.52-0.83). Conclusions: This study demonstrates the rising use of RT for stage III melanoma in recent years and identifies demographic, social, clinical, and hospital-specific factors associated with patients receiving adjuvant RT. Further investigation is needed to explore disease benefits to improve guidance on the utilization of RT in melanoma.

Dermatologic toxicities of chemotherapy: an educational intervention for skin of color women with breast cancer.

Minority patients are more likely to require dose adjustments for chemotherapy, with cultural barriers and access to medical care cited as contributory factors. Objective: We sought to pilot an educational intervention, in the form of a pamphlet, to evaluate the effectiveness of this tool in teaching skin of color (SoC) patients about potential dermatologic toxicities of chemotherapy that are relevant to their skin type. Methods: At a chemotherapy infusion center, SoC patients (n = 26) who were receiving chemotherapy for breast cancer voluntarily consented to read an educational pamphlet and complete a series of survey questions before and after this educational intervention. Results: Most participants identified as female (96%), African American/Black (81%), and non-Hispanic (85%); all respondents had obtained at least a high school degree. Survey responses revealed a significant increase in knowledge about the potential dermatologic effects of cancer treatment after this intervention. Notably, 100% of participants either agreed or strongly agreed that they would like to see other doctors use this educational tool as a form of patient education, that they would recommend this pamphlet to other patients who are starting cancer treatment, and that the pamphlet was easy to understand. Limitations: Limitations of this study include small sample size and single-institution recruitment, which may limit generalizability. Furthermore, this study only included patients who are proficient in English. Conclusion: This study pilots an effective educational tool that addresses dermatologic toxicities of chemotherapy that are relevant to SoC patients. Further multi-institutional studies with larger sample sizes and translation to other languages can overcome the limitations of this pilot study.