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.

Incidence of Nonkeratinocyte Skin Cancer After Breast Cancer Radiation Therapy.

Importance: Previous studies have suggested that radiation therapy may contribute to an increased risk of subsequent nonkeratinocyte (ie, not squamous and basal cell) skin cancers. Objective: To test the hypothesis that radiation therapy for breast cancer increases the risk of subsequent nonkeratinocyte skin cancers, particularly when these cancers are localized to the skin of the breast or trunk. Design, Setting, and Participants: This population-based cohort study used longitudinal data from the Surveillance, Epidemiology, and End Results (SEER) Program for January 1, 2000, to December 31, 2019. The SEER database includes population-based cohort data from 17 registries. Patients with newly diagnosed breast cancer were identified and were evaluated for subsequent nonkeratinocyte skin cancer development. Data analysis was performed from January to August 2023. Exposures: Radiation therapy, chemotherapy, or surgery for breast cancer. Main Outcomes and Measures: The primary outcomes were standardized incidence ratios (SIRs) for subsequent nonkeratinocyte skin cancer development from 2000 to 2019 based on treatment type (radiation therapy, chemotherapy, or surgery), skin cancer site on the body, and skin cancer subtype. Results: Among the 875 880 patients with newly diagnosed breast cancer included in this study, 99.3% were women, 51.6% were aged older than 60 years, and 50.3% received radiation therapy. A total of 11.2% patients identified as Hispanic, 10.1% identified as non-Hispanic Black, and 69.5% identified as non-Hispanic White. From 2000 to 2019, there were 3839 patients with nonkeratinocyte skin cancer, including melanoma (3419 [89.1%]), Merkel cell carcinoma (121 [3.2%]), hemangiosarcoma (104 [2.7%]), and 32 other nonkeratinocyte skin cancers (195 [5.1%]), documented to occur after breast cancer treatment. The risk of nonkeratinocyte skin cancer diagnosis after breast cancer treatment with radiation was 57% higher (SIR, 1.57 [95% CI, 1.45-1.7]) than that of the general population when considering the most relevant site: the skin of the breast or trunk. When risk at this site was stratified by skin cancer subtype, the SIRs for melanoma and hemangiosarcoma were both statistically significant at 1.37 (95% CI, 1.25-1.49) and 27.11 (95% CI, 21.6-33.61), respectively. Receipt of radiation therapy was associated with a greater risk of nonkeratinocyte skin cancer compared with chemotherapy and surgical interventions. Conclusions and Relevance: In this study of patients with breast cancer, an increased risk of melanoma and hemangiosarcoma after breast cancer treatment with radiation therapy was observed. Although occurrences of nonkeratinocyte skin cancers are rare, physicians should be aware of this elevated risk to help inform follow-up care.

Shared and distinct mechanisms of UBA1 inactivation across different diseases.

Most cellular ubiquitin signaling is initiated by UBA1, which activates and transfers ubiquitin to tens of E2 enzymes. Clonally acquired UBA1 missense mutations cause an inflammatory-hematologic overlap disease called VEXAS (vacuoles, E1, X-linked, autoinflammatory, somatic) syndrome. Despite extensive clinical investigation into this lethal disease, little is known about the underlying molecular mechanisms. Here, by dissecting VEXAS-causing UBA1 mutations, we discovered that p.Met41 mutations alter cytoplasmic isoform expression, whereas other mutations reduce catalytic activity of nuclear and cytoplasmic isoforms by diverse mechanisms, including aberrant oxyester formation. Strikingly, non-p.Met41 mutations most prominently affect transthioesterification, revealing ubiquitin transfer to cytoplasmic E2 enzymes as a shared property of pathogenesis amongst different VEXAS syndrome genotypes. A similar E2 charging bottleneck exists in some lung cancer-associated UBA1 mutations, but not in spinal muscular atrophy-causing UBA1 mutations, which instead, render UBA1 thermolabile. Collectively, our results highlight the precision of conformational changes required for faithful ubiquitin transfer, define distinct and shared mechanisms of UBA1 inactivation in diverse diseases, and suggest that specific E1-E2 modules control different aspects of tissue differentiation and maintenance.

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.

Managing hyperglycemia and rash associated with alpelisib: expert consensus recommendations using the Delphi technique.

Hyperglycemia and rash are expected but challenging adverse events of phosphatidylinositol-3-kinase inhibition (such as with alpelisib). Two modified Delphi panels were conducted to provide consensus recommendations for managing hyperglycemia and rash in patients taking alpelisib. Experts rated the appropriateness of interventions on a 1-to-9 scale; median scores and dispersion were used to classify the levels of agreement. Per the hyperglycemia panel, it is appropriate to start alpelisib in patients with HbA1c 6.5% (diabetes) to <8%, or at highest risk for developing hyperglycemia, if they have a pre-treatment endocrinology consult. Recommend prophylactic metformin in patients with baseline HbA1c 5.7% to 6.4%. Metformin is the preferred first-line anti-hyperglycemic agent. Per the rash panel, initiate prophylactic nonsedating H1 antihistamines in patients starting alpelisib. Nonsedating H1 antihistamines and topical steroids are the preferred initial management for rash. In addition to clinical trial evidence, these recommendations will help address gaps encountered in clinical practice.

Shared and Distinct Mechanisms of UBA1 Inactivation Across Different Diseases.

Most cellular ubiquitin signaling is initiated by UBA1, which activates and transfers ubiquitin to tens of E2 enzymes. Clonally acquired UBA1 missense mutations cause an inflammatory-hematologic overlap disease called VEXAS (vacuoles, E1, X-linked, autoinflammatory, somatic) syndrome. Despite extensive clinical investigation into this lethal disease, little is known about the underlying molecular mechanisms. Here, by dissecting VEXAS-causing UBA1 mutations, we discovered that p.Met41 mutations alter cytoplasmic isoform expression, whereas other mutations reduce catalytic activity of nuclear and cytoplasmic isoforms by diverse mechanisms, including aberrant oxyester formation. Strikingly, non-p.Met41 mutations most prominently affect transthioesterification, revealing ubiquitin transfer to cytoplasmic E2 enzymes as a shared property of pathogenesis amongst different VEXAS syndrome genotypes. A similar E2 charging bottleneck exists in some lung cancer-associated UBA1 mutations, but not in spinal muscular atrophy-causing UBA1 mutations, which instead, render UBA1 thermolabile. Collectively, our results highlight the precision of conformational changes required for faithful ubiquitin transfer, define distinct and shared mechanisms of UBA1 inactivation in diverse diseases, and suggest that specific E1-E2 modules control different aspects of tissue differentiation and maintenance.

Evolution of a Project to Improve Inpatient-to-Outpatient Dermatology Care Transitions: Mixed Methods Evaluation.

BACKGROUND: In-hospital dermatological care has shifted from dedicated dermatology wards to consultation services, and some consulted patients may require postdischarge follow-up in outpatient dermatology. Safe and timely care transitions from inpatient-to-outpatient specialty care are critical for patient health, but communication around these transitions can be disjointed, and workflows can be complex. OBJECTIVE: In this 3-phase quality improvement effort, we developed and evaluated an intervention that leveraged an electronic health record (EHR) feature, known as SmartPhrase, to enable a new workflow to improve transitions from inpatient care to outpatient dermatology. METHODS: Phase 1 (February-March 2021) included interviews with patients and process mapping with key stakeholders to identify gaps and inform an intervention: a SmartPhrase table and associated workflow to promote collection of patient information needed for scheduling follow-up and closed-loop communication between dermatology and scheduling teams. In phase 2 (April-May 2021), semistructured interviews-with dermatologists (n=5), dermatology residents (n=5), and schedulers (n=6)-identified pain points and refinements. In phase 3, the intervention was evaluated by triangulating data from these interviews with measured changes in scheduling efficiency, visit completion, and messaging volume preimplementation (January-February 2021) and postimplementation (April-May 2021). RESULTS: Preintervention pain points included unclear workflow for care transitions, limited patient input in follow-up planning, multiple messaging channels (eg, EHR based, email, and phone messages), and time-inefficient patient tracking. The intervention addressed most pain points; interviewees reported the intervention was easy to adopt and improved scheduling efficiency, workload, and patient involvement. More visits were completed within the desired timeframe of 14 days after discharge during the postimplementation period (21/47, 45%) than the preimplementation period (28/41, 68%; P=.03). The messaging workload also decreased from 88 scheduling-related messages sent for 25 patients before implementation to 30 messages for 8 patients after implementation. CONCLUSIONS: Inpatient-to-outpatient specialty care transitions are complex and involve multiple stakeholders, thus requiring multifaceted solutions. With deliberate evaluation, broad stakeholder input, and iteration, we designed and implemented a successful solution using a standard EHR feature, SmartPhrase, integrated into a standardized workflow to improve the timeliness of posthospital specialty care and reduce workload.

Immunotherapy for keratinocyte cancers. Part II: Identification and management of cutaneous side effects of immunotherapy treatments.

Keratinocytic cancers (KCs), specifically cutaneous squamous cell and basal cell carcinomas, can respond to topical, intralesional, or systemic immunotherapies, but cutaneous adverse events (CAEs) may occur. Understanding these risks, early recognition of these CAEs, and effective treatment may enable patients to continue their anticancer immunotherapies without dose impact. Immune checkpoint inhibitor-related CAEs after KCs can have multiple clinical presentations, with specific observed types including psoriasis and bullous pemphigoid. Cutaneous toxicities can require biopsies to confirm the diagnosis, especially in patients who are not responsive to topical or oral steroids, since the selection of biologic drugs depends on accurate diagnosis. Different types of CAEs from immune checkpoint inhibitors have been associated with different oncologic outcomes in various primary cancer types, and this remains to be determined for KC patients. CAE characterization and management after immune checkpoint inhibitors in KC patients is a rapidly growing field that needs specific and prospective studies.

Development of a Framework for Addressing Skin Biopsy Tray Waste in Dermatology Clinics: A Quality Improvement Study.

Importance: The US health care system generates substantial global waste. Skin biopsies are frequently performed by dermatologists and represent a practical and scalable opportunity for waste reduction interventions in dermatology clinics. Objective: To develop and implement a systematic framework for decreasing skin biopsy tray waste in dermatology clinics. Design, Setting, and Participants: This quality improvement study was conducted at 4 outpatient clinic sites within a single institution between October 2021 and April 2022. The clinic site with the greatest skin biopsy tray waste production was selected for intervention. Waste audits before and after the intervention quantified the number of wasted supplies per skin biopsy tray in dermatology clinics. The participants were dermatology residents, faculty, nurses, medical assistants, and clinic managers. Interventions: Provision of educational materials about climate change and health care and standardizing biopsy tray setup to decrease wasted supplies. Main Outcomes and Measures: Quantity of wasted skin biopsy tray supplies (gauze squares, alcohol pads, cotton swabs, and adhesive bandages) before and after interventions. Results: In waste audits in 4 outpatient dermatology clinics (comprising 98 skin biopsy trays), prior to intervention, 100% of skin biopsy trays had more than 2 wasted supplies within targeted outpatient dermatology clinics at the Stanford Cancer Institute with a mean (SD) of 10.1 (3.4) wasted items per biopsy tray. Following the quality improvement-based interventions, only 16% of skin biopsy trays had more than 2 wasted supplies and the mean (SD) number of wasted supplies per tray decreased to 1.6 (1.3). Conclusions and Relevance: Results of this quality improvement study suggest that through collaboration with all members of the clinical team including physicians, medical assistants, nurses, and clinic managers, skin biopsy tray setup modifications may be associated with reduced waste in outpatient dermatology clinics. This study presents a framework that accounts for different factors in the production of waste in individual clinic settings, and thus can be adapted within additional dermatology clinics.

Association of Intraoperative Antibiotic Irrigation With Systemic Contact Dermatitis.

This case series describes the development of morbilliform drug eruption after breast surgery.

Radiation Therapy for Primary Cutaneous Gamma Delta Lymphoma Prior to Stem Cell Transplantation.

We present a patient with widespread PCGD-TCL of the bilateral arms and legs, who underwent radiotherapy with 34 Gy in 17 fractions using circumferential VMAT and 3-D printed bolus to the four extremities prior to planned stem cell transplant, who was then found to have progression in the liver, lung, and skin, followed by drastic regression of all in and out-of-field lesions on imaging 1.5 months later. The cause of regression may be related to a radiation-induced abscopal effect from the immunomodulatory effects of radiation, or related to immune reactivation in the setting of cessation of systemic immunosuppressive agents.

Teledermatology to Facilitate Patient Care Transitions From Inpatient to Outpatient Dermatology: Mixed Methods Evaluation.

BACKGROUND: Both clinicians and patients have increasingly turned to telemedicine to improve care access, even in physical examination-dependent specialties such as dermatology. However, little is known about whether teledermatology supports effective and timely transitions from inpatient to outpatient care, which is a common care coordination gap. OBJECTIVE: Using mixed methods, this study sought to retrospectively evaluate how teledermatology affected clinic capacity, scheduling efficiency, and timeliness of follow-up care for patients transitioning from inpatient to outpatient dermatology care. METHODS: Patient-level encounter scheduling data were used to compare the number and proportion of patients who were scheduled and received in-clinic or video dermatology follow-ups within 14 and 90 days after discharge across 3 phases: June to September 2019 (before teledermatology), June to September 2020 (early teledermatology), and February to May 2021 (sustained teledermatology). The time from discharge to scheduling and completion of patient follow-up visits for each care modality was also compared. Dermatology clinicians and schedulers were also interviewed between April and May 2021 to assess their perceptions of teledermatology for postdischarge patients. RESULTS: More patients completed follow-up within 90 days after discharge during early (n=101) and sustained (n=100) teledermatology use than at baseline (n=74). Thus, the clinic's capacity to provide follow-up to patients transitioning from inpatient increased from baseline by 36% in the early (101 from 74) and sustained (100 from 74) teledermatology periods. During early teledermatology use, 61.4% (62/101) of the follow-ups were conducted via video. This decreased significantly to 47% (47/100) in the following year, when COVID-19-related restrictions started to lift (P=.04), indicating more targeted but still substantial use. The proportion of patients who were followed up within the recommended 14 days after discharge did not differ significantly between video and in-clinic visits during the early (33/62, 53% vs 15/39, 38%; P=.15) or sustained (26/53, 60% vs 28/47, 49%; P=.29) teledermatology periods. Interviewees agreed that teledermatology would continue to be offered. Most considered postdischarge follow-up patients to be ideal candidates for teledermatology as they had undergone a recent in-person assessment and might have difficulty attending in-clinic visits because of competing health priorities. Some reported patients needing technological support. Ultimately, most agreed that the choice of follow-up care modality should be the patient's own. CONCLUSIONS: Teledermatology could be an important tool for maintaining accessible, flexible, and convenient care for recently discharged patients needing follow-up care. Teledermatology increased clinic capacity, even during the pandemic, although the timeliness of care transitions did not improve. Ultimately, the care modality should be determined through communication with patients to incorporate their and their caregivers' preferences.

A 10-year retrospective cohort study of ruxolitinib and association with nonmelanoma skin cancer in patients with polycythemia vera and myelofibrosis.

BACKGROUND: Clinical trials report occurrence of nonmelanoma skin cancers (NMSCs) with ruxolitinib in patients with polycythemia vera (PV) or myelofibrosis (MF); however, the level of risk and effect of covariates are not known in the real-world setting. OBJECTIVE: To systematically assess the risk of developing NMSC after ruxolitinib exposure in patients with PV or MF. METHODS: A 10-year retrospective cohort of patients with PV or MF at Stanford Medical Center was identified and matched according to age, gender, race, Charlson Comorbidity Index, disease diagnosis, and follow-up time. The main outcome measure was hazard ratio (HR) for NMSC (comprised of basal cell carcinoma and squamous cell carcinoma [SCC]) after ruxolitinib exposure, adjusted for covariates. RESULTS: The study cohort consisted of 564 patients (188 exposed to ruxolitinib for at least 4 weeks, 376 unexposed). Ruxolitinib-exposed patients with PV or MF had an adjusted NMSC HR of 2.69 (95% CI, 1.03-7.02). In particular, ruxolitinib exposure was associated with SCC (HR, 3.24; 95% CI, 1.45-7.22), with non-Janus kinase 2-mutated patients showing even higher SCC risk (HR, 7.40; 95% CI, 2.54-21.63). LIMITATIONS: Retrospective design. CONCLUSIONS: Our real-world results indicate that SCC risk is increased in patients with PV or MF taking ruxolitinib and support consideration of skin cancer monitoring.

Clinical features of drug-induced hypersensitivity syndrome to BRAF inhibitors with and without previous immune checkpoint inhibition: a review.

PURPOSE: Cutaneous reactions to BRAF inhibitors are common, but severe reactions resembling or consistent with drug-induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) are relatively rare. Several reports suggest that cutaneous reactions including DRESS/DIHS to BRAF inhibitors are more frequent and severe in the setting of previous immune checkpoint inhibition (ICI). METHODS: To characterize existing literature on these reports, we queried the PubMed/MEDLINE database for cases of DIHS/DRESS to BRAF inhibitors. RESULTS: We identified 23 cases of DIHS to BRAF inhibitors following checkpoint inhibition and 14 cases without prior checkpoint inhibitor therapy. In both cohorts, DIHS occurred relatively early, with median time to onset from drug exposure of 8-10 days. Patients who received prior ICI were less likely to have peripheral eosinophilia (26% vs 71%), atypical lymphocytes (9% vs 50%), renal involvement (61% vs 79%), hepatic involvement (52% vs 86%), and lymphadenopathy (9% vs 43%) compared to patients who did not receive prior ICI. Thrombocytopenia was more common with prior ICI (17% vs 7%). Only patients who received prior ICI experienced hypotension (26%) during the course of their DIHS. All cases of BRAF-induced DIHS generally improved on systemic steroids/supportive care, and no cases of death were identified. CONCLUSION: Dermatologists should consider a diagnosis of DIHS following BRAF inhibitor initiation, particularly in the setting of past checkpoint inhibition, with atypical features including relatively rapid onset and steroid responsiveness, lack of peripheral eosinophilia, lymphocytosis, or lymphadenopathy, and increased risk of thrombocytopenia and hypotension.

Cutaneous reactive angiomatosis associated with intravascular cryoprotein deposition as the presenting finding in a patient with underlying lymphoplasmacytic lymphoma: A case report and review of the literature.

Cutaneous reactive angiomatosis, a group of disorders defined by benign vascular proliferation, is associated with a number of systemic processes, including intravascular occlusion by cryoproteins. We report a case of a 64-year-old female patient who presented with a 1-year history of nontender petechiae of the bilateral arms and lower legs. Dermoscopic evaluation showed increased vascularity with a globular pattern. Over a period of months, her findings progressed to erythematous to violaceous plaques with admixed hypopigmented stellate scarring of the bilateral lower extremities, forearms, and lateral neck. Biopsy showed increased thin-walled, small dermal blood vessels with focal inter-anastamosis. Some vessels were occluded by eosinophilic globules suspicious for cryoprotein. Subsequent laboratory studies confirmed a diagnosis of type 1 cryoglobulinemia, prompting a bone marrow biopsy that revealed lymphoplasmacytic lymphoma. Herein, we report the fourth case of angiomatosis secondary to intravascular cryoproteins as the initial presentation of an underlying hematologic malignancy. We also present a review of the literature and emphasize the need for thorough initial workup and close and prolonged clinical monitoring for underlying systemic disease in these patients.

Dermatologic Events Associated with the Anti-CCR4 Antibody Mogamulizumab: Characterization and Management.

The CCR4-directed monoclonal antibody mogamulizumab has been shown to significantly improve progression-free survival and overall response rate compared with vorinostat in adults with relapsed/refractory mycosis fungoides (MF) and Sézary syndrome (SS). One of the most common adverse events seen with mogamulizumab in MF/SS patients is rash. Because of the protean nature of MF/SS and the variable clinical and histopathological features of mogamulizumab-associated rash, healthcare providers may have difficulty distinguishing rash from disease, and may not be aware of appropriate treatment strategies for this generally manageable adverse event. The objective of this report was to combine results from published literature with experiences and recommendations from multiple investigators and institutions into clinical best practice recommendations to assist healthcare providers in identifying and managing mogamulizumab-associated rash. Optimal management, which includes biopsy confirmation and steroid treatment, requires a multidisciplinary approach among oncology, dermatology, and pathology practitioners. INFOGRAPHIC.