Cytokines and Epidermal Lipid Abnormalities in Atopic Dermatitis: A Systematic Review.

Atopic dermatitis (AD) is the most common chronic inflammatory skin disease and presents a major public health problem worldwide. It is characterized by a recurrent and/or chronic course of inflammatory skin lesions with intense pruritus. Its pathophysiologic features include barrier dysfunction, aberrant immune cell infiltration, and alterations in the microbiome that are associated with genetic and environmental factors. There is a complex crosstalk between these components, which is primarily mediated by cytokines. Epidermal barrier dysfunction is the hallmark of AD and is caused by the disruption of proteins and lipids responsible for establishing the skin barrier. To better define the role of cytokines in stratum corneum lipid abnormalities related to AD, we conducted a systematic review of biomedical literature in PubMed from its inception to 5 September 2023. Consistent with the dominant TH2 skewness seen in AD, type 2 cytokines were featured prominently as possessing a central role in epidermal lipid alterations in AD skin. The cytokines associated with TH1 and TH17 were also identified to affect barrier lipids. Considering the broad cytokine dysregulation observed in AD pathophysiology, understanding the role of each of these in lipid abnormalities and barrier dysfunction will help in developing therapeutics to best achieve barrier homeostasis in AD patients.

Development of a Skin-Directed Scoring System for Stevens-Johnson Syndrome and Epidermal Necrolysis: A Delphi Consensus Exercise.

Importance: Scoring systems for Stevens-Johnson syndrome and epidermal necrolysis (EN) only estimate patient prognosis and are weighted toward comorbidities and systemic features; morphologic terminology for EN lesions is inconsistent. Objectives: To establish consensus among expert dermatologists on EN terminology, morphologic progression, and most-affected sites, and to build a framework for developing a skin-directed scoring system for EN. Evidence Review: A Delphi consensus using the RAND/UCLA appropriateness criteria was initiated with a core group from the Society of Dermatology Hospitalists to establish agreement on the optimal design for an EN cutaneous scoring instrument, terminology, morphologic traits, and sites of involvement. Findings: In round 1, the 54 participating dermatology hospitalists reached consensus on all 49 statements (30 appropriate, 3 inappropriate, 16 uncertain). In round 2, they agreed on another 15 statements (8 appropriate, 7 uncertain). There was consistent agreement on the need for a skin-specific instrument; on the most-often affected skin sites (head and neck, chest, upper back, ocular mucosa, oral mucosa); and that blanching erythema, dusky erythema, targetoid erythema, vesicles/bullae, desquamation, and erosions comprise the morphologic traits of EN and can be consistently differentiated. Conclusions and Relevance: This consensus exercise confirmed the need for an EN skin-directed scoring system, nomenclature, and differentiation of specific morphologic traits, and identified the sites most affected. It also established a baseline consensus for a standardized EN instrument with consistent terminology.

Detection of novel therapies using a multi-national, multi-institutional registry of cutaneous immune-related adverse events and management.

BACKGROUND: Cutaneous immune-related adverse events (cirAEs) remain a prevalent and common sequelae of immune checkpoint inhibitor (ICI) therapy, often necessitating treatment interruption and prolonged immune suppression. Treatment algorithms are still poorly defined, based on single-institution case reports without adequate safety assessments, and subject to publication bias. METHODS: Data in this registry were collected through a standardized REDCap form distributed to dermatologists via email listserv. RESULTS: Ninety-seven cirAEs were reported from 13 institutions in this registry. Topical and systemic steroids were the most common treatments used; however, targeted treatment matched to disease morphology was identified at numerous sites. Novel cirAE therapy uses that to our knowledge have not been previously described were captured including tacrolimus for the treatment of follicular, bullous, and eczematous eruptions and phototherapy for eczematous eruptions. Moreover, further evidence of cirAE treatment applications sparsely described in literature were also captured in this study including dupilumab and rituximab for bullous eruptions, phototherapy for lichenoid and psoriasiform eruptions, and acitretin for psoriasiform eruptions, among others. No serious adverse events were reported. Numerous targeted therapeutics including dupilumab, rituximab, and psoriasis biologics, among others, were associated with a cirAE grade improvement of ≥2 grades in every patient treated. CONCLUSION: This study suggests that a multi-institutional registry of cirAEs and management is not only feasible but that the information collected can be used to detect, evaluate, and rigorously assess targeted treatments for cirAEs. Further expansion and modification to include treatment progression may allow for sufficient data for specific treatment recommendations to be made.

Assessing the Efficacy of Imiquimod Use in Patients With Persistent Locally Advanced Melanoma In Situ

BACKGROUND: The standard of care when treating melanoma in situ (MMIS) is an excision with at least 5 mm surgical margins.1 Some studies have suggested up to 9 mm margins to maximize local recurrence-free survival.2 This retrospective review aims to assess the efficacy of imiquimod as a topical treatment for persistently positive MMIS at the margins of prior excisions or where surgery is not an option. METHODS: Retrospective study conducted at Moffitt Cancer Center between 2019 and 2021 with patients aged > 18 years with MMIS at the margins of excision of an invasive melanoma or MMIS. Included patients were not ideal candidates for primary or additional surgical resection due to non-feasibility of surgery because of comorbidity or cosmetically sensitive location and/or the need for repeated skin grafting, or due to patient's refusal. Patients received imiquimod on protocol for 16 weeks and were monitored for treatment response and side effects. Following completion of the treatment, scouting biopsies were performed to assess histological response, and dermoscopy was used to determine the clinical disease status. RESULTS: Ten patients completed 16 weeks of imiquimod. Seven (75%) had a median of 2 surgical resections, and 3 refused surgery despite discussion that surgery was standard of care. Seven were deemed free of disease on post-imiquimod treatment scouting biopsies, while 2 were found to be clinically free of disease following confocal microscopy, indicating a tumor clearance rate of 90% with imiquimod treatment. One patient was found to have persistent residual disease following 2 rounds of imiquimod and was taken for an additional surgical excision after which they were deemed free of disease. Median follow-up duration from the onset of imiquimod therapy to the last clinic visit was 18 months, without any recurrences to date. CONCLUSION: Imiquimod appears to demonstrate an encouraging tumor clearance among patients with persistent MMIS after surgery where further surgical resection may not be feasible. Although long-term durability has not been demonstrated in this study, a 90% tumor clearance rate is promising. J Drugs Dermatol. 2023;22(5): doi:10.36849/JDD.6987.

Perspectives on and Quality of Life in Skin of Color Patients With Mycosis Fungoides/Sézary Syndrome: A Qualitative Analysis.

Background Prior quantitative studies have described the diminished health-related quality of life (HRQoL) faced by the overall mycosis fungoides (MF)/Sézary syndrome (SS) population; yet, little is known about how the disease affects HRQoL in skin of color (SOC) patients. This qualitative study sought to explore the lived experiences of SOC patients with MF/SS and gain deeper insights into the impact the disease has on various facets of HRQoL.  Methodology Interviews with SOC patients with MF/SS ≥18 were recruited from a cutaneous lymphoma clinic. A thematic analysis was performed to identify overarching themes. Results Ten patients were invited to participate from July to September 2021. One patient with SS and seven patients with MF (four in the early stage and four in the advanced stage), with a median age of 60.5 years, agreed to participate. Emerging themes included diagnostic and therapeutic delays frequently due to initial misdiagnoses with other skin conditions. Physical and functional burdens significantly hindered participants' abilities to carry out daily responsibilities and maintain employment, and impacts on physical appearance (e.g., darkened skin) led to increased self-consciousness and lack of social acceptance. Participants regarded family and faith as main sources of support in addition to developing healthy coping strategies, such as self-acceptance and adaptability. All participants reported feeling satisfied with their access to healthcare information and the quality of care received. Conclusions Our findings provide greater insights into how HRQoL is impacted across SOC patients with MF/SS, which can help raise awareness among healthcare providers and assist with creating interdisciplinary healthcare approaches to better support the needs of this population.

Characteristics and Outcomes for Hospitalized Patients With Cutaneous T-Cell Lymphoma.

Importance: Cutaneous T-cell lymphoma (CTCL) is a group of rare, complex cutaneous malignant neoplasms associated with significant disease burden on patients and the health care system. Currently, the population of patients with CTCL admitted to the hospital remains largely uncharacterized and poorly understood. Objective: To characterize the clinical characteristics, course of hospitalization, and mortality outcomes of an inpatient CTCL cohort. Design, Setting, and Participants: This multicenter retrospective cohort study reviewed medical records for adult patients (age ≥18 years) with a CTCL diagnosis per National Comprehensive Cancer Network guidelines admitted for inpatient hospitalization at 5 US academic medical centers with inpatient dermatology consult services and CTCL clinics between August 2016 and August 2020. Main Outcomes and Measures: Patient demographics, clinical history and findings, hospitalization courses, and mortality outcomes. Results: A total of 79 hospitalized patients with CTCL were identified, including 52 (70.3%) men and 22 (29.7%) women, with a median (IQR) age at hospitalization of 62.9 (27-92) years. The majority of admitted patients with CTCL were White (65 patients [82.3%]), had disease classified as mycosis fungoides (48 patients [61.5%]), and had advanced-stage disease (≥IIB, 70 patients [89.7%]). Most hospitalizations were complicated by infection (45 patients [57.0%]) and required intravenous antibiotic therapy (45 patients [57.0%]). In-hospital mortality occurred in 6 patients (7.6%) and was associated with higher body mass index (36.5 vs 25.3), history of thromboembolic disease (50.0% vs 12.3%), and diagnosis of sepsis on admission (66.7% vs 20.5%). At 1-year postdischarge, 36 patients (49.3%) patients had died, and mortality was associated with history of solid organ cancers (27.8% vs 10.8%), wound care as the reason for dermatology consultation (58.3% vs 24.3%), and presence of large cell transformation (58.3% vs 22.9%). Conclusions and Relevance: The findings of this cohort study improve the understanding of hospitalized patients with CTCL and lend valuable insight into identifying factors associated with both in-hospital and long-term mortality outcomes. This refined understanding of the inpatient CTCL population provides a foundation for larger, more robust studies to identify causal risk factors associated with mortality, development of prognostic scoring systems to estimate the probability of hospital mortality. Overall, the findings may prompt physicians caring for patients with CTCL to implement preventive strategies to diminish hospitalization and improve clinical management across this unique disease spectrum.

Update in Diagnosis and Management of Primary Cutaneous B-Cell Lymphomas.

Primary cutaneous lymphomas are a rare group of diseases, with an estimated incidence of 0.5-1 case per 100,000 people per year. Primary cutaneous B-cell lymphomas (pCBCLs) represent 25-30% of all primary cutaneous lymphomas. There are three main subtypes of pCBCL: primary cutaneous marginal zone lymphoma, primary cutaneous follicle center lymphoma, and primary cutaneous diffuse large B-cell lymphoma, leg type. Cutaneous B-cell lymphomas have a broad spectrum of clinical presentations, which makes diagnostic and therapeutic strategies challenging. To date, treatment recommendations for cutaneous B-cell lymphomas have been largely based on small retrospective studies and institutional experience. Recently, the pharmacotherapeutic landscape has expanded to include drugs that may modify the underlying disease pathology of pCBCLs, representing new therapeutic modalities for this rare group of diseases. Novel therapies used for other systemic B-cell lymphomas show promise for the treatment of pCBCLs and are being increasingly considered. These new therapies are divided into five main groups: monoclonal antibodies, immune checkpoint inhibitors, small-molecule inhibitors, bispecific T-cell engaging, and chimeric antigen receptor T cell. In this review, we discuss the clinical, histopathological, molecular, and cytogenetic features of the most common pCBCL subtypes with a focus on current and innovative therapeutic developments in their management. These emerging treatment strategies for B-cell lymphomas and cutaneous B-cell lymphomas may represent novel first-line options for the management of these rare diseases.

Efficacy and Safety of Topical Hypericin Photodynamic Therapy for Early-Stage Cutaneous T-Cell Lymphoma (Mycosis Fungoides): The FLASH Phase 3 Randomized Clinical Trial.

Importance: Given that mycosis fungoides-cutaneous T-cell lymphoma (MF/CTCL) is chronic, there is a need for additional therapies with minimal short- and long-term adverse effects. Topical synthetic hypericin ointment, 0.25%, activated with visible light is a novel, nonmutagenic photodynamic therapy (PDT). Objectives: To determine the efficacy and safety of topical synthetic hypericin ointment, 0.25%, activated with visible light as a nonmutagenic PDT in early-stage MF/CTCL. Design, Settings, and Participants: This was a multicenter, placebo-controlled, double-blinded, phase 3 randomized clinical trial (FLASH study) conducted from December 2015 to November 2020 at 39 academic and community-based US medical centers. Participants were adults (≥18 years) with early-stage (IA-IIA) MF/CTCL. Interventions: In cycle 1, patients were randomized 2:1 to receive hypericin or placebo to 3 index lesions twice weekly for 6 weeks. In cycle 2, all patients received the active drug for 6 weeks to index lesions. In cycle 3 (optional), both index and additional lesions received active drug for 6 weeks. Main Outcomes and Measures: The primary end point was index lesion response rate (ILRR), defined as 50% or greater improvement in modified Composite Assessment of Index Lesion Severity (mCAILS) score from baseline after 6 weeks of therapy for cycle 1. For cycles 2 and 3, open label response rates were secondary end points. Adverse events (AEs) were assessed at each treatment visit, after each cycle, and then monthly for 6 months. Data analyses were performed on December 21, 2020. Results: The study population comprised 169 patients (mean [SD] age, 58.4 [16.0] years; 96 [57.8%] men; 120 [72.3%] White individuals) with early-stage MF/CTCL. After 6 weeks of treatment, hypericin PDT was more effective than placebo (cycle 1 ILRR, 16% vs 4%; P = .04). The ILRR increased to 40% in patients who received 2 cycles of hypericin PDT (P < .001 vs cycle 1 hypericin) and to 49% after 3 cycles (P < .001 vs cycle 1 hypericin). Significant clinical responses were observed in both patch and plaque type lesions and were similar regardless of age, sex, race, stage IA vs IB, time since diagnosis, and number of prior therapies. The most common treatment-related AEs were mild local skin (13.5%-17.3% across cycles 1-3 vs 10.5% for placebo in cycle 1) and application-site reactions (3.2%-6.9% across cycles 1-3 vs 4% for placebo in cycle 1). No drug-related serious AEs occurred. Conclusion and Relevance: The findings of this randomized clinical trial indicate that synthetic hypericin PDT is effective in early-stage patch and plaque MF/CTCL and has a favorable safety profile. Trial Registration: ClinicalTrials.gov Identifier: NCT02448381.

"Alterations in the Skin Microbiota Are Associated With Symptom Severity in Mycosis Fungoides".

Cutaneous T cell lymphoma (CTCL), a non-Hodgkin lymphoma, is thought to arise from mature tissue-resident memory T cells. The most common subtypes include Mycosis Fungoides and Sezary Syndrome. The role of skin microbiota remains unclear in the symptom manifestation of MF. Among 39 patients with MF, we analyzed bacteria colonizing MF lesions and non-lesional skin in the contralateral side and characterized regional changes in the skin microbiota related to MF involvement using the difference in relative abundance of each genus between lesional and contralateral non-lesional skin. We investigated the relationship between these skin microbiota alterations and symptom severity. No statistically significant difference was found in bacterial diversity and richness between lesional and non-lesional skin. Different skin microbiota signatures were associated with different symptoms. More pronounced erythema in the lesions was associated with an increase in Staphylococcus. Pain and thick skin in the lesions were associated with a decrease in Propionibacterium. The results of this pilot study suggest that the skin microbiota plays an important role in changing skin phenotypes among patients with MF. Larger skin microbiota studies are needed to confirm these findings and support the use of antibiotic treatment to mitigate CTCL symptoms.

Genomic and Single-Cell Landscape Reveals Novel Drivers and Therapeutic Vulnerabilities of Transformed Cutaneous T-cell Lymphoma.

ABSTRACT: Cutaneous T-cell lymphoma (CTCL) is a rare cancer of skin-homing T cells. A subgroup of patients develops large cell transformation with rapid progression to an aggressive lymphoma. Here, we investigated the transformed CTCL (tCTCL) tumor ecosystem using integrative multiomics spanning whole-exome sequencing (WES), single-cell RNA sequencing, and immune profiling in a unique cohort of 56 patients. WES of 70 skin biopsies showed high tumor mutation burden, UV signatures that are prognostic for survival, exome-based driver events, and most recurrently mutated pathways in tCTCL. Single-cell profiling of 16 tCTCL skin biopsies identified a core oncogenic program with metabolic reprogramming toward oxidative phosphorylation (OXPHOS), cellular plasticity, upregulation of MYC and E2F activities, and downregulation of MHC I suggestive of immune escape. Pharmacologic perturbation using OXPHOS and MYC inhibitors demonstrated potent antitumor activities, whereas immune profiling provided in situ evidence of intercellular communications between malignant T cells expressing macrophage migration inhibitory factor and macrophages and B cells expressing CD74. SIGNIFICANCE: Our study contributes a key resource to the community with the largest collection of tCTCL biopsies that are difficult to obtain. The multiomics data herein provide the first comprehensive compendium of genomic alterations in tCTCL and identify potential prognostic signatures and novel therapeutic targets for an incurable T-cell lymphoma. This article is highlighted in the In This Issue feature, p. 1171.

Treatment of early-stage mycosis fungoides with oral bexarotene and phototherapy: A systematic review and meta-analysis.

Mycosis fungoides (MF) is a rare subtype of non-Hodgkin lymphoma, for which no standard treatment exists. The objective of this study is to provide evidence-based recommendations for adult patients with early-stage MF treated with oral bexarotene and phototherapy. A systematic review and meta-analysis was conducted utilizing studies identified via Embase, Pubmed, Web of Science, and the Cochrane Library from inception to April 2020 to evaluate the clinical efficacy and adverse events of oral bexarotene and phototherapy. Of 645 abstracts retrieved, 17 full-text articles with 143 subjects were included for analysis. There were nine case reports, five retrospective cohort studies, two prospective cohort studies, and one randomized controlled trial. Most subjects were men (24.48%) with stage IB disease (54.4%), and the mean age at presentation was 63. One patient had folliculotropic disease. The retrospective studies' analysis included 67 subjects and indicated that the partial response was 40.36% (95% CI 18.24-64.92), complete response was 34.06% (95% CI 10.73-62.56), and overall response was 64.48% (95% CI 48.56-78.89). Side effects from bexarotene were hypertriglyceridemia (54%), hypothyroidism (50%), and hypercholesterolemia (46%). Similar results were noted in the prospective studies. The literature consists mostly of uncontrolled studies, which suggest that combination therapy with oral bexarotene and phototherapy is a therapeutic option. Future randomized control studies with longer follow-up and standardized definitions of treatment responses and dosages are needed to support the development of evidence-based approaches for the treatment of early-stage MF.

An ulcerating plaque of the lower lip.

A middle-aged man presented to a cancer centre with a painful, ulcerating plaque of the lower lip, which had been diagnosed as squamous cell carcinoma. Computed tomography revealed increased focal metabolic activity in the lip, and histology revealed spirochaetes.