Granuloma Annulare Exhibits Mixed Immune and Macrophage Polarization Profiles with Spatial Transcriptomics.

Granuloma annulare (GA) is an idiopathic condition characterized by granulomatous inflammation in the skin. Prior studies have suggested that GA develops from various triggers, leading to a complex interplay involving innate and adaptive immunity, tissue remodeling, and fibrosis. Macrophages are the major immune cells comprising GA granulomas, however, the molecular drivers and inflammatory signaling cascade behind macrophage activation is poorly understood. Histologically, GA exhibits both palisaded and interstitial patterns on histology, however the molecular composition of GA at the spatial level remains unexplored. GA is a condition without FDA-approved therapies despite the significant impact of GA on quality of life. Spatial transcriptomics is a valuable tool for profiling localized, genome-wide gene expression changes across tissue with emerging applications in clinical medicine. To improve our understanding of the spatially localized gene expression patterns underlying GA, we profiled the spatial gene expression landscape from six patients with GA. Our findings revealed mixed Th1 and Th2 signals comprising the GA microenvironment and spatially distinct M1 and M2 macrophage polarization characteristics. IFN-γ and TNF signals emerged as important regulators of GA granulomatous inflammation and interleukin-32 emerged as a key driver of granulomatous inflammation. Overall, our spatial transcriptomics data indicate that GA exhibits mixed immune and macrophage polarization.

Micronutrient Deficiencies in Patients With Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) can cause micronutrient deficiencies that have cutaneous manifestations. Dermatologists may be the first to identify an undiagnosed micronutrient deficiency in the affected population. The approach to monitoring and repleting a micronutrient deficiency may be impacted by factors such as IBD activity and potential interactions between supplements and medications used to treat IBD. In this article, we review the most common micronutrient deficiencies observed in patients with IBD and their associated cutaneous manifestations. We also provide guidance for monitoring and supplementing each micronutrient discussed.

Perioperative management and clinical outcomes of peristomal pyoderma gangrenosum.

Peristomal pyoderma gangrenosum is an uncommon subtype of pyoderma gangrenosum mainly affecting stoma sites of patients with inflammatory bowel disease. While surgical treatments are often used to assist healing, little is known about the relationship between surgical interventions and the rate of recurrence of peristomal pyoderma gangrenosum. The aim of this study was to identify patient and clinical factors associated with peristomal pyoderma gangrenosum recurrence following surgical intervention. A multi-institutional retrospective case series and literature review was conducted to evaluate patient characteristics and perioperative treatment. Patients of any age with peristomal pyoderma gangrenosum undergoing surgical operations related to their pyoderma gangrenosum or due to another comorbidity were included. Descriptive statistics were used to characterize demographic information. Associations were evaluated using Wilcoxon's rank-sum test for continuous variables and Fisher's exact test for categorical data. Thirty-seven cases were included, 78.3% of which had a history of inflammatory bowel disease. Overall, 13 (35.1%) cases experienced recurrence at 30 days. There was no significant association identified between patient demographics, stoma location, surgical intervention, or perioperative treatment with rate of recurrence at 30 days post-operation. While no clinical risk factors or treatments were associated with recurrence, our work underscores the importance of a multidisciplinary approach to this disease to address gastrointestinal, dermatologic, and surgical components of treatment.

SpatialView: an interactive web application for visualization of multiple samples in spatial transcriptomics experiments.

MOTIVATION: Spatial transcriptomics (ST) experiments provide spatially localized measurements of genome-wide gene expression allowing for an unprecedented opportunity to investigate cellular heterogeneity and organization within a tissue. Statistical and computational frameworks exist that implement robust methods for pre-processing and analyzing data in ST experiments. However, the lack of an interactive suite of tools for visualizing ST data and results currently limits the full potential of ST experiments. RESULTS: To fill the gap, we developed SpatialView, an open-source web browser-based interactive application for visualizing data and results from multiple 10× Genomics Visium ST experiments. We anticipate SpatialView will be useful to a broad array of clinical and basic science investigators utilizing ST to study disease. AVAILABILITY AND IMPLEMENTATION: SpatialView is available at https://github.com/kendziorski-lab/SpatialView (and https://doi.org/10.5281/zenodo.10223907); a demo application is available at https://www.biostat.wisc.edu/˜kendzior/spatialviewdemo/.

Culprits of Medication-Induced Telogen Effluvium, Part 2.

Telogen effluvium (TE) is a common mechanism underlying medication-related alopecia. The inciting cause of TE may be difficult to identify due to delays in clinically apparent hair loss. Because medication-induced TE is a nonscarring alopecia that typically is reversible, appropriate management requires identification of the underlying trigger and cessation of potential culprit medications. In part 2 of this 2-part series on medication-induced TE, we focus on anticoagulant and antihypertensive medications.

Cutaneous granulomas associated with rubella virus: A clinical review.

Since the initial identification of vaccine-derived rubella virus (RuV) in the cutaneous granulomas of pediatric patients with inborn errors of immunity in 2014, more than 80 cases of RuV granulomas have been reported implicating both vaccine-derived and wild type RuV. Previously thought to arise exclusively in patients with significant immunocompromise, the identification of RuV granulomas in clinically immunocompetent patients adds nuance to our understanding of the interplay between host environment, immune dysregulation, and RuV granuloma formation. This review summarizes the literature on RuV granulomas including clinical and histopathologic features, proposed pathomechanisms supporting granuloma development, and potential therapeutic options. There is no standardized algorithm to guide the workup and diagnosis of suspected RuV granulomas. We highlight the importance of contributing RuV granuloma cases to ongoing Centers for Disease Control and Prevention surveillance efforts to monitor wild type and vaccine-derived RuV transmission. Studies advancing our understanding of RuV granulomas may provide insights into the role of viral infectious agents in granulomatous disease pathogenesis and guide the development of improved therapeutic options.

Serum Ferritin Levels: A Clinical Guide in Patients With Hair Loss.

Ferritin is a key regulator of iron homeostasis that serves as an important clinical indicator of body iron status. Low serum ferritin is a highly specific and sensitive marker for diagnosing iron deficiency. In patients presenting with diffuse hair loss, serum ferritin may be a clinically useful tool for ruling out underlying iron deficiency as a cause of alopecia. As an acute-phase reactant, ferritin may be nonspecifically elevated in a wide range of inflammatory conditions; however, the role of ferritin in disorders of the skin and hair is not well understood. In this article, we review the structure and function of ferritin, and we provide a guide for clinical use.

Healthcare educational debt in the united states: unequal economic impact within interprofessional team members.

BACKGROUND: Advancing healthcare access and quality for underserved populations requires a diverse, culturally competent interprofessional workforce. However, high educational debt may influence career choice of healthcare professionals. In the United States, health professions lack insight into the maximum educational debt that can be supported by current entry-level salaries. The purpose of this interprofessional economic analysis was to examine whether average educational debt for US healthcare graduates is supportable by entry-level salaries. Additionally, the study explored whether trainees from minoritized backgrounds graduate with more educational debt than their peers in physical therapy. METHODS: The study modeled maximum educational debt service ratios for 12 healthcare professions and 6 physician specialties, incorporating profession-specific estimates of entry-level salary, salary growth, national average debt, and 4 loan repayment scenarios offered by the US Department of Education Office of Student Financial Aid. Net present value (NPV) provided an estimate for lifetime "economic power" for the modeled careers. The study used a unique data source available from a single profession (physical therapy, N = 4,954) to examine whether educational debt thresholds based on the repayment model varied between minoritized groups and non-minoritized peers. RESULTS: High salary physician specialties (e.g. obstetrics/gynecology, surgery) and professions without graduate debt (e.g. registered nurse) met debt ratio targets under any repayment plan. Professions with strong salary growth and moderate debt (e.g. physician assistant) required extended repayment plans but had high career NPV. Careers with low salary growth and high debt relative to salary (e.g. physical therapy) had career NPV at the lowest range of modeled professions. 29% of physical therapy students graduated with more debt than could be supported by entry-level salaries. Physical therapy students from minoritized groups graduated with 10-30% more debt than their non-minoritized peers. CONCLUSIONS: Graduates from most healthcare professions required extended repayment plans (higher interest) to meet debt ratio benchmarks. For several healthcare professions, low debt relative to salary protected career NPV. Students from minoritized groups incurred higher debt than their peers in physical therapy.

Molecularly Targeted Therapies for Inflammatory Cutaneous Granulomatous Disorders: A Review of the Evidence and Implications for Understanding Disease Pathogenesis.

Inflammatory cutaneous granulomatous diseases, including granuloma annulare, cutaneous sarcoidosis, and necrobiosis lipoidica, are distinct diseases unified by the hallmark of macrophage accumulation and activation in the skin. There are currently no Food and Drug Administration-approved therapies for these conditions except prednisone and repository corticotropin injection for pulmonary sarcoidosis. Treatment of these diseases has generally been guided by low-quality evidence and may involve broadly immunomodulatory medications. Development of new treatments has in part been limited by an incomplete understanding of disease pathogenesis. Recently, there has been substantial progress in better understanding the molecular pathogenesis of these disorders, opening the door for therapeutic innovation. Likewise, reported outcomes of treatment with immunologically targeted therapies may offer insights into disease pathogenesis. In this systematic review, we summarize progress in deciphering the pathomechanisms of these disorders and discuss this in the context of emerging evidence on the use of molecularly targeted therapies in treatment of these diseases.

Treatment options for necrobiosis lipoidica: a systematic review.

BACKGROUND: Necrobiosis lipoidica (NL) is a rare, idiopathic, and recalcitrant disease of collagen degeneration for which treatment options have been poorly studied. Due to its recurring nature, risk for ulceration, and high morbidity, there is a need to understand existing treatment modalities to better inform clinical care. OBJECTIVE: This review aims to describe the therapeutic modalities reported in the literature for the treatment of NL. METHODS: A literature search of treatments was performed by searching for publications between January 2016 and May 2022 on PubMed and Scopus. Given the limited high-quality evidence, case reports and series were included. Only publications presenting information on both attempted treatments and outcomes were included. RESULTS: A total of 60 novel articles were identified (54 case reports, two case series, and four retrospective cohort studies). These studies cumulatively reported on 274 patients and covered treatments including phototherapy, topical corticosteroids, topical calcineurin inhibitors, biologics, immunosuppressants, JAK inhibitors, combination therapies, and several others. The greatest amount of evidence was found for photodynamic therapy (improvement in 72 of 80 patients), UVA-based phototherapy (12 of 33), topical corticosteroids (21 of 46), compression therapy (15 of 20), and topical calcineurin inhibitors (11 of 17). Several newer treatments were also described, including ustekinumab and JAK inhibitors. CONCLUSIONS: This systematic review provides a comprehensive summary of recently published treatments for NL. As the existing data comes predominantly from case reports and series, statistical conclusions are not assessed. A greater number of randomized controlled trials with standardized endpoints are necessary to compare treatment efficacy.

COVID-19 associated severe mucocutaneous blistering eruptions: A case series.

Mucocutaneous eruptions are associated with numerous infectious processes and can present as erythema multiforme (EM), reactive infectious mucocutaneous eruption (RIME), Stevens Johnson syndrome (SJS), or toxic epidermal necrolysis (TEN). Limited reports have detailed the association of these eruptions with SARS-CoV-2 infection. We present a series of eight cases of severe mucocutaneous blistering eruptions associated with SARS-CoV-2 infection. A retrospective case series was performed at six tertiary medical centers from March 1, 2020 to August 1, 2022. Inclusion criteria were met with a clinical diagnosis of EM, RIME, SJS, or TEN and a positive SARS-CoV-2 test (rapid antigen or polymerase chain reaction) less than 4 weeks prior to onset of dermatologic manifestation. Data was collected at time of each patient encounter. Eight patients met criteria with six pediatric patients (<18 years of age) having a median age of 15 years and two adult patients (>18 years of age) having a median age of 36 years. Patients were found to have a clinical diagnosis of RIME in 85.7% of cases. Oral mucosal involvement was the most common clinical finding (100%), followed by ocular (50.0%), urogenital (50.0%), and skin (37.5%) involvement. Evaluation did not reveal any additional infectious triggers in four patients. Evidence of possible concurrent or previous infectious triggers were identified in four patients. This case series highlights the development of severe mucocutaneous eruptions in association with COVID-19 infection, as well as the potential contributing role of concurrent or prior infections.

Leprosy in the Upper Midwest.

INTRODUCTION: Leprosy is a life-threatening infection caused by Mycobacterium leprae with an average 5-year long incubation period. It is curable when treated early. Early diagnosis requires knowledge of its myriad clinical features as risk factors may not be readily apparent. CASE PRESENTATION: We report the case of a male patient from Wisconsin who tested positive for leprosy without a known exposure or recent travel to endemic areas. DISCUSSION: The clinical presentation of leprosy exists on a spectrum and correlates with cell immunity levels. The Ridley-Jopling and World Health Organization classifications are used to define leprosy subtypes and guide treatment. Histopathologic examination may aid in diagnosis of suspicious presentations. CONCLUSIONS: Leprosy may present with nonspecific clinical features and elevated inflammatory markers leading to a misdiagnosis. It should be considered on the differential diagnosis for suspicious presentations and appropriately worked up with various diagnostic modalities. A multidisciplinary approach to treatment may prevent spread and permanent damage.

Cutaneous Signs of Malnutrition Secondary to Eating Disorders.

Patients with eating disorders (EDs) frequently experience malnutrition that may lead to nutritional dermatoses. Effects of malnutrition and starvation on the skin may include xerosis, lanugo, pruritus, acrocyanosis, carotenoderma, telogen effluvium, and other hair and mucosal findings. Although these dermatologic sequelae often are reported among patients with EDs, the pathomechanisms of these cutaneous symptoms are poorly understood. This article reviews the existing literature on nutritional dermatoses to clarify visible signs that should heighten clinical suspicion for an underlying ED. The skin may present the first visible signs of an otherwise occult ED diagnosis, offering the dermatologist a special opportunity for early diagnosis and coordination with a multidisciplinary team for ED treatment.

Penicillin allergy evaluation in hospitalized patients with hematologic malignancy.

A penicillin allergy testing service (PATS) assessed penicillin allergy in patients with hematologic malignancies; 17 patients who met criteria had negative skin testing. Patients who underwent penicillin challenge passed and were delabeled. Of delabeled patients, 87% received and tolerated ß-lactams during follow-up. Providers found the PATS valuable.

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.

Alpha-gal syndrome: A review for the dermatologist.

Alpha-gal syndrome (AGS) is an allergy to "red meat" and other mammalian products due to immunoglobulin E (IgE) antibodies against the sugar moiety galactose-alpha-1,3-galactose (alpha-gal), which is acquired following tick bites. Clinically, AGS presents with urticaria, abdominal pain, nausea, and occasionally anaphylaxis, and has wide inter- and intra-personal variability. Because symptom onset is generally delayed by 2 to 6 hours after meat consumption, AGS can be easily confused with other causes of urticaria and anaphylaxis, such as chronic spontaneous urticaria (CSU) and mast cell activation syndrome (MCAS). Diagnosis relies on a combination of clinical history, positive alpha-gal IgE blood testing and improvement on a mammalian-restricted diet. Management of the syndrome centers primarily on avoidance of mammalian meats (and occasionally dairy and other products) as well as acute management of allergic symptoms. Counseling about tick avoidance measures is also important as AGS will wane over time in many patients.

The Role of Dietary Antioxidants in Melanoma and Nonmelanoma Skin Cancer.

Dietary supplements, including vitamins and their derivatives, have been utilized within the field of dermatology to treat a variety of skin conditions. Antioxidants inhibit oxidation and decrease cellular damage caused by free radicals, potentially preventing DNA damage due to UV radiation. Laboratory studies have demonstrated promising results supporting the possible role of antioxidants for prevention of skin cancer related to UV exposure. We review the effects of frequently encountered antioxidants and vitamins suggested for the chemoprevention of melanoma and nonmelanoma skin cancer (NMSC) in humans.

Utility of angiotensin-converting enzyme and serum calcium levels in cutaneous sarcoidosis.

BACKGROUND: Sarcoidosis is a granulomatous disease of unknown etiology but is theorized to result from immune overactivity in the setting of an environmental or genetic trigger. It most commonly affects the lungs and lymph nodes but can affect other organ systems, with cutaneous involvement in 30% of patients. The granulomas associated with sarcoidosis lead to increased activity of angiotensin-converting enzyme (ACE) and 1α-hydroxylase resulting in an uncontrolled synthesis of 1,25-dihydroxyvitamin D3 by macrophages, along with elevated serum ACE and calcium levels. Serum ACE and calcium levels are frequently ordered when a patient is diagnosed with cutaneous sarcoidosis. However, their clinical utility in this setting remains unknown. METHODS: In this retrospective chart review, we assessed serum ACE and calcium levels in 19 patients with cutaneous sarcoidosis diagnosed by histopathology without preceding evidence of systemic involvement. Serum ACE and calcium levels were also investigated as markers in the progression from mono-organ cutaneous sarcoidosis to systemic sarcoidosis. RESULTS: No patients with biopsy-proven cutaneous sarcoidosis had abnormal levels of serum calcium at presentation in a cohort of 17 patients at a single institution. An abnormally elevated ACE level was only seen in one of 13 patients presenting with cutaneous sarcoidosis. CONCLUSIONS: Our data suggest that serum ACE and calcium levels are not reliable markers of either cutaneous sarcoidosis or the progression to systemic sarcoidosis.

Improvement in Cutaneous Lupus Erythematosus After Twenty Weeks of Belimumab Use: A Systematic Review and Meta-Analysis.

OBJECTIVE: Cutaneous lupus erythematosus (CLE), with or without systemic lupus erythematosus (SLE), can be debilitating and cause psychological distress. Belimumab, a monoclonal antibody that inhibits B cell activation, is a Federal Drug Administration-approved SLE medication, but less is known on its use in CLE. Moreover, the time to response after starting belimumab in CLE is unknown, which may lead to premature discontinuation in the absence of early perceivable benefits. Thus, the objectives of this meta-analysis were to examine the efficacy of belimumab, as well as the time to response after starting belimumab in patients with CLE with or without SLE. METHODS: A comprehensive literature search was performed to include studies that examined clinical response in patients with CLE with or without SLE receiving belimumab. A clinical response at 52 weeks in belimumab users versus nonusers was summarized in a random-effects model. Additionally, we calculated the pooled odds ratio (OR) for each consecutive 4-week observation interval to identify time to a clinical response in CLE with or without SLE after starting belimumab. RESULTS: Among 747 screened studies, 14 were included. The pooled odds of clinical response at 52 weeks in belimumab users were 44% higher compared to nonusers (OR 1.44 [95% confidence interval (95% CI) 1.20-1.74], I2  = 0%). A clinical response was first noted after 20 weeks of starting belimumab (OR 1.35 [95% CI 1.01-1.81], I2  = 0%), with a sustained clinical response through 1 year. CONCLUSION: The findings support belimumab as an effective therapy for CLE with SLE. Likewise, the findings inform patient counseling regarding estimates of 20 weeks to achieve a response.