Pansclerotic morphea is characterized by IFN-γ responses priming dendritic cell fibroblast crosstalk to promote fibrosis.

Pansclerotic morphea (PSM) is a rare, devastating disease characterized by extensive soft tissue fibrosis, secondary contractions, and significant morbidity. PSM pathogenesis is unknown, and aggressive immunosuppressive treatments rarely slow disease progression. We aimed to characterize molecular mechanisms driving PSM and to identify therapeutically targetable pathways by performing single-cell and spatial RNA-Seq on 7 healthy controls and on lesional and nonlesional skin biopsies of a patient with PSM 12 months apart. We then validated our findings using immunostaining and in vitro approaches. Fibrotic skin was characterized by prominent type II IFN response, accompanied by infiltrating myeloid cells, B cells, and T cells, which were the main IFN-γ source. We identified unique CXCL9+ fibroblasts enriched in PSM, characterized by increased chemokine expression, including CXCL9, CXCL10, and CCL2. CXCL9+ fibroblasts were related to profibrotic COL8A1+ myofibroblasts, which had enriched TGF-ß response. In vitro, TGF-ß and IFN-γ synergistically increased CXCL9 and CXCL10 expression, contributing to the perpetuation of IFN-γ responses. Furthermore, cell-to-cell interaction analyses revealed cDC2B DCs as a key communication hub between CXCL9+ fibroblasts and COL8A1+ myofibroblasts. These results define PSM as an inflammation-driven condition centered on type II IFN responses. This work identified key pathogenic circuits between T cells, cDC2Bs, and myofibroblasts, and it suggests that JAK1/2 inhibition is a potential therapeutic option in PSM.

Clinical Characteristics Associated with Musculoskeletal Extracutaneous Manifestations in Pediatric and Adult Morphea: A Prospective, Cohort Study.

Morphea is an autoimmune condition of the skin associated with functional sequelae resulting from musculoskeletal involvement. Systematic investigation of risk for musculoskeletal involvement is limited, particularly in adults. This knowledge gap impairs patient care because practitioners are unable to risk stratify patients. To address this gap, we determined the frequency, distribution, and type of musculoskeletal (MSK) extracutaneous manifestations affecting joint and bone with overlying morphea lesions using cross-sectional analysis of 1,058 participants enrolled in two prospective cohort registries (Morphea in Children and Adults Cohort [n = 750] and National Registry for Childhood Onset Scleroderma [n = 308]). Additional analysis included the identification of clinical features associated with MSK extracutaneous manifestations. MSK extracutaneous manifestations occurred in 274 of 1,058 participants (26% overall, 32% pediatric, and 21% adults). Children had a limited range of motion of larger joints (i.e., knees/hips/shoulders), whereas the involvement of smaller joints (i.e., toes/temporomandibular joint) was more common in adults. Multivariable logistic regression showed that deep tissue involvement had the strongest association with musculoskeletal features, with a lack of deep tissue involvement having a negative predictive value of 90% for MSK extracutaneous manifestations. Our results underscore the need to evaluate MSK involvement in adult and pediatric patients and the utility of using depth of involvement in addition to anatomic distribution to risk stratify patients.

Gene Expression Signatures in Inflammatory and Sclerotic Morphea Skin and Sera Distinguish Morphea from Systemic Sclerosis.

Morphea is an inflammatory fibrotic disorder of the skin that has been likened to systemic sclerosis (SSc). We sought to examine the molecular landscape of morphea by examining lesional skin gene expression and blood biomarkers and comparing the gene expression profiles with those from site-matched nonlesional and SSc lesional skin. We found the morphea transcriptome is dominated by IFN-γ-mediated T helper 1 immune dysregulation, with a relative paucity of fibrosis pathways. Specifically, expression profiles of morphea skin clustered with the SSc inflammatory subset and were distinct from the those of SSc fibroproliferative subset. Unaffected morphea skin also differed from unaffected SSc skin because it did not exhibit pathological gene expression signatures. Examination of downstream IFN-γ-mediated chemokines, CXCL9 and CXCL10, revealed increased transcription in the skin but not in circulation. In contrast to transcriptional activity, CXCL9 was elevated in serum and was associated with active, widespread cutaneous involvement. Taken together, these results indicate that morphea is a skin-directed process characterized by T helper 1 immune-mediated dysregulation, which contrasts with fibrotic signatures and systemic transcriptional changes associated with SSc. The similarity between morphea and the inflammatory subset of SSc on transcriptional profiling indicates that therapies under development for this subset of SSc are also promising for treatment of morphea.

Patients with Limited Life Expectancy Are Biopsied for Keratinocyte Cancers at Similar Frequency to Healthy Patients.

BACKGROUND: In many fields of medicine, guidelines recommend reduced cancer screening in patients of advanced age with limited life expectancy (LLE). In dermatology, there are currently no guidelines for adjusted evaluation and management practices of keratinocyte cancer (KC) in patients with LLE. Little is known regarding evaluation and management patterns and frequency of biopsies in these patients. OBJECTIVE: We sought to determine if dermatology providers biopsy LLE patients with similar frequency to their age-matched peers and quantify frequency of associated complications. METHODS: This was a retrospective cohort study of evaluations for skin cancer quantified by skin biopsy frequency at the North Texas Veterans Affairs Health System dermatology clinic for 3,062 patients between 2005 and 2009, including a 5-year follow-up period. Life expectancy was quantified by the validated Charlson Comorbidity Index (CCI) with a Deyo adaptation. RESULTS: There was no significant difference in biopsy frequency of KC in LLE versus non-LLE patients in most age-controlled groups, with increased biopsy frequency in LLE patients in the 65-74 age category (p = 0.02). There was also an increased risk of complications from biopsy in the 75-84 (many comorbidities subgroup: RR = 3.27, p = 0.002; some comorbidities subgroup: RR = 2.26, p = 0.048) and 65-74 (many comorbidities subgroup: RR = 1.52, p = 0.004) age groups when compared to age-matched healthy controls. CONCLUSION: Biopsy frequency is similar or increased in patients with LLE compared with age-matched controls, with increased frequency of complications. Further studies are needed to understand the underlying factors driving these practice patterns.

CXCL9 Links Skin Inflammation and Fibrosis through CXCR3-Dependent Upregulation of Col1a1 in Fibroblasts.

Morphea is characterized by initial inflammation followed by fibrosis of the skin and soft tissue. Despite its substantial morbidity, the pathogenesis of morphea is poorly studied. Previous work showed that CXCR3 ligands CXCL9 and CXCL10 are highly upregulated in the sera and lesional skin of patients with morphea. We found that an early inflammatory subcutaneous bleomycin mouse model of dermal fibrosis mirrors the clinical, histological, and immune dysregulation observed in human morphea. We used this model to examine the role of the CXCR3 chemokine axis in the pathogenesis of cutaneous fibrosis. Using the REX3 (Reporting the Expression of CXCR3 ligands) mice, we characterized which cells produce CXCR3 ligands over time. We found that fibroblasts contribute the bulk of CXCL9-RFP and CXCL10-BFP by percentage, whereas macrophages produce high amounts on a per-cell basis. To determine whether these chemokines are mechanistically involved in pathogenesis, we treated Cxcl9-, Cxcl10-, or Cxcr3-deficient mice with bleomycin and found that fibrosis is dependent on CXCL9 and CXCR3. Addition of recombinant CXCL9 but not CXCL10 to cultured mouse fibroblasts induced Col1a1 mRNA expression, indicating that the chemokine itself contributes to fibrosis. Taken together, our studies provide evidence that CXCL9 and its receptor CXCR3 are functionally required for inflammatory fibrosis.

Efficacy of a lay community health worker (promotoras de salud) program to improve adherence to emollients in Spanish-speaking Latin American pediatric patients in the United States with atopic dermatitis: A randomized, controlled, evaluator-blinded study.

BACKGROUND: Latin American patients in the United States experience significant health disparities. Community health workers (promotoras de salud) reduce disparities by providing culturally appropriate education. While educational interventions have been studied in atopic dermatitis (AD), a chronic dermatologic condition affecting children, none have evaluated the use of promotoras in Spanish-speaking pediatric patients in the United States. OBJECTIVE: To create and evaluate a promotora-led education program for Spanish-speaking caregivers of Latin American, pediatric patients with AD through a randomized, controlled, evaluator-blinded study. METHODS: Children with moderate/severe AD (n = 48) were recruited from the pediatric dermatology clinic at Children's Health℠ in Dallas, TX and randomized to receive clinic education (n = 26) or clinic education plus promotora home visits (n = 22). The primary outcome was overall adherence to topical emollients over the 12-week study, quantified by MEMSCap™ devices; several secondary endpoints were evaluated. RESULTS: Intention-to-treat analysis revealed a trend toward increased overall adherence to emollients over the 12-week study period in promotora (median [interquartile range, IQR]: 43% [26%-61%]) versus non-promotora (median [IQR]: 20% [11%-49%]) (p = .09) groups. SCORAD, AD knowledge, and Spanish-language Parental Quality of Life Questionnaire for AD (Sp-PIQoL-AD) improved in both groups, although there was no statistically significant difference between groups. There was a trend toward increased AD knowledge at Week 4 (p = .06) in the promotora group. CONCLUSIONS: A promotora-led educational intervention is a promising approach in increasing caregiver medication adherence in pediatric, Latin American patients with AD in the United States. Further research using creative and culturally appropriate strategies to increase medication adherence is necessary to reduce health disparities in other racial and ethnic minority populations in the United States.

Evaluation of sun-protective behaviors in transplant clinic patients: a longitudinal analysis.

Organ transplant recipients (OTRs) are at a significantly elevated risk for developing cutaneous malignancies. In recent years, the advent of dermatology clinics dedicated to this specific patient population has aimed to provide increased access and specialized care, including important sun-protective behavior education. It has been shown that OTRs tend to have poor sun-protective practices, and care at these specialized dermatology clinics has facilitated an improvement in sun-protective behavior. Previously, sun-protective behavior of patients within these specialized clinics has been characterized longitudinally, though only for a short duration of 3 months. We retrospectively analyzed a cohort of 230 OTRs seen at a single academic institution's transplant clinic between 2016-2020 and sought to characterize sun-protective behavior at baseline and longitudinally. 78 patients returned for at least one follow-up visit, and the median follow-up duration was 15.1 months (IQR 8.4-24.3 months). Sun-protective behavior was quantified using the average score of questions addressing sunscreen usage frequency, consistency, circumstance of application, reapplication, and sun avoidance. We utilized paired Wilcoxon signed-rank tests to analyze changes in sun-protective behavior between initial visits and subsequent follow-up visits. Sun-protective behavior was increased at the first follow-up visit (median change in sun-protective score - 0.04, p = 0.017) and second follow-up visit (median change in sun-protective score - 0.25, p = 0.026) compared to the initial visit. Multivariable logistic regression and mixed effects modeling were employed to quantify patient features associated with increased sun-protective behavior. Female sex [OR 3.79, 95% CI (1.83, 8.04)] and personal history of skin cancer [OR 3.06, 95% CI (1.25, 7.76)] were associated with stronger sun-protective behaviors at baseline. Female sex [OR 13.77, 95% CI (2.44, 77.52)] was the only characteristic associated with increased sun-protective behavior over time. Our findings identify patient characteristics that are associated with increased sun-protective behavior after education in a dermatology clinic dedicated to OTRs.

The Genetic Landscape of Cutaneous Lupus Erythematosus.

Cutaneous lupus erythematosus (CLE) is an autoimmune connective tissue disease that can exist as a disease entity or within the context of systemic lupus erythematosus (SLE). Over the years, efforts to elucidate the genetic underpinnings of CLE and SLE have yielded a wealth of information. This review examines prior studies investigating the genetics of CLE at the DNA and RNA level and identifies future research areas. In this literature review, we examined the English language literature captured within the MEDLINE and Embase databases using pre-defined search terms. First, we surveyed studies investigating various DNA studies of CLE. We identified three predominant areas of focus in HLA profiling, complement deficiencies, and genetic polymorphisms. An increased frequency of HLA-B8 has been strongly linked to CLE. In addition, multiple genes responsible for mediating innate immune response, cell growth, apoptosis, and interferon response confer a higher risk of developing CLE, specifically TREX1 and SAMHD1. There was a strong association between C2 complement deficiency and CLE. Second, we reviewed literature studying aberrations in the transcriptomes of patients with CLE. We reviewed genetic aberrations initiated by environmental insults, and we examined the interplay of dysregulated inflammatory, apoptotic, and fibrotic pathways in the context of the pathomechanism of CLE. These current learnings will serve as the foundation for further advances in integrating personalized medicine into the care of patients with CLE.

Evaluating the impact of a community health worker (Promotora de Salud) program on attitudes and beliefs regarding atopic dermatitis among Spanish-speaking Latin-American caregivers.

INTRODUCTION: Community health workers (CHWs), or promotora de salud, have an important role in healthcare education and advocacy in the Latin American community. We aimed to determine the impact of a promotora de salud program on attitudes and beliefs regarding AD management among Latin American caregivers of pediatric patients with atopic dermatitis. METHODS: This is a sub-study of an ongoing randomized, investigator-blinded, placebo-controlled trial. Mann-Whitney U tests compared questionnaire responses in the standard education group to the promotora group. RESULTS: Caregivers in the promotora group were more likely to state that they knew how to apply wet wraps and use bleach (sodium hypochlorite) baths at 1 month (wet wraps p = .027, bleach baths p = .005) and 3 months (wet wraps p = .005, bleach baths p < .001) demonstrating greater self-efficacy, defined as an individual's belief in their capacity to execute a certain behavior to achieve a desired outcome, compared with the standard education group. CONCLUSIONS: Culturally competent and language concordant educational interventions may improve confidence in utilizing wet wraps and bleach baths among Latin-American caregivers of children with atopic dermatitis, which may improve AD outcomes in the Latin-American community.

Autoantigen microarrays reveal myelin basic protein autoantibodies in morphea.

BACKGROUND: Morphea is an autoimmune, sclerosing skin disorder. Despite the recent emphasis on immune dysregulation in morphea, the role of autoantibodies in morphea pathogenesis or utility as biomarkers are poorly defined. METHODS: Autoantigen microarray was used to profile autoantibodies from the serum of participants from the Morphea in Adults and Children (MAC) cohort. Clinical and demographic features of morphea patients with myelin basic protein (MBP) autoantibodies were compared to those without. MBP immunohistochemistry staining was subsequently performed in morphea skin to assess for perineural inflammation in areas of staining. Immunofluorescence staining on mouse brain tissue was also performed using patient sera and mouse anti-myelin basic protein antibody to confirm the presence of MBP antibodies in patient sera. RESULTS: Myelin basic protein autoantibodies were found in greater frequency in morphea (n = 50, 71.4%) compared to systemic sclerosis (n = 2, 6.7%) and healthy controls (n = 7, 20%). Patients with MBP antibodies reported pain at higher frequencies. Morphea skin biopsies, highlighted by immunohistochemistry, demonstrated increased perineural inflammation in areas of MBP expression. Immunofluorescence staining revealed an increased fluorescence signal in myelinated areas of mouse brain tissue (i.e. axons) when incubated with sera from MBP antibody-positive morphea patients compared to sera from MBP antibody-negative morphea patients. Epitope mapping revealed target epitopes for MBP autoantibodies in morphea are distinct from those reported in MS, and included fragments 11-30, 41-60, 51-70, and 91-110. CONCLUSIONS: A molecular classification of morphea based on distinct autoantibody biosignatures may be used to differentially classify morphea. We have identified anti-MBP as a potential antibody associated with morphea due to its increased expression in morphea compared to healthy controls and systemic sclerosis patients.

Ichthyosiform sarcoidosis: Report of a case and comprehensive review of the literature.

Sarcoidosis is a disease that can affect a multitude of organs and manifest as cutaneous disease. Cutaneous manifestations of sarcoidosis vary widely in morphology, earning the nickname of "great imitator," and the diagnosis often requires clinicopathologic correlation and additional laboratory and radiographic workup. We present the case of a 42-year-old African American woman with ichthyosiform sarcoidosis on the bilateral lower extremities. As one of the rarest specific variants of cutaneous sarcoidosis, ichthyosiform is understudied and has been primarily documented in case reports and series. We undertake a comprehensive review of the literature to identify key clinicopathologic features including the characterization of sites of cutaneous and systemic involvement, as well as typical histopathological findings. Lower extremities were the most involved body site (85.7%). Extracutaneous organ involvement centered around pulmonary (65.7%), lymph node (57.1%), and ocular (31.4%) involvement. Of the histopathological features reported, hyperkeratosis (51.4%) and diminished stratum granulosum (62.9%) were most frequently reported in conjunction with dermal granulomas (100%). We hope that these findings will serve to aid clinicopathological correlation and accurate diagnosis of ichthyosiform sarcoidosis.

Emerging treatments for scleroderma/systemic sclerosis.

Systemic sclerosis (SSc) is a connective tissue disease characterized by progressive fibrosis of the skin and internal organs and has significant clinical sequelae. Management of SSc cutaneous disease remains challenging and often is driven by extracutaneous manifestations. Methotrexate is the typical first-line therapy for patients with early progressive cutaneous disease. However, in patients with diffuse progressive skin disease and inflammatory arthritis, methotrexate or rituximab monotherapy should be considered. First-line therapy for patients with concomitant myositis includes methotrexate or intravenous immunoglobulin (IVIG). For patients with both cutaneous findings and interstitial lung disease, studies have suggested the efficacy of mycophenolate mofetil or rituximab. Second-line therapies, including UVA-1 phototherapy, IVIG, or rituximab, can be considered in patients with disease refractory to first-line treatments. Clinical trials investigating the utility of emerging therapies such as abatacept and tocilizumab in the treatment of SSc are under way, and preliminary results are promising. Nonetheless, all patients with SSc benefit from a gentle skin-care regimen to alleviate pruritis, which is a commonly reported symptom. Additional cutaneous manifestations of SSc include telangiectasias, calcinosis cutis, microstomia, and Raynaud's phenomenon. Telangiectasia may be managed with camouflage techniques, pulse dye laser, and intense pulse light. Calcinosis cutis therapy is guided by the size of the calcium deposits, although treatment options are limited. Mouth augmentation and oral stretching exercises are recommended for patients with reduced oral aperture. Raynaud's phenomenon is treated with a combination of lifestyle modification and calcium channel blockers, such as amlodipine. Overall, SSc is a clinically heterogenous disease that affects multiple organ systems. Providers should assess extracutaneous involvement and use evidence-based recommendations to select the most appropriate therapy for patients with SSc.

Changes in Use of Radiotherapy Among Dermatologists From 2013 to 2017.

Importance: Concerns have been raised about the use of radiotherapy (RT) by dermatologists. Little is known about temporal trends in payment for RT among dermatologists. Objective: To characterize changes in RT use and payment among dermatologists treating patients enrolled in Medicare. Design, Setting, and Participants: A cross-sectional, population-based retrospective analysis of dermatologists submitting Medicare claims was conducted. Dermatologists identified in the 2013-2017 Medicare Physician and Other Supplier Public Use File, which includes information on fee-for-service payments and service use among physicians caring for Medicare beneficiaries, were included in the analysis. The study was conducted from March 18 to October 22, 2020. Main Outcomes and Measures: Numbers and types of RT, current terminology codes billed by dermatologists, number of dermatologists providing RT services, total payments and median payments per dermatologist for RT services, total services and median services per dermatologist, and number of dermatologists billing for both RT and Mohs micrographic surgery services. Results: From 2013 to 2017, dermatologists billed RT codes, which included RT planning, preparation, delivery, and management services with varying levels of complexity. The number of dermatologists using RT increased from 115 to 198 between 2013 to 2017. Total payments and total services for RT have fluctuated over time. Median payments per dermatologist and median services provided per dermatologist for RT reached their highest level in 2017 ($80 810 and 629 services). In 2013, RT delivery was the highest reimbursed RT service type (total paid, $9 121 505). By 2017, clinical treatment planning and simulation was the highest reimbursed service type (total paid, $20 288 796). Conclusions and Relevance: The findings of this cross-sectional study indicate that dermatologist use of RT continues to increase. A wide variety of RT services are billed by dermatologists. Further research is needed to ensure expanded use is safe, efficacious, and cost-effective.

Time event ontology (TEO): to support semantic representation and reasoning of complex temporal relations of clinical events.

OBJECTIVE: The goal of this study is to develop a robust Time Event Ontology (TEO), which can formally represent and reason both structured and unstructured temporal information. MATERIALS AND METHODS: Using our previous Clinical Narrative Temporal Relation Ontology 1.0 and 2.0 as a starting point, we redesigned concept primitives (clinical events and temporal expressions) and enriched temporal relations. Specifically, 2 sets of temporal relations (Allen's interval algebra and a novel suite of basic time relations) were used to specify qualitative temporal order relations, and a Temporal Relation Statement was designed to formalize quantitative temporal relations. Moreover, a variety of data properties were defined to represent diversified temporal expressions in clinical narratives. RESULTS: TEO has a rich set of classes and properties (object, data, and annotation). When evaluated with real electronic health record data from the Mayo Clinic, it could faithfully represent more than 95% of the temporal expressions. Its reasoning ability was further demonstrated on a sample drug adverse event report annotated with respect to TEO. The results showed that our Java-based TEO reasoner could answer a set of frequently asked time-related queries, demonstrating that TEO has a strong capability of reasoning complex temporal relations. CONCLUSION: TEO can support flexible temporal relation representation and reasoning. Our next step will be to apply TEO to the natural language processing field to facilitate automated temporal information annotation, extraction, and timeline reasoning to better support time-based clinical decision-making.

Utilizing UVA-1 Phototherapy.

There is a long history of utilization of phototherapy for treatment of skin conditions. Because of its longer wavelength, UVA1 phototherapy is able to penetrate into the dermis and subcutis. This depth of penetration, combined with its unique immunomodulating properties, makes UVA1 an effective treatment modality for many immune-mediated skin diseases. In some cases, it performs better than other types of phototherapy.