Spatial characterization of interface dermatitis in cutaneous lupus reveals novel chemokine ligand-receptor pairs that drive disease.

Chemokines play critical roles in the recruitment and activation of immune cells in both homeostatic and pathologic conditions. Here, we examined chemokine ligand-receptor pairs to better understand the immunopathogenesis of cutaneous lupus erythematosus (CLE), a complex autoimmune connective tissue disorder. We used suction blister biopsies to measure cellular infiltrates with spectral flow cytometry in the interface dermatitis reaction, as well as 184 protein analytes in interstitial skin fluid using Olink targeted proteomics. Flow and Olink data concordantly demonstrated significant increases in T cells and antigen presenting cells (APCs). We also performed spatial transcriptomics and spatial proteomics of punch biopsies using digital spatial profiling (DSP) technology on CLE skin and healthy margin controls to examine discreet locations within the tissue. Spatial and Olink data confirmed elevation of interferon (IFN) and IFN-inducible CXCR3 chemokine ligands. Comparing involved versus uninvolved keratinocytes in CLE samples revealed upregulation of essential inflammatory response genes in areas near interface dermatitis, including AIM2. Our Olink data confirmed upregulation of Caspase 8, IL-18 which is the final product of AIM2 activation, and induced chemokines including CCL8 and CXCL6 in CLE lesional samples. Chemotaxis assays using PBMCs from healthy and CLE donors revealed that T cells are equally poised to respond to CXCR3 ligands, whereas CD14+CD16+ APC populations are more sensitive to CXCL6 via CXCR1 and CD14+ are more sensitive to CCL8 via CCR2. Taken together, our data map a pathway from keratinocyte injury to lymphocyte recruitment in CLE via AIM2-Casp8-IL-18-CXCL6/CXCR1 and CCL8/CCR2, and IFNG/IFNL1-CXCL9/CXCL11-CXCR3.

Light-Related Cutaneous Symptoms of Erythropoietic Protoporphyria and Associations With Light Sensitivity Measurements.

Importance: Erythropoietic protoporphyria (EPP) is a rare and underdiagnosed genetic disease characterized by painful sensitivity to light. A better understanding and characterization of its light-induced cutaneous symptoms may aid in the identification of EPP in patients. Objectives: To describe the cutaneous symptoms of erythropoietic protoporphyria (EPP) and to determine if these symptoms are associated with the degree of light sensitivity. Design, Setting, and Participants: This was a cross-sectional study of adolescent and adult (≥15 years) patients with EPP across the US conducted by a single academic hospital via a remotely administered survey, measurements of light sensitivity by light dosimetry and by text message symptom assessments. Data analyses were conducted from November 2020 to April 2022. Exposures: Sunlight exposure. Main Outcomes and Measures: Self-reported symptoms and association with measured light sensitivity. Results: The study sample consisted of 35 patients with EPP (mean [SD] age, 39.1 (15.5) years; 21 [60%] female; 14 [40%] male; 35 [100%] White individuals). The patients' median [range] skin tone was 3.0 (1.0-8.0), based on self-reporting from 1 (lightest) to 12 (darkest). A total of 24 participants completed the light dosimeter measurements. Phototoxic reactions were characterized by pain (97%; 34 patients), burning (97%; 34), tingling (97%; 34), pruritus (83%; 29), allodynia (89%; 31), improvement of symptoms with cold (89%; 31), achiness (24%; 12), fatigue (46%; 16), mild swelling (83%; 29), severe swelling (63%; 22), erythema (51%; 18), petechiae (40%; 14), skin cracking (43%; 15), scabbing (46%; 16), scarring (66%; 23), and other chronic skin changes (40%; 14). Patients with EPP reported that their hands, feet, and face were most sensitive to light and that their shoulders and legs were least sensitive; 25.7% (9 patient) reported no chronic skin changes, and 5.7% (2 patients) reported never having had any visible symptoms. None of these findings varied with the degree of light sensitivity except that lower overall light sensitivity was associated with lower ranked sensitivity of the neck and arms. Conclusions and Relevance: The findings of this cross-sectional study suggest that patients with EPP have distinctive cutaneous symptoms that may aid in identification of this underdiagnosed disease. Characteristic EPP symptoms include light-induced cutaneous burning pain and occasional swelling, particularly over the hands, with a prodrome of pruritus and paresthesias. Minimal skin changes or the absence of visible skin changes during reactions to light, including lack of erythema, do not exclude an EPP diagnosis nor suggest low EPP disease burden.

Evidence-based consensus guidelines for the diagnosis and management of erythropoietic protoporphyria and X-linked protoporphyria.

Erythropoietic protoporphyria and X-linked protoporphyria are rare genetic photodermatoses. Limited expertise with these disorders among physicians leads to diagnostic delays. Here, we present evidence-based consensus guidelines for the diagnosis, monitoring, and management of erythropoietic protoporphyria and X-linked protoporphyria. A systematic literature review was conducted, and reviewed among subcommittees of experts, divided by topic. Consensus on guidelines was reached within each subcommittee and then among all members of the committee. The appropriate biochemical and genetic testing to establish the diagnosis is reviewed in addition to the interpretation of results. Prevention of symptoms, management of acute phototoxicity, and pharmacologic and nonpharmacologic treatment options are discussed. The importance of ongoing monitoring for liver disease, iron deficiency, and vitamin D deficiency is discussed with management guidance. Finally, management of pregnancy and surgery and the safety of other therapies are summarized. We emphasize that these are multisystemic disorders that require longitudinal monitoring. These guidelines provide a structure for evidence-based diagnosis and management for practicing physicians. Early diagnosis and management of these disorders are essential, particularly given the availability of new and emerging therapies.

Topical treatments for erythromelalgia.

Erythromelalgia is a rare neurovascular disease that causes episodes of pain, redness, and warmth in the extremities, and can be debilitating. Currently, there is no universally effective treatment for erythromelalgia. As the precise etiology of erythromelalgia remains obscure, presently available treatments are aimed at alleviating erythromelalgia's wide-ranging symptoms. In general, topical therapies for erythromelalgia are preferred for their more limited side effects and for those with contraindications to systemic therapies. This review will summarize the current topical therapies available to treat erythromelalgia and discuss emerging therapies based on our growing understanding of erythromelalgia pathophysiology.

Coalescing skin-colored papules.

The rash's distinct clinical appearance and the patient's age pointed to an uncommon diagnosis.

Successful Treatment of Brunsting-Perry Cicatricial Pemphigoid With Dupilumab.

Brunsting-Perry is a rare variant of cicatricial pemphigoid, characterized by subepidermal bullae localized to the head and neck. Currently, treatment relies on non-specific immunosuppression, which in many cases, does not lead to a remission of treatment or significant clinical improvement. Dupilumab, a human monoclonal antibody against IL-4 receptor alpha, has been shown to provide relief of allergic inflammatory lesions and is the first biologic agent approved for the treatment of moderate-to-severe atopic dermatitis. We present the case of a 63-year-old patient with history of Brunsting-Perry cicatricial pemphigoid who proved refractory to multiple conventional therapies but was successfully treated with a dupilumab regimen of 300 mg every two weeks. This case suggests the potential role of dupilumab in the management of Brunsting-Perry cicatricial pemphigoid. J Drugs Dermatol. 2021;20(10):1113-1115. doi:10.36849/JDD.6032.

Gene Expression Analysis in Four Dogs With Canine Pemphigus Clinical Subtypes Reveals B Cell Signatures and Immune Activation Pathways Similar to Human Disease.

Pemphigus is a group of autoimmune-mediated mucocutaneous blistering diseases characterized by acantholysis. Pemphigus has also been recognized in dogs and shares similar clinical characteristics and variants with human pemphigus. While relationships between human and canine pemphigus have been reported, gene expression patterns across species have not been described in the literature. We sought to perform gene expression analysis of lesional skin tissue from four dogs with various forms of pemphigus to examine gene expression during spontaneous disease in dogs. We found increased T and B cell signatures in canine pemphigus lesions compared to controls, as well as significant upregulation of CCL3, CCL4, CXCL10, and CXCL8 (IL8), among other genes. Similar chemokine/cytokine expression patterns and immune infiltrates have been reported in humans, suggesting that these genes play a role in spontaneous disease. Direct comparison of our dataset to previously published human pemphigus datasets revealed five conserved differentially expressed genes: CD19, WIF1, CXCL10, CD86, and S100A12. Our data expands our understanding of pemphigus and facilitates identification of biomarkers for prediction of disease prognosis and treatment response, which may be useful for future veterinary and human clinical trials.

Vulvar Pruritus: A Review of Clinical Associations, Pathophysiology and Therapeutic Management.

Vulvar pruritus is an unpleasant sensation and frequent symptom associated with many dermatologic conditions, including infectious, inflammatory and neoplastic dermatoses affecting the female genitalia. It can lead to serious impairment of quality of life, impacting sexual function, relationships, sleep and self-esteem. In this review, common conditions associated with vulvar itch are discussed including atopic and contact dermatitis, lichen sclerosus, psoriasis and infectious vulvovaginitis. We review the potential physiologic, environmental and infectious factors that contribute to the development of vulvar itch and emphasize the importance of addressing their complex interplay when managing this disruptive and challenging symptom.

Does Gross Margin Examination Reduce Re-excision Rate in Breast Conservation for Invasive Carcinoma? CALLER Review.

OBJECTIVE: Determine if Gross Margin Examination reduces margin re-excision rate. Our institutional practice is to perform Gross Margin Examination (GME) with Real-time re-excision (RRE) for all breast conservation specimens with Invasive Carcinoma. MATERIALS AND METHODS: Chart review was done to determine if this practice is helpful. 51 CALLER charts were reviewed from December 2016 to December 2017. RESULTS: Thirty-three underwent margin RRE based on the GME. 11 had cancer in the re-resected margin, 6 of which were cleared with the RRE. The other 5 were reoperated on to clear the margin because on final pathology a margin other than the re-resected margin was positive for malignancy. GME was helpful in preventing reoperation in 55%. None of the remaining 22 patients receiving were found to have a positive margin on final pathology, with 1.6 margins on average re-resected. 13/18 patients did not have RRE and had a final clear margin, but of the other 5, final margin was positive for DCIS in 2 and Invasive Cancer in 3. GME missed invasive disease at the margin in 3 of these 18 patients. CONCLUSION: GME was helpful in preventing reoperation in 6 of 11 patients who would have had a positive margin. However, this resulted in the unnecessary removal of additional normal breast tissue in 22 patients. 3 patients' positive margins were missed with GME and required reoperation. 13 patients were able to avoid re-excision and 11 were able to clear their margin in real-time, improving outcomes 24/51 patients. GME therefore does appear useful.

Correction to: Medical Options for the Adjuvant Treatment and Management of Pediatric Melanoma.

Study NCT01519323 (A study of vemurafenib in pediatric patients with stage IIIC or stage IV melanoma harbouring BRAFV600 mutations) was included in a table listing ongoing clinical trials of adjuvant therapies for pediatric melanoma (Table 1) in error. The study was in fact closed early due to low enrollment as correctly noted in section 4 of the article.

Medical Options for the Adjuvant Treatment and Management of Pediatric Melanoma.

Although melanoma is a rare diagnosis in the pediatric population, advances in the management of adults with melanoma offer the prospect of promising therapeutic options for children. At this time, medical management is not considered curative but may reduce the risk of recurrence or prolong survival. Surgical management remains the mainstay of treatment. Medical therapy of pediatric melanoma is not thought to have a role for in situ, early-stage, or localized disease, but adjuvant therapy may have a role in improving the prognosis of patients with positive sentinel lymph node biopsy (SLNB), spread beyond the regional lymph node basin, metastatic disease, or recurrent disease. Medical treatment options include immunotherapies, particularly checkpoint inhibitors, and targeted therapies, which have provided improved toxicity profiles compared with traditional chemotherapy regimens in the setting of advanced disease. There is a growing body of pediatric-specific data relevant to the use of adjuvant therapies for advanced melanoma in children.