Staphylococcal phosphatidylglycerol antigens activate human T cells via CD1a.

Expressed on epidermal Langerhans cells, CD1a presents a range of self-lipid antigens found within the skin; however, the extent to which CD1a presents microbial ligands from bacteria colonizing the skin is unclear. Here we identified CD1a-dependent T cell responses to phosphatidylglycerol (PG), a ubiquitous bacterial membrane phospholipid, as well as to lysylPG, a modified PG, present in several Gram-positive bacteria and highly abundant in Staphylococcus aureus. The crystal structure of the CD1a-PG complex showed that the acyl chains were buried within the A'- and F'-pockets of CD1a, while the phosphoglycerol headgroup remained solvent exposed in the F'-portal and was available for T cell receptor contact. Using lysylPG and PG-loaded CD1a tetramers, we identified T cells in peripheral blood and in skin that respond to these lipids in a dose-dependent manner. Tetramer+CD4+ T cell lines secreted type 2 helper T cell cytokines in response to phosphatidylglycerols as well as to co-cultures of CD1a+ dendritic cells and Staphylococcus bacteria. The expansion in patients with atopic dermatitis of CD4+ CD1a-(lysyl)PG tetramer+ T cells suggests a response to lipids made by bacteria associated with atopic dermatitis and provides a link supporting involvement of PG-based lipid-activated T cells in atopic dermatitis pathogenesis.

Incidence estimates for lichen planopilaris and frontal fibrosing alopecia in a New York City health care system.

Lichen planopilaris (LPP) and frontal fibrosing alopecia (FFA) are scarring alopecias that cause significant distress and psychological morbidity. Limited studies have been performed examining the epidemiology of FFA and LPP. We performed a retrospective case cohort analysis by querying for patients with the ICD 10 code L66.1 (LPP, FFA) between 2015 and 2018 using the Clinical Data Warehouse (CDW) at NewYork-Presbyterian Hospital and Columbia Doctors. We calculated the one-year incidence of LPP/FFA between January 1, 2018 to December 31, 2018 by identifying all patients without a previously recorded ICD code for L66.1 who presented as a new hair loss patient based on chart review. A total of 170 patients were identified with a new diagnosis of LPP or FFA in 2018 among 1,187,583 patients. The standardized incidence per 100,000 was 12.75 for LPP and FFA combined, 7.35 for LPP alone, and 5.41 for FFA alone. The incidence peaked in the 51 to 60 age range (3.36). The incidence was highest in non-Hispanic White patients (17.27), White patients of unknown ethnicity (26.26), and non-Hispanic Asian patients (17.27). In New York City, LPP and FFA are uncommon diseases that are most common in middle-aged females and non-Hispanic White patients.

Tofacitinib for the treatment of lichen planopilaris: A case series.

Lichen planopilaris (LPP) is an inflammatory cicatricial alopecia for which many different therapies are attempted with varying success. The Janus kinase (JAK) inhibitor, tofacitinib, has been shown to be effective in treating the noncicatricial alopecia, alopecia areata. As in alopecia areata, upregulation of interferon and JAK signaling may play a role in LPP. We retrospectively reviewed the cases of 10 patients with recalcitrant LPP who were treated with oral tofacitinib. Patients received oral tofacitinib 5 mg twice or three times daily for 2-19 months as either monotherapy or adjunctive therapy to other ongoing treatments including intralesional triamcinolone, hydroxychloroquine, and tacrolimus ointment. Eight patients had clinical improvement in LPP with tofacitinib as either monotherapy (4/10) or adjunctive therapy (4/10). LPP Activity Index (LPPAI) before and after treatment was measured in seven patients and was significantly different (6.22 before treatment, 3.08 after treatment; p value = .0014). Reduction in LPPAI ranged from 30 to 94%. One patient complained of 10 pound (4.5 kg) weight gain after 12 months on tofacitinib. No other adverse effects were reported. Treatment with oral tofacitinib either as monotherapy or adjunctive therapy can lead to measurable improvement in recalcitrant LPP.

Low-Dose Metformin and Profibrotic Signature in Central Centrifugal Cicatricial Alopecia.

Importance: Central centrifugal cicatricial alopecia (CCCA) is a scarring alopecia predominantly affecting Black female individuals. Current conventional treatments target inflammation but not the underlying fibrotic processes, often leading to permanent hair loss. Objective: To investigate the associations of low-dose oral metformin, an antidiabetic medication with antifibrotic properties, with clinical symptoms and scalp gene expression patterns in patients with CCCA. Design, Setting, and Participants: This retrospective clinical case series and transcriptomic analysis included patients treated at a single tertiary academic medical center between January 2023 and March 2024. All patients had biopsy-confirmed CCCA refractory to standard treatments. Transcriptomic analysis was performed on patients with previously banked, paired scalp biopsies before and after treatment with adjuvant metformin for at least 6 weeks. Exposure: Extended-release metformin, 500 mg, once daily was added to participants' baseline CCCA treatment regimens. Main Outcomes and Measures: Clinical assessments included pruritus, inflammation, scalp resistance, and hair regrowth. Gene expression profiling via bulk RNA sequencing analysis evaluated differential gene expression and pathway enrichment. Results: A total of 12 Black female participants were included in the study, and transcriptomic analysis was performed in 4 participants. After at least 6 months of metformin treatment, 9 participants experienced improvement in disease, including scalp pain, inflammation, and/or pruritus, and 6 demonstrated clinical evidence of hair regrowth. The addition of metformin led to reversal of many prominent gene pathways previously identified in CCCA. Transcriptomic analysis revealed upregulation of pathways and genes (keratin-associated proteins [KRTAPs]) involved in keratinization, epidermis development, and the hair cycle (absolute log2-fold change > 4), with concomitant downregulation of fibrosis-related pathways and genes (eg, MMP7, COL6A1) (fold change >1.5; all false discovery rate <.05). Gene set analysis showed reduced expression of helper T cell 17 and epithelial-mesenchymal transition pathways and elevated adenosine monophosphate kinase signaling and KRTAPs after metformin treatment. Conclusions and Relevance: In this case series of patients with treatment-refractory CCCA, low-dose oral metformin was associated with symptomatic improvement and dual modulation of gene expression, stimulating hair growth pathways while suppressing fibrosis and inflammation markers. These findings provide a rationale for future clinical trials studying metformin as a targeted therapy for CCCA and other cicatricial alopecias.

Inborn Errors of Immunity Contribute to the Burden of Skin Disease and Create Opportunities for Improving the Practice of Dermatology.

Opportunities to improve the clinical management of skin disease are being created by advances in genomic medicine. Large-scale sequencing increasingly challenges notions about single-gene disorders. It is now apparent that monogenic etiologies make appreciable contributions to the population burden of disease and that they are underrecognized in clinical practice. A genetic diagnosis informs on molecular pathology and may direct targeted treatments and tailored prevention strategies for patients and family members. It also generates knowledge about disease pathogenesis and management that is relevant to patients without rare pathogenic variants. Inborn errors of immunity are a large class of monogenic etiologies that have been well-studied and contribute to the population burden of inflammatory diseases. To further delineate the contributions of inborn errors of immunity to the pathogenesis of skin disease, we performed a set of analyses that identified 316 inborn errors of immunity associated with skin pathologies, including common skin diseases. These data suggest that clinical sequencing is underutilized in dermatology. We next use these data to derive a network that illuminates the molecular relationships of these disorders and suggests an underlying etiological organization to immune-mediated skin disease. Our results motivate the further development of a molecularly derived and data-driven reorganization of clinical diagnoses of skin disease.

Primary cicatricial alopecias are characterized by dysregulation of shared gene expression pathways.

The primary forms of cicatricial (scarring) alopecia (PCA) are a group of inflammatory, irreversible hair loss disorders characterized by immune cell infiltrates targeting hair follicles (HFs). Lichen planopilaris (LPP), frontal fibrosing alopecia (FFA), and centrifugal cicatricial alopecia (CCCA) are among the main subtypes of PCAs. The pathogenesis of the different types of PCAs are poorly understood, and current treatment regimens yield inconsistent and unsatisfactory results. We performed high-throughput RNA-sequencing on scalp biopsies of a large cohort PCA patients to develop gene expression-based signatures, trained into machine-learning-based predictive models and pathways associated with dysregulated gene expression. We performed morphological and cytokine analysis to define the immune cell populations found in PCA subtypes. We identified a common PCA gene signature that was shared between LPP, FFA, and CCCA, which revealed a significant over-representation of mast cell (MC) genes, as well as downregulation of cholesterogenic pathways and upregulation of fibrosis and immune signaling genes. Immunohistological analyses revealed an increased presence of MCs in PCAs lesions. Our gene expression analyses revealed common pathways associated with PCAs, with a strong association with MCs. The indistinguishable differences in gene expression profiles and immune cell signatures between LPP, FFA, and CCCA suggest that similar treatment regimens may be effective in treating these irreversible forms of hair loss.

Validation of Case Identification for Alopecia Areata Using International Classification of Diseases Coding.

BACKGROUND: Search algorithms used to identify patients with alopecia areata (AA) need to be validated prior to use in large databases. OBJECTIVES: The aim of the study is to assess whether patients with an International Statistical Classification of Diseases and Related Health Problems (ICD) 9 or 10 code for AA have a true diagnosis of AA. MATERIALS AND METHODS: A multicenter retrospective review was performed at Columbia University Irving Medical Center, Brigham and Women's Hospital, and Massachusetts General Hospital to determine whether patients with an ICD 9 codes (704.01 - AA) or ICD 10 codes (L63.0 -Alopecia Totalis, L63.1 - Alopecia Universalis, L63.2 - Ophiasis, L63.8 - other AA, and L63.9 - AA, unspecified) for AA met diagnostic criteria for the disease. RESULTS: Of 880 charts, 97.5% had physical examination findings consistent with AA, and 90% had an unequivocal diagnosis. AA was diagnosed by a dermatologist in 87% of the charts. The positive predictive value (PPV) of the ICD 9 code 704.01 was 97% (248/255). The PPV for the ICD 10 codes were 64% (75/118) for L63.0, 86% (130/151) for L63.1, 50% (1/2) for L63.2, 91% (81/89) for L63.8, and 93% (247/265) for L63.9. Overall, 89% (782/880) of patients with an ICD code for AA were deemed to have a true diagnosis of AA. CONCLUSIONS: Patients whose medical records contain an AA-associated ICD code have a high probability of having the condition.