Publications

IMPORTANCE: Frontal fibrosing alopecia (FFA) is an inflammatory and scarring form of hair loss of increasing prevalence that most commonly affects women. An improved understanding of the genetic basis of FFA will support the identification of pathogenic mechanisms and therapeutic targets.

OBJECTIVE: To identify novel genomic loci at which common genetic variation affects FFA susceptibility and assess nonadditive effects on genetic risk between susceptibility loci.

DESIGN, SETTING, AND PARTICIPANTS: Four genome-wide association studies were combined using an SE-weighted meta-analysis. Within the major histocompatibility complex (MHC) locus, stepwise conditional analysis was undertaken to determine independently associated classical MHC class I alleles. Statistical tests for epistatic interaction were performed between risk alleles at the MHC and endoplasmic reticulum aminopeptidase 1 (ERAP1) loci.

MAIN OUTCOMES AND MEASURES: Genome-wide significant locus associated with FFA and nonadditive effects on genetic risk between susceptibility loci.

RESULTS: Of 6668 included patients, there were 1585 European female individuals with FFA and 5083 controls. Genome-wide significant associations were identified at 4 genomic loci, including a novel susceptibility locus at 5q15, and the association signal could be fine-mapped to a single nucleotide substitution (rs10045403) in the 5' untranslated region of ERAP1 (rs10045403; odds ratio, 1.30; 95% CI, 1.19-1.43; P = 3.6 × 10-8). Within the MHC, FFA risk was statistically independently associated with HLA-A*11:01, HLA-A*33:01, HLA-B*07:02, and HLA-B*35:01. FFA risk was affected by genetic variation at the ERAP1 locus only in individuals who carried at least 1 of the MHC class I risk alleles.

CONCLUSIONS AND RELEVANCE: In this genome-wide meta-analysis, a supra-additive effect of genetic variation was found that affected peptide trimming and antigen presentation on FFA susceptibility. Patients with FFA may benefit from emerging therapeutic approaches that modulate ERAP-mediated processes.

BACKGROUND: Alopecia areata (AA) is an autoimmune disease characterized by non-scarring hair loss that can affect children, adolescents, and adults. Ritlecitinib, an orally administered Janus kinase (JAK) 3/tyrosine kinase expressed in hepatocellular carcinoma (TEC) kinase family inhibitor, is the first and currently the only treatment approved by the US Food and Drug Administration for adolescents (aged 12-17 years) with severe AA.

SUMMARY: The ALLEGRO phase 2b-3 trial demonstrated that 25% and 50% of adolescents with a Severity of Alopecia Tool (SALT) score ≥50 at baseline achieved a SALT score ≤20 at week 24 and week 48 after receiving 50 mg ritlecitinib daily, respectively. The most common adverse events were headache, acne, and nasopharyngitis in adolescents. This review summarizes the mechanism of action, clinical trial evidence on efficacy and safety profile, factors associated with treatment response to JAK inhibitors for AA, and vaccination considerations for adolescents.

KEY MESSAGES: This review aims to facilitate the risk-benefit assessment and shared decision-making between clinicians and patients and provide clinical considerations and management recommendations for ritlecitinib use in adolescents with AA.

The pathophysiology of lichen planopilaris (LPP), a lymphocytic primary cicatricial alopecia, is largely unknown. We evaluated RNA expression of lesional scalp biopsies taken before and after 6 months of treatment monotherapy with oral hydroxychloroquine (HCQ), narrow band ultraviolet B (NB-UVB), or low level laser light therapy (LLLLT). PTGER4 and DOCK2 were significantly increased in all patients after treatment. CYP1A2, a drug metabolism enzyme, and SSR2, a gene involved in B cell activation and maturation, were increased posttreatment for the HCQ arm. VEGFA, which has been reported to be downregulated by phototherapy was decreased post NB-UVB treatment, while SAA1, an apolipoprotein gene present in plasma that is upregulated in response to tissue injury, was increased posttreatment for the NB-UVB arm. No significant differentially expressed genes (DEGs) in the LLLLT arm before and after treatment. The expressions of CD68, COL5A1, MMP9, COL6A3, and CD44 were significantly higher at the baseline in biopsies from patients with a Lichen Planopilaris Activity Index (LPPAI) score ≥ 4 compared with those with an LPPAI < 4. These genes are involved in extracellular matrix organization and M2, or profibrotic, macrophage polarization, which is congruent with follicular scarring. Our data identify potential RNA biomarkers of LPPAI and suggest that M2 macrophages may play a role in LPP immunopathogenesis.

Lichen planopilaris (LPP) is a primary cicatricial alopecia suggested to be associated with various comorbid medical conditions, including autoimmune, endocrine, and metabolic disorders. However, there is conflicting data regarding these associations. This study quantitatively evaluated the prevalence and odds of comorbidities among patients with LPP. PubMed/MEDLINE, EMBASE, Cochrane Library, and Web of Science were searched from inception to December 25, 2023, to include observational studies reporting prevalent/incident cases of at least one comorbidity in LPP patients. The study adhered to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA). Risk-of-bias assessment was performed using the Newcastle-Ottawa scale. Random-effect models were utilized to analyze available data. Of the 2535 studies screened, 59 studies were included for meta-analysis, comprising 15,178 LPP patients and 64,735,181 non-LPP controls. Among LPP patients, comorbidities with the highest risk (odds ratio, OR [95% confidence interval, Cl]; prevalence) compared with non-LPP controls and data available from more than one study included lichen planus (15.78 [1.79-139.30]; 6.5%), psoriasis (3.55 [1.10-11.51]; 4.3%), rosacea (3.15 [2.25-4.40]; 10.4%), melanoma (3.11 [1.41-6.87]; 2.3%), systemic lupus erythematosus (3.06 [2.29-4.09]; 1.8%), cutaneous squamous cell carcinoma (3.04 [1.64-5.66]; 4.8%), vitiligo (2.89 [1.60-5.24]; 2.0%), coronary artery disease (1.66 [1.46-1.88]; 7.6%), rheumatoid arthritis (1.50 [1.22-1.84]; 3.5%), hypothyroidism (1.48 [1.12-1.96]; 17.8%), thyroiditis (1.26 [1.08-1.48]; 3.9%), and iron deficiency anemia (1.18 [1.05-1.33]; 9.1%). LPP is significantly associated with autoimmune disorders, thyroid diseases, and skin cancer. Further investigation is required to elucidate the underlying pathogenesis and establish appropriate screening criteria.