JAMA dermatology最新文献

Importance: UV-induced mutagenesis leads to a higher tumor mutational burden (TMB) in cutaneous melanoma relative to other cancer types. TMB is an important prognostic marker in advanced melanoma; higher TMB is associated with greater clinical response to immune checkpoint inhibition and improved survival.

Objective: To evaluate the association between cutaneous melanoma TMB and indoor tanning exposure, as well as other demographic, dermatologic, and tumor characteristics.

Design, setting, and participants: This retrospective cohort study took place at Dana-Farber Cancer Institute, a tertiary-care cancer treatment center in Boston, Massachusetts, between 2013 and 2022. Patients with a diagnosis of cutaneous melanoma for whom next-generation sequencing data and tanning bed exposure history were available were included.

Exposures: Indoor tanning exposure history, tumor characteristics, demographics, and dermatologic history were collected via retrospective medical record review.

Main outcomes and measures: The association of tanning bed use with TMB was modeled using inverse probability of treatment weighted, multivariable modeling.

Results: Among 617 patients (median [IQR] age at diagnosis, 61 [50-71] years; 337 [62.9%] male), there was no association between indoor tanning exposure and TMB after adjustment for demographic, tumor, and dermatologic characteristics (yes vs no: log2 TMB [SE], 4.07 [0.44] vs 3.97 [0.45]; P = .39). However, there was a statistically significant association between higher TMB and older age at diagnosis, history of nonmelanoma skin cancer, and head and neck tumors relative to other primary sites. Average TMB was statistically significantly lower in patients with a history of abnormal nevi (yes vs no: log2 TMB [SE], 3.89 [0.44] vs 4.15 [0.44]; P = .01).

Conclusions and relevance: This cohort study suggests that indoor tanning exposure, while known to increase risk of melanoma, may not be meaningfully associated with melanoma TMB. Additional characteristics were associated with higher TMB and, thus, potentially improved immune checkpoint inhibitor response.

Importance: Palmoplantar keratoderma poses diagnostic challenges due to its clinical and genetic heterogeneity, and knowledge on the value of systematic genetic testing on clinically well-described patient cohorts is sparse.

Objective: To improve knowledge of the clinical and genetic spectrum of patients with palmoplantar keratoderma.

Design, setting, and participants: This cohort study prospectively recruited patients and affected family members with palmoplantar keratoderma between September 1, 2016, and December 31, 2022. Patients were recruited from private practitioners in dermatology and dermatology departments in Denmark. Study participants were patients 18 years or older either newly diagnosed with palmoplantar keratoderma or being followed up for the disease at referral centers.

Main outcomes and measures: Phenotypes and clinical subtypes were classified. Genetic testing was performed by whole-exome or genome sequencing using an in silico panel containing genes related to palmoplantar keratoderma, or by Sanger sequencing for specific variants. Descriptive analysis, such as proportions and frequency, were used to describe clinical characteristics, distribution of disease-causing variants, and genotype-phenotype associations.

Results: This study included 142 study participants from 76 families (90 [63%] female; median [range] age, 52 [18-92] years). Clinical subtypes included 42 punctate (55%), 26 diffuse (34%), 5 focal (7%), and 3 striate (4%). A genetic diagnosis was found in 63 of 76 families (83%), including 27 disease-causing variants within 13 different genes: AAGAB (n = 39), DSG1 (n = 8), KRT1 (n = 3), DSP (n = 2), KRT9 (n = 2), AQP5 (n = 2), KRT16 (n = 1), SERPINA12 (n = 1), ABCA12 (n = 1), COL7A1 (n = 1), CARD14 (n = 1), DST (n = 1), and LORICRIN (n = 1). All participants with AAGAB variants presented with punctate palmoplantar keratoderma, showing a clear genotype-phenotype correlation. The other subtypes (diffuse, focal, and striate) proved more challenging to clinically subclassify, and disease-causing variants were identified in 12 genes, contributing to more complex genotype-phenotype patterns. Patients with palmoplantar keratoderma due to DSP variants were found, which is important to identify because of an associated risk of cardiomyopathy.

Conclusion and relevance: This study provides novel insights into the clinical and genetic spectrum of patients with palmoplantar keratoderma. It demonstrates the value of genetic testing for accurate diagnoses and to distinguish between different subtypes. The established and well-described cohort lays the foundation for future research in palmoplantar keratoderma.

Importance: Patients with recessive dystrophic epidermolysis bullosa (RDEB) experience neuropathic pain and itch. There is a lack of evidence on any treatment for these symptoms in patients with RDEB.

Objectives: To test the efficacy of pregabalin in the treatment of neuropathic pain and itch in patients with RDEB.

Design, setting, and participants: A randomized, double-blinded, crossover trial of oral pregabalin (50-300 mg/d) vs placebo was conducted at 2 sites, Toronto (Canada) and Santiago (Chile) from January 1, 2019, to December 31, 2020. Patients eligible to participate were diagnosed with RDEB, aged 8 to 40 years, not pregnant or lactating (if female), and had evidence of probable neuropathic pain and itching defined as distal thermal sensory loss (confirmed by thermal roller), score of 4 or greater on the Douleur Neuropathique 4 questionnaire (DN4), and score greater than 4 on the 10-point visual analog scale [VAS]). Patients with a clinically important or poorly controlled medical or psychiatric condition or pregabalin intolerance or allergy were excluded. Of 41 patients screened, 3 were not eligible and 28 declined enrollment. Data analyses were performed in 2021 through 2023.

Intervention: Participants received both pregabalin and matched placebo (titrated to a maximum-tolerated dose of 300 mg/day) in a randomized sequence so that comparisons could be made within participants and between groups.

Main outcomes and measures: Difference in the mean pain and itch scores between pregabalin and placebo treatment (measured using VAS) before and after intervention.

Results: In all, 10 participants were randomized to 2 groups, 6 patients (mean [SD] age, 26.7 [8.1] years; 3 females [50%]) in group 1, and 4 patients (mean [SD] age, 26.5 [7.8] years, 2 females [50%]) in group 2. Group 1 received a sequence of pregabalin-placebo while group 2 received placebo-pregabalin. Pregabalin significantly reduced mean (SD) pain scores by 1.9 (1.5) points when controlling for sequence and treatment period vs baseline, while placebo had 0.1 (2.0) points of reduction. The effect of pregabalin was a mild but significant reduction in itch compared to baseline (mean [SD] points, 0.9 [2.2]), whereas the placebo produced no reduction (0.1 [2.5]). The mean pregabalin dose was generally well tolerated.

Conclusions and relevance: The results of this randomized crossover trial indicate that pregabalin significantly reduced pain and itch scores from baseline compared to placebo in patients with RDEB. This feasibility study provided preliminary data on the efficacy of pregabalin in managing pain and itch in RDEB and gathered essential data to inform the design of a larger cohort trial.

Trial registration: ClinicalTrials.gov Identifier: NCT03928093.

Importance: Nail lichen planus has the potential to cause permanent destruction of the nail unit and remains challenging to treat. Studies suggest that low-dose naltrexone is a safe and potentially effective treatment for other dermatologic conditions, including lichen planopilaris.

Objective: To assess the effectiveness of low-dose naltrexone in treating nail lichen planus.

Design, setting, and participants: This case series evaluates 7 adult patients with biopsy-proven nail lichen planus who were treated with low-dose naltrexone (3 mg per day) at the University of Miami dermatologic clinics from November 2022 to December 2023. The data were analyzed in March 2024. Patients were treated for at least 2 months and had in-person follow-up evaluation while receiving treatment.

Main outcomes and measures: The main outcome was posttreatment clinical nail lichen planus severity index, which was scored as clear, mild, moderate, or severe. Patients were evaluated for oral and cutaneous disease during the course of treatment. Tolerance and adverse events were noted.

Results: A total of 7 patients (mean [range] age, 60 [38-77] years; 3 female individuals) were included. All but 1 patient had been previously treated and did not respond to at least 1 prior treatment (median [range], 2.5 [0-4.0] treatments). Treatment duration ranged from 2 to 11 months. Clinical response was observed in 4 of 7 patients, with an overall 35% reduction in nail lichen planus severity index. Two patients with severe disease achieved a reduction to mild severity. None of the patients had to discontinue low-dose naltrexone due to adverse events, and no adverse events were reported.

Conclusions and relevance: The results of this study suggest that low-dose naltrexone may be a therapeutic approach for treating nail lichen planus. Further controlled studies are warranted to better understand its clinical efficacy and safety profile in treating nail lichen planus.