JAMA dermatology最新文献

Importance: Acanthosis nigricans (AN) is commonly associated with impaired glucose tolerance, but early, severe presentation in individuals with normoglycemia may identify individuals at risk for systemic disease. While gain of function epidermal growth factor receptor (EGFR) pathogenic variants are associated with pulmonary cancers, their role in syndromic skin disease has not been clearly defined. This study identified activating EGFR variants that were associated with a syndrome characterized by generalized acquired keratoderma accentuated at flexural sites, woolly hair, palmoplantar keratoderma, and pulmonary disease with lung nodules, and the results suggest EGFR inhibitor therapeutic efficacy.

Objectives: To determine the genetic basis of early-onset, syndromic AN and assess response to pathogenesis-directed therapy.

Design, setting, and participants: Patients included 2 individuals with normoglycemia with early-onset periorificial hyperpigmentation and flexural skin thickening that subsequently generalized and 1 individual with an original diagnosis of widespread epidermal nevus. Participants underwent whole-exome sequencing and studies of affected skin and keratinocytes.

Main outcomes and measures: EGFR variant identification and assessment of pathway activation in lesional skin and keratinocytes, pulmonary function testing, lung imaging, and clinical response to EGFR inhibition.

Results: All 3 participants (aged 8, 18, and 17 years; 2 male individuals and 1 female individual) had an EGFR L858R variant, which arose as either de novo in generalized cases or a somatic variant in mosaic disease. Lesional skin and cultured keratinocytes demonstrated increased EGFR pathway activity, which was suppressed by pharmacologic inhibition in vitro. Systemic treatment with EGFR inhibitors was associated with skin disease regression, improvement in pulmonary disease, and resolution or reduction of the number of pulmonary nodules.

Conclusions and relevance: The findings of this case series study define a syndromic disorder with increased risk of pulmonary disease and lung nodules in patients with acquired, generalized AN that is associated with activating EGFR variants. Pulmonary nodules are precursor lesions for lung cancer, and treatment with EGFR inhibitions is associated with near-complete resolution of skin and pulmonary disease. Early recognition of syndromic EGFR AN will permit identification of individuals at risk for systemic disease who are candidates for EGFR-targeted therapy.

Importance: The long-term effectiveness of biologic therapies in psoriasis may decline over time. Gut microbiota alterations induced by antibiotics have been proposed as a potential mechanism impairing biologic persistence.

Objective: To evaluate the association between antibiotic exposure and the persistence of biologic therapies in patients with psoriasis.

Design, setting, and participants: This retrospective cohort study used data from the French National Health Insurance database between June 2011 and December 2022. Adults initiating a biologic therapy for psoriasis were included, excluding those with preexisting inflammatory bowel disease at baseline. Data were analyzed from January to September 2024.

Exposures: At baseline, antibiotics exposure was classified as none, 1, or 2 or more dispensations in the 6 months preceding the index date. During follow-up, time-dependent antibiotics exposure was defined as none, 1, or 2 or more antibiotics dispensations in the 6 months prior to each time of follow-up.

Main outcomes and measures: The primary outcome was discontinuation or switch of the initial biologic therapy. Exposure to antibiotics was assessed within 6 months prior to biologic initiation and during follow-up. A weighted Cox marginal structural model was used to estimate adjusted hazard ratios.

Results: Of 36 129 included patients, 11 228 (42.0%) were female, 20 192 (55.9%) were male, and the mean (SD) age was 48.4 (15.1) years. A total of 9366 (25.9%) were exposed to antibiotics at baseline and 21 900 (60.6%) during follow-up. The most commonly prescribed antibiotic classes were β-lactams, macrolides, and fluoroquinolones. Antibiotic exposure was associated with a higher risk of biologic discontinuation (weighted hazard ratio, 1.12; 95% CI, 1.08-1.16), with a stronger effect observed for multiple dispensations (weighted hazard ratio, 1.29; 95% CI, 1.24-1.35), suggesting a dose-response relationship.

Conclusions and relevance: In this cohort study, antibiotic exposure was significantly associated with an increased risk of discontinuation of biologic therapies in psoriasis. These findings support the hypothesis that antibiotics, potentially through gut dysbiosis, may reduce biologic persistence. However, unmeasured confounders limit causal interpretation. Further studies are necessary to validate these findings.