Therapeutic JAK Inhibition in Idiopathic Subglottic Stenosis.

Abstract

Idiopathic subglottic stenosis (iSGS) is a fibroinflammatory airway disease causing airway narrowing. Standard treatments are surgical and range from endoscopic procedures to open tracheal resections; there are no adjuvant medical therapies to reduce disease burden. In similar fibroinflammatory diseases such as rheumatoid arthritis (RA), Janus kinase (JAK) inhibitors show great promise in reducing disease severity and recurrence. Therefore, this study sought to identify the potential impact of JAK inhibitors (JAKi) as a novel treatment in iSGS. A retrospective chart review of over 250 patients with iSGS was conducted at a single institution. Demographic information, timing of medications, adverse reactions, and surgical-free interval were reviewed. Using the NoAAC iSGS single-cell RNA sequencing atlas, unsupervised cell clustering was performed, and JAK/STAT pathway activation scores were calculated. Three patients initiated JAKi therapy for RA following diagnosis of iSGS. The mean surgical-free interval increased from 317 days before to 631 days after JAKi initiation, and the annualized dilation rate decreased from 1.24 to 0.38 dilations per patient-year. Single-cell RNA sequencing demonstrated JAK-STAT pathway activation scores were most elevated in iSGS CD4⁺ T cells and neutrophils, and least activated in epithelial cell subtypes. Gene expression for JAK1 and JAK3 was most active in iSGS immune cell subsets compared to normal controls. Our series of three patients suggests that the JAK/STAT pathway may be a therapeutic target in iSGS. Future investigation exploring the impact of JAKi in prospective clinical trials may be a cornerstone in advancing treatment.