Background/Objectives: Janus kinase inhibitors (JAKis) have transformed the treatment of alopecia areata (AA), but pivotal trials had short follow-ups and real-world long-term safety data remain scarce. We compared incident adverse outcomes between patients with AA exposed and not exposed to JAKis. Methods: In this retrospective cohort study of the TriNetX Global Collaborative Network, adults (≥18 years) with ≥2 diagnoses of AA (ICD-10-CM L63) and ≥2 medication events for baricitinib, tofacitinib, ritlecitinib, or oral ruxolitinib were matched 1:1 by propensity score on demographics and 13 comorbidities to patients with AA and no recorded exposure to these agents. Cox models estimated hazard ratios (HRs); p values for the 19 estimable outcomes were adjusted using the Benjamini–Hochberg procedure (false discovery rate 5%), and E-values assessed unmeasured confounding. Drug-specific and eight sensitivity analyses were performed. Results: Matching yielded 1771–1805 patients per cohort, depending on the outcome domain. Acne was more frequent with JAKis (HR, 2.425; 95% CI, 1.838–3.200; q < 0.001) in all analyses, including versus conventional immunosuppressants (HR, 1.688; 95% CI, 1.321–2.157), whereas upper respiratory tract infections (HR, 0.620; 95% CI, 0.476–0.808; q = 0.004) and urinary tract infections (HR, 0.458; 95% CI, 0.290–0.724; q = 0.006) were recorded less frequently. Cutaneous cancer was more frequent (HR, 2.639; 95% CI, 1.322–5.270; q = 0.024) and persisted after 30- and 180-day latency periods but was attenuated under a fixed 2-year follow-up and after exclusion of other JAKi indications. Severe infections, herpes zoster, and autoimmune and psychiatric outcomes did not differ significantly. Conclusions: In real-world AA care, JAKis were not associated with a statistically significant increase in severe infections or incident psychiatric outcomes, although power for rare serious outcomes was limited. Acne was the most consistent adverse-event signal, whereas the cutaneous cancer finding was not fully robust across specifications and requires confirmation.

Background/Objectives: Alopecia areata (AA) is a common, noncicatricial autoimmune hair loss disorder characterized by relapsing inflammation and breakdown of hair follicle immune privilege. Increasing amounts of evidence suggest that pyroptosis, a lytic and inflammatory form of programmed cell death mediated by gasdermins and inflammasome activation, may play a role in AA pathogenesis. This review aims to synthesize current data on the molecular mechanisms linking inflammasome-driven pyroptosis with AA and to highlight emerging therapeutic opportunities. Methods: A comprehensive literature review was conducted focusing on mechanistic studies, ex vivo human scalp models, murine AA models, and interventional clinical data. A structured system of Levels of Evidence (LoE) and standardized nomenclature for experimental models was applied to ensure transparency in evaluating the role of pyroptosis and treatment strategies in AA. Results: Available evidence indicates that outer root sheath keratinocytes express functional inflammasome components, including NOD-like receptor family, pyrin domain containing 3 (NLRP3), adaptor-apoptosis-associated-speck-like protein (ASC), and caspase-1, and contribute to interleukin (IL)-1β release and pyroptotic cell death. Mitochondrial dysfunction, mediated by regulators such as PTEN and PINK1, amplifies NLRP3 activation and cytokine secretion, linking mitophagy impairment with follicular damage. Animal and human biopsy studies confirm increased inflammasome activity in AA lesions. Therapeutic approaches targeting pyroptosis include Janus kinase (JAK) inhibitors, biologics, Phosphodiesterase 4 (PDE4) inhibitors, mesenchymal stem cell therapy, natural compounds, and inflammasome inhibitors such as MCC950. While some agents demonstrated efficacy in clinical trials, most strategies remain at preclinical or early clinical stages. Conclusions: Pyroptosis represents a critical mechanism driving hair follicle structural and functional disruption and immune dysregulation in AA. By integrating evidence from molecular studies, disease models, and early clinical data, this review underscores the potential of targeting inflammasome-driven pyroptosis as a novel therapeutic strategy.