JAK3 Inhibitor Ritlecitinib Links Molecular Change to Visible Regrowth

This article was originally published by Dermatology Times^®.

Long considered irreversible, scarring alopecias may not be as final as once believed. Emerging translational data from Emma Guttman-Yassky, MD, PhD, and colleagues at the Icahn School of Medicine at Mount Sinai, in collaboration with Pfizer, is reshaping how clinicians approach autoimmune hair loss disorders. Their recent studies with ritlecitinib, a selective JAK3/TEC family kinase inhibitor, reveal that inflammation—not fibrosis alone—drives disease activity in both scarring and nonscarring alopecia phenotypes. By dampening JAK3-mediated immune signaling early, ritlecitinib appears capable of reopening the window for hair regrowth and recovery once thought permanently closed.¹

The work builds on her group’s presentation at the 2025 European Academy of Dermatology and Venereology (EADV) meeting held in Paris, France, where they presented a late-breaker session on ritlecitinib in scarring alopecias, and the 2025 multiomics analysis in Allergy exploring its molecular effects in AA subtypes.²

“We’ve done a study in scarring alopecia that showed for the first time that they are not all about fibrosis. There is actually an inflammatory component,” Guttman-Yassky explained in a recent interview with Dermatology Times. “And particularly, it involves elevation of JAK3.”

Targeting JAK3-Mediated Inflammation

Ritlecitinib’s dual inhibition of JAK3 and TEC family kinases (IL-2–inducible T-cell kinase [ITK], Bruton tyrosine kinase [BTK]) positions it to modulate both lymphocyte activation and downstream cytokine signaling. In Allergy’s 2025 report, scalp biopsy analyses from the ALLEGRO2a trial (NCT04517864) revealed that treatment with ritlecitinib led to downregulation of key type I (CCL5, CD8A, GZMB) and type II (CCL13, CCL18, IL13RA1) immunity genes while upregulating hair keratin genes (eg, KRT74, KRT81, HOXC13). These changes aligned with visible hair regrowth and clinical improvements measured by the Severity of Alopecia Tool (SALT) at 12 to 24 weeks.

Baseline and on-treatment gene expression profiles correlated strongly with efficacy, suggesting that early transcriptional normalization predicts subsequent clinical response. The authors concluded that “treatment with ritlecitinib improves the gene expression profile in AA lesional scalp and is correlated with subsequent hair regrowth response.”

Clinical and Molecular Correlation

Researchers found patients with patch-type AA (AAP) exhibited a stronger molecular response than those with alopecia totalis/universalis (AT/AU), consistent with earlier disease being more reversible. In AAP lesions, immune-activation genes were suppressed and keratin expression increased to a greater extent than in AT/AU lesions at weeks 12 and 24.

The correlation between reduction in JAK3, ITK, and BTK expression and improved SALT scores indicates that successful clinical response depends on effective inhibition of these key signaling nodes. As the paper describes, “The positive correlation observed between reduced JAK3 expression at week 12 and reduced SALT score at week 24 suggests that early immunomodulation may play an important role in immune suppression of cell populations such as autoreactive resident T cells and NK [natural killer] cells.”

Translational Findings

The research team emphasized that similar immune mechanisms may underlie scarring alopecias, traditionally considered irreversible due to fibrosis. The research group’s histologic and molecular work identified persistent inflammatory infiltrates and JAK3 activation in affected follicles, providing rationale for targeted intervention.

“When you dampen the inflammation, you will be able to also change the fibrosis component and allow hair growth,” Guttman-Yassky noted.
This concept was reinforced by findings from the ritlecitinib study in AA: Early modulation of inflammation, particularly within the first few years of disease, produced greater regrowth. The study findings published in Allergy similarly observed that patients with AAP, representing less chronic disease, responded faster than those with extensive AT/AU involvement.

“The other thing that we showed is that in order for hair regrowth to actually happen, you need to be early in the game,” Guttman-Yassky noted. “If you are within 3.5 years of the time when you develop scarring alopecia, you are much more likely to have hair regrowth.”

Serum Biomarker Correlations

Beyond transcriptomics, the study examined systemic protein markers. Changes in serum levels of Type I and II immunity proteins—CD40L, CCL4, MCP-4, and HB-EGF—correlated with improvements in SALT scores at weeks 12 and 24. These reductions reflected suppression of both helper T (TH) 1– and TH2-driven inflammation, whereas increases in proteins linked to tissue repair (LEP, VEGFD, IL-17C) suggested restoration of follicular homeostasis.

Importantly, higher baseline expression of hair structural genes (KRT83, HOXC13, DSG4) and lower baseline expression of IL-15, IL-2Rα, and tumor necrosis factor predicted better treatment responses, highlighting the potential for biomarker-guided patient stratification.

Clinical Implications

Ritlecitinib has been approved for severe AA in adults and adolescents in several regions, and findings from ongoing long-term trials (eg, ALLEGRO-LT [NCT04006457]) continue to refine its efficacy and safety profile. These molecular insights underscore its mechanistic precision and potential extension to fibrosing alopecias, which currently lack approved therapies.

At present, treatment of scarring alopecias relies on corticosteroids, hydroxychloroquine, or calcineurin inhibitors—agents that offer partial and inconsistent control. The integration of targeted JAK3 inhibition may represent a paradigm shift by addressing the inflammatory core before irreversible fibrosis develops. Although the Allergy analysis was limited by sample size and a 24-week observation period, the consistent link between early molecular suppression and later clinical regrowth provides a compelling mechanistic foundation for extended studies.

Looking Ahead

Guttman-Yassky remains optimistic about the clinical translation of these findings: “Our patients need the drugs sooner rather than later, and I’m very hopeful that Pfizer will actually take it to the market because our patients really need additional treatments.” Together, the multiomics data and scarring alopecia trial findings highlight a unifying principle: Ritlecitinib can recalibrate immune and structural signatures of the hair follicle, reversing pathogenic pathways previously thought irreversible. As precision medicine evolves, ritlecitinib’s translational framework provides a prototype for biomarker-driven therapy in autoimmune hair disorders, bridging basic immunology and clinical practice.

References

1. Xi L, Peeva E, Yamaguchi Y, et al. Multiomics analysis of the response to ritlecitinib in alopecia areata subtypes and correlation with efficacy. Allergy. 2025;80(8):2348-2360. doi:10.1111/all.16659

2. Kurosky S. Real-world ritlecitinib treatment of severe alopecia areata (AA) in the US: patient characteristics and physician satisfaction. Presented at: European Academy of Dermatology and Venereology Congress 2025; September 17-20, 2025; Paris, France.