Successful Treatment of Extensive Ritlecitinib-Refractory Alopecia Areata with Upadacitinib

Introduction

Alopecia areata (AA)—a disorder characterized by partial or complete hair loss—is conventionally attributed to autoimmune reactions against hair follicles. Besides cosmetic concerns, AA can induce psychological distress and adversely affect the quality of life. Consequently, it necessitates efficacious treatment. Molecularly targeted drugs—namely, ruxolitinib, tofacitinib, baricitinib, and ritlecitinib—are the latest in the line of therapeutic interventions.¹ Ritlecitinib is a JAK3 inhibitor in the Janus kinase and signal transducer and activator of transcription (JAK-STAT) signaling pathway, which has been implicated in the autoimmune reactions involved in alopecia. Similarly, upadacitinib is known to selectively inhibit JAK1. However, there is a lack of sufficient documentation regarding the treatment of patients who do not respond to JAK3 inhibitors. Current research has demonstrated that upadacitinib positively affects alopecia areata.^2,3 This report details a severe case of ritlecitinib-resistant AA that was successfully treated with upadacitinib, resulting in restoration of normal hair volume in the patient.

Case Presentation

Our patient, a 38-year-old man, suffered for two years from hair loss induced by alopecia. He initially experienced localized alopecia that progressively exacerbated, leading to complete loss of eyebrows, eyelashes, as well as pubic and axillary hair. Prior treatment with traditional Chinese medicine had proved ineffective. He presented to our hospital in January 2025 and was subsequently diagnosed with AA. Examination revealed multiple patches of hair loss on the entire scalp (Figure 1), a positive hair pull test, a Severity of Alopecia Tool (SALT) score of 79, and a Dermatology Life Quality Index self-assessment score of 18. Furthermore, blood tests evidenced the absence of syphilis antibodies, along with normal thyroid, liver, and kidney functions. Complete autoimmune panel results were also obtained from the patient. He was initially treated with ritlecitinib (50 mg/day). During the follow-up period from January to May 2025, no notable hair regrowth and exacerbation of the SALT score to 83 was noted (Figure 2). Consequently, the patient requested a change in medication and was prescribed upadacitinib (15 mg/day). Seven-week upadacitinib treatment resulted in patches of new black hair growth and a SALT score of 65 (Figure 3). The patient’s hair volume increased gradually, and by the 15-week follow-up, 80% of the normal hair volume was restored, accompanied by partial regrowth of eyebrows and beard and a SALT score of 20 (Figure 4). At the 24-week follow-up, hair growth had completely normalized, with no discernible areas of alopecia (Figure 5). No adverse events or abnormal laboratory test results occurred during treatment and follow-up.

Figure 1 Before treatment. Examination revealed multiple patches of hair loss on the entire scalp, Severity of Alopecia Tool (SALT) score was 79.

Figure 2 After ritlecitinib treatment for 100 days. No notable hair regrowth and exacerbation of the SALT score to 83 was noted.

Figure 3 After upadacitinib treatment for 7 weeks.Patches of new black hair growth was observed and SALT score was 65.

Figure 4 After upadacitinib treatment for 15 weeks.80% of the normal hair volume was restored, accompanied by partial regrowth of eyebrows and beard and a SALT score of 20.

Figure 5 After upadacitinib treatment for 24 weeks.Hair growth had completely normalized, with no discernible areas of alopecia.

Discussion

The pathogenesis of AA remains poorly understood and can be potentially attributed to a combination of genetic, immunological, as well as environmental factors. Moreover, several cytokines are implicated in the pathogenesis of AA, including JAK-STAT signaling.⁴ Interferon-gamma (IFN-γ) activates the JAK-STAT1 signaling pathway, which subsequently upregulates interleukin-15 (IL-15) expression in hair follicle epithelial cells. Thereafter, IL-15 can bind to receptors on CD8⁺ T cell surfaces and upregulate IFN-γ expression via downstream JAK1, JAK3, and STAT5 signaling pathways, thereby forming a positive feedback loop in the pathogenesis of alopecia areata.⁵ Upadacitinib is a selective JAK1 inhibitor approved by the US Food and Drug Administration, the European Medicines Agency, and other global regulatory agencies for treating various chronic inflammatory diseases. In dermatology, upadacitinib is prescribed for conditions such as moderate-to-severe atopic dermatitis, psoriatic arthritis, and ankylosing spondylitis.⁶ The efficacy of upadacitinib against refractory AA is already well-known.^7,8 Furthermore, it has also demonstrated potential in treating baricitinib-resistant AA.⁸ Although upadacitinib treatment for AA is yet to receive approval, the present case study documents its efficacy in treating severe ritlecitinib-resistant AA. This can be attributed to ritlecitinib being a JAK3 inhibitor, whereas upadacitinib functions primarily as a selective JAK1 inhibitor. The pathogenesis of AA may involve JAK1-mediated signaling pathways more predominantly, thus potentially rendering upadacitinib more effective in inhibiting this pathway. Although both ritlecitinib and upadacitinib act by inhibiting JAK signaling pathways, their impact on different immune cell types and cytokines may differ, consequently influencing their efficacy in specific patients. Furthermore, significant variations in genetic background, immune status, and disease phenotype among patients may lead to different responses to various JAK inhibitors. The limitation of this case is the lack of a washout period, this does not preclude the potential for a synergistic impact or a delayed pharmacodynamic response following the treatment switch. Therefore, further research on the effects of upadacitinib on AA can elucidate its potential as an efficacious therapeutic modality for refractory AA.

Conclusion

This report demonstrated the efficacy of upadacitinib in treating severe ritlecitinib-resistant AA. It indicated the clinical implications of using an alternative JAK inhibitor in cases where other common JAK drugs exhibit failure. Nevertheless, further research is required to determine the efficacy and safety of upadacitinib in diverse patient populations, along with establishing its optimal applicability in AA remediation.