JAK Inhibition With Upadacitinib and Abrocitinib Shows Potential in Rosacea Treatment

Mild erythematotelangiectatic rosacea | Image credit: DermNet

A recent study¹ published in Frontiers in Immunology assessed the use of JAK1 inhibitors upadacitinib and abrocitinib for the treatment of refractory rosacea. Zhang et al presented 2 cases of patients who received upadacitinib and 4 cases of patients who received abrocitinib. Overall, the study authors deemed the 2 JAK inhibitors as potential promising treatment options for refractory rosacea but noted that prospective controlled studies are needed to further assess the long-term safety and efficacy of both therapeutics for the treatment of rosacea.

In their discussion, Zhang et al addressed that the exact etiology of rosacea is not clear, however, it may include heredity factors, innate immune system disorders, facial vascular regulatory dysfunction, neurogenic inflammation, skin barrier disruption, and increased levels of Demodex mites. Current traditional treatments may include oral antibiotics, topical medications, and laser therapy, but are “limited in effectiveness and prone to recurrence,” according to the study authors.

Zhang et al noted that the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling has gained interest due to its role in modulating immune and inflammatory responses. Inhibiting this pathway may prove to be a new treatment method for rosacea. “Notably, selective JAK1 inhibitors have found widespread application in alleviating inflammatory conditions such as atopic dermatitis, rheumatoid arthritis, and psoriatic arthritis,” wrote the study authors.

Methods

Zhang et al reviewed 6 cases of patients with symptoms and diagnoses of erythematotelangiectatic rosacea at West China Hospital. All patients had been trying to manage their symptoms and disease for up to 4 years. Diagnosis criteria of rosacea in this study followed the National Rosacea Society Expert Committee’s criteria of a confirmed diagnosis of rosacea; conventional treatments proven ineffective; exclusion of differential diagnosis of lupus erythematosus, seborrheic dermatitis, etc; and absence of cardiovascular disease and autoimmune disease.

Case 1: A 28-year-old woman with symptoms of facial erythema, dryness, flushing, burning, and pruritus who received a diagnosis of erythematotelangiectatic rosacea.

Case 2: A 45-year-old woman with symptoms of facial erythema, dryness, tingling, and flushing who received a diagnosis of erythematotelangiectatic rosacea.

Case 3: A 37-year-old woman with symptoms of facial erythema, dryness, burning, pruritus, and visible telangiectasias who received a diagnosis of erythematotelangiectatic rosacea.

Case 4: A 41-year-old woman with symptoms of facial erythema, dryness, and tingling who received a diagnosis of erythematotelangiectatic rosacea.

Case 5: A 38-year-old woman with symptoms of facial erythema, burning, and pruritus who received a diagnosis of erythematotelangiectatic rosacea.

Case 6: A 35-year-old woman with symptoms of facial erythema, dryness, and flushing who received a diagnosis of erythematotelangiectatic rosacea.

Patients from cases 1 and 2 were prescribed upadacitinib 15mg once daily and patients from cases 3 through 6 were prescribed abrocitinib 100mg once daily.

Results

Case 1: Within 48 hours after the first dose of upadacitinib, the patient reported “noteworthy improvement in symptoms such as erythema, flushing, and pruritus.” At the patient’s 2-week follow-up, her facial erythema was significantly reduced, and her flushing, pruritus, and burning sensations were improved. After 8 weeks, her upadacitinib dosage was to every 2 days but experienced a transient rebound of erythema, flushing, and pruritus symptoms. After 12 weeks of treatment, the patient’s dosage was reduced to every 3 days, and she did not experience any exacerbation. The patient reported overall improvements in quality of life.

Case 2: During the 4 weeks of treatment with upadacitinib, the patient experienced significant improvements in facial erythema, tingling, flushing, pruritus, and dry symptoms. The patient also reported improvements in psychological well-being and quality of life. However, the patient was lost to follow-up due to personal reasons.

Case 3: Within one week after the first dose of abrocitinib, the patient reported improvements in burning and tingling symptoms. After 4 weeks of treatment, the patient reported improvements in pruritus and life quality. Currently, the patient is receiving maintenance treatment with 100 mg of abrocitinib once every 4 days.

Case 4: Throughout 20 weeks of treatment with abrocitinib, the patient only experienced mild improvement in pruritus and no significant improvement in quality of life. At week 20, the patient discontinued abrocitinib due to hepatitis B DNA positivity and elevated transaminases on a retest.

Case 5: During 16 weeks of treatment with abrocitinib, the patient showed mild improvement in pruritus, with no significant improvement in burning and tingling symptoms and no significant improvement in quality of life. The patient was lost to follow-up due to personal reasons.

Case 6: During 12 weeks of treatment with abrocitinib, the patient showed no significant improvement in symptoms or quality of life and is currently not using abrocitinib.

Conclusions

Zhang et al reiterated the critical role of the JAK/STAT pathway in the pathogenesis of rosacea, writing, “The JAK/STAT pathway intricately participates in the orchestration of inflammatory responses, and this signaling pathway upregulates the expression of proinflammatory cytokines, encompassing TNF-α, ILs such as IL-6, IL-8, and monocyte chemoattractant protein-1 (MCP1), which can cause facial flushing, erythema, and pruritus.”

The study authors also cited a previous study that identified STAT3 as a key gene linked to rosacea and skin barrier dysfunction using weighted gene coexpression network analysis (WGCNA). In vivo experiments showed that skin barrier dysfunction significantly elevates STAT3 expression and augments CD4+ T-cell infiltration in LL37-induced rosacea-like lesions in mice.²

“We hypothesize that the activation of the JAK/STAT pathway may be involved in the pathogenesis of rosacea. Given the foundational role of the JAK/STAT signaling pathway in rosacea, JAK inhibitors hold promise as a prospective therapeutic paradigm for the management of rosacea. The possible mechanisms of JAK inhibitors in the treatment of rosacea may include inhibition of the inflammatory response, modulation of vascular permeability, inhibition of angiogenesis, and improvement of skin barrier function,” wrote Zhang et al.

The study authors concluded that upadacitinib and abrocitinib may be promising therapeutics for refractory rosacea and that the long-term safety and efficacy of upadacitinib and abrocitinib require additional prospective controlled studies.

References

1. Zhang T, Liu X, Zhang L, Jiang X. Treatment of rosacea with upadacitinib and abrocitinib: case report and review of evidence for Janus kinase inhibition in rosacea. Front Immunol. 2024;15:1416004. Published 2024 Jul 9. doi:10.3389/fimmu.2024.1416004
2. Wang Y, Wang B, Huang Y, Li Y, Yan S, Xie H, et al. Multi-transcriptomic analysis and experimental validation implicate a central role of STAT3 in skin barrier dysfunction induced aggravation of rosacea. J Inflamm Res. (2022) 15:2141–56. doi: 10.2147/JIR.S356551