Date of Award

January 2024

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

William Damsky

Abstract

Granuloma annulare (GA) is an inflammatory cutaneous granulomatous diseasethat lacks satisfying and effective targeted therapies. Janus kinase (JAK) inhibitors are of interest as they inhibit upregulated cytokines in GA including IFN-γ, IL-4, IL-13, IL-15, IL-21, and oncostatin M. Further investigation is needed to establish the safety profile, optimal route or formulation, and efficacy of JAK inhibitors for GA. We conducted single-arm, open-label clinical trials of abrocitinib, a JAK1-specific inhibitor, and AC- 1101, a topically applied JAK inhibitor, in patients with GA and hypothesized that each medication would be safe, tolerable, and effective at treating GA. In the first study, adult patients with GA (n=10) were treated for 6 months with oral abrocitinib 200 mg and primarily assessed for change in body surface area (BSA) involvement along with other efficacy and safety outcomes. In the second study, adult patients with GA (n=13) were treated for 4 weeks with AC-1101, a topically applied tofacitinib citrate 2% gel, and primarily assessed for safety and tolerability, with secondary efficacy outcomes. After 1 month, patients treated with abrocitinib trended toward improvement in GA as measured by Granuloma Annulare Severity and Morphology Instrument (GASMI) and Granuloma Annulare-Investigator Global Assessment (GA-IGA) scores, with significant improvement in GA-IGA erythema scores (mean difference -0.5 points, p=0.03). Preliminary results indicate that the two patients who completed treatment with abrocitinib for 6 months experienced improvement in their GA with reduction in body surface area (BSA) involvement, GASMI, and GA-IGA scores. The other patients are actively enrolled in the trial and yet to complete 6 months of treatment. Treatment with AC-1101 was well-tolerated by patients with no significant change in Dermal Rating Scale scores before and after application, and GA-IGA induration scores significantly improved by a mean of 0.83 points (p=0.03) after 4 weeks of treatment. There were no serious adverse events in either trial. Oral abrocitinib demonstrates efficacy after 1 month of use, and two individual patients who completed 6 months of treatment experienced substantial clinical improvement. Further results from this trial will clarify the efficacy of abrocitinib over 6 months of use. AC-1101 was well-tolerated and demonstrated evidence of efficacy following 4 weeks of daily topical application. Both medicines demonstrated favorable safety profiles during these trials. JAK inhibition is a promising avenue for treatment of GA, and JAK1-specific inhibition with oral abrocitinib and topically applied AC-1101 are appealing options that warrant further investigation of their use in GA.

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This is an Open Access Thesis.

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