Utilization of Topical Ruxolitinib in Dermatology

A Review

Nadia Kashetsky, MSc; Irina Turchin, MD, FRCPC

Skin Therapy Letter. 2023;28(3):8-13.

Abstract and Introduction

Abstract

As systemic administration of Janus kinase-inhibitors is associated with safety concerns, local alternatives, such as topical ruxolitinib, have been developed. This review summarizes utilization of topical ruxolitinib in dermatology. A literature search was performed of studies reporting topical use of ruxolitinib in dermatologic conditions. Twenty-four articles were included, representing 2618 patients. Results show improvement with topical ruxolitinib formulations in atopic dermatitis, vitiligo, psoriasis, and lichen planus. Results are conflicting in alopecia areata. Minimal bioavailability and low rates of mild-to-moderate treatment-related adverse events support a favorable safety profile and higher tolerability of topical ruxolitinib compared to oral Janus kinase-inhibitors.

Introduction

Immune-mediated skin conditions are common and cause significant morbidity and healthcare utilization.^[1,2] Treatment of these conditions was previously focused on symptom management and nonspecific immunosuppression, however, recent advances in understanding the pathogenesis of immunologic disease has led to novel therapeutic targets.^[2,3]

The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway, shown to be vital in downstream signaling of inflammatory cytokines, is amongst these novel therapeutic targets, for which JAK-inhibitors have been developed.^[4–6] JAK-dependent cytokines are important in the immunopathology of diverse immune-mediated skin diseases, leading to the utilization of JAK-inhibitors in dermatology.^[4,6] However, as systemic administration of JAK-inhibitors are associated with safety concerns, local alternatives, such as topical ruxolitinib (RUX), have been developed.^[7,8] Topical 1.5% RUX cream was US FDA approved for AD in September 2021 and nonsegmental vitiligo in July 2022.^[9]

Although several systematic reviews have described the utilization of JAK-inhibitors in dermatology, a summary of topical RUX in dermatology is lacking.^[10–12] Accordingly, this review comprehensively summarizes the available data on efficacy and safety outcomes of topical RUX in dermatological conditions.

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Table 1. Summary of dermatologic conditions, study characteristics, and outcomes of included studies.
Condition	Study Characteristics and Methodology					Outcomes
Condition	Study Design	Author (year)	Sample Size (N)	Inclusion Criteria	Topical RUX Dose, Frequency, Duration	TEAE/TRAE with Topical RUX	Efficacy
AD	• Phase I • Open-label, maximumuse trial • Extension period	Bissonnette (2022)	41	Aged 12–65 years, disease duration ≥2 years, IGA score ≥2, ≥25% BSA	• 1.5% RUX cream, BID, 4 weeks (n=41) • Extension period: 1.5% RUX cream, BID, 4 weeks (n=37)	• No severe • TRAE TEAE (n=6): increase in aspartate aminotransferase (n=2) and alanine aminotransferase, neutropenia, dyspnea, hemoglobin decrease (n=1 each)	At weeks 4 and 8: • IGA treatment success: 35.9% and 56.8% of patients • Mean BSA decrease from 38.1% at baseline to 6.5% and 3.1% • EASI-75: 79.5% and 94.6% of patients • ≥4-point improvement in itch NRS: 82.6% and 90.5% of patients
AD	• Phase II Randomized, vehicle and active-controlled trial • Open-label extension period	Kim (2020)	307	Aged 18–70 years, disease duration ≥2 years, IGA 2–3, 3%-20% BSA	• 1.5% RUX cream, BID, 8 weeks (n=50) • 1.5% RUX cream, daily, 8 weeks (n=52) • 0.5% RUX cream, daily, 8 weeks (n=51) • 0.15% RUX cream, daily, 8 weeks (n=51) • 0.1% triamcinolone cream, BID, 4 weeks then vehicle, BID, 4 weeks (n=51) • Vehicle, BID, 8 weeks (n=52) • Open-label period: 1.5% RUX cream, BID, 4 weeks (n=252 patients)	• No severe TRAE • TRAE occurred in 5.4% of patients, most commonly application site pain	At week 4: • Mean percentage change in EASI score from baseline was 71.6% vs. 15.5% (P<0.0001), for 1.5% RUX cream BID vs. vehicle
AD	• Analysis of pooled data from Kim et al. (2020)	Kim (2020)	As above	As above	As above	As above	Within 36 hours after 1.5% RUX cream application BID: • Itch NRS scores significantly reduced compared to the vehicle (-1.8 vs. -0.2, P<0.0001) • Significantly more patients achieved itch MCID (42.5% vs. 13.6%, P<0.01) Within 2 weeks: • All RUX cream regimens decreased itch NRS scores • Significant improvements in QoL measured by Skindex-16
AD	• Phase III • Randomized, doubleblind, vehicle-controlled studies • 2 trials of identical design	Papp (2021)	631 and 618	Aged ≥12 years, disease duration ≥2 years, IGA score 2–3, 3%-20% BSA	• 1.5% RUX cream, BID, 8 weeks (n=253/n=246) • 0.75% RUX cream, BID, 8 weeks (n=252/n=248) • Vehicle cream, BID, 8 weeks (n=126/n=124)	• No severe TRAE • TRAE occurred in 4.7% of patients, most commonly application site pain and pruritus	At week 8: • IGA treatment success: achieved by significantly more patients in both Study 1/2 with 1.5% RUX cream (53.8%/51.3%) and 0.75% RUX cream (50.0%/39.0%) compared vehicle (15.1%/7.6%, all P<0.0001)
AD	• Analysis of pooled data from Papp et al. (2021)	Blauvelt (2023)	As above	As above	As above	As above	Within 12 hours: • Significant rapid itch reduction with 1.5% & 0.75% RUX cream (-0.5 and -0.4 vs. vehicle -0.1; both P<0.02) Within 36 hours: • ≥4-point itch NRS improvement achieved by significantly more patients with 1.5% and 0.75% RUX cream (11.2% and 8.9%, compared to 2.1% for vehicle, P<0.005)
AD	• Analysis of pooled data from Papp et al. (2021)	Blauvelt (2023)	As above	As above	As above	As above	Within 36 hours: Significantly more patients achieved itch free state vs. vehicle
AD	• Post hoc analysis of data from Papp et al. (2021)	Bloudek (2022)	As above	As above	As above	As above	At week 8: • Significant mean improvements in presenteeism, overall work impairment scores, and activity impairment vs. vehicle Annually: • Estimated incremental indirect cost savings for patients were US$5302/US$4228 for 1.5%/0.75% RUX cream
AD	• Long term data from Papp et al. (2021)	Papp (2022)	1072	As above	• 1.5% RUX cream, BID, 44-week extension (n=446) • 0.75% RUX cream, BID, 44-week extension (n=426) • Vehicle cream switched to 1.5% RUX cream, BID, for 44-week extension (n=99) • Vehicle cream switched to 0.75% RUX cream, BID, for 44-week extension (n=101)	• Over 52 weeks: TRAE occurred in 4.1% of patients, commonly application site pain and application site pruritus	At week 52 of as-needed treatment: • 74.1%-77.8% of patients using 1.5%/0.75% RUX cream had IGA0/1, and mean affected BSA was low (1.4%-1.8%)
Vitiligo	• Phase II • Open-label, nonrandomized pilot study	Rothstein (2017)	11	Aged ≥18 years, ≥1% BSA	• 1.5% RUX cream, BID, 20 weeks	• No severe TRAE • Erythema over the affected lesion (n=8 patients), hyperpigmentation surrounding vitiligo patches (n=9 patients), transient acne (n=2 patients)	At week 20: • Significant mean improvement of VASI from baseline (23%, P=0.02)
Vitiligo	• Extension study of Rothstein et al. (2017)	Joshipura (2018)	8	As above	• 1.5% RUX cream, BID, 32 weeks • Concomitant NB-UVB (n=3)	• No severe TRAE • Erythema (n=3 patients), transient acne (n=2 patients)	At 52 weeks: • Significant mean improvement of VASI from baseline (37.6%, P=0.011)
Vitiligo	• Phase II • Randomized, double-blind, dose-ranging study	Rosmarin (2020)	157	Aged 18–75 years, 0.5% facial BSA and ≥3% non-facial BSA	• 1.5% RUX cream, BID, 52 weeks (n=33) • 1.5% RUX cream, daily, 52 weeks (n=30) • 0.5% RUX cream, daily, 52 weeks (n=31) • 0.15% RUX cream, daily, 52 weeks (n=31) • Vehicle cream, BID, 52 weeks (n=32)	• No severe TRAE • TRAE occurred in 36.0% of patients, most commonly application site pruritis, acne	At week 24: • F-VASI50: 50% and 45% patients with 1.5% RUX daily and BID compared to vehicle (3%, P<0.001 and P=0.001)
Vitiligo	• Analysis of data from Rosmarin et al. (2020)	Rosmarin (2022)	As above	As above	• Patients who received 1.5% RUX cream BID from Rosmarin et al. (2020)	As above	At week 24: • A larger proportion of F-VASI50 responders were ≤50 years, women, had baseline ≤1.5% facial BSA, disease duration >20 years, and were refractory to other treatments • All body areas had regimentation, including acral areas
Vitiligo	• Open-label extension period of Rosmarin et al. (2020)	Pandya (2022)	19	As above	• 1.5% ruxolitinib cream, BID, up to week 156	None	At week 104: • Overall mean improvement: 50.1% for F-VASI and 29.5% for T-VASI vs. the last visit before adding NB-UVB • Of the 12 patients that were non-responders at week 24 in the double-blind period, mean improvement of 47.8%
Vitiligo	• Phase III • Double-blind, vehicle-controlled • 2 trials of identical design	Rosmarin (2022)	330 and 344	Aged ≥12 years, ≤10% BSA, ≥0.5% facial BSA, and ≥3% non-facial BSA	• 1.5% RUX cream, BID, 24 weeks (n=221/n=229) • Vehicle cream, BID, 24 weeks (n=109/n=115)	• No severe TRAE • TRAE occurred in 17.2%/12.8% of patients, most commonly application site acne, pruritus	At week 24: • F-VASI75: achieved by significantly more patients in both studies with 1.5% RUX cream daily (29.8%/30.9%) vs. vehicle (7.4%/11.4%,P<0.001)
AA	• Phase I • Prospective, doubleblind, placebo controlled, pilot study	Bokhari (2018)	16	Patients with alopecia universalis	• 1% RUX ointment, BID, 28 weeks • 2% tofacitinib ointment, BID, 28 weeks • 0.05% clobetasol dipropionate ointment, BID, 28 weeks • Vehicle, BID, 28 weeks	None	At 28 weeks: • Partial regrowth achieved in 5, 6, 10, and 2 patients treated with 1% RUX, 2% tofacitinib, 0.05% clobetasol dipropionate, and vehicle
AA	• Phase II • 2-part • Double-blind, randomized, vehiclecontrolled study	Olsen (2020)	Part A: 12 Part B: 78	Aged 18–70 years, SALT score of 25%-99%	• Part A: • 1.5% RUX cream, BID, 24 weeks (n=12) Part B: • 1.5% RUX cream, BID, 24 weeks (n=39) • Vehicle, BID, 24 weeks (n=39)	• No severe TRAE • TRAE in 7 patients (local site reactions)	At week 24: • Part A: SALT50 was achieved by 50.0% of patients • Part B: Patients achieving SALT50 between 1.5% RUX cream and vehicle was not significant (12.8% vs. 12.8%, P=0.99)
AA	• Case report	Craiglow (2015)	1	NA	• 2% RUX in a liposomal base, BID, 1% tofacitinib liposomal base BID, 3 months • 1% RUX in a liposomal base, BID, 18 months	None	At 12 weeks: • Marked improvement
AA	• Case series	Bayart (2017)	2	NA	• 2% RUX in a liposomal base, BID, 1% tofacitinib liposomal base BID, 3 months • 1% RUX in a liposomal base, BID, 18 months	None	At 3 months and 18 months • None and partial regrowth, respectively (n=1 each)
AA	• Case report	Deeb (2017)	1	NA	• 0.6% RUX cream, daily, 2 months, increased to BID, 1.5 months	None	At 3.5 months: • Lack of improvement
Plaque psoriasis	• Phase II • Double-blind, vehicle or active comparator study	Punwani (2012)	29	Aged 18–75 years, <20% BSA	• 0.5% RUX cream, daily, 4 weeks • 1.0% RUX cream, daily, 4 weeks • 1.5% RUX cream, BID, 4 weeks • Vehicle, daily, 4 weeks • Vehicle, BID, 4 weeks • 0.005% calcipotriene cream, BID, 4 weeks • 0.05% betamethasone dipropionate, BID, 4 weeks	• No severe TRAE • TRAE occurred in 20% of lesions including application site stinging, itching, irritation, pain, dryness, exfoliation, redness	At 4 weeks: • Mean total lesion score decreased by 53% and 54% for 1.0% RUX daily and 1.5% RUX BID, respectively, vs. vehicle (32%, P=0.033 and P=0.056)
Plaque psoriasis	• Phase II • Open-label, multicenter, cohort, dose-escalation study	Punwani (2015)	25	Aged 12–65 years	• 1.5% RUX cream, BID, 4 weeks, to 2–7% BSA • 1.5% RUX cream, BID, 4 weeks, to 8–13% BSA • 1.5% RUX cream, daily, 4 weeks, to 14–20% BSA • 1.0% RUX cream, BID, 4 weeks, to 14–20% BSA • 1.5% RUX cream, BID, 4 weeks, to 14–20% BSA	• No severe TRAE • TEAE/TRAE (n=4): application site irritation, transient hypoaesthesia of the fingertips, transient mild leucopenia and mild reticulocytosis (n=1 each)	At 4 weeks: • Mean lesion scores decreased and PGA scores improved in all cohorts
LP	• Phase II • Single-arm, open-label trial	Brumfiel (2022)	12	Aged ≥18 years, biopsy proven LP, ≤20% BSA and ≥4 lesions	• 1.5% RUX cream, BID, 8 weeks	• No severe TRAE • TEAE (n=1): abnormal taste	At 8 weeks: • Significant decrease in change in lesion count (median change: 50 lesions, P<0.001) • Significant decrease in mCAILS vs. control lesions (-7.6, P=0.016)
Necrobiosis lipoidica	• Case report	Nugent (2022)	1	NA	• 1.5% RUX cream, BID, 3 months	None	At 3 months: • Marked improvement
DLE	• Case report	Park (2022)	1	NA	• 1.5% RUX cream, daily, 2 months	None	At 2 months: • Improvement
Seborrheic dermatitis and rosacea	• Case report	Pope (2022)	1	NA	• 1.5% RUX cream, BID, 2 weeks	None	At 2 weeks: • Complete response of seborrheic dermatitis, partial response of rosacea

AA: alopecia areata; AD: atopic dermatitis; BID: twice daily; BSA: body surface area; DLE: discoid lupus erythematosus; EASI-75: ≥75% improvement in Eczema Area and Severity Index; IGA: Investigator's Global Assessment; IGA treatment success: an IGA score of 0/1 with a ≥2 grade improvement from baseline; Itch free state: itch NRS score of 0 or 1 as the most severe level during each 24-hour period; LP: lichen planus; mCAILS: Mean modified Composite Assessment of Index Lesion Severity; MCID: minimally clinically important difference; NA: not applicable; NB-UVB: narrowband ultraviolet B; NRS: Numerical Rating Scale; RUX: ruxolitinib; SALT: severity of alopecia tool; SALT50: ≥50% improvement in SALT; TEAE: treatment-emergent adverse events; TRAE: treatment-related adverse events; T-VASI: total body VASI; VASI: Vitiligo Area Scoring Index

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Utilization of Topical Ruxolitinib in Dermatology

A Review

Abstract and Introduction

Abstract

Introduction

Tables

References

Authors and Disclosures

Authors and Disclosures

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