Nadia Kashetsky, MSc1 and Irina Turchin, MD, FRCPC2-5
1Faculty of Medicine, Memorial University of Newfoundland, St. John’s, NL, Canada
2Brunswick Dermatology Center, Fredericton, NB, Canada;
3Skin Investigation Network of Canada (SkIN Canada), Toronto, ON, Canada; 4Dalhousie University, Halifax, NS, Canada; 5Probity Medical Research, Waterloo, ON, Canada
Conflict of interest: Nadia Kashetsky reports no conflicts of interest. Irina Turchin was a consultant, speaker and/or investigator for AbbVie, Amgen, Arcutis, Aristea, Bausch Health, Boehringer Ingelheim, Celgene, Eli Lilly, Galderma, Incyte, Janssen, Kiniksa, Leo Pharma, Novartis, Pfizer, Sanofi, UCB.
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.
Keywords: ruxolitinib, topical, Opzelura™, Janus kinase-inhibitors, JAK-inhibitors, vitiligo, atopic dermatitis, eczema, psoriasis, alopecia areata, lichen planus
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.
Methods
A literature search was performed of studies reporting topical RUX utilization in dermatologic conditions (Figure 1).
Figure 1. Diagram of study selection process. Articles were included if they reported i) efficacy and/or safety outcomes of topical ruxolitinib in dermatological conditions, ii) were observational or experimental studies, with human subjects, and iii) had data in the English language. References of relevant articles were reviewed. Conference abstracts were excluded.
Results
Twenty-five articles were included in this review, representing 2618 patients (Table 1). Articles reported data on topical RUX use in atopic dermatitis (AD, n=8), vitiligo (n=6), alopecia areata (AA, n=5), psoriasis (n=2), and lichen planus (LP), necrobiosis lipoidica, discoid lupus erythematosus, and seborrheic dermatitis (n=1 each).
| Condition | Study Characteristics and Methodology | Outcomes | |||||
| Study Design | Author (year) | Sample Size (N) | Inclusion Criteria | Topical RUX Dose, Frequency, Duration | TEAE/TRAE with Topical RUX | Efficacy | |
| AD |
| Bissonnette (2022) | 41 | Aged 12-65 years, disease duration ≥2 years, IGA score ≥2, ≥25% BSA |
|
| At weeks 4 and 8:
|
| AD |
| Kim (2020) | 307 | Aged 18-70 years, disease duration ≥2 years, IGA 2-3, 3%-20% BSA |
|
| At week 4:
|
| AD |
| Kim (2020) | As above | As above | As above | As above | Within 36 hours after 1.5% RUX cream application BID:
|
| AD |
| Papp (2021) | 631 and 618 | Aged ≥12 years, disease duration ≥2 years, IGA score 2-3, 3%-20% BSA |
|
| At week 8:
|
| AD |
| Blauvelt (2023) | As above | As above | As above | As above | Within 12 hours:
|
| AD |
| Blauvelt (2023) | As above | As above | As above | As above | Within 36 hours:
|
| AD |
| Bloudek (2022) | As above | As above | As above | As above | At week 8:
Annually:
|
| AD |
| Papp (2022) | 1072 | As above |
|
| At week 52 of as-needed treatment:
|
| Vitiligo |
| Rothstein (2017) | 11 | Aged ≥18 years, ≥1% BSA |
|
| At week 20:
|
| Vitiligo |
| Joshipura (2018) | 8 | As above |
|
| At 52 weeks:
|
| Vitiligo |
| Rosmarin (2020) | 157 | Aged 18-75 years, 0.5% facial BSA and ≥3% non-facial BSA |
|
| At week 24:
|
| Vitiligo |
| Rosmarin (2022) | As above | As above |
| As above | At week 24:
|
| Vitiligo |
| Pandya (2022) | 19 | As above |
| None | At week 104:
|
| Vitiligo |
| Rosmarin (2022) | 330 and 344 | Aged ≥12 years, ≤10% BSA, ≥0.5% facial BSA, and ≥3% non-facial BSA |
|
| At week 24:
|
| AA |
| Bokhari (2018) | 16 | Patients with alopecia universalis |
| None | At 28 weeks:
|
| AA |
| Olsen (2020) | Part A: 12 Part B: 78 | Aged 18-70 years, SALT score of 25%-99% |
|
| At week 24:
|
| AA |
| Craiglow (2015) | 1 | NA |
| None | At 12 weeks:
|
| AA |
| Bayart (2017) | 2 | NA |
| None | At 3 months and 18 months
|
| AA |
| Deeb (2017) | 1 | NA |
| None | At 3.5 months:
|
| Plaque psoriasis |
| Punwani (2012) | 29 | Aged 18-75 years, <20% BSA |
|
| At 4 weeks:
|
| Plaque psoriasis |
| Punwani (2015) | 25 | Aged 12-65 years |
|
| At 4 weeks:
|
| LP |
| Brumfiel (2022) | 12 | Aged ≥18 years, biopsy proven LP, ≤20% BSA and ≥4 lesions |
|
| At 8 weeks:
|
| Necrobiosis lipoidica |
| Nugent (2022) | 1 | NA |
| None | At 3 months:
|
| DLE | • Case report | Park (2022) | 1 | NA |
| None | At 2 months:
|
| Seborrheic dermatitis and rosacea | • Case report | Pope (2022) | 1 | NA |
| None | At 2 weeks:
|
Table 1. Summary of dermatologic conditions, study characteristics, and outcomes of included studies. 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 | |||||||
Efficacy
Atopic Dermatitis
A 4-week, phase I, open-label, maximum-use trial investigated efficacy of RUX cream in patients with AD, aged 12-65 years, disease duration ≥2 years, Investigator’s Global Assessment (IGA) score ≥2, and ≥25% body surface area (BSA) involvement (n=41).13,14 Patients applied 1.5% RUX cream twice-daily (BID) for 4 weeks. An extension period to week 8 was completed by 37 patients. IGA treatment success (an IGA score of 0/1 with a ≥2-grade improvement from baseline) was reported in 20% of patients at day 15, 35.9% of patients at day 28, and 56.8% of patients at day 56. Mean standard deviation (SD) BSA decreased from 38.1% (16.3%) at baseline to 6.5% (8.2%) at day 28 and 3.1% (5.4%) at day 56; 79.5% and 94.6% of patients achieved ≥75% improvement in Eczema Area and Severity Index (EASI-75) at day 28 and day 56; and 82.6% and 90.5% of patients achieved ≥4-point improvement in the itch Numerical Rating Scale (NRS) at days 28 and 56, respectively. The mean daily application amount of RUX cream over the first 4 weeks was 20.2 g compared to 5.4 g in the phase III studies.13,14
An 8-week, phase II, randomized study with vehicle control and active control (0.1% triamcinolone acetonide cream) investigated efficacy of RUX cream in patients with AD, aged 18-70 years, disease duration ≥2 years, IGA score 2-3, and 3%-20% BSA (n=307).15 Patients were randomly assigned to 1.5% RUX cream BID (n=50), 1.5% daily (n=52), 0.5% daily (n=51), 0.15% daily (n=51), 0.1% triamcinolone BID for 4 weeks then vehicle for 4 weeks (n=51), or vehicle BID (n=52). Mean percentage change in EASI score from baseline at week 4 was 71.6% versus 15.5% for 1.5% RUX cream BID versus vehicle (P<0.0001). At week 4, IGA response defined as a patient achieving an IGA score of 0 to 1, with 2 or more points improvement from baseline was achieved by 38% of patients in the RUX 1.5% arm compared to 25.5% of patients in the 0.1% triamcinolone arm.
Within 36 hours after the first 1.5% RUX cream application BID, itch NRS was significantly reduced compared to vehicle (-1.8 versus -0.2, P<0.0001), and significantly more patients achieved minimally clinically important difference (42.5% versus 13.6%, P<0.01).16 Within 2 weeks, all RUX cream regimens decreased itch NRS and achieved significant improvements in quality of life as measured by Skindex-16.16
Two, 8-week, phase III, randomized, double-blind, vehicle-controlled studies of identical study design, investigated efficacy of RUX cream in patients with AD, aged ≥12 years, disease duration ≥2 years, IGA score 2-3, and 3%-20% BSA (n=631/n=618 in Study 1/2).17,18 Patients were randomized to apply 1.5% RUX cream BID (n=253/n=246), 0.75% BID (n=252/n=248), or vehicle cream BID (n=126/n=124). IGA treatment success at week 8 was achieved by significantly more patients in both Study 1 and Study 2 with 1.5% RUX cream (53.8%/51.3%) and 0.75% RUX cream (50.0%/39.0%) compared to vehicle (15.1%/7.6%, all P<0.0001).
Pooled data demonstrated significant rapid itch reduction within 12 hours of 1.5%/0.75% RUX cream application (-0.5/-0.4, versus -0.1 for vehicle; both P<0.02).19 At 36 hours, a ≥4-point itch NRS improvement was achieved by significantly more patients with 1.5%/0.75% RUX cream (11.2%/8.9%, versus 2.1% for vehicle; both P<0.005),19 and significantly more patients achieved an itch free state versus vehicle.20
At week 8, significant impact on work productivity and activity impairment were achieved.21 Estimated incremental annual indirect cost savings for patients were US$5302/US$4228 for 1.5%/0.75% RUX cream.21
Long-term safety and efficacy of 1.5% and 0.75% RUX cream was further investigated in the long-term extension of the phase III studies.22 Patients initially randomized to twice-daily 0.75%/1.5% cream were maintained in their assigned arms for 44 weeks, and patients randomized to vehicle were re-assigned at week 8 to either RUX cream strength. At week 52 of as-needed treatment, 74.1%-77.8% of patients had IGA0/1, and a mean affected BSA was low (1.4%-1.8%).
Vitiligo
A 20-week, phase II, open-label proof-of-concept study investigated efficacy of RUX cream in patients with vitiligo, ≥18 years, with ≥1% BSA (n=11).23 Patients applied 1.5% RUX cream BID for 20 weeks.23 Mean improvement in Vitiligo Area Scoring Index (VASI) at week 20 was significant (23%, P=0.02). An extension of this study included 8 patients without previous response, and showed significant overall mean improvement from baseline at 52 weeks (37.6%, P=0.011).24
A 52-week, phase II, randomized, double-blind, dose-ranging study investigated the efficacy of RUX cream in patients with vitiligo, aged 18-75 years, 0.5% facial BSA, and ≥3% non-facial BSA (n=157).25,26 Patients were randomly assigned to 1.5% RUX cream BID (n=33), 1.5% daily (n=30), 0.5% daily (n=31), 0.15% daily (n=31), or vehicle cream BID (n=32). A ≥50% improvement in facial Vitiligo Area Scoring Index (F-VASI50) at week 24, was achieved by 50%/45% of patients with 1.5% RUX daily/BID versus 3% with vehicle (P<0.001/P=0.001). In patients who received 1.5% RUX cream BID in this trial, a sub-analysis indicated a larger proportion of F-VASI50 responders were aged ≤50 years, women, had baseline ≤1.5% facial BSA, disease duration >20 years, and received previous phototherapy.27 All body areas had repigmentation, including difficult to treat acral areas.27
Following the double-blind period of this phase II study, an open-label phase assessed the efficacy of RUX cream with narrowband ultraviolet B (NB-UVB) (n=19).28 At week 104, overall mean improvement was 50.1% for F-VASI and 29.5% for total body VASI (T-VASI) versus the last visit before adding NB-UVB.
Two 24-week, phase III, double-blind, vehicle-controlled trials of identical study design investigated the efficacy of RUX cream in patients with vitiligo, aged ≥12 years, ≤10% BSA, ≥0.5% facial BSA, and ≥3% non-facial BSA (n=330/n=344 in Study 1/2).29,30 Patients were randomized to apply 1.5% RUX cream BID (n=221/n=229) or vehicle cream BID (n=109/n=115) for 24 weeks. At week 24, F-VASI75 was achieved by 29.8%/30.9% of patients in the RUX cream arms compared to vehicle (7.4%/11.4%, P<0.001).
Alopecia Areata
A 28-week, phase I, prospective, double-blind, placebo controlled, pilot study investigated the efficacy of 1% RUX ointment, 2% tofacitinib ointment, 0.05% clobetasol dipropionate ointment, and vehicle in patients with alopecia areata (AA) (n=16).31 All 4 ointments were applied to designated areas BID. Partial regrowth was achieved in 5/6/10/2 patients treated with 1% RUX/2% tofacitinib/0.05% clobetasol dipropionate/vehicle.
A phase II, 2-part, double-blind, randomized, vehicle-controlled study, investigated the efficacy of RUX cream in patients with AA, aged 18-70 years, Severity of Alopecia Tool (SALT) score 25%-99% (Part A: n=12; Part B: n=78).32 In Part A patients applied 1.5% RUX cream BID for 24 weeks. A ≥50% improvement in SALT (SALT50) was achieved by 50% of patients at week 24. In Part B patients were randomized to 1.5% RUX cream BID (n=39) or vehicle BID (n=39) for 24 weeks. Percentage of patients achieving SALT50 between RUX cream and vehicle at week 24 was not significant (12.8% versus 12.8%, P=0.99).
Moreover, 4 case reports utilizing RUX cream in patients with AA demonstrate conflicting results. A teenaged female had marked improvement with 0.6% RUX cream BID for 12 weeks,33 whereas a 66-year-old female who exhibited lack of improvement with 0.6% RUX cream daily for 8 weeks, increased to BID for 6 weeks.34 Finally, 2 patients, a 17-year-old female, and 4-year-old male, showed partial and no regrowth, with 1% RUX in a liposomal base BID for 18 months, and 2% RUX in a liposomal base BID then 1% tofacitinib liposomal base BID for 3 months, respectively.35
Psoriasis
A 4-week, phase II, double-blind, vehicle or active comparator study assessed efficacy of RUX cream in patients with stable and active plaque psoriasis, aged 18-75 years, <20% BSA (n=29).36 Patients were randomized to 0.5% or 1.0% RUX cream daily, 1.5% RUX BID, vehicle daily or BID, 0.005% calcipotriene cream BID, or 0.05% betamethasone dipropionate cream BID for 4 weeks. At 4 weeks, mean total lesion score decreased by 53%/54% for 1.0% RUX daily/1.5% RUX BID versus vehicle (32%, P=0.033/P=0.056).
A 4-week, phase II, open-label, multicenter, cohort, doseescalation study evaluated efficacy of RUX cream in patients with stable and active psoriasis, aged 12-65 years (n=25).37 Patients applied 1.0% or 1.5% RUX cream daily or BID for 4 weeks to 2%-20% BSA. In all cohorts, at 4 weeks, mean total lesion scores decreased and PGA scores improved.
Other
An 8-week, phase II, single-arm, open-label trial investigated the efficacy of RUX cream in patients with biopsy proven lichen planus (LP), aged ≥18 years, ≤20% BSA and ≥4 lesions (n=12).38 Patients applied 1.5% RUX cream BID for 8 weeks. At week 4, lesion count significantly decreased by a median of 50 lesions (P<0.001); and mean modified Composite Assessment of Index Lesion Severity of index versus control lesions decreased significantly by a mean of 7.6 points (P=0.016).
A 19-year-old female with refractory necrobiosis lipoidica showed marked improvement with 1.5% RUX cream BID for 3 months.39 A 28-year-old female with discoid lupus erythematosus exhibited improvement of scalp lesions with 1.5% RUX cream daily for 2 months.40 A 74-year-old male with seborrheic dermatitis and rosacea showed complete and partial response, respectively, with 1.5% RUX cream BID for 2 weeks.41
Safety and Tolerability
Bioavailability of RUX cream was limited.13,14,25,36,37,42,43 The highest strength average steady-state trough plasma concentrations were well below clinically relevant systemic pharmacological activity, remaining below the half-maximal inhibitory concentration of JAK-mediated myelosuppression.13,14,25,36,37,42,43
No serious treatment related adverse events (TRAE) were reported across all topical RUX data. Mild-to-moderate TRAE were reported in minority of patients, most commonly including application-site pain, pruritus, acne, erythema, and hyperpigmentation. Rare treatment-emergent adverse events included increase in aspartate aminotransferase and alanine aminotransferase, leukopenia, hemoglobin decrease, mild reticulocytosis, dyspnea, abnormal taste, and transient hypoaesthesia of the fingertips.
Discussion
This review summarizes the utilization of topical RUX in dermatological conditions. Results show improvement with topical RUX formulations in AD, vitiligo, psoriasis, and LP. Results are conflicting in AA. Minimal bioavailability and low rates of mild-to-moderate TRAEs support higher tolerability of topical RUX as compared to oral JAK-inhibitors.
RUX is a targeted inhibitor of JAK1/2, selectively interrupting effects of the cytokines which signal through JAK1/2 proteins.44 AD pathogenesis involves JAK1/2 mediated cytokines interleukin (IL)-4, IL-13, IL-31, and IL-33.6,45 Vitiligo and AA, both involve JAK1/2 mediated interferon (IFN)-gamma and IL-15 in their pathogenesis.6 IFN-gamma is also important in the pathogenesis of LP and psoriasis.4,6,38 Psoriasis pathogenesis also has shown involvement of other JAK1/2 mediated cytokines including IL-6, IL-21, IL-22, and IL-23.4,6
Conclusion
Available clinical trial data support the efficacy of topical RUX in AD, vitiligo, psoriasis, and LP with a favorable safety profile and tolerability compared to oral JAK-inhibitors suggesting that topical RUX is a promising new therapy in dermatology.
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