Irina Turchin – Skin Therapy Letter

Utilization of Topical Ruxolitinib in Dermatology: A Review

STL Volume 28 Number 3 — Thu, 15 Jun 2023 21:21:53 +0000

Nadia Kashetsky, MSc¹ and Irina Turchin, MD, FRCPC^2-5

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
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
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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Extracorporeal Photopheresis and Its Use in Clinical Dermatology in Canada

STL Volume 27 Number 5 — Sat, 15 Oct 2022 22:44:49 +0000

François Lagacé, MD¹; Elena Netchiporouk, MD, MSc, FRCPC¹; Irina Turchin, MD, FRCPC^2-4; Wayne Gulliver, MD, FRCPC⁵; Jan Dutz, MD, PhD, FRCPC⁶; Mark G. Kirchhof, MD, PhD, FRCPC⁷; Gizelle Popradi, MD, FRCPC⁸; Robert Gniadecki, MD, PhD, FRCPC⁹; Charles Lynde, MD, FRCPC¹⁰; Ivan V. Litvinov, MD, PhD, FRCPC¹

¹Division of Dermatology, McGill University, Montreal, QC, Canada
²Brunswick Dermatology Center, Fredericton, NB, Canada
³Division of Clinical Dermatology & Cutaneous Science, Dalhousie University, Halifax, NS Canada
⁴Probity Medical Research, Waterloo, ON, Canada
⁵Department of Dermatology, Discipline of Medicine, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, NL, Canada
⁶Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada
⁷Division of Dermatology, University of Ottawa, Ottawa, ON, Canada
⁸Division of Hematology, Department of Medicine, McGill University, Montreal, QC, Canada
⁹Division of Dermatology, University of Alberta, Edmonton, AB, Canada
¹⁰Division of Dermatology, University of Toronto, Toronto, ON, Canada

Conflict of interest: Elena Netchiporouk has received grants, research support from Novartis, Sanofi, Sun Pharma, AbbVie, Biersdorf, Leo Pharma, Eli Lilly; speaker fees/honoraria from Bausch Health, Novartis, Sun Pharma, Eli Lilly, Sanofi Genzyme, AbbVie, Galderma, Novartis, Sanofi Genzyme, Sun Pharma, Bausch Health and Leo Pharma and consulting fees from Bausch Health, Novartis, Sun Pharma, Eli Lilly, Sanofi Genzyme, AbbVie, Galderma, Novartis, Sanofi Genzyme, Sun Pharma, Bausch Health and Leo Pharma. Irina Turchin served as advisory board member, consultant, speaker and/or investigator for AbbVie, Amgen, Arcutis, Aristea, Bausch Health, Boehringer Ingelheim, Celgene, Eli Lilly, Galderma, Incyte, Janssen, Kiniksa, Leo Pharma, Mallinckrodt, Novartis, Pfizer, Sanofi, UCB. Wayne Gulliver received grants/research support from AbbVie, Amgen, Eli Lilly, Novartis and Pfizer; honoraria for advisory boards/invited talks from AbbVie, Actelion, Amgen, Arylide, Bausch Health, Boehringer, Celgene, Cipher, Eli Lilly, Galderma, Janssen, Leo Pharma, Merck, Novartis, PeerVoice, Pfizer, Sanofi-Genzyme, Tribute, UCB, Valeant and clinical trial (study fees) from AbbVie, Asana Biosciences, Astellas, Boehringer-Ingelheim, Celgene, Corrona/National Psoriasis Foundation, Devonian, Eli Lilly, Galapagos, Galderma, Janssen, Leo Pharma, Novartis, Pfizer, Regeneron, UCB. Gizelle Popradi has received honoraria or speaker fees from Jazz Pharma, Seattle Genetics, Abbvie, Kite Gilead, Pfizer, Taiho, Servier, Novartis, Merck, Kyowa Kirin, Abbvie, Avir Pharma, Mallinckrodt. Robert Gniadecki reports carrying out clinical trials for Bausch Health, AbbVie and Janssen and has received honoraria as consultant and/or speaker from AbbVie, Bausch Health, Eli Lilly, Janssen, Mallincrodt, Novartis, Kyowa Kirin, Sun Pharma and Sanofi. Charles Lynde was a consultant, speaker, and advisory board member for Amgen, Pfizer, AbbVie, Janssen, Novartis, Mallincrodt, and Celgene, and was an investigator for Amgen, Pfizer, AbbVie, Janssen, Lilly, Novartis, and Celgene. Ivan V. Litvinov received research grant funding from Novartis, Merck, AbbVie and Bristol Myers Squibb and honoraria from Janssen, Bausch Health, Galderma, Novartis, Pfizer, Sun Pharma, Johnson & Johnson and Actelion. Topics included in this article were based on, but not limited to, broad discussions at an advisory board meeting, which was sponsored and funded by Mallinckrodt, Inc. Consultancy fees were paid to meeting participants (EN, IT, WG, JD, MK, RG, CL and IVL). All other authors declare no existing competing interests.

Abstract:
Extracorporeal photopheresis (ECP) is an immunomodulatory therapy that has been used for over 35 years to treat numerous conditions. ECP was initially approved by the US FDA in 1988 for the treatment of Sézary syndrome, a leukemic form of cutaneous T-cell lymphoma (CTCL). Although CTCL remains the only FDA-approved indication, ECP has since been used off-label for numerous other conditions, including graft-versus-host disease (GvHD), systemic sclerosis, autoimmune bullous dermatoses, Crohn’s disease, and prevention of solid organ transplant rejection. In Canada, ECP is mainly used to treat CTCL, acute and chronic GvHD, and in some instances systemic sclerosis. Herein, we review the current concepts regarding ECP mechanism of action, treatment considerations and protocols, and efficacy.

Key Words:
extracorporeal photopheresis, cutaneous T-cell lymphoma, S.zary syndrome, systemic sclerosis, graft-versus-host disease, safety.

Introduction

Extracorporeal photopheresis (ECP) is an immunomodulatory therapy that has been used for over 35 years to treat numerous conditions (Figure 1).^1,2ECP was initially approved by the Food and Drug Administration (FDA) in the United States in 1988 for the treatment of S.zary syndrome (SS), a leukemic form of cutaneous T-cell lymphoma (CTCL) with an aggressive clinical course, characterized by a triad of circulating neoplastic T-cells, erythroderma, and lymphadenopathy.¹Although CTCL remains the only FDA-approved indication, ECP has since been used as an off-label treatment for numerous other conditions, including graft-versus-host (GvHD) disease, systemic sclerosis (SSc), autoimmune bullous dermatoses, Crohn’s disease, and to prevent solid organ transplant rejection.^1,2In Canada, ECP is mainly used to treat CTCL, acute and chronic GvHD, and in some instances systemic sclerosis (Tables 1-2). The goal of this article is to review the current concepts regarding ECP mechanism of action, treatment considerations as well as suggested treatment protocols and efficacy in CTCL, GvHD, systemic sclerosis and other skin diseases.

Figure 1. Mechanism of action of ECP. Figure adapted from Comprehensive Dermatologic Drug Therapy by Wolverton SE.¹

Table 1. The use of ECP by hospital and by city in Canada in 2020.

Center (City, Province)	# of Procedures (# of Patients)
Atlantic Health Sciences (Saint John, NB)	416 (18)
Foothills Centre (Calgary, AB)	407 (15)
L’Enfant-Jesus (Quebec City, QC)	426 (19)
Hospital for Sick Children (Toronto, ON)	40 (1)
University Health Network (Toronto, ON)	N/A
Maisonneuve-Rosemont (Montreal, QC)	546 (25)
Royal Victoria (Montreal, QC)	294 (11)
Vancouver General Hospital (Vancouver, BC)	336 (20)
Total	2,465 (109)
Table 1. The use of ECP by hospital and by city in Canada in 2020. Data from the University Health Network, Toronto, ON, where service is available, was not provided for this analysis. Data source: 2020 Canadian Apheresis Society.

Table 2. The use of ECP by city and by indication in Canada in 2020.

# of Procedures (# of Patients)
Indication	Calgary	Montreal	Quebec City	Saint John	Vancouver	Total
CTCL (MF/SS)	131 (8)	145 (5)	195 (7)	40 (2)	84 (5)	595 (27)
aGvHD	137 (3)	33 (3)	28 (2)	8 (1)	55 (3)	261 (12)
cGvHD	137 (3)	631 (27)	89 (5)	310 (13)	197 (12)	1,364 (60)
SSc	0 (0)	0 (0)	92 (3)	30 (1)	0 (0)	122 (4)
Other	2 (1)	31 (1)	22 (2)	28 (1)	0 (0)	83 (5)
Total	407 (15)	840 (36)	426 (19)	416 (18)	336 (20)	2,425 (108)
Table 2. The use of ECP by city and by indication in Canada in 2020. Data from the University Health Network, Toronto, ON, where service is available, was not provided for this analysis. Data source: 2020 Canadian Apheresis Society. CTCL - cutaneous T-cell lymphoma; MF - mycosis fungoides; SS - Sézary syndrome; aGvHD- acute graft vs host disease; cGvHD - chronic graft vs. host disease; SSc - systemic sclerosis

ECP involves placing a catheter to gain access to the venous circulation and collecting blood via continuous or discontinuous cycles, which is then centrifuged to create a leukocyte-rich buffy coat. The isolated leukocytes are then placed in a sterile treatment cassette, injected with liquid 8-methoxypsoralen (8-MOP) and exposed to ultraviolet A (UVA) radiation. Afterwards, the photochemically-altered white blood cells are returned to the patient’s venous circulation (Figure 1).^1,2 The Therakos^® ECP machine (the only available unit for this treatment) represents an automated closed system. Each treatment lasts approximately 1.5-3 hours, and the scheduling and frequency of treatments depend on the disease being treated.

The exact mechanism of action of ECP remains unknown, however, in CTCL, it is believed that the procedure leads to DNA-crosslinking and apoptosis of pathogenic T cells induced by 8-MOP with UVA exposure, the differentiation of monocytes to dendritic cell that present tumor antigens from apoptotic lymphocytes, stimulation of anti-tumor immune responses, and shifting of immunoregulatory cytokines to Th1 cytokine profile, such as interferon-gamma and tumor necrosis factor (TNF) alpha, thus restoring the Th1/Th2 balance.^1-4 In particular, ECP targets mostly tumor cells since the absolute number of normal T cells remains relatively stable after the procedure.¹ Given its therapeutic benefit in transplant rejection and autoimmune diseases, ECP is also believed to have unique immunomodulatory properties generating needed responses in an autoimmune setting, which are thought to be similarly mediated by DNA-crosslinking and apoptosis of autoreactive leucocytes (natural killer (NK) and T cells) and induction of T-regulatory cells after treatment, although this phenomenon was not observed in patients with SS.² However, unlike immunosuppressive therapies, ECP is not associated with an increased risk of opportunistic infections.² In fact, ECP is overall well-tolerated, with no reports of post-treatment Grade III or IV side effects, as per the World Health Organization classification.² In particular, ECP is not associated with side-effects that are observed with skin systemic psoralen with UVA (PUVA) therapy, since the psoralen is not ingested orally nor applied to the skin.² The side-effects are primarily related to fluid shifts and the need for a central catheter. Rare side-effects of ECP include nausea, photosensitivity, transient hypotension, flushing, tachycardia, congestive heart failure and thrombocytopenia.^1,2 Contraindications to the use of ECP are summarized in Table 3. Currently, ECP is available in over 200 treatment centers across the world treating numerous diseases.² The use of ECP by hospital, region and indication in Canada is summarized in Tables 1-2. Unfortunately, treatment access is limited in Canada and significant knowledge gaps are recognized (i.e., paucity of randomized clinical trials and real-world evidence) amongst physicians and patients. As a result, this treatment may be significantly underused in Canada.

Table 3. Summary of contraindications to the use of ECP

Contraindications
Absolute	Known sensitivity to psoralen compounds; Pregnancy/lactation; Aphakia; Severe cardiac disease.
Relative	Poor venous access; Thrombocytopenia; Hypotension; Congestive heart failure; Photosensitivity; Personal history of heparin-induced thrombocytopenia; Low hematocrit; Rapidly progressing disease.
Table 3. Summary of contraindications to the use of ECP

CTCL

CTCL represents a group of lymphoproliferative disorders where there is an accumulation of malignant T-cell clones in the skin.² The most commonly recognized forms of CTCL are mycosis fungoides (MF) and SS. There are currently no curative treatments for CTCL, except for allo-transplantation which has been successful in select patients.² ECP is often used as a first-line treatment for SS, as well as for patients with erythrodermic MF or advanced CTCL.¹ Its use in early stages of CTCL remains controversial and impractical in Canada as many other effective treatment modalities are available (Table 4).^5,6 ECP can be used as monotherapy or it can be safely given in combination with phototherapy (narrow band or broadband UVB), radiotherapy, total skin electron beam (TSEB), systemic retinoids, interferons, anti-CCR4 monoclonal antibodies, histone deacetylase inhibitors, methotrexate, and/or other treatments.^1,2 One meta-analysis of 400 patients with all stages of CTCL showed a combined overall response rate (ORR) of 56% both when ECP was used as monotherapy and in combination with other therapies.² The complete response (CR) rates were 15% and 18% for monotherapy and combination therapy, respectively.² However, the ORR and CR were 58% and 15%, respectively, in erythrodermic patients, and 43% and 10% in patients with SS.² The CR was defined as a complete resolution of clinical evidence of disease and for normalization of CD4/CD8 ratio for at least 1 month. The partial response (PR) was defined as greater than 25% but less than 100% decrease in lesions and no development of new lesions for at least 1 month. ORR was defined as a sum of PR and CR. Furthermore, the United Kingdom consensus statement analyzed 30 studies between 1987 to 2007 and determined that the mean ORR and CR rates were 63% (range 33-100%) and 20% (range 0-62%), respectively, with higher response rates observed in erythrodermic patients. Many factors can explain the variability in the results of these studies, such as patient selection bias, stage of the disease, ECP treatment schedule, prior treatments, and end-point definitions.² In addition, there is a significant amount of inter-subject variability in response rates to ECP and factors that predict treatment response, as summarized in Table 5.²

Table 4. Treatment options for CTCL (MF)

Topical therapies	Corticosteroids Bexarotene gel (United States) Chlormethine gel/nitrogen mustard Tazaroten Imiquimod
Ultravioletlight therapies	Narrow band UVB (if patches only) PUVA (alone or in combination)
Systemic therapies	Interferon alpha Oral bexarotene Oral alitretinoin Mogamulizumab (anti-CCR4) Brentuximab vedotin (anti-CD30 with monomethyl auristatin E) Histone deacetylase inhibitors Methotrexate (low dose) Alemtuzumab (low dose)
Chemotherapy	Pralatrexate (United States) Gemcitabine (low dose) Pegylated liposomal doxorubicin CHOP (chemotherapy combination)
Additional treatments	Local radiotherapy (solitary or few tumors) Total skin electron beam (generalized thick plaques and tumors) Extracorporeal photopheresis (erythrodermic MF) Allogenic hematopoietic stem cell transplantation
Table 4. Treatment options for CTCL (MF)^5,6

Table 5. Baseline parameters and predictors of response to ECP in the treatment of cutaneous T-cell lymphoma, as per the European Dermatology Forum.

Skin
Erythroderma Plaques <10-15% total skin surface
Blood and immune system
Low percentage of elevated circulating Sézary cells Presence of a discrete number of Sézary cells (10-20% mononuclear cells) CD4/CD8 ratio <10-15 Percentage of CD4+CD7- <30% Percentage of CD4+CD26- <30% Normal LDH levels Blood stage B0 or B1 Lymphocyte count <20,000/μL Percentage of monocytes >9% Eosinophil count >300/mm³ No previous intense chemotherapy Increased NK cell count at 6 months into ECP therapy Near-normal NK cell activity CD3+CD8+ cell count >200/mm³ High levels of CD4+Foxp3+CD25- cells at baseline
Lymph nodes
Lack of bulky adenopathy
Visceral organs
Lack of visceral organ involvement
Other
Short disease duration before ECP (<2 years from diagnosis) Increased peripheral blood mononuclear cell microRNA levels at 3 months into ECP monotherapy Decreased soluble IL-2 receptor at 6 months into ECP Decreased neopterin at 6 months into ECP Decreased beta2-microglobulin at 6 months into ECP Response at 5-6 months of ECP
Table 5. Baseline parameters and predictors of response to ECP in the treatment of cutaneous T-cell lymphoma, as per the European Dermatology Forum. LDH - lactate dehydrogenase; NK - natural killer; CD - cluster of differentiation; ECP - extracorporeal photopheresis

Different countries have varying guidelines with respect to the use of ECP in CTCL. Most recently, the European Dermatology Forum (EDF) published new recommendations in 2020. They recommend considering ECP as first-line therapy in patients with MF clinical stages IIIA or IIIB (erythroderma), or MF/SS stages IVA1 or IVA2 (Tables 6-7). Treatments are recommended every 2 weeks for the first 3 months, then every 3-4 weeks, with a treatment period of at least 6 months or until remission is achieved, followed by a maintenance period (Table 8).² ECP can take 3-6 months before a clinical response is appreciated, and therefore, no conclusions regarding its success should be drawn before that timeframe in erythrodermic patients.^1,2

Table 6. TNMB classification of MF and SS

T (skin)	T1: limited patch/plaque (involving <10% of total skin surface) T2: generalized patch/plaque (involving ≥10% of total skin surface) T3: tumor(s) T4: erythroderma
N (lymph node)	N0: no enlarged lymph odes N1: enlarged lymph nodes, histologically uninvolved N2: enlarged lymph nodes, histologically involved (nodal architecture uneffaced) N3: enlarged lymph nodes, histologically involved (nodal architecture (partially) effaced)
M (viscera)	M0: no visceral involvement M1: visceral involvement
B (blood)	B0: no circulating atypical (Sézary) cells (or <5% of lymphocytes) B1: low blood tumor burden (≥5% of lymphocytes are Sézary cells, but not B2) B2: high blood tumor burden (≥1000/mcl Sézary cells + positive clone)
Table 6. TNMB classification of MF and SS.⁶ TNMB - tumor-node-metastasis-blood; MF - mycosis fungoides; SS - Sézary syndrome

Table 7. Clinical staging for MF and SS.

Clinical Stage	T (skin)	N (lymph node)	M (viscera)	B (blood)
IA	T1	N0	M0	B0-1
IB	T2	N0	M0	B0-1
IIA	T1-2	N1-2	M0	B0-1
IIB	T3	N0-1	M0	B0-1
III	T4	N0-2	M0	B0-1
IVA1	T1-4	N0-2	M0	B2*
IVA2	T1-4	N3*	M0	B0-2
IVB	T1-4	N0-3	M1*	B0-2
Table 7. Clinical staging for MF and SS.⁶ MF - mycosis fungoides; SS - Sézary syndrome * The required features for the three subdivisions of stage IV disease

Table 8. ECP recommendations by cutaneous disease, as per the revised guidelines by the European Dermatology Forum in 2020.

Cutaneous Disease	Patient Selection	Treatment Schedule	Maintenance Treatment	Response Assessment
CTCL (MF/SS)	First-line treatment in erythrodermic stage IIIA or IIIB, or stage IVA1-IVA2	One cycle every 2 weeks at first, then every 3-4 weeks. Continue treatment for at least 6-12 months	Treatment should not be stopped, but prolonged for >2 years, with treatment intervals up to 8 weeks	To be conducted every 3 months. Treatment failure with ECP cannot be established before 6 months
aGvHD	Second-line therapy in patients that are refractory to corticosteroids at a dose of 2 mg/kg/day	2-3 treatments per week for 4 weeks	There is no evidence that maintenance therapy is beneficial. Discontinue ECP in patients with complete response	Every 7 days with staging
cGvHD	Second-line therapy in patients that are refractory to corticosteroids at a dose of 2 mg/kg/day or steroid intolerant or steroid dependant	One cycle every 1-2 weeks for 12 weeks followed by interval prolongation depending on response	Treatment intervals can be increased by 1 week every 3 months depending on response, and only after 12 weeks of treatment	Disease monitoring as per the National Institutes of Health guidelines
SSc	Second-line or adjuvant therapy as monotherapy or in combination with other therapy. Can be used to treat skin (but not internal organ involvement)	One cycle every 4 weeks for 12 months	Based on clinical response, increase intervals by 1 week every 3 months	Clinically, and with validated scoring systems and photography
Atopic dermatitis	Second-line therapy if: >18 months duration SCORAD >45 refractory to all first-line therapies and one second line therapy	One cycle every 2 weeks for 12 weeks	Intervals depend on the individual response; at maximal treatment response, ECP should be tapered by one treatment cycle every 6-12 weeks	SCORAD assessment every 2 weeks for the first 12 weeks, then every ≥4 weeks
Pemphigus, epidermolysis bullosa acquisita, erosive oral lichen planus	Recalcitrant to conventional systemic therapies	One cycle every 2-4 weeks for 12 weeks, then one cycle every 4 weeks	Taper by increasing intervals by 1 week every 3 months	Clinically, and with validated scoring systems and photography (and with antibody titers in the case of pemphigus)
Lupus erythematosus, psoriasis, morphea, nephrogenic fibrosing dermopathy and scleromyxedema			No current recommendations, more studies needed
Table 8. ECP recommendations by cutaneous disease, as per the revised guidelines by the European Dermatology Forum in 2020.^2,11 SCORAD - SCORing atopic dermatitis; ECP - extracorporeal photopheresis; CTCL - cutaneous T-cell lymphoma; MF - mycosis fungoides; SS - Sézary syndrome; aGvHD - acute graft vs. host disease; cGvHD - chronic graft vs. host disease; SSc - systemic sclerosis

GvHD

GvHD can be either acute or chronic based on clinical presentation and time to disease development.¹ Classic acute GvHD (aGvHD) occurs within 100 days of the transplantation with typical features, whereas chronic GvHD (cGvHD) presents after 100 days. However, persistent, recurrent or lateonset aGvHD can occur after 100 days with typical features of aGvHD. If features of both aGvHD and cGvHD are present, it is considered an overlap syndrome.⁷ cGvHD occurs in 30- 50% of patients receiving an allogenic transplant, involves multiple systems and most commonly presents with mucosal, skin, gastrointestinal and liver involvement.² First-line therapy consists of systemic glucocorticosteroids with or without a calcineurin inhibitor. Second-line therapies include ruxolitinib, ECP, mycophenolate mofetil, mTOR inhibitors, methotrexate, calcineurin inhibitor. Second-line therapies include ruxolitinib, ECP, mycophenolate mofetil, mTOR inhibitors, methotrexate, imatinib, ibrutinib and rituximab.² Notably, phase III randomized clinical trials evaluating ruxolitinib versus best available therapy for steroid refractory or dependent cGvHD demonstrated superiority of this drug when compared to ECP and other agents (ORR 50% vs. 26%, p<0.001).⁸ The average response rate to ECP is approximately 60% and studies have shown ORR rates ranging from 36-83%. In addition, CR in the skin, oral disease, and liver ranged from 31-93%, 21-100% and 0-84%, respectively.² Best responses using ECP are seen in skin followed by gastrointestinal and then hepatic GvHD. The EDF recommends considering ECP as an additional secondline therapy in patients with cGvHD that is steroid-dependent, steroid-intolerant, or steroid-resistant, as well as for those with recurrent infections or with a high-risk of relapse (Table 8). Also, steroid-dependent patients (i.e., inability to reduce corticosteroid dose to <0.5 mg/kg/day without recurrence of Grade II or worse cGvHD) could benefit from ECP.

Similarly, systemic glucocorticoids are currently used as firstline therapy for aGvHD.² However, response rates are <50%.² In 2019, the US FDA approved ruxolitinib for steroid-refractory aGVHD in adult and pediatric patients ≥12 years of age. This approval was based on an open-label, single-arm, multicenter study of ruxolitinib that enrolled 49 patients with steroidrefractory aGVHD Grades II-IV occurring after allogeneic hematopoietic stem cell transplantation.⁹ Clinical trials have shown the superiority of ruxolitinib therapy when compared to ECP and other treatments (ORR 62% vs. 39%, p<0.001).¹⁰ In these patients, ECP may serve as an additional second-line treatment with ORR of 65-100% in the skin, 0-100% in the liver, and 40-100% in the gastrointestinal tract.² As such, the EDF recommends adjunct ECP, as second-line therapy, in patients not responding to appropriate doses of systemic corticosteroids (Table 8). Interestingly, it is also showing promising results as a prophylaxis therapy to prevent cGvHD.¹ This treatment option may be considered by dermatologists consulting on these patients in acute setting in the hospital especially at times when the diagnosis is uncertain, as ECP is recognized as not being an immunosuppressive therapy.

SSc

SSc is a multisystemic connective tissue disease characterized by collagen deposits in the skin and other visceral organs.^1,11 Although there are currently no FDA-approved treatments for cutaneous involvement in SSc, limited studies have investigated the use of ECP and have shown promising results.¹¹ For example, one multicenter trial showed that ECP was well-tolerated and improved disease severity, the mean percentage of skin involvement (-7.7% from baseline after 10 months, p=0.01) and the mean oral aperture measurements (+2.1 mm from baseline after 10 months, p=0.02).^11,12 Other studies have shown that ECP leads to improvement in dermal edema and skin elasticity, normalization of collagen synthesis, and improvement of extracutaneous symptoms, and that ECP-treated patients with SSc have a favorable long-term survival.^1,13 Further, one study found that, in most patients, ECP leads to a reduced usage of corticosteroids and other immunosuppressive agents, which have numerous adverse effects.¹⁴ The EDF currently recommends ECP as second-line or adjuvant therapy for SSc, either as monotherapy or in combination with other treatments (Table 8).¹¹

Other Cutaneous Conditions

ECP has been studied in numerous other cutaneous diseases, including atopic dermatitis (AD), immunobullous diseases, eosinophilic fasciitis and others. Although there are many other treatment options for AD, including emollients, topical therapies, phototherapy/photochemotherapy, immunosuppressive medications, targeted therapies¹⁵ and monoclonal antibodies, several small open-label trials have shown that ECP is beneficial in patients with severe AD, including erythrodermic AD, that are not responding to standard therapy. Although previous guidelines have not recommended routinely treating AD with ECP given the lack of consistent findings and the multiple other treatment options available, the EDF’s revised guidelines recommend its use as second-line therapy in patients that meet specific criteria (Table 8).¹¹ However, as new effective treatments are emerging for the treatment of AD, ECP should only be reserved for exceptional patients. Studies have also shown promising results for the use of ECP in pemphigus. One study of 11 patients with severe treatment-resistant pemphigus vulgaris or foliaceus showed an OR rate of 91% and CR rate of 73%.¹¹ As such, the EDF recommends ECP in patients with pemphigus vulgaris or foliaceus that is recalcitrant to conventional first- and second-line therapies.¹¹ Further, the EDF recommends considering ECP for severe epidermolysis bullosa acquisita (EBA) and erosive oral lichen planus that is refractory to conventional topical and/or systemic therapies.¹¹ Low level evidence suggests a possible role for ECP in the treatment of lupus erythematosus, however, further controlled clinical trials are needed to assess its efficacy. For this reason, no official recommendations for the use of ECP in lupus erythematosus have been published to date.¹¹ Studies have also investigated the use of ECP in other cutaneous diseases, including psoriasis, nephrogenic fibrosing dermopathy, morphea and scleromyxedema, however, the results have been inconclusive.¹¹

Pediatric Population

Many studies support the use of ECP in a pediatric population. It has been used as an off-label treatment for various conditions, including aGvHD and cGvHD.¹¹ In this patient population, the ECP protocol is adapted and can vary depending on the patient’s weight. Importantly, very few side effects are reported in this population, which further supports the favorable safety profile of ECP.¹¹

Conclusion

In conclusion, ECP has been used on- and off-label for decades to treat numerous diseases, including SS, CTCL, GvHD, and SSc, among others. Results from multiple studies have shown promising response rates, and ECP has an overall excellent safety profile with very few adverse events reported.^2,11 Unlike many other immunomodulatory therapies, an increased risk of infection has not been observed with ECP, which can be a significant cause of morbidity and mortality for patients on other immunosuppressive therapies.¹¹ Although ECP is still being studied for multiple diseases, in Canada clinicians should restrict its use to the diseases that have been extensively studied, as per the EDF guidelines.

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Funding: The genesis of the paper was initiated at a meeting organized by a pharmaceutical company (Mallinckrodt Inc.) and EN, IT, WG, JD, MK, RG, CL and IVL were provided honoraria to attend that meeting. No funding bodies or other organizations had any role in data collection and analysis, decision to publish, or preparation of the manuscript.

Acknowledgment: We thank RBC Consultants for editorial support, facilitating the preparation of tables, and coordinating the review of the manuscript.

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