Research Letter
Topical PDE-4 Inhibitors are Emerging for Psoriasis Treatment
Journal of Cutaneous Medicine and Surgery 00(0) 1–2 © The Author(s) 2020 Article reuse guidelines: sagepub.com/journals-permissions DOI: 10.1177/1203475420960429 journals.sagepub.com/home/cms
Zainab Ridha1 , Lydia Ouchene2 , Elena Netchiporouk3 , and Melinda J. Gooderham4,5
Keywords psoriasis, roflumilast, PDE-4 inhibitors, topical treatment
The latest Canadian expert statement favored high-potency topical glucocorticoids, retinoids, and vitamin D3 analogs as first- line therapies, either alone or in combination, for mild-moderate psoriasis.1 However, current topicals are limited by their side- effect profile especially when treating inverse psoriasis, or when used uninterruptedly. Phosphodiesterase-4 (PDE-4) is found in keratinocytes and immune cells, and it is overexpressed in psoriasis. PDE-4 inhibition by apremilast in psoriasis increases cyclic adenosine monophosphate levels and normalizes aberrant inflammation by reducing proinflammatory cytokines (tumor necrosis factor alpha, interleukin 1 beta, interleukin 12) while increasing anti-inflammatory cytokines (IL-10).2 In a phase 1 randomized trial, roflumilast, a topical PDE-4 inhibitor, was shown to reduce inflammation and disease severity in patients with plaque psoriasis.3 Lebwohl et al have recently published a randomized, double- blinded, vehicle-controlled phase 2b trial to evaluate the efficacy and safety of roflumilast cream administered daily for the treatment of plaque psoriasis.4 Their results were published in the New England Journal of Medicine. A total of 331 adult patients with chronic plaque psoriasis affecting 2%-20% of the body surface area were included and randomized in a 1:1:1 ratio to receive roflumilast 0.3% cream, roflumilast 0.15% cream, or vehicle cream. Roflumilast or vehicle cream was applied to all psoriasis lesions, excluding the scalp. The primary outcome was an investigator’s global assessment (IGA) status of clear or almost clear at week 6. Results revealed that roflumilast was successful in reducing psoriasis severity: at week 6, an IGA of clear or almost clear was observed in 28% of the patients receiving roflumilast 0.3% (P < .001) and in 23% receiving roflumilast 0.15% (P = .004), compared to only 8% in the vehicle group. Furthermore, for patients with intertriginous psoriasis, reaching clear or almost clear and a 2-grade improvement in the intertriginous region IGA score at week 6 occurred in 73% of patients receiving roflumilast 0.3% and in 44% of patients receiving roflumilast 0.15%, compared to 29% of patients in the vehicle group. Interestingly, as early as week 2, a greater improvement in the impact of psoriasis symptoms on a patient’s life was demonstrated for roflumilast in comparison to the vehicle cream. Moreover, the roflumilast 0.3%
group showed numerically higher outcomes than the roflumilast 0.15% group, indicating potential benefits of the higher concentration. Importantly, application-site reactions were low and occurred with a comparable incidence in the 3 groups. Further, a recent double-blinded controlled trial of 21 patients with intertriginous, anogenital, and facial psoriasis demonstrated that following 4 weeks of twice-daily application of crisaborole, another topical PDE-4 inhibitor, patients showed 66% improvement in the Target Lesion Severity Scale (TLSS) compared to 9% in the placebo control group.5 Following the second phase of the trial, 71% of the crisaborole group reached clinical clearance (TLSS ≤1).5 Topical PDE-4 inhibitors are emerging for the treatment of mild-to-moderate plaque and special site psoriasis. While efficacy and safety have been demonstrated in vehicle-controlled studies, further randomized controlled trials comparing PDE-4 inhibitors to standard topical therapies and combination treatments (ie, tazarotene/halobetasol, calcipotriol/betamethasone dipropionate) will help to clarify their place in our therapeutic arsenal. Declaration of Conflicting Interests The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: MG is an investigator, speaker, and advisor for Amgen, Arcutis Biotherapeutics, and Pfizer.
1
Faculty of Medicine, Université Laval, Quebec, QC, Canada Faculty of Medicine, McGill University, Montreal, QC, Canada 3 Division of Dermatology, McGill University Health Centre, Montreal, QC, Canada 4 SKiN Centre for Dermatology, Peterborough, ON, Canada 5 Division of Dermatology, Queen's University, Kingston, ON, Canada 2
Corresponding Author: Elena Netchiporouk, Department of Medicine, Division of Dermatology, Montreal General Hospital, 1650 Avenue Cedar, Montreal, QC H3G 1A4, Canada. Email: elena.netchiporouk@mail.mcgill.ca
2
Journal of Cutaneous Medicine and Surgery 00(0)
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
ORCID iDs Zainab Ridha https://orcid.org/0000-0002-1325-1146 Lydia Ouchene https://orcid.org/0000-0002-1556-5851 Elena Netchiporouk https://orcid.org/0000-0002-6692-7787 Melinda J. Gooderham https://orcid.org/0000-0001-8926-0113
References 1. Canadian Psoriasis Guidelines Addendum Committee. 2016 addendum to the Canadian guidelines for the management of plaque psoriasis 2009. J Cutan Med Surg. 2016;20(5):375-431. doi:10.1177/1203475416655705
2. Moustafa F, Feldman SR. A review of phosphodiesterase- inhibition and the potential role for phosphodiesterase 4- inhibitors in clinical dermatology. Dermatol Online J. 2014; 20(5):22608. 3. Snape SD, Wigger-Alberti W, Goehring UM. A phase I randomized trial to assess the effect on skin infiltrate thickness and tolerability of topical phosphodiesterase inhibitors in the treatment of psoriasis vulgaris using a modified psoriasis plaque test. Br J Dermatol. 2016;175(3):479-486. doi:10.1111/bjd. 14634 4. Lebwohl MG, Papp KA, Stein Gold L, et al. Trial of roflumilast cream for chronic plaque psoriasis. N Engl J Med. 2020;383(3):229-239. d oi:10.1056/NEJMoa2000073 5. Hashim PW, Chima M, Kim HJ, et al. Crisaborole 2% ointment for the treatment of intertriginous, anogenital, and facial psoriasis: a double-blind, randomized, vehicle-controlled trial. J Am Acad Dermatol. 2020;82(2):360-365. doi:10.1016/j.jaad. 2019.06.1288
Topical PDE-4 Inhibitors are Emerging for Psoriasis Treatment
Journal of Cutaneous Medicine and Surgery 00(0) 1–2 © The Author(s) 2020 Article reuse guidelines: sagepub.com/journals-permissions DOI: 10.1177/1203475420960429 journals.sagepub.com/home/cms
Zainab Ridha1 , Lydia Ouchene2 , Elena Netchiporouk3 , and Melinda J. Gooderham4,5
Keywords psoriasis, roflumilast, PDE-4 inhibitors, topical treatment
The latest Canadian expert statement favored high-potency topical glucocorticoids, retinoids, and vitamin D3 analogs as first- line therapies, either alone or in combination, for mild-moderate psoriasis.1 However, current topicals are limited by their side- effect profile especially when treating inverse psoriasis, or when used uninterruptedly. Phosphodiesterase-4 (PDE-4) is found in keratinocytes and immune cells, and it is overexpressed in psoriasis. PDE-4 inhibition by apremilast in psoriasis increases cyclic adenosine monophosphate levels and normalizes aberrant inflammation by reducing proinflammatory cytokines (tumor necrosis factor alpha, interleukin 1 beta, interleukin 12) while increasing anti-inflammatory cytokines (IL-10).2 In a phase 1 randomized trial, roflumilast, a topical PDE-4 inhibitor, was shown to reduce inflammation and disease severity in patients with plaque psoriasis.3 Lebwohl et al have recently published a randomized, double- blinded, vehicle-controlled phase 2b trial to evaluate the efficacy and safety of roflumilast cream administered daily for the treatment of plaque psoriasis.4 Their results were published in the New England Journal of Medicine. A total of 331 adult patients with chronic plaque psoriasis affecting 2%-20% of the body surface area were included and randomized in a 1:1:1 ratio to receive roflumilast 0.3% cream, roflumilast 0.15% cream, or vehicle cream. Roflumilast or vehicle cream was applied to all psoriasis lesions, excluding the scalp. The primary outcome was an investigator’s global assessment (IGA) status of clear or almost clear at week 6. Results revealed that roflumilast was successful in reducing psoriasis severity: at week 6, an IGA of clear or almost clear was observed in 28% of the patients receiving roflumilast 0.3% (P < .001) and in 23% receiving roflumilast 0.15% (P = .004), compared to only 8% in the vehicle group. Furthermore, for patients with intertriginous psoriasis, reaching clear or almost clear and a 2-grade improvement in the intertriginous region IGA score at week 6 occurred in 73% of patients receiving roflumilast 0.3% and in 44% of patients receiving roflumilast 0.15%, compared to 29% of patients in the vehicle group. Interestingly, as early as week 2, a greater improvement in the impact of psoriasis symptoms on a patient’s life was demonstrated for roflumilast in comparison to the vehicle cream. Moreover, the roflumilast 0.3%
group showed numerically higher outcomes than the roflumilast 0.15% group, indicating potential benefits of the higher concentration. Importantly, application-site reactions were low and occurred with a comparable incidence in the 3 groups. Further, a recent double-blinded controlled trial of 21 patients with intertriginous, anogenital, and facial psoriasis demonstrated that following 4 weeks of twice-daily application of crisaborole, another topical PDE-4 inhibitor, patients showed 66% improvement in the Target Lesion Severity Scale (TLSS) compared to 9% in the placebo control group.5 Following the second phase of the trial, 71% of the crisaborole group reached clinical clearance (TLSS ≤1).5 Topical PDE-4 inhibitors are emerging for the treatment of mild-to-moderate plaque and special site psoriasis. While efficacy and safety have been demonstrated in vehicle-controlled studies, further randomized controlled trials comparing PDE-4 inhibitors to standard topical therapies and combination treatments (ie, tazarotene/halobetasol, calcipotriol/betamethasone dipropionate) will help to clarify their place in our therapeutic arsenal. Declaration of Conflicting Interests The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: MG is an investigator, speaker, and advisor for Amgen, Arcutis Biotherapeutics, and Pfizer.
1
Faculty of Medicine, Université Laval, Quebec, QC, Canada Faculty of Medicine, McGill University, Montreal, QC, Canada 3 Division of Dermatology, McGill University Health Centre, Montreal, QC, Canada 4 SKiN Centre for Dermatology, Peterborough, ON, Canada 5 Division of Dermatology, Queen's University, Kingston, ON, Canada 2
Corresponding Author: Elena Netchiporouk, Department of Medicine, Division of Dermatology, Montreal General Hospital, 1650 Avenue Cedar, Montreal, QC H3G 1A4, Canada. Email: elena.netchiporouk@mail.mcgill.ca
2
Journal of Cutaneous Medicine and Surgery 00(0)
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
ORCID iDs Zainab Ridha https://orcid.org/0000-0002-1325-1146 Lydia Ouchene https://orcid.org/0000-0002-1556-5851 Elena Netchiporouk https://orcid.org/0000-0002-6692-7787 Melinda J. Gooderham https://orcid.org/0000-0001-8926-0113
References 1. Canadian Psoriasis Guidelines Addendum Committee. 2016 addendum to the Canadian guidelines for the management of plaque psoriasis 2009. J Cutan Med Surg. 2016;20(5):375-431. doi:10.1177/1203475416655705
2. Moustafa F, Feldman SR. A review of phosphodiesterase- inhibition and the potential role for phosphodiesterase 4- inhibitors in clinical dermatology. Dermatol Online J. 2014; 20(5):22608. 3. Snape SD, Wigger-Alberti W, Goehring UM. A phase I randomized trial to assess the effect on skin infiltrate thickness and tolerability of topical phosphodiesterase inhibitors in the treatment of psoriasis vulgaris using a modified psoriasis plaque test. Br J Dermatol. 2016;175(3):479-486. doi:10.1111/bjd. 14634 4. Lebwohl MG, Papp KA, Stein Gold L, et al. Trial of roflumilast cream for chronic plaque psoriasis. N Engl J Med. 2020;383(3):229-239. d oi:10.1056/NEJMoa2000073 5. Hashim PW, Chima M, Kim HJ, et al. Crisaborole 2% ointment for the treatment of intertriginous, anogenital, and facial psoriasis: a double-blind, randomized, vehicle-controlled trial. J Am Acad Dermatol. 2020;82(2):360-365. doi:10.1016/j.jaad. 2019.06.1288
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