SKIN November 2021 Volume 5 Issue 6 Copyright 2021 The National Society for Cutaneous Medicine 568 CLINICAL MANAGEMENT RECOMMENDATIONS Psoriasis Therapy Beyond Biologics Connor R. Buechler, MD1,2, Jesse Veenstra, MD, PhD3, Linda Stein Gold, MD3 1Department of Dermatology, University of Minnesota, Minneapolis, MN 2Department of Internal Medicine, University of Minnesota, Minneapolis, MN 3Department of Dermatology, Henry Ford Health System, Detroit, MI Psoriasis is a chronic, relapsing, immune- mediated condition that affects roughly 3% of the US population and an estimated 125 million individuals worldwide. Plaque psoriasis is the most common form of the disease, manifesting as well-demarcated scaly erythematous patches and plaques on extensor surfaces, often with intense pruritus. The advent of biologics, including TNF inhibitors, IL-12/23 inhibitors, IL-17 inhibitors, and IL-23 inhibitors, as treatment for psoriasis has heralded an era of remarkably improved therapies, particularly for moderate to severe plaque psoriasis and psoriatic arthritis. However, these medications are not necessarily appropriate or needed for every patient. In this review we will discuss available treatments and pearls regarding non- biologic options for psoriasis, with a brief review of non-biologic systemic therapies followed by an in-depth discussion of recent advances in topical therapeutics and recommendations as to their inclusion in patient care. As biologic systemic therapies available for the treatment of psoriasis have proliferated in recent years, traditional oral systemic ABSTRACT Although psoriasis patients have benefited from the advent of biologic treatments over the past two decades, these medications are not appropriate for all patients and can be augmented by additional therapy. Differences among the manifold options can be difficult to parse, though essential for matching treatment with an individual patient. UV-light therapies, including both UV-B and psoralen with UV-A light, continue to play an important role in treatment, as do non-biologic systemic options including methotrexate, cyclosporine, apremilast, and acitretin. Recent years have seen a dramatic expansion in available topical therapies, the most common modality for the treatment of psoriasis, including new foam, spray, lotion, and cream formulations of topical corticosteroids (TCS) and new fixed-dose combination offerings of TCS with tazarotene and calcipotriene. Newer advances, including the oral tyrosine kinase 2 inhibitor deucravacitinib and non-steroidal topicals such as roflumilast, a PDE-4 inhibitor, and tapinarof, a first-in-class non-steroidal small-molecule, will soon provide even more options for treatment. It is vital for clinicians to remain aware of this ever- expanding armamentarium, allowing for more productive shared decision-making with patients, improved satisfaction, and better disease control. INTRODUCTION ORAL SYSTEMIC TREATMENT SKIN November 2021 Volume 5 Issue 6 Copyright 2021 The National Society for Cutaneous Medicine 569 treatments [Table 1] have fallen relatively out of favor. Since the approval of apremilast in 2014, there have been no new oral agents approved for the treatment of plaque psoriasis. The side effect profiles of therapies in this category should be carefully considered before initiating therapy. Table 1. Non-biologic systemic therapies for plaque psoriasis Medication Treatment success rates* Advantages Methotrexate 45.2% at week 12 or 163 Highly effective therapy at low cost Acitretin 47% at week 1246 No immune suppression Cyclosporine 50-97% at week 10-1647 Excellent bridge to alternative therapy for control of severe disease Apremilast 30-40% at week 1611-13 No monitoring needed Deucravacitinib† 50.3%-53.6% at week 1616 Oral dosing with efficacy approaching injectable biologics *Based on reported PASI75 over multiple studies †Phase III trials ongoing, application for regulatory approval pending Methotrexate One of the oldest treatments for psoriasis available today and the most commonly prescribed for psoriatic arthritis, methotrexate, is a dihydrofolate reductase inhibitor usually dosed at 15-20 mg once weekly for psoriasis.2 Studies have shown that patients achieve at least a 75% improvement in the Psoriasis Area and Severity Index (PASI75) at week 12 or 16 in 45.2% of patients as compared to 4.4% with placebo.3 However, use can cause hepatic fibrosis and cirrhosis, irreversible lung injury, bone marrow suppression, renal toxicity, diarrhea and ulcerative stomatitis, birth defects, and predisposition to infections.4 Many insurers still require a trial of methotrexate prior to initiation of biologic therapy, and its effectiveness and cost make it a fair option for most patients. Cyclosporine The cyclophilic peptide cyclosporine, originally approved for treatment of psoriasis in 1997, acts via calcineurin inhibition and independent dampening of T-cell activation.5 A recent network meta-analysis found that 2.5–5 mg/kg/day for 12–16 weeks results in a PASI90 equivalent to that of Methotrexate.6 However, potential adverse effects are also a significant barrier to treatment, including nephrotoxicity, hepatotoxicity, hypertension, paresthesia, hypertrichosis, gingival hyperplasia, electrolyte disturbances, increased risk of infections, and increased risk for skin and lymphoproliferative malignancies.7 Cyclosporine is typically used as a bridging therapy to assist with rapid control of severe or poorly controlled psoriasis while another long-term therapy is being initiated. Long- term use of cyclosporine beyond 3 months is uncommon and use over 1 year is not recommended. Acitretin Acitretin is a vitamin A derivative whose mechanism of action involves binding of an intracellular receptor, leading to improved regulation of epidermal proliferation.8 Studies of acitretin since its approval for the treatment of psoriasis in 1996 have demonstrated that doses of 25-50 mg/day prove less effective than other traditional systemic agents.9 Acitretin use is likewise limited by side effects, including skeletal toxicity, hepatotoxicity, hyperlipidemia, mucocutaneous effects, arthralgia, myalgia, SKIN November 2021 Volume 5 Issue 6 Copyright 2021 The National Society for Cutaneous Medicine 570 and pseudotumor cerebri.10 However, its lack of immunosuppressive side effects makes it a good choice for patients for whom another systemic therapy would not be appropriate. It would not be an appropriate choice in most women of child- bearing age, given teratogenic effects that persist for 2-3 years even after cessation of therapy, nor for those with concomitant PsA, on which it has no effect.9 Apremilast The newest non-biologic systemic therapy for psoriasis, apremilast, is a phosphodiesterase-4 (PDE-4) inhibitor that modulates both the immune response and epithelial proliferation.11 Studies have shown that 30-40% of patients achieve PASI75 after 16 weeks of treatment with 30 mg twice daily.11-13 Use is limited by the most prominent side effects of diarrhea and weight loss, infections, depression, and headache, though no standard blood draws are required for routine monitoring, unlike all other oral options, making it a better choice for those who would be unable to sustain a monitoring visit schedule.10 Emerging oral therapies While JAK inhibitors such as tofacitinib showed good results in clinical trials, doses needed for control of plaques proved too high, and potential safety issues too significant, to recommend their use in treatment beyond PsA.14 Although not yet approved by the FDA, the oral tyrosine kinase 2 (TYK2) inhibitor deucravacitinib has shown great promise in recent trials. A phase II trial testing various dosing regimens noted up to 75% PASI75,15 and phase III trials of 6 mg daily treatment are ongoing, with preliminary data showing superiority to both apremilast and placebo over 16 and 24-week treatment courses.16 Although use of phototherapy for the treatment of psoriasis has decreased dramatically since the advent of biologic therapy,1 it remains an important option in the right patient setting. UV-B UV-B light was originally used in broadband form (290-320 nm), but is now almost exclusively used as narrowband (311 nm) light for the treatment of psoriasis, given improved clinical efficacy.17 Treatment with UV-B light decreases DNA synthesis, inducing apoptosis of pathogenic T-cells and proliferating keratinocytes, as well as causing local and systemic immunosuppression.18 Treatment begins at up to 3 times weekly, though can eventually be tapered to twice per week or less. Excimer laser/lamp, which uses a monochromatic UV-B source at 308 nm, can be used for highly targeted therapy of individual lesions. PUVA Psoralen and UV-A light (PUVA) provide a photochemotherapy in which a photosensitizing drug, psoralen, is given either systemically or topically prior to UVA (320-400 nm) radiation. Similar to UVB treatment, administrations start at 2-3 times weekly, with tapering over the longer term once disease control has been established. Although PUVA has proven more efficacious than UVB for refractory disease,18 concerns over the long-term carcinogenic risk of UVA as well as GI distress caused by systemic psoralens tend to limit its usage in the clinic.19 PHOTOTHERAPY SKIN November 2021 Volume 5 Issue 6 Copyright 2021 The National Society for Cutaneous Medicine 571 Eighty percent of psoriasis patients are thought to have disease amenable to topical therapy,20 though significant issues in compliance prove to be a formidable barrier to disease control.21 The therapeutic options in this space are constantly advancing [Table 2], driven largely by patient dissatisfaction with current options.22 Reviewing all available topical therapies is beyond the scope of this brief article, and there are excellent reviews of topical therapies elsewhere in the literature,23,24 so here we will review the most recent advances in the field along with recommendations as to their inclusion in clinical practice. As patient preferences for topical therapies can be heterogeneous and difficult to predict, with many valuing delivery mode more than proven efficacy,25,26 it is imperative that the choice of topical therapy be a collaborative decision. Steroidal formulations Topical corticosteroids (TCS) have been the cornerstone of psoriasis therapy since the 1950s, largely offered as creams, ointments, and lotions that act through anti- inflammatory, antimitotic, immunomodulatory, apoptotic, and vasoconstrictive functions. Advances in vehicle technology have allowed for the development of sprays and foams, as well as improvements upon lotion vehicles, all of which can dramatically improve the user experience by leaving less residue and being less bothersome to apply than traditional formulations. Betamethasone dipropionate (BD) 0.05%, previously available in ointment, lotion, and cream formulations, is now available as a twice- daily spray, which outperforms vehicle alone and provides relief comparable to the corresponding superpotent lotion, while rating only mid-potency by vasoconstrictive assay, indicating a decreased risk for atrophy, HPA-suppression, and other common TCS side effects.27,28 Halobetasol propionate (HP) 0.05%, likewise previously available in ointment, lotion, and cream formulations, is now offered as a twice-daily foam that can provide control of symptoms after a two-week course.29 This foam also appears to show minimal systemic absorption and no HPA axis suppression in those age 12-18, though pediatric use is currently off-label.30 HP is also now available as a 0.01% lotion, one-fifth of the traditional 0.05% concentration, that can be used daily over an extended 8-week treatment course, useful for those patients who desire a more extended therapeutic treatment without sacrificing efficacy.31,32 Finally, clobetasol propionate (CP) is newly available as a 0.025% cream that not only halves the traditional concentration of 0.05% without the loss of super-potent (class I) status, but also avoids traditional potency enhancers that are the leading cause of TCS contact allergy, making this an excellent option for those with proven allergies to other TCS, propylene glycol, or sorbitan sesquioleate.33 Fixed-dose combination formulations The combination of calcipotriene, a vitamin D analogue, and TCS has previously required either the application of two separate medications or the use of a fixed combination suspension or ointment. As of 2015 and 2020, respectively, both a foam and cream fixed-dose combination therapy of BD 0.064% and calcipotriene 0.005% (Cal/BD) are now available. Given increased TOPICAL THERAPIES SKIN November 2021 Volume 5 Issue 6 Copyright 2021 The National Society for Cutaneous Medicine 572 Table 2. New and Upcoming Topical Therapies for Psoriasis Medication Treatment success rates* Advantages Calcipotriene 0.005% plus betamethasone dipropionate 0.064% aerosol foam 38-54.6% after 4 weeks of daily application48-50 Foam vehicle; combined therapy; once-daily application Betamethasone dipropionate spray, 0.05% 34.5% after 4 weeks of twice-daily application51 Spray vehicle; decreased side effects Clobetasol propionate cream, 0.025% 30.1-30.2% after 2 weeks of twice- daily application33 Lower steroid concentration than traditional; elimination of allergens Halobetasol propionate foam, 0.05% 25.3%-30.7% after 2 weeks of twice- daily application29 Foam vehicle Halobetasol propionate lotion, 0.01% 37-38% after 8 weeks of daily application31,32 Lower steroid concentration than traditional Halobetasol propionate 0.01% plus tazarotene 0.045% lotion 35.8%-45.3% after 8 weeks of daily application39 Combined therapy; extended application regimens Calcipotriene 0.005% plus 37.4% after 8 weeks of daily Combined therapy; new less greasy cream formulation; SKIN November 2021 Volume 5 Issue 6 Copyright 2021 The National Society for Cutaneous Medicine 573 betamethasone dipropionate 0.064% cream application52 extended application regimens Tapinarof 1% cream† 35.4-40.2% after 12 weeks of daily application44,53 Non-steroidal; extended application regimens Roflumilast 0.3% cream† 37.5-42.4% after 8 weeks of daily application42 Non-steroidal; extended application regimens Roflumilast 0.3% foam† ‡ Foam vehicle; non-steroidal; extended application regimens *Physician’s Global Assessment of clear or almost clear, with success rate based on phase III trials only † Phase III trials ongoing, application for regulatory approval pending ‡ Phase III trial data not yet released Adapted from Buechler et al, 202154 SKIN November 2021 Volume 5 Issue 6 Copyright 2021 The National Society for Cutaneous Medicine 574 bioavailability and enhanced penetration with the foam formulation,34 Cal/BD foam provides greater treatment efficacy than Cal foam, BD foam, Cal/BD gel, and Cal/BD ointment.35 A crossover trial showed that half of patients studied strongly preferred Cal/BD foam to Cal/BD gel as well as their latest topical treatment, particularly if that topical treatment had been an ointment or cream.26 Cal/BD cream, meanwhile, relies on a proprietary cream with decreased surfactant and thus improved medication delivery with decreased irritation, and it has outperformed topical suspension in trials.36,37 Tazarotene, a vitamin A derivative, can also be used alongside topical steroids to increase efficacy and alleviate safety concerns, although it does carry an independent risk of teratogenicity, photosensitivity, and irritation.38 A fixed-dose lotion of HP 0.01% plus tazarotene 0.045% (HP/Taz) approved in 2019 can be used as topical monotherapy for courses of 8 weeks, with greater treatment success than either therapy alone and sustained treatment effect over the ensuing 4 weeks.39 If this extended course of therapy is insufficient, recent data suggest HP/Taz lotion can be used daily for up to a year in repeated 4-week intervals on an as-needed basis without adverse events or local skin changes.40 Emerging non-steroidal topicals While shortened courses and combination therapy help decrease the risk of TCS side effects, such issues continue to be a long- term concern for many patients, and as such non-corticosteroid topicals have long been a focus of drug development. Existing non- steroidal topical therapies include tazarotene and calcipotriene, as mentioned above, as well as calcineurin inhibitors, coal tar, and keratolytics such as salicylic acid. These therapies can be particularly useful for pediatric applications, intertriginous and sensitive locations, and long-term therapy. However, the stronger anti-inflammatory and antiproliferative effects as well as the ease- of-use of TCS has led to the marginalization of these therapies in the clinic. This therapeutic category stands to make a marked resurgence in the coming years with new PDE-4 inhibitor and small-molecule topical therapies soon to seek FDA approval. Both of these novel therapies offer promising efficacy, good local tolerability and the potential for a durable remission. Roflumilast, a PDE-4 inhibitor, may soon be available in both cream and foam vehicles.41 Clinical trials of Roflumilast cream show rates of treatment success comparable to available topical treatments with a safety profile that has allowed enrollees as young as two years of age.42 Though farther away from regulatory approval, Roflumilast foam has shown similar promise, and would pair the safety profile of the PDE-4 inhibitor with the popular and easy-to-use foam vehicle.43 Tapinarof, a novel, first-in-class, non- steroidal small-molecule, has shown treatment efficacy at 12 weeks that is similar to that of other topicals,44 as well as further efficacy from continued daily use for up to a year without evidence of tachyphylaxis or any new adverse effects.45 While the advent of biologic therapies has shifted treatment strategy, non-biologic options remain essential for psoriasis care at all stages of severity. Currently available and emerging oral, topical, and UV-light based therapies can achieve excellent disease control, in addition to being adjuncts to biologic therapy when appropriate. Upcoming advances in therapy with new oral TYK2 inhibitors and non-steroidal CONCLUSION SKIN November 2021 Volume 5 Issue 6 Copyright 2021 The National Society for Cutaneous Medicine 575 topical options will dramatically affect the future treatment paradigm. It is imperative for dermatologists to remain informed about this changing landscape, as shared decision-making with patients regarding desired characteristics, unwanted side- effects, and level of expected efficacy of treatment modalities can lead to improved satisfaction and disease control. Conflict of Interest Disclosures: Dr. Buechler and Dr. Veenstra have nothing to disclose. Dr. Stein Gold reports grants and personal fees from Leo Pharma, Arcutis, Abbvie, UCB, BMS, Amgen, Incyte, Ortho Derm, Pfizer, Dermavant, and Sun. Funding: None Corresponding Author: Linda Stein Gold, MD Department of Dermatology Henry Ford Health System 6530 Farmington Rd West Bloomfield, MI 48322 Telephone: 248-661-8764 Email: lstein1@hfhs.org References: 1. Armstrong AW, Read C. Pathophysiology, Clinical Presentation, and Treatment of Psoriasis: A Review. JAMA. 2020;323(19):1945-1960. 2. Coates LC, Merola JF, Grieb SM, Mease PJ, Callis Duffin K. Methotrexate in Psoriasis and Psoriatic Arthritis. The Journal of Rheumatology. 2020;96:31. 3. West J, Ogston S, Foerster J. Safety and efficacy of methotrexate in psoriasis: a meta- analysis of published trials. PloS one. 2016;11(5):e0153740. 4. Liu Q, Wu DH, Han L, et al. Roles of microRNAs in psoriasis: Immunological functions and potential biomarkers. Exp Dermatol. 2017;26(4):359-367. 5. Matsuda S, Koyasu S. Mechanisms of action of cyclosporine. Immunopharmacology. 2000;47(2):119-125. 6. Sbidian E, Chaimani A, Garcia-Doval I, et al. 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Expert Rev Clin Immunol. 2018;14(9):719-730. 15. Papp K, Gordon K, Thaçi D, et al. Phase 2 Trial of Selective Tyrosine Kinase 2 Inhibition in Psoriasis. N Engl J Med. 2018;379(14):1313-1321. 16. Bristol Myers Squibb Presents Positive Data from Two Pivotal Phase 3 Psoriasis Studies Demonstrating Superiority of Deucravacitinib Compared to Placebo and Otezla® (apremilast) [press release]. April 23, 2021. SKIN November 2021 Volume 5 Issue 6 Copyright 2021 The National Society for Cutaneous Medicine 576 17. Coven TR, Burack LH, Gilleaudeau P, Keogh M, Ozawa M, Krueger JG. Narrowband UV-B produces superior clinical and histopathological resolution of moderate-to- severe psoriasis in patients compared with broadband UV-B2. Archives of dermatology. 1997;133(12):1514-1522. 18. Zhang P, Wu MX. A clinical review of phototherapy for psoriasis. Lasers in Medical Science. 2018;33(1):173-180. 19. Weatherhead SC, Farr PM, Reynolds NJ. Spectral effects of UV on psoriasis. Photochemical & Photobiological Sciences. 2013;12(1):47-53. 20. Stein Gold LF. Topical Therapies for Psoriasis: Improving Management Strategies and Patient Adherence. Semin Cutan Med Surg. 2016;35(2 Suppl 2):S36-44; quiz S45. 21. Armstrong AW, Robertson AD, Wu J, Schupp C, Lebwohl MG. Undertreatment, Treatment Trends, and Treatment Dissatisfaction Among Patients With Psoriasis and Psoriatic Arthritis in the United States: Findings From the National Psoriasis Foundation Surveys, 2003-2011. JAMA Dermatology. 2013;149(10):1180-1185. 22. Brown KK, Rehmus WE, Kimball AB. Determining the relative importance of patient motivations for nonadherence to topical corticosteroid therapy in psoriasis. J Am Acad Dermatol. 2006;55(4):607-613. 23. Bark C, Brown C, Svangren P. Systematic literature review of long-term efficacy data for topical psoriasis treatments. Journal of Dermatological Treatment. 2021:1-11. 24. Elmets CA, Korman NJ, Prater EF, et al. Joint AAD-NPF Guidelines of care for the management and treatment of psoriasis with topical therapy and alternative medicine modalities for psoriasis severity measures. J Am Acad Dermatol. 2021;84(2):432-470. 25. Florek AG, Wang CJ, Armstrong AW. Treatment preferences and treatment satisfaction among psoriasis patients: a systematic review. Archives of Dermatological Research. 2018;310(4):271- 319. 26. Hong C-H, Papp KA, Lophaven KW, Skallerup P, Philipp S. Patients with psoriasis have different preferences for topical therapy, highlighting the importance of individualized treatment approaches: randomized phase IIIb PSO-INSIGHTFUL study. Journal of the European Academy of Dermatology and Venereology. 2017;31(11):1876-1883. 27. Stein Gold L, Jackson JM, Knuckles ML, Weiss JS. Improvement in Extensive Moderate Plaque Psoriasis With a Novel Emollient Spray Formulation of Betamethasone Dipropionate 0.05. J Drugs Dermatol. 2016;15(3):334-342. 28. Fowler JF, Jr., Hebert AA, Sugarman J. DFD- 01, a Novel Medium Potency Betamethasone Dipropionate 0.05% Emollient Spray, Demonstrates Similar Efficacy to Augmented Betamethasone Dipropionate 0.05% Lotion for the Treatment of Moderate Plaque Psoriasis. J Drugs Dermatol. 2016;15(2):154- 162. 29. Bhatia N, Stein Gold L, Kircik LH, Schreiber R. Two Multicenter, Randomized, Double- Blind, Parallel Group Comparison Studies of a Novel Foam Formulation of Halobetasol Propionate, 0.05% vs Its Vehicle in Adult Subjects With Plaque Psoriasis. J Drugs Dermatol. 2019;18(8):790-796. 30. Hebert A, Schrieber R, Glaab D, Eichenfield L. Phase IV Open Label Evaluation of the Adrenal Suppression Potential and Pharmacokinetic Properties of Twice Daily Halobetasol propionate Foam, 0.05% in Adolescent Subjects with Plaque Psoriasis. SKIN The Journal of Cutaneous Medicine. 2020;4(6):s77-s77. 31. Sugarman JL, Weiss JS, Tanghetti EA, et al. Safety and efficacy of halobetasol propionate lotion 0.01% in the treatment of moderate to severe plaque psoriasis: a pooled analysis of 2 phase 3 studies. Cutis. 2019;103(2):111- 116. 32. Green LJ, Kerdel FA, Cook-Bolden FE, et al. Safety and Efficacy of a Once-Daily Halobetasol Propionate 0.01% Lotion in the Treatment of Moderate-to-Severe Plaque Psoriasis: Results of Two Phase 3 Randomized Controlled Trials. J Drugs Dermatol. 2018;17(10):1062-1069. 33. Del Rosso JQ. Topical Corticosteroid Therapy for Psoriasis-A Review of Clobetasol Propionate 0.025% Cream and the Clinical Relevance of Penetration Modification. The Journal of clinical and aesthetic dermatology. 2020;13(2):22-29. 34. Lind M, Nielsen KT, Schefe LH, et al. Supersaturation of Calcipotriene and Betamethasone Dipropionate in a Novel Aerosol Foam Formulation for Topical Treatment of Psoriasis Provides Enhanced Bioavailability of the Active Ingredients. Dermatol Ther (Heidelb). 2016;6(3):413-425. SKIN November 2021 Volume 5 Issue 6 Copyright 2021 The National Society for Cutaneous Medicine 577 35. Stein Gold L, Lebwohl M, Menter A, Villumsen J, Rosen M, Koo J. Aerosol Foam Formulation of Fixed Combination Calcipotriene Plus Betamethasone Dipropionate is Highly Efficacious in Patients With Psoriasis Vulgaris: Pooled Data From Three Randomized Controlled Studies. J Drugs Dermatol. 2016;15(8):951-957. 36. Selmer J VB, Præstegaard M, and Gold LS. MC2-01 Cream Has Improved Overall Psoriasis Treatment Efficacy Compared to Calcipotriene Plus Betamethasone Dipropionate Topical Suspension. J Psoriasis Psoriatic Arthritis 2019;4(3):166-167. 37. Daniel D, Waddell A. Compliance with National Comprehensive Cancer Network anti-emesis guidelines in a Community Hospital Cancer Center. J Oncol Pharm Pract. 2016;22(1):26-30. 38. Gollnick H, Menter A. Combination therapy with tazarotene plus a topical corticosteroid for the treatment of plaque psoriasis. The British journal of dermatology. 1999;140 Suppl 54:18-23. 39. Gold LS, Lebwohl MG, Sugarman JL, et al. Safety and efficacy of a fixed combination of halobetasol and tazarotene in the treatment of moderate-to-severe plaque psoriasis: Results of 2 phase 3 randomized controlled trials. J Am Acad Dermatol. 2018;79(2):287- 293. 40. Lebwohl MG, Sugarman JL, Gold LS, et al. Long-term safety results from a phase 3 open-label study of a fixed combination halobetasol propionate 0.01% and tazarotene 0.045% lotion in moderate-to- severe plaque psoriasis. J Am Acad Dermatol. 2019;80(1):282-285. 41. Li H, Zuo J, Tang W. Phosphodiesterase-4 Inhibitors for the Treatment of Inflammatory Diseases. Front Pharmacol. 2018;9:1048. 42. Arcutis Announces Positive Topline Results from Pivotal DERMIS-1 and -2 Phase 3 Trials of Topical Roflumilast Cream (ARQ-151) in Plaque Psoriasis. https://www.biospace.com/article/releases/ar cutis-announces-positive-topline-results- from-pivotal-dermis-1-and-2-phase-3-trials- of-topical-roflumilast-cream-arq-151-in- plaque-psoriasis/. Published 2021. Updated February 1. Accessed. 43. Kircik LH, Moore A, Bhatia N, et al. Once- daily Roflumilast foam 0.3% for scalp and body psoriasis: a randomized, double-blind, vehicle-controlled phase 2b study. American Academy of Dermatology Virtual Meeting Experience; 2021. 44. Gold LS, Blauvelt A, Armstrong A, et al. Tapinarof Cream 1% Once Daily for Plaque Psoriasis: Secondary Efficacy Outcomes from Two Pivotal Phase 3 Trials. American Academy of Dermatology Virtual Meeting Experience; 2021. 45. Dermavant: Promising Interim Analysis from Third Phase 3 Trial for Tapinarof in Psoriasis. https://practicaldermatology.com/news/derma vant-promising-interim-analysis-from-third- phase-3-trial-for-tapinarof-in-psoriasis. Published 2021. Updated February 18. Accessed. 46. Dogra S, Jain A, Kanwar AJ. Efficacy and safety of acitretin in three fixed doses of 25, 35 and 50 mg in adult patients with severe plaque type psoriasis: a randomized, double blind, parallel group, dose ranging study. J Eur Acad Dermatol Venereol. 2013;27(3):e305-311. 47. Maza A, Montaudié H, Sbidian E, et al. Oral cyclosporin in psoriasis: a systematic review on treatment modalities, risk of kidney toxicity and evidence for use in non-plaque psoriasis. Journal of the European Academy of Dermatology and Venereology. 2011;25(s2):19-27. 48. Lebwohl M, Tyring S, Bukhalo M, et al. Fixed Combination Aerosol Foam Calcipotriene 0.005% (Cal) Plus Betamethasone Dipropionate 0.064% (BD) is More Efficacious than Cal or BD Aerosol Foam Alone for Psoriasis Vulgaris: A Randomized, Double-blind, Multicenter, Three-arm, Phase 2 Study. J Clin Aesthet Dermatol. 2016;9(2):34-41. 49. Koo J, Tyring S, Werschler WP, et al. Superior efficacy of calcipotriene and betamethasone dipropionate aerosol foam versus ointment in patients with psoriasis vulgaris--A randomized phase II study. J Dermatolog Treat. 2016;27(2):120-127. 50. Paul C, Stein Gold L, Cambazard F, et al. Calcipotriol plus betamethasone dipropionate aerosol foam provides superior efficacy vs. gel in patients with psoriasis vulgaris: randomized, controlled PSO-ABLE study. J Eur Acad Dermatol Venereol. 2017;31(1):119-126. 51. Sidgiddi S, Pakunlu RI, Allenby K. Efficacy, Safety, and Potency of Betamethasone Dipropionate Spray 0.05%: A Treatment for Adults with Mild-to-moderate Plaque https://www.biospace.com/article/releases/arcutis-announces-positive-topline-results-from-pivotal-dermis-1-and-2-phase-3-trials-of-topical-roflumilast-cream-arq-151-in-plaque-psoriasis/ https://www.biospace.com/article/releases/arcutis-announces-positive-topline-results-from-pivotal-dermis-1-and-2-phase-3-trials-of-topical-roflumilast-cream-arq-151-in-plaque-psoriasis/ https://www.biospace.com/article/releases/arcutis-announces-positive-topline-results-from-pivotal-dermis-1-and-2-phase-3-trials-of-topical-roflumilast-cream-arq-151-in-plaque-psoriasis/ https://www.biospace.com/article/releases/arcutis-announces-positive-topline-results-from-pivotal-dermis-1-and-2-phase-3-trials-of-topical-roflumilast-cream-arq-151-in-plaque-psoriasis/ https://www.biospace.com/article/releases/arcutis-announces-positive-topline-results-from-pivotal-dermis-1-and-2-phase-3-trials-of-topical-roflumilast-cream-arq-151-in-plaque-psoriasis/ https://practicaldermatology.com/news/dermavant-promising-interim-analysis-from-third-phase-3-trial-for-tapinarof-in-psoriasis https://practicaldermatology.com/news/dermavant-promising-interim-analysis-from-third-phase-3-trial-for-tapinarof-in-psoriasis https://practicaldermatology.com/news/dermavant-promising-interim-analysis-from-third-phase-3-trial-for-tapinarof-in-psoriasis SKIN November 2021 Volume 5 Issue 6 Copyright 2021 The National Society for Cutaneous Medicine 578 Psoriasis. J Clin Aesthet Dermatol. 2018;11(4):14-22. 52. Stein Gold L, Green LJ, Dhawan S, Vestbjerg B, Praestegaard M, Selmer J. A Phase 3, Randomized Trial Demonstrating the Improved Efficacy and Patient Acceptability of Fixed Dose Calcipotriene and Betamethasone Dipropionate Cream. J Drugs Dermatol. 2021;20(4):420-425. 53. Bissonnette R, Strober B, Lebwohl M, et al. Tapinarof Cream 1% Once Daily for Plaque Psoriasis: Patient-reported Outcomes from Two Pivotal Phase 3 Trials. American Academy of Dermatology Virtual Meeting Experience; 2021. 54. Buechler CR, Veenstra J, Stein Gold L. New topical therapies for psoriasis. Dermatological Reviews. 2021.