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An Update in the Psoriatic Treatment Algorithm and Therapies

An Update in the Psoriatic Treatment Algorithm and Therapies

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Dr LebwohlPsoriasis continues to be a fast-paced avenue of dermatologic research. From elucidating how psoriasis influences physical activity and quality of life1 to approaching care during a pandemic,2 the past few years have seen a number of breakthroughs in our understanding of the disease process and its systemic effect as well as efficacious options for treatment of this chronic disease. This article summarizes the treatment algorithm as well as some of the latest developments in therapeutic options for psoriatic disease.

Treatment Algorithm

Determining the best treatment approach for psoriasis requires analysis of comorbidities, adherence-related factors, efficacy, safety, and cost.3,4 However, when considering therapeutic options for the management of psoriasis, dermatologists should also consider psoriatic body surface area (BSA) at presentation. Remember that a general rule of thumb with BSA is 1% is approximately equivalent to the entire palmar surface of one hand including the thumb and fingers.5 A limited BSA (<5%) and localized disease are prime for topical therapy with corticosteroids and emollients. Moderate (>5%) to severe (≥10%) disease generally needs to be approached with systemic therapy and/or phototherapy, as it is well-documented that severe disease can greatly impact patient quality of life and comorbid disease burden. Note, though, that psychosocial effect of psoriasis is critical, so consideration of patient perception of disease severity may be warranted.6-8

The number of options for the treatment of psoriatic disease continues to increase. Early oral systemic options, many of which are still in use today, include methotrexate, acitretin, and cyclosporine. Another systemic oral option is apremilast, a phosphodiesterase (PDE) 4 inhibitor, which has also shown to be safe and effective for the treatment of psoriatic arthritis.9 

Phototherapy (chiefly, narrowband UV-B, broadband UV-B, and psoralen plus UV-A photochemotherapy) remains an option for many patients with psoriasis. While safe and effective, phototherapy can be a hassle, as the frequency of treatment needed to achieve improvement in disease (eg, three times per week) can be time-consuming and impractical for the patient’s lifestyle. This has prompted the evaluation of the efficacy of home options as well.10,11 With newer and safer systemic therapies growing in popularity, the use of phototherapy has seen some decline, but it has been used during the pandemic.

The advent of biologics into the dermatologic space have made a dramatic difference in the lives of patients with psoriatic disease. Biologics seemingly approach the root cause of psoriasis. These immune-mediating therapies inhibit pathways involving TNF alpha, IL-12, IL-17, and IL-23, thereby reducing the production and activity of psoriatic cytokines (IL-17) responsible for the inflammatory response manifested in cutaneous symptoms such as epidermal thickening, erythema, and pruritus.12 

Biologics are generally assessed by the improvement in Investigator’s Global Assessment (IGA) or Physicians Global Assessment (PGA) to a status of clear (0) or almost clear (1) and by Psoriasis Area and Severity Index (PASI). Historically, PASI 75 was considered the gold standard in therapeutic response, but newer therapies are seeing a higher number of patients achieve PASI 100 than ever before. For patients with less than PASI 100 on systemic therapy, combination therapy with emollients, topical corticosteroids, calcipotriene or calcitriol, tazarotene, and calcineurin inhibitors is a likely and effective option.

New Treatment Options

Topical therapies. The areas where physicians find trouble with topical steroids are generally the face and intertriginous areas. Steroids can cause cataracts, glaucoma,13 and chronic perioral dermatitis14 when applied to the face, as well as irreversible stretch marks under the breasts, in the armpits, and in the groin.15 Despite these adverse events, dermatologists continue to use steroids because there have not been any effective alternatives.

Topical application of roflumilast cream, a PDE-4 inhibitor, may be an efficacious nonsteroidal option for the treatment of plaque psoriasis. In a phase 2b, double-blind trial comparing roflumilast 0.3% cream vs roflumilast 0.15% cream vs vehicle, 28% of patients who received roflumilast 0.3% cream and 23% who received roflumilast 0.15% achieved an IGA score of clear or almost clear after 12 weeks of treatment.16 This particular study looked specifically at areas where dermatologists should be hesitant to use a steroid (eg, face, intertriginous areas). The research group created a separate intertriginous area score that showed a dramatic level of improvement in psoriatic disease, achieving somewhat of a virtual clearing in those areas for the large majority of patients.

The excellent response of roflumilast cream was equivalent to using a fairly strong topical steroid, but without the steroidal side effects with virtually no irritation. There are few negatives with roflumilast cream, given its benign mechanism of action through PDE-4 inhibition.

Roflumilast works similarly to crisaborole, a topical PDE-4 inhibitor already on the market approved for the treatment of mild to moderate atopic dermatitis. It has been used to successfully treat facial and intertriginous psoriasis,17 and a report of two cases demonstrated success in the treatment of psoriasis.18

Tapinarof cream is a topical therapy that modulates the aryl hydrocarbon receptor, and its mode of action may make it a treatment option for both psoriasis and atopic dermatitis. A double-blind, vehicle-controlled study compared tapinarof cream 0.5% vs tapinarof cream 1.0% vs vehicle at once- or twice-daily application for 12 weeks (total number of treatment groups = 6).19 At week 12, all tapinarof groups showed improvements in PGA response, change in PGA, and PASI scores, with responses as early as week 2 and significant response at week 8 maintained through week 16 of treatment.

Biologic therapies. A number of biologics are in the pipeline and are approaching evaluation by the FDA.

Bimekizumab, an IL-17A and IL-17F inhibitor, has demonstrated efficacy in the treatment of plaque psoriasis20,21 and psoriatic arthritis.22 It has the highest percentage of patients achieving PASI 100 of any of the currently available therapies as well as the highest percentage of patients achieving American College of Rheumatology (ACR) composite scores of 70% improvement in joint pain and swelling. This is a significant increase from the ACR scores of 20% seen with earlier systemic therapies.

Ixekizumab, an anti-IL-17 biologic, most recently received FDA approval for the treatment of moderate to severe plaque psoriasis in patients as young as 6 years in March 2020.23 It is the third biologic to be approved for pediatric patients, following behind ustekinumab and etanercept. A randomized, double-blind, placebo-controlled, phase 3 study found that a weight-based dose of ixekizumab every 4 weeks was superior to placebo, with 89% of patients on ixekizumab achieving PASI 75 and 81% achieving a static PGA score of 0 or 1 vs 25% and 11%, respectively, of the placebo arm.24 The observed safety profile of ixekizumab in pediatric patients was considered consistent with the safety profile for adult patients.25

Another anti-IL-17 biologic currently being studied in a randomized, double-blind, placebo-controlled, multicenter, phase 2b trial is M1095.26 This latest study is expected to reach completion in August 2020. 

It is worth noting that guselkumab, while not new for the treatment of psoriasis, was approved in July 2020 for the treatment of psoriatic arthritis.26 Trial results shared at the 2019 ACR/Association of Rheumatology Professionals Meeting noted that 4-week dosing of guselkumab prevented radiographic progression of joint disease,27 which could mean a significant impact on quality of life and outcomes for patients with comorbid psoriasis and psoriatic arthritis.

Mirikizumab modifies the inflammatory response by binding to the p19 subunit of IL-23. In a multicenter, double-blind, phase 2 trial, 29%, 59%, and 67% of patients who received 30-, 100-, or 300-mg doses of mirikizumab, respectively, at weeks 0 and 8 of treatment achieved PASI 90 at week 16.28 An additional 104-week study demonstrated that a high-level response to mirikizumab is maintained over a 2-year period, with patients who achieve PASI 90 or PASI 100 during the first 16 weeks of treatment also maintaining a high-level of response with as needed treatment.29 

An interesting pathway warranting further exploration in the treatment of psoriasis is IL-36, which is believed to be a key player in the pathophysiology of pustular psoriasis.30,31 A phase 1 study of BI 655130, an IL-36 antibody, has shown efficacy and safety in a small patient cohort (n=7).32 After 1 week of treatment, five patients achieved a score of 0/1 on the Generalized Pustular Psoriasis PGA (GPPGA), and all seven patients achieved a GPPGA score of 0/1 by week 4 of treatment. Further study of BI 655130 is currently in the recruitment phase.33,34

Oral therapies. A novel avenue of research in the treatment of psoriatic disease is the Janus kinase (JAK) signal transducer and activator of transcription protein (STAT) pathway.35 Dermatologists may already be familiar with tofacitinib, a JAK1 and JAK3 inhibitor already approved for the treatment of psoriatic arthritis. However, the FDA declined to approve tofacitinib for the treatment of plaque psoriasis, citing concerns of the clinical efficacy and long-term safety.36

Despite this minor setback, other JAK inhibitors are making good strides in improving patient outcomes. In particular, tyrosine kinase 2 (TYK2) has been shown to mediate the signals triggered by proinflammatory cytokines.37 A phase 2, double-blind trial found 75% (33/44) of patients who received 12 mg of TYK2 inhibitor BMS-986165 once daily achieved PASI 75 or greater after week 12 of treatment.38 Additionally, this study found 69% (31/45) and 67% (30/45) of patients receiving BMS-986165 3 mg twice daily and 6 mg twice daily, respectively, achieved at least PASI 75. BMS-986165 also demonstrated a respectable PASI 90 for all experimental groups after 12 weeks. Its side effect profile is incredibly clean, with no deaths or serious adverse events reported. While the rate of respiratory infections was higher in the 6-mg arm than placebo, the rate of the 12-mg arm was not higher than placebo. 

Oral small molecule inhibitors may be a key therapy option in the near future for psoriatic arthritis as well. Two phase 3 clinical trials39,40 are currently active for upadacitinib, a JAK1 inhibitor previously approved for the treatment of rheumatoid arthritis. Similarly, filgotinib is the subject of two phase 3 studies.41,42

Several other small molecule oral therapies are in the beginning stages of development, including:

  • ABV-157, an retinoic-acid-related orphan receptor gamma (RORγ) inverse-agonist43;
  • BI 730357, a nuclear receptor antagonist44; and
  • PF-06826647, a TYK2 inhibitor.45

Conclusion
The present day is the most exciting time yet to be treating dermatologic conditions such as psoriasis. The number of safe, effective options available for the care and management of disease and the related comorbidities in this patient group is significant, and the therapeutic pipeline holds promising options for the near future. n


Dr Lebwohl is the Waldman Professor and Chairman of the Kimberly and Eric J. Waldman Department of Dermatology at the Icahn School of Medicine at Mount Sinai in New York City, NY. 

Disclosure: Dr Lebwohl is an employee of Mount Sinai and receives research funds from AbbVie; Amgen; Arcutis Biotherapeutics; Boehringer Ingelheim; Dermavant Sciences; Eli Lilly; Incyte; Janssen Research & Development; LEO Pharmaceuticals; Ortho Dermatologics; Pfizer; and UCB, Inc. He is also a consultant for Aditum Bio; Allergan, Inc; Almirall; Arcutis, Inc; Avotres Therapeutics; BirchBioMed, Inc; BMD skincare; Boehringer Ingelheim; Bristol Myers Squibb; Cara Therapeutics; Castle Biosciences; Corrona; Dermavant Sciences; Evelo; Facilitate International Dermatologic Education; Foundation for Research and Education in Dermatology; Inozyme Pharma; LEO Pharma; Meiji Seika Pharma; Menlo; Mitsubishi; Neuroderm; Pfizer; Promius Pharma - Dr. Reddy’s Laboratories; Serono; Theravance; and Verrica.


References
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17. 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

18. Lee EB, Lebwohl MG, Wu JJ. Treatment of psoriasis with crisaborole. J Dermatolog Treat. 2019;30(2):156-157. doi:10.1080/09546634.2018.1480747

19. Stein Gold L, Bhatia N, Tallman AM, Rubenstein DS. A phase IIb, randomized clinical trial of tapinarof cream for the treatment of plaque psoriasis: secondary efficacy and patient-reported outcomes. J Am Acad Dermatol. Published online May 21, 2020. doi:10.1016/j.jaad.2020.04.181

20. Reich K, Papp KA, Blauvelt A, et al. Efficacy and safety of bimekizumab in patients with moderate-to-severe plaque psoriasis: results from BE VIVID, a 52-week phase 3, randomized, double-blinded, ustekinumab- and placebo-controlled study. Presented at: American Academy of Dermatology Virtual Meeting Experience 2020; June 12-14, 2020.

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22. Ritchlin CT, Kavanaugh A, Merola JF, et al. Bimekizumab in patients with active psoriatic arthritis: results from a 48-week, randomised, double-blind, placebo-controlled, dose-ranging phase 2b trial. Lancet. 2020;395(10222):427-440. doi:10.1016/S0140-6736(19)33161-7

23. Lilly’s Taltz® (ixekizumab) receives U.S. FDA approval for the treatment of pediatric patients with moderate to severe plaque psoriasis. News release. Eli Lilly and Company; March 30, 2020. Accessed July 21, 2020. https://investor.lilly.com/news-releases/news-release-details/lillys-taltzr-ixekizumab-receives-us-fda-approval-treatment-1

24. Paller AS, Seyger MMB, Alejandro Magariños G, et al; IXORA-PEDS Study Group. Efficacy and safety of ixekizumab in a phase III, randomized, double-blind, placebo-controlled study in paediatric patients with moderate-to-severe plaque psoriasis (IXORA-PEDS). Br J Dermatol. Published online April 21, 2020. doi:10.1111/bjd.1914

25. A Phase 2b study of the efficacy, safety, and tolerability of M1095 in subjects with moderate to severe psoriasis. ClinicalTrials.gov identifier: NCT03384745. January 18, 2020. Accessed July 28, 2020. https://clinicaltrials.gov/ct2/show/NCT03384745

26. TREMFYA® (guselkumab) approved by U.S. Food and Drug Administration as the first selective interleukin (IL)-23 inhibitor for active psoriatic arthritis. News release. Janssen Pharmaceutical Companies of Johnson & Johnson; July 14, 2020. Accessed July 21, 2020. https://www.prnewswire.com/news-releases/tremfya-guselkumab-approved-by-us-food-and-drug-administration-as-the-first-selective-interleukin-il-23-inhibitor-for-active-psoriatic-arthritis-301093009.html

27. Mease PJ, Rahman P, Gottlieb AB, et al. Guselkumab, an anti-interleukin-23p19 monoclonal antibody, in biologic-naïve patients with active psoriatic arthritis: week 24 results of the phase 3, randomized, double-blind, placebo-controlled study. Presented at: 2019 ACR/ARP Annual Meeting; October 23, 2019.

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29. Bissonnette R, Maari C, Menter A, et al. Efficacy and safety of mirikizumab in patients with moderate-to-severe plaque psoriasis: 104-week results from a randomized phase 2 study. Presented at: American Academy of Dermatology Virtual Meeting Experience 2020; June 12-14, 2020.

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32. Bachelez H, Choon SE, Marrakchi S, et al. Inhibition of the interleuk-36 pathway for the treatment of generalized pustular psoriasis. N Engl J Med. 2019;380(10):981-983. doi:10.1056/NEJMc1811317

33. A study to test whether BI 655130 (spesolimab) prevents flare-ups in patients with generalized pustular psoriasis. ClinicalTrials.gov identifier: NCT04399837. July 28, 2020. Accessed July 28, 2020. https://clinicaltrials.gov/ct2/show/NCT04399837

34. A study to test BI 655130 in patients with a flare-up of a skin disease called generalized pustular psoriasis. ClinicalTrials.gov identifier: NCT03782792. July 15, 2020. Accessed July 28, 2020. https://clinicaltrials.gov/ct2/show/NCT03782792

35. Solimani F, Meir K, Ghoreschi K. Emerging topical and systemic JAK inhibitors in dermatology. Front Immunol. 2019;10:2847. doi:10.3389/fimmu.2019.02847

36. Berekmeri A, Mahmood F, Wittmann M, Helliwell P. Tofacitinib for the treatment of psoriasis and psoriatic arthritis. Expert Rev Clin Immunol. 2018;14(9):719-730. doi:10.1080/1744666X.2018.1512404

37. Ishizaki M, Akimoto T, Muromoto R, et al. Involvement of tyrosine kinase-2 in both the IL-12/Th1 and IL-23/Th17 axes in vivo. J Immunol. 2011;187(1):181-189. doi:10.4049/jimmunol.1003244

38. 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. doi:10.1056/NEJMoa1806382

39. A study comparing upadacitinib (ABT-494) to placebo and to adalimumab in participants with psoriatic arthritis who have an inadequate response to at least one non-biologic disease modifying anti-rheumatic drug (SELECT - PsA 1). ClinicalTrials.gov identifier: NCT03104400. June 16, 2020. Accessed July 28, 2020. https://clinicaltrials.gov/ct2/show/NCT03104400

40. A study comparing upadacitinib (ABT-494) to placebo in participants with active psoriatic arthritis who have a history of inadequate response to at least one biologic disease modifying anti-rheumatic drug (SELECT - PsA 2). ClinicalTrials.gov identifier: NCT03104374. July 16, 2020. Accessed July 28, 2020. https://clinicaltrials.gov/ct2/show/NCT03104374

41. An open-label, long-term extension study with filgotinib in active psoriatic arthritis. ClinicalTrials.gov identifier: NCT03320876. April 17, 2020. Accessed July 28, 2020. https://clinicaltrials.gov/ct2/show/NCT03320876

42. Study to evaluate the efficacy and safety of filgotinib in participants with active psoriatic arthritis who are naive to biologic DMARD therapy (PENGUIN 1). ClinicalTrials.gov identifier: NCT04115748. June 25, 2020. Accessed July 28, 2020. https://clinicaltrials.gov/ct2/show/NCT04115748

43. A study to evaluate the pharmacokinetics, safety and tolerability of ABBV-157 in healthy volunteers and in participants with chronic plaque psoriasis. ClinicalTrials.gov identifier: NCT03922607. July 1, 2020. Accessed July 28, 2020. https://clinicaltrials.gov/ct2/show/NCT03922607

44. A study to test how well patients with plaque psoriasis tolerate BI 730357 over a longer period and how effective it is. ClinicalTrials.gov identifier: NCT03835481. July 17, 2020. Accessed July 28, 2020. https://clinicaltrials.gov/ct2/show/NCT03835481

45. A study to evaluate safety and efficacy of PF-06826647 for moderate to severe plaque psoriasis. ClinicalTrials.gov identifier: NCT03895372. June 4, 2020. Accessed July 28, 2020. https://clinicaltrials.gov/ct2/show/NCT03895372

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