Emerging Therapeutic Options in the Treatment of Moderate to Severe Plaque Psoriasis
Psoriasis is a very common, chronic and recurrent, inflammatory systemic disease, which affects the skin and/or joints. It has several clinical variants, but plaque psoriasis is the most common and around 20% of patients have a moderate to severe form. With conventional treatment some patients experience an absence or loss of efficacy, side effects or inadequate response, so with the increasing knowledge on the pathophysiology of psoriasis, drugs with more specific targets have been developed in recent decades. The objective of this paper is to present new treatment options for moderate to severe plaque psoriasis in adults. A literature review was carried out on PubMed database and ClinicalTrials.gov for information on approved drugs, as well as on the results of clinical trials of emerging systemic therapies and currently in phase III. TNF-α inhibitors, a pioneering class of biologicals approved for psoriasis have been used successfully for several years. However, they also have limitations and, therefore, clinical research has been carried out focused on the search for new therapeutic targets. The discovery of participation of IL-23/ Th17 pathway in psoriasis oriented the development of novel immunomodulatory drugs, with encouraging results that validate the pro-inflammatory role of this pathway in the disease. Also, new orally available ‘small molecules’ are in development for the treatment of psoriasis. In practice, there isn’t a single most correct treatment for all patients with moderate to severe plaque psoriasis, in terms of efficacy, safety, dosing regimen and route of administration. Although new drugs have a long way to go before their approval, they represent a promise of more targeted, effective and safe treatment, with less interference with other biological functions and better control of the disease.
Parisi R, Symmons DP, Griffiths CE, Ashcroft DM. Global epidemiology of psoriasis: a systematic review of incidence and prevalence. J Invest Dermatol. 2013; 133:377-85.
Christophers E. Psoriasis — epidemiology and clinical spectrum. Clin Exp Dermatol. 2001; 26:314-20.
Nestle FO, Kaplan DH, Barker J. Psoriasis. N Engl J Med. 2009; 36:496-509.
Pearce DJ, Morrison AE, Higgins KB, Crane MM, Balkrishnan R, Fleischer AB Jr., et al. The comorbid state of psoriasis patients in a university dermatology practice. J Dermatolog Treat. 2005; 16:319-23.
Gelfand JM, Neimann AL, Shin DB, Wang X, Margolis DJ, Troxel AB. Risk of myocardial infarction in patients with psoriasis. JAMA. 2006; 296:1735-41.
Horreau C, Pouplard C, Brenaut E, Barnetche T, Misery L, Cribier B, et al. Cardiovascular morbidity and mortality in psoriasis and psoriatic arthritis: a systematic literature review. J Eur Acad Dermatol Venereol. 2013;27:12-29.
Prey S, Paul C, Bronsard V, Puzenat E, Gourraud P-A, Aractingi S, et al. Cardiovascular risk factors in patients with plaque psoriasis: a systematic review of epidemiological studies. J Eur Acad Dermatol Venereol. 2010;24:23-30.
Bernstein CN, Wajda A, Blanchard JF. The clustering of other chronic inflammatory diseases in inflammatory bowel disease: a population-based study. Gastroenterology. 2005; 129:827-36.
Wu JJ, Nguyen TU, Poon KY, Herrinton LJ. The association of psoriasis with autoimmune diseases. J Am Acad Dermatol. 2012; 67:924-30.
Feldman SR, Zhao Y, Shi L, Tran ME. Economic and comorbidity burden among patients with moderate-to-severe psoriasis. J Mang Care Spec Pharm. 2015;
Nast A, Gisondi P, Ormerod AD, Saiag P, Smith C, Spuls PI, et al. EuropeanS3-Guidelines on the systemic treatment of psoriasis vulgaris - Update 2015 - Short version - EDF in cooperation with EADV and IPC. J Eur Acad Dermatol Venereol. 2015; 29:2277-94.
Menter A, Gottlieb A, Feldman SR, Van Voorhees AS, Leonardi CL, Gordon KB, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis. Section 1: Overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics. J Am Acad Dermatol. 2008; 58:826-50.
Menter A, Griffiths CE. Current and future management of psoriasis. Lancet. 2007; 370:272-84.
Sandoval LF, Pierce A, Feldman SR. Systemic therapies for psoriasis: an evidence-based update. Am J Clin Dermatol. 2014; 15:165-80.
Nestle FO, Conrad C, Tun-Kyi A, Homey B, Gombert M, Boyman O, et al. Plasmacytoid predendritic cells initiate psoriasis through interferon-alpha production. J Exp Med. 2005; 202:135-43.
Farkas A, Kemény L. Interferon-α in the generation of monocyte-derived dendritic cells: recent advances and implications for dermatology. Br J Dermatol. 2011; 165(2):247-54.
Zaba LC, Krueger JG, Lowes MA. Resident and "inflammatory" dendritic cells in human skin. J Invest Dermatol. 2009; 129:302-08.
Nograles KE, Krueger JG. Anti-cytokine therapies for psoriasis. Exp Cell Res. 2011; 317:1293-300.
Resumo das Características do Medicamento: Etanercept. Disponível em: http://www.ema.europa.eu/docs/pt_PT/document_library/EPAR_-_Product_Information/human/000262/WC500027361.pdf
Resumo das Características do Medicamento: Infliximab. Disponível em: http://www.ema.europa.eu/docs/pt_PT/document_library/EPAR_-_Product_Information/human/000240/WC500050888.pdf
Resumo das Características do Medicamento: Adalimumab. Disponível em: http://www.ema.europa.eu/docs/pt_PT/document_library/EPAR_-_Product_Information/human/000481/WC500050870.pdf
Blauvelt A. T-helper 17 cells in psoriatic plaques and additional genetic links between IL-23 and psoriasis. J Invest Dermatol. 2008; 128:1064-7.
Ghoreschi K, Laurence A, Yang XP, Tato CM, McGeachy MJ, Konkel JE, et al. Generation of pathogenic T(H)17 cells in the absence of TGF-beta signalling. Nature. 2010; 467:967-71.
Kagami S, Rizzo HL, Lee JJ, Koguchi Y, Blauvelt A. Circulating Th17, Th22, and Th1 cells are increased in psoriasis. The Journal of Investigative Dermatology. 2010; 130: 1373-83.
Mudigonda P, Mudigonda T, Feneran AN, Alamdari HS, Sandoval L, Feldman SR. Interleukin-23 and interleukin- 17: importance in pathogenesis and therapy of psoriasis. Dermatol. Online J. 2012; 18:1.
Resumo das Características do Medicamento: Ustekinumab. http://www.ema.europa.eu/docs/pt_PT/document_library/EPAR_-_Product_Information/human/000958/WC500058513.pdf
Lee E, Trepicchio WL, Oestreicher JL, Pittman D, Wang F, Chamian F, et al. Increased expression of interleukin 23 p19 and p40 in lesional skin of patients with psoriasis vulgaris. J Exp Med. 2004; 199:125-30.
Yilmaz SB, Cicek N, Coskun M, Yegin O, Alpsoy E. Serum and tissue levels of IL-17 in different clinical subtypes of psoriasis. Arch Dermatol Res. 2012; 304: 465-9.
Wang F, Lee E, Lowes MA, Haider AS, Fuentes-Duculan J, Abello MV,et al. Prominent production of IL-20 by CD68+/CD11c+ myeloid-derived cells in psoriasis: gene regulation and cellular effects. J Invest Dermatol. 2006; 126:1590-9.
Volpe E, Servant N, Zollinger R, Bogiatzi SI, Hupé P, Barillot E, et al. critical function for transforming growth factor-beta, interleukin 23 and proinflammatory cytokines in driving and modulating human T(H)-17 responses. Nat Immunol. 2008; 9:650-7.
Chiricozzi A, Guttman-Yassky E, Suarez-Farinas M, Nograles KE, Tian S, Cardinale I, et al. Integrative responses to IL-17 and TNF-alpha in human keratinocytes account for key inflammatory pathogenic circuits in psoriasis. J Invest Dermatol. 2011; 131:677-87.
Martin DA, Towne JE, Kricorian G, Klekotka P, Gudjonsson JE, Krueger JG, et al. The emerging role of IL-17 in the pathogenesis of psoriasis: preclinical and clinical findings. J Invest Dermatol. 2013; 133:17-26.
Di Cesare A, Di Meglio P, Nestle FO. The IL-23/Th17 axis in the immunopathogenesis of psoriasis. J Invest Dermatol. 2009; 129:1339-50.
Gaffen S, Kramer JM, Yu JJ, Shen F. The IL-17 cytokine family. Vitam Horm. 2006; 74:255-82.
Gaffen SL. Structure and signalling in the IL-17 receptor family. Nat Rev Immunol. 2009; 9:556-67.
Lynde CW, Poulin Y, Vender R, Bourcier M, Khalil S. Interleukin 17A: toward a new understanding of psoriasis pathogenesis. J Am Acad Dermatol. 2014; 71:141-50.
Lin AM, Rubin CJ, Khandpur R, Wang JY, Riblett M, Yalavarthi S, et al. Mast cells and neutrophils release IL-17 through extracellular trap formation in psoriasis. J Immunol. 2011; 187:490-500.
Liang SC, Tan XY, Luxenberg DP, Karim R, Dunussi-Joannopoulos K, Collins M, et al. Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J Exp Med. 2006; 203: 2271-9.
Nograles KE, Zaba LC, Guttman-Yassky E, Fuentes-Duculan J, Suarez-Farinas M, Cardinale I, et al. Th17 cytokines interleukin IL-17 and IL-22 modulate distinct
inflammatory and keratinocyte-response pathways. Br J Dermatol. 2008; 159:1092-02.
Shi X, Jin L, Dang E, Chang T, Feng Z, Liu Y, et al. IL-17A upregulates keratin 17 expression in keratinocytes through STAT1-and STAT3-dependent mechanisms. J Invest Dermatol. 2011; 131:2401-08.
Houslay MD, Schafer P, Zhang KY. Keynote review: phosphodiesterase-4 as a therapeutic target. Drug Discov Today. 2005; 10:1503-19.
Gooderham M. Small molecules: an overview of emerging therapeutic options in the treatment of psoriasis. Skin Therapy Lett. 2013; 18:1-4.
Hald A, Andres RM, Salskov-Iversen ML, Kjellerup RB, Iversen L, Johansen C. STAT1 expression and activation is increased in lesional psoriatic skin. Br J Dermatol. 2013; 168:302-10.
Andres RM, Hald A, Johansen C, Kragballe K, Iversen L. Studies of Jak/STAT3 expression and signalling in psoriasis identifies STAT3-Ser727 phosphorylation as a modulator of transcriptional activity. Exp Dermatol. 2013; 22:323-8.
Müller CE, Jacobson KA. Recent developments in adenosine receptor ligands and their potential as novel drugs. Biochim Biophys Acta. 2011; 1808:1290-308.
Ellis CN, Krueger GG. Treatment of chronic plaque psoriasis by selective targeting of memory effector T lymphocytes. N Engl J Med. 2001; 345:248-55.
Chamian F, Lowes MA, Lin SL, Lee E, Kikuchi T, Gilleaudeau P, et al. Alefacept reduces infiltrating T cells, activated dendritic cells, and inflammatory genes in psoriasis vulgaris. Proc Natl Acad Sci USA. 2005; 102, 2075-80.
Guttman-Yassky E, Vugmeyster Y, Lowes MA, Chamian F, Kikuchi T, Kagen M, et al. Blockade of CD11a by efalizumab in psoriasis patients induces a unique state of Tcell hyporesponsiveness. J Invest Dermatol. 2008;128:1182-91.
Gottlieb A, Korman NJ, Gordon KB, Feldman SR, Lebwohl M, Koo JY, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis. Section 2: Psoriatic arthritis: Overview and guidelines of care for treatment with an emphasis on the biologics. J Am Acad Dermatol. 2008; 58:851-64.
Sicotte NL, Voskuhl RR. Onset of multiple sclerosis associated with antiTNF therapy. Neurology. 2001; 57:1885-8.
Kwon HJ, Coté TR, Cuffe MS, Kramer JM, Braun MM. Case reports of heart failure after therapy with a tumor necrosis factor antagonist. Ann Intern Med. 2003; 138:807-11.
Mohan VP, Scanga CA, Yu K, Scott HM, Tanaka KE, Tsang E, et al. Effects of tumor necrosis factor alpha on host immune response in chronic persistent tuberculosis: possible role for limiting pathology. Infect Immun. 2001; 69:1847-55.
Wallis RS, Broder MS, Wong JY, Hanson ME, Beenhouwer DO. Granulomatous infectious diseases associated with tumor necrosis factor antagonists. Clin Infect Dis. 2004; 38:1261-65.
Doherty SD, Van Voorhees A, Lebwohl MG, Korman NJ, Young MS, Hsu S, et al. National Psoriasis Foundation consensus statement on screening for latent tuberculosis infection in patients with psoriasis treated with systemic and biologic agents. J Am Acad Dermatol. 2008; 59:209-17.
Marques Pinto G, Filipe P. Recommendations for high-quality use of biologic therapies in adults with plaque psoriasis. Acta Méd Port. 2012; 25:125-41.
Reich K, Ortonne JP, Gottlieb AB, Terpstra IJ, Coteur G, Tasset C, et al. Successful treatment of moderate to severe plaque psoriasis with the PEGylated Fab' certolizumab pegol: Results of a phase II randomized, placebo-controlled
trial with a re-treatment extension. Br J Dermatol. 2012; 167: 180-90.
ClinicalTrials.govUS National Institutes of Health [consultado em Dezembro 2015]. Disponível em: https://clinicaltrials.gov/ct2/show/NCT02326298?term=CIMPASI&rank=1.
ClinicalTrials.govUS National Institutes of Health [consultado em Dezembro 2015]. Disponível em: https://clinicaltrials.gov/ct2/show/NCT02326272?term=CIMPASI&rank=2.
ClinicalTrials.govUS National Institutes of Health [consultado em Dezembro 2015]. Disponível em: https://clinicaltrials.gov/ct2/show/NCT02346240?term=CIMPACT&rank=2.
Carvalho S, Torres T, Selores M. Tratamento da psoríase com agentes biológicos: para além dos inibidores do TNF α – O Presente e o Futuro. Rev Soc Port Dermatol Venereol. 2012; 70: 299-310.
Papp K, Thaçi D, Reich K, Riedl E, Langley RG, Krueger JG, et al. Tildrakizumab (MK-3222), an AntiIL-23p19 Monoclonal Antibody, Improves Psoriasis in a Phase 2b Randomized Placebo Controlled Trial. Br J Dermatolog.
ClinicalTrials.gov US National Institutes of Health [consultado em Dezembro 2015]. Disponível em: https://clinicaltrials.gov/ct2/show/NCT01722331?term=TILDRAKIZUMAB&rank=3.
ClinicalTrials.gov US National Institutes of Health [consultado em Dezembro 2015]. Disponível em: https://clinicaltrials.gov/ct2/show/NCT01729754?term=TILDRAKIZUMAB&rank=1.
Gordon KB, Duffin KC, Bissonnette R, Prinz JC, Wasfi Y, Li S, et al. A Phase 2 Trial of Guselkumab versus Adalimumab for Plaque Psoriasis. N Engl J Med. 2015;
ClinicalTrials.gov US National Institutes of Health [consultado em Dezembro 2015]. Disponível em: http://clinicaltrials.gov/ct2/show/NCT02207244?term=CNTO1959&rank=8.
ClinicalTrials.gov US National Institutes of Health [consultado em Dezembro 2015]. Disponível em: http://clinicaltrials.gov/ct2/show/NCT02207231?term=CNTO1959&rank=7.
ClinicalTrials.gov US National Institutes of Health [consultado em Dezembro 2015]. Disponível em: http://clinicaltrials.gov/ct2/show/NCT02203032?term=CNTO1959&rank=9.
Krueger JG, Ferris LK, Menter A, Wagner F, White A, Visvanathan S, et al. Anti-IL-23A mAb BI 655066 for treatment of moderate-to-severe psoriasis: Safety, efficacy, pharmacokinetics, and biomarker results of a single-rising-
dose, randomized, double-blind, placebo-controlled trial. J Allergy Clin Immunol. 2015; 136:116-24.
K Papp. Onset and duration of clinical response following treatment with a selective IL-23p19 inhibitor (BI 655066) compared with ustekinumab in patients with moderate-to-severe chronic plaque psoriasis. Presentation at: 24th
European Academy of Dermatology and Venereology (EADV) congress; 2015; Copenhagen, Denmark. [consultado em Março 2016]. Disponível em: http://www.
Boehringer-Ingelheim] [consultado em Março 2016]. Disponível em: https://www.boehringer-ingelheim.com/research-development/research-development/pipeline.
Chiricozzi A, Krueger JG. IL-17 targeted therapies for psoriasis. Expert Opin Investig Drugs. 2013; 22:993-05.
Huppler AR, Bishu S, Gaffen SL. Mucocutaneous candidiasis: the IL-17 pathway and implications for targeted immunotherapy. Arthritis Res Ther. 2012; 14:217.
Resumo das Características do Medicamento: Secukinumab. http://passthrough.fw-notify.net/download/709 867/http://ec.europa.eu/health/documents/community- register/2015/20150115130444/anx_130444_pt.pdf.
Langley R, Elewski B, Lebwohl M, Reich K, Griffiths C, Papp K, et al. Secukinumab in plaque psoriasis – results of two phase 3 trials. N Engl J Med. 2014; 371:326-38.
Reich K, Puig L, Draelos Z, Notter M, Papavassilis C. Sustainability of response with secukinumab to 52 weeks in moderate-to-severe plaque psoriasis: data from the full year investigative examination of secukinumab vs etanercept using 2 dosing regimens to determine efficacy in psoriasis (FIXTURE) study. Abstract/Program number 8101; Presented at the American Academy of
Dermatology. 2014; 21-5.
Resumo das Características do Medicamento: Ixekizumab. http://passthrough.fw-notify.net/download/744806/ http://ec.europa.eu/health/documents/community-register/
Gordon K, Blauvelt A, Langley R. Ixekizumab for treatment of moderate-to-severe plaque psoriasis: 60-week results from a double-blind phase 3 induction and randomized withdrawal study (UNCOVER-1). Abstract presented at: American Academy of Dermatology 73rd Annual Meeting; 2015; SanFrancisco. [consultado em Dezembro 2015]. Disponível em: https://www.aad.org/
Griffiths CE, Reich K, Lebwohl M, van de Kerkhof P, Paul C, Menter A, et al. Comparison of ixekizumab with etanercept or placebo in moderate-to-severe psoriasis (UNCOVER-2 and UNCOVER-3): results from two phase 3 randomised trials. Lancet. 2015; 386: 541-51.
Lebwohl M, Strober B, Menter A, Gordon K, Weglowska J, Puig L, et al. Phase 3 studies comparing brodalumab with ustekinumab in psoriasis. N Engl J Med. 2015; 373: 1318-28.
AstraZeneca [consultado em Março 2016]. Disponível em: https://www.astrazeneca.com/media-centre/press-
Shutty B, West C, Pellerin M, Feldman S. Apremilast as a treatment for psoriasis. Expert Opin Pharmacother. 2012; 13:1761-70.
Resumo das Características do Medicamento: Apremilast. http://ec.europa.eu/health/documents/community-
Papp K, Reich K, Leonardi CL, Kircik L, Chimenti S, Langley RG, et al. Apremilast, an oral phosphodiesterase 4 (PDE4) inhibitor, in patients with moderate to severe plaque psoriasis: Results of a phase III, randomized,
controlled trial (Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis [ESTEEM] 1). J Am Acad Dermatol 2015; 73:37-49.
Paul C, Cather J, Gooderham M, Poulin Y, Mrowietz U, Ferrandiz C, et al. Efficacy and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with moderate-to-severe plaque psoriasis over 52 weeks: a phase III, randomized controlled trial (ESTEEM 2). Br J Dermatol. 2015; 173:1387-99.
Ghoreschi K, Gadina M. Jakpot! New small molecules in autoimmune and inflammatory diseases. Exp Dermatol. 2014; 23:7-11.
Menter A, Papp KA, Tan H, Tyring S, Wolk R, Buonanno M. Efficacy of tofacitinib, an oral janus kinase inhibitor, on clinical signs of moderate-to-severe plaque psoriasis in different body regions. J Drugs Dermatol. 2014;13:252-6.
Papp KA, Menter MA, Abe M, Elewski B, Feldman SR, Gottlieb AB, et al. Tofacitinib, an oral Janus kinase inhibitor, for the treatment of chronic plaque psoriasis: results from two randomized, placebo-controlled, phase III trials. Br J Dermatol. 2015; 173:949-61.
Bachelez H, van de Kerkhof PC, Strohal R, Kubanov A, Valenzuela F, Lee JH, et al. Tofacitinib versus etanercept or placebo in moderate-to-severe chronic plaque psoriasis: A phase 3 randomised non-inferiority trial. Lancet. 2015; 386: 552-61.
Strober B, Buonanno M, Clark JD, Kawabata T, Tan H, Wolk R, et al. Effect of tofacitinib, a Janus kinase inhibitor, on haematological parameters during 12 weeks of psoriasis treatment. Br J Dermatol. 2013; 169:992-9.
David M, Akerman L, Ziv M, Kadurina M, Gospodinov D, Pavlotsky F, et al. Treatment of plaque-type psoriasis with oral CF101: data from an exploratory randomized phase 2 clinical trial. J Eur Acad Dermatol Venereol. 2012; 26:361-7.
PR Newswire [consultado em Novembro 2015]. Disponível em: http://www.prnewswire.com/news-releases/
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