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Biological Therapies in Psoriasis - Revisited

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Biological Therapies in Psoriasis - Revisited REVIEW Biological therapies in psoriasis - revisited MARIA-ISABELA SÂRBU1, SIMONA-ROXANA GEORGESCU1,2, MIRCEA TAMPA1,2, ALEXANDRA-ELENA SÂRBU3, OLGA SIMIONESCU1,4 1“Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania 2“Victor Babeş” Hospital of Infectious and Tropical Diseases, Dermatology Department, Bucharest, Romania 3“Hexamed” Clinic, Ophthalmology Department, Bucharest, Romania 4“Colentina” Clinical Hospital, Dermatology Department I, Bucharest, Romania Psoriasis is a chronic, immune mediated disorder affecting approximately 2% of the population. Even in our days, patients with psoriasis are confronted with stigmatization and social rejection. As a result, their quality of life is significantly impaired. Biological therapies have revolutionized the treatment of moderate to severe psoriasis. The aim of this paper is to look over the most important biological therapies available for the management of plaque-type psoriasis. Key words: psoriasis, biological therapies, TNF-α, IL-17, anti-IL-12/23. INTRODUCTION matory cells in the psoriatic plaque by inducing adhesion molecules on vascular endothelial cells. It Psoriasis is a chronic, immune-mediated skin also stimulates keratinocytes production and activates disorder with a worldwide occurrence, affecting macrophages and dendritic cells. Other cells also approximately 2% of the population. It has a polygenic produce cytokines with an important role in the predisposition. Environmental factors like trauma, pathogenesis of psoriasis. Therefore, keratinocytes infections or medications can trigger the eruption produce IL-8, IL-12, IL-15, IL-18 and TNFα while of psoriasis. It is clinically characterized by ery- dendritic cells produce IFNα, TNFα, IL-20 and IL-23. thematous, well demarcated plaques covered by The interaction of all these cytokines is believed to silvery-white scales, most often affecting the extensor determine the appearance of the psoriatic plaque [1, 4]. areas of the extremities, the scalp and the lower The burden of disease is significant in patients lumbosacral area. However, any area can be involved. with psoriasis. Even in our days, patients with The disease can occur at any age but two peaks in psoriasis are confronted with stigmatization and age of onset were recognised: one between 20 and social rejection. The incidence of mood disorders 30 years and the second between 50 and 60 years. like depression and anxiety in those patients is higher Almost 90% of patients have plaque-type psoriasis than in general population. The quality of life is [1-3]. also significantly impaired due to the constant need The pathogenesis of psoriasis is not completely of treatment, hospitalizations, missed work days, understood. It was initially considered an epidermal itching and interference with daily activities, among disease and several mediators like cyclic AMP, others [6-9]. protein kinase C, phospholipase C, eicosanoids, The treatment of psoriasis has evolved a lot transforming growth factor-α (TGF-α) were in- over the years. In 1500 BC, before psoriasis was criminated. In recent years however it has been recognized as a separate entity, cat and dog’s dung, regarded as a T-cell driven disease and the role of mixtures of onions, salt and urine or wasp’s dung lymphocytes and cytokines was intensely studied in milk of sycamore were considered appropriate th [4, 5]. Th1 cells produce IFNγ, TNFα and TNFβ treatments for skin disorders. In the 19 century while Th17 cells produce IL-17, IL-21 and IL-22. psoriasis was treated with arsenic, mercury, alkaline IL-17 has an important role in neutrophil chemotaxis salts, phosphorus, thyroid extracts and salicylates and angiogenesis while IL-22 determines hyper- [10]. In our days patients with psoriasis have proliferation of keratinocytes. IFNγ increases the several treatment options for topical or systemic production of IL-23 in dendritic cells which expands use. Conventional treatments for psoriasis include Th17 and Th22 cells. TNFα is a pro-inflammatory topical corticosteroids, topical retinoids, vitamin D cytokine which facilitates the entry of inflam- analogs, dithranol, tars, salicylic acid, phototherapy, ROM. J. INTERN. MED., 2018, 56, 2, 75–84 DOI: 10.1515/rjim-2017-0045 76 Maria-Isabela Sârbu et al. 2 methotrexate, acitretin and cyclosporine A. Non- BIOLOGICAL THERAPIES compliance to therapy is however often encountered because of the messiness associated with applying Biological therapies revolutionized the treatment topical treatments, the limited efficacy of all agents of plaque psoriasis. Advances in molecular and the high rate of adverse events. Under those technology as well as a better understanding of the circumstances, the identification of new therapies pathogenic mechanisms in psoriasis allowed the for psoriasis was of utmost importance [11]. development of more targeted treatments (Table 1). Table 1 Biological agents for psoriasis [1, 12, 27, 46, 49, 53, 64] Class Drug Target Administration Dosing regimen in psoriasis 15 mg/week for 12 weeks. Alefacept (Amevive®) CD2 receptor on T cells i.m 12 weeks pause. Multiple T-cell modulators 12 weeks courses are possible Efalizumab CD11a subunit of LFA1 s.c 1 mg/kg weekly. (Raptiva®) Etanercept TNF-α s.c 25 mg or 50 mg twice weekly (Enbrel®) 80 mg loading dose followed TNF antagonists Adalimumab (Humira®) TNF-α s.c by 40 mg every 2 weeks Infliximab 5 mg/kg at weeks 0, 2, 6 and TNF-α i.v (Remicade®) every 8 weeks thereafter 45 mg for patients who weigh< 100 kg and 90 mg for Ustekinumab P40 subunit of IL12 and IL23 s.c patients who weigh > 100 kg (Stelara®) at weeks 0, 4 and every 12 weeks thereafter Anti-IL biologic agents Sekukinumab 300 mg at weeks 0, 1, 2, 3, 4 IL17A s.c (Cosentyx®) and every 4 weeks thereafter 160 mg at week 0; 80 mg at Ixekizumab IL-17A s.c weeks 2, 4, 6, 8, 10, 12 and (Taltz®) 80 mg every 4 weeks thereafter. Tofacitinib Under investigation for JAK kinase inhibitors JAK 1 and JAK 3 inhibitor oral (Xeljanz®/Jakvinus) psoriasis Phosphodiesterase Apremilast PDE4 oral 30 mg/week inhibitors (Otezla®) Abbreviations: TNF – tumor necrosis factor; LFA – Lymphocyte function-associated antigen; SRCR-D1 – scavenger receptor cysteine-rich domain 1; JAK – Janus kinase; IL – interleukin; PDE4 – Phosphodiesterase 4; i.m – intramuscular; i.v – intravenous; s.c – subcutaneous. T cell modulators apoptosis in memory T cells by binding of the IgG1 portion to the CD 16 receptor of NK cells [1, Alefacept 11, 13-15]. Alefacept was the first targeted immune Alefacept is administered at doses of 15 mg modulator specifically designed for the treatment intramuscularly once weekly for 12 weeks followed of chronic plaque psoriasis. It was approved by the by a 12 weeks period without treatment. Multiple Food and Drug Administration (FDA) in 2003 for 12 weeks courses are possible in responders. Studies moderate to severe plaque psoriasis. In Europe, it showed that alefacept was superior to placebo in was approved only in Switzerland in 2004. psoriasis patients. PASI 75 was obtained in ap- Alefacept is a human fusion protein composed proximately 30% of patients after one course of of the extracellular CD2-binding portion of the treatment with alefacept. In the 12 weeks follow-up human leukocyte function antigen-3 (LFA-3) and period 71% of patients maintained at least PASI 50. the Fc portion of human IgG1 [2, 11, 12]. It Multiple courses of treatment are associated with inhibits T cell activation by binding to the CD2 better results [2, 16-18]. receptor on T lymphocytes and blocking the inter- Studies showed that Alefacept is generally action between LFA-3 expressed on antigen presenting safe and well tolerated. The most frequent side cells and CD2 expressed on T cells. It also induces effects are mild headache and injection site inflam- 3 Biological therapies in psoriasis 77 mation and pain. Increased transaminase levels and TNF-α antagonists hepatitis were rarely reported. Anti-alefacept anti- bodies are present in up to 4% of patients but they Etanercept are non-neutralizing and were not correlated with Etanercept is a fully human soluble dimeric adverse reactions [17, 18]. fusion protein consisting of the extracellular domain In 2011 the promotion and distribution of of the TNF-α receptor linked to the constant region alefacept was stopped. This event was not related (Fc) of human IgG1. Etanercept prevents the inter- to any safety concerns [15]. action between TNF-α and its cell surface receptors and therefore inhibits its activity. It was approved Efalizumab in 2004 for the treatment of moderate to severe Efalizumab is a recombinant humanized mono- psoriasis in patients who have not responded to clonal IgG1 antibody directed against CD11a, the conventional systemic therapies or who have contra- alpha subunit of the leukocyte function associated indications or do not tolerate those [1, 2, 11, 24]. antigen-1 (LFA-1). LFA-1 interacts with intercellular Etanercept is administered subcutaneously at adhesion molecule-1 (ICAM-1) located on antigen a dose of 25 mg twice weekly or 50 mg twice presenting cells and endothelial cells thus promoting weekly for 12 weeks. The maintenance dose is T-cell activation and migration to the skin. Efalizumab 50 mg weekly or 50 mg twice weekly [2, 11]. therefore prevents T cell activation and migration Leonardi et al. performed a study on 672 patients to activation sites which are important steps in the with chronic plaque psoriasis to evaluate the safety pathogenesis of psoriasis [2, 11, 12, 19]. and efficacy of different regimens
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