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      Targeting p19 as a treatment option for psoriasis: an evidence-based review of guselkumab

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          Abstract

          Further understanding of psoriasis pathogenesis has led to the development of effective biologic medications. Guselkumab (GUS) is a subcutaneously administered monoclonal antibody that targets the p19 cytokine subunit in IL-23 and IL-39 and is US Food and Drug Administration (FDA) approved for the treatment of moderate-to-severe psoriasis in adult patients. This review evaluates the pharmacology, safety and efficacy of GUS in patients with psoriasis. We performed a literature review by searching online databases including PubMed and Google Scholar. In clinical trials, GUS improved diseases including psoriatic arthritis (PsA) and specific areas of disease (scalp, feet, hands and fingernails). In the Phase III trials VOYAGE 1 and 2, more GUS than adalimumab (ADM) patients experienced a ≥90% reduction in Psoriasis Area and Severity Index (PASI) score (PASI90) (VOYAGE 1: 80.2% vs 53.0%; VOYAGE 2: 75.2% vs 54.8%; P<0.001 for both) and Investigator Global Assessment score of 0 or 1 (VOYAGE 1: 84.2% vs 61.7%; VOAYGE 2: 83.5% vs 64.9%; P<0.001 for both) at Week 24. GUS was also successful in treating patients unresponsive to ADM and ustekinumab in the VOYAGE 2 and NAVIGATE trials, respectively. While long-term data are necessary, GUS appears to have a favorable side effect profile with most common adverse effects including nasopharyngitis and upper respiratory tract infections. GUS is a well-tolerated and effective medication for patients with psoriasis. Continued study of GUS and the p19 subunit will help to determine GUS’s ultimate place in therapy.

          Most cited references31

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          Ustekinumab induction and maintenance therapy in refractory Crohn's disease.

          In patients with Crohn's disease, the efficacy of ustekinumab, a human monoclonal antibody against interleukin-12 and interleukin-23, is unknown. We evaluated ustekinumab in adults with moderate-to-severe Crohn's disease that was resistant to anti-tumor necrosis factor (TNF) treatment. During induction, 526 patients were randomly assigned to receive intravenous ustekinumab (at a dose of 1, 3, or 6 mg per kilogram of body weight) or placebo at week 0. During the maintenance phase, 145 patients who had a response to ustekinumab at 6 weeks underwent a second randomization to receive subcutaneous injections of ustekinumab (90 mg) or placebo at weeks 8 and 16. The primary end point was a clinical response at 6 weeks. The proportions of patients who reached the primary end point were 36.6%, 34.1%, and 39.7% for 1, 3, and 6 mg of ustekinumab per kilogram, respectively, as compared with 23.5% for placebo (P=0.005 for the comparison with the 6-mg group). The rate of clinical remission with the 6-mg dose did not differ significantly from the rate with placebo at 6 weeks. Maintenance therapy with ustekinumab, as compared with placebo, resulted in significantly increased rates of clinical remission (41.7% vs. 27.4%, P=0.03) and response (69.4% vs. 42.5%, P<0.001) at 22 weeks. Serious infections occurred in 7 patients (6 receiving ustekinumab) during induction and 11 patients (4 receiving ustekinumab) during maintenance. Basal-cell carcinoma developed in 1 patient receiving ustekinumab. Patients with moderate-to-severe Crohn's disease that was resistant to TNF antagonists had an increased rate of response to induction with ustekinumab, as compared with placebo. Patients with an initial response to ustekinumab had significantly increased rates of response and remission with ustekinumab as maintenance therapy. (Funded by Janssen Research and Development; CERTIFI ClinicalTrials.gov number, NCT00771667.).
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            T(H)-17 cells in the circle of immunity and autoimmunity.

            CD4(+) effector T cells have been categorized into two subsets: T helper type 1 (T(H)1) and T(H)2. Another subset of T cells that produce interleukin 17 (IL-17; 'T(H)-17 cells') has been identified that is highly proinflammatory and induces severe autoimmunity. Whereas IL-23 serves to expand previously differentiated T(H)-17 cell populations, IL-6 and transforming growth factor-beta (TGF-beta) induce the differentiation of T(H)-17 cells from naive precursors. These data suggest a dichotomy between CD4(+) regulatory T cells positive for the transcription factor Foxp3 and T(H)-17 cells: TGF-beta induces Foxp3 and generates induced regulatory T cells, whereas IL-6 inhibits TGF-beta-driven Foxp3 expression and together with TGF-beta induces T(H)-17 cells. Emerging data regarding T(H)-17 cells suggest a very important function for this T cell subset in immunity and disease.
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              A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes.

              We performed a multitiered, case-control association study of psoriasis in three independent sample sets of white North American individuals (1,446 cases and 1,432 controls) with 25,215 genecentric single-nucleotide polymorphisms (SNPs) and found a highly significant association with an IL12B 3'-untranslated-region SNP (rs3212227), confirming the results of a small Japanese study. This SNP was significant in all three sample sets (odds ratio [OR](common) 0.64, combined P [Pcomb]=7.85x10(-10)). A Monte Carlo simulation to address multiple testing suggests that this association is not a type I error. The coding regions of IL12B were resequenced in 96 individuals with psoriasis, and 30 additional IL12B-region SNPs were genotyped. Haplotypes were estimated, and genotype-conditioned analyses identified a second risk allele (rs6887695) located approximately 60 kb upstream of the IL12B coding region that exhibited association with psoriasis after adjustment for rs3212227. Together, these two SNPs mark a common IL12B risk haplotype (OR(common) 1.40, Pcomb=8.11x10(-9)) and a less frequent protective haplotype (OR(common) 0.58, Pcomb=5.65x10(-12)), which were statistically significant in all three studies. Since IL12B encodes the common IL-12p40 subunit of IL-12 and IL-23, we individually genotyped 17 SNPs in the genes encoding the other chains of these cytokines (IL12A and IL23A) and their receptors (IL12RB1, IL12RB2, and IL23R). Haplotype analyses identified two IL23R missense SNPs that together mark a common psoriasis-associated haplotype in all three studies (OR(common) 1.44, Pcomb=3.13x10(-6)). Individuals homozygous for both the IL12B and the IL23R predisposing haplotypes have an increased risk of disease (OR(common) 1.66, Pcomb=1.33x10(-8)). These data, and the previous observation that administration of an antibody specific for the IL-12p40 subunit to patients with psoriasis is highly efficacious, suggest that these genes play a fundamental role in psoriasis pathogenesis.
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                Author and article information

                Journal
                Ther Clin Risk Manag
                Ther Clin Risk Manag
                Therapeutics and Clinical Risk Management
                Therapeutics and Clinical Risk Management
                Dove Medical Press
                1176-6336
                1178-203X
                2018
                22 August 2018
                : 14
                : 1489-1497
                Affiliations
                [1 ]Stony Brook Medicine, Stony Brook, NY, USA, todd.wechter@ 123456stonybrookmedicine.edu
                [2 ]Center for Dermatology Research, Department of Dermatology, Wake Forest School of Medicine, Winston-Salem, NC, USA
                [3 ]Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC, USA
                [4 ]Department of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA
                Author notes
                Correspondence: Todd Wechter, Stony Brook Medicine, 101 Nicolls Road, Stony Brook, NY 11794, USA, Tel +1 917 841 1097, Fax +1 631 444 9376, Email todd.wechter@ 123456stonybrookmedicine.edu
                Article
                tcrm-14-1489
                10.2147/TCRM.S177127
                6110646
                30174431
                118ddb6b-3d94-420e-937e-159fba106ea7
                © 2018 Wechter et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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                Medicine
                biologics,il-23,il-39,monoclonal antibody
                Medicine
                biologics, il-23, il-39, monoclonal antibody

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