Janus Kinase 1

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Christopher Banfield - One of the best experts on this subject based on the ideXlab platform.

  • Molecular and Cellular Responses to the TYK2/JAK1 Inhibitor, PF 06700841, Reveal Reduction of Skin Inflammation in Plaque Psoriasis: TYK2/JAK1 inhibitor in plaque psoriasis
    Journal of Investigative Dermatology, 2020
    Co-Authors: Karen Page, Elizabeth Kieras, Weidong Zhang, Mayte Suárez-fariñas, Maria Suprun, Sandra Garcet, Judilyn Fuentes-duculan, Xuan Li, Matthew Scaramozza, Christopher Banfield
    Abstract:

    The IL-23/T helper type 17 cell axis is a target for psoriasis. The TYK2/Janus Kinase 1 inhibitor PF-06700841 will directly suppress TYK2-dependent IL-12 and IL-23 signaling and Janus Kinase 1–dependent signaling in cells expressing these signaling molecules, including T cells and keratinocytes. This clinical study sought to define the inflammatory gene and cellular pathways through which PF-06700841 improves the clinical manifestations of psoriasis. Patients (n = 30) with moderate-to-severe psoriasis were randomized to once-daily 30 mg (n = 14) or 100 mg (n = 7) PF-06700841 or placebo (n = 9) for 28 days. Biopsies were taken from nonlesional and lesional skin at baseline and weeks 2 and 4. Changes in the psoriasis transcriptome and genes induced by IL-17 in keratinocytes were evaluated with microarray profiling and reverse transcriptase–PCR. Reductions in IL-17A, IL-17F, and IL-12B mRNA were observed as early as 2 weeks and approximately 70% normalization of lesional gene expression after 4 weeks. Immunohistochemistry showed significant decreases in markers of keratinocyte activation, epidermal thickness, KRT16 and Ki-67 expression, and immune cell infiltrates CD3+/CD8+ (T cells) and CD11c (dendritic cells) after 2 weeks of treatment, corresponding with improvement in histologic score. PF-06700841 improves clinical symptoms of chronic plaque psoriasis by inhibition of proinflammatory cytokines that require TYK2 and Janus Kinase 1 for signal transduction.

  • evaluation of a Janus Kinase 1 inhibitor pf 04965842 in healthy subjects a phase 1 randomized placebo controlled dose escalation study
    British Journal of Clinical Pharmacology, 2018
    Co-Authors: E Peeva, Martin R Hodge, Elizabeth Kieras, Michael L Vazquez, Kosalaram Goteti, Sanela Tarabar, Christine Alvey, Christopher Banfield
    Abstract:

    To determine the safety, tolerability, pharmacokinetics and pharmacodynamics of the Janus Kinase 1-selective inhibitor, PF-04965842.This was a phase 1, first-in-human, randomized, double-blind, placebo-controlled, combination single- and multiple-dose escalation, parallel design study in healthy subjects (http://clinicaltrials.gov, NCT01835197). Subjects received a single dose of placebo or 3, 10, 30, 100, 200, 400 or 800 mg PF-04965842 (single ascending dose phase) and placebo or 30 mg once daily (QD), 100 mg QD, 200 mg QD, 400 mg QD, 100 mg twice daily (BID) or 200 mg BID PF-04965842 for 10 consecutive days (multiple ascending dose phase). The primary objective was to determine the safety and tolerability of PF-04965842.Seventy-nine subjects were randomized and received study treatments. There were no deaths or serious adverse events. The most frequent treatment-emergent adverse events were headache (n = 13), diarrhoea (n = 11) and nausea (n = 11). PF-04965842 was absorbed rapidly (median time at which maximum plasma concentration occurred generally ≤1 h following either single- or multiple-dose administration) and eliminated rapidly (mean t½ 2.8-5.2 h after 10 days of QD or BID administration in the multiple ascending dose phase). Increases in maximum plasma concentration and area under the concentration-time curve were dose proportional up to 200 mg (single or total daily doses) with an apparent trend towards greater than proportional increases with higher doses. Less than 4.4% of the dose was recovered unchanged in urine. Changes in pharmacodynamic biomarkers were consistent with the known effects of Janus Kinase signalling inhibition.These results support further evaluation of PF-04965842 for clinical use in patients with inflammatory diseases.

  • efficacy and safety of the Janus Kinase 1 inhibitor pf 04965842 in patients with moderate to severe psoriasis phase ii randomized double blind placebo controlled study
    British Journal of Dermatology, 2018
    Co-Authors: G J Schmieder, Martin R Hodge, Elizabeth Kieras, Christopher Banfield, Z D Draelos, David M Pariser, D Parsonsrich, Sandeep Menon, M Salganik, Karen Page
    Abstract:

    Background PF-04965842 is an oral Janus Kinase 1 inhibitor being investigated for treatment of plaque psoriasis. Objectives To evaluate the efficacy, safety and tolerability of PF-04965842 in patients with moderate to severe plaque psoriasis. Methods Patients in this phase 2, placebo-controlled study (NCT02201524) were randomised to receive placebo, 200 mg once-daily (QD), 400 mg QD, or 200 mg twice-daily (BID) PF-04965842 for 4 weeks. The primary endpoint was change from baseline in Psoriasis Area Severity Index (PASI) at Week 4. Study enrolment was discontinued on 25 June 2015 due to changes in the sponsor's development priorities. Results Fifty-nine patients were randomised and received at least one dose of PF-04965842 or placebo. The estimated treatment effect (active-placebo PASI change from baseline) and 90% CI at Week 4 was –5·1 (–9·2, –1·0), –5·6 (–9·6, –1·6) and –10·0 (–14·2, –5·8) for the 200 mg QD, 400 mg QD and 200 mg BID groups, respectively. At Week 4, the proportion of patients achieving PASI75 was 17% for the placebo and 200 mg QD groups, 50% for the 400 mg QD group and 60% for the 200 mg BID group. There were more abnormal laboratory test results of clinical interest (low neutrophil, reticulocyte and platelet counts) in the 200 mg BID group vs the QD treatment groups. No serious infections or bleeding events related to neutropenia or thrombocytopenia, respectively, were reported. Conclusions These results suggest that treatment with PF-04965842 improves symptoms and is well tolerated in patients with moderate to severe psoriasis. This article is protected by copyright. All rights reserved.

Scott K Durum - One of the best experts on this subject based on the ideXlab platform.

  • inhibiting Janus Kinase 1 and bcl 2 to treat t cell acute lymphoblastic leukemia with il7 rα mutations
    Oncotarget, 2018
    Co-Authors: Emilee Senkevitch, Wenqing Li, Julie A Hixon, Caroline Andrews, Sarah D Cramer, Gary T Pauly, Timothy C Back, Kelli Czarra, Scott K Durum
    Abstract:

    // Emilee Senkevitch 1 , Wenqing Li 1 , Julie A. Hixon 1 , Caroline Andrews 1, 2, 3 , Sarah D. Cramer 1, 2, 4 , Gary T. Pauly 6 , Timothy Back 1 , Kelli Czarra 5 and Scott K. Durum 1 1 Cytokines and Immunity Section, Cancer and Inflammation Program, National Cancer Institute, National Institutes of Health, Frederick, MD, USA 2 Comparative Biomedical Scientist Training Program, NIH, Bethesda, MD, USA 3 Michigan State University, East Lansing, MI, USA 4 Department of Veterinary Medicine, University of Maryland, College Park, MD, USA 5 Laboratory Animal Sciences Program, Cancer and Inflammation Program, National Cancer Institute, National Institutes of Health, Frederick, MD, USA 6 Chemical Biology Laboratory, National Cancer Institute, National Institutes of Health, Frederick, MD, USA Correspondence to: Scott K. Durum, email: durums@mail.nih.gov Keywords: JAK1; BCL-2; T-ALL; ruxolitinib; venetoclax Received: June 23, 2017      Accepted: April 04, 2018      Published: April 27, 2018 ABSTRACT Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Current chemotherapy is quite toxic in growing children and more directed therapeutics are being sought. The IL-7R pathway is a major driver of ALL and here we evaluate two drugs directed to that pathway using a model of T cell ALL. Mutant gain-of-function IL-7Rα was transduced into an IL-7-dependent murine thymocyte line conferring ligand-independent survival and growth. JAK1 is associated with IL-7Rα and mediates signaling from the mutant receptor. In vitro , treating the transformed cell line with the JAK1/2 inhibitor ruxolitinib inhibited ligand-independent signaling and induced cell death. Transfer of the transformed cell line into mice resulted in aggressive leukemia and untreated mice succumbed in about three weeks. Treatment with ruxolitinib incorporated into chow showed a potent therapeutic benefit with reduction in leukemic burden and extension of survival. BCL-2 is an anti-apoptotic downstream mediator of the IL-7R survival mechanism. Venetoclax, an inhibitor of BCL-2, showed activity against the transformed cell line in vitro and could be combined with ruxolitinib in vivo . These findings support the therapeutic potential of treating T-ALL by targeting the IL-7R pathway.

  • interleukin il 7 induces rapid activation of pyk2 which is bound to Janus Kinase 1 and il 7rα
    Journal of Biological Chemistry, 2000
    Co-Authors: Naima Benbernou, Kathrin Muegge, Scott K Durum
    Abstract:

    Abstract Interleukin-7 (IL-7) receptor signaling begins with activation of the Janus tyrosine Kinases Jak1 and Jak3, which are associated with the receptor complex. To identify potential targets of these Kinases, we examined Pyk2 (a member of the focal adhesion Kinase family) using an IL-7-dependent murine thymocyte line, D1. We demonstrate that stimulation of D1 (or normal pro-T) cells by IL-7 rapidly increased tyrosine phosphorylation and enzymatic activity of Pyk2, with kinetics slightly lagging that of Jak1 and Jak3 phosphorylation. Conversely, IL-7 withdrawal resulted in a marked decrease of Pyk2 phosphorylation. Pyk2 was found to be physically associated with Jak1 prior to IL-7 stimulation and to increase its association with IL-7Rα chain following IL-7 stimulation. Pyk2 appeared to be involved in cell survival, because antisense Pyk2 accelerated the cell death process. Activation of Pyk2 via the muscarinic and nicotinic receptors using carbachol or via intracellular Ca2+ rise using ionomycin/phorbol myristate acetate promoted survival in the absence of IL-7. These data support a role for Pyk2 in coupling Jak signaling to the trophic response.

E Peeva - One of the best experts on this subject based on the ideXlab platform.

  • efficacy and safety of oral Janus Kinase 1 inhibitor abrocitinib for patients with atopic dermatitis a phase 2 randomized clinical trial
    JAMA Dermatology, 2019
    Co-Authors: Melinda Gooderham, Seth Forman, Robert Bissonnette, Jean Beebe, Weidong Zhang, Chris Banfield, J Papacharalambous, Michael Vincent, E Peeva
    Abstract:

    Importance Atopic dermatitis is associated with substantial patient and caregiver burden. Currently available treatments for atopic dermatitis are inadequate or contraindicated for some patients. Abrocitinib (PF-04965842) is an oral Janus Kinase 1 selective inhibitor under investigation for the treatment of atopic dermatitis. Objective To investigate the efficacy and safety of abrocitinib for patients with moderate to severe atopic dermatitis. Design, Setting, and Participants A phase 2b, randomized, double-blinded, placebo-controlled, parallel-group trial was conducted from April 15, 2016, to April 4, 2017, at 58 centers in Australia, Canada, Germany, Hungary, and the United States among 267 patients 18 to 75 years of age with a clinical diagnosis of moderate to severe atopic dermatitis for 1 year or more and inadequate response or contraindication to topical medications for 4 weeks or more within 12 months. Efficacy was assessed in the full analysis set, which was a modified intention-to-treat population that included all patients who received 1 dose or more of the study drug except for 4 patients from 1 site. Interventions Participants were randomly assigned 1:1:1:1:1 to receive abrocitinib (200 mg, 100 mg, 30 mg, or 10 mg) or placebo once daily for 12 weeks. Main Outcomes and Measures The primary outcome was the proportion of patients achieving an Investigator’s Global Assessment of clear (0) or almost clear (1) with an improvement from baseline of 2 grades or more at week 12. The secondary outcome was the percentage change from baseline in the Eczema Area and Severity Index at week 12. Results Of the 267 participants, 144 were women (mean [SD] age, 40.8 [16.1] years). At week 12, 21 of 48 patients receiving 200 mg of abrocitinib (43.8%;P  Conclusions and Relevance Once-daily oral abrocitinib was effective and well tolerated for short-term use in adults with moderate to severe atopic dermatitis. Additional trials are necessary to evaluate long-term efficacy and safety. Trial Registration ClinicalTrials.gov identifier:NCT02780167

  • evaluation of a Janus Kinase 1 inhibitor pf 04965842 in healthy subjects a phase 1 randomized placebo controlled dose escalation study
    British Journal of Clinical Pharmacology, 2018
    Co-Authors: E Peeva, Martin R Hodge, Elizabeth Kieras, Michael L Vazquez, Kosalaram Goteti, Sanela Tarabar, Christine Alvey, Christopher Banfield
    Abstract:

    To determine the safety, tolerability, pharmacokinetics and pharmacodynamics of the Janus Kinase 1-selective inhibitor, PF-04965842.This was a phase 1, first-in-human, randomized, double-blind, placebo-controlled, combination single- and multiple-dose escalation, parallel design study in healthy subjects (http://clinicaltrials.gov, NCT01835197). Subjects received a single dose of placebo or 3, 10, 30, 100, 200, 400 or 800 mg PF-04965842 (single ascending dose phase) and placebo or 30 mg once daily (QD), 100 mg QD, 200 mg QD, 400 mg QD, 100 mg twice daily (BID) or 200 mg BID PF-04965842 for 10 consecutive days (multiple ascending dose phase). The primary objective was to determine the safety and tolerability of PF-04965842.Seventy-nine subjects were randomized and received study treatments. There were no deaths or serious adverse events. The most frequent treatment-emergent adverse events were headache (n = 13), diarrhoea (n = 11) and nausea (n = 11). PF-04965842 was absorbed rapidly (median time at which maximum plasma concentration occurred generally ≤1 h following either single- or multiple-dose administration) and eliminated rapidly (mean t½ 2.8-5.2 h after 10 days of QD or BID administration in the multiple ascending dose phase). Increases in maximum plasma concentration and area under the concentration-time curve were dose proportional up to 200 mg (single or total daily doses) with an apparent trend towards greater than proportional increases with higher doses. Less than 4.4% of the dose was recovered unchanged in urine. Changes in pharmacodynamic biomarkers were consistent with the known effects of Janus Kinase signalling inhibition.These results support further evaluation of PF-04965842 for clinical use in patients with inflammatory diseases.

Elizabeth Kieras - One of the best experts on this subject based on the ideXlab platform.

  • Molecular and Cellular Responses to the TYK2/JAK1 Inhibitor, PF 06700841, Reveal Reduction of Skin Inflammation in Plaque Psoriasis: TYK2/JAK1 inhibitor in plaque psoriasis
    Journal of Investigative Dermatology, 2020
    Co-Authors: Karen Page, Elizabeth Kieras, Weidong Zhang, Mayte Suárez-fariñas, Maria Suprun, Sandra Garcet, Judilyn Fuentes-duculan, Xuan Li, Matthew Scaramozza, Christopher Banfield
    Abstract:

    The IL-23/T helper type 17 cell axis is a target for psoriasis. The TYK2/Janus Kinase 1 inhibitor PF-06700841 will directly suppress TYK2-dependent IL-12 and IL-23 signaling and Janus Kinase 1–dependent signaling in cells expressing these signaling molecules, including T cells and keratinocytes. This clinical study sought to define the inflammatory gene and cellular pathways through which PF-06700841 improves the clinical manifestations of psoriasis. Patients (n = 30) with moderate-to-severe psoriasis were randomized to once-daily 30 mg (n = 14) or 100 mg (n = 7) PF-06700841 or placebo (n = 9) for 28 days. Biopsies were taken from nonlesional and lesional skin at baseline and weeks 2 and 4. Changes in the psoriasis transcriptome and genes induced by IL-17 in keratinocytes were evaluated with microarray profiling and reverse transcriptase–PCR. Reductions in IL-17A, IL-17F, and IL-12B mRNA were observed as early as 2 weeks and approximately 70% normalization of lesional gene expression after 4 weeks. Immunohistochemistry showed significant decreases in markers of keratinocyte activation, epidermal thickness, KRT16 and Ki-67 expression, and immune cell infiltrates CD3+/CD8+ (T cells) and CD11c (dendritic cells) after 2 weeks of treatment, corresponding with improvement in histologic score. PF-06700841 improves clinical symptoms of chronic plaque psoriasis by inhibition of proinflammatory cytokines that require TYK2 and Janus Kinase 1 for signal transduction.

  • evaluation of a Janus Kinase 1 inhibitor pf 04965842 in healthy subjects a phase 1 randomized placebo controlled dose escalation study
    British Journal of Clinical Pharmacology, 2018
    Co-Authors: E Peeva, Martin R Hodge, Elizabeth Kieras, Michael L Vazquez, Kosalaram Goteti, Sanela Tarabar, Christine Alvey, Christopher Banfield
    Abstract:

    To determine the safety, tolerability, pharmacokinetics and pharmacodynamics of the Janus Kinase 1-selective inhibitor, PF-04965842.This was a phase 1, first-in-human, randomized, double-blind, placebo-controlled, combination single- and multiple-dose escalation, parallel design study in healthy subjects (http://clinicaltrials.gov, NCT01835197). Subjects received a single dose of placebo or 3, 10, 30, 100, 200, 400 or 800 mg PF-04965842 (single ascending dose phase) and placebo or 30 mg once daily (QD), 100 mg QD, 200 mg QD, 400 mg QD, 100 mg twice daily (BID) or 200 mg BID PF-04965842 for 10 consecutive days (multiple ascending dose phase). The primary objective was to determine the safety and tolerability of PF-04965842.Seventy-nine subjects were randomized and received study treatments. There were no deaths or serious adverse events. The most frequent treatment-emergent adverse events were headache (n = 13), diarrhoea (n = 11) and nausea (n = 11). PF-04965842 was absorbed rapidly (median time at which maximum plasma concentration occurred generally ≤1 h following either single- or multiple-dose administration) and eliminated rapidly (mean t½ 2.8-5.2 h after 10 days of QD or BID administration in the multiple ascending dose phase). Increases in maximum plasma concentration and area under the concentration-time curve were dose proportional up to 200 mg (single or total daily doses) with an apparent trend towards greater than proportional increases with higher doses. Less than 4.4% of the dose was recovered unchanged in urine. Changes in pharmacodynamic biomarkers were consistent with the known effects of Janus Kinase signalling inhibition.These results support further evaluation of PF-04965842 for clinical use in patients with inflammatory diseases.

  • efficacy and safety of the Janus Kinase 1 inhibitor pf 04965842 in patients with moderate to severe psoriasis phase ii randomized double blind placebo controlled study
    British Journal of Dermatology, 2018
    Co-Authors: G J Schmieder, Martin R Hodge, Elizabeth Kieras, Christopher Banfield, Z D Draelos, David M Pariser, D Parsonsrich, Sandeep Menon, M Salganik, Karen Page
    Abstract:

    Background PF-04965842 is an oral Janus Kinase 1 inhibitor being investigated for treatment of plaque psoriasis. Objectives To evaluate the efficacy, safety and tolerability of PF-04965842 in patients with moderate to severe plaque psoriasis. Methods Patients in this phase 2, placebo-controlled study (NCT02201524) were randomised to receive placebo, 200 mg once-daily (QD), 400 mg QD, or 200 mg twice-daily (BID) PF-04965842 for 4 weeks. The primary endpoint was change from baseline in Psoriasis Area Severity Index (PASI) at Week 4. Study enrolment was discontinued on 25 June 2015 due to changes in the sponsor's development priorities. Results Fifty-nine patients were randomised and received at least one dose of PF-04965842 or placebo. The estimated treatment effect (active-placebo PASI change from baseline) and 90% CI at Week 4 was –5·1 (–9·2, –1·0), –5·6 (–9·6, –1·6) and –10·0 (–14·2, –5·8) for the 200 mg QD, 400 mg QD and 200 mg BID groups, respectively. At Week 4, the proportion of patients achieving PASI75 was 17% for the placebo and 200 mg QD groups, 50% for the 400 mg QD group and 60% for the 200 mg BID group. There were more abnormal laboratory test results of clinical interest (low neutrophil, reticulocyte and platelet counts) in the 200 mg BID group vs the QD treatment groups. No serious infections or bleeding events related to neutropenia or thrombocytopenia, respectively, were reported. Conclusions These results suggest that treatment with PF-04965842 improves symptoms and is well tolerated in patients with moderate to severe psoriasis. This article is protected by copyright. All rights reserved.

Karen Page - One of the best experts on this subject based on the ideXlab platform.

  • Molecular and Cellular Responses to the TYK2/JAK1 Inhibitor, PF 06700841, Reveal Reduction of Skin Inflammation in Plaque Psoriasis: TYK2/JAK1 inhibitor in plaque psoriasis
    Journal of Investigative Dermatology, 2020
    Co-Authors: Karen Page, Elizabeth Kieras, Weidong Zhang, Mayte Suárez-fariñas, Maria Suprun, Sandra Garcet, Judilyn Fuentes-duculan, Xuan Li, Matthew Scaramozza, Christopher Banfield
    Abstract:

    The IL-23/T helper type 17 cell axis is a target for psoriasis. The TYK2/Janus Kinase 1 inhibitor PF-06700841 will directly suppress TYK2-dependent IL-12 and IL-23 signaling and Janus Kinase 1–dependent signaling in cells expressing these signaling molecules, including T cells and keratinocytes. This clinical study sought to define the inflammatory gene and cellular pathways through which PF-06700841 improves the clinical manifestations of psoriasis. Patients (n = 30) with moderate-to-severe psoriasis were randomized to once-daily 30 mg (n = 14) or 100 mg (n = 7) PF-06700841 or placebo (n = 9) for 28 days. Biopsies were taken from nonlesional and lesional skin at baseline and weeks 2 and 4. Changes in the psoriasis transcriptome and genes induced by IL-17 in keratinocytes were evaluated with microarray profiling and reverse transcriptase–PCR. Reductions in IL-17A, IL-17F, and IL-12B mRNA were observed as early as 2 weeks and approximately 70% normalization of lesional gene expression after 4 weeks. Immunohistochemistry showed significant decreases in markers of keratinocyte activation, epidermal thickness, KRT16 and Ki-67 expression, and immune cell infiltrates CD3+/CD8+ (T cells) and CD11c (dendritic cells) after 2 weeks of treatment, corresponding with improvement in histologic score. PF-06700841 improves clinical symptoms of chronic plaque psoriasis by inhibition of proinflammatory cytokines that require TYK2 and Janus Kinase 1 for signal transduction.

  • efficacy and safety of the Janus Kinase 1 inhibitor pf 04965842 in patients with moderate to severe psoriasis phase ii randomized double blind placebo controlled study
    British Journal of Dermatology, 2018
    Co-Authors: G J Schmieder, Martin R Hodge, Elizabeth Kieras, Christopher Banfield, Z D Draelos, David M Pariser, D Parsonsrich, Sandeep Menon, M Salganik, Karen Page
    Abstract:

    Background PF-04965842 is an oral Janus Kinase 1 inhibitor being investigated for treatment of plaque psoriasis. Objectives To evaluate the efficacy, safety and tolerability of PF-04965842 in patients with moderate to severe plaque psoriasis. Methods Patients in this phase 2, placebo-controlled study (NCT02201524) were randomised to receive placebo, 200 mg once-daily (QD), 400 mg QD, or 200 mg twice-daily (BID) PF-04965842 for 4 weeks. The primary endpoint was change from baseline in Psoriasis Area Severity Index (PASI) at Week 4. Study enrolment was discontinued on 25 June 2015 due to changes in the sponsor's development priorities. Results Fifty-nine patients were randomised and received at least one dose of PF-04965842 or placebo. The estimated treatment effect (active-placebo PASI change from baseline) and 90% CI at Week 4 was –5·1 (–9·2, –1·0), –5·6 (–9·6, –1·6) and –10·0 (–14·2, –5·8) for the 200 mg QD, 400 mg QD and 200 mg BID groups, respectively. At Week 4, the proportion of patients achieving PASI75 was 17% for the placebo and 200 mg QD groups, 50% for the 400 mg QD group and 60% for the 200 mg BID group. There were more abnormal laboratory test results of clinical interest (low neutrophil, reticulocyte and platelet counts) in the 200 mg BID group vs the QD treatment groups. No serious infections or bleeding events related to neutropenia or thrombocytopenia, respectively, were reported. Conclusions These results suggest that treatment with PF-04965842 improves symptoms and is well tolerated in patients with moderate to severe psoriasis. This article is protected by copyright. All rights reserved.