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      Ustekinumab: an evidence-based review of its effectiveness in the treatment of psoriasis

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          Abstract

          Introduction:

          Psoriasis is a chronic inflammatory skin disease affecting approximately 2% to 3% of the population worldwide. Discoveries over the past 3 to 5 years have significantly altered our view of psoriasis as primarily a T-cell mediated condition. The most recent research has demonstrated the essential role of specific cytokines in the development of this complex disease, including TNF-α, interleukin-23 (IL-23), and potentially, IL-22. These are all part of a newly defined autoimmune pathway directed by specialized T cells called Th17 helper T cells. Ustekinumab is a fully human monoclonal antibody that targets IL-12 and IL-23, thus targeting both Th1 and Th17 arms of immunity. It has a promising efficacy and safety profile that not only represents a valuable treatment alternative, but also a continuation in our constantly evolving understanding of this disorder.

          Aims:

          To review the emerging evidence supporting the use of ustekinumab in the management of moderate to severe plaque psoriasis.

          Evidence review:

          There is clear evidence that ustekinumab is effective in the treatment of moderate to severe psoriasis. Phase III trials (PHOENIX 1 and 2) demonstrated a statistically significant difference between Psoriasis Area and Severity Index (PASI) 75 responses achieved by patients receiving ustekinumab, given as a 45 mg or 90 mg subcutaneous injection every 12 weeks, than their placebo counterparts. Treatment with this novel agent resulted in a rapid onset of action, with over 60% of treated patients attaining Physician’s Global Assessment (PGA) scores of “cleared” or “minimal” by week 12. Quality of life assessments paralleled clinical improvements.

          Clinical potential:

          Ustekinumab is an effective and efficient therapeutic option for patients with moderate to severe psoriasis. Although further studies are required to establish ustekinumab’s place in the therapy of psoriasis, with its convenient dosing schedule and rapid onset of action, this drug could provide a great addition to the current therapeutic armamentarium available for psoriatic patients.

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          Most cited references41

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          Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2).

          Ustekinumab, a human monoclonal antibody against interleukins 12 and 23, has shown therapeutic potential for psoriasis. This study assessed the efficacy and safety of ustekinumab in psoriasis patients and assessed dosing intensification in partial responders. In this multicentre, phase III, double-blind, placebo-controlled study, 1230 patients with moderate-to-severe psoriasis (defined by a psoriasis area and severity index [PASI] score > or =12, and at least 10% total body surface area involvement) were randomly assigned to receive ustekinumab 45 mg (n=409) or 90 mg (n=411) at weeks 0 and 4, then every 12 weeks, or placebo (n=410). Partial responders (ie, patients achieving > or =50% but <75% improvement from baseline in PASI) were re-randomised at week 28 to continue dosing every 12 weeks or escalate to dosing every 8 weeks. Both randomisations were done with a minimisation method via a centralised interactive voice response. The primary endpoint was the proportion of patients achieving at least 75% improvement in PASI (PASI 75) at week 12. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00307437. All randomised patients were included in the efficacy analysis. 273 (66.7%) patients receiving ustekinumab 45 mg, 311 (75.7%) receiving ustekinumab 90 mg, and 15 (3.7%) receiving placebo achieved the primary endpoint (difference in response rate 63.1%, 95% CI 58.2-68.0, p<0.0001 for the 45 mg group vs placebo and 72.0%, 67.5-76.5, p<0.0001 for the 90 mg group vs placebo). More partial responders at week 28 who received ustekinumab 90 mg every 8 weeks achieved PASI 75 at week 52 than did those who continued to receive the same dose every 12 weeks (22 [68.8%] vs 11 [33.3%]; difference in response rate 35.4%, 95% CI 12.7-58.1, p=0.004). There was no such response to changes in dosing intensity in partial responders treated with ustekinumab 45 mg. During the placebo-controlled phase, 217 (53.1%) patients in the 45 mg group, 197 (47.9%) in the 90 mg group, and 204 (49.8%) in the placebo group experienced adverse events; serious adverse events were seen in eight (2.0%) patients in the 45 mg group, five (1.2%) in the 90 mg group, and eight (2.0%) in the placebo group. Although treatment with ustekinumab every 12 weeks is effective for most patients with moderate-to-severe psoriasis, intensification of dosing to once every 8 weeks with ustekinumab 90 mg might be necessary to elicit a full response in patients who only partially respond to the initial regimen.
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            Amelioration of epidermal hyperplasia by TNF inhibition is associated with reduced Th17 responses

            Biological agents have dramatically improved treatment options for patients with severe psoriasis. Etanercept (tumor necrosis factor [TNF] receptor–immunoglobulin fusion protein) is an effective treatment for many psoriasis patients, and blockade of TNF is considered to be its primary action. However, in this clinical trial, we show that etanercept has early inhibitory effects on a newly appreciated type of T cells: T helper type 17 (Th17) cells. Etanercept reduced the inflammatory dendritic cell products that drive Th17 cell proliferation (interleukin [IL] 23), as well as Th17 cell products and downstream effector molecules (IL-17, IL-22, CC chemokine ligand 20, and β-defensin 4). In contrast, Th1 cellular products and effector molecules (interferon γ, lymphotoxin α, and myxovirus resistance 1) were reduced late in disease resolution. This study suggests a role for Th17 in addition to Th1 cells in the pathogenesis of psoriasis. Th17 cells may be particularly important in driving epidermal activation in psoriatic plaques, whereas Th1 cells must also be eliminated for final disease resolution.
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              Sequence and haplotype analysis supports HLA-C as the psoriasis susceptibility 1 gene.

              Previous studies have narrowed the interval containing PSORS1, the psoriasis-susceptibility locus in the major histocompatibility complex (MHC), to an approximately 300-kb region containing HLA-C and at least 10 other genes. In an effort to identify the PSORS1 gene, we cloned and completely sequenced this region from both chromosomes of five individuals. Two of the sequenced haplotypes were associated with psoriasis (risk), and the other eight were clearly unassociated (nonrisk). Comparison of sequence of the two risk haplotypes identified a 298-kb region of homology, extending from just telomeric of HLA-B to the HCG22 gene, which was flanked by clearly nonhomologous regions. Similar haplotypes cloned from unrelated individuals had nearly identical sequence. Combinatorial analysis of exonic variations in the known genes of the candidate interval revealed that HCG27, PSORS1C3, OTF3, TCF19, HCR, STG, and HCG22 bore no alleles unique to risk haplotypes among the 10 sequenced haplotypes. SPR1 and SEEK1 both had messenger RNA alleles specific to risk haplotypes, but only HLA-C and CDSN yielded protein alleles unique to risk. The risk alleles of HLA-C and CDSN (HLA-Cw6 and CDSN*TTC) were genotyped in 678 families with early-onset psoriasis; 620 of these families were also typed for 34 microsatellite markers spanning the PSORS1 interval. Recombinant haplotypes retaining HLA-Cw6 but lacking CDSN*TTC were significantly associated with psoriasis, whereas recombinants retaining CDSN*TTC but lacking HLA-Cw6 were not associated, despite good statistical power. By grouping recombinants with similar breakpoints, the most telomeric quarter of the 298-kb candidate interval could be excluded with high confidence. These results strongly suggest that HLA-Cw6 is the PSORS1 risk allele that confers susceptibility to early-onset psoriasis.
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                Author and article information

                Journal
                Core Evid
                Core Evidence
                Core Evidence
                Dove Medical Press
                1555-1741
                1555-175X
                27 July 2010
                2010
                2010
                : 5
                : 11-22
                Affiliations
                NorthShore University HealthSystem, University of Chicago, Pritzker School of Medicine, Skokie, IL, USA
                Author notes
                Correspondence: Kenneth B Gordon, MD, Head of Dermatology NorthShore University HealthSystem, Associate Professor of Dermatology, University of Chicago, Pritzker School of Medicine, 9933 Woods Dr Skokie, IL 60077, USA, Tel +1 (847) 663-8539, Fax +1 (847) 663-8536, Email kgordon@ 123456northshore.org
                Article
                ce-5-011
                2915500
                20694136
                847694e1-fefd-49c8-9096-f349ed0d175f
                © 2010 Krulig and Gordon, publisher and licensee Dove Medical Press Ltd.

                This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.

                History
                : 3 July 2010
                Categories
                Review

                Pharmacology & Pharmaceutical medicine
                ustekinumab,psoriasis,biologics,interleukin-12 (il-12),interleukin-23 (il-23),il-12/23,evidence

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