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Psoriasis treatment with ustekinumab

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Psoriasis is a chronic, immune-mediated, inflammatory skin disease that typically presents as well defined, demarcated erythematous plaques covered by silvery white scales.1 It can also present as inverse psoriasis in skin folds or flexural areas, generalised erythrodermic psoriasis, pustular psoriasis of the soles and palms or as papular guttate psoriasis.2,3 It typically affects extensor surfaces of the limbs, trunk, buttocks, scalp, nails, palms or soles.2 Prevalence is estimated to be around 1.5–2.0%2 but this can vary between racial groups and with latitude.3,4 The severity of psoriasis symptoms can be expressed using the Psoriasis Area and Severity Index (PASI).2 PASI is an overall measure of both severity and coverage, including body surface area, erythema, induration and scaling.2 75% improvement in PASI (PASI 75) is a commonly used outcome measure in clinical trials of psoriasis treatments to determine efficacy.

Eight separate chromosomal loci have been identified as associated with the emergence of psoriasis and the JunB gene is implicated in the cause of both psoriasis and psoriatic arthritis.2,5 Environmental factors such as drugs, skin trauma, infection and stress are also thought to play a role.2 Other likely risk factors include deletion of LCE3C and LCE3B genes,6 weight gain7 and smoking.8

The pathogenesis of psoriasis involves hyperproliferation of basal stem keratinocytes.2 While many factors contribute to the emergence of psoriatic lesions, a primarily T-cell based immunopathogenesis is believed to be responsible.9 This is supported by evidence that psoriasis responds to treatments targeting lymphocytes (such as cyclosporine and monoclonal antibodies directed against CD2, CD11a or CD4) and the generation of psoriasis-like lesions in animal models with T-cell dysregulation.1 Changes in several cytokines and chemokines have also been implicated in pathogenic pathways leading to psoriasis, such as IL-12, IL-23, TNF-α, IL-10, interferon-γ, IL-2, macrophage inflammatory protein 3α, CCL27 and others.1

 

Psoriasis image

For more information about the different types of psoriasis and characteristics define them, see Psoriasis Subtypes.

Treatments

The appropriate treatment strategy for psoriasis is largely determined by severity: 70–80% of all psoriasis patients are treated with topical therapies, such as vitamin D3 analogues (e.g. Daivonex, Daivobet), tazarotene (e.g. Zorac), anthralin, coal tar or topical corticosteroids.1 Moderate to severe psoriasis affecting larger surface areas may warrant the use of phototherapy or systemic drugs, alone or in combination with topical therapies.1 However, these therapies are often limited in their application, due to safety concerns in long-term use and patient inconvenience leading to non-compliance.1

An improved understanding of the genetic and immunological mechanisms mediating the development of psoriasis has permitted the discovery of novel therapeutic targets and biological therapies.10 These can target antigens known to mediate psoriasis pathogenesis pathways, such as IL-12, IL-23, leukocyte function-associated antigen-3, CD-11a and TNF-α.10  There is considerable circumstantial evidence that IL-12 and IL-23 are involved in the pathogenesis of psoriasis. Over-expression of p40 subunits of IL-12 and IL-23 is found in psoriasis plaques13 and p40-containing cytokines are implicated in psoriasis development in animal models.14 Genetic polymorphisms in the genes encoding for the common p40 component of the IL-12B subunit and the IL-23 receptor subunit have been linked to an increased risk of psoriasis.15 Furthermore, many therapies already in use against psoriasis have been shown to modulate IL-12 and IL-23 levels.16

Ustekinumab (Stelara) is a recombinant human monoclonal antibody that binds and inhibits the activity of interleukins 12 and 23.11 Ustekinumab binds to the shared p40 subunit to prevent it interacting with cell surface receptors.10 Both of these cytokines are mainly produced by activated dendritic cells; IL-12 activates T-helper 1 cell interferon-γ, TNF-α and cells producing interleukin 2. IL-23 stimulates the development of T-helper 17 cells, IL-22 and cells producing TNF-α.12

Clinical trials of ustekinumab have already shown promising results.17,18 A phase II trial of ustekinumab in patients with moderate-to-severe psoriasis plaques showed good efficacy compared to placebo. Patients were randomised to receive one subcutaneous dose (45 mg or 90 mg), four weekly doses (45 mg or 90 mg) or placebo and reviewed at week 12.17 Of particular interest was a dose-dependent effect on psoriasis plaques that lasted for many weeks.17 To assess the safety and efficacy of ustekinumab, two large, multi-centre phase III trials were conducted in parallel, called the PHOENIX 1 and PHOENIX 2 trials.10,19


 

Psoriasis image

 

For more information on the different types of treatments available for psoriasis and how effective they are, see Treatment Options for Psoriasis.



Clinical trials of ustekinumab

Both of the PHOENIX trials were placebo-controlled phase III trials, with the primary outcome defined as the proportion of patients who achieved a 75% improvement in PASI score (PASI 75) by week 12. Patients were also randomised to withdrawal of ustekinumab and the time to loss of the PASI 75 response was measured.


PHOENIX 1

The PHOENIX 1 trial randomised 766 patients to ustekinumab (45 mg or 90 mg) or placebo. Patients randomised to the intervention group received treatment at the commencement of the trial, week 4 and then every 12 weeks for the trial duration. However, at week 40, patients in this group who achieved and maintained a PASI 75 score (defined as PASI 75 at weeks 28 and 40) were subsequently re-randomised to either a maintenance ustekinumab therapy (continuing on the same 12-weekly regimen) or treatment withdrawal to determine the time to loss of response and the duration of a significant therapeutic effect. Conversely, patients randomised to placebo were on an identical schedule until week 12, when they were crossed over to receive ustekinumab therapy. This permitted a detection of effect in both intervention and placebo groups.10

In this trial, ustekinumab therapy proved statistically significantly efficacious at both 45 mg and 90 mg doses. Approximately two-thirds of patients in the intervention groups reached PASI 75 by week 12, compared to only 3.1% in the placebo group. By week 40, nearly 60% of patients on 45 mg doses and 67% of patients on 90 mg doses had maintained a PASI 75 for at least a 12-week period (weeks 28 to 40).10 In the second phase that randomised patients to withdrawal or continuation of ustekinumab, the average time to loss of PASI 75 after withdrawal was 15 weeks. Comparatively, those patients that continued on ustekinumab had a significantly better PASI score 1 year later.10


PHOENIX 2

The PHOENIX 2 trial used a very similar trial design to PHOENIX 1; however, PHOENIX 2 aimed to compare the effect of different dosing schedules. As with PHOENIX1, 1,230 moderate-to-severe psoriasis patients were randomised to receive ustekinumab (45 mg or 90 mg) at weeks 0 and 4, then every 12 weeks, or placebo at weeks 0 and 4 with crossover to ustekinumab at week 12. However, the researchers also identified those patients who partially responded to treatment, defined as patients who reached PASI 50 or higher, but did not reach PASI 75, by week 28. These “partial responders” were re-randomised to either continue on the previous 12-week dosing schedule, or to increase frequency to an 8-week dosing schedule.19 The researchers hypothesised that those patients who demonstrated some sensitivity to ustekinumab, but did not experience a PASI 75 effect, may benefit from more frequent dosing.

As with PHOENIX 1, by week 12 ustekinumab was significantly effective at both 45 mg and 90 mg doses (66.7% and 75.7% reached PASI 75 respectively) compared to just 3.7% in the placebo group. However, the partial responder group demonstrated more interesting results: an 8-week dosing schedule in those partial responders only proved effective for patients on 90 mg of ustekinumab. Partial responders that received only 45 mg doses demonstrated no significant improvement in symptoms when the dosing schedule was increased to 8 weeks.19 From this finding, the authors concluded that it is reasonable to increase dosing frequency from 12-weekly to 8-weekly in those patients who experience some benefit (PASI 50) from ustekinumab by 28 weeks, but only in the context of 90 mg doses.19


Safety and Efficacy

The PHOENIX 1 trial participants were followed up for a period of 3 years of treatment to assess the long-term safety and efficacy of ustekinumab.20 This follow-up included all patients who received ustekinumab at any point during the trial, including those who had since withdrawn from therapy.20 The 3 year follow-up rate of PHOENIX 1 participants was nearly 80%; those patients that had remained on ustekinumab for the entire period were continuing to experience benefit from therapy. Safety data from this follow-up was also reassuring. By year 3, it appeared that ustekinumab was well tolerated, with no detectable dose-response effect in adverse events or infections, nor evidence of cumulative organ damage from constant use.20

A similar study pooled the safety data from the phase II PHOENIX 1 and PHOENIX 2 trials to further assess the safety profile of ustekinumab over 3 years.21 As with the 3 year follow up of PHOENIX 1 patients, it supported the conclusion that ustekinumab exposure was safe. Rates of adverse events did not differ between placebo or treatment groups, and there was no dose-dependent effect on adverse events or infections.21


A separate analysis of ustekinumab combined safety data from the PHOENIX 1, PHOENIX 2 and ACCEPT trials.22 The ACCEPT trial compared safety and efficacy of ustekinumab to etanercept in the treatment of moderate-to-severe psoriasis; ustekinumab proved to be the superior treatment in these patients.12 Among these three trials, ustekinumab treatment did not appear to significantly increase the rate of adverse events overall, or the rate of adverse events leading to discontinuation of treatment. Rates of adverse events were comparable to the general population. This meta-analysis concluded that up to 4 years of continuous ustekinumab treatment showed no evidence of cumulative toxicity or specific safety concerns.22


Conclusion

Better understanding of the underlying cytokine-mediated pathogenic pathways of diseases such as psoriasis has enabled the emergence of biologically targeted therapies. The human recombinant monoclonal antibody drug ustekinumab inhibits the activity of the p40 subunit of IL-12 and IL-23 known to mediate moderate-to-severe psoriasis. Following multiple phase II and III trials, ustekinumab has been established as a safe and effective treatment for moderate-to-severe psoriasis for up to 4 years of continuous treatment.18-20

 

 

Psoriasis image

 

For more information about the causes of psoriasis, incidence statistics, predisposing factors and more, see Psoriasis.

 

References

  1. Schön MP, Boehncke WH. Psoriasis. N Engl J Med. 2005; 352(18): 1899-912. [Abstract | Full Text]
  2. Menter A, Gottlieb A, Feldman SR, 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(5): 826-50. [Abstract]
  3. Griffiths CE, Barker JN. Pathogenesis and clinical features of psoriasis. Lancet. 2007; 370(9583): 263-71. [Abstract]
  4. Christophers E. Psoriasis – epidemiology and clinical spectrum. Clin Exp Dermatol.  2001; 26: 314-320. [Abstract]
  5. Zenz R, Eferl R, Kenner L, et al. Psoriasis-like skin disease and arthritis caused by inducible epidermal deletion of Jun proteins. Nature. 2005; 437(7057): 369-75. [Abstract]
  6. Riveira-Munoz E, He SM, Escaramís G, et al. Meta-analysis confirms the LCE3C_LCE3B deletion as a risk factor for psoriasis in several ethnic groups and finds interaction with HLA-Cw6. J Invest Dermatol. 2011; 131(5): 1105-9. [Abstract | Full Text]
  7. Setty AR, Curhan G, Choi HK. Obesity, waist circumference, weight change, and the risk of psoriasis in women: Nurses’ Health Study II. Arch Intern Med. 2007; 167(15): 1670-5. [Abstract | Full Text]
  8. Huerta C, Rivero E, Rodríguez LA. Incidence and risk factors for psoriasis in the general population. Arch Dermatol. 2007; 143(12): 1559-65. [Abstract | Full Text]
  9. Christophers E. The immunopathology of psoriasis. Int Arch Allergy Immunol. 1996; 110: 199-206. [Abstract]
  10. Leonardi CL, Kimball AB, Papp KA, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet. 2008; 371(9625): 1665-74. [Abstract]
  11. Australian Medicines Handbook. Dermatological drugs [online]. AMH 2012 [cited 10th May 2012]. Available from: URL Link
  12. Garcia-Valladares I, Cuchacovich R, Espinoza LR. Comparative assessment of biologics in treatment of psoriasis: drug design and clinical effectiveness of ustekinumab. Drug Des Devel Ther. 2011; 5: 41-9. [Abstract | Full Text]
  13. Piskin G, Sylva-Steenland RMR, Bos JD, Teunissen MBM. In vitro and in situ expression of IL-23 by keratinocytes in healthy skin and psoriasis lesions: enhanced expression in psoriatic skin. J Immunol. 2006; 176: 1908–15. [Abstract | Full Text]
  14. Hong K, Chu A, Ludviksson BR, et al. IL-12, independently of IFN-γ, plays a crucial role in the pathogenesis of a murine psoriasis-like skin disorder. J Immunol. 1999; 162: 7480–91. [Abstract | Full Text]
  15. Cargill M, Schrodi SJ, Chang M, et al. A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am J Hum Genet. 2007; 80: 273–90. [Abstract | Full Text]
  16. Torti DC, Feldman SR. Interleukin-12, interleukin-23, and psoriasis: current prospects. J Am Acad Dermatol. 2007; 57: 1059–68. [Abstract]
  17. Krueger GG, Langley RG, Leonardi C, et al. A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis. N Engl J Med. 2007; 356: 580–92. [Abstract | Full Text]
  18. Kimball A, Gordon KB, Langley RG, et al. Safety and efficacy of ABT-874, a fully human interleukin 12/23 monoclonal antibody, in the treatment of moderate to severe chronic plaque psoriasis: results of a randomized, placebo-controlled, phase 2 trial. Arch Dermatol. 2008; 144: 200–07. [Abstract | Full Text]
  19. Papp KA, Langley RG, Lebwohl M, et al. 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). Lancet. 2008; 371(9625): 1675-84. [Abstract]
  20. Kimball AB, Gordon KB, Fakharzadeh S, et al. Long-term efficacy of ustekinumab in patients with moderate-to-severe psoriasis: results from the PHOENIX 1 trial through up to 3 years. Br J Dermatol. 2012; 166(4): 861-72. [Abstract]
  21. Lebwohl M, Leonardi C, Griffiths CE, et al. Long-term safety experience of ustekinumab in patients with moderate-to-severe psoriasis (Part I of II): Results from analyses of general safety parameters from pooled Phase 2 and 3 clinical trials. J Am Acad Dermatol. 2012; 66(5): 731-41. [Abstract]
  22. Reich K, Papp KA, Griffiths CE, et al. An update on the long-term safety experience of ustekinumab: results from the psoriasis clinical development program with up to four years of follow-up. J Drugs Dermatol. 2012; 11(3): 300-12. [Abstract]

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Dates

Posted On: 13 June, 2012
Modified On: 20 March, 2014

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