The Efficacy of Ustekinumab in Psoriasis
March 2013 | Volume 12 | Issue 3 | Original Article | 317 | Copyright © 2013
Shannon Famenini BSa and Jashin J. Wu MDb
aDavid Geffen School of Medicine at UCLA, Los Angeles, CA bDepartment of Dermatology, Kaiser Permanente Medical Center, Los Angeles, CA
Psoriasis is an immune-mediated cutaneous disease affecting 2% of the worldwide population. While topical therapy, phototherapy, oral systemic therapy, and biologic agents have been used, the treatment of psoriasis still remains a challenge. Ustekinumab is a biologic therapy that provides a novel avenue for management by blocking interleukin-12/23. The purpose of this article is to review the mechanism of action of ustekinumab and its efficacy in psoriatic patients. The use of ustekinumab in other immune-mediated diseases is also discussed. It is our goal to provide dermatologists with the knowledge to enable them to incorporate ustekinumab into their practice.
J Drugs Dermatol. 2013;12(3):317-320.
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Psoriasis is an immune-mediated disease characterized by the presence of scaly, erythematous plaques and affecting 2% to 3% of the population.1,2 Psoriasis can impact patient quality of life (QOL) and is also associated with other comorbidities, including increased cardiovascular risk and psoriatic arthritis.3,4
Recent research has elucidated the role of interleukin (IL)-12 and IL-23 in the development of psoriatic lesions.5,6 IL-12 and IL-23 are cytokines sharing the p40 subunit5 and have been implicated in mediating inflammatory processes via induction of cell surface markers important for skin homing and the release of other cytokines by immune cells.7 In transgenic mice, the overexpression of IL-12 has been linked to the development of inflammatory lesions. Alternatively, IL-12 knockout mice and humans genetically deficient in IL-12 have demonstrated enhanced susceptibility to intracellular pathogens and impaired delayed-type hypersensitivity reaction.5 Interestingly, psoriatic lesions have shown increased concentrations of IL-12 and IL-23 compared with normal skin,6,8,9 and genetic polymorphisms of the p40 subunit have been linked to psoriasis.10
Generally, mild psoriasis has been managed with topical treatments, including topical corticosteroids, vitamin D derivatives, topical retinoids, and calcineurin inhibitors. Phototherapy and oral agents such as methotrexate, cyclosporine, and acitretin have been used for moderate to severe psoriasis.11,12 Methotrexate and cyclosporine directly inhibit T-cell activation or co-stimulatory molecules required for activation.12 Biologics, mainly tumor necrosis factor (TNF)-α inhibitors, have been used in patients with severe psoriasis and/or those with psoriatic arthritis.11,13 New knowledge in the inflammatory pathogenesis of the disease offers a new option for those patients failing the traditional treatment modalities.
Ustekinumab was approved in 2009 for the treatment of moderate to severe psoriasis. It is a human monoclonal antibody that binds to the shared p40 subunit of IL-12 and IL-23, and interferes with binding of these cytokines to IL-12RB1 receptor present on T cells and other immune cells.14,15 This results in downstream downregulation of the inflammatory cytokines generated by these cells.16,17 In fact, patients treated with ustekinumab have demonstrated reduced mRNA levels of IL-8, IL-18, and interferon (IFN)-γ in plaques with improved Psoriasis Area and Severity Index (PASI) score posttreatment. Reduced infiltration of T cells has also been evaluated posttreatment.18
The efficacy of ustekinumab in improving psoriatic lesions has been shown in clinical trials. In a phase 1 study of subjects with plaque psoriasis, a single intravenous administration of anti-IL-12-p40 demonstrated 75% improvement in PASI (PASI 75) in 67% of the subjects after a 16-week period. The reduction in psoriatic lesions was concentration dependent.19 Likewise, a single subcutaneous administration of human monoclonal antibody against p40 subunit resulted in achieving PASI 75 in 13 of 17 subjects. Reduced expression of IL-8, IL-18, and IFN-γ was measured in these patients, providing further support for the role of cytokines in the pathogenesis of psoriasis.18 However, these phase 1 trials were limited in the number of subjects studied. Later trials validated the results of these studies.
In a double-blind, placebo-controlled trial, phase 2 trial, 320 patients were randomized to receive one of the following treatments: one 45-mg dose, one 90-mg dose, 4 weekly 45-mg doses, or 4 weekly 90-mg doses or placebo. The PASI 75 was 52%, 59%, 67%, 81%, and 2% for each group, respectively. Thus, a clinically significant dose-dependent improvement in PASI (P<.001) was observed in patients treated with IL-12/23 monoclonal antibody compared with those receiving placebo.20 In a double-blind, placebo-con-trolled, multicenter phase 3 study (PHOENIX 1), 766 patients were randomly treated with 1 of 2 doses of ustekinumab (45 mg or 90 mg) or received placebo. Treatment was administered at weeks 0 and 4, and then every 12 weeks. After 12 weeks, 67.1% of patients administered ustekinumab 45 mg, 66.4% of patients administered ustekinumab 90 mg, and 3.1% of patients receiving placebo