Ustekinumab: A Review in the Treatment of Plaque Psoriasis and Psoriatic Arthritis
February 2012 | Volume 11 | Issue 2 | Original Article | 160 | Copyright © 2012
Psoriasis is a complex, multigenic immune/inflammatory-mediated disorder that variably affects the skin, nails, and joints. In September 2009, ustekinumab (Stelara®), a monoclonal antibody that targets interleukin 12 (IL-12) and 23 (IL-23), was approved in the United States for treatment of moderate-to-severe plaque psoriasis. The drug's mechanism of action is derived from extensive immunologic and genomic research identifying IL-12 and IL-23 of the Th1 and Th17 inflammatory pathways, respectively, as key mediators of psoriasis. Ustekinumab is a completely human monoclonal antibody to the shared p40 subunit of IL-12 and IL-23. The drug has demonstrated efficacy, short-term safety, and convenience of use in the treatment of plaque psoriasis and psoriatic arthritis. Though long-term safety concerns remain, ustekinumab adds to the current treatment armamentarium and holds promise to improve quality of life. This is a concise and current review of ustekinumab in the treatment of plaque psoriasis and psoriatic arthritis, with focus on data from the seven published clinical trials.
J Drugs Dermatol. 2012;11(2):160-167.
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Psoriasis is a chronic, inflammatory/immune disorder mediated by a host of genetic and environmental risk factors. According to the National Institutes of Health, the disorder afflicts between 5.8 and 7.5 million people in the United States.1 Patients with psoriasis are also at risk for developing psoriatic arthritis, a sero-negative inflammatory arthropathy that develops in 5% to 30% of patients with cutaneous disease.2
Psoriasis disrupts many aspects of life, including sleep, sexual activities, walking, and use of hands.3 Nearly 60% of patients with psoriatic skin and 40% with psoriatic arthritis report that the disorder is a large problem in their everyday life,4 with the quality of life impairment mirroring chronic illnesses like cancer, heart disease and diabetes.5 It is estimated that 56 million hours of work are lost each year nationwide by people with psoriasis,6 bringing the total cost of the disorder in the U.S. to $1500 per patient per year or approximately $11.25 billion annually for the treatment of psoriasis in the US.7
Over the last decade, new biologic agents that target tumor necrosis factor and T-lymphocyte mechanisms have been added to the otherwise limited armamentarium of therapies for psoriasis that traditionally have included ultraviolet light, methotrexate, cyclosporine, and acitretin. Although these biologic drugs have demonstrated efficacy, tolerability, and short-and long-term safety, many patients either do not respond to these agents or have experienced adverse events. With improved understanding of the relatively new Th17 immunologic pathway, a new targeted biologic therapy known as ustekinumab has emerged and shows excellent promise as an addition to our array of psoriasis treatments.
Immunology of Psoriasis: IL-12 and IL-23
IL-12 and IL-23 are both heterodimers, the former comprised of a p40 and p35 subunit, the latter comprised of a p40 subunit identical to the IL-12p40 subunit and a unique p19 subunit. Both cytokines are produced by antigen-presenting cells such as Langerhans cells, keratinocytes, and T-cells and function as activators of other T-cells and natural killer cells. IL-12 stimulates naïve CD4+ cells to commit to the Th1 pathway, a pathway known to mediate autoimmunity and to regulate cell-mediated immunity against intracellular pathogens.8 IL-23 is necessary for the initiation and maintenance of a recently discovered