INTRODUCTION
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
