Ustekinumab for the treatment of psoriatic arthritis

Abstract

Ustekinumab is a fully human monoclonal antibody directed against the p40 subunit shared by interleukin 12 and interleukin 23, two naturally occurring protein regulators that play an important role in immune-mediated inflammatory diseases, including psoriatic arthritis (PsA). In September of 2009, the US FDA approved ustekinumab for the treatment of adult patients with moderate to severe plaque psoriasis. Beginning in November of 2009, Janssen Biotech (formerly Centocor Biotech), the developer of ustekinumab, initiated clinical trials to investigate the efficacy of ustekinumab in the treatment of other inflammatory disorders, including PsA. Phase II and Phase III studies showed both a good safety profile and significant efficacy for ustekinumab in the treatment of PsA, leading to the drug's approval in both Europe and the USA. In an immunotherapy market currently dominated by anti-TNF-α drugs for the treatment of PsA, ustekinumab offers an alternative option for patients with PsA, including those unresponsive to methotrexate and the TNF-α inhibitory agents currently approved for this potentially debilitating disease.

Keywords::

• biologic therapy
• IL-12
• IL-23
• immunotherapy
• inflammatory arthritis
• monoclonal antibody
• psoriatic arthritis
• ustekinumab

Financial & competing interests disclosure

A Menter is on the Advisory board for Abbott, Amgen, Galderma, Janssen and Wyeth. The author has been a consultant for Abbott, Amgen, Eli Lilly, Galderma, Janssen, LEO Pharma, Stiefel and Wyeth. The author has been a speaker for Abbott, Amgen, Galderma, Janssen, LEO Pharma and Wyeth. The author has been an investigator and received grants from Abbott, Allergan, Amgen, Celgene, Eli Lilly, Janssen, Novartis, Novo Nordisk, Pfizer, Stiefel, Syntrix Biosystems and Wyeth. He has also received honoraria from Abbott, Amgen, Galderma, Janssen, LEO Pharma, Stiefel and Wyeth. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Psoriasis afflicts approximately 1–2% of the world's population and as many as 30% of these individuals will develop psoriatic arthritis (PsA) up to 10 years after the onset of their skin disease.

• Numerous studies have substantiated the significant impact of PsA on the quality of life of those affected.

• PsA is an immune-mediated disease with multiple inflammatory molecules playing crucial roles in potentiating the disease. These include, but are not limited to, TNF-α, IL-12, IL-17, IL-23 and IFN-γ.

• IL-12 is directly involved in stimulating the differentiation of naïve T cells into the Th1 cell line, in inducing the production of IFN-γ and TNF-α and in enhancing the cytotoxic activity of CD8⁺ T cells.

• Studies have found elevated levels of Th17 cells and IL-17 in the synovial fluid of joint affected by PsA.

• IL-23 has been shown to directly stimulate naïve CD4⁺ T cells to differentiate into the Th17 cells, which produce IL-17.

• Ustekinumab is a fully human monoclonal antibody directed against the p40 subunit shared by both IL-12 and IL-23. This drug inhibits the interaction of IL-12 and IL-23 with their respective receptors.

• In clinical trials, ustekinumab has been shown to be both safe and effective in reducing disease activity in patients with PsA.

• Large Phase III trials indicate that, when treated with ustekinumab, approximately 50% of patients will achieve a 20% reduction in their disease activity (ACR20) and approximately 25% of patients will achieve a 50% reduction in disease activity (ACR50) after 24 weeks of treatment.

• Clinical trials also indicate minimal to no difference in the frequency of adverse events in patients treated with ustekinumab compared with those treated with placebo.

• Ustekinumab showed similar efficacy in patients with PsA, regardless of concomitant treatment with methotrexate or prior treatment failure with TNF-α inhibiting drugs.

• Ustekinumab is now US FDA and EMA approved for the treatment of adults with active PsA.

• Ustekinumab comes in 45 mg or 90 mg subcutaneous injection dosages. After an initial dose and a second dose 4 weeks later, ustekinumab is dosed every 12 weeks.

• Head-to-head comparisons between ustekinumab and other approved biologic agents for PsA are currently lacking.

• Data regarding the effects of ustekinumab on the radiographic progression of psoriatic joint disease and on other comorbid conditions associated with PsA (including increased cardiovascular disease risk) will be forthcoming in the near future.