Ustekinumab in the Treatment of Psoriasis and Psoriatic Arthritis

Abstract

Biologics have revolutionized the therapy of the psoriatic disease spectrum. These new classes of drugs also allow deeper insight into the pathogenesis of the disease and highlight the existence of distinct "molecular" disease subgroups as evidenced by the spectrum of clinical response seen. Molecules associated with both the interleukin (IL)-17 and interferon (IFN)γ pathways have important functions in psoriatic inflammation, and both are targeted by drugs acting on the p40 subunit shared by IL-12 and IL-23. These IL-12 family members are upstream of pathways characterized by the production of IFNγ and IL-17 related molecules, including IL-17, IL-22, and CCL20. We here summarize the mode of action and clinical studies of the p40 inhibitor ustekinumab with focus on both psoriasis and psoriatic arthritis.

Keywords: IL-12/IL-23 inhibition; Psoriasis; Psoriatic arthritis; Treatment; Ustekinumab.

Fig. 1

Schematic, simplified overview of IL-12/IL-23 dependent action on molecules involved in psoriatic inflammation. Only positive/activating pathways are depicted. Both IL-12 and IL-23 are produced by activated APCs including macrophages. Upon receptor ligation, these heterodimeric cytokines activate the Stat4/3 pathways ultimately resulting in upregulation of cell surface receptors and secretion of cytokines. Of importance, type 17 cells, which are dependent on IL-23 stimulation, express high levels of CCR6 which enables the cell to follow a chemokine gradient build by CCL20 which is produced by IL-17/IL-22 stimulated keratinocytes. Thus type 17 cells will home into CCL20 rich tissues. On the other hand, IL-12, via activation of Stat4, acts on expression of the skin homing receptor CLA but also CXCR3 which interacts with the chemokines CXCL9, 10, 11 which are all highly expressed by keratinocytes which have been exposed to IFNs. IFNγ is one of the strongest priming signal for APC to induce the production of the IL-12 family members IL-12 and IL-23. Negative regulatory feedback actions are not depicted in this figure. However, there is significant negative cross-regulation between type 1 and type 17 cells. Blocking the p40 subunit of both IL-12 and IL-23 could therefore result in “paradoxical” effects where this negative regulatory influence plays an important role in disease pathology. APC Antigen presenting cell, CLA Cutaneous lymphocyte antigen, IFN Interferon, IL Interleukin