Ustekinumab in psoriatic arthritis and related phenotypes

Abstract

Psoriatic arthritis (PsA) is an inflammatory arthritis that commonly occurs with psoriasis and is attributed to genetic, immunologic and environmental factors. The T-helper (Th)-17 pathway and the interleukin (IL)-23/IL-17 axis have become prominent players in PsA and considerably increased our understanding of disease pathogenesis. In this review article, we will focus on the emerging role of IL-12/23 and its blockade, in the pathogenesis and management of PsA as well as of psoriasis and inflammatory bowel disease. Ustekinumab, is a fully human monoclonal immunoglobulin (Ig)G1 antibody that binds specifically to the p40 subunit of IL-12 and IL-23, primarily inhibiting downstream Th-17 signalling pathways. Ustekinumab produced consistent and sustained clinical efficacy in two phase III clinical trials in PsA, PSUMMIT-1 and PSUMMIT-2, with data out to 52 weeks, and no new safety signals. PSUMMIT-1 included patients with active PsA despite conventional therapy who were all naïve to anti-tumour necrosis factor (TNF) agents, whereas PSUMMIT-2 also included anti-TNF experienced patients. Similarly, ustekinumab produced consistent clinical efficacy in two phase III clinical trials in psoriasis, PHOENIX-1 and PHOENIX-2, and in both induction and maintenance of moderate-to-severe Crohn's disease, UNITI-1, UNITI-2 and IM-UNITI, without an increased safety signal. Currently, ustekinumab is used in the treatment of PsA following the failure of nonsteroidal anti-inflammatory drugs (NSAIDs) and conventional disease-modifying antirheumatic drugs (DMARDs), and as an alternative to, or after failure of an anti-TNF agent.

Role of the IL-23/IL-17 Pathway in Rheumatic Diseases: An Overview

“…Ustekinumab has produced consistent and sustained clinical efficacy in two phase three clinical trials in PsA, PSUMMIT-1 and PSUMMIT-2, with data out to 52 weeks, and no new safety signals. PSUMMIT-1 included patients with active PsA despite conventional therapy who were all naïve to anti-TNF-α agents, whereas PSUMMIT-2 also included anti-TNF-α experienced patients ( 192 ).…”

Extracellular Signal-Regulated Kinase: A Regulator of Cell Growth, Inflammation, Chondrocyte and Bone Cell Receptor-Mediated Gene Expression

“…Perhaps one can argue that the increased focus on other signaling pathways besides the ERK1/2 pathway, including PI-3K/Akt/mTOR [67] and JAK/STAT [42], has occurred because they have been implicated in diseases characterized by chronic inflammation. Thus, many targets have been justified for further study based on results of experimental and pre-clinical studies, and some studies have resulted in the development of new drugs, including those targeting IL-12/IL-23/p40 (i.e., ustekinumab) [140], IL-23/p19 (i.e., guselkumab) [141], IL-17A (i.e., secukinumab; ixekizumab) [142,143], IL-17R (i.e., brodalizumab) [143], and IL-23 (i.e., tidrakizumab) [143]. There has also been a renewed interest in developing MMP, ADAMTS, and A Disintegrin and Metalloproteinase (ADAMs) inhibitors [144], since these molecules are the product of MAPK and/or JAK/STAT signaling in response to IL-1β, IL-6, IL-17 and TNF-α [144].…”

Polyethylene Glycol Ointment Alleviates Psoriasis-Like Inflammation Through Down-Regulating the Function of Th17 Cells and MDSCs

“…It is well known that the IL-23/IL-17 axis is the key pathway leading to the pathogenesis of psoriasis. In the dermis, the IL-23 secreted by DCs induces the activation of Th17 cells, which subsequently releases various cytokines including IL-17A, IL-17F, and IL-22 to promote epidermal hyperplasia ( 37 , 38 ). In addition, Th17 cells can also induce keratinocytes to produce IL-8 and antimicrobial peptides (e.g., S100A8 and S100A9) for the recruitment of neutrophils, the activation of vascular endothelial growth factor, and angiogenesis ( 39 ).…”