A Review of Guselkumab, an IL-23 Inhibitor, for Moderate-to-Severe Plaque Psoriasis

Zeena Nawas, MD; Michael Hatch, MD; Elmira Ramos; Melinda Liu; Yun Tong, MD; Andrew Peranteau, MD; Stephen Trying, MD, PhD


Skin Therapy Letter. 2017;22(2) 

In This Article

Abstract and Introduction


Psoriasis is a chronic inflammatory skin disorder that affects 2% of the population. Evidence suggests that interleukin (IL)-23 plays a pivotal role in the pathogenesis of psoriasis. Guselkumab is a subcutaneously administered, humanized anti-IL23 monoclonal antibody indicated for the treatment of moderate-to-severe plaque psoriasis. Data from Phase I-III trials in this patient population reveal that guselkumab has proven to be superior to placebo or adalimumab based on achieving a Psoriasis Area and Severity Index (PASI) 90% reduction, or a static Physician Global Assessment (sPGA) score of 0 or 1 from baseline. This article reviews the current status of guselkumab as a therapy for moderate-to-severe plaque psoriasis.


Psoriasis is the most common chronic autoimmune skin condition affecting about 2% of the population.[1] This disease has a significant impact on quality of life, mental health and work productivity, and it is linked to other comorbid conditions such as cardiovascular disease, metabolic syndrome, and arthritis.[2,3] Psoriasis is thought to arise from a combination of pathogenic factors including genetic susceptibility and environmental exacerbation, which results in activation of dendritic cells in the skin and differentiation of T cells.[4] In turn, these T cells produce cytokines that induce keratinocyte hyperproliferation and result in characteristic raised, well-demarcated erythematous lesions of psoriasis.

Accumulating evidence suggests that the proinflammatory cytokine interleukin (IL)-23 and its resulting T helper 17 (Th17) pathway play a more important role in mediating psoriasis than IL-12.[5,6] IL-23 induces differentiation and maintenance of Th17 cells, which produce the effector cytokines IL-17, IL-22, and tumor necrosis factor-alpha (TNFα).[7,8] IL-23 is a heterodimer composed of two subunits, p40 and p19.[8] While p40 is also present in IL-12, p19 is specific for IL-23.[8] Levels of IL-23p19 and IL-12/23p40 messenger RNA (mRNA) are upregulated in psoriatic plaques and decrease with effective treatment.[7–11]

This paper focuses on guselkumab, a fully human immunoglobulin G1 (IgG1) monoclonal antibody that specifically inhibits intracellular IL-23 and downstream signaling by targeting the p19 subunit.[12,13] Guselkumab decreases blood and skin lesion levels of effector IL-17A and decreases epidermal hyperplasia and inflammation by downregulating T cells and myeloid dendritic cells.[12] This evidence further establishes the IL-23/Th17 axis as the primary driver of psoriatic inflammation. Additionally, another goal for guselkumab is increased safety by maintaining the IL-12/Th1 axis, an important regulator of immune function, unlike the previous medications that targeted both IL-12 and IL-23. IL-12 is required for appropriate Th1 response and defense against intracellular pathogens due to its role in the production of interferon gamma (INFγ) by T- and natural killer (NK)-cells.[14] Animal studies have demonstrated that anti-p40 antibodies enhance mycobacterial growth, but that p19-deficient mice are indistinguishable from wild type animals as long as IL-12 is functional.[6] In contrast, patients deficient in the p40 subunit are more susceptible to low virulence nontuberculous Mycobacterium and Salmonella.[6]

Additional monoclonal antibodies targeting both IL-12/23 have been investigated for the treatment of psoriasis. Briakinumab, has been found to be associated with a significantly higher rate of major adverse cardiovascular events, infections, and nonmelanoma skin cancers as compared with placebo. Resultantly, this drug has been withdrawn from the market.[15] Conversely, ustekinumab, has shown a safer profile with a similar rate of adverse events in comaparison to placebo.[12]