Ramya Kollipara, MD1; Christopher Downing, MD1; Rachel Gordon, MD2; Stephen Tyring, MD, PhD1

1Center for Clinical Studies, Houston, TX, USA
2Department of Dermatology, University of Texas Health Science Center at Houston, Houston, TX, USA

In the past three decades, major advances have been made in understanding the pathogenesis of psoriasis. The currently accepted theory is that T-cell mediated immune dysregulation triggers keratinocyte hyperproliferation in psoriasis. Recent research indicates that the Th17/interleukin (IL)-23 pathway plays a prominent role in the amplification phase of psoriasis. The discovery of the Th17/ IL-23 pathway provides targets for new drug development. This review focuses on the role of IL-23 in psoriasis pathogenesis and the current therapies targeting IL-23 that are in clinical trials.

Key Words:
cytokine, interleukin-23, IL-23, guselkumab, tildrakizumab, Th17, psoriasis


In the past three decades, major strides have been made in understanding the pathogenesis of psoriasis. While psoriasis pathogenesis originally focused on keratinocyte hyperproliferation, the currently accepted theory is that of T-cell mediated immune dysregulation.1,2 While the T helper cell (Th) 1/interferon-gamma (IFN-γ) pathway was originally heavily implicated in the amplification phase, recent research indicates that the Th17/interleukin (IL)-23 pathway plays the more dominant role.3 This review focuses on the role of IL-23 in psoriasis pathogenesis and the current therapies targeting IL-23 that are in clinical trials.


IL-23 is composed of two subunits, p19 and p40, which are linked by a disulfide bond. The p19 subunit is a unique component of IL-23. Alternatively, the p40 subunit is a component of IL-12 as well.4 IL-23 is produced by keratinocytes and activated antigen-presenting cells (APCs), specifically Langerhans cells, macrophages and dendritic cells. IL-23 is expressed by APCs in the presence of Toll-like receptor (TLR) agonists (lipopolysaccharde, CpG and PolyI:C).5 The IL-23 receptor is present on memory T cells, natural killer (NK) T cells, macrophages, dendritic cells and naïve T cells.6

IL-23 is the key cytokine that propels naïve T cell differentiation to Th17 cells.6 It is essential in bridging the innate and adaptive immune responses and orchestrating the early local immune response. When IL-23 binds to the IL-23 receptor, the complex activates Jak2 and Tyk, members of the Janus family of tyrosine kinases, leading to phosphorylation of the receptor complex and eventually phosphorylation of signal transducer and activator of transcription 3 (STAT3). STAT3 phosphorylation triggers differentiation to Th17 cells.7 Transforming growth factor-beta (TGF-β), IL-6, IL-1β and IL-21 are also needed to coordinate production of Th17 cells.8 However, IL-23 appears to be the main cytokine in this process as studies have shown that IL-6, IL-1β and TGF-β in the absence of IL-23 result in production of regulatory T cells that inhibit inflammation.9

The Th17/IL-23 Pathway in the Immunopathogenesis of Psoriasis

In considering the pathophysiology of psoriasis, it can be divided into two distinct immune-mediated phases: the initial and amplification phases.5 In the initial phase, trauma to keratinocytes or stimulation of TLR receptors in genetically predisposed skin leads to activation of the innate immune system. This cataclysm of macrophages, dendritic cells and diverse cytokines triggers the production of IL-12 and IL-23. These two cytokines provide the bridge to the amplification phase, which is characterized by the adaptive immune response.5 The intricacies of this amplification have been the source of much debate over the last three decades, specifically in regards to which Th pathway drives this phase.

In the 1990s, clinical studies demonstrated elevated levels of the p40 subunit in psoriatic lesions. At the time, the high expression of p40 was correlated to elevated levels of IL-12 (a component of the Th1 pathway) because IL-23 had not yet been discovered.10 This theory further propagated the theory that the Th1 pathway is key in orchestrating the amplification phase of psoriasis. However, recent evidence has revealed that the elevated p40 level in psoriasis is due to IL-23, not IL-12. In a study done by Lee and colleagues, p40 and p19 mRNA were elevated in psoriatic lesions, but p35 mRNA, which is specific to IL-12, was not increased in lesional skin.3 Another study highlighted the presence of IL-23- staining cells in palmoplantar pustulosis, hyperkeratotic hand dermatitis and lesional psoriasis biopsies. Furthermore, IL-23 levels in psoriatic skin appear to correspond with the clinical course of the patient.11 IL-23 injections in mice skin have also induced histological changes seen in psoriatic skin, specifically epidermal acanthosis and parakeratosis. IL-12 injections did not have the same effect.12 Finally, many genetic studies in psoriasis patients have demonstrated a strong association with genetic loci encoding the IL-23 p19 subunit and IL-12/23 p40 subunit, but not the IL-12 p35 subunit.13,14 Taken together, this data points to the prevailing role of the Th17/IL-23 pathway in psoriatic disease.

The Th17/IL-23 pathway promotes chronic inflammation. Th17 cells secrete two IL-17 cytokines, IL-17A and IL-F, and also IL-21, IL-22, IL-26 and IFN-γ. All of these cytokines activate the inflammatory cascade and provoke irregular cellular replication and maturation in psoriasis.15 IL-17A is a potent pro-inflammatory cytokine that triggers keratinocyte production of pro-neutrophilic chemokines, including CXCL1, CXCL5, and CXCL8. These chemokines orchestrate neutrophilic migration into psoriatic lesions, which stimulates keratinocyte proliferation.16 IL-17 also inhibits neutrophil apoptosis, stimulates angiogenesis, augments tissue remodeling and synergistically with tumor necrosis factor-alpha enhances inflammation.17 IL-22 causes keratinocyte hyperproliferation and increases keratinocyte production of antimicrobial proteins. It is because of these antimicrobial proteins that psoriatic skin lesions are rarely infected.17 Both IL-17A and IL-22 have also been found to stimulate keratinocyte production of CCL20, a chemokine overproduced in psoriasis. It is hypothesized that CCL20 promotes maintenance of psoriatic lesions by enhancing chemotaxis of CCR6+ Th17 and dendritic cells to diseased skin.18

Although there is convincing data about the significant role the Th17/IL-23 pathway plays in late-stage psoriasis, there remain many questions. It is still unclear why IL-23 is preferentiallyproduced in psoriatic skin. Is it a genetic predisposition or a dysregulation of the innate immune response? Furthermore, it is unclear what the specific antigen is that dendritic cells present to antigen-specific Th17 cells. Hypotheses have ranged from an external antigen to an autoantigen.17

Psoriasis Therapies Targeting IL-23

Given the initial discovery of elevated p40 levels in psoriatic skin, novel biologics, specifically ustekinumab and briakinumab, were developed to target this p40 subunit. These agents target the p40 subunit of IL-12 and IL-23 and, thus, both the IL-12/Th1 and Th17/IL-23 pathways.10 Despite the efficacy and favorable safety profile of ustekinumab, drug development has moved towards solely targeting the IL-23/Th1 pathway given its dominant role in psoriatic disease and the theoretical risk of blocking the IL-12/Th1 pathway.


Tildrakizumab, alternatively known as MK-3222 or SCH900222, is a human immunoglobulin G1 (IgG1) monoclonal antibody that targets only the p19 portion of IL-23. Since tildrakizumab does not target the p40 subunit of IL-23, it does not affect IL-12 activity.19

The results of a Phase IIb randomized, controlled, dose-ranging study for tildrakizumab were presented at the American Academy of Dermatology 71st Annual Meeting in March 2013. In this study, 335 patients with moderate to severe plaque psoriasis were randomized to receive tildrakizumab 5 mg, 25 mg, 100 mg, 200 mg or placebo at weeks 0, 4, and then every 12 weeks for 52 weeks. The primary endpoint, PASI-75 at week 16, was attained by 33%, 64%, 66%, 74%, and 4% of the 5 mg, 25 mg, 100 mg, 200 mg, and placebo groups respectively. The secondary endpoint, achieving a physician global assessment (PGA) of “clear” or “minimal” at week 16, was achieved by 33%, 58%, 62%, 74%, and 2% of the 5 mg, 25 mg, 100 mg, 200 mg, and placebo groups respectively. The adverse event rate in the treatment groups ranged from 60% to 71% compared to 69% in the placebo group. The most common adverse event was nasopharyngitis. Serious adverse events (including one death) were rare, occurring in only four patients. None of the serious adverse events were linked to tildrakizumab.19,20

Of note, data from the proof of concept study demonstrated that 18% of patients treated with three doses of tildrakizumab developed antidrug antibodies. Of these patients with antibodies, 55% had decreased serum drug levels in contrast to patients without antidrug antibodies. However, patients with antidrug antibodies still attained PASI improvement comparable to patients without antidrug antibodies. Similarly, the safety profile did not differ either.21

Tildrakizumab is the first anti-IL-23 therapy for psoriasis to enter Phase III trials. There are currently two Phase III trials underway. The projected date for final collection of primary outcome data is June or July 2015 for both trials. This data has yet to be published. The study completion date for both studies is 2019.21,22


Guselkumab, or CNTO 1959, is a humanized IgG1 monoclonal antibody that targets the p19 subunit of IL-23.23

The results of X-PLORE, a Phase IIb randomized, controlled, doseranging study for guselkumab, were presented at the American Academy of Dermatology 72nd Annual Meeting in March 2014. In this study, patients with moderate to severe plaque psoriasis were randomized to receive either guselkumab 5 mg, 15 mg, 50 mg, 100 mg or 200 mg, placebo or adalimumab. The guselkumab was given at weeks 0, 4 and then every 12 weeks. The patients in the adalimumab group received an initial dose of 80 mg and then 40 mg every other week (starting one week after the initial dose). The primary endpoint, patients achieving a PGA of “clear” or “minimal” at week 16, was met by 34%, 61%, 79%, 86%, 83%, and 7% of patients in the guselkumab 5 mg, 50 mg, 15 mg, 100 mg, 200 mg, and placebo groups respectively. At week 16, PASI-75 was achieved by 44%, 76%, 81%, 79%, 81%, and 5% of the patients receiving guselkumab 5 mg, 15 mg, 50 mg, 100 mg, 200 mg, and placebo respectively. PASI 90 was achieved by 34%, 34%, 45%, 62%, 57%, and 2% of guselkumab 5 mg, 15 mg, 50 mg, 100 mg, 200 mg, and placebo-treated patients respectively. Comparatively, in the adalimumab group, 58%, 70%, and 44% of patients attained a PGA of “clear” or “minimal”, PASI-75 and PASI-90 respectively at week 16. At week 52, adverse events occurred in 66% of patients treated with guselkumab. Serious adverse events were experienced by 3% of guselkumab treated patients. Three patients had either a myocardial infarction or cerebrovascular accident but these were not linked to guselkumab treatment. No serious or opportunistic infections occurred in patients on guselkumab. One patient on guselkumab reported a malignancy (cervical cancer).24

Based on the above promising Phase II results, Phase III trials to further asses the efficacy of guselkumab are planned.25-27 Currently, there is a Phase II trial evaluating guselkumab for palmoplantar pustulosis as well as a Phase I trial to evaluate the pharmacokinetics of guselkumab in lyophilized versus liquid formulations.28,29 The estimated primary completion date for the palmoplantar pustulosis study is August 2014.28

Other Drugs Targeting IL-23 in the Pipeline

BI655066, manufactured by Boehringer Ingelheim Pharmaceuticals, is another drug targeting IL-23 that is currently in Phase II trials for psoriasis.30 It is a human IgG1 monoclonal antibody. MP-196, another monoclonal antibody targeting IL-23, is manufactured by TcL Pharma and is in preclinical development for psoriasis. Finally, there are several IL-23 receptor antagonists that have been patented but not tested in pre-clinical or clinical trials. Neutralization of the IL-23 receptor is a promising approach for psoriasis management as the IL-23 is only present on developing Th17 cells. Thus, blocking the IL-23 receptor can prevent activation of STAT3 and naïve T cell differentiation to a Th-17 cell.5


The discovery of the Th17/IL-23 pathway adds to the complexity of psoriasis pathogenesis and provides targets for new drug development. Not only are there upstream IL-23 p19 and IL-23 receptor neutralizing drugs in development, there are currently also downstream IL-17 antagonists in trials as well. Although these drugs are still years away from being FDA approved, they offer promise of more targeted, efficacious and safe psoriasis therapy in the future.


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