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Although the histological changes seen in psoriasis have long been well characterized, the underlying cellular and molecular mechanisms have only begun to be elucidated over the past 20 years. Proinflammatory factors such as tumor necrosis factor (TNF)-α have a central role in psoriasis pathogenesis, and many T-helper 1 (Th1) cytokines and messenger RNAs are elevated in psoriatic lesions. IL-17A, IL-17F, and other Th17 cell–derived cytokines have been shown in murine models to induce features that mimic human psoriasis. This review focuses on the emerging biology of the IL-17 cytokine family in psoriasis, and on the molecular and genetic information gained from animal models and human clinical studies that confirm IL-17 as a crucial proinflammatory cytokine in psoriasis. Expression of IL-17A, IL-17C, and IL-17F is strikingly increased in psoriatic lesions, and successful therapy is associated with restoration of the expression of a wide range of genes (including effector molecules downstream of IL-17 such as cytokines, chemokines, and antimicrobial peptides) to near-normal levels. Therapeutic agents in development that target IL-17 are discussed, and an emerging model of the key role of IL-17 in the pathogenesis of psoriasis is presented.
Abbreviations
AMPs
antimicrobial peptides
mRNA
messenger RNAs
PASI
psoriasis area and severity index
Tc
cytotoxic T
Th1, T-helper 1; TNF-α
tumor necrosis factor-α
Introduction
Psoriasis is a chronic debilitating disease, affecting 1–2% of the Caucasian population (
). The histological changes observed within lesional skin include (1) a thickened epidermis from rapid keratinocyte proliferation and aberrant differentiation, (2) a reduced or absent granular layer, (3) marked dilatation of blood vessels in the papillary dermis, and (4) dense clusters of inflammatory cells composed of T cells and dendritic cells in the dermis, and CD8+ T cells and neutrophils in the epidermis (
). Histological abnormalities in psoriasis have been well described for decades and include multiple elements that indicate immune-mediated inflammation. However, the cellular and molecular mechanisms underlying the pathophysiological changes have only recently been brought into sharp focus by studies describing global alterations in the psoriasis lesional transcriptome, as well as the impressive success of targeted therapeutics in the clinic.
Our understanding of the role of various immune cells and inflammatory factors involved in psoriasis pathogenesis has progressed over the past 20 years. Early clinical studies, such as those with calcineurin inhibitors (
). The central role of proinflammatory factors in the development of psoriasis was demonstrated by the success of therapeutic agents that target tumor necrosis factor (TNF)-α in the treatment of psoriasis (
). TNF-α, a proinflammatory factor, is secreted by activated T cells and dendritic cells. The T-helper 1 (Th1) subset of activated T cells is the numerically dominant T-cell subset in psoriatic lesions (
) and has been the focus of much attention in psoriasis since the mid 1980s. Many recognized Th1 cytokines and messenger RNAs (mRNAs), including IFN-γ and TNF-α, are elevated in psoriatic skin lesions (
The majority of epidermal T cells in Psoriasis vulgaris lesions can produce type 1 cytokines, interferon-gamma, interleukin-2, and tumor necrosis factor-alpha, defining TC1 (cytotoxic T lymphocyte) and TH1 effector populations: a type 1 differentiation bias is also measured in circulating blood T cells in psoriatic patients.
). Development of Th1 cells is driven by IL-12, and a recent therapeutic agent targeting IL-12 through the shared IL-12/23p40 subunit, has also shown strong efficacy (
Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1).
). However, more recently, the focus has shifted toward a novel subset of T cells expressing IL-17: Th17 cells, which are also elevated in psoriatic lesions (
). Development of Th17 cells is driven by IL-23 and therefore, similar to Th1 cells, would be reduced by inhibition of the IL-12/23p40 shared subunit. Results from multiple rodent models of autoimmunity have led to a significant paradigm shift, with Th17 cells and IL-17 replacing the Th1 cells and associated cytokines as dominant mediators of tissue damage (
Genome-wide association studies and analysis of candidate genomic regions have implicated components of the IL-23 and IL-17 signaling pathways in the development of psoriasis (Table 1), further focusing attention on Th17 cells in this disease. This review will focus on the emerging role of IL-17 in psoriasis, with particular emphasis on the biology of IL-17 in the skin and the lessons learned from animal models and human clinical studies that confirm IL-17 as a crucial cytokine in psoriasis.
Table 1Summary of genetic association data for IL-17–related genes involved in psoriasis
The Role of IL-17 in Immune Defense and in Preclinical Disease Models
T-helper 17 cells are CD4+ effector T-helper cells that are distinct from the classic Th1 and Th2 lineages. They are defined most notably by the ability to produce large quantities of IL-17A and are thought to have evolved to provide both innate and adaptive immunity against pathogens (
Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells.
). Th17 cells are subsequently activated by IL-23, IL-1β, and IL-21 to produce multiple inflammatory factors in addition to IL-17A, including IL-17F and IL-22, although this latter cytokine is produced to a much greater extent in murine Th17 cells than in human cells (
). In humans, Th17 and a separate type of IL-22–producing cells called Th22 cells have been identified, but the classification of T-helper sets is not simple. Human dermal T cells have been shown to produce any combination of IL-17, IL-22, and IFN-γ, although the number of cells uniquely producing either IL-17 or IL-22 exceeds the number producing both (
). The relative production of various cytokines in individual Th17 cells is influenced by the levels of different activating signals, most notably from cytokines and pathogens (
). In addition to Th17 cells, a subset of cytotoxic T cells (Tc) that also produce IL-17 (Tc17) is present in psoriatic lesions; these cells also produce Th17-related cytokines, including IL-17A (
IL-17 is part of a family of cytokines consisting of the prototypical ligand, IL-17 (IL-17A), and five other IL-17 ligands (IL-17B through IL-17F; Figure 1;
). The IL-17 receptors consist of five receptor family members, namely, IL-17 receptor A through IL-17 receptor E. Among the several members of the IL-17 receptor family, IL-17 receptor A contains an extended cytoplasmic domain with unique signaling properties (
) and has been implicated as a heteromeric partner for other IL-17 receptors, when binding various ligands. IL-17A and IL-17F homodimers and heterodimers signal through the heteromeric receptor consisting of IL-17 receptor A and IL-17 receptor C (
). It is unclear whether the receptors for IL-17B and IL-17D are heteromeric, and whether IL-17 receptor A may be a common co-receptor for all IL-17 family ligands.
Figure 1IL-17 family ligands and receptors. There are six well-defined IL-17 ligands and five receptors. The IL-17A, IL-17F, and IL-17C ligands have elevated expression in psoriatic skin and have their presumed major cellular sources in the skin highlighted, although other sources may contribute. Those three ligands, and IL-17E (IL-25), have demonstrated heteromeric receptor complexes, which in all cases include the IL-17 receptor A subunit and one specific other IL-17 receptor subunit partner. Major cytoplasmic factors interacting with the IL-17 receptor complex are shown, as an example, for the IL-17RA/RC complex, where they are best studied. The IL-17A and IL-17F ligands form homo- and heterodimeric complexes. A dimeric state of the other ligands is illustrated by analogy, but has not been demonstrated, and the exact stoichiometries of the heteromeric receptor complexes are not fully determined. The ligand–receptor interactions are less well defined for IL-17B and IL-17D, and the requirement for an IL-17 receptor A subunit is unknown. GI, gastrointestinal; IL-17R, IL-17 receptor; LTi, lymphoid tissue inducer; Mφs, macrophages; NKT, natural killer T; Th17, T-helper 17.
IL-17A acts on a variety of cell types including endothelial cells, fibroblasts, chondrocytes, synovial cells, monocytes, and epithelial cells including keratinocytes (
). IL-17A and IL-17F act directly on keratinocytes to stimulate the production of a number of molecules known to be elevated in psoriasis lesional tissue such as cytokines, β-defensins, and antimicrobial peptides (AMPs), and neutrophil-, macrophage-, and lymphocyte-attracting chemokines such as IL-8, CCL20 (also called macrophage inflammatory protein-3α), and CCL2 (also called monocyte chemotactic protein 1;
). IL-17C, similar to IL-17A and IL-17F, has also recently been demonstrated to act on keratinocytes to induce human β-defensin 2 and granulocyte colony–stimulating factor (
). IL-17E (IL-25) is distinct from IL-17A, IL-17C, and IL-17F in that it is generally produced by epithelial cells during an allergic response and acts to induce Th2-type responses (
); therefore, these cytokines likely do not have a major role in the development of psoriasis.
There is evidence suggesting involvement of the IL-17 system in antimicrobial defense via the maintenance of mucocutaneous immunity. In contrast to the low fungal burdens in mice lacking IL-12 or IL-22, IL-17RA-deficient mice are more susceptible to Candida albicans infections (
). This susceptibility is also evident in rare human genetic diseases associated with chronic mucocutaneous candidiasis that are linked to lack of IL-17 signaling, either through autosomal IL17RA or IL17F mutations (
). Finally, in a distinct but phenotypically related genetic twist-of-fate, most patients with hyper-IgE syndrome, who tend to be affected by mucocutaneous candidiasis and Staphylococcus aureus infections, have dominant negative mutations in STAT3, which can lead to Th17 and IL-17 deficiency due to a loss in the IL-6 and IL-23 signaling required for Th17 lineage induction and stabilization (
). The degree to which these human genetic diseases that affect either IL-17/IL-17R or Th17 cells (and hence affect a broad number of cytokines) are relevant to partial blockade with antagonists specific to IL-17/IL-17R will be further informed by ongoing clinical studies.
In addition to their potential role in mucocutaneous immunity, Th17 cells also may be involved in vascular inflammation, including atherosclerotic plaque responses to Chlamydophila pneumoniae (
). A proatherogenic role for IL-17A is supported by the lack of atherosclerotic changes associated with coronary artery defects in patients with hyper-IgE syndrome (
8-methoxypsoralen plus ultraviolet A therapy acts via inhibition of the IL-23/Th17 axis and induction of Foxp3+ regulatory T cells involving CTLA4 signaling in a psoriasis-like skin disorder.
8-methoxypsoralen plus ultraviolet A therapy acts via inhibition of the IL-23/Th17 axis and induction of Foxp3+ regulatory T cells involving CTLA4 signaling in a psoriasis-like skin disorder.
), suggesting that IL-23 is the dominant p40-containing cytokine in psoriasis. IL-23 is known to induce IL-22 in addition to IL-17A, and inhibition of IL-22 has been shown to be efficacious in at least one mouse model of psoriasis (
). Direct injection of IL-22 into mouse ears or human skin equivalents is sufficient to induce some gene expression changes similar to psoriasis, as well as keratinocyte hyperplasia and parakeratosis (
The effects of IL-20 subfamily cytokines on reconstituted human epidermis suggest potential roles in cutaneous innate defense and pathogenic adaptive immunity in psoriasis.
). It is therefore possible that inhibition of IL-22 in addition to IL-17A would be required for full efficacy seen with IL-23 inhibition. However, IL-17 receptor A knockout mice (which lack signaling through multiple IL-17 family members) were shown to be as resistant as IL-23 knockout mice in a psoriasis-like model in which lesions are induced by imiquimod, a toll-like receptor 7/8 ligand (
We sought to address the question of differential efficacy by comparing IL-23 and IL-17 (both ligand and receptor) inhibition in a preclinical model of skin inflammation (Amgen, unpublished data on file). In this model, IL-36α (IL-36α/IL-1F6; an IL-1 ligand family member) transgenic mice under the control of a keratinocyte (K14) promoter were treated with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (
). This model allowed direct comparison of inhibition of IL-12/23p40, IL-23, IL-17A and IL-17F, and IL-17 receptor A. Similar to published studies, IL-12/23p40– and IL-23–specific antagonism was highly efficacious (
), whereas IL-17A–specific inhibition was only moderately effective (Amgen, unpublished data on file). Antagonism of IL-17F alone was similar to isotype control antibody. Interestingly, inhibition of IL-17 receptor A provided greater benefit over IL-17A-specific inhibition and was as efficacious as IL-23 inhibition. These data suggest that combined inhibition of multiple IL-17 family ligands through targeting of IL-17 receptor A may have more profound effects in the skin than inhibition of IL-17A alone and that inhibition of IL-22 is not necessary to achieve efficacy comparable to IL-23 inhibition (Amgen, unpublished data on file). Furthermore, these data suggest that another IL-17 family member in addition to IL-17A and IL-17F may be playing a role in the skin. IL-17C has recently been demonstrated to act on keratinocytes to induce proinflammatory cytokines, chemokines, and AMPs, and this activity requires both IL-17 receptor E and IL-17 receptor A (
), further suggesting that IL-17C, in addition to IL-17A, could be contributing to the efficacy seen with IL-17 receptor A inhibition in the IL-36 transgenic model of psoriasis. These data collectively suggest that inhibition of one or more IL-17 family members has therapeutic potential for psoriasis.
Biology of IL-17 in Human Psoriasis
There is substantial evidence demonstrating the central contribution of Th17 cells and, more directly, IL-17 to plaque psoriasis in humans (
). Genome-wide association and other genetic studies clearly have linked multiple IL-17–related genes to psoriasis pathogenesis (Table 1). The molecular and cellular analyses of psoriatic skin have increased our understanding of disease pathogenesis beyond a Th1-driven disease, which was generally accepted until relatively recently. Finally, the remarkable and exciting results in clinical trials have confirmed the central contribution of IL-17 to psoriasis, including both a correlation of IL-17 pathway changes with successful therapy as well as demonstration of the direct effects of inhibition of both IL-17A and IL-17 receptor A.
Expression of IL-17A, IL-17C, and IL-17F is elevated in psoriatic lesional tissue compared with nonlesional tissue (
Blockade of the IL-17R with AMG 827 leads to rapid reversal of gene expression and histopathologic abnormalities in psoriatic skin, including substantial pathway-specific effects within one week (abstract 065).
). Paired punch biopsies from lesional skin from patients with psoriasis showed significantly higher protein levels of IL-17A, IL-17C, and IL-17F (6.7-fold, 4.1-fold, and 8-fold higher, respectively) compared with nonlesional skin (
). Recent studies have suggested that many of these IL-17–positive cells could be CD8+ T cells (Tc17), lymphoid tissue–inducer cells, mast cells, and/or neutrophils rather than T-helper cells (
). The relative contribution of these different cell types will be important in understanding their role in psoriasis pathogenesis.
Human genetic studies have shown that several of the risk alleles involved in psoriasis may be risk alleles for other autoimmune disorders (recently reviewed by
): IL23A, IL12B, IL23R, and tyrosine kinase 2 (TYK2). IL23A and IL23R are specific to IL-23 signaling and IL12B codes for the shared IL12/23p40 subunit; TYK2 is a signaling kinase downstream of IL-12 and IL-23 (
). Notably, the association studies have failed to demonstrate a role for IL-12/Th1 pathway–specific genes such as IL12A, IL12RB2, and IFNG. Thus, the genetic evidence aligns more closely with a Th17 rather than Th1 immune skewing in psoriasis.
There are a number of genes associated with psoriasis that may function downstream of the IL-17 receptor signaling. Of particular recent interest is TRAF3IP2 coding for the Act-1 protein (also known as TRAF3-interacting protein 2), an intracellular protein that directly binds the IL-17 receptor complex (
). Act-1 can initiate two different signal transduction pathways in response to IL-17R activation. NF-κB signaling events can be initiated through interactions with TRAF6 (
). In the TRAF6-independent pathway, Act-1 can bind to TRAF5 and sequester the RNA binding factor SF2, leading to stabilization of inflammatory mRNAs (
) and thus presumably have decreased IL-17R–dependent NF-κB signaling, although this was not specifically demonstrated. This suggests the possibility that the psoriasis risk may be driven by increased proinflammatory activity through the Act1-TRAF5 mRNA stabilization pathway. Additional candidate genes implicated in psoriasis include other NF-κB pathway regulatory genes (REL, TNIP1, TNFAIP3, and NFKBIA) and increased copy number of the gene segment harboring the IL-17–regulated gene, DEFB4, which encodes for human β-defensin 2 (Table 1).
The presence of both Th1 and Th17 subsets in psoriasis may seem counterintuitive given that these two polarized subsets have counter inhibitory effects on each other (
). In addition, there appears to be considerable plasticity in this system; Th17 cells have the ability to differentiate into IFN-γ–producing Th1 cells (
) although not vice versa. CD8+ T cells are found in increased numbers in the psoriatic epidermis, including subsets producing IFN-γ (Tc1), IL-17 (Tc17), and/or IL-22 (Tc22;
). The notable presence of Tc17 cells in the epidermis, where IL-17 receptor is abundantly expressed on keratinocytes, suggests a potential pathogenic role for this subset of IL-17–producing cells (Figure 2).
Figure 2A model for the central role of IL-17 in psoriasis pathogenesis. This model includes core inflammatory elements that establish a self-reinforcing cycle, including T-helper 17 (Th17) skewing of naive T cells in the presence of IL-23 leading to the local production of IL-17 ligands. Keratinocytes in turn are stimulated by these IL-17 ligands, leading to an aberrant differentiation program and elevated production of proinflammatory factors including antimicrobial peptides (AMPs) and chemokines (including CCL20, which attracts both Th17 cells and dendritic cells [DCs]). These keratinocyte-derived factors in turn stimulate further recruitment of inflammatory cells, including IL-17–producing cells, and establish a self-sustaining inflammatory feedback loop. CXCLs, CXC ligands; Tc, T cytotoxic; TNF, tumor necrosis factor.
Global gene expression studies have consistently demonstrated the upregulation of the IL-17 pathway in psoriasis. Several studies have used quantitative real-time PCR assays to show increased expression of IL-17 ligands and the IL-23 subunits in lesional skin compared with both nonlesional and normal skin (
), and successful therapy is accompanied by rapid and nearly complete reversion of expression of a wide range of genes (including cytokines, AMPs, and downstream effector molecules) to near normal (nonlesional) levels, suggesting that these alterations in gene expression are necessary for therapeutic response (
Blockade of the IL-17R with AMG 827 leads to rapid reversal of gene expression and histopathologic abnormalities in human psoriatic skin (abstract 273).
Blockade of the IL-17R with AMG 827 leads to rapid reversal of gene expression and histopathologic abnormalities in psoriatic skin, including substantial pathway-specific effects within one week (abstract 065).
). Again, elements upstream and downstream of IL-17 show higher expression, implicating the pathway in psoriasis. Notably, among the genes that are universally overexpressed across several studies are those for IL-17A and IL-17F, IL-23, and a number of proinflammatory genes regulated by IL-17A in keratinocytes, such as β-defensin, neutrophil chemoattractants, and the chemokine CCL20 (
Consistent with the results described above is the observation that IL-17 ligands (including both IL-17A and IL-17C) and TNF-α amplify each other's effects, both additively and synergistically, and their combined activity accounts for many of the key inflammatory pathways in psoriasis (
). Some of this synergy may be the result of the distinct mechanisms by which IL-17 and TNF each regulate downstream gene expression. The TNF receptor stimulates several pathways that activate gene transcription, while major activities downstream of the IL-17 receptor include modulation of NF-κB signaling and stabilization of mRNAs induced by TNF (
). The synergistic interaction between IL-17 and TNF, as well as the regulation of IL-17 by IL-23, is a potential unifying theme in understanding the success of different therapeutic agents in psoriasis, including the calcineurin inhibitors, and antibodies targeting TNF, IL-12/23-p40, IL-23p19, IL-17A, and IL-17 receptor A.
Role of IL-17 Inhibition in the Clinic
Along with our understanding of disease pathophysiology, therapeutic efficacy in psoriasis has also advanced tremendously over the past 20 years. Clinical response to TNF antagonism in psoriasis has been shown to correlate with the rapid early reduction of IL-23 and IL-17A, followed by later reductions in Th1-associated genes (
Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1).
Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2).
Results of a single ascending dose study to assess the safety and tolerability of CNTO 1959 following intravenous or subcutaneous administration in healthy subjects and in subjects with moderate to severe psoriasis (abstract FC-21).
) antagonists have also demonstrated clinical efficacy and support the role of IL-12/IL-23 and Th17 cells in the pathogenesis of psoriasis. Although the key cytokines released from human Th17 cells that drive psoriasis pathogenesis, including IL-22 and/or IL-17, remain unclear, direct antagonism of the IL-17A ligand (
LY2439821, a humanized anti-interleukin-17 monoclonal antibody, in the treatment of patients with rheumatoid arthritis: a phase I randomized, double-blind, placebo-controlled, proof-of-concept study.
Inhibition of IL-17A by secukinumab is ineffective for Crohn's disease (CD) (abstract 10).
in: Paper presented at the 6th Congress of the European Crohn′s and Colitis Organisation-Inflammatory Bowel Diseases, Dublin, Ireland; 24–26 February 20112011
Blockade of the IL-17R with AMG 827 leads to rapid reversal of gene expression and histopathologic abnormalities in human psoriatic skin (abstract 273).
Blockade of the IL-17R with AMG 827 leads to rapid reversal of gene expression and histopathologic abnormalities in psoriatic skin, including substantial pathway-specific effects within one week (abstract 065).
) have demonstrated striking results in early-phase clinical trials in psoriasis.
Secukinumab (AIN457) is an anti–IL-17A ligand mAb that has been assessed for the treatment of psoriasis, rheumatoid arthritis, chronic noninfectious uveitis, and Crohn's disease (
Inhibition of IL-17A by secukinumab is ineffective for Crohn's disease (CD) (abstract 10).
in: Paper presented at the 6th Congress of the European Crohn′s and Colitis Organisation-Inflammatory Bowel Diseases, Dublin, Ireland; 24–26 February 20112011
). A phase 1 study in 36 patients with psoriasis showed that a single dose of secukinumab at 3mgkg−1 significantly reduced disease severity (mean psoriasis area and severity index [PASI] score) by 63% at week 12 versus 9% for placebo (
). Clinical responses were associated with reductions in epidermal hyperplasia, expression of IL-17A+ and CD3+ cells from immunostained micrographs, and gene expression of various cytokines and chemokines (e.g., IL-17A, IL-21, IL-22, CCL20, KRT16, and DEFB4;
). Data from three phase 2 studies showed 12-week PASI75 response rates of 81% in patients with psoriasis treated with subcutaneous secukinumab 150mg (three or four doses) and 83% in patients treated with intravenous secukinumab 10mgkg−1 (three doses;
Secukinumab, a new fully human monoclonal anti-interleukin-17A antibody, in the treatment of moderate-to-severe plaque psoriasis: interim efficacy and safety data from a phase II regimen-finding trial (oral presentation FC01.6).
in: Paper presented at the 20th Congress of the European Academy of Dermatology and Venereology, Lisbon, Portugal; 20–24 October 20112011
Secukinumab efficacy and safety preliminary results from a phase II subcutaneous dose-ranging study in the treatment of moderate-to-severe plaque psoriasis (oral presentation FC01.5).
in: Paper presented at the 20th Congress of the European Academy of Dermatology and Venereology, Lisbon, Portugal; 20–24 October 20112011
Secukinumab, a novel fully human antibody to interleukin-17A in the treatment of moderate-to-severe plaque psoriasis: efficacy and safety interim results from a phase II intravenous induction dose-ranging study (oral presentation FC01.7).
in: Paper presented at the 20th Congress of the European Academy of Dermatology and Venereology; 20–24 October 20112011
LY2439821, a humanized anti-interleukin-17 monoclonal antibody, in the treatment of patients with rheumatoid arthritis: a phase I randomized, double-blind, placebo-controlled, proof-of-concept study.
). Recent data from a phase 2 study showed week 12 PASI75 response rates of 77%, 83%, and 82% following administration of subcutaneous ixekinumab 25mg, 75mg, and 150mg (weeks 0, 2, 4, 8, and 12), respectively, versus 7.7% for placebo (
). Up to 72% of patients in the active-treatment groups achieved clear/almost clear status according to Physician's Global Assessment.
Brodalumab (AMG 827) is an IL-17 receptor A mAb that is under investigation for a number of inflammatory conditions, including psoriasis, psoriatic arthritis, and asthma. A phase 1 proof-of-concept study in patients with psoriasis demonstrated significant improvements in clinical parameters: seven of eight and five of eight patients achieved PASI75 by week 6 in the high (700mg intravenous) and moderate (350mg subcutaneous) single-dose groups, respectively (
Blockade of the IL-17R with AMG 827 leads to rapid reversal of gene expression and histopathologic abnormalities in human psoriatic skin (abstract 273).
Blockade of the IL-17R with AMG 827 leads to rapid reversal of gene expression and histopathologic abnormalities in psoriatic skin, including substantial pathway-specific effects within one week (abstract 065).
). Improvements in histopathological parameters included reductions in epidermal thickness, Ki-67 counts (an index of proliferation-specific nuclear antigen;
Blockade of the IL-17R with AMG 827 leads to rapid reversal of gene expression and histopathologic abnormalities in human psoriatic skin (abstract 273).
Blockade of the IL-17R with AMG 827 leads to rapid reversal of gene expression and histopathologic abnormalities in psoriatic skin, including substantial pathway-specific effects within one week (abstract 065).
). In a phase 2 dose-ranging study, AMG 827 (70, 140, or 210mg at weeks 0, 1, and 2, then every other week or 280mg monthly) produced dose-dependent improvements in PASI and Physician Global Assessment responses (
). Significant mean PASI improvements at week 12 were 45%, 86%, 86%, and 76% in the AMG 827 70-, 140-, 210-, and 280-mg groups, respectively, compared with 16% in the placebo group. PASI75 responses were observed in 33%, 77%, 82%, and 67% of patients, respectively, in the AMG 827 groups and 0% in the placebo group. Similar results were observed for other PASI measures and Physician's Global Assessment, with up to 85% of patients in the AMG 827 groups achieving clear/almost clear status.
The significant clinical responses in patients with psoriasis following blockade of either IL-17 receptor A (with brodalumab) or its ligand IL-17A (with secukinumab and ixekinumab) confirm the hypothesis that IL-17 signaling has a critical role in this immune-mediated disease. Furthermore, the complete reversal of regenerative epidermal hyperplasia and high PASI responses seen with AMG 827 implies that factors signaling through the IL-17 receptor A, including IL-17A, IL-17C, and IL-17F, are central drivers of psoriasis immunopathogenesis.
An Emerging Model for the Role of IL-17 in Psoriasis Pathogenesis
This review has focused on the emerging role of IL-17 in the pathogenesis of psoriasis, including preclinical results, genetic data, and both indirect and direct evidence from clinical studies. These findings demonstrate the central importance of this innate family of proinflammatory cytokines in psoriasis. A model for the role of various factors in psoriasis pathogenesis is presented in Figure 2. Notable features in this model include a set of core inflammatory elements that establish a self-reinforcing cycle, along with ancillary proinflammatory elements that synergize with and amplify the core elements. The core elements include: (a) naive T-cell skewing into the Th17 lineage following interaction with activated dendritic cells in the presence of IL-23; (b) local Th17 production of IL-17A and IL-17F; and (c) keratinocyte stimulation by IL-17 ligands leading to aberrant differentiation and proliferation and the production of proinflammatory AMPs, chemokines, and angiogenic factors, which in turn stimulate further recruitment of inflammatory cells, setting up a positive feedback loop. The chemokine CCL20 is a notable keratinocyte-derived core component that functions to recruit both inflammatory dendritic cells and Th17 cells into active lesional skin. Additional ancillary factors in this inflammatory network include cytokines (e.g., IL-22, which promotes keratinocyte alterations, and TNF, which can synergize with IL-17 ligands to promote inflammation); Th1 and Th22 cells, which amplify the core response via the production of inflammatory factors; and keratinocyte-derived angiogenic and chemoattractant factors. The core and ancillary elements in this model function together to establish an activated inflammatory network, ultimately resulting in the formation of psoriasis lesions.
Advances in genetics and immunology have enabled the development of targeted therapeutics in psoriasis, a number of which have shown impressive clinical efficacy. Clinical and molecular data from these therapeutic successes have provided additional opportunities to focus on and identify inhibitors or central drivers of psoriasis pathogenesis, including therapeutics targeting the IL-17 family. As our understanding of psoriasis pathogenesis increases, the parallel evolution of increasingly selective therapies may provide patients with an optimal balance between increased clinical benefit and reduced risk for side effects. The early clinical results from inhibition of IL-17 (ligand or receptor) have established this cytokine as a core downstream element in psoriasis, and ongoing late-phase studies will allow further confirmation of these findings.
ACKNOWLEDGMENTS
We thank Rick Davis, whose work was funded by Amgen, and Meera Kodukulla of Amgen for assistance in drafting the manuscript. JEG is supported by NIH K08 AR060802 and A. Alfred Taubman Medical Research Institute as the Kenneth and Frances Eisenberg Emerging Scholar. We also thank Dirk Smith, of Amgen, for graphical support.
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Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells.
The majority of epidermal T cells in Psoriasis vulgaris lesions can produce type 1 cytokines, interferon-gamma, interleukin-2, and tumor necrosis factor-alpha, defining TC1 (cytotoxic T lymphocyte) and TH1 effector populations: a type 1 differentiation bias is also measured in circulating blood T cells in psoriatic patients.
LY2439821, a humanized anti-interleukin-17 monoclonal antibody, in the treatment of patients with rheumatoid arthritis: a phase I randomized, double-blind, placebo-controlled, proof-of-concept study.
Inhibition of IL-17A by secukinumab is ineffective for Crohn's disease (CD) (abstract 10).
in: Paper presented at the 6th Congress of the European Crohn′s and Colitis Organisation-Inflammatory Bowel Diseases, Dublin, Ireland; 24–26 February 20112011
Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1).
Secukinumab efficacy and safety preliminary results from a phase II subcutaneous dose-ranging study in the treatment of moderate-to-severe plaque psoriasis (oral presentation FC01.5).
in: Paper presented at the 20th Congress of the European Academy of Dermatology and Venereology, Lisbon, Portugal; 20–24 October 20112011
Secukinumab, a novel fully human antibody to interleukin-17A in the treatment of moderate-to-severe plaque psoriasis: efficacy and safety interim results from a phase II intravenous induction dose-ranging study (oral presentation FC01.7).
in: Paper presented at the 20th Congress of the European Academy of Dermatology and Venereology; 20–24 October 20112011
Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2).
Secukinumab, a new fully human monoclonal anti-interleukin-17A antibody, in the treatment of moderate-to-severe plaque psoriasis: interim efficacy and safety data from a phase II regimen-finding trial (oral presentation FC01.6).
in: Paper presented at the 20th Congress of the European Academy of Dermatology and Venereology, Lisbon, Portugal; 20–24 October 20112011
Blockade of the IL-17R with AMG 827 leads to rapid reversal of gene expression and histopathologic abnormalities in psoriatic skin, including substantial pathway-specific effects within one week (abstract 065).
Blockade of the IL-17R with AMG 827 leads to rapid reversal of gene expression and histopathologic abnormalities in human psoriatic skin (abstract 273).
The effects of IL-20 subfamily cytokines on reconstituted human epidermis suggest potential roles in cutaneous innate defense and pathogenic adaptive immunity in psoriasis.
8-methoxypsoralen plus ultraviolet A therapy acts via inhibition of the IL-23/Th17 axis and induction of Foxp3+ regulatory T cells involving CTLA4 signaling in a psoriasis-like skin disorder.
Results of a single ascending dose study to assess the safety and tolerability of CNTO 1959 following intravenous or subcutaneous administration in healthy subjects and in subjects with moderate to severe psoriasis (abstract FC-21).
published online 7 June 2012 The “bench” and “bedside” may never come together at one site, as depicted in this fictitious scenario of a “molecular surgeon” using a pipette instead of a scalpel to treat her patient, directly in the laboratory. Nevertheless, advances in clinical care are most likely when laboratory-based investigators and clinicians work together closely in beside-to-bench and bench-to-bedside collaborations. This image symbolizes the need for such interactions in order to best serve our patients' needs. Examples of needed unity among stakeholders across the broad dermatology community will be the subject of monthly editorials and cover images throughout 2013, which we have designated the Year of Unity. Image created by Thomas M. Ruenger, Deputy Editor.
Footnotes
DAM, CBR, JET, GK, and PK are employees and stock holders of Amgen. JEG has been a consultant for Novartis. JGK has been a consultant for Astellas, Amgen, Biogen, Boehringer, Centocor (Janssen), Celgene, GSK, Lilly, Merck, Novartis, and Pfizer; has been an investigator for Boehringer, Centocor (Janssen), Lilly, Merck, Novartis, and Pfizer; has received honoraria from Astellas, Biogen, Boehringer, Centocor (Janssen), Celgene, Lilly, Merck, and Pfizer; and has received research grants from Amgen, Boehringer, Centocor (Janssen), Lilly, Merck, and Pfizer.
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