Discovery of the IL-23/IL-17 Signaling Pathway and the Treatment of Psoriasis

Psoriasis vulgaris is a common, heterogeneous disease associated with the spontaneous development of inflammatory skin lesions and systemic inflammation (1). The systemic inflammation associated with psoriasis results in an increased risk for death (2, 3) and significant psoriasis-associated comorbidities such as psoriatic arthritis, cardiovascular disease, stroke, metabolic syndrome (obesity, hypertension, dyslipidemia, and diabetes), chronic kidney disease, gastrointestinal disease, mood disorder, and malignancy (4). For the last three decades, patients with moderate-to-severe psoriasis have been treated with phototherapy or a variety of systemic medications including methotrexate, cyclosporine, and targeted mAbs such as TNF-α antagonists. However, a substantial proportion of psoriasis patients have disease that is inadequately treated with these first-generation systemic therapies either because of a primary response failure or gradual loss of efficacy. Patients also occasionally discontinue therapy because of treatment-related adverse events or comorbid conditions.

The discovery of the roles for IL-17 and IL-23 on the development of psoriatic disease has led to substantial increases in our understanding of the pathogenic immune events in psoriasis and has led to a paradigm shift in the treatment of this condition. Over the last few years, we have witnessed the Food and Drug Administration (FDA) approve several inhibitors of the IL-23/IL-17 signaling axis for the treatment of psoriasis. These new biologic therapies have proved to be highly effective and result in dramatic improvements in ∼80–90% of psoriasis patients. The unprecedented success of selective IL-17 and IL-23 antagonists for the treatment of psoriasis underscores the essential nature of these cytokines in the pathogenesis of this chronic inflammatory condition. In this article, we provide an overview of the major laboratory findings that led to the discovery of the dominant role of the IL-23/IL-17 axis in psoriatic disease and the subsequent development and clinical testing of novel IL-17 and IL-23 antagonists.

As definitive proof emerged showing that psoriasis was a T cell–mediated condition (5), subsequent work focused on the identification and characterization of the various T cell subsets found in the skin and blood. The initial characterization of specific T cell populations was determined by the cytokines produced by specific lymphocyte subsets. For example, CD4⁺ type 1 Th (Th1) cells were defined by their production of IFN-γ, whereas Th2 cells were associated with the production of IL-4, IL-5, and IL-13. These “polar” T lymphocyte subsets were frequently used as a method of categorizing autoimmune and inflammatory diseases based on their differential expression of Th1 versus Th2 cells. In this way, psoriasis was primarily considered to be a predominant Th1 condition because of a strong IFN-γ signature found in lesional tissues (6). Therefore, early disease models of psoriasis suggested that IFN-γ in cooperation with IL-12, a master regulator of Th1 cell development and differentiation, could be the principal driver of this disease (7, 8).

In the late 1990s, laboratory advances and structure-based alignment tools led to the discovery of novel cytokines related to IL-12. These “gene hunting” technologies identified a new dimeric cytokine that was structurally similar to IL-12 in that it shared its p40 subunit but also contained a unique p19 subunit (9). The pairing of these p40 and p19 subunits resulted in a novel heterodimeric cytokine that was later named IL-23. Given the structural similarities between IL-23 and IL-12, as well as their concomitant production by activated phagocytic and dendritic cells (DCs), it was reasonable to assume that IL-23 could also regulate the differentiation of the Th1 cell subset. However, it was shown that IL-23 stimulated the production of IL-17 from a subset of CD4⁺ T cells that were negative for IFN-γ and IL-4, a finding that challenged the conventional Th1–Th2 classification system (10).

Definitive proof for a novel IL-17–producing subset of T helper cells (Th17) under the regulation of IL-23 came as a result of studies involving the experimental autoimmune encephalomyelitis (EAE) murine model. Much like human psoriasis, the EAE murine model was initially thought to be mediated by the Th1 cell subset because the disease phenotype of these mice was prevented by the absence (Il12p40^−/−) or neutralization of the p40 subunit (11, 12). However, the idea that the EAE model was driven primarily by aberrant Th1 signaling was incongruous with the finding that mice deficient in IFN-γ and STAT1 signaling still developed an autoimmune disease phenotype (13). Subsequent work using mice deficient in IL-12, IL-23, or both found that the EAE model was critically dependent on IL-23, which regulates the differentiation of IL-17– and IL-22–producing subsets of CD4⁺ lymphocytes (14). A more severe autoimmune phenotype was observed in mice deficient in IL-12 compared with wild-type controls (12), suggesting a potential protective role for the IL-12/Th1 axis in this particular mouse model. Additionally, it was also shown that IL-23 did not stimulate IL-17 production in Th1- and Th2-polarized subsets. These findings challenged the conventional Th1–Th2 classification system and broadened our understanding of the various effector T cell lineages, such as the Th17 subset.

Following the discovery of the Th17 lineage, investigators sought to determine if this lymphocyte subset was associated with human diseases such as psoriasis. Consistent with findings from the EAE mouse model, psoriatic plaques were found to contain an increased number of IL-17–producing lymphocytes (15, 16) as well as the p40 and p19 subunits that make functional IL-23 (17). In contrast, the p35 subunit of IL-12 was not increased in psoriatic tissues, indicating that IL-23 rather than IL-12 was the primary regulator of the pathogenic Th17 cells found in psoriasis lesions. IL-22–producing cells were also found in the cellular infiltrate of psoriatic plaques, leading to the further characterization of the distinct Th22 subset found in humans. IL-17 and IL-22 were shown to induce a number of psoriasis-related genes (e.g., the S100 proteins), whereas IFN-γ had no appreciable effect on these molecules (18). Thus, investigators began to incorporate the presence of multiple T lymphocyte subsets (i.e., Th1, Th17, and Th22) into updated models of psoriasis based on the idea that the sum of genes activated in psoriasis was produced by distinct actions of polar T cell cytokines on keratinocytes and other tissue-resident cells (19).

Psoriasis is typified by the presence of large, erythematous, scaly plaques commonly found on the scalp, trunk, and extensor surfaces of affected patients. Histologically, psoriatic skin lesions are characterized by hyperproliferative keratinocytes and a mixed cellular infiltrate in the epidermal and dermal layers of the skin. The initiation of psoriasis lesions begins with immune activation in susceptible individuals following environmental stimuli (e.g., exogenous trauma or infection) and/or loss of immune tolerance via the recognition of three recently described psoriasis autoantigens (e.g., LL37/cathelicidin, ADAMTSL5, and PLA2G4D-generated neolipid Ags) (20–22). Psoriatic autoantigens are then presented to CD4⁺ or CD8⁺ T lymphocytes by DC subsets that include TNF-α/iNOS–producing (TIP) DC (BDCA-1⁻), resident DC (BDCA-1 and CD11c⁺), and/or mature DC populations. TNF-α and IL-23 secreted by these activated DCs drive the polarization and clonal expansion of CD4⁺ and CD8⁺ IL-17– and IL-22–producing T cells (subsequently referred to as T17 and T22 cells, respectively), leading to the production of considerable amounts of IL-17 and IL-22 in psoriatic plaques (Fig. 1).

Activated T17 cells in the skin produce several cytokines, including IL-17 (IL-17A/IL-17F), TNF-α, IL-26, and IL-29. IL-17, the major effector cytokine in psoriasis, acts alone or synergistically with TNF-α to induce the expression and release of many psoriasis-related proteins from keratinocytes, including hBD2, LCN2, S100 proteins, and LL37/cathelicidin (23). The effects of IL-17 on epidermal keratinocytes produce a feed-forward inflammatory response by activating C/EBPβ and δ, STAT1, and NF-κB, which amplify the primary signals driving the development of mature psoriatic plaques (24). IL-22, IL-19, and IL-36, in response to IL-17, contribute to the development of epidermal hyperplasia that gives the skin a thickened, scaly appearance with retained nuclei (parakeratosis) seen histologically. Additionally, the production of keratinocyte-derived antimicrobial peptides, such as LL37/cathelicidin, enhances innate immunity and protects the skin from cutaneous infection, whereas the upregulation of CCL20, CXCL1, CXCL2, CXCL3, CXCL5, and CXCL8 promotes the influx of various immune cell populations (e.g., neutrophils, macrophages, DCs, and CCR6⁺ cells) into inflamed skin (25–27). Keratinocytes also synthesize IL-17C in response to IL-17A/F, and this cytokine amplifies many psoriasis-associated genes that can also stimulate T17 cells to increase IL-17A/F production. Myeloid DCs, which produce significant amounts of IL-23, also promote the differentiation of T17 cells that produce a positive feedback loop that sustains the IL-23/IL-17 signaling pathway in psoriasis lesions.

The production of IL-26 and IL-29 by activated T17 cells also drives STAT1 signaling in keratinocytes, leading to the subsequent release of proinflammatory chemokines CXCL9, CXCL10, and CXCL11 from keratinocytes that recruit Th1 cells into lesional skin (28, 29). Inflammatory TIP-DCs in lesional skin also secrete IL-12 and contribute to the recruitment of Th1 cells in psoriatic plaques. Both keratinocyte-driven chemotaxis and DC-driven T cell polarization/clonal expansion likely contribute to the abundant infiltration of Th1 cells found in psoriasis skin lesions. Of note, infiltration of Th1 cells in psoriatic plaques likely contributes little to the pathogenesis of this condition as demonstrated by the limited clinical efficacy of IFN-γ blockade in patients with psoriasis (30), whereas the IL-12/Th1 axis is potentially suppressive of the IL-23/T17 axis that drives psoriasiform hyperplasia (12).

The dysregulation of DCs and skin-derived antimicrobial peptides in psoriatic skin underscore the importance of the innate immune system in this inflammatory disease. As a result, scientists have sought to better understand the specific actions of innate immune cell populations in the initiation and maintenance of psoriasis skin lesions. Neutrophils, innate lymphoid cells (ILCs), and NK cells are among the innate immune cell populations that may contribute to the pathogenesis of psoriasis.

Neutrophils have long been recognized as a common immune cell infiltrate in lesional psoriatic skin, which are recruited into the stratum corneum during early psoriasis and form aggregates known as Munro microabscesses. The recruitment of neutrophils into psoriatic skin is likely driven by the increase of TNF-α and IL-17 signaling in lesional psoriatic skin, which triggers keratinocytes to secrete neutrophil-recruiting factors such as CXCL1, CXCL2, CXCL3, CXCL5, and CXCL8 (IL-8) (26). In turn, neutrophils can secrete a variety of proinflammatory signals, including reactive oxygen species, IL-17, LL37/cathelicidin, and neutrophil extracellular traps (31). However, the role of neutrophils in the pathogenesis of psoriasis is not entirely clear because many psoriatic plaques and murine models of skin inflammation lack Munro microabscesses, and neutrophils are not the predominant cellular source of IL-17 in the skin (32–34).

ILCs are another innate immune cell population that may play a pathogenic role in skin disease. ILCs are a rare population of immune cells in healthy skin and blood that are characterized by the lack of Ag-specific TCR or BCR. Their primary function in the skin is to form a protective barrier in epithelial tissues (e.g., mucosal skin) by initiating a nonspecific immune response to skin damage, environmental exposures, or microorganisms. ILCs can be categorized into three major groups characterized by transcription factor expression and cytokine production, respectively: Type 1 (T-bet/Th1), Type 2 (RORα and GATA3/Th2), and Type 3 (RORγt/Th17 and Th22) (35). The role of Type 3 ILC (ILC3) cells in psoriatic disease is of particular interest because of the upregulation of this group in psoriasis skin and blood (36, 37) as well as their expression of IL23R, response to IL-23 and IL-1β signaling, and ability to produce IL-23 and IL-17A cytokines. However, despite the association between ILC3s and factors implicated in the IL-23/T17 signaling pathway, no studies have clearly defined the relative contribution of IL-17 by ILC3s versus other cellular sources of IL-17 in the skin of psoriasis patients. Further, the clinical significance and impact of targeted, systemic therapies on ILC3s in the skin have not been determined in a large cohort of plaque psoriasis patients.

NK cells, the prototypical ILC, and NKT cells have also been implicated in psoriasis. NK cells are capable of producing cytokines central to the pathogenesis of psoriasis, including IFN-γ, TNF-α, and IL-22 (38, 39). In vitro experiments suggest a potential contributory role for NKT cells in psoriasis because the incubation of NKT cells with CD1d-expressing keratinocytes led to increases in IFN-γ production (40, 41). Studies also involving the engraftment of either allogenic normal or prepsoriatic skin onto SCID mice, followed by the injection of NKT cells from psoriasis patients, led to the development of psoriatic plaques (41, 42). However, the exact role of NK and NKT cells in psoriasis and the extent of their involvement in the pathogenesis of the disease have yet to be determined.

The recognition of psoriasis as an autoinflammatory disease heralded the use of systemic biological agents for the treatment of this condition. By deciphering the immune axes activated in psoriasis, greater specificity and targeting of pathogenic cytokines became possible (Table I). Among the first biologics used for the treatment of psoriasis were antagonists against TNF-α, a broad-acting proinflammatory cytokine secreted by a variety of immune cells, including macrophages and monocytes. The production of IFN-α and TNF-α by plasmacytoid DCs in psoriatic skin drives the production of IL-23 by myeloid DCs and the subsequent activation of IL-17–producing lymphocytes. TNF-α also acts synergistically with IL-17 to upregulate the expression of inflammatory genes implicated in psoriasis (24).

Etanercept, adalimumab, infliximab, and certolizumab received FDA approval for moderate-to-severe plaque psoriasis in 2004, 2005, 2006, and 2018, respectively. Phase 3 clinical trials for these agents revealed that ∼50–80% of all treated plaque psoriasis patients achieved a 75% improvement in the psoriasis area and severity index (PASI) response compared with placebo (43–51). All of these anti–TNF-α agents have also proved to be effective at reducing inflammation in the joints of patients with psoriatic arthritis. Approximately 50–65% of patients achieve a 20% improvement in their American College of Rheumatology score (ACR20) after 24 wk. The efficacy of this drug class appears to be significantly less than their observed benefits in the skin. The primary mechanism by which TNF-α antagonists result in disease improvement in treated psoriasis patients is most likely a result of its indirect effect on IL-17 signaling via the regulation of IL-23 production from myeloid or CD11c⁺ DCs. The exact mechanism for the benefits in the joints is not entirely understood.

Common adverse events associated with TNF-α antagonists include increased infection risk, reactivation of tuberculosis, injection site reactions, and possibly lymphoma. Worsening of pre-existing congestive heart failure and the development of demyelinating disease have also been reported; thus, the use of TNF-α antagonists should be avoided in these patient populations. Interestingly, TNF-α inhibitors have also been implicated in the development of paradoxical psoriasiform and eczematous-like cutaneous eruptions that are characterized by a strong type I IFN (IFN-α and IFN-β) molecular signature that is inconsistent with the diagnosis of psoriasis or atopic dermatitis (52–54).

As a human mAb against the shared p40 subunit of the IL-12 and IL-23 cytokines, ustekinumab inhibits both the Th1 and T17 signaling pathways that are upregulated in psoriasis. In phase 3 clinical trials (55, 56), ustekinumab demonstrated a 75% improvement in the PASI response of 50–80% of patients. It subsequently received FDA approval for the treatment of moderate-to-severe plaque psoriasis in 2009. In the head-to-head phase 3 ACCEPT trial (57), ustekinumab showed superior efficacy to etanercept over a 12-wk period, with 70% of patients achieving a 75% improvement in the PASI response with ustekinumab compared with 57% of those receiving etanercept. Ustekinumab also demonstrated efficacy in the treatment of psoriatic arthritis (58, 59), with 40% of patients achieving an ACR20 response after 24 wk. As a result, ustekinumab received FDA approval for psoriatic arthritis in 2013.

The common adverse events reported with ustekinumab include headache, upper respiratory tract infection, nasopharyngitis, arthralgias, and infections (55, 56), with a comparable safety profile to that of etanercept (57). Rare cases of nonmelanoma skin cancers and reversible posterior leukoencephalopathy syndrome have also been reported in patients treated with ustekinumab for psoriasis (60).

Although secukinumab and ixekizumab are human mAbs against IL-17A, brodalumab antagonizes the IL-17RA and disrupts signaling of IL-17A, IL-17C, IL-17F, and IL-17A/F heterodimers, giving it potential advantages over selective IL-17A inhibition with secukinumab or ixekizumab. In phase 3 clinical trials (61–65), 30–60% of patients treated with IL-17 inhibitors demonstrated a 100% improvement in the PASI response, showcasing the importance of IL-17 in the pathogenesis of plaque psoriasis. Head-to-head clinical trials of secukinumab versus ustekinumab (66), ixekizumab versus etanercept (61, 62), and brodalumab versus ustekinumab (64) have demonstrated the superior efficacy of the IL-17 antagonists. Secukinumab and ixekizumab have also been FDA approved for the treatment of psoriatic arthritis based on phase 3 trial results showing 50–60% of patients achieving an ACR20 response after 24 wk (67–70). Results from the phase 3 trials evaluating the efficacy of brodalumab in patients with psoriatic arthritis are currently pending.

Given similarities in their mechanisms of action, IL-17 antagonists exhibit comparable safety profiles in clinical trials, with nasopharyngitis, upper respiratory tract infections, mucocutaneous candidiasis, transient neutropenia, and injection site reactions being the most common adverse effects. Mucocutaneous candidiasis seen with IL-17 inhibition or genetic deficiencies (e.g., chronic mucocutaneous candidiasis) (71) reflects the innate, protective role of this cytokine against microbial pathogens on the skin. Secukinumab and brodalumab were also tested for clinical efficacy in inflammatory bowel disease (IBD) patients without comorbid inflammatory skin disease, and these trials reported some worsening of gastrointestinal symptoms with IL-17 blockade, suggesting use with caution in psoriasis patients with comorbid gastrointestinal disease (72, 73). Importantly, four patients in the AMAGINE 1 and 2 trials committed suicide during the treatment period, prompting investigations into a possible association between brodalumab and increased suicidality. This resulted in a black box warning for brodalumab, mandating surveillance under the Risk Evaluation and Mitigation Strategy program. However, an analysis of more than 4000 patients treated with brodalumab (9161 patient-years of exposure) did not support a causal relationship between brodalumab and psychiatric adverse events (74).

With the discovery of IL-23 as the “master regulator” of T17 cells, several antagonists against the p19 subunit of IL-23 are currently being investigated for the treatment of psoriasis, including guselkumab, tildrakizumab, risankizumab, and mirikizumab. In contrast to ustekinumab, this class of medication targets IL-23 by inhibiting the p19 subunit without disrupting the IL-12 signaling pathway.

Guselkumab was the first selective IL-23 antagonist to receive FDA approval for moderate-to-severe plaque psoriasis in July 2017. In March 2018, tildrakizumab received FDA approval for the same indication. The results of phase 3 clinical trials have indicated that more than 50% of treated patients reach a 90% improvement in the PASI response (75–77), with head-to-head trials of guselkumab versus ustekinumab (78) and tildrakizumab versus etanercept (75) demonstrating superiority of these two biologics. Guselkumab and tildrakizumab are not currently approved for the treatment of psoriatic arthritis.

The most common adverse events associated with the use of guselkumab and tildrakizumab include upper respiratory tract infections, nasopharyngitis, and headaches (75–77). Rates of urticaria and mucocutaneous candidiasis were infrequent and comparable to healthy control subjects. Moreover, no new cases or exacerbation of IBD occurred in the tildrakizumab trials. The impact of IL-23 blockade on the gastrointestinal system or IBD is not fully understood and is under investigation. Follow-up studies investigating the long-term efficacy and safety of guselkumab are needed.

Several other agents that selectively target IL-23 are currently undergoing clinical testing. These other agents include risankizumab (BI 655066) and mirikizumab (LY3074828). These two agents are humanized mAbs against the p19 subunit of IL-23 and are in various stages of clinical testing for psoriasis, psoriatic arthritis, and/or IBD. Risankizumab is in phase 2 testing for psoriatic arthritis and asthma as well as phase 3 testing for plaque psoriasis and Crohn disease. Finally, mirikizumab is in phase 2 testing for plaque psoriasis, Crohn disease, and ulcerative colitis.

The ability to selectively target the IL-23/T17 signaling axis in psoriasis has resulted in a number of highly efficacious systemic therapies with excellent safety profiles. As a result of these novel selective therapies, as many as 80–90% of treated patients are experiencing dramatic improvements in their psoriatic disease. Clinicians, however, continue to encounter subsets of psoriasis patients (e.g., palmoplantar psoriasis and psoriatic arthritis) with severe or recalcitrant disease that does not improve following treatment with novel biologic therapies. The current inability to predict which psoriasis patients will respond to specific therapies often results in a frustrating cycle of medication trial and error for the patient and clinician.

The variable clinical responses to specific systemic therapies and the recalcitrant psoriasis patient population highlight some important open questions in psoriasis research. One promising area of ongoing translational research is the development and testing of bispecific Abs that would allow for the simultaneous targeting of two molecules with a single Ab (79). For example, early proof-of-concept studies comparing the clinical efficacy of bimekizumab, a humanized IgG Ab that neutralizes IL-17A and IL-17F, suggest that dual blockade may have advantages over therapies that inhibit IL-17A alone (80). Phase 2 clinical trials for bimekizumab in the treatment of psoriasis were recently completed; however, study results will not be available until later this year.

In a recent phase 2 clinical trial of 166 patients with moderate-to-severe plaque psoriasis (81), investigators compared the clinical efficacy of risankizumab (antagonist of the p19 subunit of IL-23) against ustekinumab (antagonist of the p40 subunit that is common to both IL-12 and IL-23). This head-to-head trial allowed for the direct comparison of selective IL-23 blockade versus dual inhibition of IL-12 and IL-23 in the treatment of plaque psoriasis. Interestingly, selective blockade of IL-23 with risankizumab showed clinical superiority over inhibition of IL-12 and IL-23 via ustekinumab. This finding was somewhat of a surprise given that both drugs effectively inhibit IL-23. It also demonstrates the complexity of inflammation driven by IL-23 in which there is a family of dimeric cytokines that can alternatively share subunits to create six distinct cytokines with differing pro- and anti-inflammatory properties (Fig. 2).

Using the imiquimod-induced mouse model of psoriasiform dermatitis, which is dependent on the induction of IL-23 and T cells producing IL-17, Kulig et al. (82) showed that mice lacking the p35 subunit of IL-12 (Il12a^−/−) or the IL-12–specific receptor subunit (Il12rb2^−/−) developed significantly increased skin inflammation, similar to an earlier finding in the EAE model of multiple sclerosis, in which IL-12 knockout led to worsening inflammation (12). Thus, dual blockade of IL-12 and IL-23 with ustekinumab might lead to lesser disease improvement compared with single blockade of IL-23, as suggested by clinical trial outcomes. Note that an Ab against the p19 subunit can also theoretically neutralize IL-39 (Fig. 2), which is another proinflammatory cytokine likely expressed in psoriatic skin. Additionally, blockade of IL-23 through the inhibition of the p19 subunit would also allow IL-12 and IL-Y to maintain their beneficial anti-inflammatory effects on T17-centered inflammation in the skin. Further studies are needed to systematically explore the individual roles of the extended IL-12 cytokine family, which includes IL-12, IL-23, IL-27, IL-35, IL-39, and IL-Y, in psoriasis, as there are reports that the individual subunits of this family (with the exception of p35) are all upregulated in psoriasis lesions.

One major obstacle hampering the elucidation of the role of the IL-12 cytokine family and the mechanisms of other signaling pathways in psoriasis is the lack of a single animal model that recapitulates the complexity of this inflammatory skin condition in humans. Although more than 40 murine models of psoriasis have been proposed to date, each of these models have significant drawbacks. The advantages and disadvantages of the three most common model types used (i.e., inducible, genetically engineered, and xenotransplantation) have been reviewed in detail elsewhere (83–85). In short, these limitations are primarily due to 1) the methods by which inflammation in the skin or joints are induced and evaluated, 2) the inherent immune system and genetic background of the mice, or 3) the human donor tissue variability and technical challenges associated with xenotransplantation (84). Still, the most faithful model of psoriasis may be xenotransplantation of nonlesional psoriatic skin onto the AGR129 mouse background (mice that lack type I and II IFN receptors in addition to being Rag-2^−/−) (86). The AGR129 murine model has been used to demonstrate the importance of IL-23 in the generation of psoriasis and has also shown that T cell infiltration into and within the epidermis is essential for disease induction (86, 87). This model also demonstrated that IL-23 inhibition could prevent psoriatic disease induction before clinical studies showed efficacy of this approach. Nevertheless, continued efforts to develop a robust murine model that mimics the genetic perturbations and immune dysregulation observed in human disease is crucial if we are to advance our understanding of immunologic mechanisms driving psoriasis.

The discovery of the IL-23/T17 signaling pathway and significant therapeutic advances made over the last two decades have made psoriasis one of the most effectively treated chronic inflammatory conditions in all of medicine. It serves as a model of how meticulous research discoveries directly led to the development and approval of highly effective, targeted psoriasis therapies. As our understanding of the etiology and immunologic signals driving psoriatic disease continues to expand, we look forward with optimism toward more effective antipsoriatic medications and improved treatment strategies for patients with severe or recalcitrant disease.

J.E.H. acknowledges support from the National Psoriasis Foundation. T.C.C. thanks the Eighth Core Laboratory, Department of Medical Research, National Taiwan University Hospital for support.

J.E.H. serves as an investigator/consultant for Pfizer Inc. and Novartis. J.G.K. has been a consultant to and has received research support from the following companies that have developed or are developing therapeutics for psoriasis: AbbVie, Amgen, Boehringer, Bristol-Myers Squibb, Celgene, Dermira, Idera, Janssen, Leo, Lilly, Merck, Novartis, Pfizer, Regeneron, Sanofi, Serono, Sun, Valeant, and Vitae. The other authors have no financial conflicts of interest.