Psoriasis is a chronic inflammatory skin disease affecting 1–3% of the adult population in western countries.1 About 20–30% of patients develop psoriatic arthritis and an association with an increased risk for cardiovascular disease and other cardiometabolic comorbidities has also been described.2,3

Treatment options include topical therapy, phototherapy and systemic agents such as retinoids, cyclosporine and methotrexate. However, a significant proportion of patients do not respond, are intolerant or have contraindications to these therapeutic options. Over the past few years, the introduction of biologic therapies targeting selective inflammatory mediators, namely TNF-α (adalimumab, etanercept and infliximab) and IL12/IL23p40 (ustekinumab), has improved treatment options for patients with moderate-to-severe psoriasis. Nonetheless there is still a subset of patients that do not respond to these biologic agents, lose treatment response over time or do not reach the highest clearance rate.4 These unmet needs lead to the development of biologic agents against other targets.4 Anti-IL17 drugs (including secukinumab and ixekizumab) are a promising therapy for psoriasis that act by neutralizing IL-17A, a key cytokine in the pathogenesis of the disease. This article aims to review the role of IL-17 in psoriasis immunopathogenesis and summarizes the data on efficacy and safety of ixekizumab.

Psoriasis is an immune-mediated disease initially considered to be a result of a Th1 response with the signature cytokines INF-γ and IL-12. However, recent studies investigating the molecular basis of psoriasis identified the key role of the adaptive Th17 cells.5

The actual model of immunopathogenesis (Fig. 1) proposes that an unknown antigen or environmental trigger activates macrophages, natural killer (NK) T cells and plasmacytoid dendritic cells (DCs) to secrete TNF-α, INF-α, INF-γ, IL-1β and Il-6, which trigger myeloid DCs activation. Activated myeloid DCs produce IL-12 and IL-23, leading to the differentiation of Th1 cells and Th17 cells, respectively.6,7 Th17 cells are important producers of IL-17A. Other cells, such as mast cells, neutrophils and NK cells, can also secrete IL-17A.8–10

Figure 1.

Immunopathogenesis model of psoriasis. DC, dendritic cell; KC, keratinocyte; Th, T helper cell.

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IL-17A is a pro-inflammatory cytokine that belongs to the IL-17 cytokine family, which comprises six members (IL-17A-F).11 IL-17A,-C and-F expression is increased in psoriatic skin lesions.12 IL-17A shows similarities with IL-17F and both cytokines bind to the same receptor IL-17RA. The biologically active form of IL-17A comprises either an IL-17A homodimer or an IL-17A-IL-17F heterodimer, although the first one has greater biological activity.13,14

Serum levels of IL-17A are significantly increased in patients with psoriasis compared with healthy individuals and IL-17A positive T cells are found in elevated number in psoriatic lesions.15,16 The major pathogenic importance of the IL-23/Th17 axis over the IL-12/TH1 pathway is demonstrated by the higher expression of IL-23 in psoriatic skin lesions and its pathogenicity in inducing the psoriasiform phenotype in an experimental model injected with IL-23, but not with IL-12.17,18 Besides, the IL23/Th17 axis contributes to genetic susceptibility of psoriasis, linked to specific IL23p19 gene variants and to other genes such as the IL-23 receptor gene.19

IL-17A action includes: (i) activation of STAT3 signaling in keratinocytes, inducing their proliferation and expression of proinflammatory cytokines associated with skin inflammation; (ii) overexpression of antimicrobial peptides (AMPs), such as S100 proteins and β-defensins, which also have pro-inflammatory properties, (iii) secretion of several chemoattractants (CXCL1, CXCL3, CXCL5, CXCL6 and CXCL8) responsible for neutrophils accumulation in psoriatic epidermis; and (iv) increased expression of CCL20, which can attract CCR6-expressing DCs and T cells, creating a proinflammatory loop in the skin.20–24

Currently, there are three new biologic drugs targeting the IL-17A pathway used in clinical trials for psoriasis treatment. Ixekizumab is a humanized IgG4 IL-17A monoclonal antibody and secukinumab is a fully human IgG1 IL-17A monoclonal antibody, both acting by neutralizing IL-17A. Brodalumab is a human IgG2 monoclonal antibody that binds and blocks the IL-17RA receptor.

Secukinumab is already approved by FDA and EMA and it is commercially available in several countries, including Spain. Ixekizumab has been recently approved by FDA and EMA, and like secukinumab, is indicated for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy. The development of brodalumab was halted over concerns about suicidal ideation that could potentially lead to restrictive labeling.

A point of concern is the finding that patients with deficiencies in the IL-17 pathway have a high risk of developing chronic mucocutaneous candidiasis.36 In the phase II trial and in the open-label extension study no cases of fungal infections were reported.26,27 In UNCOVER-2 and -3, candida spp infections were higher in patients receiving ixekizumab (12 patients receiving ixekizumab every 2 weeks, 4 patients receiving ixekizumab every 4 weeks vs 5 patients receiving etanercept and 2 patients receiving placebo).30 In UNCOVER-1, during the induction and maintenance period, more cases of candida infections were reported in patients receiving ixekizumab (during the induction period, 3 patients in the ixekizumab every 4 weeks group and 4 patients in the ixekizumab every 2 weeks group vs. 2 patients in the placebo group, during the maintenance period, 4 patients in the ixekizumab every 12 weeks group and 8 patients in the ixekizumab every 4 weeks vs.2 patients in the placebo group).28 All infections resolved with standard treatment, no patient needed to discontinue the study drug and no invasive fungal infection was reported.28,30

The role of IL-17A in the differentiation and maturation of neutrophil granulocytes lead to a concern about the development of neutropenia in patients receiving IL-17A inhibitors.37 In the phase II study, asymptomatic grade 2 neutropenia occurred in 2 patients receiving 75 and 150mg of ixekizumab.26 In the open-label extension study, no effect on mean neutrophil count was observed in patients with prolonged ixekizumab treatment.27 In UNCOVER-J, grade 1 neutropenia was observed in 15 patients and grade 2 neutropenia in 4 patients.34 In UNCOVER-2 and -3, grade 3 neutropenia was found in 2 patients receiving ixekizumab every 2 weeks, 4 patients receiving etanercept and 1 patient receiving placebo. Grade 4 neutropenia was observed in 1 patient receiving ixekizumab every 4 weeks.30 However, no patients with grade 3 or 4 neutropenia had a concurrent infection.30

Previous clinical trials with anti-IL17 drugs in patients with Crohn's disease (CD) suggested worsening of the disease and no evidence of clinical efficacy with IL-17A inhibition.38,39 Among 3858 patients included in UNCOVER-1, -2 and 3, the occurrence of CD (2 cases, 1 case in ixekizumab every 2 weeks group and 1 case in ixekizumab every 4 weeks group) and ulcerative colitis (2 cases, both in ixekizumab every 2 weeks group) was uncommon during the induction period.40

Integrated data from 5 phase III clinical trials (UNCOVER-A, -J, -1, -2 and -3) demonstrated that Major Adverse Cardiac Events (MACE) were uncommon and balanced across treatment groups.41 The incidence rate of MACE stayed stable over time among patients treated with ixekizumab, suggesting that ixekizumab is not associated with an increased risk of MACE.41

Regarding the increased risk of suicidal ideation, that has been associated with brodalumab, available data do not support an association of ixekizumab with suicidal behaviour.42

No cases of tuberculosis reactivation were reported in the phase II and III studies.26,30,34

The most common reported adverse events (AEs) in the phase II and III studies were nasopharingitis, upper respiratory infection, injection sites reactions and headaches.26,30 There were no severe AEs observed in the phase II study.26 In the UNCOVER 2-3, serious AEs were reported in less than 2% of patients across all study groups.30 In these studies, no clear difference was seen in rates of serious infections or malignancies among patients receiving placebo and those receiving ixekizumab. Patients who reached complete or almost complete clear skin did not appear to be at increased risk for infections or severe AEs.43 This finding is observed in patients treated either with ixekizumab or etanercept during 12 weeks.43

Immunogenicity is an issue of concern with the use of monoclonal antibodies. In UNCOVER-1,-2 and -3, at week 12, neutralizing anti-drug antibodies (ADA) were observed at low titers in 5.7% and 8.0%, at moderate titers in 1.6% and 3.0% and at high titers in 1.7% and 2.4% of patients receiving ixekizumab every 2 weeks and every 4 weeks, respectively.44 Only high ADA titers (≥1280) were associated with reduced efficacy. In UNCOVER-1 and -2, at week 60, ADA were reported at low titers in 14.2% and at moderate titers in 0.9% of patients receiving ixekizumab every 2 weeks re-randomized to ixekizumab every 4 weeks.44 None of these patients had high ADA titers. Efficacy was similar between negative ADA patients and patients with low and moderate ADA titers at week 60. No association between ADA and treatment AEs was detected.44

Psoriasis is a chronic, debilitating skin disorder that has a negative impact in health-related quality of life. Recent evidence supports that IL-17 is a key mediator in the pathogenesis of psoriasis. A new class of biologic agents, which includes secukinumab and ixekizumab, was designed to inhibit IL-17A action. Data from Phase I-III studies has demonstrated a high efficacy of ixekizumab for treatment of moderate-to-severe psoriasis with 78–90% of the patients achieving PASI 75 at week 12. The two large phase III studies demonstrated that ixekizumab not only had greater efficacy over placebo but also over etanercept, a widely used anti-TNFα biologic agent. A greater proportion of patients receiving ixekizumab achieved PASI 90 (60–71% of the patients) and PASI 100 (31–41% of the patients), which was markedly superior to the results of etanercept treatment (19–26% and 5–7% of patients, respectively). Moreover, the findings of phase II and III trials showed that patients who achieved 90–99% or 100% PASI improvement had significantly greater enhancement in health related quality of life and pruritus symptom relief compared with patients with lesser improvement in PASI.30,45 This finding encourages the upgrade of the treatment goals to PASI 90 or 100, with the consequently positive impact in patient's quality of life.46 Higher clearance rates were not associated with increased risk for infections or serious AEs.43

These promising results at short term appeared to be maintained at long term as demonstrated in UNCOVER-1, as 86-88% of responder patients maintained PASI 75 and over 50% maintained or reached complete clear skin at week 60.

Ixekizumab therapy also demonstrated improvement in scalp and palmoplantar psoriasis.

Additionally, ixekizumab showed high efficacy in the treatment of psoriatic arthritis with reduction of signs and symptoms and inhibition of bone destruction. Even though no head-to-head studies have been performed, results for ixekizumab (58–62% of patients with ACR20) seem to be slightly higher than secukinumab (51–54% of patients with ACR20) in patients with psoriatic arthritis at week 24.35,47 So, it is expectable that ixekizumab becomes useful in the management of this patients, in the same way of secukinumab, which was already approved for treatment of psoriatic arthritis. Lxekizumab showed a safety profile at week 12 comparable with other anti-IL17 agents and etanercept. There is a concern about the risk of development of mucocutaneous candidiasis and neutropenia. So far, these AE were infrequently observed, mild or moderate in severity and did not lead to discontinuation of the study drug. Clinical monitoring for skin and mucosal infections and laboratorial monitoring of neutrophils blood count may be advisable during ixekizumab treatment.

Psoriasis patients are approximately 2.5-times more likely to have CD and 1.6-times more likely to have ulcerative colitis compared with age- and sex-matched controls.48 Previous studies with brodalumab and secukinumab revealed that blockade of IL-17A did not improved CD and can even result in disease worsening.38,39 An alteration of gut mycobiome, with Candida albicans proliferation secondary to loss of control by IL-17, may play a role in worsening of CD.49 The incidence of inflammatory bowel disease in patients receiving ixekizumab was low during the first 12 weeks. Still it is important to be alert for symptoms and signs of inflammatory bowel disease (IBD) in patients receiving ixekizumab. Ixekizumab and other anti-IL17 drugs should be avoid in patients with a diagnosis of IBD.

The humanization process used to generate ixekizumab allows optimization of its affinity for IL-17A, resulting in a molecule with a very high binding affinity.50 This results in high potency in blocking the IL-17A-mediated biological activities in vitro and in vivo.50 Unlike secukinumab, ixekizumab is a humanized IgG4 monoclonal antibody and retain a murine-derived sequence, which can raise the risk of immunogenicity. Still, IgG4 is thought to be less immunogenic than IgG1 molecules as secukinumab because it does not activate the classic complement system.51 Human or humanized antibodies still have potential for immunogenicity due to unique complementarity-determining regions (CDR).52 During inducing treatment with ixekizumab, only a small number of patients (1.7–2.4%) develop high ADA titers, which are associated with reduced efficacy. During maintenance treatment among initial responder patients, ixekizumab revealed low immunogenicity with no loss of efficacy. Although there is no direct comparison, secukinumab appears to be moderately superior in this point, with minimal immunogenicity up to Week 12 (ADA in 0% to 0.41%. of patients).53–57 Secukinumab maintained a low rate (0.4%) of treatment-emergent ADA up to Week 52, across six phase 3 clinical trials.58 Furthermore, there is no report of loss of secukinumab efficacy.58

Both ixekizumab and secukinumab have impressive results that have never been achieved with previous therapeutics. Even though there are no direct comparisons available, small details may make a difference in the choice between ixekizumab and secukinumab. Reported efficacy for ixekizumab is apparently superior to secukinumab efficacy for treatment of psoriasis30,53. Conversely, immunogenicity data favors secukinumab. Differences in the posology of these two anti-IL17 drugs may affect treatment adherence. Ixekizumab shows a more favorable posology at long term with only one injection for each monthly dose vs. two injection of secukinumab for each monthly dose.

For the first time, two biological drugs have been approved as first line therapy for systemic treatment in moderate to severe psoriasis. This decision reflects the remarkable efficacy associated with a favorable safety profile of ixekizumab and secukinumab in clinical trials. Both may provide an answer to the unmet needs of patients who did not respond to or did not tolerate previous treatments. Notably, anti-IL-17 drugs may initiate a new era in the psoriasis treatment, where PASI 90 or 100 becomes the new therapeutic goal. The next years may clarify the possible economic burden on healthcare systems by the use of these anti-IL-17 drugs as first line systemic therapies for psoriasis.

T. Tiago has participated in clinical trials sponsored by AbbVie, Amgen and Novartis and has received honoraria for acting as a consultant and/or as a speaker at events sponsored by AbbVie, Boehringer Ingelheim, Janssen, Leo-Pharma, Lilly, MSD, Novartis and Pfizer. A. Azevedo has no conflicts of interest to disclosure.