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. Author manuscript; available in PMC: 2019 Dec 1.
Published in final edited form as: Ophthalmology. 2018 Jul 4;125(12):1977–1983. doi: 10.1016/j.ophtha.2018.05.014

Targeting Interleukin-23 in the Treatment of Noninfectious Uveitis

Kathryn L Pepple 1,*, Phoebe Lin 2,*
PMCID: PMC6538052  NIHMSID: NIHMS1029804  PMID: 30458922

Abstract

The interleukin (IL)-23/IL-17 axis plays a central role in the pathogenesis of immune-mediated diseases such as psoriasis, psoriatic arthritis, Crohn’s disease, and uveitis. Therefore, targeting the IL-23/IL-17 axis has become the focus of multiple clinical trials for drug development in patients with autoimmune diseases. We briefly describe the biology of the IL-23/IL-17 axis and its relevance to the pathogenesis of experimental and clinical uveitis, and review the monoclonal antibody therapies targeting this pathway. Finally, 2 ongoing phase 2 trials of the anti-IL-23 biologic therapy ustekinumab (STELARA, Janssen Biotech Inc, Horsham, PA) in patients with noninfectious uveitis are introduced.

The treatment of patients with uveitis has come a long way since glucocorticoids were first identified as an effective method for controlling ocular inflammation and preventing blindness.1 Through the use of immune-modulating medications, the detrimental side effects of systemic corticosteroids can now be largely avoided while maintaining durable disease remission.2 Unfortunately, the ideal therapy, one that perfectly controls active ocular inflammation and prevents relapses without serious systemic or ocular side effects, has remained an elusive goal. However, the fairly recent and fast-moving field of biologic therapies, in which monoclonal antibodies target specific immune mediators, has provided new hope and opportunities for realizing this goal. The successful VISUAL-I and VISUAL-II studies and subsequent Food and Drug Administration approval of the anti‒tumor necrosis factor-α agent adalimumab (Humira, AbbVie, Chicago, IL) led the way and provided uveitis specialists with a powerful new tool. In addition, these trials demonstrated that targeted biologic therapy can have a profound steroid-sparing effect in patients with uveitis.3,4

Since these studies were initiated, there has been an explosion of biologic therapies brought to market for the treatment of systemic inflammatory diseases. Only a handful of these new agents have been tested systematically in patients with uveitis.5,6 Moving forward, the growing challenge will be determining which of these therapies should be prioritized for clinical trials in uveitis. There simply are not enough resources available to support testing every option. So how do we choose? The evidence-based medicine approach calls for an ordered process including identification of central mechanisms of disease followed by development and testing of targeted therapies. In other fields where tissue collection from patients with active inflammatory disease is relatively safe and easy, and provides large samples for study, key pathogenic mechanisms have been identified by studying human samples. In ophthalmology, human samples are challenging to acquire during active uveitis flares and inherently limited in quantity. Thus, animal models of disease have had a central role in developing the foundations of our understanding of the mechanisms of ocular inflammation and generating the preclinical information supporting new treatments intended to save and preserve vision. However, this approach also has limitations because rodent eyes and immune systems are not identical to the human systems they model, and there can be layers of complexity in the roles of individual cytokines in immune health and disease that are not always appreciated until clinical trials fail to recapitulate the results seen in animal studies.7 Furthermore, classic animal models of uveitis require co-administration of a self-antigen peptide with certain adjuvants like mycobacterium, whereas the potential organisms or environmental products that might trigger uveitis in susceptible humans is unknown and limits generalizing what we learn in animal models to our human subjects. Other models in which animals are genetically modified with T-cell receptors against self-antigens to develop uveitis spontaneously perhaps are even less likely to represent a majority of cases of human uveitis. Despite these shortcomings, experimental autoimmune uveitis (EAU) and other animal models of uveitis are of great benefit, and with a larger depth of understanding of these models’ limitations and benefits, or similarities/dissimilarities to human disease, they could potentially guide successful treatment targets for human uveitis.

The key to moving forward will be the continued collaboration of basic and clinical scientists working together to untangle the complex immune mechanisms initiating and sustaining pathologic inflammation in the human eye. In this translational review, we will highlight the history and biology of the interleukin (IL)-23/IL-17 axis in uveitis, and provide an evidence-based rationale for continuing efforts to target this axis as a promising avenue for new targeted therapies in our patients with uveitis.

T-Helper 17 Cells in the Pathogenesis of Uveitis

At the center of the IL-23/IL-17 inflammatory axis lies the T-helper (Th) 17 cell.8 The Th17 cells are named for their signature cytokine, IL-17, which they produce in abundance once activated. T-helper 17 cells are an important subpopulation of CD4+ Th cells that were identified in 2005 and expanded the prior Th1 versus Th2 paradigm of Th cell subpopulations (reviewed in Tesmer et al9). T-helper 17 cells have been identified in the eyes of mice with EAU, and uveitis severity has been linked to the total burden of intraocular Th17 cells.10–12 In humans, peripheral blood Th17 cells have been identified in patients with scleritis and active uveitis,10 and an elevated ratio of Th17 to regulatory T cells has been correlated to disease activity in patients with human leukocyte antigen B27eassociated uveitis.13

T-helper 17 cells are a heterogeneous group of cells that function both in autoimmunity and in mucosal immunity to protect from pathogens such as fungi, bacteria, and viruses. The pathologic and homeostatic functions of Th17 cells appear to segregate within at least 2 distinct subpopulations. One type of Th17 cell is highly pathogenic and can be identified by the expression of IL-17, interferon γ, granulocyte- macrophage colony-stimulating factor, and IL-6. The second population has beneficial homeostatic functions and can be identified by the expression of IL-17 and IL-10.14–16 Although it is informative to consider these as 2 distinct subpopulations, the relationships are complex and fluid, because transdifferentiation of pathogenic Th17 cells into IL-10 expressing regulatory cells during resolution of inflammation has been demonstrated in multiple experimental models.17 In the absence of disease, the majority of vertical and horizontal cells reside in the intestines where their development is induced by the presence of certain types of commensal bacteria and where they act on intestinal epithelial cells to maintain a healthy mucosal barrier.18,19 The importance of these beneficial Th17 cells is highlighted by the development of infections, such as chronic mucocutaneous candidiasis, in patients with Th17 deficiency.20

In the case of autoimmunity, pathogenic Th17 cells deviate from their protective functions and drive destructive tissue inflammation. One of the main pathologic roles of Th17 cells is to produce and release IL-17. In the context of inflammation, IL-17 is a potent chemotactic agent for cells that mediate tissue injury, such as neutrophils, monocytes, and macrophages. Interleukin-17 also acts as an autocrine and paracrine signal to continue local production of inflammatory cytokines, chemokines, and matrix metalloproteases from T cells, epithelial cells, and stromal cells, which further causes additional inflammation and tissue injury.8

Considerable excitement was generated around targeting IL-17 as a possible therapy for uveitis after animal studies using the EAU model demonstrated that treatment with anti‒IL-17 antibodies ameliorated disease, and that there was an increase in serum levels of IL-17 in patients with uveitis associated with Behçet’s disease.21–23 However, 3 clinical trials of the anti‒IL-17 antibody secukinumab, SHIELD, ENSURE, and ENDURE, in the treatment of patients with noninfectious uveitis failed to reach their primary end points.24 Of note, these were not the only trials of anti‒IL-17 therapy with unexpected clinical trial results. In patients with psoriasis treated with secukinumab, paradoxical exacerbations of inflammatory bowel disease were also reported.25

Subsequent studies in experimental models of uveitis have determined that the roles of IL-17 and Th17 cells in homeostasis and autoimmunity are more complex than initially appreciated. Early studies suggested that IL-17 had a purely pathogenic and prouveitic function, but more recent studies have identified a beneficial effect on EAU from treatment with recombinant IL-17.10,15,26 In EAU, the frequency of homeostatic Th17 cells outnumbers the retina-specific Th17 cells by 10:1, produce the anti-inflammatory cytokine IL-10, and neutralize the uveitogenic effect of pathogenic Th17 cells upon adoptive transfer.15,16 Thus, Th17 cells and IL-17 can contribute to both disease pathogenesis and recovery of homeostasis in experimental uveitis. This effect of IL-17 has also been described in other auto-immune disease models.8,27–29 Therefore, the role of IL-17 is also likely to be complex in human uveitis, and these animal studies would imply that unless the inflammatory and anti-inflammatory roles of Th17 cells and IL-17 can be uncoupled, anti‒IL-17 therapy may not provide the desired therapeutic benefit. With the discovery of IL-23 and the subsequent development of anti‒IL-23 therapy, this may become a possibility.

Interleukin-23 in Autoimmunity

The cytokine environment in which a naïve T-cell experiences its cognate antigen helps determine what type of T-cell will ultimately develop. Multiple lines of evidence point to IL-23 as the key checkpoint used by naïve T cells to make the decision whether to become a homeostatic Th17 or pathogenic Th17 effector cell.23,30,31 To begin Th17 differentiation, naïve T-cells require exposure to transforming growth factor-b and IL-6, and in the absence of these cytokines Th17 cells fail to develop. Interleukin-23 is not necessary for the initial stages of Th17 differentiation, but when it is present it preferentially drives the developing Th17 cells into the highly inflammatory pathogenic subtype. Interleukin-23 also maintains this fate by upregulating the expression of its own receptor (interleukin-23 receptor [IL-23R]), which stabilizes and allows expansion of this harmful Th17 population.32,33

Interleukin-23 belongs to the IL-12 family of cytokines (IL-12, IL-23, IL-35, and fusokine) and is a heterodimeric protein made of p40 and p19 subunits (Fig 1).34 The p40 subunit is shared in common with IL-12 (p40/p35), whereas the p19 subunit is unique to IL-23 (p40/p19). Biological activity of IL-23 is mediated by binding to the IL-23R, which is expressed on activated T cells, including Th17 cells, γδ T cells, natural killer cells, and innate lymphoid cells.35

Figure 1.

Figure 1

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Targeting interleukin (IL)-23. Interleukin-23 is a crucial checkpoint for the development of pathogenic T-helper (Th) 17 cells implicated in various types of immune-mediated conditions, including uveitis. Preventing IL-23 binding to its receptor by targeting the p40 subunit of IL-23, for instance, can disrupt formation of pathogenic Th17 cells without affecting potentially beneficial homeostatic Th17 cells. TGF = transforming growth factor.

Interleukin-23/IL-23R signaling activates the intracellular JAK/STAT signaling pathway (using JAK2, Tyk2, STAT3, and STAT4) in Th17 cells, resulting in the production of type 17 cytokines (IL-17, IL-22, and granulocyte-macrophage colony stimulating factor) that can drive chronic tissue inflammation. Interleukin-23 is expressed by dendritic cells, macrophages, B cells, and endothelial cells when they detect pathogen-associated molecular patterns generated by infectious organisms or host-associated innate signals known as “danger-associated molecular proteins” generated by inflammation-associated tissue injury.36

Evidence for Interleukin-23 as a Mediator of Uveitis

In human studies, increased IL-23 has been found in the serum and the supernatants of peripheral blood mononuclear cells from patients with active Vogt‒Koyonagi‒Harada and Behçet’s uveitis compared with patients with inactive uveitis and normal control subjects.21,37,38 Przepiera-Bedzak et al39 have shown that increased serum levels of IL-23 are associated with increased risk of acute anterior uveitis in patients with spondyloarthropathy (in addition to elevated IL-6, IL-18, and decreased endothelin-1 levels).39 Using proteomics of several hundred inflammatory markers, Velez et al40 found increased IL-23 production in the vitreous obtained from 15 patients with posterior uveitis compared with nonuveitic control subjects.40 Yang and Foster41 discovered elevated serum levels of IL-23 in patients with treatment-naïve birdshot chorioretinopathy, greater than levels found in normal subjects and patients with birdshot chorioretinopathy who had a history of immunosuppressive treatment.

Additional support for the importance of IL-23 in uveitis comes from multiple genetic association studies. Several single nucleotide polymorphisms (SNPs) in the IL-23R gene have been found to be associated with chronic inflammatory diseases, including inflammatory bowel disease,42 ankylosing spondylitis, uveitis,43 and psoriasis.44 Dong et al45 reported that although 3 IL-23R gene SNPs were no different between patients with ankylosing spondylitis and a control group, the homozygous GG genotype of SNP rs17375018 in the IL-23R gene was significantly associated with patients with ankylosing spondylitis and uveitis. This same SNP is increased in Behçet’s disease uveitis as well. Hou et al46 subsequently discovered that IL-23A and IL-17F gene copy number variants >2 were associated with Behçet’s disease uveitis and Vogt‒Koyonagi‒Harad uveitis. Kim et al44 demonstrated that the IL-23R gene SNPs rs11465804 and rs11209026 were associated with sarcoid uveitis compared with control subjects. These clinical data are also supported experimentally because Il-23‒deficient animals are resistant to EAU.23,36

Clinical Trials and Agents Targeting the Interleukin-23/17 Axis

Biologic agents targeting the IL-23/IL-17 axis have been studied in inflammatory bowel disease, psoriasis, ankylosing spondylitis, and uveitis. Because of the proximal relationship of IL-23 and IL-17, initially these 2 cytokines were believed to be interchangeable as targets for autoimmune disease. However, initial clinical results found some surprising differences in therapeutic efficacy of anti‒IL-17 and anti‒IL-23 agents. Continuing studies into the complexity of type-17 cell biology and the dichotomous effects that IL-17 and IL-23 have on immunity have provided some answers to help explain these clinical trial results, but ultimately determining the ability of these agents to affect noninfectious uveitis will require well-designed clinical trials.

The biologic agents specifically targeting the IL-17/IL-23 axis that are currently available or are under development are summarized in Table 1.47–64 In patients with uveitis, secukinumab (an anti‒IL-17A antibody) is the only agent with completed trial results. Although secukinumab was not successful in several phase 3 clinical trials in patients with noninfectious uveitis, caveats in study design, including mode of administration of the drug, may have affected the study results.65 It remains to be determined whether or not targeting IL-17 or the IL-17 receptor using a different approach or drug will prove to be more efficacious.

Table 1.

Anti-Interleukin-17 and Anti-Interleukin-23 Monoclonal Antibody Therapies

Agent Drug Name Target Nonocular Indications with FDA Approval or in Active Clinical Trials Trials in Patients with Noninfectious Uveitis
Ixekizumab Taltz (Eli Lilly and Co., Indianapolis, IN) IL-17A Moderate to severe plaque psoriasis47 Active psoriatic arthritis48,49 None
Brodalumab Siliq (Valeant, Quebec, Canada) IL-17RA Moderate to severe plaque psoriasis50–52 None
Secukinumab Cosentyx (Novartis, East Hanover, NH) IL-17A Plaque psoriasis,53,54 psoriatic arthritis,55,56 ankylosing spondylitis57 • One phase 2 trial of intravenous administration65
• Three phase 3 trials subcutaneous administration24 (SHIELD, INSURE, ENDURE)
Ustekinumab STELARA (Janssen Biotech Inc, Horsham, PA) p40 subunit of and IL-12 IL-23 Moderately to severely active Crohn’s disease,58,59 moderate to severe plaque psoriasis,60–62 active psoriatic arthritis63,64 • NCT02648581: Phase 2 trials on the efficacy and safety of ustekinumab, in patients with Behçet disease (STELABEC-1) and active posterior and panuveitis
• NCT02911116: Phase 2 STELARA for the Treatment of Active Sight-Threatening Uveitis trial
Guselkumab Tremfya (Janssen Biotech, Inc) IL-23 p19 Moderate to severe plaque psoriasis68–70 none
Tildrakizumab IL-23 p19 Moderate to severe plaque psoriasis71 none
Brazikumab (MEDI2070) IL-23 p19 In development for Crohn’s disease (NCT01714726)72 none
Risankizumab IL-23 p19 In development for psoriasis,73 Crohn’s disease,74 psoriatic arthritis (NCT02986373) none
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FDA = Food and Drug Administration; IL = interleukin.

Ustekinumab, which targets the p40 subunit that is shared by both IL-23 and IL-12, has been reported to effectively control uveitis in 2 patients treated for coexisting severe psoriatic arthritis and plaque psoriasis or Behçet’s disease.66,67 In 2016, 2 phase 2 studies studying the efficacy of subcutaneous ustekinumab (STELARA, Janssen Biotech Inc, Horsham, PA) in patients with uveitis began enrollment. In the STELABEC trial, ustekinumab will be tested in 30 patients with Behçet’s disease with active posterior and panuveitis (clinicaltrials.gov NCT02648581). Treatment will be administered at weeks 0, 4, and 16, with end point assessment at week 24. In the STELARA for the Treatment of Active Sight-Threatening Uveitis trial, 7 patients with active, sight-threatening, noninfectious, intermediate, posterior, or panuveitis uveitis will be treated at weeks 0, 4, and 8, with end point assessment at 16 weeks (clinicaltrials.gov NCT02911116). The results of these studies are anticipated for release in 2019 or 2020.

In addition to ustekinumab, newer IL-23 specific agents have been developed that target the p19 subunit. Phase 3 trials for the human monoclonal antibodies tildrakizumab and guselkumab in patients with psoriasis were both successful, and these agents are now Food and Drug Administration approved for the treatment of moderate to severe disease.68–71 Other p19-specific agents that are in development include brazikumab for Crohn’s disease (clinicaltrials.gov NCT01714726)72 and risankizumab for psoriasis,73 Crohn’s disease,74 and psoriatic arthritis (clinicaltrials.gov NCT02986373). In anti-IL-23 studies, a common adverse event was nasopharyngitis, but serious adverse events were not significantly different when compared with placebo. However, as with many other immune-modifying medications, there may be a need for dermatologic monitoring because nonmelanoma skin cancers were found in 14 patients in the PHOENIX trial for ustekinumab.75 Overall, the rate of antibodies against the anti‒IL-23 biologics was variable and relatively rare.

Despite the growing body of literature supporting IL-23 as a good therapeutic target for the treatment of immune- mediated uveitis, how to target IL-23 or its receptor for best treatment efficacy in uveitis remains unknown. Keino et al76 discovered that an oral IL-12/IL-23 small molecule inhibitor, STA-5326, that targets expression of the p40 subunit through c-Rel (a member of the nuclear factor-kb family of transcription factors) was found to reduce the severity of uveitis in EAU mice at 2 different doses, 5 mg/kg and 20 mg/kg.76 The STELARA for the Treatment of Active Sight-Threatening Uveitis and STELABAC trials both deliver anti-IL-23 therapy via the subcutaneous route, which was effective for treatment of patients with Crohn’s disease, psoriasis, and psoriatic arthritis but was not effective in a phase 2 clinical trial in patients with relapsing-remitting multiple sclerosis.77 The route of drug delivery was only 1 possible reason cited for failure, along with inclusion of patients with late-stage disease who were unlikely to benefit from treatment and inability of ustekinumab to cross the bloodebrain barrier.78 Because the pending uveitis trials of ustekinumab are relatively small, they may be susceptible to some of the pitfalls encountered in the multiple sclerosis trial. However, the prior anecdotal support for efficacy of this route still provides optimism that these trials will provide the first clear evidence for use of anti-IL-23 therapy as the next option for biologic therapy in patients with uveitis.

In conclusion, both IL-17 and IL-23 appear to play a crucial role in noninfectious uveitis. However, although targeting IL-23 and IL-17 still holds significant promise, the complex effects that result from modification of this immune axis will likely require refinement in patient selection, timing of therapy, and route of drug administration to determine the true efficacy.

Acknowledgments

Financial Disclosure(s):

The author(s) made the following disclosures: K.P.: Support Research to Prevent Blindness Career Development Award (New York, NY), The Alcon Research Institute Young Investigators Grant (Fort Worth, TX), and the National Institute of Health, NEI K08EY023998.

P.L.: Supported National Eye Institute Grant K08 EY022948, a Collins Medical Trust Grant, Research to Prevent Blindness Career Development Award. The manuscript is supported by Core Grants P30 EY010572 and P30 EY01730 from the National Institute of Health (Bethesda, MD) and by unrestricted departmental funding from Research to Prevent Blindness (New York, NY).

Abbreviations and Acronyms:

EAU

experimental autoimmune uveitis

IL

interleukin

IL-23R

interleukin 23 receptor

SNP

single nucleotide polymorphism

Th

T-helper

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