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. 2018 Mar 9;32(7):1111–1119. doi: 10.1111/jdv.14868

Shifting the focus – the primary role of IL‐23 in psoriasis and other inflammatory disorders

MJ Gooderham 1,✉, KA Papp 2, CW Lynde 3,4
PMCID: PMC6033004  PMID: 29438576

Abstract

Insights into the pathophysiology of autoimmune inflammatory diseases including psoriasis have advanced considerably in recent years, and in parallel, so too have the available treatment options. Current clinical paradigms for the treatment of psoriasis have evolved to include targeted biologic therapies, starting with tumour necrosis factor‐alpha (TNF‐α) inhibitors and later, agents targeting interleukin (IL)‐12/23 and IL‐17. The most recent evidence suggests that IL‐23 might be an even more potent target for the effective treatment of psoriasis and other autoimmune inflammatory disorders. This review will describe recent developments leading to the current understanding of the key role of IL‐23 as a ‘master regulator’ of autoimmune inflammation and the clinical evidence for agents that specifically target this modulator in the context of treating psoriasis, spondyloarthropathy and inflammatory bowel disease.

Introduction

Psoriasis was originally believed to be a disease originating from dysregulation of keratinocyte proliferation (Fig. 1) based on histological evidence.1, 2 Through the 1980–90s, evidence pointed to psoriasis as an immune‐mediated disease.3, 4, 5 Cytotoxic T cells were identified around capillaries3 and within the dermis and epidermis4 of psoriatic lesions. That T‐cell‐targeted therapies improved psoriasis outcomes further solidified this role in the disease pathophysiology.6, 7

Figure 1.

Figure 1

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Historical timeline of discoveries and evolving pathophysiologic concepts. Time (x‐axis) not to scale. IL, interleukin; PsO, psoriasis; Th, T‐helper cell.

Subpopulations of T cells, T helper 1 (Th1) and T helper 2 (Th2) cells were identified based on their cytokine secretory profile.8, 9 Th1 cells secrete interferon (IFN)‐γ, tumour necrosis factor (TNF)‐α and interleukin (IL)‐2, whereas Th2 cells secrete IL‐4, ‐5, ‐10 and ‐13.8, 9 Differentiation of naïve T cells is cytokine‐dependent: IL‐12 driving Th1 cell differentiation10 and IL‐2 and ‐4 driving Th2 differentiation.11

With this increased understanding, psoriasis was deemed a Th1‐mediated disease, as elevated levels of TNF‐α12 and the p40 subunit of IL‐1213 were identified in psoriatic lesions. These data supported the clinical development of TNF‐α blockers as biologic treatments for psoriasis.14

Subsequently, IL‐23 was discovered comprised of a unique p19 subunit and sharing the p40 subunit of IL‐12.15 This shared subunit suggested that IL‐23, and perhaps not IL‐12, could play a role in the pathogenesis of psoriasis. The p40 and p19 subunits of IL‐23, but not the p35 subunit of IL‐12, are elevated in multiple forms of psoriasis,13, 16, 17 but not in other dermatitides,18 highlighting the central role of IL‐23 in psoriasis. Two IL‐12/23p40 blockers, ustekinumab19, 20 and briakinumab,21, 22, 23 were demonstrated more effective than placebo or etanercept, at improving symptoms of psoriasis (Psoriasis Area and Severity Index [PASI] 75 response). Although effective, the commercial development of briakinumab was terminated.24

Th17 cells and the pathophysiology of autoimmune inflammation

IL‐23 maintains the differentiation of naïve T cells into a distinct T‐cell lineage, Th17, characterized by the secretion of pro‐inflammatory IL‐17 (Fig. 2).25 IL‐17 had previously been associated with animal models of inflammation,26, 27 and this led to the investigation of IL‐17 inhibition in the treatment of various autoimmune diseases including psoriasis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and inflammatory bowel disease (IBD). Both Th17 cells and IL‐17 are elevated in these conditions.28 Three biologics were developed targeting IL‐17 signalling: secukinumab and ixekizumab target the IL‐17A isoform specifically, while brodalumab blocks the IL‐17 receptor A subunit (IL‐17RA) thereby blocking several cytokines from the IL‐17 family.29, 30, 31 These anti‐IL‐17A biologics have been shown effective in psoriasis as demonstrated by their high PASI 75 response rates (71–83% at 12 weeks).29, 30, 31 Anti‐IL‐17A biologics have also been shown to improve symptoms of psoriatic arthritis,32, 33 ankylosing spondylitis34 and rheumatoid arthritis.35 In Phase II studies of patients with IBD, blocking IL‐17A was ineffective. In fact, a worsening of the Crohn's disease was observed in some cases.36, 37 One hypothesis for this observation is that the gut microbiotic environment may be contributing to the pathophysiology of this disease.36 In addition, studies have shown that IL‐17 plays a role in maintenance of the intestinal epithelial barrier and in tissue repair.38, 39 A fourth IL‐17 inhibitor, bimekizumab, which targets both IL‐17A/F, is in early stages of clinical development.40

Figure 2.

Figure 2

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Cytokine secretory profiles of T cells. Native T cells differentiate along three known pathways (Th1, Th2 and Th17) depending on the cytokine environment. These unique T‐helper cells then secrete a distinct set of cytokines resulting in different physiological responses. Current psoriasis treatment approaches include blocking the cytokines produced by the differentiated T cells, or blocking the cytokines that drive pathogenic differentiation of certain T‐cell lineages. IFN, interferon; IL, interleukin; Th, T‐helper cell; TNF, tumour necrosis factor.

Systemic downregulation of IL‐17 has been associated with adverse effects related to the key role of IL‐17 in protecting the skin and mucous membranes from infection, specifically candidiasis.41 In clinical trials, approximately 2–4% of patients treated with IL‐17 blockers developed candidiasis, mostly oral infections.41 Case reports of suicidal ideation and completed suicides have been reported in patients taking brodalumab,42 although a recent review of the evidence suggests that this may not be directly related to the drug itself.43 Cases of IBD flare or new onset IBD have been reported in a small proportion of psoriasis patients exposed to ixekizumab (0.29 per 100 patient‐years)44 or secukinumab (0.33 per 100 patient‐years)45 in safety analyses of Phase II and III trials. This, coupled with the Phase II evidence of worsening of disease in patients with an established diagnosis of IBD,36, 37 has raised concerns about an association between IL‐17 inhibition and IBD. However, at this time, a causal relationship has not been definitively established for IL‐17 inhibitors and risk of IBD in patients with psoriasis, psoriatic arthritis or ankylosing spondylitis.46

Role of IL‐23 in the pathophysiology of autoimmune disorders

The differentiation of Th17 cells is activated upon exposure to transforming growth factor (TGF)‐β and IL‐6, resulting in the upregulation of the transcription factor retinoid‐related orphan receptor (ROR)‐γt.47 (ROR)‐γt promotes the expression of IL‐17A and of the IL‐23 receptor (IL‐23R).48 Subsequent exposure to IL‐23 is required for the maintenance and expansion of the Th17 lineage.26, 49, 50 In the absence of IL‐23, the Th17 phenotype is lost.49 IL‐23 is produced by antigen‐presenting Langerhans cells,51 dendritic cells52 and monocytes/macrophages53 of the innate immune system in response to an inflammatory or biochemical insult, specifically at barrier sites such as the skin, gut and entheses. Binding of IL‐23 to its receptor initiates a signalling cascade phosphorylating and activating Jak2 and STAT3,54 ultimately leading to increased expression of IL‐17 and ROR‐γt.55 Together, these observations highlight the fundamental role of IL‐23 in the production of IL‐17.

Given the essential role of IL‐23 in maintaining pathogenic Th17 cell populations, blocking IL‐23 could be safer and more effective therapeutic target. Blocking IL‐23 decreases levels of circulating IL‐17A, likely due to a reduction in the number and/or activity of pathogenic Th17 cells.56 However, IL‐17 is not completely eliminated, possibly because other cells produce IL‐17 independent of IL‐23 stimulation.41, 57, 58 IL‐23 bridges the innate and adaptive immune system in that it can stimulate IL‐17 production from natural killer cells and neutrophils to control an acute infection (innate) and from T cells leading to an inflammatory autoimmune response (adaptive).59 Therefore, a response to candida infection or other barrier insult can still be mounted in the setting of IL‐23 blockade.41, 57, 58

Selectively blocking the IL‐23 subunit p19 also has potential benefits over blocking the p40 subunit shared by IL‐23 and IL‐12. IL‐12 is essential for driving Th1 differentiation and therefore the immune response to infectious pathogens.10, 60 Many host defense processes can function if IL‐12 remains intact even when IL‐23 is blocked.61 As Th1 cells secrete IFN‐γ, these cells can also decrease the effects of IL‐23 by downregulating the IL‐23 receptor and further reducing Th17 differentiation.62

Targeting IL‐23 instead of TNF‐α may also confer a benefit in terms of risk of tuberculosis or hepatitis reactivation, as well as ‘paradoxical psoriasis’ or psoriasiform eruption.63 It has been speculated that paradoxical psoriasis arises from a cytokine imbalance that favours dendritic cell activation and the unopposed production of IFN‐α.63, 64 Increased IFN‐α causes upregulation of the chemokine receptor CXCR3 in Th1 cells, which could induce migration to the psoriatic lesion.63

IL‐23: The ‘master regulator’ in psoriasis, spondyloarthropathy and inflammatory bowel disease

While there is considerable evidence that IL‐23 may be a key regulator in autoimmune conditions in general, primary research supports a role for IL‐23 in the pathophysiology of psoriasis specifically. Rodent models have shown that injection of IL‐23 into healthy mice resulted in psoriasis‐like lesions.65 Conversely, p19 knock‐out mice are protected against imiquimod‐induced psoriasis, suggesting that blocking IL‐23 could prevent the development of the disease.66 Similarly, single nucleotide polymorphisms (SNPs) in the genes expressing the p40 subunit of IL‐12/23 or the IL‐23 receptor can confer either protection against67 or susceptibility to68, 69 the development of psoriasis in humans (Fig. 3).

Figure 3.

Figure 3

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Current model of the pathophysiology of psoriasis. IL‐23 bridges the innate and adaptive immune responses and plays a key role in inducing Th17 cell differentiation. The resulting elevated IL‐17 secretion maintains the pathological response of keratinocytes, resulting in psoriatic plaque formation. IL, interleukin; Th, T‐helper cell; TGF, transforming growth factor; TNF, tumour necrosis factor.

A growing body of the literature supports a central role of IL‐23 in the pathophysiology of spondyloarthropathy. Cells harbouring IL‐23 receptors have been identified in the entheses and have been shown to induce the production of pro‐inflammatory IL‐17.70 In a murine model, administration of IL‐23 resulted in entheseal inflammatory arthritis and bone erosion similar to spondyloarthritis.71 The same gene polymorphisms in the IL‐23 receptor associated with psoriasis have been shown to be associated with psoriatic arthritis72 and ankylosing spondylitis.73

Murine IBD models have shown that IL‐23 is a requirement for the induction of intestinal mucosal inflammation.74 Elevated transcription of IL‐23 has been found in the inflamed mucosa of patients with Crohn's disease, with a dose‐dependent effect on disease severity.75 Studies suggest that blocking IL‐23 does not impair IL‐17 production by innate non‐T‐cell lymphocytes76 thereby preserving intestinal epithelial integrity and tissue repair mechanisms.38, 39

These data support a unifying aspect of IL‐23 in the pathophysiology of autoinflammatory diseases and suggest that targeting IL‐23 may present a common approach to the treatment of diseases including psoriasis, IBD and spondyloarthropathy which are often overlapping (Fig. 4).77

Figure 4.

Figure 4

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Unifying concept of IL‐23 as a ‘master regulator’ in the pathogenesis of autoimmune disorders. Psoriasis, rheumatoid diseases and inflammatory bowel disease are all characterized by the pathogenic overproduction of IL‐23 at barrier sites, i.e. the skin, the joints and the gut, respectively. This makes IL‐23 an attractive target for all three conditions. IBD, inflammatory bowel disease; IL, interleukin; Th, T‐helper cell.

Clinical data support a principal role for IL‐23 in psoriasis

Understanding the pathophysiology of disease may identify therapeutic targets. Conversely, the clinical application of targeted therapies provides information about the mechanisms underlying disease. The clinical development of anti‐IL‐23p19 drugs for psoriasis will be described below.

Guselkumab

A Phase I study examined the safety, efficacy and biomarker response of a single dose of guselkumab in 24 patients with psoriasis.56 Blocking IL‐23 modulated the expression of several genes in psoriatic skin lesions including IL‐17A, IL‐17F and CXCL1 with limited effects on the Th1 pathway and decreased levels of circulating IL‐17A, likely due to a reduction in the number and/or activity of pathogenic Th17 cells. Reductions in levels of other cytokines including IL‐17F, IL‐22 and TNF‐α did not reach statistical significance.

In a Phase II study, varying doses of guselkumab (i.e. 5, 15, 50, 100 and 200 mg) were compared to placebo (weeks 0–16) and to adalimumab (weeks 0–52).78 For all efficacy measures, dose–response improvements in the guselkumab‐treated groups were greater than placebo.78 Clinical improvements in the guselkumab‐treated groups peaked at ~20 weeks and were maintained through 40 weeks.78 The incidence of adverse effects was low, with similar rates of infection in the placebo, guselkumab and adalimumab arms. The VOYAGE‐1 Phase III trial confirmed the superiority of guselkumab over placebo and adalimumab (PASI 90 response rates 73.3%, 2.9% and 49.7%, respectively).79 Adverse event rates in this trial were also similar between treatment groups.79 In VOYAGE‐2, adalimumab non‐responders (not achieving PASI 90 by week 24) were switched to guselkumab at week 28.80 After 48 weeks of treatment, 66.1% of adalimumab non‐responders treated with guselkumab achieved a PASI 90 response and 28.6% achieved PASI 100.80 In NAVIGATE, guselkumab demonstrated superiority over the IL‐12/23 inhibitor, ustekinumab, in patients who failed to respond to ustekinumab compared to those who remained on ustekinumab (51.1% vs. 24.1% of patients with PASI 90 at week 52; P < 0.001).81 Guselkumab has been shown to reduce IL‐17 levels in blood and psoriatic lesions, supporting a causal relation between a reduction in the number, or activity, of Th17 cells and clinical improvements in psoriasis.56

Tildrakizumab

In a Phase IIb trial, tildrakizumab 5, 25, 100 and 200 mg was compared to placebo for 52 weeks.82 The PASI 75 response rate (primary endpoint) was significantly higher in tildrakizumab‐treated patients compared to placebo by week 16 (33–74% compared to 4% for placebo; P < 0.001 vs. placebo for all doses) and was generally maintained through 52 weeks.82 PASI 90 rates were 12–52% at week 16, and 73–81% of week 16 responders maintained PASI 90 at week 52.82 Adverse events were similar between active treatment and placebo groups.82 The Phase III trial, reSURFACE‐1, confirmed these results (PASI 75 response rates ranged from 62% to 64% at week 12 and 80% to 82% at week 28).83 In reSURFACE‐2, 37–39% of patients treated with tildrakizumab achieved PASI 90 at 28 weeks compared to 21% with etanercept and 1% with placebo.83 Adverse events were similarly low between tildrakizumab and etanercept.83

Risankizumab

In a Phase I trial, PASI 75, 90 and 100 response rates were significantly higher in the risankizumab group compared to placebo at 12 weeks (87%, 58%, 16% and 0%, respectively), and responses were maintained through 24 weeks.84 Adverse events were not different between treatment and placebo groups.84 Significant reductions in IL‐23, IL‐23R and IL‐17 were demonstrated in lesional skin biopsies with active treatment compared to control.85 In a Phase II trial, risankizumab was superior to ustekinumab in the proportion of patients achieving PASI 90 (77% vs. 40%; P < 0.001 pooled risankizumab groups vs. ustekinumab).85 Adverse events were similar between treatments.85 Expression of the IL‐23 receptor was shown to be downregulated in the risankizumab‐treated group but not in patients treated with ustekinumab. Levels of downstream IL‐17 were not reported.85

Benefits of reducing Th17 clonal expansion with IL‐23 blockers

There is clear clinical evidence that specific IL‐23p19 blockade is effective, safe and superior to other biologics that act on downstream cytokines of the IL‐23/Th17 pathway. A potential benefit of reducing the clonal expansion of Th17 cells via IL‐23 inhibition is low dosing frequency and a sustained drug effect. After induction, IL‐23 blockers are effective when dosed every 8–12 weeks compared to every 2 weeks for adalimumab78 or 4 weeks for IL‐17 blockers. A single dose of 18 mg of risankizumab resulted in a 53% PASI 75 and 28% PASI 90 response rate.85 At higher doses of risankizumab, PASI 75 and 90 response rates generally persisted for up to 32 weeks following the final treatment.85 In a randomized withdrawal study of guselkumab, PASI 90 response rates began to diverge from patients who continued maintenance treatment around week 32.80 It is postulated that blocking IL‐23 may be more effective and the effects longer lasting due to an upstream effect including reduced expression of several downstream pro‐inflammatory cytokines secreted by Th17 cells (e.g. IL‐17A, IL‐17F, IL‐21 and IL‐22).86 This could be due to impaired survival or a phenotypic change in the pathogenic Th17 cells, or a restoration of altered T‐reg function:86 important as Th17 cells are long‐lived and metabolically active, even after skin healing.87, 88 Preventing initial production of these cells could prove beneficial.

Evidence for role of IL‐23 in other disease states

An accumulating body of evidence suggests that the benefits of IL‐23 blockade are not limited to psoriasis as IL‐23 and IL‐12/23 blockers have been investigated in clinical trials for various other inflammatory diseases.89 Clinical data in the investigation of rheumatoid diseases (i.e. psoriatic arthritis, ankylosing spondylitis and rheumatoid arthritis) have reported varying results. Significant improvements in symptoms, physical function and quality of life were observed with guselkumab in psoriatic arthritis patients.90 Ustekinumab reduced signs and symptoms of ankylosing spondylitis in a proof‐of‐concept study.91 In contrast, neither ustekinumab nor guselkumab was effective at reducing signs and symptoms of active rheumatoid arthritis.92

Mixed results have also been reported in other inflammatory diseases. Ustekinumab, risankizumab and MEDI2070 (anti‐p19 monoclonal antibody) have demonstrated effectiveness for the treatment of Crohn's disease.93, 94, 95 Ustekinumab was not effective in treating symptoms of multiple sclerosis, although it was well tolerated.96

Conclusions

Psoriasis is recognized as a Th17‐mediated inflammatory disorder. A growing body of evidence supports IL‐23 as the ‘master regulator’ of the immune‐inflammatory response in psoriasis and other inflammatory disorders due to its critical role in maintaining the population of cytotoxic Th17 cells that produce pro‐inflammatory cytokines including IL‐17 and IL‐22. Emerging results of randomized clinical trials suggest that selectively blocking IL‐23 (p19 subunit) offers benefits above and beyond current treatment strategies for psoriasis producing high levels of efficacy, a favourable safety/tolerability profile, and the convenience of infrequent dosing. IL‐23 blockers represent an important step forward in the continued evolution of the treatment landscape. Patients with psoriasis and other inflammatory diseases can expect better outcomes as therapies become more targeted and refined.

Source of Molecular Data for Illustrated Figures

Molecular images were drawn based on molecular data viewed using NGL Viewer software and based on the following research: Image of 1F45 (C. Yoon, S.C. Johnston, J. Tang, J.F. Tobin, W.S. Somers (2000) human interleukin‐12 Embo J. 19: 3530–3541), 4 HR 9 (S. Liu, X. Song, B.A. Chrunyk, S. Shanker, L.R. Hoth, E.S. Marr, M.C. Griffor (2013) human interleukin 17A Nat Commun 4: 1888–1888), 3D87 (B.M. Beyer, R. Ingram, L. Ramanathan, P. Reichert, H.V. Le, V. Madison, P. Orth (2008) crystal structure of Interleukin‐23 J.Mol.Biol. 382: 942–955) and 3 HMW (J. Luo, S.J. Wu, E.R. Lacy, Y. Orlovsky, A. Baker, A. Teplyakov, G. Obmolova, G.A. Heavner, H.T. Richter, J. Benson (2010) crystal structure of ustekinumab FAB J.Mol.Biol. 402: 797–812) created with NGL (A.S. Rose, A.R. Bradley, Y. Valasatava, J.M. Duarte, A. Prlić, P.W. Rose (2016) Web‐based molecular graphics for large complexes. ACM Proceedings of the 21st International Conference on Web3D Technology (Web3D ‘16): 185–186; A.S. Rose, P.W. Hildebrand (2015) NGL Viewer: a web application for molecular visualization. Nucl Acids Res (1 July 2015) 43 (W1): W576–W579 first published online April 29, 2015).

Acknowledgements

We would like to thank Ardeane Healthcare Solutions and Christina Clark for their assistance in the preparation of this manuscript and Kryski Biomedia for creating the illustrations.

Disclosures

M.J.G. was an advisory board member, principal investigator, speaker and/or consultant for Abbvie Inc., Actelion Pharmaceuticals, Akros Pharma Inc., AMGEN Inc., Boehringer Ingelheim International GmbH, Bristol‐Myers Squibb Company, Celgene Corporation, Dermira Inc., Eli Lilly and Company, Galderma SA, GlaxoSmithKleine, Janssen Inc., LEO Pharma, MedImmune, Novartis Pharmaceuticals, Pfizer Inc., Regeneron Pharmaceuticals Inc., Roche Laboratories, Sanofi Genzyme, UCB, and Valeant Pharmaceuticals Inc. K.A.P. was a consultant, speaker, scientific officer, advisory board or steering committee member and/or received clinical research grants or honoraria from AbbVie, Akros, Allergan, Amgen, Anacor, Astellas, AstraZeneca, Baxalta, Baxter, Boehringer Ingelheim, Bristol‐Myers Squibb, CanFite, Celgene, Coherus, Dermira, Dow Pharma, Eli Lilly, Forward Pharma, Galderma, Genetech, GSK, Janssen, Kyowa Hakko Kirin, Leo, MedImmune, Meiji Seika Pharma, Merck (MSD), Merck‐Serono, Mitsubishi Pharma, Novartis, Pfizer, Regeneron, Roche, Sanofi‐Aventis/Genzyme, Takeda, UCB, and Valeant. C.W.L. was a consultant, speaker, principal investigator and/or received honoraria from Abbvie, Amgen, Boehringer, Eli Lilly, GSK, Janssen, LeoPharma, Merck, Novartis, Takeda, and Valeant.

Funding sources:

Janssen Inc. funded this work and provided formal review of the manuscript. Funding was also provided to Ardeane Healthcare Solutions for assistance with manuscript preparation and editing, and for artwork.

References

  • 1. Lynde CW, Poulin Y, Vender R, Bourcier M, Khalil S. Interleukin 17A: toward a new understanding of psoriasis pathogenesis. J Am Acad Dermatol 2014; 71: 141–150. [DOI] [PubMed] [Google Scholar]
  • 2. Wagner EF, Schonthaler HB, Guinea‐Viniegra J, Tschachler E. Psoriasis: what we have learned from mouse models. Nat Rev Rheumatol 2010; 6: 704–714. [DOI] [PubMed] [Google Scholar]
  • 3. Bjerke RJ. In situ characterization and counting of mononuclear cells in lesions of different clinical forms of psoriasis. Acta Derm Venereol 1982; 62: 93–100. [PubMed] [Google Scholar]
  • 4. Hammar H, Gu S‐H, Johannesson A, Sundkvist K‐G, Biberfeld P. Subpopulations of Mononuclear Cells in Microscopic Lesions of Psoriatic Patients. Selective accumulation of suppressor/cytotoxic T cells in epidermis during the evolution of the lesion. J Invest Dermatol 1984; 83: 416–420. [DOI] [PubMed] [Google Scholar]
  • 5. Gottlieb SL, Gilleaudeau P, Johnson R et al Response of psoriasis to a lymphocyte‐selective toxin (DAB389IL‐2) suggests a primary immune, but not keratinocyte, pathogenic basis. Nat Med 1995; 1: 442–447. [DOI] [PubMed] [Google Scholar]
  • 6. Mueller W, Herrmann B. Cyclosporin A for psoriasis. N Engl J Med 1979; 301: 555. [DOI] [PubMed] [Google Scholar]
  • 7. Ellis CN, Gorsulowsky DC, Hamilton TA et al Cyclosporine improves psoriasis in a double‐blind study. JAMA 1986; 256: 3110–3116. [PubMed] [Google Scholar]
  • 8. Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL. Two types of murine helper T cell clone, I: definition according to profiles of lymphokine activities and secreted proteins. J Immunol 1986; 136: 2348–2357. [PubMed] [Google Scholar]
  • 9. Biedermann T, Röcken M, Carballido JM. TH1 and TH2 lymphocyte development and regulation of TH cell‐mediated immune responses of the skin. J Investig Dermatol Symp Proc 2004; 9: 5–14. [DOI] [PubMed] [Google Scholar]
  • 10. Manetti R, Parronchi P, Giudizi MG et al Natural killer cell stimulatory factor (interleukin‐12 [IL‐12]) induces T helper type 1 (Th1)‐specific immune responses and inhibits development of IL‐4‐producing Th cells. J Exp Med 1993; 177: 1199–1204. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11. Le Gros G, Ben‐Sasson SZ, Seder R, Finkelman FD, Paul WE. Generation of interleukin 4 (IL‐4)‐producing cells in vivo and in vitro: IL‐2 and IL‐4 are required for in vitro generation of IL‐4‐producing cells. J Exp Med 1990; 172: 921–929. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12. Ettehadi P, Greaves MW, Wallach D, Aderka K, Camp RD. Elevated tumour necrosis factor‐alpha (TNF‐a) biological activity in psoriatic skin lesions. Clin Exp Immunol 1994; 96: 146–151. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13. Yawalkar N, Karlen S, Hunger R, Brand CU, Braathen LR. Expression of interleukin‐12 is increased in psoriatic skin. J Invest Dermatol 1998; 111: 1053–1057. [DOI] [PubMed] [Google Scholar]
  • 14. Mease PJ, Goffe BS, Metz J, VanderStoep A, Finck B, Burge DJ. Etanercept in the treatment of psoriatic arthritis and psoriasis: a randomised trial. Lancet 2000; 356: 385–390. [DOI] [PubMed] [Google Scholar]
  • 15. Oppmann B, Lesley R, Blom B et al Novel p19 protein engages IL‐12p40 to form a cytokine, IL‐23, with biological activities similar as well as distinct from IL‐12. Immunity 2000; 13: 715–725. [DOI] [PubMed] [Google Scholar]
  • 16. Lee E, Trepicchio WL, Oestreicher JL et al Increased expression of interleukin 23 p19 and p40 in lesional skin of patients with psoriasis vulgaris. J Exp Med 2004; 199: 125–130. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17. Piskin G, Sylva‐Steenland RM, Bos JD, Teunissen MB. In vitro and in situ expression of IL‐23 by keratinocytes in healthy skin and psoriasis lesions: enhanced expression in psoriatic skin. J Immunol 2006; 176: 1908–1915. [DOI] [PubMed] [Google Scholar]
  • 18. Guttman‐Yassky E, Lowes MA, Fuentes‐Duculan J et al Low expression of IL‐23/TH17 pathway in atopic dermatitis compared to psoriasis. J Immunol 2008; 181: 7420–7427. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19. Leonardi CL, Kimball AM, Papp KA et al Efficacy and safety of ustekinumab, a human interleukin‐12/23 monoclonal antibody, in patients with psoriasis: 76‐week results from a randomized, double‐blind, placebo‐controlled trial (PHOENIX 1). Lancet 2008; 371: 1665–1674. [DOI] [PubMed] [Google Scholar]
  • 20. Papp KA, Langley RG, Lebwohl M et al Efficacy and safety of ustekinumab, a human interleukin‐12/23 monoclonal antibody, in patients with psoriasis: 52‐week results from a randomized, double‐blind, placebo‐controlled trial (PHOENIX 2). Lancet 2008; 371: 1675–1684. [DOI] [PubMed] [Google Scholar]
  • 21. Gordon KB, Langley RG, Gottlieb AB et al A phase III, randomized, controlled trial of the fully human IL‐12/23 mAB briakinumab in moderate‐to‐severe psoriasis. J Invest Dermatol 2012; 132: 304–314. [DOI] [PubMed] [Google Scholar]
  • 22. Strober BE, Crowley JJ, Yamauchi PS, Olds M, Williams DA. Efficacy and safety results from a phase III, randomized controlled trial comparing the safety and efficacy of briakinumab with etanercept and placebo in patients with moderate to severe chronic plaque psoriasis. Br J Dermatol 2011; 165: 661–668. [DOI] [PubMed] [Google Scholar]
  • 23. Gottlieb AB, Leonardi C, Kerdel F, Mehlis S, Olds M, Williams DA. Efficacy and safety of briakinumab vs. etanercept and placebo in patients with moderate to severe chronic plaque psoriasis. Br J Dermatol 2011; 165: 652–660. [DOI] [PubMed] [Google Scholar]
  • 24. Traczewski P, Rudnicka L. Briakinumab for the treatment of plaque psoriasis. BioDrugs 2012; 26: 9–20. [DOI] [PubMed] [Google Scholar]
  • 25. Aggarwal S, Ghilardi N, Xie MH, de Sauvage FJ, Gurney AL. Interleukin‐23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin‐17. J Biol Chem 2003; 278: 1910–1914. [DOI] [PubMed] [Google Scholar]
  • 26. Langrish CL, Chen Y, Blumenschein WM et al IL‐23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med 2005; 201: 233–240. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27. Nakae S, Saijo S, Horai R, Sudo K, Mori S, Iwakura Y. IL‐17 production from activated T cells is required for the spontaneous development of destructive arthritis in mice deficient in IL‐1 receptor antagonist. Proc Natl Acad Sci U S A 2003; 100: 5986–5990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28. Eyerich K, Dimartino V, Cavani A. IL‐17 and IL‐22 in immunity: Driving protection and pathology. Eur J Immunol 2017; 47: 607–614. [DOI] [PubMed] [Google Scholar]
  • 29. Langley RG, Elewski BE, Lebwohl M et al Secukinumab in plaque psoriasis – results of two Phase 3 trials. N Eng J Med 2015; 371: 326–338. [DOI] [PubMed] [Google Scholar]
  • 30. Gordon KB, Blauvelt A, Papp KA et al Phase 3 trials of ixekizumab in moderate‐to‐severe plaque psoriasis. N Engl J Med 2016; 375: 345–356. [DOI] [PubMed] [Google Scholar]
  • 31. Papp KA, Reich K, Paul C et al A prospective phase III, randomized, double‐blind, placebo‐controlled study of brodalumab in patients with moderate‐to‐severe plaque psoriasis. Br J Dermatol 2016; 175: 273–286. [DOI] [PubMed] [Google Scholar]
  • 32. Mease PJ, van der Heijde D, Ritchlin CT et al Ixekizumab, an interleukin‐17A specific monoclonal antibody, for the treatment of biologic‐naïve patients with active psoriatic arthritis: Results from the 24‐week randomized, double‐blind, placebo‐controlled and active (adalimumab)‐controlled period of the phase III trial SPIRIT‐P1. Ann Rheum Dis 2017; 76: 79–87. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33. Kavanaugh A, Mease PJ, Reimold AM et al Secukinumab for long‐term treatment of psoriatic arthritis: A two‐year follow‐up from a Phase III, randomized, double‐blind placebo‐controlled study. Arthritis Care Res 2017; 69: 347–355. [DOI] [PubMed] [Google Scholar]
  • 34. Baeten D, Sieper J, Braun J et al Secukinumab, an interleukin‐17A inhibitor, in ankylosing spondylitis. N Engl J Med 2015; 373: 2534–2548. [DOI] [PubMed] [Google Scholar]
  • 35. Blanco FJ, Moricke R, Dokoupilova E et al Secukinumab in active rheumatoid arthritis: A Phase III randomized, double‐blind, active comparator‐ and placebo‐controlled study. Arthritis Rheumatol 2017; 69: 1144–1153. [DOI] [PubMed] [Google Scholar]
  • 36. Hueber W, Sands BE, Lewitzky S et al Secukinumab, a human anti‐IL‐17A monoclonal antibody, for moderate to severe Crohn's disease: Unexpected results of a randomized, double‐blind placebo‐controlled trial. Gut 2012; 61: 1693–1700. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37. Targan SR, Feagan B, Vermeire S et al A randomized, double‐blind, placebo‐controlled Phase 2 study of brodalumab in patients with moderate‐to‐severe Crohn's Disease. Am J Gastroenterol 2016; 111: 1599–1607. [DOI] [PubMed] [Google Scholar]
  • 38. Lee JS, Tato CM, Joyce‐Shaikh B et al Interleukin‐23‐independent IL‐17 production regulates intestinal epithelial permeability. Immunity 2015; 43: 727–738. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39. Maxwell JR, Zhang Y, Brown WA et al Differential roles for interleukin‐23 and interleukin‐17 in intestinal immunoregulation. Immunity 2015; 43: 739–750. [DOI] [PubMed] [Google Scholar]
  • 40. Glatt S, Helmer E, Haier B et al First‐in‐human randomized study of bimekizumab, a humanized monoclonal antibody and selective dual inhibitor of IL‐17A and IL‐17F, in mild psoriasis. Br J Clin Pharmacol 2017; 83: 991–1001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41. Saunte DM, Mrowietz U, Puig L, Zachariae C. Candida infections in psoriasis and psoriatic arthritis patients treated with IL‐17 inhibitors and their practical management. Br J Dermatol 2017; 177: 47–62. [DOI] [PubMed] [Google Scholar]
  • 42. Farahnik B, Beroukhim K, Abrouk M et al Brodalumab for the treatment of psoriasis: A review of Phase III trials. Dermatol Ther (Heidelb) 2016; 6: 111–124. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43. Chiricozzi A, Romanelli M, Saraceno R, Torres T. No meaningful association between suicidal behavior and the use of IL‐17A‐neutralizing or IL‐17RA‐blocking agents. Expert Opin Drug Saf 2016; 15: 1653–1659. [DOI] [PubMed] [Google Scholar]
  • 44. Reich K, Leonardi C, Langley RG et al Inflammatory bowel disease among patients with psoriasis treated with ixekizumab: A presentation of adjudicated data from an integrated database of 7 randomized controlled and uncontrolled trials. J Am Acad Dermatol 2017; 76: 441–448. [DOI] [PubMed] [Google Scholar]
  • 45. van de Kerkhof PCM, Griffiths CEM, Reich K et al Secukinumab long‐term safety experience: A pooled analysis of 10 phase II and III clinical studies in patients with moderate to severe plaque psoriasis. J Am Acad Dermatol 2016; 75: 83–98. [DOI] [PubMed] [Google Scholar]
  • 46. Deodhar AA, Schreiber S, Gandhi K, Fox T, Gaillez C, Karyekar C. No increased risk of inflammatory bowel disease among secukinumab‐treated patients with moderate to severe psoriasis, psoriatic arthritis, or ankylosing spondylitis: Data from 14 Phase 2 and Phase 3 clinical studies [abstract]. Arthritis Rheumatol 2016; 68(suppl 10): 962. [Google Scholar]
  • 47. Kimura A, Naka T, Kishimoto T. IL‐6‐dependent and –independent pathways in the development of interleukin 17‐producing T helper cells. Proc Natl Acad Sci U S A 2007; 104: 12099–12104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48. Ivanov II, McKenzie BS, Zhou L et al The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL‐17+ T helper cells. Cell 2006; 126: 1121–1133. [DOI] [PubMed] [Google Scholar]
  • 49. Wilson NJ, Boniface K, Chan JR et al Development, cytokine profile and function of human interleukin 17‐producing helper T cells. Nat Immunol 2007; 8: 950–957. [DOI] [PubMed] [Google Scholar]
  • 50. Stritesky GL, Yeh N, Kaplan MH. IL‐23 promotes maintenance but not commitment to the Th17 lineage. J Immunol 2008; 181: 5948–5955. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51. Yoshiki R, Kabashima K, Honda T et al IL‐23 from Langerhans cells is required for the development of imiquimod‐induced psoriasis‐like dermatitis by induction of IL‐17A‐producing γδ T cells. J Invest Dermatol 2014; 134: 1912–1921. [DOI] [PubMed] [Google Scholar]
  • 52. Wohn C, Ober‐Blobaum JL, Haak S et al Langerin(neg) conventional dendritic cells produce IL‐23 to drive psoriatic plaque formation in mice. Proc Natl Acad Sci U S A 2013; 110: 10723–10728. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53. Arnold IC, Mathisen S, Schulthess J, Danne C, Hegazy AN, Powrie F. CD11c+ monocyte/macrophages promote chronic Helicobacter hepaticus‐induced intestinal inflammation through the production of IL‐23. Mucosal Immunol 2016; 9: 352–363. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54. Levin AA, Gottlieb AB. Specific targeting of interleukin‐23p19 as effective treatment for psoriasis. J Am Acad Dermatol 2014; 70: 555–561. [DOI] [PubMed] [Google Scholar]
  • 55. Mathur AN, Chang H‐C, Zisoulis DG et al Stat3 and Stat4 direct development of IL‐17‐secreting Th cells. J Immunol 2007; 178: 4901–4907. [DOI] [PubMed] [Google Scholar]
  • 56. Sofen H, Smith S, Matheson RT et al Guselkumab (an IL‐23‐specific mAb) demonstrates clinical and molecular response in patients with moderate‐to‐severe psoriasis. J Allergy Clin Immunol 2014; 133: 1032–1040. [DOI] [PubMed] [Google Scholar]
  • 57. Cua DJ, Tato CM. Innate IL‐17‐producing cells: the sentinels of the immune system. Nat Rev Immunol 2010; 10: 479–489. [DOI] [PubMed] [Google Scholar]
  • 58. Jones SA, Sutton CE, Cua D, Mills KH. Therapeutic potential of targeting IL‐17. Nature Immunol 2012; 13: 1022–1025. [DOI] [PubMed] [Google Scholar]
  • 59. Langrish CL, McKenzie BS, Wilson NJ, de Waal Malefyt R, Kastelein RA, Cua DJ. IL‐12 and IL‐23: Master regulators of innate and adaptive immunity. Immunol Rev 2004; 202: 96–105. [DOI] [PubMed] [Google Scholar]
  • 60. Gately MK, Renzetti LM, Magram J et al The interleukin‐12/interleukin‐12‐receptor system: Role in normal and pathologic immune responses. Annu Rev Immunol 1998; 16: 495–521. [DOI] [PubMed] [Google Scholar]
  • 61. Kleinschek MA, Muller U, Brodie SJ et al IL‐23 enhances the inflammatory cell response in Cryptococcus neoformans infection and induces a cytokine pattern distinct from IL‐12. J Immunol 2006; 176: 1098–1106. [DOI] [PubMed] [Google Scholar]
  • 62. Iwakura Y, Ishigame H. The IL‐23/IL‐17 axis in inflammation. J Clin Invest 2006; 116: 1218–1222. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63. Collamer AN, Battafarano DF. Psoriatic skin lesions induced by tumor necrosis factor antagonist therapy: clinical features and possible immunopathogenesis. Semin Arthritis Rheum 2010; 40: 233–240. [DOI] [PubMed] [Google Scholar]
  • 64. Wendling D, Prati C. Paradoxical effects of anti‐TNF‐α agents in inflammatory diseases. Expert Rev Clin Immunol 2014; 10: 159–169. [DOI] [PubMed] [Google Scholar]
  • 65. Rizzo HL, Kagami S, Phillips KG, Kurtz SE, Jacques SL, Blauvelt A. IL‐23‐mediated psoriasis‐like epidermal hyperplasia is dependent on IL‐17A. J Immunol 2011; 186: 1495–1502. [DOI] [PubMed] [Google Scholar]
  • 66. van der Fits L, Mourits S, Voerman JS et al Imiquimod‐induced psoriasis‐like skin inflammation in mice is mediated via the IL‐23/IL‐17 axis. J Immunol 2009; 182: 5836–5845. [DOI] [PubMed] [Google Scholar]
  • 67. Capon F, Di Meglio P, Szaub J et al Sequence variants in the genes for the interleukin‐23 receptor and its ligand (IL12B) confer protection against psoriasis. Hum Genet 2007; 122: 201–206. [DOI] [PubMed] [Google Scholar]
  • 68. Cargill M, Schrodi SJ, Chang M et al A large‐scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis‐risk genes. Am J Hum Genet 2007; 80: 273–290. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 69. Nair RP, Ruether A, Stuart PE et al Polymorphisms of the IL12B and IL23R genes are associated with psoriasis. J Invest Dermatol 2008; 128: 1653–1661. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 70. Reinhardt A, Yevsa T, Worbs T et al Interleukin‐23‐dependent γ/δ T cells produce interleukin‐17 and accumulate in the enthesis, aortic valve, and ciliary body in mice. Arthritis Rheumatol 2016; 68: 2476–2486. [DOI] [PubMed] [Google Scholar]
  • 71. Sherlock JP, Joyce‐Shaikh B, Turner SP et al IL‐23 induces spondyloarthropathy by acting on ROR‐γt+ CD3+CD4‐CD8‐entheseal resident T cells. Nat Med 2012; 18: 1069–1076. [DOI] [PubMed] [Google Scholar]
  • 72. Rahman P, Inman RD, Maksymowych WP, Reeve JP, Peddle L, Gladman DD. Association of interleukin 23 receptor variants with psoriatic arthritis. J Rheumatol 2009; 36: 137–140. [DOI] [PubMed] [Google Scholar]
  • 73. Rahman P, Inman RD, Gladman DD, Reeve JP, Peddle L, Maksymowych WP. Association of interleukin‐23 receptor variants with ankylosing spondylitis. Arthritis Rheum 2008; 58: 1020–1025. [DOI] [PubMed] [Google Scholar]
  • 74. Hue S, Ahern P, Buonocore S et al Interleukin‐23 drives innate and T cell mediated intestinal inflammation. J Exp Med 2006; 203: 2473–2483. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 75. Schmidt C, Giese T, Ludwig B et al Expression of interleukin‐12 related cytokine transcripts in inflammatory bowel disease: elevated interleukin‐23p19 and interleukin‐27p28 in Crohn's disease but not in ulcerative colitis. Inflamm Bowel Dis 2005; 11: 16–23. [DOI] [PubMed] [Google Scholar]
  • 76. Whibley N, Gaffen SL. Gut‐busters – IL‐17 ain't afraid of no IL‐23. Immunity 2015; 43: 620–622. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 77. Essers I, Ramiro S, Stolwijk C et al Characteristics associated with the presence and development of extra‐articular manifestations in ankylosing spondylitis: 12‐year results from OASIS. Rheumatology (Oxford) 2015; 54: 633–640. [DOI] [PubMed] [Google Scholar]
  • 78. Gordon KM, Duffin KC, Bissonnette R et al A Phase 2 trial of guselkumab versus adalimumab for plaque psoriasis. N Engl J Med 2015; 373: 136–144. [DOI] [PubMed] [Google Scholar]
  • 79. Blauvelt A, Papp KA, Griffiths CE et al Efficacy and safety of guselkumab, an anti‐interleukin‐23 monoclonal antibody, compared with adalimubab for the continuous treatment of patients with moderate to severe psoriasis: Results from the phase III, double‐blinded, placebo‐ and active comparator‐controlled VOYAGE 1 trial. J Am Acad Dermatol 2017; 76: 405–417. [DOI] [PubMed] [Google Scholar]
  • 80. Reich K, Armstrong AW, Foley P et al Efficacy and safety of guselkumab, an anti‐interleukin‐23 monoclonal antibody, compared with adalimumab for the treatment of patients with moderate to severe psoriasis with randomized withdrawal and retreatment: Results from the phase III, double‐blind, placebo‐ and active comparator‐controlled VOYAGE 2 trial. J Am Acad Dermatol 2017; 76: 418–431. [DOI] [PubMed] [Google Scholar]
  • 81. Langley RG, Tsai TF, Flavin S et al Efficacy and safety of guselkumab in patients with psoriasis who have an inadequate response to ustekinumab: Results of the randomized, double‐blind, Phase 3 NAVIGATE trial. Br J Dermatol 2017;178: 114–123. https://doi.org/10.1111/bjd.15750. [DOI] [PubMed] [Google Scholar]
  • 82. Papp K, Thaci D, Reich K et al Tildrakizumab (MK‐3222), an interleukin‐23p19 monoclonal antibody, improves psoriasis in a phase IIb randomized placebo‐controlled trial. Br J Dermatol 2015; 173: 930–939. [DOI] [PubMed] [Google Scholar]
  • 83. Reich K, Papp K, Blauvelt A et al Tildrakizumab versus placebo or etanercept for chronic plaque psoriasis (reSURFACE1 and reSURFACE2): results from two randomised controlled, phase 3 trials. Lancet 2017; 390: 276–288. [DOI] [PubMed] [Google Scholar]
  • 84. Krueger JG, Ferris LK, Menter A et al Anti‐IL‐23A mAb 655066 for treatment of moderate‐to‐severe psoriasis: Safety, efficacy, pharmacokinetics, and biomarker results of a single‐rising‐dose, randomized, double‐blind, placebo‐controlled trial. J Allergy Clin Immunol 2015; 136: 116–124. [DOI] [PubMed] [Google Scholar]
  • 85. Papp KA, Blauvelt A, Bukhalo M et al Risankizumab versus ustekinumab for moderate‐to‐severe plaque psoriasis. N Engl J Med 2017; 376: 1551–1560. [DOI] [PubMed] [Google Scholar]
  • 86. Puig L. The role of IL 23 in the treatment of psoriasis. Expert Rev Clin Immunol 2017; 13: 525–534. [DOI] [PubMed] [Google Scholar]
  • 87. Kryczek I, Zhao E, Liu Y et al Human TH17 cells are long‐lived effector memory cells. Sci Transl Med 2011; 3: 104ra100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 88. Cheuk S, Wiken M, Blomqvist L et al Epidermal Th22 and Tc17 cells form a localized disease memory in clinically healed psoriasis. J Immunol 2014; 192: 3111–3120. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 89. Fragoulis GE, Siebert S, McInnes IB. Therapeutic targeting of IL‐17 and IL‐23 cytokines in immune‐mediated diseases. Annu Rev Med 2016; 67: 337–353. [DOI] [PubMed] [Google Scholar]
  • 90. Gottlieb A, Deodhar A, Boehncke W‐H et al Efficacy and safety results of guselkumab, an anti‐IL23 monoclonal antibody, in patients with active psoriatic arthritis: A Phase 2a, randomized, double‐blind, placebo‐controlled study. J Am Acad Dermatol 2017; 76(suppl 1): AB111. [Google Scholar]
  • 91. Poddubnyy D, Hermann KG, Callhoff J, Listing J, Sieper J. Ustekinumab for the treatment of patients with active ankylosing spondylitis: Results of a 28‐week, prospective, open‐label, proof‐of‐concept study (TOPAS). Ann Rheum Dis 2014; 73: 817–823. [DOI] [PubMed] [Google Scholar]
  • 92. Smolen JS, Agarwal SK, Ilivanova E et al A randomised phase II study evaluating the efficacy and safety of subcutaneously administered ustekinumab and guselkumab in patients with active rheumatoid arthritis despite treatment with methotrexate. Ann Rheum Dis 2017; 76: 831–839. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 93. Deepak P, Loftus EV. Ustekinumab in treatment of Crohn's disease: Design, development and potential place in therapy. Drug Des Devel Ther 2016; 10: 3685–3698. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 94. Feagan BG, Sandborn WJ, D'Haans G et al Induction therapy with the selective interleukin‐23 inhibitor risankizumab in patients with moderate‐to‐severe Crohn's disease: a randomised, double‐blind, placebo‐controlled phase 2 study. Lancet 2017; 389: 1699–1709. [DOI] [PubMed] [Google Scholar]
  • 95. Sands BE, Chen J, Feagan BG et al Efficacy and safety of MEDI2070, an antibody against interleukin 23, in patients with moderate to severe Crohn's Disease: A Phase 2a study. Gastroenterology 2017; 153: 77–86. [DOI] [PubMed] [Google Scholar]
  • 96. Segal BM, Constantinescu CS, Raychaudhuri A et al Repeated subcutaneous injections of IL12/23 p40 neutralising antibody, ustekinumab, in patients with relapsing‐remitting multiple sclerosis: a phase II, double‐blind, placebo‐controlled, randomised, dose‐ranging study. Lancet Neurol 2008; 7: 796–804. [DOI] [PubMed] [Google Scholar]

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