Where Do We Begin? The Key Role of the IL-23 Pathway in Psoriasis and Psoriatic Arthritis - European Medical Journal
×

Browse

Where Do We Begin? The Key Role of the IL-23 Pathway in Psoriasis and Psoriatic Arthritis

| Download as | PDF
10 Mins

Each article is made available under the terms of the Creative Commons Attribution-Non Commercial 4.0 License.

Receive our free quarterly newsletters and your choice of journal publication alerts, straight to your inbox.

Join our mailing list

Speakers: Kilian Eyerich,¹,² Rik Lories³

1. Division of Dermatology and Venereology, Karolinska Institutet, Stockholm, Sweden
2. Technical University of Munich, Germany
3. Department of Development and Regeneration KU Leuven, Clinical Division of Rheumatology, UZ Leuven, Belgium

Disclosure: Eyerich has received honoraria from AbbVie, Almirall, BMS, Boehringer Ingelheim, Eli Lilly, Galapagos, Janssen, Leo, Novartis, Sanofi, and UCB; and is a shareholder and co-founder of Dermagnostix. Rik Lories has received research funding from Excellence of Science financing FWO/FNRS, Innovative Medicines Initiative-2, KU Leuven, Flanders Research Foundation (FWO), Horizon 2020 – Marie-Curie ITN, and VIB (Flanders Institute for Biotechnology); and KU Leuven has received honoraria or research grants on behalf of Rik Lories from AbbVie, Amgen, Biosplice Therapeutics (Samumed), Boehringer Ingelheim, Eli Lilly, Fresenius Kabi, Galapagos, Janssen, Eli Lilly, MSD, Novartis, Pfizer, Sandoz, and UCB.

Acknowledgements: Medical writing assistance was provided by Fiona Powell of Excerpta Medica, Amsterdam, the Netherlands.

Support: The symposium and publication of this article were funded by Janssen. The views and opinions expressed are those of the speakers and not necessarily of Janssen.

Citation: EMJ Dermatol. 2021;9[Suppl 5]:2-8.

Meeting Summary

This Janssen-sponsored live satellite symposium, entitled ‘Where do we begin? The key role of the IL-23 pathway in psoriasis and psoriatic arthritis,’ took place at the 6th World Psoriasis and Psoriatic Arthritis Conference (WPPAC) 2021. The symposium focused on the role of the IL-23 pathway in the management of psoriasis and psoriatic arthritis (PsA). Kilian Eyerich and Rik Lories presented an overview of the IL-23 axis as a driver of pathophysiology in psoriasis and PsA, providing a comprehensive rationale for the therapeutic targeting of IL-23.

Eyerich evaluated the latest data to emerge following IL-23 inhibition in patients with psoriasis, noting the high rates of sustained Psoriasis Area Severity Index (PASI) responses, including the continued efficacy demonstrated in a subset of patients following treatment withdrawal. He discussed the modification of immune memory within the skin as a potential explanation for the activity observed following IL-23 inhibition in patients with psoriasis.

Lories highlighted the heterogeneous nature of PsA and the challenges conferred by the chronicity and progressive damage associated with the condition. He evaluated recent clinical data of IL-23 inhibition in patients with active PsA, with particular attention given to the progressively increasing rates of American College of Rheumatology (ACR) responses observed through 2 years.

With improvements in clinical parameters and patient-reported outcomes paralleled by a reassuring long-term safety profile, the faculty emphasised the need for optimised treatment positioning to facilitate a personalised management strategy for patients.

Where It All Started

Kilian Eyerich and Rik Lories

The IL-23 cytokine pathway is heavily involved in the pathogenesis of both psoriasis and PsA.1-4 Psoriasis is driven by an epidermal immune response initiated by the release of danger signals, such as antimicrobial peptides, and recognition of cellular damage. This triggers the release of cytokines including IL-23, which acts as a master regulator, driving the differentiation and proliferation of T-helper (Th) 17 cells, and their secretion of pro-inflammatory cytokines including IL-17A, IL-17F, IL-21, IL-22, and TNF-α. These cytokines are the hallmark of psoriasis pathology, promoting keratinocyte activation and proliferation, epidermal hyperplasia, and the recruitment of innate immune cells into the epidermis, with the subsequent release of antimicrobial peptides creating a self-sustaining pro-inflammatory cycle (Figure 1).1,2,5,6

Figure 1: The steering role of IL-23 in the pathogenesis of psoriasis.
AMP: antimicrobial peptide; CCL: chemokine (C-C motif) ligand; CXCL: (C–X–C motif) ligand; DC: dendritic cell; Foxp3: forkhead box P3; IFN: interferon; ILC: innate lymphoid cell; TC: T cytotoxic cell; TH: T helper cell; TReg: regulatory T cell; VEGF: vascular endothelial growth factor; γδ-T: γδ T cell.
Adapted from Nestle et al.,⁵ Krueger and Bowcock,⁷ Bovenschen et al.,⁸ Leung et al.,⁹ Zhu et al.,10 Zúñiga et al.,11 Cai et al.,⁶ and Gaffen et al.¹

The role of IL-23 as a driver of effector cytokine secretion by Th17 cells is also key in steering the development of PsA,4 and multiple cell types are capable of cytokine release within the joint following IL-23 stimulation.12,13 Furthermore, the entheses contain unconventional T-cell populations that are thought to play a role in the monitoring of local tissues. These cells may react to localised microdamage, creating an amplifying pro-inflammatory loop which drives the pathological pathways characteristic of arthritis.14-16

With the role of IL-23 as a key steerer of pathogenesis well established, this cytokine presents an attractive cross-disciplinary therapeutic target; this has led to the development of several inhibitors of the p19 subunit of IL-23. Of these, guselkumab, tildrakizumab, and risankizumab are approved by the European Medicines Agency (EMA) for the treatment of moderate-to-severe plaque psoriasis, with guselkumab currently the only IL-23 inhibitor approved by the EMA for patients with active PsA who responded inadequately or were intolerant to a previous disease-modifying anti-rheumatic drug.17-19

The IL-23 Pathway: Navigating the Latest Updates in Skin Research

Kilian Eyerich

Recent data to emerge from clinical trials of IL-23 inhibitors for the treatment of psoriasis have highlighted some distinguishing features of this therapeutic approach.

IL-23 inhibition has been shown to induce tight and long-term disease control in the majority of patients. In the Phase III trial VOYAGE 1, patients with moderate-to-severe plaque psoriasis were randomised to guselkumab 100 mg at Weeks 0, 4, 12, and then every 8 weeks (q8w); placebo at Weeks 0, 4, and 12, followed by guselkumab 100 mg at Weeks 16, 20, and then q8w; or adalimumab 80 mg at Week 0, followed by 40 mg at Week 1 then 40 mg q2w through to Week 47. Of the patients who received guselkumab from Week 0, PASI 90 responses were achieved by 82% (as observed analysis) at Week 52 and 86% at Week 252 (Figure 2).20 Furthermore, treatment with guselkumab led to complete skin clearance, which was maintained for over 3 years in 23% of patients within VOYAGE 1.21 Similarly, in the pooled Phase III trials reSURFACE 1 and 2, high rates of PASI 75 (100%), 90 (71–73%), and 100 (29–37%) responses were reported at Week 28 for patients with moderate-to-severe psoriasis who received tildrakizumab 100 mg or 200 mg at Weeks 0 and 4, and then q12w. These response rates were also sustained through Week 244,22 suggesting long-term control is a class effect of IL-23 inhibition.

Figure 2: PASI 90 response through Week 252 in patients randomised to guselkumab from baseline in the Phase III clinical trial VOYAGE 1.
*NRI through Week 48, then TFR beyond Week 48.
GUS: guselkumab; NRI: non-responder imputation; OBS: as observed; PASI 90: ≥90% improvement in Psoriasis Area and Severity Index response; TFR: treatment failure rules.
Adapted from Griffiths et al.20

Secondly, the effects of IL-23 have been shown to extend beyond the withdrawal of treatment. This is clearly illustrated by data from VOYAGE 2, a Phase III trial in which patients who achieved ≥PASI 90 response at Week 28 having received guselkumab (100 mg at Weeks 0, 4, and then q8w) were re-randomised to guselkumab or the placebo. Although a higher proportion of patients who continued to receive guselkumab maintained PASI 90 response through Week 48 than those who had treatment withdrawn (89% versus 37%), more than one-half of the re-randomised placebo group maintained PASI 75 response, with 20% maintaining PASI 100 through Week 48.23 This effect was still noticeable at Week 72 when 12% of patients who had treatment withdrawn maintained a PASI 90 response. The maintenance of PASI response following treatment withdrawal was associated with the suppression of IL-17A, IL-17F, and IL-22, supporting the role of IL-23 in driving Th17 and Th22 responses.24 Additionally, shorter disease duration, lower BMI, and lower levels of IL-17F and macrophage inflammatory protein 1β at baseline, together with PASI 100, Investigator’s Global Assessment (IGA) 0, and higher guselkumab concentration at Week 28, were predictive of maintaining PASI 90 response following the withdrawal of guselkumab.25 A similar trend was reported in the IMMhance Phase III trial, where patients with moderate-to-severe plaque psoriasis who achieved a static Physician’s Global Assessment (sPGA) 0/1 response to risankizumab (150 mg at Weeks 0, 4, and 16) at Week 28 were re-randomised to risankizumab (q12w) or the placebo. Of the patients who had IL-23 inhibition withdrawn, 61% maintained sPGA at Week 52 versus 87% of patients who continued risankizumab. This dropped to 7% and 81% respectively at Week 104. Furthermore, PASI 90 responses were maintained through Week 52 by 86% of patients who continued risankizumab versus 52% of patients who had treatment withdrawn. By Week 104, PASI 90 response rates were 78% and 4%, respectively.26

The concept of localised immune memory is now well established, with non-circulating tissue-resident memory (TRM) T cells identified in epithelial barrier tissues including the skin. Atypical activation of these persistent TRM T cells has been shown to drive inflammatory diseases, such as psoriasis, through the secretion of IL-17.

Furthermore, these memory cells have been identified in non-lesional skin, suggesting they are likely to be associated with disease relapse.27,28 Indeed, the presence of these distinct, specialised effector memory cells is evidenced in psoriasis by the continued recurrence of plaques at the same sites. It is feasible, therefore, that long-term control of psoriasis may depend on the suppression of these TRM T cells.27 Potential modification of immune memory within the skin by IL-23 inhibitors may explain the long-term causative effects observed in patients with psoriasis. The mechanisms behind the tight and long-term clinical responses generated by IL-23 inhibition are now being investigated in the GUIDE trial, which is evaluating differences between ‘super-responders’ and non-responders in an effort to predict response to IL-23 inhibition and evaluate future therapeutic strategies.29

Learnings from IL-23 Pathway Data in Psoriatic Arthritis

Rik Lories

IL-23 is also established as a key driver of pathology in PsA,3,4 although this is a more heterogeneous disease than psoriasis, with the added dimension of progressive joint damage and loss of function impacting management strategies. Interestingly, despite common pathological pathways, there is only a modest correlation between the severity of skin and joint disease.30,31

PsA is characterised by diverse musculoskeletal and skin manifestations. The majority of patients present with peripheral arthritis and/or psoriasis, with dactylitis and enthesitis reported in approximately one-third to one-half of patients,32–36 and this is reflected in the selection criteria of PsA clinical trials.

IL-23 inhibition has demonstrated efficacy in patients with active PsA in Phase II clinical trials, with significantly and consistently higher rates of ACR20 responses reported at Week 24 versus the placebo in trials of guselkumab (100 mg at Weeks 0, 4, and then q8w; 58% ACR20), risankizumab (150 mg at varying frequency; 43–59% ACR20), and tildrakizumab (20–200 mg every 4 weeks [q4w] or q12w; 71–80% ACR20).37-40

The more stringent ACR50 response is often considered more clinically relevant by rheumatologists; in Phase III clinical trials, this was achieved by 36% of biologic-naïve or biologic-experienced patients with active PsA at Week 24 following guselkumab 100 mg q4w, versus 9% of patients who received the placebo in the Phase III DISCOVER-1 trial. Interestingly, the response rate rose to 54% in the guselkumab group at Week 52, and this trend for progressive improvement was echoed in the ACR70 response rate, which rose from 20% at Week 24 to 29% at Week 52.41 These data are supported by longer-term follow-up within the Phase III DISCOVER-2 trial, in which biologic-naïve patients with active PsA received guselkumab (100 mg q8w or q4w) or the placebo with cross-over to guselkumab 100 mg q4w at Week 24. ACR50 responses at Week 24 were reported for 32% and 33% of patients who received guselkumab q8w and q4w, respectively, and 14% of patients who received the placebo. However, at Week 100, response rates had risen to 55%, 56%, and 48%, respectively, with similar trends noted for ACR70 responses, suggesting responses to IL-23 inhibition have the potential to grow over time (Figure 3).42

Figure 3: ACR50 response through Week 100 in biologic-naïve patients with psoriatic arthritis in the Phase III clinical trial DISCOVER-2.
*p≤0.001
†p<0.05.
‡Includes randomised patients who received ≥1 dose of study drug.
GUS: guselkumab; NRI: non-responder imputation; PBO: placebo; q4w: every 4 weeks; q8w: every 8 weeks.
Adapted from McInnes et al.42

The Phase IIIB COSMOS trial evaluated guselkumab (100 mg Weeks 0, 4, and then q8w) in a more challenging-to-treat population of patients with active PsA and inadequate response to TNF inhibitor. At Week 24, ACR20 responses were observed in 48% of patients who received guselkumab versus 20% of those who received the placebo.43

Long-term efficacy data clearly demonstrate the clinical benefits of extended IL-23 inhibition, and it is reassuring to note that the safety profile of continuous guselkumab remained manageable and stable through 5 years in the pooled VOYAGE 1 and 2 trials, with low rates of adverse events.44 These data facilitate the long-term management of chronic conditions by IL-23 inhibition.

Managing the complexities of pain and fatigue are two additional challenges associated with the treatment of rheumatological diseases and this is beginning to be reflected in the endpoints of clinical trials. Within the DISCOVER 1 and 2 trials, IL-23 inhibition demonstrated independent treatment effects on fatigue at Week 24, with 54–61% of patients who received guselkumab 100 mg q8w achieving a clinically meaningful improvement (≥4 points) in FACIT-Fatigue from baseline, versus 35–46% of patients who received the placebo.45

Summary

Disease modification is a well-established concept in rheumatology, with the aim of preventing long-term structural damage. The high rates of sustained clinical response that are observed with IL-23 inhibition in patients with psoriasis suggest that this may also be a possibility in dermatology. However, although the emerging data are impressive, whether the presence of localised immune memory cells will permit symptomatic and chronic disease modification in the skin remains to be determined.

While IL-23 inhibition has demonstrated encouraging clinical activity in patients with PsA, the level of benefit may differ depending on the extent of joint damage in patients with advanced disease. Intriguingly, however, there is evidence to suggest that the joint may be partially restored if inflammation is sufficiently suppressed, and it will be interesting to establish whether IL-23 inhibition could play a role in this process.

As clinical data establish the importance of IL-23 inhibition in managing psoriasis and PsA, it will be vital to define the role and positioning of these therapies to optimise the personalisation of therapeutic strategies.

References
Gaffen SL et al. The IL-23-IL-17 immune axis: from mechanisms to therapeutic testing. Nat Rev Immunol. 2014;14(9):585-600. Di Cesare A et al. The IL-23/Th17 axis in the immunopathogenesis of psoriasis. J Invest Dermatol. 2009;129(6):1339-50. Tsukazaki H, Kaito T. The role of the IL-23/IL-17 pathway in the pathogenesis of spondyloarthritis. Int J Mol Sci. 2020;21(17):6401. Vecellio M et al. The IL-17/IL-23 axis and its genetic contribution to psoriatic arthritis. Front Immunol. 2020;11:596086. Nestle FO et al. Psoriasis. N Engl J Med. 2009;361(5):496-509. Cai Y et al. New insights of T cells in the pathogenesis of psoriasis. Cell Mol Immunol. 2012;9(4):302-9. Krueger JG, Bowcock A. Psoriasis pathophysiology: current concepts of pathogenesis. Ann Rheum Dis. 2005;64(Suppl 2):ii30-6. Bovenschen HJ et al. Foxp3+ regulatory T cells of psoriasis patients easily differentiate into IL-17A-producing cells and are found in lesional skin. J Invest Dermatol. 2011;131(9):1853-60. Leung S et al. The cytokine milieu in the interplay of pathogenic Th1/Th17 cells and regulatory T cells in autoimmune disease. Cell Mol Immunol. 2010;7(3):182-9. Zhu J et al. Differentiation of effector CD4 T cell populations (*). Annu Rev Immunol. 2010;28:445-89. Zúñiga LA et al. Th17 cell development: from the cradle to the grave. Immunol Rev. 2013;252(1):78-88. Brown MA et al. Genetics of ankylosing spondylitis—insights into pathogenesis. Nat Rev Rheumatol. 2016;12(2):81-91. Chen S et al. Histologic evidence that mast cells contribute to local tissue inflammation in peripheral spondyloarthritis by regulating interleukin-17A content. Rheumatology (Oxford). 2019;58(4):617-27. Lories RJ, McInnes IB. Primed for inflammation: enthesis-resident T cells. Nat Med. 2012;18(7):1018-9. Gracey E et al. Tendon and ligament mechanical loading in the pathogenesis of inflammatory arthritis. Nat Rev Rheumatol. 2020;16(4):193-207. Tan AL et al. The relationship between the extensor tendon enthesis and the nail in distal interphalangeal joint disease in psoriatic arthritis—a high-resolution MRI and histological study. Rheumatology (Oxford). 2007;46(2):253-6. European Medicines Agency (EMA). Tremfya summary of product characteristics. Available at: https://www.ema.europa.eu/en/documents/product-information/tremfya-epar-product-information_en.pdf. Last accessed: 23 August 2021. European Medicines Agency (EMA). Ilumetri summary of product characteristics. 2018. Available at: https://www.ema.europa.eu/en/documents/overview/ilumetri-epar-medicine-overview_en.pdf. Last accessed: 23 August 2021. European Medicines Agency (EMA). Skyrizi summary of product characteristics. Available at: https://www.ema.europa.eu/en/documents/product-information/skyrizi-epar-product-information_en.pdf. Last accessed: 23 August 2021. Griffiths CEM et al. Maintenance of response through 5 years of continuous guselkumab treatment: results from the phase-3 VOYAGE 1 trial.  Ann Rheum Dis. 2021;80(Suppl 1):1297-8. Costanzo A et al. Maintenance of complete skin clearance throughout 3 years of continuous guselkumab treatment in patients with moderate-to-severe psoriasis: a post hoc analysis of 5-year data from the VOYAGE 1 trial. J Am Acad Dermatol. 2021;85(Suppl 3):AB108. Thaçi D et al. Five-year efficacy and safety of tildrakizumab in patients with moderate-to-severe psoriasis who respond at week 28: pooled analyses of two randomized phase III clinical trials (reSURFACE 1 and reSURFACE 2). Br J Dermatol. 2021;185(2):323-34. Reich K 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(3):418-31. Gordon KB et al. Guselkumab efficacy after withdrawal is associated with suppression of serum IL-23-regulated IL-17 and IL-22 in psoriasis: VOYAGE 2 study. J Invest Dermatol. 2019;139(12):2437-46.e1. Liu X et al. Identification of clinical and biomarker parameters associated with long-term maintenance of PASI 90 response following guselkumab treatment withdrawal in psoriasis. Abstract 22. Australasian College of Dermatologists 2019 Dermcoll, 52nd Annual Scientific Meeting, 18-21 May, 2019. Blauvelt A et al. Efficacy and safety of continuous q12w risankizumab versus treatment withdrawal: 2-year double-blinded results from the phase 3 immhance trial. Abstract. 24th World Congress of Dermatology. 10-15 June, 2019. Matos TR et al. Clinically resolved psoriatic lesions contain psoriasis-specific IL-17-producing αβ T cell clones. J Clin Invest. 2017;127(11):4031-41. Clark RA. Resident memory T cells in human health and disease. Sci Transl Med. 2015;7(269):269rv1. Medicine USNLo. A study to evaluate further therapeutic strategies with guselkumab in participants with moderate-to-severe plaque-type psoriasis (GUIDE). NCT03818035. https://clinicaltrials.gov/ct2/show/NCT03818035. Mease PJ et al. Understanding the association between skin involvement and joint activity in patients with psoriatic arthritis: experience from the Corrona Registry. RMD Open. 2019;5(1):e000867. Boehncke WH et al. Association between clinical specialty setting and disease management in patients with psoriatic arthritis: results from LOOP, a cross-sectional, multi-country, observational study. J Eur Acad Dermatol Venereol. 2020;34(9):2035-43. López-Medina C et al. Prevalence and distribution of peripheral musculoskeletal manifestations in spondyloarthritis including psoriatic arthritis: results of the worldwide, cross-sectional ASAS-PerSpA study. RMD Open. 2021;7(1):e001450. Peluso R et al. Extra-articular manifestations in psoriatic arthritis patients. Clin Rheumatol. 2015;34(4):745-53. Liu JT et al. Psoriatic arthritis: epidemiology, diagnosis, and treatment. World J Orthop. 2014;5(4):537-43. Baraliakos X et al. The involvement of the spine in psoriatic arthritis. Clin Exp Rheumatol. 2015;33(5 Suppl 93):S31-5. Fotiadou C, Lazaridou E. Psoriasis and uveitis: links and risks. Psoriasis (Auckl). 2019;9:91-6. Deodhar A et al. Efficacy and safety of guselkumab in patients with active psoriatic arthritis: a randomised, double-blind, placebo-controlled, phase 2 study. Lancet. 2018;391(10136):2213-24. Mease PJ et al. Efficacy and safety of risankizumab, a selective IL-23p19 inhibitor, in patients with active psoriatic arthritis over 24 weeks: results from a phase 2 trial. Ann Rheum Dis. 2018;77(Suppl 2):200-1. Ostor A et al. Efficacy and safety of risankizumab for active psoriatic arthritis, including patients with inadequate response or intolerance to biologic therapies: 24-week results from the phase 3, randomized, double-blind, KEEPSAKE 2 trial. Ann Rheum Dis. 2021;80(Suppl 1):138-9. Mease PJ et al. Efficacy and safety of tildrakizumab in patients with active psoriatic arthritis: results of a randomised, double-blind, placebo-controlled, multiple-dose, 52-week phase IIb study. Ann Rheum Dis. 2021;80(9):11-47-57. [Epub ahead of print]. Ritchlin CT et al. Guselkumab, an inhibitor of the IL-23p19 subunit, provides sustained improvement in signs and symptoms of active psoriatic arthritis: 1 year results of a phase III randomised study of patients who were biologic-naïve or TNFα inhibitor-experienced. RMD Open. 2021;7(1):e001457. McInnes I et al. Efficacy and safety of guselkumab, a monoclonal antibody specific to the p19-subunit of interleukin-23, through 2 years: results from a phase 3, randomized, double-blind, placebo-controlled study conducted in biologic-naïve patients with active psoriatic arthritis. Ann Rheum Dis. 2021;80(Suppl 1):783-4. Coates LC et al. Efficacy and safety of guselkumab in patients with active psoriatic arthritis who demonstrated inadequate response to tumor necrosis factor inhibition: week 24 results of a phase 3b, randomized, controlled study. Ann Rheum Dis. 2021;80(Suppl 1):140-1. Blauvelt A et al. Long-term safety of guselkumab: results from the VOYAGE 1 and VOYAGE 2 trials with up to 5 years of treatment. American Academy of Dermatology Virtual Meeting Experience, 23-25 April, 2021. Helliwell P et al. Guselkumab demonstrated an independent treatment effect on fatigue after adjustment for clinical response (ACR20) in patients with psoriatic arthritis: results from phase-3 trials DISCOVER 1 & 2. Ann Rheum Dis. 2020;79(Suppl 1):1164.