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Spondyloarthritis: From disease phenotypes to novel treatments

Paramarta, Jacky

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Citation for published version (APA):Paramarta, J. E. (2014). Spondyloarthritis: From disease phenotypes to novel treatments.

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Download date: 26 Jun 2019

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9The IL-23/IL-17 immune axis

as a promising new target in the treatment of spondyloarthritis

Nataliya Yeremenko1,2, Jacqueline E. Paramarta2,

Dominique Baeten1,2

1Department of Clinical Immunology and Rheumatology and 2Laboratory of Experimental Immunology, Academic Medical Center/

University of Amsterdam, Amsterdam, The Netherlands

Curr Opin Rheumatol. 2014 Jul;26(4):361-70

ABSTRACT

Purpose of review

Various novel therapies for spondyloarthritis (SpA) are currently under development. In this

review, we discuss the scientific rational to target the interleukin (IL)-23/IL-17 axis in SpA and

give an overview of the proof-of-concept trials with drugs directed towards this axis.

Recent findings

Cumulative evidence from genetics (e.g. the strong genetic association with the IL-23 receptor

gene), in-vitro models (e.g. the increased IL-23 production upon HLA-B27 misfolding), human

expression studies (e.g. the expansion of IL-17 producing innate cells in SpA) and animal models

(e.g. the increased IL-17 production in HLA-B27 transgenic rats) strongly supports the involvement

of the IL-23/IL-17 axis in the pathogenesis of SpA. Ustekinumab (a monoclonal antibody directed

against the common p40 subunit of IL-23 and IL-12), secukinumab, ixekizumab (both monoclonal

antibodies directed against IL-17A), and brodalumab a monoclonal antibody against the IL-17RA

receptor) have been recently used in proof-of-concept and randomized trials in the ankylosing

spondylitis and/or psoriatic arthritis subforms of SpA, with overall very promising clinical efficacy.

Summary

The first results for novel drugs blocking key cytokines in the IL-23/IL-17 axis are promising in

SpA and more novel compounds are upcoming. This will teach us more on the role of the IL-23/

IL-17 axis in the pathophysiology of SpA.

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INTRODUCTIONSpondyloarthritis (SpA) affects approximately 0.5–1.5% of the Western population and is

characterized by inflammation of axial and peripheral joints, and extra-articular manifestations

such as skin psoriasis and inflammatory bowel disease (IBD). The disease presentation is

heterogeneous and comprises the various phenotypic subtypes ankylosing spondylitis,

nonradiographic axial SpA (nr-axSpA), psoriatic arthritis (PsA), IBD-related SpA (IBD-SpA),

reactive arthritis (ReA) and undifferentiated peripheral SpA (USpA).1 Although the management

of SpA patients has improved enormously since the introduction of tumor necrosis factor

(TNF) inhibitors more than 10 years ago,2,3 there is still a high unmet need for novel therapeutic

alternatives. Up to 40% of patients do not respond sufficiently to TNF inhibitors, either due to

intolerance or inefficacy. Moreover, in patients in whom TNF blockade is effective, remission

is not long-lasting since a large majority of patients experience relapse of symptoms after

treatment discontinuation.4-6 Finally, even when clinical symptoms and inflammation are

completely suppressed, TNF blockade does not appear to halt new bone formation.1

Considering the medical need for other therapeutic agents in SpA, proof-of-concept (PoC)

studies have been performed with biological agents directed towards interleukin (IL)-1, IL-6,

B cells and costimulatory molecules. However, none of these strategies resulted in significant

clinical improvement. More recently, several lines of evidence suggest that the IL-23/IL-17

immune axis may be a promising new target in the treatment of SpA. Our knowledge of this

cytokine axis has expanded dramatically over the past decade. The potential importance of the

IL-23/IL-17 axis for chronic tissue inflammation was originally described in experimental models

of T-cell-driven autoimmune diseases,7 but now starts to be confirmed by PoC studies with

drugs targeting this axis in a series of human immune-mediated inflammatory diseases.8 In this

review, we give a short overview of the IL-23/IL-17 axis, discuss the lines of evidence linking

IL-23/IL-17 with SpA, and summarize the emerging results of clinical trials with compounds

targeting IL-23/IL-17 in SpA and related inflammatory diseases.

THE INTERLEUKIN-23/INTERLEUKIN-17 AXISStudies using IL-23-deficient mice have indicated a crucial role for this cytokine in the

pathogenesis of autoimmune inflammation. In particular, it has been demonstrated that

animals lacking functional IL-23 are resistant to experimental autoimmune encephalomyelitis

(EAE)7 and collagen-induced arthritis.9 Later, it has been recognized that IL-23 mediates this

effect by promoting the development of a novel subset of T cells that produce the signature

cytokine IL-17 (Th17).9,10 IL-23 is secreted by activated macrophages and dendritic cells as a

heterodimer that comprises a unique p19 subunit and the p40 subunit shared with IL-12 (Fig. 1).

IL-23 binds to IL-23R on IL-23R-expressing cells. Engagement of IL-23 with the IL-23R complex,

composed of IL-23R and IL-12Rβ1, leads to activation of signal transducer and activator of

transcription 3’ (STAT-3), which subsequently up-regulates the expression of retinoic acid

receptor-related orphan receptor C (RORC), a Th17-specific transcriptional regulator that

is critical for the expression of two members of IL-17 family – IL-17A and IL-17F. IL-17A and

IL-17F are by far the best characterized cytokines from the six highly conserved IL-17 family

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members (IL-17A–F). IL-17A and IL-17F are both covalent homodimers, but the single subunits

can also form IL-17A–IL-17F heterodimers.11 IL-17A, IL-17F and IL-17A–IL-17F all signal through a

heteromeric receptor complex consisting of the IL-17RA and IL-17RC subunits (Fig. 1), mainly

expressed on epithelial, endothelial and fibroblast cells resulting in activation of (nuclear factor

kappa-light-chain-enhancer of activated B cells) pathway, which then leads to the production

of pro-inflammatory cytokines, chemokines, adhesion molecules, leukocyte recruitment

and activation of endothelium hereby playing an important role in directing development of

subsequent immune responses. Remarkably, IL-17A is not only a potent inducer of TNF-α, but

also synergizes with this cytokine to promote induction of nearly all its target genes, and in

many cases synergy has also been observed with IFN-γ and IL-1β (reviewed in 12).

Recent studies have indicated three new important concepts in Th17/IL-17 biology. Firstly,

Th17 cells display a marked functional plasticity. Depending on cytokines or pathogens present in

the milieu, Th17 cells can change into interferon (IFN)-γ-producing Th1 cells or IL-4-producing

Th2 cells,13 or even coexpress IL-10,14,15* exerting tissue-protective and immunosuppressive

effects. Secondly, IL-17A is not only produced by canonical Th17 cells but also by a variety of

innate and acquired immune cells, including γδ T cells, myeloid cells and innate lymphoid cells

(Fig. 1).16 This implies that the IL-23/IL-17 axis can still play a pathogenic role in disorders which

are not primarily driven by (autoreactive) T cells. And thirdly, the role of Th17 cells depends not

only on IL-17A but also on other Th17-derived cytokines such as IL-21 and IL-22, as well as on the

specific immunological and tissue context in which they are operating.8 At mucosal surfaces,

for example, IL-17 may have a dual role in promoting tissue inflammation and also protecting

from fungal infections. Another good example is IL-22, which drives psoriasis-like dermal

inflammation and protects from colitis.

TARGETING THE INTERLEUKIN-23/INTERLEUKIN-17 AXIS IN SPONDYLOARTHRITISThere are multiple lines of indirect evidence for therapeutic targeting of the IL-23/IL-17 axis in

SpA (Table 1).17-19,20**,21-30,31*,32*,33-37,38*,39,40* First, the disease shows a strong genetic association with

a series of protective polymorphisms in the IL-23 receptor (IL23R) gene, including rs11209026

(Arg381Gln). This IL23R gene variant grants protection from IBD,41 psoriasis42 and ankylosing

spondylitis17 through selective impairment of IL-17A production43 due to decreased STAT-3

phosphorylation.44 Furthermore, identification of additional risk genes related to IL-17 signaling

supported significance of the IL-23/IL-17 axis in the pathogenesis of SpA (Table 1). Second,

experimental in-vitro and in-vivo models indicate that (Human Leukocyte Antigen (HLA) B27)

(the major genetic risk factor for ankylosing spondylitis) heavy chain has a specific propensity

to misfold during the assembly in the endoplasmic reticulum, which in specific conditions can

lead to an unfolded protein response and increased IL-23 production.37 HLA-B27 heavy chain

can also form aberrant disulfide-linked homodimers on the cell surface, which directly trigger

KIR3DL2-positive T cells and natural killer (NK) cells to produce IL-17.27 Third, analysis of the

peripheral blood compartment in humans shows that the number of circulating CD4+ IL-17+

cells (including KIR3DL2-expressing T cells27 and IL-17-producing γδ T cells31*) is expanded in

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Figure 1. The IL-23/IL-17 pathway. Heterodimeric IL-23 consists of p19 (IL-23A) and p40 (IL-12B) subunits and is secreted by activated macrophages and dendritic cells. IL-23 signals via IL-23R in a STAT3-dependent manner. This leads to typical Th17 effector cytokines production by the lineage expressing specific transcription factor RorC. IL-17A, IL-17F and IL-17A–IL-17F-heterodimer signal through heteromeric receptor complex consisted of IL-17RA and IL-17RC subunits. DC, dendritic cell; IL, interleukin; mφ, macrophage; RorC, retinoic acid receptor-related orphan nuclear receptor; STAT, signal transducer and activator of transcription.

ankylosing spondylitis.29 Expression studies in the inflamed target tissues, including axial

skeleton, peripheral synovitis and subclinically affected gut tissue, indicate a SpA-specific

increase in IL-23 and IL-17-producing innate immune cells (Table 1). Fourth, experimental SpA

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Table 1. Rationales for targeting IL-23/IL-17 axis in spondyloarthritis

I. Genetics

IL23R R381Q gene variant grants protection from AS17 through selective impairment of IL-17A production.Other genes involved in SpA susceptibility:IL-12B, which encodes the 40-kd (p40) chain, a component of both IL-12 and IL-23;18,19 STAT-3, JAK-2 and TYK-2, which encodes the major signalling molecules activated by the IL-23R.18,20**

Caspase recruitment domain 9 (CARD-9), which encodes a major signalling intermediate in the pathway whereby fungal products induce IL-23 production from dendritic cells (DCs);21

Prostaglandin E receptor 2 subtype EP2 (PTGER-4), which encodes a prostaglandin receptor that

drives IL-23 secretion by DCs.22

II. In vitro models

Misfolding of HLA-B27 can generate ER stress that orchestrates the unfolded protein response leading to IL-23 production. There are evidences for UPR activation in cells from humans with spondyloarthritis:Gene expression profiling revealed enhanced expression of immunoglobulin heavy chain binding protein (BiP) in SpA PBMCs.23

Increased expression of GRP78 in macrophages isolated from peripheral joints of AS compared with OA patients.24

Ankylosing spondylitis macrophages produce increased levels of IL-23.25

HLA-B27 is capable of forming H chain homodimers (“B272”) that interact with the killer-cell Ig-like

receptor (KIR) KIR3DL2.26

TCR-stimulated peripheral blood KIR3DL2+CD4+ T cell lines from SpA patients secrete increased levels of IL-17.27

III. Human expression studies

Peripheral blood

Increase in Th17 cell (SpA, AS28-30).Specific increase in killer immunoglobulin receptor (KIR) KIR3DL2+CD4+ Th17 cells (AS27).Increase in IL23R+ γδ T cell (active AS31).Monocyte-derived macrophages from the peripheral blood of AS patients produce more IL-23 in response to LPS than healthy controls.25

Monocyte-derived DCs from AS patients and healthy controls produced more IL-23 than cells from rheumatoid arthritis (RA) patients.32*

Target tissues

CD15+ neutrophils and MPO+ myeloid cells are the major cellular sources of IL-17 in the inflamed bone marrow of affected facet joints.33

IL-23 is overexpressed in AS spinal facet joints comparing to osteoarthritis patients and localized in MPO+CD15- myeloid precursors and to a lesser extent in CD68+ or CD163+ macrophages.34

Specifically increased mast cells are the major source of IL-17 in the inflamed synovial joints of psoriatic and non-psoriatic SpA.35

IL-23 is increased in the gut of SpA patients and has been localized to infiltrating monocytes and Paneth cells.36

IV. Animal models

Spondyloarthritis in HLA-B27 transgenic rat is associated with CD4+ Th17 T cell activation.37,38*

Experimental ankylosing enthesitis in (BXSB×NZB) F1 mice is associated with an increase in IL-17 production by T cells.39

IL-23 overexpression induces a spondyloarthritis-like disease in B10.RIII mice via RORγt(+)CD3(+)CD4(–)CD8(–) T cells that produce IL-17 and IL-22.40*

AS, ankylosing spondylitis; GRPT78, glucose-regulated protein, 78 kDa; IL-23R, interleukin-23 receptor; JAK-2, Janus kinase 2; LPS, lipopolysaccharides; STAT-3, signal transducer and activator of transcription 3; TYK-2, tyrosine kinase 2.

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in HLA-B27 transgenic rats and experimental ankylosing enthesitis in (BXSB × NZB) F1 mice are

associated with an expansion of Th17 cells and an increase in IL-17 production.39,45 Moreover,

IL-23 overexpression induces SpA-like disease in B10.RIII mice via a previously unidentified

population of IL-23R+ resident cells expressing RoRγt (RAR-related orphan receptor gamma)

that produce IL-17 and IL-22.40*

Thus, cumulative evidence from genetics, in-vitro models, human expression studies and

animal models strongly supports the involvement of the IL-23/IL-17 axis in the pathogenesis

of SpA. It is important to note, however, that all this evidence is circumstantial and that the

data emerging from these studies should be interpreted carefully. Indeed, genetic risk factors

do not always predict pathogenic involvement of a pathway, as exemplified by the genetic

association with IL-6R,46 but the lack of effect of IL-6 blockade in ankylosing spondylitis.47

Similarly, the UPR (unfolded protein response) induced by HLA-B27 misfolding has been

elegantly shown in cell lines and HLA-B27 tg rats, but it remains to be demonstrated that this

phenomenon is also occurring in vivo in our patients.32*,48 Also, the exact cellular source of IL-23

and IL-17 in the target tissues remains to be fully defined. Interestingly, IL-23 serum levels are

not specifically elevated and do not correlate with disease activity and/or treatment response

in SpA.49,50 And finally, animal models are key to study mechanistic aspects of the pathways of

interest, but poorly mimic human diseases. Systemic IL-23 overexpression, for example, does

not only lead to SpA-like enthesitis but can also induce a very severe and destructive myeloid-

driven polyarthritis in the same mice.51,52 These data indicate that preclinical studies should be

interpreted carefully, and highlight the crucial importance of PoC studies in human patients.

CLINICAL TRIALS TARGETING THE INTERLEUKIN-23/INTERLEUKIN-17 AXISRecognition of the importance of the IL-23/IL-17 axis resulted in a rapidly expanding repertoire

of compounds targeting this axis. Ustekinumab53 (a monoclonal antibody directed against

the common p40 subunit of IL-23 and IL-12), secukinumab,54 ixekizumab55 (both monoclonal

antibodies directed against IL-17A), and brodalumab56 [a monoclonal antibody against the

IL-17RA receptor, thereby blocking IL-17A, IL-17F and IL-17E (also known as IL-25)] have all

successfully completed preclinical development programs and have subsequently been tested

in randomized controlled trials (RCTs) in psoriasis as first-choice target disease (Fig. 2). All

compounds showed very significant clinical efficacy in psoriasis, with 75% improvement in

Psoriasis Area and Severity Index (PASI75) scores of 65–85% at week 12.

As psoriasis, ankylosing spondylitis and Crohn’s disease are clinically related conditions

sharing the same polymorphisms in the IL-23R; these impressive clinical data in psoriasis

provided further indirect support for testing these agents in SpA. However, PoC data in Crohn’s

disease showed a quite different picture. A phase II trial with ustekinumab did not reach its

primary endpoint, but showed a positive trend in TNF inhibitor failers in a post-hoc analysis.57 A

phase III trial specifically designed to address this question showed a significant effect: 34–40%

of the ustekinumab groups versus 24% of the placebo group reached the primary endpoint

(clinical response at week 6).58 In contrast with p40 blockade by ustekinumab, however, PoC

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Figure 2. The IL-23/IL-17 pathway as a target in the treatment of spondyloarthritis. The pharmacological mechanism of action is depicted schematically for inhibitors of IL-23 and IL-12 synthesis (apilimod), IL-23p40 (ustekinumab, briakinumab), IL-23p19 (tildrakizumab, guselkumab), IL-17A (secukinumab, ixekizumab), IL-22 (fezakinumab) and a blocker of the receptor IL-17RA (brodalumab).

trials with IL-17 blockers did not show any benefit. A RCT with secukinumab in 60 patients with

Crohn’s disease did not reach its primary endpoint and, if anything, showed deterioration in the

active treatment arm versus placebo (<0.1% probability that active treatment was better than

placebo at the week 6 primary endpoint).59 A similar trial with brodalumab was terminated by

the sponsor after interim analysis (www.clinicaltrials.gov).

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With discrepant results in psoriasis versus Crohn’s disease, the clinical efficacy of drugs targeting

the IL-23/IL-17 axis was explored in PoC trials in SpA, in particular, in the ankylosing spondylitis

and PsA subtypes (summarized in Table 2).60,61*-65*,66 Blocking IL-17A with secukinumab was very

efficacious in ankylosing spondylitis (Fig. 2). In a PoC phase II trial with 30 patients, the primary

endpoint Assessment of SpondyloArthritis International Society 20% improvement criteria

(ASAS20) at week 6 was 59% in secukinumab and 24% in placebo. Moreover, not only the clinical

signs and symptoms but also the serum biomarkers of inflammation C-reactive protein (CRP) and

S100A8 and S100A9, as well as MRI scores for inflammation, decreased upon active treatment.65*

Subsequently, a PoC open-label trial with ustekinumab in 20 ankylosing spondylitis patients

showed clear signs of clinical improvement, with an ASAS40 of 65% at week 24,63* but there was

no significant effect on CRP levels in the whole group but only in the clinical responders and the

clinical improvement should thus first be confirmed in a RCT before making firm conclusions.

Results for ixekizumab and brodalumab in ankylosing spondylitis are not known yet (Fig. 2).

In PsA, the superiority of ustekinumab above placebo has already been shown in several

RCTs.60,61* The phase II trial with 146 patients showed that 42% of the ustekinumab-treated

PsA patients versus 14% of the placebo-treated patients reached the American College of

Rheumatology 20% (ACR20) improvement criteria.60 This was confirmed in two phase III trials

(n=615 and n=312), where ACR20 at week 24 was reached in 42–50% of the ustekinumab group

versus 20–23% of the placebo group.61*,67 This response was still maintained at week 50 for the

various ACR scores, and also for the PASI75 score and the Health Assessment Questionnaire-

Disability Index (HAQ-DI). Moreover, ustekinumab was also efficacious in patients who

previously failed on TNF blockers (week 24 ACR20 response: ustekinumab 36% versus placebo

15%).67 Of the IL-17 blocking agents, only secukinumab was yet tested and reported in a RCT in

PsA, with a trend towards clinical efficacy (week 6 ACR20: secukinumab 39% versus placebo

23%) in a phase II PoC trial with 42 patients.64* The first results with brodalumab in PsA were

reported in abstract form, but are not yet published:66 in a phase II trial with 168 patients,

37–39% of the brodalumab group reached the ACR20 primary endpoint at week 12 compared

to 18% of the placebo group. Importantly, these various compounds did not show unexpected

safety concerns so far. Results for ixekizumab are still pending.

Taken together, the first PoC trials with drugs blocking key cytokines of the IL-23/IL-17 axis

showed promising results in SpA (Table 2). Both larger long-term trials with these compounds

and PoC trials with new compounds are currently in progress. The latter include briakinumab

(another IL-12/23 inhibitor targeting the common p40 subunit), tildrakizumab and guselkumab

(both monoclonal antibodies targeting the p19 subunit of IL-23), apilimod (a small molecule that

selectively suppresses synthesis of IL-12 and IL-23) and fezakinumab (a monoclonal antibody

directed against compounds targeting IL-23R, Janus kinases (JAKs) and RORγt (RAR-related

orphan receptor gamma), are also in preclinical or clinical development.

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Tabel 2. Summary of clinical trials targeting the IL-23/IL-17 axis in SpA

Drug Study designSpA

subtype Treatment arms Main results

Monoclonal antibodies targeting the common p40 subunit of IL-23 and IL-12

Ustekinumab60 Randomized, double blind, placebo-controlled,

cross-over, phase II trial

PsA Placebo (n=70)Ustekinumab (n=76)

ACR20 week 12:- Placebo: 14%

- Ustekinumab: 42%

Ustekinumab61* Randomized, double blind, placebo-controlled,

phase III trial

PsA Placebo (n=206)Ustekinumab 45 mg (n=205)Ustekinumab 90 mg (n=204)


- Ustekinumab 45 mg: 42%- Ustekinumab 90 mg: 50%

Ustekinumab62* Randomized, double blind, placebo-controlled,

phase III trial

PsA Placebo (n=104)Ustekinumab 45 mg (n=103)Ustekinumab 90 mg (n=105)


- Ustekinumab 45 mg: 44%- Ustekinumab 90 mg: 44%

Ustekinumab63* Open label single-arm trial AS Ustekinumab (n=20) ASAS40 week 24:- Ustekinumab: 65%

Briakinumab Not yet tested in SpA

Small molecules suppressing the synthesis of IL-23 and IL-12

Apilimod Not yet tested in SpA

Monoclonal antibodies targeting the p19 subunit of IL-23

Tildrakizumab Not yet tested in SpA

Guselkumab Not yet tested in SpA

Monoclonal antibodies targeting IL-17A

Secukimumab64* Randomized, double blind, placebo-controlled,

phase II trial

PsA Placebo (n=14)Secukinumab (n=28)


- Secukinumab: 39%

Secukimumab65* Randomized, double blind, placebo-controlled,

phase II trial

AS Placebo (n=6)Secukinumab (n=24)

ASAS20 week 6:- Placebo: 24%

- Secukinumab: 59%

Ixekizumab Randomized, double blind, placebo-controlled trial

PsA Still recruiting

Monoclonal antibodies targeting IL-17RA

Brodalumab66 Randomized, double blind, placebo-controlled,

phase II trial

PsA Placebo (n=55)Brodalumab 140 mg (n=57)Brodalumab 280 mg (n=56)

ACR week 12:- Placebo: 18%

- Brodalumab 140 mg: 37%- Brodalumab 280 mg: 39%

Monoclonal antibodies targeting IL-22

Fezakinumab Not yet tested in SpA

ACR20 = American College of Rheumatology 20% improvement criteria; ASAS20 = Assessment of SpondyloArthritis international Society 20% improvement criteria; IL-17RA = IL-17-receptor A.

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CONCLUSIONThe strong albeit circumstantial evidence that the IL-23/IL-17 axis contributes to SpA pathogenesis

has now been confirmed by a series of PoC trials with ustekinumab, targeting the p40 subunit of

IL-23 and IL-12, and secukinumab, a monoclonal anti-IL17A antibody, in ankylosing spondylitis and

PsA. These promising results open new avenues for treatment of patients with SpA, but many

fundamental and clinical questions remain to be answered. Obviously, the long-term efficacy and

safety of IL-23 and IL-17 blockers need to be demonstrated in large phase III and IV trials.

Three additional questions, however, are of key translational and clinical relevance. Firstly,

how does the IL-23/IL-17 axis relate to the TNF axis? Are both pathways synergistic, as suggested

by in-vitro data, or are they redundant in vivo? Are patients failing TNF inhibitors responding well

to IL-23/IL-17 blockade or, on the contrary, are nonresponders to inhibition of one pathway also

nonresponders to blockade of the other axis? Or should we even consider combination treatment

with blockade of both axes? Secondly, at what level should the IL-23/IL17 axis be targeted? Is it more

effective to target an upstream component of the pathway, such as p19, as this will not only block

IL-17A but also other IL-17 family members and IL-22? Or is it safer to target downstream effectors,

such as one specific IL-17 isotype or even one specific cell type producing IL-17 in the target tissue of

interest? Thirdly and finally, will inhibition of the IL-23/IL-17 axis not only suppress inflammation but

also modify disease progression, in particular, with regard to new bone formation? And, if so, what

is then the relative contribution of the different cytokines of this axis (e.g. IL-17A, which is known to

costimulate osteoclasts, versus IL-22, which promotes stromal repair) to structural damage?

Answering these key questions will require an integrated approach combining the ongoing

clinical trials with translational research into the molecular and cellular pathways of disease.

KEY POINTS - Cumulative evidence from genetics, in-vitro models, human expression studies and animal

models strongly supports the involvement of the IL-23/IL-17 axis in the pathogenesis of SpA.

- Clinical trials with ustekinumab (anti-p40) and secukinumab (anti-IL-17A) generally showed

good clinical efficacy in ankylosing spondylitis and PsA; proof-of-concept trials with

ixekizumab (anti-IL-17A) and brodalumab (anti-IL-17R) are ongoing.

- Targeting the IL-23/IL-17 axis is also effective in psoriasis, but this effect is less clear in

Crohn’s disease.

- More compounds targeting the IL-23/IL-17 axis at different levels are in preclinical and/or

clinical development.

- Testing these compounds in the various subtypes of SpA is expected to lead to new therapeutic

options of patients as well as to new insights in the pathophysiology of the disease.

Acknowledgements Professor Dr Baeten was supported by a VICI grant from The Netherlands

Organization for Scientific Research (NWO) and by a grant from the Dutch Arthritis Foundation

(Reumafonds).

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1 Dougados M, Baeten D. Spondyloarthritis. Lancet 2011; 377:2127–2137.

2 Brandt J, Haibel H, Cornely D, et al. Successful treatment of active ankylosing spondylitis with the antitumor necrosis factor alpha monoclonal antibody infliximab. Arthritis Rheum 2000; 43:1346–1352.

3 Van den Bosch F, Kruithof E, Baeten D, et al. Effects of a loading dose regimen of three infusions of chimeric monoclonal antibody to tumour necrosis factor alpha (infliximab) in spondyloarthropathy: an open pilot study. Ann Rheum Dis 2000; 59:428–433.

4 Baraliakos X, Listing J, Brandt J, et al. Clinical response to discontinuation of anti-TNF therapy in patients with ankylosing spondylitis after 3 years of continuous treatment with infliximab. Arthritis Res Ther 2005; 7:R439–R444.

5 Paramarta JE, Heijda TF, Baeten DL. Fast relapse upon discontinuation of tumour necrosis factor blocking therapy in patients with peripheral spondyloarthritis. Ann Rheum Dis 2013; 72:1581–1582.

6 Song IH, Althoff CE, Haibel H, et al. Frequency and duration of drug-free remission after 1 year of treatment with etanercept versus sulfasalazine in early axial spondyloarthritis: 2 year data of the ESTHER trial. Ann Rheum Dis 2012; 71:1212–1215.

7 Cua DJ, Sherlock J, Chen Y, et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 2003; 421:744–748.

8 Baeten DL, Kuchroo VK. How Cytokine networks fuel inflammation: Interleukin-17 and a tale of two autoimmune diseases. Nat Med 2013; 19:824–825.

9 Murphy CA, Langrish CL, Chen Y, et al. Divergent pro- and anti-inflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J Exp Med 2003; 198:1951–1957.

10 Aggarwal S, Ghilardi N, Xie MH, et 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.

11 Wright JF, Guo Y, Quazi A, et al. Identification of an interleukin 17F/17A heterodimer in activated humanCD4+ T cells. J Biol Chem2007; 282:13447– 13455.

12 Shen F, Gaffen SL. Structure-function relationships in the IL-17 receptor: implications for signal transduction and therapy. Cytokine 2008; 41:92–104.

13 Lee YK, Turner H, Maynard CL, et al. Late developmental plasticity in the T helper 17 lineage. Immunity 2009; 30:92–107.

14 Zielinski CE, Mele F, Aschenbrenner D, et al. Pathogen-induced human TH17 cells produce IFN-gamma or IL-10 and are regulated by IL-1beta. Nature 2012; 484:514–518.

15 *Evans HG, Roostalu U, Walter GJ, et al. TNF-alpha blockade induces IL-10 expression in human CD4+ T cells. Nat Commun 2014; 5:3199. doi:10.1038/ncomms4199.

This study demonstrates that IL-17+ CD4+ T cells can acquire regulatory activity through the expression of the anti-inflammatory cytokine IL-10.

16 Awasthi A, Riol-Blanco L, Jager A, et al. Cutting edge: IL-23 receptor gfp reporter mice reveal distinct populations of IL-17-producing cells. J Immunol 2009; 182:5904–5908.

17 Burton PR, Clayton DG, Cardon LR, et al. Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat Genet 2007; 39:1329–1337.

18 Danoy P, Pryce K, Hadler J, et al. Association of variants at 1q32 and STAT3 with ankylosing spondylitis suggests genetic overlap with Crohn’s disease. PLoS Genet 2010; 6:e1001195.

19 Evans DM, Spencer CC, Pointon JJ, et al. Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility. Nat Genet 2011;43:761–767.

20 **Cortes A, Hadler J, Pointon JP, et al. Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci. Nat Genet 2013; 45:730–738.

This important study supports mounting evidence that aberrant peptide processing before MHC class I presentation and alterations of the IL-23 pathway are key elements in the pathogenesis of ankylosing spondylitis.

21 Pointon JJ, Harvey D, Karaderi T, et al. Elucidating the chromosome 9 association with AS: CARD9 is a candidate gene. Genes Immun 2010;11:490–496.

22 Chen Q, Muramoto K, Masaaki N, et al. A novel antagonist of the prostaglandin E(2) EP(4) receptor inhibits Th1 differentiation and Th17 expansion and is orally active in arthritis models. Br J Pharmacol 2010; 160:292–310.

23 Gu J, Rihl M, Marker-Hermann E, et al. Clues to pathogenesis of spondyloarthropathy derived from synovial fluid mononuclear cell gene expression profiles. J Rheumatol 2002; 29:2159–2164.

24 Dong W, Zhang Y, Yan M, et al. Upregulation of 78-kDa glucose-regulated protein in macrophages in

REFERENCES

128

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9

peripheral joints of active ankylosing spondylitis. Scand J Rheumatol 2008; 37:427–434.

25 Zeng L, Lindstrom MJ, Smith JA. Ankylosing spondylitis macrophage production of higher levels of interleukin-23 in response to lipopolysaccharide without induction of a significant unfolded protein response. Arthritis Rheum 2011; 63:3807–3817.

26 Kollnberger S, Bird L, Sun MY, et al. Cell-surface expression and immune receptor recognition of HLA-B27 homodimers. Arthritis Rheum 2002; 46:2972–2982.

27 Bowness P, Ridley A, Shaw J, et al. Th17 cells expressing KIR3DL2+ and responsive to HLA-B27 homodimers are increased in ankylosing spondylitis. J Immunol 2011; 186:2672–2680.

28 Jandus C, Bioley G, Rivals JP, et al. Increased numbers of circulating polyfunctional Th17 memory cells in patients with seronegative spondylarthritides. Arthritis Rheum 2008; 58:2307–2317.

29 Shen H, Goodall JC, Hill Gaston JS. Frequency and phenotype of peripheral blood Th17 cells in ankylosing spondylitis and rheumatoid arthritis. Arthritis Rheum 2009; 60:1647–1656.

30 Zhang L, Li YG, Li YH, et al. Increased frequencies of Th22 cells as well as Th17 cells in the peripheral blood of patients with ankylosing spondylitis and rheumatoid arthritis. PLoS One 2012;7:e31000.

31 *Kenna TJ, Davidson SI, Duan R, et al. Enrichment of circulating interleukin-17-secreting interleukin-23 receptor-positive gamma/delta T cells in patients with active ankylosing spondylitis. Arthritis Rheum 2012;64:1420–1429.

This study demonstrates that IL-23 drives IL-17 production by gamma/delta T cells, which are possibly involved in the pathogenesis of ankylosing spondylitis.

32 *Prevosto C, Goodall JC, Hill Gaston JS. Cytokine secretion by pathogen recognition receptor-stimulated dendritic cells in rheumatoid arthritis and ankylosing spondylitis. J Rheumatol 2012;39:1918–1928.

This study shows that monocyte-derived dendritic cells from rheumatoid arthritis patients produce less IL-23 than cells from ankylosing spondylitis and healthy controls.

33 Appel H, Maier R, Wu P, et al. Analysis of IL-17(+) cells in facet joints of patients with spondyloarthritis suggests that the innate immune pathway might be of greater relevance than the Th17-mediated adaptive immune response. Arthritis Res Ther 2011;13:R95.

34 Appel H, Maier R, Bleil J, et al. In situ analysis of interleukin-23- and interleukin-12-positive cells in

the spine of patients with ankylosing spondylitis. Arthritis Rheum 2013; 65:1522–1529.

35 Noordenbos T, Yeremenko N, Gofita I, et al. Interleukin-17-positive mast cells contribute to synovial inflammation in spondylarthritis. Arthritis Rheum 2012;64:99–109.

36 Ciccia F, Bombardieri M, Principato A, et al. Overexpression of interleukin-23, but not interleukin-17, as an immunologic signature of subclinical intestinal inflammation in ankylosing spondylitis. Arthritis Rheum 2009;60:955–965.

37 DeLay ML, Turner MJ, Klenk EI, et al. HLA-B27 misfolding and the unfolded protein response augment interleukin-23 production and are associated with Th17 activation in transgenic rats. Arthritis Rheum 2009; 60:2633–2643.

38 *Glatigny S, Fert I, Blaton MA, et al. Proinflammatory Th17 cells are expanded and induced by dendritic cells in spondylarthritis-prone HLA-B27-transgenic rats. Arthritis Rheum 2012; 64:110–120.

This study demonstrates that defective function in HLA-B27-transgenic rat dendritic cells contributes to disease development by skewing CD4+ T cells toward Th17.

39 Abe Y, Ohtsuji M, Ohtsuji N, et al. Ankylosing enthesitis associated with upregulated IFN-gamma and IL-17 production in (BXSB x NZB) F(1) male mice: a new mouse model. Mod Rheumatol 2009; 19:316–322.

40 *Sherlock JP, Joyce-Shaikh B, Turner SP, et al. IL-23 induces spondyloarthropathy by acting on ROR-gammat+ CD3+CD4-CD8- entheseal resident T cells. Nat Med 2012; 18:1069–1076.

This study shows that IL-23 overexpression induces a spondyloarthritis-like disease in B10.RIII mice via (RAR-related orphan receptor gamma) ROR-γt(+)CD3(+)CD4(-)CD8(-) T cells that produce IL-17 and IL-22.

41 Duerr RH, Taylor KD, Brant SR, et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 2006; 314:1461–1463.

42 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.

43 Di MP, Di CA, Laggner U, et al. The IL23R R381Q gene variant protects against immune-mediated diseases by impairing IL-23-induced Th17 effector response in humans. PLoS One 2011; 6:e17160.

44 Sarin R, Wu X, Abraham C. Inflammatory disease protective R381Q IL23 receptor polymorphism results in decreased primary CD4+ and CD8+

129

human T-cell functional responses. Proc Natl Acad Sci U S A 2011;108:9560–9565.

45 Utriainen L, Firmin D, Wright P, et al. Expression of HLA-B27 causes loss of migratory dendritic cells in a rat model of spondylarthritis. Arthritis Rheum 2012;64:3199–3209.

46 Parkes M, Cortes A, van Heel DA, Brown MA. Genetic insights into common pathways and complex relationships among immune-mediated diseases. Nat Rev Genet 2013; 14:661–673.

47 Sieper J, Porter-Brown B, Thompson L, et al. Assessment of short-term symptomatic efficacy of tocilizumab in ankylosing spondylitis: results of randomised, placebo-controlled trials. Ann Rheum Dis 2014; 73:95–100.

48 Neerinckx B, Carter S, Lories RJ. No evidence for a critical role of the unfolded protein response in synovium and blood of patients with ankylosing spondylitis. Ann Rheum Dis 2013; 73:629–630.

49 Melis L, Vandooren B, Kruithof E, et al. Systemic levels of IL-23 are strongly associated with disease activity in rheumatoid arthritis but not spondyloarthritis. Ann Rheum Dis 2010; 69:618–623.

50 Wendling D, Cedoz JP, Racadot E. Serum and synovial fluid levels of p40 IL12/23 in spondyloarthropathy patients. Clin Rheumatol 2009;28:187–190.

51 Adamopoulos IE, Tessmer M, Chao CC, et al. IL-23 is critical for induction of arthritis, osteoclast formation, and maintenance of bone mass. J Immunol 2011;187:951–959.

52 Molle C, Zhang T, Ysebrant de Lendonck L, et al. Tristetraprolin regulation of interleukin 23 mRNA stability prevents a spontaneous inflammatory disease. J Exp Med 2013; 210:1675–1684.

53 Leonardi CL, Kimball AB, 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 randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet 2008; 371:1665–1674.

54 Papp KA, Langley RG, Sigurgeirsson B, et al. Efficacy and safety of secukinumab in the treatment of moderate-to-severe plaque psoriasis: a randomized, double-blind, placebo-controlled phase II dose-ranging study. Br J Dermatol 2013; 168:412–421.

55 Leonardi C, Matheson R, Zachariae C, et al. Antiinterleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis. N Engl J Med 2012;366:1190–1199.

56 Papp KA, Leonardi C, Menter A, et al. Brodalumab, an antiinterleukin-17-receptor antibody for psoriasis. N Engl J Med 2012; 366:1181–1189.

57 Sandborn WJ, Feagan BG, Fedorak RN, et al. A randomized trial of Ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with moderate-to-severe Crohn’s disease. Gastroenterology 2008; 135:1130–1141.

58 Sandborn WJ, Gasink C, Gao LL, et al. Ustekinumab induction and maintenance therapy in refractory Crohn’s disease. N Engl J Med 2012;367:1519–1528.

59 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 randomised, double-blind placebo-controlled trial. Gut 2012;61:1693–1700.

60 Gottlieb A, Menter A, Mendelsohn A, et al. Ustekinumab, a human interleukin 12/23 monoclonal antibody, for psoriatic arthritis: randomised, double-blind, placebo-controlled, crossover trial. Lancet 2009;373:633–640.

61 *McInnes IB, Kavanaugh A, Gottlieb AB, et al. Efficacy and safety of ustekinumab in patients with active psoriatic arthritis: 1 year results of the phase 3, multicentre, double-blind, placebo-controlled PSUMMIT 1 trial. Lancet 2013;382:780–789.

These important clinical trials show good clinical efficacy of targeting of IL-23/IL-17 axis in PsA and ankylosing spondylitis.

62 *Ritchlin C, Rahman P, Kavanaugh A, et al. Efficacy and safety of the anti-IL-12/23 p40 monoclonal antibody, ustekinumab, in patients with active psoriatic arthritis despite conventional nonbiological and biological antitumour necrosis factor therapy: 6-month and 1-year results of the phase 3, multicentre, double-blind, placebo-controlled, randomised PSUMMIT 2 trial. Ann Rheum Dis 2014. doi: 10.1136/annrheumdis-2013-204655.


63 *Poddubnyy D, Hermann KG, Callhoff J, et al. 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.


64 *McInnes IB, Sieper J, Braun J, et al. Efficacy and safety of secukinumab, a fully human antiinterleukin-17A monoclonal antibody, in patients with moderate-tosevere psoriatic arthritis: a 24-week, randomised, double-blind, placebocontrolled, phase II proof-of-concept trial. Ann Rheum Dis 2014; 73:349–356.

130

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xIs a

s prom

IsIng

new

Targ

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65 *Baeten D, Baraliakos X, Braun J, et al. Anti-interleukin-17A monoclonal antibody secukinumab in treatment of ankylosing spondylitis: a randomised, double-blind, placebo-controlled trial. Lancet 2013; 382:1705–1713.


66 Mease PJ, Genovese MC, Greenwald MW, et al. Efficacy of brodalumab, an anti-IL-17R antibody, in subjects with psoriatic arthritis [abstract]. Ann Rheum Dis 2013; 72 (Suppl3):85.

67 Ritchlin CT, Gottlieb AB, McInnes IB, et al. Ustekinumab in active psoriatic arthritis including patients previously treated with anti-TNF agents: results of a phase 3, multicenter, double-blind, placebo-controlled study [abstract]. Arthritis Rheum 2012; 64 (Suppl):S1080–S1081.

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