The advent of IL-17A blockade in ankylosing spondylitis: secukinumab, ixekizumab and beyond

Dubash, Sayam; Bridgewood, Charlie; McGonagle, Dennis; Marzo‐Ortega, Helena

doi:10.1080/1744666x.2019.1561281

Cited by 56 publications

(47 citation statements)

References 85 publications

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“…Recent studies have pointed to the non-efficacy of anti-IL-23 therapy for ankylosing spondylitis,10 whereas anti-IL-17A therapy is effective in AS 15 16. A potential explanation for this surprising finding is that early experimental SpA, but not established disease, is dependent on IL-23,17 which points to the importance of innate immunity in disease onset.…”

Section: Introductionmentioning

confidence: 99%

Evidence that tissue resident human enthesis γδT-cells can produce IL-17A independently of IL-23R transcript expression

et al. 2019

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ObjectivesMurine models of interleukin (IL)-23-driven spondyloarthritis (SpA) have demonstrated entheseal accumulation of γδT-cells which were responsible for the majority of local IL-17A production. However, IL-23 blockers are ineffective in axial inflammation in man. This study investigated γδT-cell subsets in the normal human enthesis to explore the biology of the IL-23/17 axis.MethodsHuman spinous processes entheseal soft tissue (EST) and peri-entheseal bone (PEB) were harvested during elective orthopaedic procedures. Entheseal γδT-cells were evaluated using immunohistochemistry and isolated and characterised using flow cytometry. RNA was isolated from γδT-cell subsets and analysed by qPCR. Entheseal γδT-cells were stimulated with phorbol 12-myristate 13-acetate (PMA) and ionomycin, anti-CD3/28 or IL-23 and IL-17A production was measured by high-sensitivity ELISA and qPCR.ResultsEntheseal γδT-cells were confirmed immunohistochemically with Vδ1 and Vδ2 subsets that are cytometrically defined. Transcript profiles of both cell populations suggested tissue residency and immunomodulatory status. Entheseal Vδ2 cells expressed high relative abundance of IL-23/17-associated transcripts including IL-23R, RORC and CCR6, whereas the Vδ1 subset almost completely lacked detectable IL-23R transcript. Following PMA stimulation IL-17A was detectable in both Vδ1 and Vδ2 subsets, and following CD3/CD28 stimulation both subsets showed IL-17A and IL-17F transcripts with neither transcript being detectable in the Vδ1 subset following IL-23 stimulation.ConclusionSpinal entheseal Vδ1 and Vδ2 subsets are tissue resident cells with inducible IL-17A production with evidence that the Vδ1 subset does so independently of IL-23R expression.

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Section: Introductionmentioning

confidence: 99%

Evidence that tissue resident human enthesis γδT-cells can produce IL-17A independently of IL-23R transcript expression

et al. 2019

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“…Secukinumab, a fully human monoclonal antibody against IL-17A, is the first non-TNF-α inhibitor agent approved for AS, which opens up a therapeutic step of other cytokine targets beyond TNF (18). The benefits of secukinumab are generally seen regardless of whether patients were naive or not to TNF inhibitor therapy, and were persistent up to 5 years treatment; secukinumab was also associated with visible improvement of mobility and physical function, quality of life and work productivity in some of the trials (19).…”

Section: Immunopathogenesis Of Ankylosing Spondylitismentioning

confidence: 99%

New insights into IL‑17/IL‑23 signaling in ankylosing spondylitis (Review)

et al. 2020

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Ankylosing spondylitis (AS) is a progressive common autoimmune inflammatory disease, part of the spondylarthritis group, characterized, besides clinical spinal and peripheral joint inflammation, by enthesitis and new bone formation, that can lead to severe functional impairment. Beyond intensive and continuous research on the pathogenic process extensively performed in recent years, their impact on therapeutic management remains open to future development. Better knowledge of AS pathogenesis have shown results progressively and studies are being performed to advance our current understanding of the disease. It is well known that tumor necrosis factor (TNF) exerts a central role, along with interleukin-17 (IL-17) and interleukin-23 (IL-23), demonstrated by several clinical studies. Similar to other rheumatic inflammatory conditions, SA is associated with an early process of systemic bone loss, both trabecular and cortical, consecutive osteopenia, osteoporosis, and high fracture risk. Current personalized therapeutic options benefit from new published data, to prevent future complications and to improve quality of life. Contents 1. Introduction 2. Immunopathogenesis of ankylosing spondylitis 3. Effects of IL-23 and IL-17 on the bone 4. Conclusions

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“…[23] In recent years, anti IL17A has been shown to inhibit AS, [24] and some related drugs have been developed. For instance, Dubash et al [25] showed that secukinumab was an IL-17A depressor, which can remedy AS. In this experiment, we discovered that it meaningfully improved cell viability, migration, and expression of inflammatory factors when IL-17 was added to ATDC5 cells.…”

Section: Il-17 Is An Early Promoter Of T Cell-induced Inflammatorymentioning

confidence: 99%

Bilobalide alleviates IL‐17‐induced inflammatory injury in ATDC5 cells by downregulation of microRNA‐125a

Mao

Zhang

et al. 2019

J Biochem & Molecular Tox

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Ankylosing spondylitis (AS) is a high disability and greatly destructive disease. In this study, we preliminarily studied the function and mechanism of bilobalide (BIL) on interleukin (IL)‐17‐induced inflammatory injury in ATDC5 cells. CCK‐8 and migration assays were used to detect the functions of IL‐7, BIL, and microRNA (miR)‐125a on cell viability and migration. The miR‐125a level was changed by transfection, and tested by real‐time quantitative polymerase chain reaction. Additionally, Western blot tested the levels of inflammatory factors (IL‐6 and tumor necrosis factor‐α), matrix metalloproteinases (MMPs), and pathway‐related proteins. Moreover, the enzyme‐linked immunosorbent assay also was used to detect inflammatory factor levels. IL‐7 was used to construct an inflammatory injury model in ATDC5 cells. Based on this, BIL inhibited IL‐17‐induced cell viability, migration, and expressions of inflammatory factors and MMPs. Furthermore, we found BIL negatively regulated miR‐125a, and the miR‐125a mimic could partly reverse the effects of BIL on IL‐17‐injury. Finally, we showed that BIL inhibited the c‐Jun N‐terminal kinase (JNK) and nuclear factor kappa B (NF‐κB) pathways, and the miR‐125a mimic had the opposite effect. BIL inhibited IL‐17‐induced inflammatory injury in ATDC5 cells by downregulation of miR‐125a via JNK and NF‐κB signaling pathways.

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The advent of IL-17A blockade in ankylosing spondylitis: secukinumab, ixekizumab and beyond

Cited by 56 publications

References 85 publications

Evidence that tissue resident human enthesis γδT-cells can produce IL-17A independently of IL-23R transcript expression

Evidence that tissue resident human enthesis γδT-cells can produce IL-17A independently of IL-23R transcript expression

New insights into IL‑17/IL‑23 signaling in ankylosing spondylitis (Review)

Bilobalide alleviates IL‐17‐induced inflammatory injury in ATDC5 cells by downregulation of microRNA‐125a

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