ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 404

Interleukin 17A– a Translational Target to Treat Supraspinatus Tendinopathy

Neal L Millar1, Moeed Akbar1, Eckhard Weber2, Frank Kolbinger3, Friedrich Raulf2, Olivier Leupin4, Shea Carter4, Nicolau Beckmann4, Linda Mindeholm3, Iain B. McInnes5,6 and Matthias Schieker3, 1Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom, 2Novartis Institutes for Biomedical Research, Basel,, Switzerland, 3Novartis Institutes for Biomedical Research, Basel, Switzerland, 4Novartis Institutes for Biomedical Research, Basel,, United Kingdom, 5University of Glasgow, Glasgow, United Kingdom, 6Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, Great Britain

Meeting: 2018 ACR/ARHP Annual Meeting

Keywords:

Session Information

Date: Sunday, October 21, 2018

Session Title: Orthopedics, Low Back Pain and Rehabilitation Poster – ACR/ARHP

Session Type: ACR/ARHP Combined Abstract Session

Session Time: 9:00AM-11:00AM

Background/Purpose: , Shoulder tendinopathy is a multifactorial disorder that accounts for a high proportion (approx. 30%) of referrals to orthopaedic surgeons. Experimental evidence points to the importance of the interleukin 17 (IL-17) cytokine family in the pathogenesis of several immunoinflammatory diseases. Given our previous findings of a role for IL-17A in tissue remodeling events in tendinopathy we hypothesized that blockade of IL-17A may provide a therapy for tendinopathy.

Methods: ,We confirmed evidence of IL-17 family expression in supraspinatus tendinopathy and thereafter, explored mechanisms whereby IL-17A mediated inflammation and tissue remodelling in human tenocytes. Torn supraspinatus tendon (established pathology) and matched intact subscapularis tendon (representing ‘early pathology’) along with control biopsies were collected from patients undergoing shoulder surgery. In tendon biopsies, expression of IL-17A was assessed by qRT-PCR and immunohistochemistry. In isolated tenocytes, effects of IL-17A blockade by secukinumab were assessed following IL-17A and TNF activation by whole transcriptome AmpliSeq or multiplex cytokine assays.Finally, we assessed the translational effects of IL-17A blockade on structure/function in a rat model of rotator cuff tendinopathy of the supraspinatus tendon using magnetic resonance imaging (MRI) and gait analysis.

Results: , IL-17A blockade reduces proinflammatory signature in human tenocytes. Transcriptomic datasets showed the presence of the IL-17 family members IL-17A-E and receptors IL-17RA & IL-17RC throughout the spectrum of tendinopathy. Furthermore IL-17A significantly elevated production of the proinflammatory cytokines IL-6, IL-8, CXCL-1 and CCL-2 in tenocytes. Importantly, IL-17A blockade by secukinumab significantly reduced the expression of these proinflammatory cytokines.

IL-17A blockade significantly improves tendon structure and function in vivo.The pharmacological effects of IL-17A blockade on MRI/ gait abnormalities were assessed 4 weeks after the surgical induction of tendinopathy and following once weekly dosing of anti-IL-17A antibody. The induction of tendinopathy significantly increased the MRI T2 signal in tendinopathy and triggered gait abnormalities by significant alteration of front-hind ratios of footprint contact areas. IL-17A blockade normalized both, altered MRI T2 signals (p<0.01, n=4) and gait abnormalities (p<0.05, n=8).

Conclusion:,Our study provides evidence that IL-17A operates as a cytokine modulator in human supraspinatus tendinopathy and that blockade significantly improves tendon structure and function in a rodent model of supraspinatus tendinopathy. Based on these results we have commenced a randomised multicenter trial of the effect of IL-17A blockade with secukinumab in patients with rotator cuff tendinopathy (NCT03344640).

Disclosure: N. L. Millar, Novartis, 5; M. Akbar, None; E. Weber, Novartis, 3; F. Kolbinger, Novartis, 3; F. Raulf, Novartis, 3; O. Leupin, Novartis, 3; S. Carter, Novartis, 3; N. Beckmann, Novartis, 3; L. Mindeholm, Novartis, 3; I. B. McInnes, AbbVie Inc., 5,BMS, 2, 5,Astra Zeneca, 2, 5,Eli Lilly and Co., 5,Janssen, 2, 5,Celgene Corporation, 2, 5,Leo, 2,Novartis, 5,Pfizer, Inc., 5,Oxford Biodynamics, 2,UCB, Inc., 2, 5; M. Schieker, Novartis, 3.

To cite this abstract in AMA style:

Millar NL, Akbar M, Weber E, Kolbinger F, Raulf F, Leupin O, Carter S, Beckmann N, Mindeholm L, McInnes IB, Schieker M. Interleukin 17A– a Translational Target to Treat Supraspinatus Tendinopathy [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/interleukin-17a-a-translational-target-to-treat-supraspinatus-tendinopathy/. Accessed December 13, 2019.

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