Early anti-inflammatory intervention ameliorates axial disease in the proteoglycan-induced spondylitis mouse model of ankylosing spondylitis

Hsu-Wen Tseng,Matthew A Brown,Allison R Pettit,Tibor T Glant,Gethin P Thomas,Tony J Kenna

doi:10.1186/s12891-017-1600-7

Abstract

BackgroundAnkylosing spondylitis (AS) is characterised by immune-mediated arthritis and osteoproliferation, ultimately leading to joint ankylosis. Whether inflammation is necessary for osteoproliferation is controversial, fuelled by the unclear efficacy of anti-inflammatory treatments on radiographic progression. In proteoglycan-induced spondylitis (PGISp), a mouse model of AS, inflammation is the prerequisite for osteoproliferation as osteoproliferation was only observed following inflammation-driven intervertebral disc (IVD) destruction. We hypothesised that early intervention with a potent anti-inflammatory therapy would protect IVD integrity and consequently alter disease progression.MethodsPGISp mice received vehicle or a combination of etanercept (ETN) plus prednisolone (PRD) therapy for 2 or 6 weeks initiated at an early disease stage. Peripheral arthritis was scored longitudinally. Spinal disease was assessed using a semi-quantitative histological scoring regimen including inflammation, joint destruction and excessive tissue formation.ResultsETN + PRD therapy significantly delayed the onset of peripheral arthritis. IVD integrity was significantly protected when treatment was commenced in early disease. Six-weeks of treatment resulted in trends towards reductions in intervertebral joint damage and excessive tissue formation. IVD score distribution was dichotomized, likely reflecting the extent of axial disease at initiation of therapy. In the sub-group of mice with high IVD destruction scores, ETN + PRD treatment significantly reduced IVD destruction severity, inflammation and bone erosion and reduced cartilage damage and excessive tissue formation.ConclusionsEarly intervention with anti-inflammatory treatment not only improved inflammatory symptoms but also ameliorated structural damage of spine in PGISp mice. This preclinical observation suggests that early anti-inflammatory intervention may slow radiographic progression in AS patients.

Highlights

Ankylosing spondylitis (AS) is characterised by immune-mediated arthritis and osteoproliferation, leading to joint ankylosis
We recently reported that the axial disease initiated as a intervertebral joint associated inflammatory response leading to intervertebral disc (IVD) destruction
Clear progression of IVD destruction (Fig. 1a) was seen in more than 50% of mice by 8 weeks post-priming with peak IVD destruction severity reached by 10 weeks with 100% of mice affected [16]

Summary

Introduction

Ankylosing spondylitis (AS) is characterised by immune-mediated arthritis and osteoproliferation, leading to joint ankylosis. Use of TNF-inhibitors is restricted to patients fulfilling the modified New York classification criteria for AS (i.e. presence of osteoproliferative changes in the sacroiliac joints required) [2] and who have failed NSAID therapy [3]. Both treatment approaches are effective at relieving inflammatory symptoms and suppressing objective measures of joint inflammation. It is not clear whether anti-inflammatory treatments retard progression of syndesmophyte formation, indicative of disease-associated osteoproliferation

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