Pathogenesis of ankylosing spondylitis — recent advances and future directions

Abstract

Over the past 5 years, advances in high-throughput techniques and studies involving large cohorts of patients have led to considerable advances in the identification of novel genetic associations and immune pathways involved in ankylosing spondylitis (AS). These discoveries include genes encoding cytokine receptors, transcription factors, signalling molecules and transport proteins. Although progress has been made in understanding the functions and potential pathogenic roles of some of these molecules, much work remains to be done to comprehend their complex interactions and therapeutic potential in AS. In this Review, we outline the current knowledge of AS pathogenesis, including genetic risk associations, HLA-B27-mediated pathology, perturbations in antigen-presentation pathways and the contribution of the type 3 immune response.

Three Multicenter, Randomized, Double‐Blind, Placebo‐Controlled Studies Evaluating the Efficacy and Safety of Ustekinumab in Axial Spondyloarthritis

“…A recent review highlighted differences in axial disease in AS and PsA, suggesting that spondylitis may be driven by different mechanisms in these 2 diseases . While the immunopathogenesis of axial SpA remains unknown, the interplay of genetics (HLA–B27) with exposure to microbial triggers originating from the gut or skin along with dysregulated innate and adaptive immune responses (the Th17 pathway) has been implicated . Although reports of up‐regulation of the Th17 pathway in the spine and joints have been published , there is conflicting evidence regarding dysregulation of the IL‐23/IL‐17 axis in the serum of AS patients .…”

Translating IL-6 biology into effective treatments

“…The absence of the serological markers rheumatoid factor and antibodies to cyclic citrullinated peptides differentiates SpA from RA. AS is a chronic, debilitating and gradually progressive inflammatory rheumatic disease that primarily affects the axial skeleton and sacroiliac joints, but can also affect the peripheral joints 101 . Serum IL-6 concentrations are elevated in patients with AS and correlate with disease activity 102 .…”

Shotgun metagenomics reveals an enrichment of potentially cross-reactive bacterial epitopes in ankylosing spondylitis patients, as well as the effects of TNFi therapy and the host’s genotype upon microbiome composition

“…AS has been shown in both twin and unrelated case/control studies to be highly heritable (twins >90% heritability 4,5 , unrelated case/control common variant heritability 69% (http://www.nealelab.is/blog/2017/9/15/heritability-of-2000-traits-and-disorders-in-the-uk-biobank)). Over past decade, at least 116 susceptibility genes have been identified, contributing 29% of the overall risk of the disease 6 . There is substantial evidence suggesting that the interaction between host genetics and gut microbiome is a key driver of the pathogenesis of AS.…”