Inflammatory pathways in spondyloarthritis
Introduction
Ankylosing spondylitis (AS) is the prototypical form of spondyloarthritis (SpA), a prevalent and invalidating form of chronic inflammatory arthritis of presumably autoinflammatory rather than autoimmune aetiology (Ambarus et al., 2012, Dougados and Baeten, 2011, Park et al., 2012). Extensive genome wide association scan studies have recently provided major insights in the genetic architecture of AS. The discovery of a number of novel genetic associations beyond HLA-B27 pointed towards already known as well as unexpected inflammatory cytokine pathways that may be involved in the pathogenesis of AS. Single nucleotide polymorphisms in cytokines, their receptors, and their intracellular signalling molecules identified TNF, IL-1, IL-6 and IL-23/IL-17 as cytokine pathways of major interest. Here we will review our current knowledge of the involvement of these cytokine pathways in the pathophysiology of the disease. As the current understanding is that the pathophysiology of SpA is driven by similar and broadly overlapping cellular and molecular mechanisms in the different phenotypic forms of the disease, including AS, we will discuss SpA as one disease but indicate differences between SpA subtypes where appropriate (Baeten et al., 2013). We will review the available evidence from (a) genetic associations, (b) studies in animal models, (c) expression of these cytokines in human SpA and (d) therapeutic effects of cytokine blockade in human SpA. Finally, we will discuss how these inflammatory pathways may interact with pathologic new bone formation in SpA.
Section snippets
Genetics
GWAS identified three genetic associations of AS with TNF signalling pathways: TNFRSF1A, TRADD, and TNFSF15. First, the transmembrane receptor TNFRSF1A (TNFR1) is one of the main receptors involved in TNF signalling (Corona-Sanchez et al., 2012, Davidson et al., 2011, Evans et al., 2011, Karaderi et al., 2012). Signalling through TNFR1 can be associated with NF-κB-mediated cell survival and growth or, alternatively, with apoptosis via TRADD. TNFR1 is widely expressed on hematopoietic and
Genetics
GWAS in AS indicated an association with IL1R2 (Reveille et al., 2010). However, this association was not reproduced in the Han Chinese population (Z. Lin et al., 2012). In a meta-analysis of genetic data in AS for possible SNPs in the IL-1 signalling pathway, three SNPs in the gene for the pro-inflammatory cytokine IL-1α were reported significant, though with very small odds ratios. In addition SNPs were found in the IL-1 receptor antagonist (IL1RN) gene as well in the gene encoding for IL-1R2
Genetics
AS shows a strong genetic association with IL23R polymorphisms, which has now been replicated in several Caucasian populations (Burton et al., 2007, Danoy et al., 2010, Reveille et al., 2010). The protective variant rs11209026 results in a R381Q substitution and functional studies in healthy individuals showed the variant to be a loss of function leading to impaired Th17 effector responses (Di Meglio et al., 2011, Pidasheva et al., 2011, Sarin et al., 2011). In concordance with these data,
Genetics
As mentioned previously, AS is genetically associated with a SNP in STAT3, an intracellular molecule which mediates signalling of not only IL-23 but also IL-6. Additionally, recent data also suggest an association with a SNP in IL-6 (Brown et al., unpublished data).
Animal models
The gp130 subunit of the IL-6 receptor signals through both the STAT and SHP-2/ras/Erk pathways and two different experimental models exist where IL-6 signalling is modulated by genetic modification of gp130. Mice with a specific
Disconnect between inflammation and pathological new bone formation
A key question in the molecular pathophysiology of SpA is how inflammation interacts with structural damage. Structural damage in SpA is characterised by two distinct features: erosive bone damage and pathological new bone formation. Surprisingly, both features can be observed simultaneously in the same joints such as the sacroiliac joints in AS and small joints of the hands in PsA. The mechanisms driving cartilage and bone destruction appear to be molecularly similar to RA (Vandooren et al.,
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2021, CytokineCitation Excerpt :The deletion of STAT3 binding sites of gp130 in mice results in sustained inflammation and the development of severe arthritis with cartilage metaplasia and degradation [113]. IL-6 serum levels are elevated in patients with ankylosing spondylitis and correlate with disease activity [114-116]. Although targeting IL-6 in the management of ankylosing spondylitis was promising, two trials investigating tocilizumab and sarilumab failed to show clinical efficacy, suggesting that IL-6 is not a pivotal cytokine in the pathogenesis of ankylosing spondylitis [117,118].
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