Neues zur Pathophysiologie der Spondyloarthritis

Zusammenfassung

Die Spondyloarthritiden (SpA) umfassen eine Gruppe von Erkrankungen, die durch ähnliche klinische Manifestationen und gemeinsame genetische Assoziationen gekennzeichnet sind. Die axialen Manifestationen umfassen Entzündungen im Achsenskelett, insbesondere in den Sakroiliakalgelenken und in den Wirbelkörpern; bei den peripheren Gelenkmanifestationen dominieren Enthesitiden und Daktylitiden neben oligoartikulären asymmetrischen Arthritiden. Die Pathogenese und Krankheitsentwicklung wird stark durch genetische Anlagen bestimmt. HLA-B27 gilt als wichtigster genetischer Risikofaktor, wobei die pathogenetische Funktion von HLA-B27 nach wie vor ungeklärt ist. Daneben wurden in genomweiten Assoziationsstudien u. a. Risikovarianten in Genen, die den Interleukin (IL)-23-IL-17 Signalweg kontrollieren, identifiziert. Die Bedeutung dieses Signalweges spiegelt sich auch in der klinischen Wirksamkeit von IL-17 Inhibitoren bei Patienten mit SpA wider. Histologische Untersuchungen axialer Krankheitsmanifestationen zeigten ein entzündliches Grauationsgewebe, welches destruierende und reparative Eigenschaften besitzt. So fanden sich neben dem Fibroblasten-reichen Granulationsgewebe randständige Osteoklasten, die die Destruktion der Knochenendplatte vorantreiben und Osteoblasten, die Knochenneubildung vermitteln. In Analysen der IL-23- und IL-17-Expression in Wirbelkörperproben von Patienten mit ankylosierender Spondylitis fand sich die Expression dieser Zytokine v. a. in myeloiden Zellen. Im Tiermodell wurden IL-23 Rezeptor-exprimierende Zellen in Sehnenansätzen identifiziert. Auf IL-23 Exposition reagierten diese Zellen mit der Expression von IL-17 und IL-22, was zur lokalen Entzündung gefolgt von Knochenneubildung führte. Neben der genetischen Assoziation besteht bei der SpA eine große Überlappung mit dem Bestehen einer Psoriasis oder einer chronisch-entzündlichen Darmerkrankung (CED). Darüber hinaus fand sich bei einem Großteil der SpA-Patienten, die keine klinischen Zeichen einer CED zeigen, ebenfalls eine mikroskopische Darmentzündung. Es wird angenommen, dass die entzündlichen Reaktionen an Grenzflächen im Kontext von HLA-B27 zur Entwicklung der axialen und peripheren Gelenkentzündung beitragen, wobei unklar ist, ob Translokation bakterieller Antigene oder die Immunaktivierung im Darm über die Freisetzung löslicher Faktoren oder eine Kreuzreaktivität zwischen mikrobiellen und Gelenkantigenen zu den typischen SpA-Gelenkentzündungen führt.

Abstract

Spondyloarthritis (SpA) refers to a group of diseases characterised by similar clinical manifestations and shared genetic associations. Axial manifestations include inflammation of sacroiliac joints and vertebral bodies. Peripheral manifestations are dominated by enthesitis and dactylitis as well as asymmetrical oligoarthritis. The pathogenesis and disease development is strongly driven by genetic factors. HLA-B27 is the most important genetic risk factor. However, its pathogenetic impact has not been resolved yet. Apart from HLA-B27, genome-wide association studies have found other risk variants in genes of the interleukin (IL)-23-IL-17 pathway. The impact of this pathway is reflected by the efficacy of IL-17 inhibitors in SpA patients. Histological analyses of axial manifestations have revealed inflammatory granulation tissue with destructive and reparative capabilities. Thus, osteoclasts promoting destruction of bone endplates and osteoblasts facilitating bone formation have both been found at the edges of granulation tissue rich in fibroblasts. In analyses investigating IL-23 and IL-17 expression in spine samples of patients with ankylosing spondylitis, the expression of these cytokines has mostly been detected in myeloid cells. In animal models, cells expressing the IL-23 receptor have been found in entheseal insertions. When exposed to IL-23, those cells expressed IL-17 and IL-22, leading to local inflammation followed by new bone formation. Apart from the genetic association, there is a strong association with psoriasis and chronic inflammatory bowel diseases (IBD). Moreover, even in the absence of clinical signs of IBD, the majority of patients with SpA also exhibit microscopic intestinal inflammation. It is assumed that inflammation at physiological barriers may contribute to the development of joint inflammation in the context of HLA-B27. It has not been clarified to date whether it is the translocation of bacterial antigens, immune activation within the intestine or cross reactivity between microbial and joint antigens that causes the typical inflammatory joint manifestation in SpA.

Schlüsselwörter

Spondyloarthritis - HLA-B27, Interleukin-17, IL-23R

Key words

spondyloarthritis - HLA-B27 - interleukin-17 - IL-23R

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