Download PDF
Aktuelle Rheumatologie 2019; 44(05): 315-320
DOI: 10.1055/a-0982-2732
Übersichtsarbeit
© Georg Thieme Verlag KG Stuttgart · New York

Neues zur Pathophysiologie der Spondyloarthritis

New developments in the pathophysiology of spondyloarthritis
Uta Syrbe
1   Medizinische Klinik für Gastroenterologie, Infektiologie und Rheumatology, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin
› Author Affiliations
Further Information

Publication History

Publication Date:
03 September 2019 (online)

Also available at
    Permissions and Reprints

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
 

  • Literatur

  • 1 Braun J, Sieper J. Ankylosing spondylitis. Lancet 2007; 369: 1379-1390. doi:10.1016/S0140-6736(07)60635-7
    CrossrefPubMedGoogle Scholar
  • 2 Kellgren JH, Jeffrey MR. Epidemiology of chronic rheumatism. Atlas of Standard Radiographs in Arthritis. Oxford: Blackwell Scientific Publications; 1963. 11 36-40
    Google Scholar
  • 3 Resnick D, Niwayama G, Goergen TG. Comparison of radiographic abnormalities of the sacroiliac joint in degenerative disease and ankylosing spondylitis. AJR American journal of roentgenology 1977; 128: 189-196 doi:10.2214/ajr.128.2.189
    CrossrefPubMedGoogle Scholar
  • 4 Rudwaleit M, Jurik AG, Hermann KG. et al. Defining active sacroiliitis on magnetic resonance imaging (MRI) for classification of axial spondyloarthritis: a consensual approach by the ASAS/OMERACT MRI group. Annals of the rheumatic diseases 2009; 68: 1520-1527. doi:10.1136/ard.2009.110767
    CrossrefPubMedGoogle Scholar
  • 5 Weber U, Jurik AG, Zejden A. et al. Frequency and Anatomic Distribution of Magnetic Resonance Imaging Features in the Sacroiliac Joints of Young Athletes: Exploring “Background Noise” Toward a Data-Driven Definition of Sacroiliitis in Early Spondyloarthritis. Arthritis Rheumatol 2018; 70: 736-745. doi:10.1002/art.40429
    CrossrefPubMedGoogle Scholar
  • 6 Agten CA, Zubler V, Zanetti M. et al. Postpartum Bone Marrow Edema at the Sacroiliac Joints May Mimic Sacroiliitis of Axial Spondyloarthritis on MRI. AJR American journal of roentgenology 2018; 211: 1306-1312. doi:10.2214/AJR.17.19404
    CrossrefPubMedGoogle Scholar
  • 7 Maksymowych WP, Wichuk S, Chiowchanwisawakit P. et al. Fat metaplasia and backfill are key intermediaries in the development of sacroiliac joint ankylosis in patients with ankylosing spondylitis. Arthritis Rheumatol 2014; 66: 2958-2967. doi:10.1002/art.38792
    CrossrefPubMedGoogle Scholar
  • 8 Chiowchanwisawakit P, Lambert RG, Conner-Spady B. et al. Focal fat lesions at vertebral corners on magnetic resonance imaging predict the development of new syndesmophytes in ankylosing spondylitis. Arthritis Rheum 2011; 63: 2215-2225 doi:10.1002/art.30393
    CrossrefPubMedGoogle Scholar
  • 9 Cruickshank B. Lesions of cartilaginous joints in ankylosing spondylitis. The Journal of pathology and bacteriology 1956; 71: 73-84
    CrossrefPubMedGoogle Scholar
  • 10 Bleil J, Maier R, Hempfing A. et al. Histomorphological and histomorphometric characteristics of zygapophyseal joint remodelling in ankylosing spondylitis. Arthritis Rheumatol 2014; DOI: 10.1002/art.38404.. doi:10.1002/art.38404
    CrossrefPubMedGoogle Scholar
  • 11 Gong Y, Zheng N, Chen SB. et al. Ten yearsʼ experience with needle biopsy in the early diagnosis of sacroiliitis. Arthritis Rheum 2012; 64: 1399-1406 doi:10.1002/art.33453
    CrossrefPubMedGoogle Scholar
  • 12 McGonagle D, Marzo-Ortega H, O'Connor P. et al. Histological assessment of the early enthesitis lesion in spondyloarthropathy. Annals of the rheumatic diseases 2002; 61: 534-537 doi:10.1136/ard.61.6.534
    CrossrefPubMedGoogle Scholar
  • 13 Bleil J, Maier R, Hempfing A. et al. Granulation Tissue Eroding the Subchondral Bone Also Promotes New Bone Formation in Ankylosing Spondylitis. Arthritis Rheumatol 2016; 68: 2456-2465. doi:10.1002/art.39715
    CrossrefPubMedGoogle Scholar
  • 14 Baraliakos X, Boehm H, Bahrami R. et al. What constitutes the fat signal detected by MRI in the spine of patients with ankylosing spondylitis? A prospective study based on biopsies obtained during planned spinal osteotomy to correct hyperkyphosis or spinal stenosis. Annals of the rheumatic diseases 2019; DOI: 10.1136/annrheumdis-2018-214983..
    CrossrefPubMedGoogle Scholar
  • 15 Benjamin M, McGonagle D. The anatomical basis for disease localisation in seronegative spondyloarthropathy at entheses and related sites. Journal of anatomy 2001; 199: 503-526
    CrossrefPubMedGoogle Scholar
  • 16 Ramiro S, Landewe R, van Tubergen A. et al. Lifestyle factors may modify the effect of disease activity on radiographic progression in patients with ankylosing spondylitis: a longitudinal analysis. RMD open 2015; 1: e000153. doi:10.1136/rmdopen-2015-000153
    CrossrefPubMedGoogle Scholar
  • 17 Brown MA, Kennedy LG, MacGregor AJ. et al. Susceptibility to ankylosing spondylitis in twins: the role of genes, HLA, and the environment. Arthritis Rheum 1997; 40: 1823-1828. doi:10.1002/1529-0131(199710)40:10<1823::AID-ART15>3.0.CO;2-1
    CrossrefPubMedGoogle Scholar
  • 18 Brewerton DA, Hart FD, Nicholls A. et al. Ankylosing spondylitis and HL-A 27. Lancet 1973; 1: 904-907
    PubMedGoogle Scholar
  • 19 Hammer RE, Maika SD, Richardson JA. et al. Spontaneous inflammatory disease in transgenic rats expressing HLA-B27 and human beta 2m: an animal model of HLA-B27-associated human disorders. Cell 1990; 63: 1099-1112
    CrossrefPubMedGoogle Scholar
  • 20 Taurog JD, Dorris ML, Satumtira N. et al. Spondylarthritis in HLA-B27/human beta2-microglobulin-transgenic rats is not prevented by lack of CD8. Arthritis Rheum 2009; 60: 1977-1984 doi:10.1002/art.24599
    CrossrefPubMedGoogle Scholar
  • 21 Colbert RA. The immunobiology of HLA-B27: variations on a theme. Current molecular medicine 2004; 4: 21-30
    CrossrefPubMedGoogle Scholar
  • 22 Kollnberger S, Bird L, Sun MY. et al. Cell-surface expression and immune receptor recognition of HLA-B27 homodimers. Arthritis Rheum 2002; 46: 2972-2982. doi:10.1002/art.10605
    CrossrefPubMedGoogle Scholar
  • 23 Mear JP, Schreiber KL, Munz C. et al. Misfolding of HLA-B27 as a result of its B pocket suggests a novel mechanism for its role in susceptibility to spondyloarthropathies. J Immunol 1999; 163: 6665-6670
    PubMedGoogle Scholar
  • 24 Wellcome Trust Case Control C, Australo-Anglo-American Spondylitis C, Burton PR. et al. Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nature genetics 2007; 39: 1329-1337. doi:10.1038/ng.2007.17
    CrossrefPubMedGoogle Scholar
  • 25 Robinson PC, Costello ME, Leo P. et al. ERAP2 is associated with ankylosing spondylitis in HLA-B27-positive and HLA-B27-negative patients. Annals of the rheumatic diseases 2015; 74: 1627-1629. doi:10.1136/annrheumdis-2015-207416
    CrossrefPubMedGoogle Scholar
  • 26 Evans DM, Spencer CC, Pointon JJ. et al. Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility. Nature genetics 2011; 43: 761-767 doi:10.1038/ng.873
    CrossrefPubMedGoogle Scholar
  • 27 Haroon N. Endoplasmic reticulum aminopeptidase 1 and interleukin-23 receptor in ankylosing spondylitis. Current rheumatology reports 2012; 14: 383-389. doi:0.1007/s11926-012-0268-0
    CrossrefPubMedGoogle Scholar
  • 28 Sarin R, Wu X, Abraham C. Inflammatory disease protective R381Q IL23 receptor polymorphism results in decreased primary CD4+ and CD8+ human T-cell functional responses. Proceedings of the National Academy of Sciences of the United States of America 2011; 108: 9560-9565 doi:10.1073/pnas.1017854108
    CrossrefPubMedGoogle Scholar
  • 29 Sun R, Hedl M, Abraham C. IL23 induces IL23R recycling and amplifies innate receptor-induced signalling and cytokines in human macrophages, and the IBD-protective IL23R R381Q variant modulates these outcomes. Gut 2019; DOI: 10.1136/gutjnl-2018-316830.
    CrossrefPubMedGoogle Scholar
  • 30 Ellinghaus D, Jostins L, Spain SL. et al. Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci. Nature genetics 2016; 48: 510-518. doi:10.1038/ng.3528
    CrossrefPubMedGoogle Scholar
  • 31 Sherlock JP, Joyce-Shaikh B, Turner SP. et al. IL-23 induces spondyloarthropathy by acting on ROR-gammat+ CD3+CD4-CD8- entheseal resident T cells. Nature medicine 2012; 18: 1069-1076. doi:10.1038/nm.2817
    CrossrefPubMedGoogle Scholar
  • 32 Hanson A, Brown MA. Genetics and the Causes of Ankylosing Spondylitis. Rheumatic diseases clinics of North America 2017; 43: 401-414. doi:10.1016/j.rdc.2017.04.006
    CrossrefPubMedGoogle Scholar
  • 33 Reinhardt A, Yevsa T, Worbs T. et al. Interleukin-23-Dependent gamma/delta T Cells Produce Interleukin-17 and Accumulate in the Enthesis, Aortic Valve, and Ciliary Body in Mice. Arthritis Rheumatol 2016; 68: 2476-2486. doi:10.1002/art.39732
    CrossrefPubMedGoogle Scholar
  • 34 Bridgewood C, Watad A, Russell T. et al. Identification of myeloid cells in the human enthesis as the main source of local IL-23 production. Annals of the rheumatic diseases 2019; DOI: 10.1136/annrheumdis-2018-214944.
    CrossrefPubMedGoogle Scholar
  • 35 Appel H, Maier R, Bleil J et al. In situ analysis of interleukin-23- and interleukin-12-positive cells in the spine of patients with ankylosing spondylitis.
    PubMed
  • 36 Arthritis Rheum. 2013; 65: 1522-1529. doi:10.1002/art.37937
    PubMed
  • 37 Conrad K, Wu P, Sieper J. et al. In vivo pre-activation of monocytes in patients with axial spondyloarthritis. Arthritis Res Ther 2015; 17: 179 doi:10.1186/s13075-015-0694-2
    CrossrefPubMedGoogle Scholar
  • 38 Fert I, Cagnard N, Glatigny S. et al. Reverse interferon signature is characteristic of antigen-presenting cells in human and rat spondyloarthritis. Arthritis Rheumatol 2014; 66: 841-851 doi:10.1002/art.38318
    PubMedGoogle Scholar
  • 39 Stolwijk C, van Tubergen A, Castillo-Ortiz JD. et al. Prevalence of extra-articular manifestations in patients with ankylosing spondylitis: a systematic review and meta-analysis. Annals of the rheumatic diseases 2013; DOI: 10.1136/annrheumdis-2013-203582.
    CrossrefPubMedGoogle Scholar
  • 40 Mielants H, Veys EM, Cuvelier C. et al. The evolution of spondyloarthropathies in relation to gut histology. II. Histological aspects. The Journal of rheumatology 1995; 22: 2273-2278
    PubMedGoogle Scholar
  • 41 Van Praet L, Van den Bosch FE, Jacques P. et al. Microscopic gut inflammation in axial spondyloarthritis: a multiparametric predictive model. Annals of the rheumatic diseases 2013; 72: 414-417 doi:10.1136/annrheumdis-2012-202135
    CrossrefPubMedGoogle Scholar
  • 42 Costello ME, Ciccia F, Willner D. et al. Brief Report: Intestinal Dysbiosis in Ankylosing Spondylitis. Arthritis Rheumatol 2015; 67: 686-691. doi:10.1002/art.38967
    PubMedGoogle Scholar
  • 43 Taurog JD, Richardson JA, Croft JT. et al. The germfree state prevents development of gut and joint inflammatory disease in HLA-B27 transgenic rats. The Journal of experimental medicine 1994; 180: 2359-2364
    CrossrefPubMedGoogle Scholar
  • 44 Gill T, Asquith M, Brooks SR. et al. Effects of HLA-B27 on Gut Microbiota in Experimental Spondyloarthritis Implicate an Ecological Model of Dysbiosis. Arthritis Rheumatol 2018; 70: 555-565. doi:10.1002/art.40405
    PubMedGoogle Scholar
  • 45 Kontoyiannis D, Pasparakis M, Pizarro TT. et al. Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut-associated immunopathologies. Immunity 1999; 10: 387-398
    CrossrefPubMedGoogle Scholar
  • 46 Legerlotz K, Jones GC, Screen HR. et al. Cyclic loading of tendon fascicles using a novel fatigue loading system increases interleukin-6 expression by tenocytes. Scandinavian journal of medicine & science in sports 2013; 23: 31-37 doi:10.1111/j.1600-0838.2011.01410.x
    CrossrefPubMedGoogle Scholar
  • 47 Mousavizadeh R, Khosravi S, Behzad H. et al. Cyclic strain alters the expression and release of angiogenic factors by human tendon cells. PLoS One 2014; 9: e97356 doi:10.1371/journal.pone.0097356
    CrossrefPubMedGoogle Scholar
  • 48 Cambre I, Gaublomme D, Burssens A. et al. Mechanical strain determines the site-specific localization of inflammation and tissue damage in arthritis. Nat Commun 2018; 9: 4613. doi:10.1038/s41467-018-06933-4
    CrossrefPubMedGoogle Scholar