Axial Spondyloarthritis and New Bone Formation

Abstract

Axial spondyloarthritis is an inflammatory disease of the axial skeleton. Its pathogenesis is only partly understood. At the beginning, there are inflammatory changes in the sacroiliac joints which are followed by inflammation in vertebral bodies and in facet joints. Low back pain occurring in the morning hours is the dominant clinical symptom. In the early phase, inflammatory changes are detectably by MRI. Inflammation promotes a process of joint remodelling in the sacroiliac joints which leads to erosions, sclerosis and bony bridging, i. e. ankylosis, which are detectable by X-ray. In the spine, vertical osteophytes developing at sites of previous inflammation connect vertebral bodies as syndesmophytes. Additional ossification of longitudinal ligaments contributes to the so-called bamboo spine. Ossification of the spine promotes fixation of a severe kyphosis of the thoracic spine which strongly impairs spine mobility and quality of life. High disease activity seems a prominent risk factor for development of structural damage. However, although NSAIDs improve clinical symptoms, they do not reduce new bone formation. In contrast, TNFα and IL-17 inhibitors seem to retard new bone formation apart from their clinical efficacy. Research work of the last years identified immunological pathways of inflammation. However, the trigger and cellular components of the immune reaction in the bone marrow are still poorly defined. Osteoclasts are involved in the destruction of the subchondral bone, while osteoblasts facilitate new bone formation and cartilage ossification. This review gives an overview about diagnostics and therapy of axSpA and about risk factors for the development of structural damage. Concepts about the immune pathogenesis and joint remodeling in AS are given under recognition of genetic and histopathological studies.

Zusammenfassung

Die axiale Spondyoarthritis ist eine entzündliche Erkrankung des Achsenskeletts, deren Pathogenese nach wie vor nur in Ansätzen verstanden ist. Initial finden sich entzündliche Veränderungen in den Sakroiliakalgelenken, im weiteren Verlauf kommt es zu Entzündungen in den Wirbelkörpern und im Bereich der Facettengelenke. Klinisch im Vordergrund stehen morgentlich auftretende, tiefsitzende Rückenschmerzen. Die entzündlichen Veränderungen sind in der Frühphase der Erkrankung im MRT nachweisbar. Durch die Entzündung wird ein Gelenkumbau in den Sakroiliakalgelenken initiiert, der Erosionen, Sklerosierungen und knöcherne Durchbauungen, d. h. Ankylosen, nach sich zieht, die radiologisch darstellbar sind. Im Bereich der Wirbelsäule bilden sich an entzündeten Wirbelkörperkanten vertikale Osteophyten, die als Syndesmophyten zur knöchernen Verbindung von Wirbelkörpern führen. Außerdem kommt es zur Ossifikation der Längsbänder, was zum Vollbild der sog. Bambuswirbelsäule beiträgt. Die Knochenneubildung und Ossifikation im Bereich der Wirbelsäule mit Fixierung einer oft ausgeprägten Brustkyphose führt zu einer erheblichen Einschränkung der Wirbelsäulenbeweglichkeit und Beeinträchtigung der Lebensqualität. Eine hohe Krankheitsaktivität scheint ein wesentlicher Risikofaktor für die Entwicklung dieser strukturellen Schäden zu sein. Allerdings haben NSAR trotz Besserung der klinischen Beschwerdensymptomatik keinen hemmenden Einfluss auf die Knochenneubildung. TNFα-und IL-17-Inhibitoren scheinen neben der guten klinischen Wirksamkeit auch die Knochenneubildung zu verzögern. Forschungen der letzten Jahre konnten immunologische Signalwege der Entzündung identifizieren, wobei die Trigger und zellulären Komponenten der Immunreaktion im Knochenmark noch unverstanden sind. Osteoklasten sind an der Destruktion von subchondralem Knochen beteiligt, während Osteoblasten Knochenneubildung und Knorpelossifikation vermitteln. Dieser Beitrag gibt einen Überblick über Diagnostik und Therapie der axSpA sowie Risikofaktoren für die Entwicklung struktureller Schäden. Es werden Konzepte der Immunpathogenese und des Gelenkumbaus bei der AS unter Einbeziehung genetischer und histopathologischer Studien dargestellt.

Key words

axial spondyloarthritis - ankylosing spondylitis - radiographic progression - new bone formation

Schlüsselwörter

axiale Spondyloarthritis - ankylosierende Spondylitis - radiographische Progression - Knochenneubildung

Publication History

Received: 09 July 2021

Accepted: 25 August 2021

Article published online:
18 November 2021

• References

• 1 Taurog JD, Chhabra A, Colbert RA. Ankylosing Spondylitis and Axial Spondyloarthritis. The New England journal of medicine 2016; 374: 2563-2574
• 2 Garg N, van den Bosch F, Deodhar A. The concept of spondyloarthritis: where are we now?. Best practice & research Clinical rheumatology 2014; 28: 663-672
• 3 Brewerton DA, Hart FD, Nicholls A. et al Ankylosing spondylitis and HL-A 27. Lancet 1973; 1: 904-907
• 4 Oostveen J, Prevo R, den Boer J. et al Early detection of sacroiliitis on magnetic resonance imaging and subsequent development of sacroiliitis on plain radiography. A prospective, longitudinal study. The Journal of rheumatology 1999; 26: 1953-1958
• 5 Rudwaleit M, Haibel H, Baraliakos X. et al The early disease stage in axial spondylarthritis: results from the German Spondyloarthritis Inception Cohort. Arthritis Rheum 2009; 60: 717-727
• 6 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
• 7 Renson T, Depicker A, De Craemer AS. et al High prevalence of spondyloarthritis-like MRI lesions in postpartum women: a prospective analysis in relation to maternal, child and birth characteristics. Annals of the rheumatic diseases 2020; 79: 929-934
• 8 Baraliakos X, Richter A, Feldmann D. et al Frequency of MRI changes suggestive of axial spondyloarthritis in the axial skeleton in a large population-based cohort of individuals aged<45 years. Annals of the rheumatic diseases 2020; 79: 186-192
• 9 Kiltz U, Braun J. Dgrh et al. Long version on the S3 guidelines for axial spondyloarthritis including Bechterew's disease and early forms, Update 2019 : Evidence-based guidelines of the German Society for Rheumatology (DGRh) and participating medical scientific specialist societies and other organizations. Zeitschrift fur Rheumatologie 2019; 78: 3-64
• 10 Sieper J, Poddubnyy D. Axial spondyloarthritis. Lancet 2017; 390: 73-84
• 11 van der Heijde D, Song IH, Pangan AL. et al Efficacy and safety of upadacitinib in patients with active ankylosing spondylitis (SELECT-AXIS 1): a multicentre, randomised, double-blind, placebo-controlled, phase 2/3 trial. Lancet 2019; 394: 2108-2117
• 12 Vosse D, van der Heijde D, Landewe R. et al Determinants of hyperkyphosis in patients with ankylosing spondylitis. Annals of the rheumatic diseases 2006; 65: 770-774
• 13 Ramiro S, Stolwijk C, van Tubergen A. et al Evolution of radiographic damage in ankylosing spondylitis: a 12 year prospective follow-up of the OASIS study. Annals of the rheumatic diseases 2015; 74: 52-59
• 14 Dougados M, Sepriano A, Molto A. et al Sacroiliac radiographic progression in recent onset axial spondyloarthritis: the 5-year data of the DESIR cohort. Annals of the rheumatic diseases 2017; 76: 1823-1828
• 15 Poddubnyy D, Rudwaleit M, Haibel H. et al Rates and predictors of radiographic sacroiliitis progression over 2 years in patients with axial spondyloarthritis. Annals of the rheumatic diseases 2011; 70: 1369-1374
• 16 Cortes A, Maksymowych WP, Wordsworth BP. et al Association study of genes related to bone formation and resorption and the extent of radiographic change in ankylosing spondylitis. Ann Rheum Dis. 2015; 74: 1387-93. doi: 10.1136/annrheumdis-2013-204835
• 17 Molnar C, Scherer A, Baraliakos X. et al TNF blockers inhibit spinal radiographic progression in ankylosing spondylitis by reducing disease activity: results from the Swiss Clinical Quality Management cohort. Annals of the rheumatic diseases 2018; 77: 63-69
• 18 Maas F, Arends S, Brouwer E. et al Reduction in Spinal Radiographic Progression in Ankylosing Spondylitis Patients Receiving Prolonged Treatment With Tumor Necrosis Factor Inhibitors. Arthritis care & research 2017; 69: 1011-1019
• 19 Braun J, Baraliakos X, Deodhar A. et al Secukinumab shows sustained efficacy and low structural progression in ankylosing spondylitis: 4-year results from the MEASURE 1 study. Rheumatology (Oxford) 2019; 58: 859-868
• 20 Australo-Anglo-American Spondyloarthritis C. Reveille JD, Sims AM. et al Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci. Nature genetics 2010; 42: 123-127
• 21 Cortes A, Hadler J, Pointon JP. et al Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci. Nature genetics 2013; 45: 730-738
• 22 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
• 23 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
• 24 Cruickshank B. Histopathology of diarthrodial joints in ankylosing spondylitis. Annals of the rheumatic diseases 1951; 10: 393-404
• 25 Francois RJ, Neure L, Sieper J. et al Immunohistological examination of open sacroiliac biopsies of patients with ankylosing spondylitis: detection of tumour necrosis factor alpha in two patients with early disease and transforming growth factor beta in three more advanced cases. Annals of the rheumatic diseases 2006; 65: 713-720
• 26 Maas F, Spoorenberg A, Brouwer E. et al Radiographic damage and progression of the cervical spine in ankylosing spondylitis patients treated with TNF-alpha inhibitors: Facet joints vs. vertebral bodies. Seminars in arthritis and rheumatism 2017; 46: 562-568
• 27 Bleil J, Maier R, Hempfing A. et al Histomorphological and histomorphometric characteristics of zygapophyseal joint remodelling in ankylosing spondylitis. Arthritis Rheumatol 2014; 66: 1745–54. doi:10.1002/art.38404
• 28 Gong Y, Zheng N, Chen SB. et al Ten years’ experience with needle biopsy in the early diagnosis of sacroiliitis. Arthritis Rheum 2012; 64: 1399-1406
• 29 Bleil J, Sieper J, Maier R. et al Cartilage in facet joints of patients with ankylosing spondylitis (AS) shows signs of cartilage degeneration rather than chondrocyte hypertrophy: implications for joint remodeling in AS. Arthritis Res Ther 2015; 17: 170
• 30 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
• 31 Cruickshank B. Lesions of cartilaginous joints in ankylosing spondylitis. The Journal of pathology and bacteriology 1956; 71: 73-84
• 32 Francois RJ, Gardner DL, Degrave EJ. et al Histopathologic evidence that sacroiliitis in ankylosing spondylitis is not merely enthesitis. Arthritis Rheum 2000; 43: 2011-2024
• 33 Francois RJ. Some pathological features of ankylosing spondylitis as revealed by microradiography and tetracycline labelling. Clinical rheumatology 1982; 1: 23-29
• 34 Braun J, Bollow M, Neure L. et al Use of immunohistologic and in situ hybridization techniques in the examination of sacroiliac joint biopsy specimens from patients with ankylosing spondylitis. Arthritis Rheum 1995; 38: 499-505
• 35 Menegatti S, Guillemot V, Latis E et al. Immune response profiling of patients with spondyloarthritis reveals signalling networks mediating TNF-blocker function in vivo. Ann Rheum Dis. 2020; 80: 475–86. doi: 10.1136/annrheumdis-2020-218304
• 36 van der Heijde D, Baraliakos X, Hermann KA. et al Limited radiographic progression and sustained reductions in MRI inflammation in patients with axial spondyloarthritis: 4-year imaging outcomes from the RAPID-axSpA phase III randomised trial. Annals of the rheumatic diseases 2018; 77: 699-705
• 37 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. Arthritis Rheum 2013; 65: 1522-1529
• 38 Bleil J, Maier R, Syrbe U. et al In situ analysis of interleukin-6 expression at different sites of zygapophyseal joints from patients with ankylosing spondylitis in comparison to controls. Scand J Rheumatol. 2015; 44: 296–301. doi: 10.3109/03009742.2014.1000371
• 39 Ono T, Okamoto K, Nakashima T. et al IL-17-producing gammadelta T cells enhance bone regeneration. Nat Commun 2016; 7: 10928
• 40 Mielants H, Veys EM, Cuvelier C. et al Ileocolonoscopic findings in seronegative spondylarthropathies. British journal of rheumatology 1988; 27: 95-105
• 41 Regan-Komito D, Swann JW, Demetriou P. et al GM-CSF drives dysregulated hematopoietic stem cell activity and pathogenic extramedullary myelopoiesis in experimental spondyloarthritis. Nat Commun 2020; 11: 155