Top

03-05-2015 | Ankylosing spondylitis | Review | Article

Ankylosis in ankylosing spondylitis: current concepts

Journal: Clinical Rheumatology

Author: Nigil Haroon

Publisher: Springer London

Abstract

Ankylosing spondylitis (AS) is the most common form of spondyloarthritis and is characterized by both inflammation and new bone formation. Despite many years of arduous efforts, we still do not clearly understand the pathogenesis of AS. The mechanisms behind new bone formation have been especially challenging to decipher due to the difficulty in obtaining tissue from spinal joints. The link between inflammation and bone formation looks obvious, but how inflammation drives spinal fusion is not evident. There are now two genes linked to prostaglandins (PG) that could be involved in AS pathogenesis. The first one is PTGER4 that codes for the EP4 receptor for PGE2 and the other one is PTGS1 that codes for prostaglandin-endoperoxide syntase 1 or cyclogenase 1. The bone morphogenic protein and Wnt signaling pathways could be important in signaling increased bone formation in AS. The disease-modifying potential of anti-inflammatories and tumor necrosis factor alpha inhibitors is discussed.

McGonagle D, Gibbon W, Emery P (1998) Classification of inflammatory arthritis by enthesitis. Lancet 352(9134):1137–1140CrossRefPubMed

Jacques P, Lambrecht S, Verheugen E, Pauwels E, Kollias G, Armaka M et al (2014) Proof of concept: enthesitis and new bone formation in spondyloarthritis are driven by mechanical strain and stromal cells. Ann Rheum Dis 73(2):437–445CrossRefPubMed

Carette S, Graham D, Little H, Rubenstein J, Rosen P (1983) The natural disease course of ankylosing spondylitis. Arthritis Rheum 26(2):186–190CrossRefPubMed

Haroon N, Inman RD, Learch TJ, Weisman MH, Lee M, Rahbar MH et al (2013) The impact of tumor necrosis factor alpha inhibitors on radiographic progression in ankylosing spondylitis. Arthritis Rheum 65(10):2645–2654PubMedCentralPubMed

Baraliakos X, Listing J, von der Recke A, Braun J (2009) The natural course of radiographic progression in ankylosing spondylitis–evidence for major individual variations in a large proportion of patients. J Rheumatol 36(5):997–1002CrossRefPubMed

Ramiro S, Stolwijk C, van Tubergen A, van der Heijde D, Dougados M, van den Bosch F, et al. Evolution of radiographic damage in ankylosing spondylitis: a 12 year prospective follow-up of the OASIS study. Annals of the Rheumatic Diseases 2013 Aug 16.

van Tubergen A, Coenen J, Landewe R, Spoorenberg A, Chorus A, Boonen A et al (2002) Assessment of fatigue in patients with ankylosing spondylitis: a psychometric analysis. Arthritis Rheum 47(1):8–16CrossRefPubMed

Rezvani A, Bodur H, Ataman S, Kaya T, Bugdayci DS, Demir SE et al (2014) Correlations among enthesitis, clinical, radiographic and quality of life parameters in patients with ankylosing spondylitis. Modern Rheumatol / Jap Rheumat Assoc 24(4):651–656CrossRef

Fabreguet I, Koumakis E, Burki V, Durnez A, Elhai M, Meyer M (2012) Assessment of work instability in spondyloarthritis: a cross-sectional study using the ankylosing spondylitis work instability scale. Rheumatology (Oxford, England) 51(2):333–337CrossRef

10.

Calvo-Gutierrez J, Garrido-Castro JL, Gil-Cabezas J, Gonzalez-Navas C, Ugalde PF, Carmona L et al (2015) Is spinal mobility in patients with spondylitis determined by age, structural damage, and inflammation? Arthr Care Res 67(1):74–79CrossRef

11.

Landewe R, Dougados M, Mielants H, van der Tempel H, van der Heijde D (2009) Physical function in ankylosing spondylitis is independently determined by both disease activity and radiographic damage of the spine. Ann Rheum Dis 68(6):863–867CrossRefPubMed

12.

Poddubnyy D, Haibel H, Listing J, Marker-Hermann E, Zeidler H, Braun J et al (2012) Baseline radiographic damage, elevated acute-phase reactant levels, and cigarette smoking status predict spinal radiographic progression in early axial spondylarthritis. Arthritis Rheum 64(5):1388–1398CrossRefPubMed

13.

Ramiro S, van der Heijde D, van Tubergen A, Stolwijk C, Dougados M, van den Bosch F et al (2014) Higher disease activity leads to more structural damage in the spine in ankylosing spondylitis: 12-year longitudinal data from the OASIS cohort. Ann Rheum Dis 7

14.

The Australo-Anglo-American Spondyloarthritis Consortium (TASC), the Wellcome Trust Case Control Consortium 2 (WTCCC2), The Australo-Anglo-American Spondyloarthritis Consortium (TASC), the Wellcome Trust Case Control Consortium 2 (WTCCC2), Evans DM, Spencer CC, Pointon JJ, Su Z (2011) Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility. Nat Genet 43(8):761–767CrossRef

15.

Australo-Anglo-American Spondyloarthritis Consortium (TASC), Reveille JD, Sims AM, Danoy P, Evans DM, Leo P, et al. Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci. Nat Genet 2010 Feb;42(2):123–127

16.

Chen C, Zhang X, Wang Y (2012) ANTXR2 and IL-1R2 polymorphisms are not associated with ankylosing spondylitis in Chinese Han population. Rheumatol Int 32(1):15–19CrossRefPubMed

17.

Guo C, Xia Y, Yang Q, Qiu R, Zhao H, Liu Q (2012) Association of the ANTXR2 gene polymorphism and ankylosing spondylitis in Chinese Han. Scand J Rheumatol 41(1):29–32CrossRefPubMed

18.

Xia Y, Chen K, Zhang MH, Wang LC, Ma CY, Lin YL et al (2015) MicroRNA-124 involves in ankylosing spondylitis by targeting ANTXR2. Modern Rheumatol / Jap Rheumat Assoc 4:1–24

19.

Nollet M, Santucci-Darmanin S, Breuil V, Al-Sahlanee R, Cros C, Topi M et al (2014) Autophagy in osteoblasts is involved in mineralization and bone homeostasis. Autophagy 10(11):1965–1977CrossRefPubMed

20.

Alander CB, Raisz LG (2006) Effects of selective prostaglandins E2 receptor agonists on cultured calvarial murine osteoblastic cells. Prostagland lipid Mediat 81(3–4):178–183CrossRef

21.

Mano M, Arakawa T, Mano H, Nakagawa M, Kaneda T, Kaneko H et al (2000) Prostaglandin E2 directly inhibits bone-resorbing activity of isolated mature osteoclasts mainly through the EP4 receptor. Calcif Tissue Int 67(1):85–92CrossRefPubMed

22.

Namikawa T, Terai H, Hoshino M, Kato M, Toyoda H, Yano K et al (2007) Enhancing effects of a prostaglandin EP4 receptor agonist on recombinant human bone morphogenetic protein-2 mediated spine fusion in a rabbit model. Spine 32(21):2294–2299CrossRefPubMed

23.

Simon AM, Manigrasso MB, O’Connor JP (2002) Cyclo-oxygenase 2 function is essential for bone fracture healing. J Bone Mineral Res : Off J Am Soc Bone Mineral Res 17(6):963–976CrossRef

24.

Xie C, Liang B, Xue M, Lin AS, Loiselle A, Schwarz EM et al (2009) Rescue of impaired fracture healing in COX-2−/− mice via activation of prostaglandin E2 receptor subtype 4. Am J Pathol 175(2):772–785CrossRefPubMedCentralPubMed

25.

Haroon N, Kim TH, Inman RD. NSAIDs and radiographic progression in ankylosing spondylitis Bagging big game with small arms? Annals of the Rheumatic Diseases 2012 Aug 3

26.

Cortes A, Maksymowych WP, Wordsworth BP, Inman RD, Danoy P, Rahman P, et al. Association study of genes related to bone formation and resorption and the extent of radiographic change in ankylosing spondylitis. Annals of the Rheumatic Diseases 2014 Apr 10

27.

Qian BP, Wang XQ, Qiu Y, Jiang J, Ji ML, Feng F (2014) Association of receptor activator of nuclear factor-kappaB ligand (RANKL) gene polymorphisms with the susceptibility to ankylosing spondylitis: a case–control study. J Orthop Sci : Off J Jap Orthop Assoc 19(2):207–212CrossRef

28.

Klingberg E, Nurkkala M, Carlsten H, Forsblad-d’Elia H (2014) Biomarkers of bone metabolism in ankylosing spondylitis in relation to osteoproliferation and osteoporosis. J Rheumatol 41(7):1349–1356CrossRefPubMed

29.

Lin Z, Bei JX, Shen M, Li Q, Liao Z, Zhang Y et al (2011) A genome-wide association study in Han Chinese identifies new susceptibility loci for ankylosing spondylitis. Nat Genet 44(1):73–77CrossRefPubMed

30.

Urano T, Narusawa K, Shiraki M, Sasaki N, Hosoi T, Ouchi Y et al (2011) Single-nucleotide polymorphism in the hyaluronan and proteoglycan link protein 1 (HAPLN1) gene is associated with spinal osteophyte formation and disc degeneration in Japanese women. European Spine J : Off Public Europ Spine Soc, Europ Spinal Deform Soc, Europ Sec Cerv Spine Res Soc 20(4):572–577CrossRef

31.

Wang Z, Kundu RK, Longaker MT, Quertermous T, Yang GP (2012) The angiogenic factor Del1 prevents apoptosis of endothelial cells through integrin binding. Surgery 151(2):296–305CrossRefPubMed

32.

Takai A, Inomata H, Arakawa A, Yakura R, Matsuo-Takasaki M, Sasai Y (2010) Anterior neural development requires Del1, a matrix-associated protein that attenuates canonical Wnt signaling via the Ror2 pathway. Development (Cambridge, England) 137(19):3293–3302CrossRef

33.

Haroon N, Maksymowych W, Rahman P, Tsui F, O’Shea F, Inman R. Radiographic severity in ankylosing spondylitis is associated with polymorphism in large multifunctional peptidase 2 (LMP2) in the SPARCC cohort. Arthritis and Rheumatism 2011 Oct 27

34.

Diarra D, Stolina M, Polzer K, Zwerina J, Ominsky MS, Dwyer D et al (2007) Dickkopf-1 is a master regulator of joint remodeling. Nat Med 13(2):156–163CrossRefPubMed

35.

Uderhardt S, Diarra D, Katzenbeisser J, David JP, Zwerina J, Richards W et al (2010) Blockade of Dickkopf (DKK)-1 induces fusion of sacroiliac joints. Ann Rheum Dis 69(3):592–597CrossRefPubMed

36.

Daoussis D, Liossis SN, Solomou EE, Tsanaktsi A, Bounia K, Karampetsou M et al (2010) Evidence that Dkk-1 is dysfunctional in ankylosing spondylitis. Arthritis Rheum 62(1):150–158CrossRefPubMed

37.

Heiland GR, Appel H, Poddubnyy D, Zwerina J, Hueber A, Haibel H et al (2012) High level of functional dickkopf-1 predicts protection from syndesmophyte formation in patients with ankylosing spondylitis. Ann Rheum Dis 71(4):572–574CrossRefPubMed

38.

Chen MH, Chen HA, Chen WS, Chen MH, Tsai CY, Chou CT (2015) Upregulation of BMP-2 expression in peripheral-blood mononuclear cells by proinflammatory cytokines and radiographic progression in ankylosing spondylitis. Modern Rheumatol / Jap Rheumat Assoc 2:1–22

39.

Chen HA, Chen CH, Lin YJ, Chen PC, Chen WS, Lu CL et al (2010) Association of bone morphogenetic proteins with spinal fusion in ankylosing spondylitis. J Rheumatol 37(10):2126–2132CrossRefPubMed

40.

Lories RJ, Derese I, Luyten FP (2005) Modulation of bone morphogenetic protein signaling inhibits the onset and progression of ankylosing enthesitis. J Clin Invest 115(6):1571–1579CrossRefPubMedCentralPubMed

41.

Kiltz U, van der Heijde D, Mielants H, Feldtkeller E, Braun J, PARE/EULAR patient initiative group (2009) ASAS/EULAR recommendations for the management of ankylosing spondylitis: the patient version. Ann Rheum Dis 68(9):1381–1386CrossRefPubMed

42.

Rohekar S, Chan J, Tse SM, Haroon N, Chandran V, Bessette L et al (2015) 2014 update of the Canadian rheumatology association/spondyloarthritis research consortium of Canada treatment recommendations for the management of spondyloarthritis. part II: specific management recommendations. J Rheumatol 42(4):665–681CrossRefPubMed

43.

Wanders A, Heijde D, Landewe R, Behier JM, Calin A, Olivieri I et al (2005) Nonsteroidal antiinflammatory drugs reduce radiographic progression in patients with ankylosing spondylitis: a randomized clinical trial. Arthritis Rheum 52(6):1756–1765CrossRefPubMed

44.

Kroon F, Landewe R, Dougados M, van der Heijde D (2012) Continuous NSAID use reverts the effects of inflammation on radiographic progression in patients with ankylosing spondylitis. Ann Rheum Dis 5

45.

Poddubnyy D, Rudwaleit M, Haibel H, Listing J, Marker-Hermann E, Zeidler H et al (2012) Effect of non-steroidal anti-inflammatory drugs on radiographic spinal progression in patients with axial spondyloarthritis: results from the German Spondyloarthritis Inception Cohort. Ann Rheum Dis 29

46.

Spiro AS, Beil FT, Baranowsky A, Barvencik F, Schilling AF, Nguyen K et al (2010) BMP-7-induced ectopic bone formation and fracture healing is impaired by systemic NSAID application in C57BL/6-mice. J Orthop Res : Off Public Orthop Res Soc 28(6):785–791

47.

Li Q, Zhang Z, Cai Z (2011) High-dose ketorolac affects adult spinal fusion: a meta-analysis of the effect of perioperative nonsteroidal anti-inflammatory drugs on spinal fusion. Spine 36(7):E461–E468CrossRefPubMed

48.

Herbenick MA, Sprott D, Stills H, Lawless M (2008) Effects of a cyclooxygenase 2 inhibitor on fracture healing in a rat model. Am J Orthop (Belle Mead, NJ) 37(7):E133–E137

49.

Reuben SS, Ablett D, Kaye R (2005) High dose nonsteroidal anti-inflammatory drugs compromise spinal fusion. Canadian journal of anaesthesia =. J Can d’anesthesie 52(5):506–512CrossRef

50.

Romano CL, Duci D, Romano D, Mazza M, Meani E (2004) Celecoxib versus indomethacin in the prevention of heterotopic ossification after total hip arthroplasty. J Arthroplast 19(1):14–18CrossRef

51.

Welting TJ, Caron MM, Emans PJ, Janssen MP, Sanen K, Coolsen MM et al (2011) Inhibition of cyclooxygenase-2 impacts chondrocyte hypertrophic differentiation during endochondral ossification. Europ Cells Mat 22:420–436, discussion 436–7

52.

Baraliakos X, Listing J, Rudwaleit M, Brandt J, Sieper J, Braun J (2005) Radiographic progression in patients with ankylosing spondylitis after 2 years of treatment with the tumour necrosis factor alpha antibody infliximab. Ann Rheum Dis 64(10):1462–1466CrossRefPubMedCentralPubMed

53.

Baraliakos X, Listing J, Brandt J, Haibel H, Rudwaleit M, Sieper J (2007) Radiographic progression in patients with ankylosing spondylitis after 4 yrs of treatment with the anti-TNF-alpha antibody infliximab. Rheumatology (Oxford, England) 46(9):1450–1453CrossRef

54.

van der Heijde D, Landewe R, Baraliakos X, Houben H, van Tubergen A, Williamson P et al (2008) Radiographic findings following two years of infliximab therapy in patients with ankylosing spondylitis. Arthritis Rheum 58(10):3063–3070CrossRefPubMed

55.

van der Heijde D, Salonen D, Weissman BN, Landewe R, Maksymowych WP, Kupper H et al (2009) Assessment of radiographic progression in the spines of patients with ankylosing spondylitis treated with adalimumab for up to 2 years. Arth Res Therap 11(4):R127CrossRef

56.

Baraliakos X, Haibel H, Listing J, Sieper J, Braun J (2013) Continuous long-term anti-TNF therapy does not lead to an increase in the rate of new bone formation over 8 years in patients with ankylosing spondylitis. Ann Rheum Dis 27

Medicine Matters Rheumatology

Abstract