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Ankylosis in ankylosing spondylitis: current concepts

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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.

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References

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

    Article  CAS  PubMed  Google Scholar 

  2. 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):437–445

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  4. 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):2645–2654

    PubMed Central  CAS  PubMed  Google Scholar 

  5. 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):997–1002

    Article  PubMed  Google Scholar 

  6. 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.

  7. 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):8–16

    Article  PubMed  Google Scholar 

  8. 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):651–656

    Article  Google Scholar 

  9. 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):333–337

    Article  Google Scholar 

  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):74–79

    Article  Google Scholar 

  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):863–867

    Article  CAS  PubMed  Google Scholar 

  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):1388–1398

    Article  PubMed  Google Scholar 

  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):761–767

    Article  Google Scholar 

  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):15–19

    Article  PubMed  Google Scholar 

  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):29–32

    Article  CAS  PubMed  Google Scholar 

  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

    CAS  Google Scholar 

  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):1965–1977

    Article  CAS  PubMed  Google Scholar 

  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):178–183

    Article  CAS  Google Scholar 

  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):85–92

    Article  CAS  PubMed  Google Scholar 

  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):2294–2299

    Article  PubMed  Google Scholar 

  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):963–976

    Article  CAS  Google Scholar 

  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):772–785

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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):207–212

    Article  CAS  Google Scholar 

  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):1349–1356

    Article  PubMed  Google Scholar 

  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):73–77

    Article  PubMed  Google Scholar 

  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):572–577

    Article  Google Scholar 

  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):296–305

    Article  PubMed  Google Scholar 

  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):3293–3302

    Article  CAS  Google Scholar 

  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):156–163

    Article  CAS  PubMed  Google Scholar 

  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):592–597

    Article  CAS  PubMed  Google Scholar 

  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):150–158

    Article  CAS  PubMed  Google Scholar 

  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):572–574

    Article  CAS  PubMed  Google Scholar 

  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

    CAS  Google Scholar 

  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):2126–2132

    Article  CAS  PubMed  Google Scholar 

  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):1571–1579

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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):1381–1386

    Article  CAS  PubMed  Google Scholar 

  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):665–681

    Article  PubMed  Google Scholar 

  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):1756–1765

    Article  CAS  PubMed  Google Scholar 

  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

    CAS  Google Scholar 

  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–E468

    Article  PubMed  Google Scholar 

  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

    Google Scholar 

  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):506–512

    Article  Google Scholar 

  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):14–18

    Article  Google Scholar 

  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

    CAS  Google Scholar 

  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):1462–1466

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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):1450–1453

    Article  CAS  Google Scholar 

  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):3063–3070

    Article  PubMed  Google Scholar 

  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):R127

    Article  Google Scholar 

  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

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Haroon, N. Ankylosis in ankylosing spondylitis: current concepts. Clin Rheumatol 34, 1003–1007 (2015). https://doi.org/10.1007/s10067-015-2956-4

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