Risk factors for cervical spine instability in patients with rheumatoid arthritis

Abstract

Introduction

Cervical spine (C-spine) instability is a unique and significant characteristic of rheumatoid arthritis (RA) because its occurrence is not rare and it can cause compressive cervical myelopathy, which may lead to serious neurologic sequelae. This study evaluated the prevalence and risk factors of C-spine instabilities in RA patients with a focus on anti-citrullinated protein antibody (ACPA) and biologic disease-modifying antirheumatic drug (DMARD) therapies.

Methods

The presence of C-spine instabilities in 1114 patients with RA was evaluated using C-spine radiographies according to the defined metrics. Multivariable logistic regression analyses were performed to identify independent predictors of C-spine instability. The initiation of biologic DMARDs was assessed via a Kaplan–Meier analysis and compared using log-rank tests.

Results

In total, 306 (27.5%) patients presented with C-spine instabilities. The most common type was atlantoaxial subluxation (AAS; n = 199 [17.9%]). Male sex, positivity for rheumatoid factor and ACPA, erosive change in the peripheral joints, and presence of osteoporosis were independently associated with C-spine instabilities (all P < 0.05). In particular, positivity for ACPA was the most powerful risk factor (odds ratio: 2.33 [95% confidence interval: 1.37, 3.96], P = 0.002), and it was closely associated with AAS. Patients with AAS were at a higher risk for early initiation of biologic DMARDs.

Conclusions

Positivity for ACPA was a significant risk factor for C-spine instability, and AAS was remarkably correlated to the early initiation of biologic DMARDs, a surrogate index of poor long-term outcomes.

Key Points
The presence of antibodies against citrullinated proteins was a strong risk factor for C-spine instability in patients with rheumatoid arthritis.
Atlantoaxial subluxation was significantly associated with early initiation of biologic DMARDs, a surrogate index of poor long-term outcome.

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References

  1. 1.

    Smolen JS, Aletaha D, Barton A, Burmester GR, Emery P, Firestein GS, Kavanaugh A, McInnes IB, Solomon DH, Strand V, Yamamoto K (2018) Rheumatoid arthritis. Nat Rev Dis Primers 4:18001. https://doi.org/10.1038/nrdp.2018.1

    Article  PubMed  Google Scholar 

  2. 2.

    Rawlins BA, Girardi FP, Boachie-Adjei O (1998) Rheumatoid arthritis of the cervical spine. Rheum Dis Clin N Am 24:55–65. https://doi.org/10.1016/s0889-857x(05)70377-x

    CAS  Article  Google Scholar 

  3. 3.

    Neva MH, Kaarela K, Kauppi M (2000) Prevalence of radiological changes in the cervical spine--a cross sectional study after 20 years from presentation of rheumatoid arthritis. J Rheumatol 27:90–93

    CAS  PubMed  Google Scholar 

  4. 4.

    Fujiwara K, Owaki H, Fujimoto M, Yonenobu K, Ochi T (2000) A long-term follow-up study of cervical lesions in rheumatoid arthritis. J Spinal Disord 13:519–526. https://doi.org/10.1097/00002517-200012000-00010

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Zikou AK, Alamanos Y, Argyropoulou MI, Tsifetaki N, Tsampoulas C, Voulgari PV, Efremidis SC, Drosos AA (2005) Radiological cervical spine involvement in patients with rheumatoid arthritis: a cross sectional study. J Rheumatol 32:801–806

    PubMed  Google Scholar 

  6. 6.

    Ahn JK, Hwang JW, Oh JM, Lee J, Lee YS, Jeon CH, Cha HS, Koh EM (2011) Risk factors for development and progression of atlantoaxial subluxation in Korean patients with rheumatoid arthritis. Rheumatol Int 31:1363–1368. https://doi.org/10.1007/s00296-010-1437-y

    Article  PubMed  Google Scholar 

  7. 7.

    Blom M, Creemers MC, Kievit W, Lemmens JA, van Riel PL (2013) Long-term follow-up of the cervical spine with conventional radiographs in patients with rheumatoid arthritis. Scand J Rheumatol 42:281–288. https://doi.org/10.3109/03009742.2012.747625

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Han MH, Ryu JI, Kim CH, Kim JM, Cheong JH, Bak KH, Chun HJ, Yi HJ, Jun JB, Chung JW (2017) Factors that predict risk of cervical instability in rheumatoid arthritis patients. Spine (Phila Pa 1976) 42:966–973. https://doi.org/10.1097/brs.0000000000001942

    Article  Google Scholar 

  9. 9.

    Han MH, Ryu JI, Kim CH, Kim JM, Cheong JH, Bak KH, Chun HJ (2017) Influence of systemic bone mineral density on atlantoaxial subluxation in patients with rheumatoid arthritis. Osteoporos Int 28:1931–1938. https://doi.org/10.1007/s00198-017-3972-9

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Terashima Y, Yurube T, Hirata H, Sugiyama D, Sumi M (2017) Predictive risk factors of cervical spine instabilities in rheumatoid arthritis: a prospective multicenter over 10-year cohort study. Spine (Phila Pa 1976) 42:556–564. https://doi.org/10.1097/brs.0000000000001853

    Article  Google Scholar 

  11. 11.

    Kaito T, Ohshima S, Fujiwara H, Makino T, Yonenobu K, Yoshikawa H (2017) Incidence and risk factors for cervical lesions in patients with rheumatoid arthritis under the current pharmacologic treatment paradigm. Mod Rheumatol 27:593–597. https://doi.org/10.1080/14397595.2016.1253649

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Joaquim AF, Appenzeller S (2014) Cervical spine involvement in rheumatoid arthritis--a systematic review. Autoimmun Rev 13:1195–1202. https://doi.org/10.1016/j.autrev.2014.08.014

    Article  PubMed  Google Scholar 

  13. 13.

    Smith PH, Sharp J, Kellgren JH (1972) Natural history of rheumatoid cervical subluxations. Ann Rheum Dis 31:222–223. https://doi.org/10.1136/ard.31.3.222-b

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Neva MH, Isomäki P, Hannonen P, Kauppi M, Krishnan E, Sokka T (2003) Early and extensive erosiveness in peripheral joints predicts atlantoaxial subluxations in patients with rheumatoid arthritis. Arthritis Rheum 48:1808–1813. https://doi.org/10.1002/art.11086

    Article  PubMed  Google Scholar 

  15. 15.

    Neogi T, Aletaha D, Silman AJ, Naden RL, Felson DT, Aggarwal R, Bingham CO, 3rd, Birnbaum NS, Burmester GR, Bykerk VP, Cohen MD, Combe B, Costenbader KH, Dougados M, Emery P, Ferraccioli G, Hazes JM, Hobbs K, Huizinga TW, Kavanaugh A, Kay J, Khanna D, Kvien TK, Laing T, Liao K, Mease P, Menard HA, Moreland LW, Nair R, Pincus T, Ringold S, Smolen JS, Stanislawska-Biernat E, Symmons D, Tak PP, Upchurch KS, Vencovsky J, Wolfe F, Hawker G (2010) The 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for rheumatoid arthritis: Phase 2 methodological report. Arthritis Rheum 62:2582–2591. doi:https://doi.org/10.1002/art.27580

  16. 16.

    Kroot EJ, de Jong BA, van Leeuwen MA, Swinkels H, van den Hoogen FH, van't Hof M, van de Putte LB, van Rijswijk MH, van Venrooij WJ, van Riel PL (2000) The prognostic value of anti-cyclic citrullinated peptide antibody in patients with recent-onset rheumatoid arthritis. Arthritis Rheum 43:1831–1835. https://doi.org/10.1002/1529-0131(200008)43:8<1831::Aid-anr19>3.0.Co;2-6

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Syversen SW, Gaarder PI, Goll GL, Odegard S, Haavardsholm EA, Mowinckel P, van der Heijde D, Landewe R, Kvien TK (2008) High anti-cyclic citrullinated peptide levels and an algorithm of four variables predict radiographic progression in patients with rheumatoid arthritis: results from a 10-year longitudinal study. Ann Rheum Dis 67:212–217. https://doi.org/10.1136/ard.2006.068247

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Hetland ML, Stengaard-Pedersen K, Junker P, Ostergaard M, Ejbjerg BJ, Jacobsen S, Lottenburger T, Hansen I, Tarp U, Andersen LS, Svendsen A, Pedersen JK, Lauridsen UB, Ellingsen T, Lindegaard H, Podenphant J, Vestergaard A, Jurik AG, Horslev-Petersen K (2010) Radiographic progression and remission rates in early rheumatoid arthritis - MRI bone oedema and anti-CCP predicted radiographic progression in the 5-year extension of the double-blind randomised CIMESTRA trial. Ann Rheum Dis 69:1789–1795. https://doi.org/10.1136/ard.2009.125534

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Hecht C, Englbrecht M, Rech J, Schmidt S, Araujo E, Engelke K, Finzel S, Schett G (2015) Additive effect of anti-citrullinated protein antibodies and rheumatoid factor on bone erosions in patients with RA. Ann Rheum Dis 74:2151–2156. https://doi.org/10.1136/annrheumdis-2014-205428

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Jilani AA, Mackworth-Young CG (2015) The role of citrullinated protein antibodies in predicting erosive disease in rheumatoid arthritis: a systematic literature review and meta-analysis. Int J Rheumatol 2015:728610–728618. https://doi.org/10.1155/2015/728610

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Joo YB, Park YJ, Park KS, Kim KJ (2019) Association of cumulative anti-cyclic citrullinated protein antibodies with radiographic progression in patients with rheumatoid arthritis. Clin Rheumatol 38:2423–2432. https://doi.org/10.1007/s10067-019-04554-w

    Article  PubMed  Google Scholar 

  22. 22.

    Joaquim AF, Ghizoni E, Tedeschi H, Appenzeller S, Riew KD (2015) Radiological evaluation of cervical spine involvement in rheumatoid arthritis. Neurosurg Focus 38:E4. https://doi.org/10.3171/2015.1.Focus14664

    Article  PubMed  Google Scholar 

  23. 23.

    van der Heijde D (2000) How to read radiographs according to the Sharp/van der Heijde method. J Rheumatol 27:261–263

    PubMed  Google Scholar 

  24. 24.

    Kanis JA (1994) Assessment of fracture risk and its application to screening for postmenopausal osteoporosis: synopsis of a WHO report. WHO study group. Osteoporos Int 4:368–381. https://doi.org/10.1007/bf01622200

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Teitsma XM, Jacobs JWG, Welsing PMJ, de Jong PHP, Hazes JMW, Weel A, Pethö-Schramm A, Borm MEA, van Laar JM, Lafeber F, Bijlsma JWJ (2018) Inadequate response to treat-to-target methotrexate therapy in patients with new-onset rheumatoid arthritis: development and validation of clinical predictors. Ann Rheum Dis 77:1261–1267. https://doi.org/10.1136/annrheumdis-2018-213035

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Weissman BN, Aliabadi P, Weinfeld MS, Thomas WH, Sosman JL (1982) Prognostic features of atlantoaxial subluxation in rheumatoid arthritis patients. Radiology 144:745–751. https://doi.org/10.1148/radiology.144.4.7111719

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Kuhn KA, Kulik L, Tomooka B, Braschler KJ, Arend WP, Robinson WH, Holers VM (2006) Antibodies against citrullinated proteins enhance tissue injury in experimental autoimmune arthritis. J Clin Invest 116:961–973. https://doi.org/10.1172/jci25422

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    England BR, Thiele GM, Mikuls TR (2017) Anticitrullinated protein antibodies: origin and role in the pathogenesis of rheumatoid arthritis. Curr Opin Rheumatol 29:57–64. https://doi.org/10.1097/bor.0000000000000356

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Ge C, Tong D, Liang B, Lonnblom E, Schneider N, Hagert C, Viljanen J, Ayoglu B, Stawikowska R, Nilsson P, Fields GB, Skogh T, Kastbom A, Kihlberg J, Burkhardt H, Dobritzsch D, Holmdahl R (2017) Anti-citrullinated protein antibodies cause arthritis by cross-reactivity to joint cartilage. Anti-citrullinated protein antibodies cause arthritis by cross-reactivity to joint cartilage JCI Insight 2:2. https://doi.org/10.1172/jci.insight.93688

    Article  Google Scholar 

  30. 30.

    MacKinnon DP, Krull JL, Lockwood CM (2000) Equivalence of the mediation, confounding and suppression effect. Prev Sci 1:173–181. https://doi.org/10.1023/a:1026595011371

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Smolen JS, Landewe R, Bijlsma J, Burmester G, Chatzidionysiou K, Dougados M, Nam J, Ramiro S, Voshaar M, van Vollenhoven R, Aletaha D, Aringer M, Boers M, Buckley CD, Buttgereit F, Bykerk V, Cardiel M, Combe B, Cutolo M, van Eijk-Hustings Y, Emery P, Finckh A, Gabay C, Gomez-Reino J, Gossec L, Gottenberg JE, Hazes JMW, Huizinga T, Jani M, Karateev D, Kouloumas M, Kvien T, Li Z, Mariette X, McInnes I, Mysler E, Nash P, Pavelka K, Poor G, Richez C, van Riel P, Rubbert-Roth A, Saag K, da Silva J, Stamm T, Takeuchi T, Westhovens R, de Wit M, van der Heijde D (2017) EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis 76:960–977. https://doi.org/10.1136/annrheumdis-2016-210715

    Article  Google Scholar 

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The authors received no specific funding for this work.

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Correspondence to Ki-Jo Kim.

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The study was conducted in accordance with the Helsinki Declaration and approved by the Institutional Review Board of St. Vincent’s Hospital, the Catholic University of Korea (No. VC20RISI0068).

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Baek, I., Joo, Y.B., Park, K. et al. Risk factors for cervical spine instability in patients with rheumatoid arthritis. Clin Rheumatol (2020). https://doi.org/10.1007/s10067-020-05243-9

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Keywords

  • Anti-citrullinated proteins antibody
  • Atlantoaxial subluxation
  • Cervical spine instability
  • Rheumatoid arthritis