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Occurrence of cerebral small vessel disease at diagnosis of MPO-ANCA-associated vasculitis



Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) often causes peripheral nervous system impairments. However, little is known about subclinical involvements of the central nervous system in AAV. We investigated the frequency and progression of cerebral small vessel disease (SVD) in patients with AAV.


This single-center, case–control study comprised 56 patients with myeloperoxidase (MPO)-ANCA-positive AAV. Cerebral SVD presenting periventricular and deep white matter hyperintensities was assessed using brain magnetic resonance imaging (MRI). Seventy-five patients with non-stroke-associated neurological diseases were employed as controls.


At clinical diagnosis of MPO-ANCA-positive AAV, the frequency of periventricular hyperintensities in the AAV group was significantly higher than that in the control group (P = 0.014). Shinohara and Fazekas grades of periventricular hyperintensities in the AAV group were significantly higher than those in the control group (P = 0.019 and 0.020, respectively). In the AAV group, atherosclerosis-related factors, such as age and hypertension, were not associated with the Shinohara grades of periventricular hyperintensities, whereas serum CRP levels were significantly associated (odds ratio = 6.000, 95% confidence interval 1.648–21.840, P = 0.004). MRI changes were followed in 23 patients with AAV until 2 years after 6 months of diagnosis. Six of these patients worsened the grades of periventricular hyperintensities, while two of 27 in the control group worsened the grades (P = 0.013).


Inflammatory events are associated with the occurrence of cerebral SVD before clinical diagnosis of MPO-ANCA-positive AAV. The patients may be continuously exposed to the risk of cerebral SVD after immunosuppressive therapy.

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  1. 1.

    Yates M, Watts RA, Bajema IM, Cid MC, Crestani B, Hauser T, Hellmich B, Holle JU, Laudien M, Little MA, Luqmani RA, Mahr A, Merkel PA, Mills J, Mooney J, Segelmark M, Tesar V, Westman K, Vaglio A, Yalçındağ N, Jayne DR, Mukhtyar C (2016) EULAR/ERA-EDTA recommendations for the management of ANCA-associated vasculitis. Ann Rheum Dis 75:1583–1594

    Article  CAS  PubMed  Google Scholar 

  2. 2.

    Kallenberg CG (2014) Key advances in the clinical approach to ANCA-associated vasculitis. Nat Rev Rheumatol 10:484–493

    Article  CAS  PubMed  Google Scholar 

  3. 3.

    Millet A, Pederzoli-Ribeil M, Guillevin L, Witko-Sarsat V, Mouthon L (2013) Antineutrophil cytoplasmic antibody-associated vasculitides: is it time to split up the group? Ann Rheum Dis 72:1273–1279

    Article  CAS  PubMed  Google Scholar 

  4. 4.

    Unizony S, Villarreal M, Miloslavsky EM, Lu N, Merkel PA, Spiera R, Seo P, Langford CA, Hoffman GS, Kallenberg CM, St Clair EW, Ikle D, Tchao NK, Ding L, Brunetta P, Choi HK, Monach PA, Fervenza F, Stone JH, Specks U, RAVE-ITN Research Group (2016) Clinical outcomes of treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis based on ANCA type. Ann Rheum Dis 75:1166–1169

    Article  CAS  PubMed  Google Scholar 

  5. 5.

    Walsh M, Flossmann O, Berden A, Westman K, Höglund P, Stegeman C, Jayne D, European Vasculitis Study Group (2012) Risk factors for relapse of antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 64:542–548

    Article  CAS  PubMed  Google Scholar 

  6. 6.

    Lionaki S, Blyth ER, Hogan SL, Hu Y, Senior BA, Jennette CE, Nachman PH, Jennette JC, Falk RJ (2012) Classification of antineutrophil cytoplasmic autoantibody vasculitis: the role of antineutrophil cytoplasmic autoantibody specificity for myeloperoxidase or proteinase 3 in disease recognition and prognosis. Arthritis Rheum 64:3452–3462

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Jennette JC, Falk RJ (1997) Small-vessel vasculitis. N Engl J Med 337:1512–1523

    Article  CAS  PubMed  Google Scholar 

  8. 8.

    Cattaneo L, Chierici E, Pavone L, Grasselli C, Manganelli P, Buzio C, Pavesi G (2007) Peripheral neuropathy in Wegener’s granulomatosis, Churg-Strauss syndrome and microscopic polyangiitis. J Neurol Neurosurg Psychiatry 78:1119–1123

    Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Comarmond C, Pagnoux C, Khellaf M, Cordier JF, Hamidou M, Viallard JF, Maurier F, Jouneau S, Bienvenu B, Puéchal X, Aumaître O, Le Guenno G, Le Quellec A, Cevallos R, Fain O, Godeau B, Seror R, Dunogué B, Mahr A, Guilpain P, Cohen P, Aouba A, Mouthon L, Guillevin L, French Vasculitis Study Group (2013) Eosinophilic granulomatosis with polyangiitis (Churg-Strauss): clinical characteristics and long-term followup of the 383 patients enrolled in the French Vasculitis Study Group cohort. Arthritis Rheum 65:270–281

    Article  PubMed  Google Scholar 

  10. 10.

    Seror R, Mahr A, Ramanoelina J, Pagnoux C, Cohen P, Guillevin L (2006) Central nervous system involvement in Wegener granulomatosis. Medicine (Baltimore) 85:54–65

    Article  Google Scholar 

  11. 11.

    Watts R, Lane S, Hanslik T, Hauser T, Hellmich B, Koldingsnes W, Mahr A, Segelmark M, Cohen-Tervaert JW, Scott D (2007) Development and validation of a consensus methodology for the classification of the ANCA-associated vasculitides and polyarteritis nodosa for epidemiological studies. Ann Rheum Dis 66:222–227

    Article  PubMed  Google Scholar 

  12. 12.

    Alberti KG, Zimmet PZ (1998) Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 15:539–553

    Article  CAS  Google Scholar 

  13. 13.

    Expert Panel on Detection (2001) Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III). JAMA 285:2486–2497

    Article  Google Scholar 

  14. 14.

    Mukhtyar C, Lee R, Brown D, Carruthers D, Dasgupta B, Dubey S, Flossmann O, Hall C, Hollywood J, Jayne D, Jones R, Lanyon P, Muir A, Scott D, Young L, Luqmani RA (2009) Modification and validation of the Birmingham Vasculitis Activity Score (version 3). Ann Rheum Dis 68:1827–1832

    Article  CAS  PubMed  Google Scholar 

  15. 15.

    Suppiah R, Mukhtyar C, Flossmann O, Alberici F, Baslund B, Batra R, Brown D, Holle J, Hruskova Z, Jayne DR, Judge A, Little MA, Palmisano A, Stegeman C, Tesar V, Vaglio A, Westman K, Luqmani R (2011) A cross-sectional study of the Birmingham Vasculitis Activity Score version 3 in systemic vasculitis. Rheumatology (Oxford) 50:899–905

    Article  Google Scholar 

  16. 16.

    Shinohara Y, Tohgi H, Hirai S, Terashi A, Fukuuchi Y, Yamaguchi T, Okudera T (2007) Effect of the Ca antagonist nilvadipine on stroke occurrence or recurrence and extension of asymptomatic cerebral infarction in hypertensive patients with or without History of Stroke (PICA Study). Design and results at enrollment. Cerebrovasc Dis 24:202–209

    Article  CAS  PubMed  Google Scholar 

  17. 17.

    Fazekas F, Chawluk JB, Alavi A, Hurtig HI, Zimmerman RA (1987) MR signal abnormalities at 1.5 T in Alzheimer’s dementia and normal aging. Am J Roentgenol 149:351–356

    Article  CAS  Google Scholar 

  18. 18.

    Pantoni L (2010) Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol 9:689–701

    Article  Google Scholar 

  19. 19.

    van Dijk EJ, Prins ND, Vermeer SE, Vrooman HA, Hofman A, Koudstaal PJ, Breteler MM (2005) C-reactive protein and cerebral small- vessel disease: the Rotterdam Scan Study. Circulation 112:900–905

    Article  CAS  PubMed  Google Scholar 

  20. 20.

    Wada M, Nagasawa H, Kurita K, Koyama S, Arawaka S, Kawanami T, Tajima K, Daimon M, Kato T (2008) Cerebral small vessel disease and C-reactive protein: results of a cross-sectional study in community-based Japanese elderly. J Neurol Sci 264:43–49

    Article  CAS  PubMed  Google Scholar 

  21. 21.

    Debette S, Markus HS (2010) The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: systematic review and meta-analysis. BMJ 341:c3666

    Article  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Arntz RM, van den Broek SM, van Uden IW, Ghafoorian M, Platel B, Rutten-Jacobs LC, Maaijwee NA, Schaapsmeerders P, Schoonderwaldt HC, van Dijk EJ, de Leeuw FE (2016) Accelerated development of cerebral small vessel disease in young stroke patients. Neurology 87:1212–1219

    Article  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Berden A, Göçeroglu A, Jayne D, Luqmani R, Rasmussen N, Bruijn JA, Bajema I (2012) Diagnosis and management of ANCA associated vasculitis. BMJ 344:e26

    Article  PubMed  Google Scholar 

  24. 24.

    Pagnoux C, Guillevin L (2010) Churg-Strauss syndrome: evidence for disease subtypes? Curr Opin Rheumatol 22:21–28

    Article  PubMed  Google Scholar 

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Correspondence to Shigeki Arawaka.

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Ethical standard

This study was conducted in accordance with the Declaration of Helsinki and its amendments. The study protocol was approved by the Ethics Committee of the Medical Faculty, Osaka Medical College (approval no. 2342).

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Tani, H., Nagai, K., Hosokawa, T. et al. Occurrence of cerebral small vessel disease at diagnosis of MPO-ANCA-associated vasculitis. J Neurol 266, 1708–1715 (2019).

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  • Small vessel disease
  • Vasculitis
  • C-reactive protein