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MPO and PR3 ANCA associations in hypertrophic pachymeningitis

Posted in Journal Reviews on 15th Oct 2014

Reviewer:  Huiqi Wang, Department of Clinical Neurosciences, Cambridge University and Cambridge Clinical School

Hypertrophic pachymeningitis (HP) is a rare inflammatory condition of the dura mater. Focal or diffuse fibrous thickening of the dura mater may lead to mass effect and/or compression of neurovascular structures. Cases of HP associated with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis have been reported in recent literature but the causes of a significant proportion of cases remain unidentified and are classified as ‘idiopathic’. Little is known about the demography, clinical characteristics and pathogenesis of ANCA-associated HP. To investigate these, Yokoseki and colleagues retrospectively evaluated 36 Japanese patients with immune-mediated or idiopathic HP, including 17 patients with myeloperoxidase (MPO)-ANCA, 4 patients with proteinase 3 (PR3)-ANCA and 9 patients with ‘idiopathic’ HP. Three of 17 of the MPO-ANCA-positive HP and 2/4 of the PR3-ANCA-positive HP patients developed generalised Granulomatosis with Polyangiitis (GPA) after a median course of 11.1 months, consistent with previous reports suggesting the concept of a CNS-limited form of ANCA-associated vasculitis. It would be useful if a follow-up study was done to investigate the proportion of patients with CNS-limited form of ANCA-associated HP developing systemic GPA in the long run, and if aggressive treatment at an early stage could delay or prevent progression to the systemic disease; the follow up in this study was short (median, 2.7 years). The authors concluded that MPO-ANCA positive HP had a higher frequency of lesions limited to the dura and upper airways and was associated with less severe neurological damage than PR3-ANCA-positive HP in this study. This would be in agreement with current opinion that PR3-ANCA and MPO-ANCA may be distinct clinical entities, as suggested by a recent genome-wide association study identifying different genetic association between PR3-ANCA and MPO-ANCA (Lyons et al NEJM 2012). In terms of demography, an elderly female predominance was reported in the MPO-ANCA-positive HP cohort, in keeping with a nation-wide study of HP in Japan by Yonekawa et al. 2014. It would be interesting to find out the prevalence of ANCA-associated HP and if there is a similar demographic picture in the West, although we know that MPO-ANCA is predominant in Asia whilst PR3-ANCA in Northern Europe. The study by Yokoseki and colleagues also sheds light on the poorly-understood pathogenesis of ANCA-associated HP. The observation of increased numbers of T cells, neutrophils, eosinophils, plasma cells and monocytes/macrophages in 3/7 autopsied and biopsied hypertrophied dura mater as well as increased levels of CXCL10, CXCL8 and IL-6 in CSF samples suggest a Th1-predominant inflammatory pathway underlying ANCA-associated HP, consistent with the immunopathogenesis of ANCA-associated vasculitis described in previous literature. Furthermore, the group found B cell clusters indicative of lymphoid neogenesis – a phenomenon found in diverse autoimmune, infective and malignant conditions – in biopsied hypertrophied dura mater of 2 patients. Whether the presence of lymphoid neogenesis contribute to ongoing inflammation, tissue damage and the chronicity of the disease, could not be determined in such a study but provide avenues for future research. Major drawbacks of the study are the small study size and lack of histology findings of granulomas to support the diagnosis of GPA. Further larger-scale research is warranted to further our understanding of ANCA-associated HP, a rare diagnosis not to be missed.

Yokoseki A, Saji E, Arakawa M, Kosaka T, Hokari M, Toyoshima Y, Okamoto K, Takeda S, Sanpei K, Kikuchi H, Hirohata S, Akazawa K, Kakita A, Takahashi H, Nishizawa M, Kawachi I. Hypertrophic pachymeningitis: significance of myeloperoxidase anti-neutrophil cytoplasmic antibody. BRAIN. 2014 Feb;137(Pt 2):520-36.

Lyons PA, Rayner TF, Trivedi S, Holle JU, Watts RA, Jayne DR, et al. Genetically distinct subsets within ANCA-associated vasculitis. N Engl J Med 2012; 367: 214–23.

Yonekawa T, Murai H, Utsuki S, Matsushita T, Masaki K, Isobe N, Yamasaki R, Yoshida M, Kusunoki S, Sakata K, Fujii K, Kira J. J Neurol NEUROSURG PSYCHIATRY. 2014 Jul;85(7):732-9.

ACNR 2014: V14;I4
Published online 15/10/14