Hypertrophic pachymeningitis: significance of myeloperoxidase anti-neutrophil cytoplasmic antibody

Abstract

The aim of this study was to elucidate the characteristics, pathogenesis and treatment strategy of hypertrophic pachymeningitis that is associated with myeloperoxidase anti-neutrophil cytoplasmic antibody (ANCA). We retrospectively investigated clinical, radiological, immunological and pathological profiles of 36 patients with immune-mediated or idiopathic hypertrophic pachymeningitis, including 17 patients with myeloperoxidase-ANCA, four patients with proteinase 3-ANCA, six patients with other immune-mediated disorders, and nine patients with 'idiopathic' variety. Myeloperoxidase-ANCA-positive hypertrophic pachymeningitis was characterized by: (i) an elderly female predominance; (ii) 82% of patients diagnosed with granulomatosis with polyangiitis (previously known as Wegener's granulomatosis) according to Watts' algorithm; (iii) a high frequency of patients with lesions limited to the dura mater and upper airways, developing headaches, chronic sinusitis, otitis media or mastoiditis; (iv) a low frequency of patients with the 'classical or generalized form' of granulomatosis with polyangiitis involving the entire upper and lower airways and kidney, or progressing to generalized disease, in contrast to proteinase 3-ANCA-positive hypertrophic pachymeningitis; (v) less severe neurological damage according to the modified Rankin Scale and low disease activity according to the Birmingham Vasculitis Activity Score compared with proteinase 3-ANCA-positive hypertrophic pachymeningitis; (vi) increased levels of CXCL10, CXCL8 and interleukin 6 in cerebrospinal fluids, and increased numbers of T cells, neutrophils, eosinophils, plasma cells and monocytes/macrophages in autopsied or biopsied dura mater with pachymeningitis, suggesting TH1-predominant granulomatous lesions in hypertrophic pachymeningitis, as previously reported in pulmonary or renal lesions of granulomatosis with polyangiitis; and (vii) greater efficacy of combination therapy with prednisolone and cyclophosphamide compared with monotherapy with prednisolone. Proteinase 3-ANCA may be considered a marker for more severe neurological damage, higher disease activity and a higher frequency of the generalized form compared with myeloperoxidase-ANCA-positive hypertrophic pachymeningitis. However, categorization into 'granulomatosis with polyangiitis' according to Watts' algorithm and immunological or pathological features were common in both proteinase 3- and myeloperoxidase-ANCA-positive hypertrophic pachymeningitis. These data indicate that most patients with myeloperoxidase-ANCA-positive hypertrophic pachymeningitis should be categorized as having the central nervous system-limited form of ANCA-associated vasculitis, consistent with the concept of ophthalmic-, pulmonary- or renal-limited vasculitis.

Hypertrophic pachymeningitis is a characteristic manifestation of granulomatosis with polyangiitis: A retrospective study of anti‐neutrophil cytoplasmic antibody‐associated vasculitis

“…The present study, together with previous descriptions, 2,3 suggests that HP may occur as the first involvement in approximately half of patients with AAVrelated HP who frequently present with headache and/ or cranial neuropathy as a common symptom, in addition to ENT involvement. In this regard, we should consider the previous description that the disease severity eventually developed into a systemic type of AAV in 18% of patients with MPO-ANCA positivity and 50% of those with PR3-ANCA positivity, even though they had been categorized as 'CNS-limited type' (i.e., HP without other visceral disorders), at the disease onset.…”

“…20,21 In the cohort of ANCA-related HP, all patients with PR3-ANCA positivity and 82% of those with MPO-ANCA positivity were classified as having GPA, even though neither MPA nor EGPA were shown. 3 Accordingly, HP occurrence may be strongly implicated in the classification of GPA, while some cases of HP which were diagnosed as MPA have been reported. 22,23 The mechanisms of GPArelated disorders of the CNS have been proposed as follows: (1) granulomatosis tissue may directly extend to the intracranial nervous system from adjacent lesions in the orbit or paranasal cavity; (2) granulomatosis tissue may transfer to the intracranial nervous system from the respiratory tract; and (3) vasculitis may affect intracranial vessels.…”

“…The pathological study of the involved dura mater in GPA revealed that the most common finding was necrotizing granulomatosis, 24 although vasculitis could also be seen in ANCArelated HP. 3 Regarding the pathological description of GPA, the predominance of granulomatosis is obvious in the respiratory tract lesions, while small-vessel vasculitis principally concerns the pathogenesis of renal involvement. 8,25,26 Considering these indications, existence of granulomatous lesions may be required for the formation of HP in AAV.…”

“…In this regard, we should consider the previous description that the disease severity eventually developed into a systemic type of AAV in 18% of patients with MPO-ANCA positivity and 50% of those with PR3-ANCA positivity, even though they had been categorized as 'CNS-limited type' (i.e., HP without other visceral disorders), at the disease onset. 3 In order to prevent the progression of disease by promptly initiating appropriate therapy, it is required to make a definitive diagnosis according to the clinical features of HP associated with AAV. AAV is generally recognized as a refractory autoimmune disorder, which involves frequent relapses and resistance to conventional treatments.…”

“…1,2 Considering the etiology of HP, which is associated with autoimmune disorders, anti-neutrophil cytoplasmic antibody (ANCA)-related HP is the most frequently recognized. 2,3 ANCA is implicated in small vessel vasculitis, which is designated as ANCA-associated vasculitis (AAV), and is distinct from immune complexmediated vasculitis. 4 AAV is categorized as microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), and eosinophilic granulomatosis with polyangiitis (EGPA) based on the phenotypes of ANCA, the histopathological findings of granulomatosis and/or necrotizing vasculitis formation, and clinical findings such as prior asthma, existence of respiratory tract lesions, and/or urinary tract involvement.…”