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Clinical characteristics, the diagnostic criteria and management recommendation of otitis media with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (OMAAV) proposed by Japan Otological Society

Open AccessPublished:August 04, 2020DOI:https://doi.org/10.1016/j.anl.2020.07.004

      Abstract

      Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a form of necrotizing vasculitis with few or no immune deposits. It primarily affects small and medium blood vessels. AAV is classified into three categories, granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangitis (EGPA), and two major ANCAs, proteinase 3 (PR3)-ANCA or myeloperoxidase (MPO)-ANCA are involved in their pathogenesis. Intractable otitis media frequently occurs in patients with GPA, MPA or EGPA, although all patients show similar clinical features, regardless of the type of AAV. Furthermore, approximately 15% patients with otitis media caused by AAV do not show ANCA positivity, histopathological evidence, or any other AAV-related lesions at the initial visit; therefore, these patients do not fulfill the ordinary diagnostic criteria for systemic AAV. Thus, we first proposed that this condition could be categorized as “otitis media with AAV (OMAAV)”. Subsequently, the Japanese Otological Society (JOS) conducted a nationwide survey between December 2013 and February 2014 and identified 297 patients with OMAAV. The survey revealed that OMAAV is a disease that initially occurs in the middle ear and subsequently spreads to other organs such as the lungs and kidneys, with eventual involvement of all body organs. Severe sequelae such as facial palsy, hypertrophic pachymeningitis, complete deafness, and subarachnoid hemorrhage resulting in death can also occur. In this review, we introduce the clinical features, diagnostic criteria, and treatment strategies recommended by JOS for early diagnosis and treatment of OMAAV.

      Keywords

      1. Introduction

      Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a form of necrotizing vasculitis with few or no immune deposits, and it primarily affects small and medium blood vessels. AAV is classified into three categories, granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangitis (EGPA), and two major ANCAs, proteinase 3 (PR3)-ANCA or myeloperoxidase (MPO)-ANCA are involved in their pathogenesis [
      • Jennette J.C.
      • Falk R.J.
      • Bacon P.A.
      • Basu N.
      • Cid M.C.
      • Ferrario F.
      • et al.
      2012 revised international chapel hill consensus conference nomenclature of vasculitides.
      ].
      Otitis media is one of the early symptoms or sequelae of AAV [
      • Harabuchi Y.
      • Kishibe K.
      • Komabayashi Y.
      Clinical manifestations of granulomatosis with polyangiitis (GPA: wegener's granulomatosis) in the upper respiratory tracts by otolaryngologists of Japan.
      ,
      • Nicklasson B.
      • Stangeland N.
      Wegener's granulomatosis presenting as otitis media.
      ,
      • Hoffman G.S.
      • Kerr G.S.
      • Leavitt R.Y.
      • Hallahan C.W.
      • Lebovics R.S.
      • Travis W.D.
      • et al.
      Wegener granulomatosis: an analysis of 158 patients.
      ]. There are frequent reports about the development of facial palsy and/or hypertrophic pachymeningitis in patients with otitis media caused by GPA [
      • Bradley P.J.
      Wegener's Granulomatosis of the ear.
      ,
      • Dagum P.
      • Roberson Jr., J.B.
      Otologic Wegener's granulomatosis with facial nerve palsy.
      ,
      • Bibas A.
      • Fahy C.
      • Sneddon L.
      • Bowdler D.
      Facial paralysis in Wegener's granulomatosis of the middle ear.
      ,
      • Nikolaou A.C.
      • Vlachtsis K.C.
      • Daniilidis M.A.
      • Petridis D.G.
      • Daniilidis I.C.
      Wegener's granulomatosis presenting with bilateral facial nerve palsy.
      ,
      • Bucolo S.
      • Torre V.
      • Montemagno A.
      • Beatrice F.
      Wegener's granulomatosis presenting with otologic and neurologic symptoms: clinical and pathological correlations.
      ,
      • Jacobi D.
      • Maillot F.
      • Hommet C.
      • Arsene S.
      • Cottier J.P.
      • Lamisse F.
      • et al.
      P-ANCA cranial pachymeningitis: a case report.
      ,
      • Drinias V.
      • Florentzson R.
      Facial palsy and Wegener's granulomatosis.
      ,
      • Preuss S.F.
      • Stenner M.
      • Beutner D.
      • Laudes M.
      • Klussmann J.P.
      Fatal course of Wegener's granulomatosis with bilateral otomastoiditis and bilateral facial nerve palsy.
      ,
      • Wierzbicka M.
      • Szyfter W.
      • Puszczewicz M.
      • Borucki L.
      • Bartochowska A.
      Otologic symptoms as initial manifestation of wegener granulomatosis: diagnostic dilemma.
      ,
      • Ono N.
      • Yoshihiro K.
      • Oryoji D.
      • Matsuda M.
      • Ueki Y.
      • Uezono S.
      • et al.
      Four cases of MPO-ANCA-positive vasculitis with otitis media, and review of the literature.
      ,
      • Gomez-Torres A.
      • Tirado Zamora I.
      • Abrante Jimenez A.
      • Esteban Ortega F.
      Wegener's granulomatosis causing bilateral facial paralysis and deafness.
      ,
      • Iqbal A.M.
      • Blackburn D.
      • Rafiq M.
      • Sharrack B.
      Wegener's granulomatosis presenting with multiple cranial nerve palsies and pachymeningitis.
      ,
      • Mori A.
      • Hira K.
      • Hatano T.
      • Okuma Y.
      • Kubo S.
      • Hirano K.
      • et al.
      Bilateral facial nerve palsy due to otitis media associated with myeloperoxidase-antineutrophil cytoplasmic antibody.
      ,
      • Maranhao A.S.
      • Chen V.G.
      • Rossini B.A.
      • Testa J.R.
      • Penido Nde O.
      Mastoiditis and facial paralysis as initial manifestations of Wegener's Granulomatosis.
      ], MPA [
      • Sugimoto T.
      • Sakaguchi M.
      • Deji N.
      • Uzu T.
      • Nishio Y.
      • Kashiwagi A.
      The occurrence of sensorineural hearing loss in a patient with myeloperoxidase-anti-neutrophil cytoplasmic antibody-related microscopic polyangiitis.
      ,
      • Iruku P.
      • Karanth P.
      • Tiu H.
      • Kankam C.
      • Shaheen K.
      Hearing loss and kidney dysfunction: finding a unifying diagnosis.
      , and EGPA [
      • Byun J.H.
      • Lee J.H.
      • Choi I.S.
      Churg-strauss syndrome presented with hearing impairment and facial palsy.
      ]. The initial symptoms/signs of patients with intractable otitis media were found to be similar, regardless of the association with GPA [
      • Bradley P.J.
      Wegener's Granulomatosis of the ear.
      ,
      • Dagum P.
      • Roberson Jr., J.B.
      Otologic Wegener's granulomatosis with facial nerve palsy.
      ,
      • Bibas A.
      • Fahy C.
      • Sneddon L.
      • Bowdler D.
      Facial paralysis in Wegener's granulomatosis of the middle ear.
      ,
      • Nikolaou A.C.
      • Vlachtsis K.C.
      • Daniilidis M.A.
      • Petridis D.G.
      • Daniilidis I.C.
      Wegener's granulomatosis presenting with bilateral facial nerve palsy.
      ,
      • Bucolo S.
      • Torre V.
      • Montemagno A.
      • Beatrice F.
      Wegener's granulomatosis presenting with otologic and neurologic symptoms: clinical and pathological correlations.
      ,
      • Jacobi D.
      • Maillot F.
      • Hommet C.
      • Arsene S.
      • Cottier J.P.
      • Lamisse F.
      • et al.
      P-ANCA cranial pachymeningitis: a case report.
      ,
      • Drinias V.
      • Florentzson R.
      Facial palsy and Wegener's granulomatosis.
      ,
      • Preuss S.F.
      • Stenner M.
      • Beutner D.
      • Laudes M.
      • Klussmann J.P.
      Fatal course of Wegener's granulomatosis with bilateral otomastoiditis and bilateral facial nerve palsy.
      ,
      • Wierzbicka M.
      • Szyfter W.
      • Puszczewicz M.
      • Borucki L.
      • Bartochowska A.
      Otologic symptoms as initial manifestation of wegener granulomatosis: diagnostic dilemma.
      ,
      • Ono N.
      • Yoshihiro K.
      • Oryoji D.
      • Matsuda M.
      • Ueki Y.
      • Uezono S.
      • et al.
      Four cases of MPO-ANCA-positive vasculitis with otitis media, and review of the literature.
      ,
      • Gomez-Torres A.
      • Tirado Zamora I.
      • Abrante Jimenez A.
      • Esteban Ortega F.
      Wegener's granulomatosis causing bilateral facial paralysis and deafness.
      ,
      • Iqbal A.M.
      • Blackburn D.
      • Rafiq M.
      • Sharrack B.
      Wegener's granulomatosis presenting with multiple cranial nerve palsies and pachymeningitis.
      ,
      • Mori A.
      • Hira K.
      • Hatano T.
      • Okuma Y.
      • Kubo S.
      • Hirano K.
      • et al.
      Bilateral facial nerve palsy due to otitis media associated with myeloperoxidase-antineutrophil cytoplasmic antibody.
      ,
      • Maranhao A.S.
      • Chen V.G.
      • Rossini B.A.
      • Testa J.R.
      • Penido Nde O.
      Mastoiditis and facial paralysis as initial manifestations of Wegener's Granulomatosis.
      ], MPA [
      • Sugimoto T.
      • Sakaguchi M.
      • Deji N.
      • Uzu T.
      • Nishio Y.
      • Kashiwagi A.
      The occurrence of sensorineural hearing loss in a patient with myeloperoxidase-anti-neutrophil cytoplasmic antibody-related microscopic polyangiitis.
      ,
      • Iruku P.
      • Karanth P.
      • Tiu H.
      • Kankam C.
      • Shaheen K.
      Hearing loss and kidney dysfunction: finding a unifying diagnosis.
      , or EGPA [
      • Byun J.H.
      • Lee J.H.
      • Choi I.S.
      Churg-strauss syndrome presented with hearing impairment and facial palsy.
      ]. Therefore, it is difficult to determine whether AAV-induced intractable otitis media is associated with GPA, MPA, or EGPA at the initial visit. In addition, approximately 15% patients with otitis media caused by AAV do not show ANCA positivity, histopathological evidence, or other AAV-related organ lesions at the initial visit [
      • Harabuchi Y.
      • Kishibe K.
      • Tateyama K.
      • Morita Y.
      • Yoshida N.
      • Kunimoto Y.
      • et al.
      Clinical features and treatment outcomes of otitis media with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (OMAAV): a retrospective analysis of 235 patients from a nationwide survey in Japan.
      ]. These patients do not fulfill the ordinary diagnostic criteria for systemic AAV, such as the Japanese Ministry of Health, Labour and Welfare (JMHLW) criteria [
      Research committee on intractable vasculitides, the labour and welfare of Japan.
      ] and European Medicines Evaluation Agency (EMEA) algorithm [
      • Watts R.
      • Lane S.
      • Hanslik T.
      • Hauser T.
      • Hellmich B.
      • Koldingsnes W.
      • et al.
      Development and validation of a consensus methodology for the classification of the ANCA-associated vasculitides and polyarteritis nodosa for epidemiological studies.
      ]. Therefore, we proposed that such diseases should be classified as “otitis media with AAV (OMAAV)” [
      • Yoshida N.
      • Hara M.
      • Hasegawa M.
      • Matsuzawa S.
      • Shinnabe A.
      • Kanazawa H.
      • et al.
      Reversible cochlear function with ANCA-associated vasculitis initially diagnosed by otologic symptoms.
      ,
      • Yoshida N.
      • Iino Y.
      Pathogenesis and diagnosis of otitis media with ANCA-associated vasculitis.
      ,
      • Yoshida N.
      • Kishibe K.
      • Tateyama K.
      • et al.
      Clinical features of 90 cases of otitis media with ANCA associated vasculitis.
      ]. Accordingly, OMAAV includes otitis media caused by GPA, MPA and EGPA, as well as otitis media that does not fulfill the ordinary diagnostic criteria for systemic AAV (Fig. 1).
      Fig 1
      Fig. 1Concept of otitis media with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (OMAAV). OMAAV composes of the otitis media caused by granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA), as well as that caused by ANCA)-associated vasculitis (AAV) unfulfilling the ordinary diagnostic criteria.
      The OMAAV working group, funded by the Japan Otological Society, conducted a nationwide survey between December 2013 and February 2014 and identified 297 patients with OMAAV. Subsequently, the group reported the clinical characteristics and treatment outcomes of 235 patients exhibiting the initial signs/symptoms of intractable otitis media with effusion or granulation [
      • Harabuchi Y.
      • Kishibe K.
      • Tateyama K.
      • Morita Y.
      • Yoshida N.
      • Kunimoto Y.
      • et al.
      Clinical features and treatment outcomes of otitis media with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (OMAAV): a retrospective analysis of 235 patients from a nationwide survey in Japan.
      ]. Since then, the concept of OMAAV has been gradually and widely understood [
      • Kawashima Y.
      • Noguchi Y.
      • Ito T.
      • Mizushima K.
      • Takahashi M.
      • Kitamura K.
      • et al.
      Otologic manifestations in patients with ANCA associated vasculitis-comparative analysis among microscopic polyangiitis, granulomatosis with polyangiitis and eosinophilic granulomatosis with polyangiitis.
      ,
      • Hisata Y.
      • Sasaki E.
      • Ishimaru K.
      • Harada Y.
      • Nakano H.
      • Naitou S.
      • et al.
      Do you know otitis media with ANCA-associated vasculitis (OMAAV)?.
      ,
      • Kobari Y.
      • Nagasawa T.
      Otitis media with ANCA-associated vasculitis: a new concept and the associated criteria.
      ,
      • Okada M.
      • Suemori K.
      • Takagi D.
      • Teraoka M.
      • Yamada H.
      • Hato N.
      Comparison of localized and systemic otitis media with ANCA-associated vasculitis.
      ,
      • Magliocca K.R.
      • Vivas E.X.
      • Griffith C.C.
      Idiopathic, infectious and reactive lesions of the ear and temporal bone.
      ,
      • Okada M.
      • Ogawa H.
      • Suemori K.
      • Takagi D.
      • Teraoka M.
      • Yamada H.
      • et al.
      Intractable otitis media presenting as falsely positive for proteinase 3-ANCA: a case report.
      ,
      • Peng A.
      • Yang X.
      • Wu W.
      • Xiao Z.
      • Xie D.
      • Ge S.
      Anti-neutrophil cytoplasmic antibody-associated hypertrophic cranial pachymeningitis and otitis media: a review of literature.
      ,
      • Tanaka R.
      • Shimojima Y.
      • Moteki H.
      • Kishida D.
      • Ueno K.I.
      • Sekijima Y.
      Propylthiouracil-induced otitis media with antineutrophil cytoplasmic antibody-associated vasculitis.
      ].
      If OMAAV is left untreated for a long period, there is a risk of developing permanent profound hearing loss and systemic diseases that can affect hearing and even prove fatal [
      • Harabuchi Y.
      • Kishibe K.
      • Tateyama K.
      • Morita Y.
      • Yoshida N.
      • Kunimoto Y.
      • et al.
      Clinical features and treatment outcomes of otitis media with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (OMAAV): a retrospective analysis of 235 patients from a nationwide survey in Japan.
      ]. Therefore, early diagnosis and treatment of OMAAV are critical. This review article presents diagnostic criteria and strategies for early diagnosis and treatment of OMAAV, as recommended by the Japan Otological Society on the basis of a retrospective analysis of the 297 patients identified in the nationwide survey.

      2. Clinical characteristics of 297 OMAAV patients identified by nationwide survey

      2.1 Symptoms/Signs

      OMAAV is defined as otitis media due to AAV, irrespective of the initial site of involvement [
      • Harabuchi Y.
      • Kishibe K.
      • Tateyama K.
      • Morita Y.
      • Yoshida N.
      • Kunimoto Y.
      • et al.
      Clinical features and treatment outcomes of otitis media with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (OMAAV): a retrospective analysis of 235 patients from a nationwide survey in Japan.
      ,
      • Yoshida N.
      • Hara M.
      • Hasegawa M.
      • Matsuzawa S.
      • Shinnabe A.
      • Kanazawa H.
      • et al.
      Reversible cochlear function with ANCA-associated vasculitis initially diagnosed by otologic symptoms.
      ,
      • Yoshida N.
      • Iino Y.
      Pathogenesis and diagnosis of otitis media with ANCA-associated vasculitis.
      ,
      • Yoshida N.
      • Kishibe K.
      • Tateyama K.
      • et al.
      Clinical features of 90 cases of otitis media with ANCA associated vasculitis.
      . A questionnaire-based nationwide survey of OMAAV conducted between December 2013 and February 2014 identified 297 patients with OMAAV. Table 1 shows the clinical characteristics of these patients.
      Table 1Clinical features of 297 patients with OMAAV.
      Age: median (Q25-Q75) years67 (13–89)
      Male / Female: No. (% of female)86/211 (71%)
      Follow up period: median (Q25-Q75) months26 (10–60)
      ANCA-status [at initial visit]: No. (%)
       MPO+PR3–164/293 (56%) [158/289 (55%)]
       MPO-PR3+66/293 (23%) [65/289 (22%)]
       MPO+PR3+14/293 (5%) [11/289 (4%)]
       MPO–PR3–49/293 (17%) [55/289 (19%)]
      Histological proof: No. (%)58/179 (32%) [34/178 (30%)]
      Initial symptoms: No. (%)
       Hearing loss295/297 (99%)
       Otorrhea135/297 (45%)
       Otalgia99/291 (34%)
       Tinnitus140/282 (50%)
       Vertigo or dizziness74/295 (25%)
       Headache70/224 (24%)
      Involvement sites throughout clinical course [at initial visit]: No. (%)
       Bilateral hearing loss219/297 (74%) [186/297 (63%)]
       Facial palsy94/297 (32%) [54/297 (18%)]
       Hypertrophic pachymeningiitis70/290 (24%) [44/286 (15%)]
       Nose112/297 (38%) [95/297 (32%)]
       Pharynx and/or larynx24/295 (8%) [17/290 (6%)]
       Lung113/297 (38%) [80/297 (27%)]
       Kidney77/297 (26%) [53/295 (18%)]
       Other vasculiitis-realated symptoms122/295 (41%) [99/297 (33%)]
      Treatments: No. (%)
       Corticosteroid plus immunosuppressant143/279 (51%)
      Outcomes: No. (%)
       Disease relapse125/293 (43%)
       Mortality8/297 (3%)
      Q=percentile. No.=case number having the varible/case number with data being available.
      The major clinical characteristics of the 297 patients were as follows: intractable otitis media with effusion or granulation that did not respond to ordinary treatments such as antibiotics and insertion of tympanic ventilation tubes, followed by progressive deterioration of bone conduction hearing levels; female predominance (71%); older age (median age: 67 years); predominance of MPO-ANCA positivity (56%), followed by PR3-ANCA positivity (23%) and negativity for both MPO-ANCA and PR3-ANCA (17%); frequent occurrence of facial palsy (32%) and hypertrophic pachymeningitis (24%); frequent involvement of the lungs (38%) and kidneys (26%); and bilateral complete deafness (2.4%; n = 7) and death (3%; n = 8) in occasional cases.
      There were 294 patients with complete records of the onset of the disease; these patients were classified into four subgroups according to the initial site of involvement: middle ear (80%; n = 235) [
      • Harabuchi Y.
      • Kishibe K.
      • Tateyama K.
      • Morita Y.
      • Yoshida N.
      • Kunimoto Y.
      • et al.
      Clinical features and treatment outcomes of otitis media with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (OMAAV): a retrospective analysis of 235 patients from a nationwide survey in Japan.
      ]; inner ear (4%; n = 11); parts of the upper respiratory tract, such as the nose and larynx (5%; n = 15); and other organs such as the lungs and kidneys (11%; n = 33). These four subgroups showed no significant differences in terms of otological symptoms/signs, other manifestations, the ANCA status, and the prognosis.

      2.2 ANCA status

      From the 297 patients, 293 had records of serum ANCA measurements; 164 (56%) exhibited MPO-ANCA positivity, 66 (22%) exhibited PR3-ANCA positivity, 49 (17%) exhibited ANCA negativity, and 14 (5%) exhibited both MPO- and PR3-ANCA positivity (Table 2). All groups showed female predominance, while the highest age (70 years; p < 0.001) was observed in the MPO-ANCA-positive group. The PR3-ANCA-positive group showed the least number of female patients (58%; p <0.05) and highest rates of nose (64%; p < 0.001) and lung (51%; p < 0.01) involvement. The ANCA-negative group showed the longest symptom duration before treatment (8.0 months; p < 0.05), highest rate of hypertrophic pachymeningitis (43%; p < 0.001), lowest rate of kidney involvement, and highest rate of disease-related death (6%; p < 0.05).
      Table 2Clinical features according to ANCA-status.
      MPO-ANCA-positivePR3-ANCA-positiveBoth ANCAs-negative
      No. of cases (%)164 (56%)66 (22%)49 (17%)
      Age: median (Q25-Q75) years70 (65–75)***59 (47–67)63 (46–69)
      Male/Female: No. (% of female)39/125 (76%)28/38 (58%)*14/35 (71%)
      Follow up period: median (Q25-Q75) months21 (9–48)48 (16–95)30 (12–62)
      Period with symptoms before treatment: median (Q25-Q75) months5 (2–8)3 (1–12)8 (5–15)*
      Initial symptoms: No. (%)
       Hearing loss164 (100%)64 (97%)48 (98%)
       Otorrhea76 (46%)26 (39%)30 (61%)
       Otalgia52 (32%)22 (34%)21 (43%)
       Tinnitus85 (55%)30 (48%)17 (35%)
       Vertigo or dizziness44 (27%)14 (22%)11 (22%)
       Headache41 (25%)14 (22%)14 (29%)
      Involvements throughout clinical course: No. (%)
       Facial palsy55 (34%)17 (26%)18 (37%)
       Hypertrophic pachymeningiitis36 (23%)10 (16%)21 (43%)**
       Nose44 (27%)44 (67%)***18 (37%)
       Pharynx and/or larynx13 (8%)7 (11%)3 (6%)
       Lung59 (36%)35 (53%)**12 (24%)
       Kidney46 (28%)20 (30%)6 (12%)*
       Others66 (40%)30 (45%)19 (39%)
      Treatments: No (%)
       Steroid plus immunosuppressant76 (46%)41 (62%)22 (45%)
      Outcomes: No (%)
       Disease relapse62 (39%)35 (54%)21 (43%)
       Disease-related death1 (1%)03 (6%)*
      Q=percentile. Three group comparisons were tested appropriately using Ryan's multiple comparison methods or Steel-Dwass test and expressed p-value compaed to the other two groups. *p<0.05, **p<0.01,***p<0.001.

      2.3 Eardrum findings

      On the basis of findings in the eardrum, OMAAV can be classified as the otitis media with effusion (OME) type, which shows eardrum findings similar to those observed in OME (Fig. 2a), and the otitis media with granuloma (OMG) type, which shows swelling of the eardrum due to granulation (Fig. 2b). In the OME type, the retained fluid is seen through the tympanic membrane and/or when tympanostomy is performed. The OMG type usually accompanies inflammatory findings such as redness, swelling, and turbid thickening of the tympanic membrane. When myringotomy is performed, granulation tissue is observed in the tympanic cavity. In some patients, the capillaries are dilated from the external ear canal to the post-tympanic quadrant, while in other patients, the ear canals may be too swollen to visualize the eardrum. In the nationwide survey, OMA and OMG were identified in 49% and 44% patients with OMAAV, respectively, with the clinical symptoms/signs, ANCA status, sequelae, and prognosis showing no significant between-group differences.
      Fig 2
      Fig. 2Representative findings of otitis media with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (OMAAV). (a) The right eardrum shows otitis media with effusion (OME) type, which appears to be reddish and filled with mucinous effusion. (b) The left eardrum shows otitis media with granuloma (OMG) type, which appears to be a turbid thickening of the eardrum. Granulation tissue is observed from tympanostomy incision in the tympanic cavity. (c) Microscopic photograph of the biopsy sample from the tympanic cavity. Fibrinoid degeneration is observed in the microvascular wall, accompanied by neutrophil infiltration, nuclear fragments, and hemorrhage (x360), corresponding to leukocytoclastic vasculitis. This is extremely rare and only this case shows histopathologic proof of AAV in the middle ear. The vast majority of the samples from the middle ear or mastoid cavity showed only non-specific inflammatory cell infiltrates and necrotic tissues. (d) Representative CT image of the temporal bone. The left tympanic cavity and mastoid cells are filled with soft tissue material without bone destruction. (e) Gadolinium-enhanced MRI of hypertrophic pachymeningitis. The dura is thickened and enhanced along the bilateral tentorium and parietal lobe. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

      2.4 Histopathological findings

      Histopathological findings consistent with AAV, i.e., necrotizing vasculitis predominantly affecting small vessels with or without granulomatous extravascular inflammation, were observed in 58 (32%) of 179 patients who underwent biopsy from the sites other than ear (Table 1). However, very few patients (only one) showed histopathological evidence in the middle ear (Fig. 2c). The vast majority of samples from the middle ear or mastoid cavity only showed nonspecific inflammatory cell infiltrates and necrotic tissues. Similar findings were observed in small samples collected through the external ear canal or large tissues obtained by opening the tympanic cavity or mastoidectomy. The main feature of AAV is necrotizing vasculitis, and the histopathological findings shift over time. Therefore, infiltration of inflammatory cells into the vascular wall, which is indicative of vasculitis, is a temporary phenomenon, and inflammatory cell infiltration and necrotic tissue, the endpoints of vasculitis, are observed in many patients.

      2.5 Computed tomography (CT) and magnetic resonance imaging (MRI) findings

      CT images of the temporal bone usually show soft tissue shadows without bone destruction in the tympanic and mastoid sinuses (Fig. 2d). However, bone destruction occurs when the disease progresses or is complicated by infection. Zycinska et al. [
      • Zycinska K.
      • Wardyn K.A.
      • Piotrowska E.
      • Zielonka T.M.
      • Zycinski H.
      • Bogaczewicz A.
      • et al.
      Rhinologic and sinonasal changes in PR3 ANCA pulmonary vasculitis.
      ] reported that seven of 35 (20%) patients with PR3-ANCA-positive GPA showed mastoid bone destruction on CT images. The contrast effect of the dura mater, outer ear, middle ear, and inner ear on contrast-enhanced MRI is useful for diagnosing hypertrophic pachymeningitis and inflammatory areas associated with vasculitis. Characteristic MRI findings include strong contrast effects in the cerebral dura mater and cochlea [
      • Sone M.
      • Mizuno T.
      • Naganawa S.
      • Nakashima T.
      Imaging analysis in cases with inflammation-induced sensorineural hearing loss.
      ,
      • Watanabe T.
      • Yoshida H.
      • Kishibe K.
      • Morita Y.
      • Yoshida N.
      • Takahashi H.
      • et al.
      Cochlear implantation in patients with bilateral deafness caused by otitis media with ANCA-associatedvasculitis (OMAAV): a report of four cases.
      . In addition, on 3-Tesla three-dimensional fluid-attenuated inversion recovery images of MPO-ANCA-positive OMAAV, increased signal intensity ratios for the cochlea and facial nerve are associated with severe sensorineural hearing loss and facial nerve palsy [
      • Watanabe T.
      • Yoshida H.
      • Kishibe K.
      • Morita Y.
      • Yoshida N.
      • Takahashi H.
      • et al.
      Cochlear implantation in patients with bilateral deafness caused by otitis media with ANCA-associatedvasculitis (OMAAV): a report of four cases.
      ,
      • Sriskandarajah V.
      • Bansal R.A.
      • Yeoh R.
      • Bansal A.S.
      Early intervention in localized Wegener's granulomatosis with sensorineural hearing loss preserves hearing.
      ,
      • Sone M.
      Inner ear disturbances related to middle ear inflammation.
      ]. Gadolinium-enhanced T1-weighted imaging is the most useful for diagnosing hypertrophic pachymeningitis; it shows significant contrast effects in the cerebellar tent and localized thickening of the dura in the skull base (Fig. 2).

      2.6 Hearing outcomes and vestibular function

      Audiometric data were available for 480 ears of 284 patients at the initial visit in the nationwide survey. The results showed normal hearing levels, conductive hearing loss, and mixed hearing loss in 9 (2%), 33 (10%), and 329 (69%) ears, respectively. Sensorineural hearing loss was observed in 109 (23%) ears, including 17 ears (3.5%) with complete deafness. Bilateral complete deafness was observed in four (1.4%) patients.
      Hearing outcomes were classified into three grades, complete/marked recovery (CR), partial recovery (PR) and non-recovery (NR) [
      • Harabuchi Y.
      • Kishibe K.
      • Tateyama K.
      • Morita Y.
      • Yoshida N.
      • Kunimoto Y.
      • et al.
      Clinical features and treatment outcomes of otitis media with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (OMAAV): a retrospective analysis of 235 patients from a nationwide survey in Japan.
      ,
      • Yoshida N.
      • Hara M.
      • Hasegawa M.
      • Matsuzawa S.
      • Shinnabe A.
      • Kanazawa H.
      • et al.
      Reversible cochlear function with ANCA-associated vasculitis initially diagnosed by otologic symptoms.
      ,
      • Yoshida N.
      • Iino Y.
      Pathogenesis and diagnosis of otitis media with ANCA-associated vasculitis.
      , which is modified from the criteria of hearing recovery for sudden deafness [
      • Kanzaki J.
      • Nomura Y.
      Incidence and prognosis of acute profound deafness in Japan.
      ,
      • Hoch S.
      • Vomhof T.
      • Teymoortash A.
      Critical evaluation of round window membrane sealing in the treatment of idiopathic sudden unilateral hearing loss.
      . Hearing outcomes over a median follow-up period of 24 months were as follows: CR (30%), PR (30%) and NR (40%). Hearing outcomes were not influenced by the hearing levels at the initial visit; however, complete deafness was irreversible despite treatment. During the clinical course, complete deafness developed in 35 (7.2%) ears, with bilateral complete deafness in 10 (3.5%) patients. It should be noted that no treatment could resolve complete hearing loss. Hearing outcomes were significantly worse for patients with facial palsy and/or hypertrophic pachymeningitis, whereas they were significantly better for patients receiving glucocorticoids (GCs) and immunosuppressive drugs than for those receiving glucocorticoids (GCs) alone [
      • Harabuchi Y.
      • Kishibe K.
      • Tateyama K.
      • Morita Y.
      • Yoshida N.
      • Kunimoto Y.
      • et al.
      Clinical features and treatment outcomes of otitis media with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (OMAAV): a retrospective analysis of 235 patients from a nationwide survey in Japan.
      ].
      Vestibular symptoms such as dizziness occurred in 25% of the patients identified in the nationwide survey. Morita et al. [
      • Morita Y.
      • Takahashi K.
      • Izumi S.
      • Kubota Y.
      • Ohshima S.
      • Horii A.
      Vestibular involvement in patients with otitis media with antineutrophil cytoplasmic antibody-associated vasculitis.
      ] reported that 11 of 31 patients with OMAAV had vestibular symptoms, while six of nine patients without vestibular symptoms showed unilateral or bilateral caloric weakness. Therefore, peripheral vestibular involvement was present in 84% patients with OMAAV.

      2.7 Facial palsy and hypertrophic pachymeningitis

      The nationwide survey showed that facial palsy and hypertrophic pachymeningitis were present in 18% and 15% patients, respectively, at the first visit and 32% and 24% patients, respectively, at the end of the clinical course. These incidences are considerably higher than those observed with other types of AAV [
      • Drinias V.
      • Florentzson R.
      Facial palsy and Wegener's granulomatosis.
      ,
      • Ferri E.
      • Armato E.
      • Capuzzo P.
      • Cavaleri S.
      • Ianniello F.
      Early diagnosis of Wegener's granulomatosis presenting with bilateral facial paralysis and bilateral serous otitis media.
      ,
      • Magliulo G.
      • Parrotto D.
      • Alla F.R.
      • Gagliardi S.
      Acute bilateral facial palsy and Wegener's disease.
      ,
      • Drachman D.
      Neurological complications of Wegener's granulomatosi.
      ,
      • Nishino H.
      • Rubino F.A.
      • DeRemee R.A.
      • Swanson J.W.
      • Parisi J.E.
      Neurological involvement in Wegener's granulomatosis: an analysis of 324 consecutive patients at the Mayo Clinic.
      . Facial palsy has been reported to occur in 5% to 8% patients with GPA [
      • Drinias V.
      • Florentzson R.
      Facial palsy and Wegener's granulomatosis.
      ,
      • Ferri E.
      • Armato E.
      • Capuzzo P.
      • Cavaleri S.
      • Ianniello F.
      Early diagnosis of Wegener's granulomatosis presenting with bilateral facial paralysis and bilateral serous otitis media.
      ,
      • Magliulo G.
      • Parrotto D.
      • Alla F.R.
      • Gagliardi S.
      Acute bilateral facial palsy and Wegener's disease.
      . The rate of hypertrophic pachymeningitis was previously estimated to be 6.7% for patients with GPA [
      • Drachman D.
      Neurological complications of Wegener's granulomatosi.
      ], with a more recent estimate being 0.6% [
      • Nishino H.
      • Rubino F.A.
      • DeRemee R.A.
      • Swanson J.W.
      • Parisi J.E.
      Neurological involvement in Wegener's granulomatosis: an analysis of 324 consecutive patients at the Mayo Clinic.
      ]. Furthermore, Yokoseki et al. [
      • Yokoseki A.
      • Saji E.
      • Arakawa M.
      • Kosaka T.
      • Hokari M.
      • Toyoshima Y.
      • et al.
      Hypertrophic pachymeningitis: significance of myeloperoxidase anti-neutrophil cytoplasmic antibody.
      ] found that otitis media was observed 66% of 21 patients with AAV-related hypertrophic pachymeningitis, but pulmonary, nasal, and renal lesions done in only 29%, 10%, and 10% patients, respectively. Sakairi et al. [
      • Sakairi T.
      • Sakurai N.
      • Nakasatomi M.
      • Ikeuchi H.
      • Kaneko Y.
      • Maeshima A.
      • et al.
      Hypertrophic pachymeningitis associated with antineutrophil cytoplasmic antibody-associated vasculitis: a case series of 15 patients.
      ] showed also that 66% of 15 patients with AAV-related hypertrophic pachymeningitis had otitis media and/or mastoiditis, i.e., OMAAV. We recently collected data for 100 patients with ANCA-positive hypertrophic pachymeningitis from the Japanese literature and found that the most common initial site is the ear (49%), followed by the eye (27%), kidney (7%), nose (3%), and lung (1%; data not shown). Collectively, the nationwide survey and previous reports show that frequent occurrences of facial palsy and hypertrophic pachymeningitis are the most prominent features of OMAAV.
      Hypertrophic pachymeningitis is characterized by thickening of the dura as a result of chronic inflammation of the dura mater. Headache is observed in more than 90% patients, is chronic, and occurs daily [
      • Peng A.
      • Yang X.
      • Wu W.
      • Xiao Z.
      • Xie D.
      • Ge S.
      Anti-neutrophil cytoplasmic antibody-associated hypertrophic cranial pachymeningitis and otitis media: a review of literature.
      ,
      • Yokoseki A.
      • Saji E.
      • Arakawa M.
      • Kosaka T.
      • Hokari M.
      • Toyoshima Y.
      • et al.
      Hypertrophic pachymeningitis: significance of myeloperoxidase anti-neutrophil cytoplasmic antibody.
      ,
      • Akahoshi M.
      • Yoshimoto G.
      • Nakashima H.
      • Miyake K.
      • Inoue Y.
      • Tanaka Y.
      • et al.
      MPO-ANCA-positive Wegener's granulomatosis presenting with hypertrophic cranial pachymeningitis: case report and review of the literature.
      ,
      • Shimojima Y.
      • Kishida D.
      • Hineno A.
      • Yazaki M.
      • Sekijima Y.
      • Ikeda S.I.
      Hypertrophic pachymeningitis is a characteristic manifestation of granulomatosis with polyangiitis: a retrospective study of anti-neutrophil cytoplasmic antibody-associated vasculitis.
      . Cranial nerve palsy is also a typical neurological symptom due to compression by the thickened dura mater, infiltration of inflammatory cells into the perineurium, increased brain pressure, and impaired circulation due to the thickened dura mater [
      • Peng A.
      • Yang X.
      • Wu W.
      • Xiao Z.
      • Xie D.
      • Ge S.
      Anti-neutrophil cytoplasmic antibody-associated hypertrophic cranial pachymeningitis and otitis media: a review of literature.
      ,
      • Yokoseki A.
      • Saji E.
      • Arakawa M.
      • Kosaka T.
      • Hokari M.
      • Toyoshima Y.
      • et al.
      Hypertrophic pachymeningitis: significance of myeloperoxidase anti-neutrophil cytoplasmic antibody.
      . The pathological findings are based on the proliferation of collagen fibers, infiltration of lymphocytes and plasma cells, and formation of granulomas. It can be understood that the inflammatory cells strongly infiltrate the dura mater of the cerebellar tentorium. Elevated levels of B-cell activating factor belonging to the tumor necrosis factor family (BAFF) and a proliferation-inducing ligand (APRIL) in the cerebrospinal fluid may also be involved in the pathogenesis [
      • Shimojima Y.
      • Kishida D.
      • Sekijima Y.
      Increased BAFF and APRIL levels in the cerebrospinal fluid of patients with anti-neutrophil cytoplasmic antibody-related hypertrophic pachymeningitis.
      ]. In MRI, the thickened dura mater shows low to equal signal intensity on T1-weighted images, high signal intensity on T2-weighted images, and a significant contrast effect on gadolinium-enhanced T1-weighted images (Fig. 2e). Localized hypertrophy is likely to occur in the cerebellar tent and skull base.
      Facial nerve palsy can be caused by inflammatory granulation spreading to the facial canal [
      • Yoshida N.
      • Iino Y.
      Pathogenesis and diagnosis of otitis media with ANCA-associated vasculitis.
      ]. Recurrent and/or bilateral facial palsy is not uncommon in patients with OMAAV [
      • Preuss S.F.
      • Stenner M.
      • Beutner D.
      • Laudes M.
      • Klussmann J.P.
      Fatal course of Wegener's granulomatosis with bilateral otomastoiditis and bilateral facial nerve palsy.
      ,
      • Gomez-Torres A.
      • Tirado Zamora I.
      • Abrante Jimenez A.
      • Esteban Ortega F.
      Wegener's granulomatosis causing bilateral facial paralysis and deafness.
      ,
      • Mori A.
      • Hira K.
      • Hatano T.
      • Okuma Y.
      • Kubo S.
      • Hirano K.
      • et al.
      Bilateral facial nerve palsy due to otitis media associated with myeloperoxidase-antineutrophil cytoplasmic antibody.
      ,
      • Ferri E.
      • Armato E.
      • Capuzzo P.
      • Cavaleri S.
      • Ianniello F.
      Early diagnosis of Wegener's granulomatosis presenting with bilateral facial paralysis and bilateral serous otitis media.
      ,
      • Roszkowska A.
      • Morawska-Kochman M.
      • Temporale H.
      • Sikorska-Zuk M.
      • Krecicki T.
      Bilateral facial palsy in rapidly progressive course of Wegener's granulomatosis: a case report.
      . Therefore, patients with intractable otitis media that recurrent or bilateral facial palsy during the clinical course should be suspected to have OMAAV.

      2.8 Prognostic factors

      Analysis of data from the nationwide survey revealed five prognostic factors for unfavorable hearing and life outcomes in patients with OMAAV: facial palsy, hypertrophic pachymeningitis, negativity for both MPO-ANCA and PR3-ANCA, disease relapse, and treatment with GCs alone (Fig. 3) [
      • Harabuchi Y.
      • Kishibe K.
      • Tateyama K.
      • Morita Y.
      • Yoshida N.
      • Kunimoto Y.
      • et al.
      Clinical features and treatment outcomes of otitis media with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (OMAAV): a retrospective analysis of 235 patients from a nationwide survey in Japan.
      ]. Negativity for both MPO-ANCA and PR3-ANCA and severe headache are closely associated with hypertrophic pachymeningitis. Early diagnosis of hypertrophic pachymeningitis is essential for improving hearing and life outcomes. Severe headache is a common clinical manifestation of hypertrophic pachymeningitis, although it is barely present during the acute phase of infectious otitis media. Therefore, in patients with intractable otitis media who complain of severe headache during the initial symptoms or clinical course, the presence of dural thickening should be confirmed by using gadolinium-enhanced MRI.
      Fig 3
      Fig. 3Prognostic factors of otitis media with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (OMAAV). As a result of nationwide survey analysis, the five prognostic factors of OMAAV related to hearing prognosis or life prognosis such as facial nerve palsy, hypertrophic pachymeningitis, both MPO- and PR3-ANCA negative, disease relapse, and treatment with glucocorticoid alone without an immunosuppressant were recognized. In addition, risk factors for hypertrophic pachymeningitis were both ANCA negative, facial palsy and severe headache. Treatment with glucocorticoid alone without an immunosuppressant is associated with disease relapse leading to poor survival and with the poor hearing outcome.

      3. Diagnostic criteria for OMAAV

      The JMHLW criteria [
      Research committee on intractable vasculitides, the labour and welfare of Japan.
      ] or the EMEA algorithm [
      • Watts R.
      • Lane S.
      • Hanslik T.
      • Hauser T.
      • Hellmich B.
      • Koldingsnes W.
      • et al.
      Development and validation of a consensus methodology for the classification of the ANCA-associated vasculitides and polyarteritis nodosa for epidemiological studies.
      ] is commonly used to diagnose systemic AAV. However, they cannot be useful to diagnose patients with OMAAV who do not show ANCA positivity, histopathological evidence, or involvement of organs other than the ear. In fact, the proportion of such patients at the first visit was 17% [
      • Harabuchi Y.
      • Kishibe K.
      • Tateyama K.
      • Morita Y.
      • Yoshida N.
      • Kunimoto Y.
      • et al.
      Clinical features and treatment outcomes of otitis media with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (OMAAV): a retrospective analysis of 235 patients from a nationwide survey in Japan.
      ]. It is already suggested that diagnostic criteria for AAV limited to the upper respiratory tract are necessary because half the patients show ANCA negativity and only one third the patients show histopathological evidence in biopsy specimens [
      • Harabuchi Y.
      • Kishibe K.
      • Komabayashi Y.
      Clinical manifestations of granulomatosis with polyangiitis (GPA: wegener's granulomatosis) in the upper respiratory tracts by otolaryngologists of Japan.
      ,
      • Holle J.U.
      • Gross W.L.
      • Holl-Ulrich K.
      • Ambrosch P.
      • Noelle B.
      • Both M.
      • et al.
      Prospective long-term follow-up of patients with localised Wegener's granulomatosis: does it occur as persistent disease stage?.
      . Therefore, diagnosis of OMAAV requires specialized diagnostic criteria that differ from the JMHLW criteria and EMEA algorithm.
      The diagnostic criteria for OMAAV (Table 3) are designed for early diagnosis, and they are based on three requirements consisting of the clinical course, clinical features, and differential diagnoses. A diagnosis is established when all three requirements are fulfilled.
      Table 3Diagnostic criteria of OMAAV.
      OMAAV is diagnosed, if the following three criteria (A, B, C) are fulfilled:
      (A) At least one of the following clinical courses:
      1. Intractable otitis media with effusion or granulation, which is resistant to antibiotics and insertion of tympanostomy tube.
      2. Progressive deterioration of bone conduction hearing levels.
      (B) At least one of the following features:
      1. Already diagnosed as AAV (GPA, MPA, EGPA) based on the involvement of other organs.
      2. Positivity for serum MPO- or PR3-ANCA.
      3. Histopathology consistent with AAV, i.e., necrotizing vasculitis predominantly affecting small vessels with or without granulomatous extravascular inflammation.
      4. At least one of the following accompanying signs/symptoms of AAV-related involvement:
      (1) involvements with upper airway tracts other than ear, scleritis, lung, and/or kidney, (2) facial palsy, (3) hypertrophic pachymeningitis, (4) multiple mononeuropathy
      (5) transient alleviation of symptoms/signs with administration of 0.5–1.0 mg/kg prednisolone and relapse with discontinuation of treatment
      (C) Differential diagnosis
      (1) cholesteatoma, (2) cholesterol granuloma, (3) eosinophilic otitis media, (4) tuberculosis (5) malignant otitis externa, skull-base osteomyelitis, (6) neoplasms (malignancy, inflammatory myofibroblastic tumor, etc.), (7) otitis media or inner ear inflammation caused by autoimmune diseases and vasculitis other than AAV.

      3.1 Clinical course

      During the clinical course, the vast majority of patients has intractable otitis media with effusion or granulation, which does not respond to ordinary treatments such as antibiotics and insertion of tympanic ventilation tubes. Hearing symptoms begin with gradual air-conduction hearing loss due to effusion or granulation in the middle ear, with or without progressive deterioration of bone-conduction hearing [
      • Harabuchi Y.
      • Kishibe K.
      • Komabayashi Y.
      Clinical manifestations of granulomatosis with polyangiitis (GPA: wegener's granulomatosis) in the upper respiratory tracts by otolaryngologists of Japan.
      ]. A small number (4%) of patients develop progressive deterioration of bone-conduction hearing, followed by intractable otitis media. On the basis of these findings, we propose that at least one of the following clinical courses should be present for a diagnosis of OMAAV: 1. intractable otitis media with effusion or granulation resistant to antibiotics and/or insertion of a tympanostomy tube, and 2. progressive deterioration of bone conduction hearing [
      • Harabuchi Y.
      • Kishibe K.
      • Komabayashi Y.
      Clinical manifestations of granulomatosis with polyangiitis (GPA: wegener's granulomatosis) in the upper respiratory tracts by otolaryngologists of Japan.
      ].

      3.2 Histopathological and clinical features

      The common histopathological definition of AAV, which includes GPA, MPA, and EGPA, is ``necrotizing vasculitis predominantly affecting small vessels'' [
      Research committee on intractable vasculitides, the labour and welfare of Japan.
      ,
      • Watts R.
      • Lane S.
      • Hanslik T.
      • Hauser T.
      • Hellmich B.
      • Koldingsnes W.
      • et al.
      Development and validation of a consensus methodology for the classification of the ANCA-associated vasculitides and polyarteritis nodosa for epidemiological studies.
      . As minor findings, GPA is associated with necrotic granulation with neutrophil-dominated infiltration, MPA has extravascular inflammatory cell infiltration, and EGPA has eosinophil infiltration [
      • Jennette J.C.
      • Falk R.J.
      • Bacon P.A.
      • Basu N.
      • Cid M.C.
      • Ferrario F.
      • et al.
      2012 revised international chapel hill consensus conference nomenclature of vasculitides.
      ]. However, these minor findings are not necessary for OMAAV, because OMAAV is defined as otitis media due to AAV including GPA, MPA, EGPA and unclassified AAV, the type of infiltrating cells does not restrict to the histopathological diagnosis. Thus, histopathology of OMAA for the diagnostic criteria is defined as ``necrotizing vasculitis predominantly affecting small vessels with or without granulomatous extravascular inflammation'' as listed in (B)−3 of Table 3.
      Positivity for serum MPO-ANCA or PR3-ANCA as well as histopathological evidence of AAV are important for diagnosing AAV [
      Research committee on intractable vasculitides, the labour and welfare of Japan.
      ,
      • Watts R.
      • Lane S.
      • Hanslik T.
      • Hauser T.
      • Hellmich B.
      • Koldingsnes W.
      • et al.
      Development and validation of a consensus methodology for the classification of the ANCA-associated vasculitides and polyarteritis nodosa for epidemiological studies.
      . However, analysis of the 297 patients identified in the nationwide survey revealed that 17% patients showed negativity for MPO-ANCA and PR3-ANCA, while only 32% showed histopathological findings consistent with AAV. It should be noted that only one of these patients showed histopathological findings of necrotizing vasculitis in the middle ear cavity. Furthermore, 15% patients showed neither ANCA positivity nor histopathological evidence of AAV at the initial visit. These results suggest that ANCA positivity and histopathological evidence cannot be applied to diagnose all cases of OMAAV. Repeated biopsy by tympanostomy or experimental mastoid surgery cannot be performed just because middle ear biopsy does not show histopathological evidence of AAV. Such actions can lead to delayed diagnosis and disease progression.
      In the nationwide survey, it was found that AAV-related signs/symptoms such as upper respiratory tract lesions, scleritis, lung lesions, kidney lesions, and multiple mononeuropathy were observed in 44%, 6%, 38%, 26%, and 5% patients, respectively. In addition, as noted above, frequent occurrences of facial palsy and hypertrophic pachymeningitis are the most characteristic signs in OMAAV [
      • Harabuchi Y.
      • Kishibe K.
      • Tateyama K.
      • Morita Y.
      • Yoshida N.
      • Kunimoto Y.
      • et al.
      Clinical features and treatment outcomes of otitis media with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (OMAAV): a retrospective analysis of 235 patients from a nationwide survey in Japan.
      ]. Therefore, we included these accompanying signs/symptoms related to AAV in the diagnostic criteria for OMAAV. Accordingly, patients who show neither ANCA positivity nor histopathological evidence of AAV can be diagnosed with OMAAV if they show the AAV-related signs/symptoms mentioned above or are already diagnosed with AAV (GPA, MPA, EGPA) involving another organ.
      Thus, for patients without ANCA positivity, histopathological evidence of AAV, or AAV-related lesions in organs other than the ear at the initial visit [
      • Harabuchi Y.
      • Kishibe K.
      • Tateyama K.
      • Morita Y.
      • Yoshida N.
      • Kunimoto Y.
      • et al.
      Clinical features and treatment outcomes of otitis media with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (OMAAV): a retrospective analysis of 235 patients from a nationwide survey in Japan.
      ], diagnosis of OMAAV is very difficult until other organs have developed signs/symptoms related to AAV. The purpose of the proposed diagnostic criteria is early diagnosis. The survey found that patients who received only GCs showed transient improvement of symptoms/signs and frequently experienced disease relapse [
      • Harabuchi Y.
      • Kishibe K.
      • Tateyama K.
      • Morita Y.
      • Yoshida N.
      • Kunimoto Y.
      • et al.
      Clinical features and treatment outcomes of otitis media with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (OMAAV): a retrospective analysis of 235 patients from a nationwide survey in Japan.
      ]. Therefore, we added the following criterion: “transient alleviation of symptoms/signs with administration of 0.5–1.0 mg/kg prednisolone and relapse with discontinuation of treatment.”

      3.3 Differential diagnoses

      When the requirements for the clinical course and clinical features, as detailed above, are met, and then the differential diagnoses are completed, a diagnosis of OMAAV can be confirmed. Diseases that should be distinguished from OMAAV include those causing refractory otitis media: middle ear cholesteatoma, cholesterol granuloma, eosinophilic otitis media (EOM), tuberculosis, malignant otitis externa (skull base osteomyelitis), neoplasms (malignant tumor, inflammatory myofibroblastic tumor, etc.), and autoimmune diseases other than AAV (steroid-dependent hearing loss, autoimmune inner ear disorder, Cogan syndrome, polyarteritis nodosa, antiphospholipid antibody syndrome, Vogt–Koyanagi–Harada disease, IgG4-related diseases). Among these diseases, eosinophilic otitis media (EOM), malignant otitis externa causing skull base osteomyelitis, and IgG4-related diseases are often difficult to differentiate from OMAAV.
      EOM presents as intractable otitis media with thick, glue-like, middle ear effusion caused by infiltration of eosinophils in the middle ear. It is resistant to conventional treatments such as antibiotics, tympanic tube insertion, and surgery. Similar to those in OMAAV, the eardrum findings in EOM are divided into the OME and OMG types. The diagnostic criteria are helpful for discrimination of OMAAV and EOM (Table 4) [
      • Iino Y.
      • Tomioka-Matsutani S.
      • Matsubara A.
      • Nakagawa T.
      • Nonaka M.
      Diagnostic criteria of eosinophilic otitis media, a newly recognized middle ear disease.
      ]; the presence or absence of eosinophil infiltration should be confirmed. However, OMAAV due to EGPA, similar to EOM, is also associated with bronchial asthma and eosinophil infiltration in the middle ear fluid. Therefore, the patients with OMAAV due to EGPA are often first diagnosed with EOM, and a definite diagnosis is established based on the later onset of peripheral neuritis.
      Table 4Diagnostic criteria of eosinophilic otitis media (EOM).
      Major: Otitis media with effusion or chronic otitis media with eosinophil dominant effusion
      Minor:
       1. Highly viscous middle ear effusion
       2. Resistance to conventional treatment for otitis media
       3. Association with bronchial asthma
       4. Association with nasal polyposis
      Definitive case: positive for major + two or more minor criteria
      Exclusion criteria: Churg-Strauss syndrome, hypereosinophilic syndrome
      It is also difficult to distinguish OMAAV from malignant external otitis, which progresses to skull base osteomyelitis, because the clinical course and local findings in both conditions are similar. Although diagnosis criteria are proposed (Table 5) [
      • Joshua B.Z.
      • Sulkes J.
      • Raveh E.
      • Bishara J.
      • Nageris B.I.
      Predicting outcome of malignant external otitis.
      ], different diagnosis is difficult even if any requirement of the diagnostic criteria is met, particularly when OMAAV is complicated by infection. Both diseases show otalgia, otorrhea, swelling and granulation in the external ear canal, resistance to treatment, and development of facial palsy and hypertrophic pachymeningitis. Differentiating factors for malignant external otitis include evidence of pathological microbes detected by bacterial or fungal testing, response to antibiotics, complications of diabetes, and negativity for ANCA. CT findings include the spread of petrositis and osteolytic lesions from the base of the skull to the other side. It extends to the temporomandibular joints, parotid gland, parapharyngeal space, apex of the cone, and middle cranial fossa. However, advanced cases of OMAAV show similar CT and MRI findings. Malignant otitis externa may be suspected if an effective antibiotic is administered and the patient responds, while OMAAV may be suspected if the patient responds to steroid treatment without showing a response to antibiotic treatment. In both OMAAV and malignant external otitis, the lack of early intervention can lead to disease progression and fatal outcomes; therefore, appropriate differentiation and treatment are essential.
      Table 5Diagnostic criteria for malignant external otitis (Joshua, 2008).
      * Definitive diagnosis: All mandatory findings are positive or one mandatory finding is missing, but symptoms are not improved by hospital treatment for one week or more.
      1. Mandatory findings
      1) pain, otorrhea, 2) external ear swelling, 3) external auditory canal granulation, 4) micro abscess (found in surgery), 5) bone scintigraphy positive, 6) No symptom improvement after 1 week of topical treatment
      2. Reference findings
      1) Pseudomonas aeruginosa detection, 2) Positive for imaging test, 3) Diabetes complication, 4) Cranial nerve symptoms, 5) poor performance status, 6) elderly
      Autoimmune diseases that show progressive deterioration in bone-conduction hearing and respond to GCs and immunosuppressants also require differentiation from OMAAV (Table 6). IgG4-related diseases, which are characterized by high serum IgG4 levels and infiltration of IgG4-positive plasma cells in one or more organs resulting in local enlargement, fibrosis, masses, nodules and hypertrophic lesions, are often difficult to distinguish from OMAAV. Similar to OMAAV, IgG4-related diseases can cause hypertrophic pachymeningitis and mastoiditis [
      • Schiffenbauer A.I.
      • Wahl C.
      • Pittaluga S.
      • Jaffe E.S.
      • Hoffman R.
      • Khosroshahi A.
      • et al.
      IgG4-related disease presenting as recurrent mastoiditis.
      ,
      • Barnado A.L.
      • Cunningham M.A.
      IgG4-related disease presenting as recurrent mastoiditis with central nervous system involvement.
      ,
      • Chowsilpa S.
      • Chowsilpa S.
      • Teeranoraseth T.
      • Roongrotwattanasiri K.
      Temporal bone involvement of IgG4-related disease: a rare condition misleading to petrous apicitis causing lateral rectus palsy.
      ]. Reports of patients with IgG4-related disease who developed otitis media with MPO-ANCA positivity and mixed hearing loss [
      • Ohno K.
      • Matsuda Y.
      • Arai T.
      • Sugihara T.
      • Iga S.
      • Kimura Y.
      Myeloperoxidase-antineutrophil cytoplasmic antibody-positive otitis media and rhinosinusitis with pathological features of immunoglobulin G4-related disease: a case report.
      ] as well as several case reports showing that AAV and IgG4-related disease are related or overlapping [
      • Della-Torre E.
      • Lanzillotta M.
      • Campochiaro C.
      • Bozzalla E.
      • Bozzolo E.
      • Bandiera A.
      • et al.
      Antineutrophil cytoplasmic antibody positivity in IgG4-related disease: a case report and review of the literature.
      ,
      • Danlos F.X.
      • Rossi G.M.
      • Blockmans D.
      • Emmi G.
      • Kronbichler A.
      • Durupt S.
      • et al.
      Antineutrophil cytoplasmic antibody-associated vasculitides and IgG4-related disease: a new overlap syndrome.
      ,
      • Kawashima H.
      • Utsugi A.
      • Shibamiya A.
      • Iida K.
      • Mimura N.
      • Ohashi H.
      • et al.
      Consideration concerning similarities and differences between ANCA-associated vasculitis and IgG-4-related diseases: case series and review of literature.
      ] are also available. Treatments for the two diseases are different; IgG4-related diseases respond well to GC treatment alone, whereas OMAAV can relapse if treated by GCs alone and requires both GCs and immunosuppressive agents. Therefore, in such cases, treatment with GCs alone should be attempted at first and switched to treatment with GCs and immunosuppressive agents in the absence of a response.
      Table 6Autoimmune diseases that require differentiation from OMAAV.
      • 1)
        Steroid-dependent hearing loss
      • 2)
        Autoimmune inner ear disorder
      • 3)
        Cogan syndrome
      • 4)
        Polyarteritis nodosa
      • 5)
        Antiphospholipid antibody syndrome
      • 6)
        Vogt, Koyanagi, Harada disease
      • 7)
        IgG4-rlated diseases
      steroid-dependent hearing loss, autoimmune inner ear disorder, Cogan syndrome, polyarteritis nodosa, antiphospholipid antibody syndrome, Vogt-Koyanagi-Harada disease, IgG4-related diseases

      4. Management of patients with negativity for both mpo-anca and PR3-ANCA

      In the nationwide survey, 17% patients with OMAAV showed negativity for both MPO-ANCA and PR3-ANCA (Table 2). There is a considerable number of case reports involving patients with OMAAV who showed negativity for both MPO-ANCA and PR3-ANCA or became seropositive during the clinical course [
      • Bibas A.
      • Fahy C.
      • Sneddon L.
      • Bowdler D.
      Facial paralysis in Wegener's granulomatosis of the middle ear.
      ,
      • Nikolaou A.C.
      • Vlachtsis K.C.
      • Daniilidis M.A.
      • Petridis D.G.
      • Daniilidis I.C.
      Wegener's granulomatosis presenting with bilateral facial nerve palsy.
      ,
      • Sriskandarajah V.
      • Bansal R.A.
      • Yeoh R.
      • Bansal A.S.
      Early intervention in localized Wegener's granulomatosis with sensorineural hearing loss preserves hearing.
      ,
      • Yokoseki A.
      • Saji E.
      • Arakawa M.
      • Kosaka T.
      • Hokari M.
      • Toyoshima Y.
      • et al.
      Hypertrophic pachymeningitis: significance of myeloperoxidase anti-neutrophil cytoplasmic antibody.
      ,
      • Carrie S.
      • Hughes K.B.
      • Watson M.G.
      Negative ANCA in Wegener's granulomatosis.
      ,
      • Dekker P.J.
      Wegener's granulomatosis: otological aspects.
      ,
      • Taylor S.C.
      • Clayburgh D.R.
      • Rosenbaum J.T.
      • Schindler J.S.
      Progression and management of Wegener's granulomatosis in the head and neck.
      ]. These reports provide evidence for the existence of an ANCA-negative phenotype of OMAAV. The 2012 Chapel Hill Consensus Conference definitions [
      • Jennette J.C.
      • Falk R.J.
      • Bacon P.A.
      • Basu N.
      • Cid M.C.
      • Ferrario F.
      • et al.
      2012 revised international chapel hill consensus conference nomenclature of vasculitides.
      ] proposed that ANCA-negative AAV can be caused by three possible factors: ANCA that cannot be detected by current methods, ANCA other than MPO-ANCA and PR3-ANCA that is not yet discovered, and pathogenic mechanisms not involving ANCA.
      It is difficult to diagnose OMAAV limited to the middle ear, particularly if MPO-ANCA and PR3-ANCA are absent. In the survey, patients with the ANCA-negative phenotype showed an unfavorable clinical course that affected their hearing and even proved fatal. These outcomes can be attributed to disease progression due to the long pretreatment period. Delayed diagnosis can cause irreversible progressive hearing loss, facial palsy, and hypertrophic pachymeningitis.
      Recently, an international consensus regarding testing for ANCA recommended that screening for PR3-ANCA and MPO-ANCA by indirect immunofluorescence (IIF) and secondary immunoassay testing should be considered for patients with negative results. IIF and immunoassay testing can increase the sensitivity of diagnosis in cases with clinically suspected disease and increase the specificity in cases with low antibody levels [
      • Cohen Tervaert J.W.
      • Damoiseaux J.
      Antineutrophil cytoplasmic autoantibodies: how are they detected and what is their use for diagnosis, classification and follow-up?.
      ]. Tateyama et al. [
      • Tateyama K.
      • Kodama S.
      • Kishibe K.
      • Harabuchi Y.
      • Suzuki M.
      A novel strategy with combined assays for detection of anti-neutrophil cytoplasmic antibody (ANCA) in clinically ANCA-negative granulomatosis with polyangiitis patients.
      ] reported that eight of 17 ANCA-negative patients with OMAAV were reclassified as ANCA-positive patients after analysis using a combination of ANCA detection methods. They also demonstrated that bactericidal/permeability increasing protein (BPI)-ANCA with systemic vasculitis accompanied by suppurative lung disease [
      • Park J.
      • Banno S.
      • Sugiura Y.
      • Yoshikawa K.
      • Naniwa T.
      • Wakita K.
      • et al.
      Microscopic polyangiitis associated with diffuse panbronchiolitis.
      ] and elastase-ANCA associated with necrotizing crescentic glomerulonephritis [
      • Seidowsky A.
      • Hoffmann M.
      • Ruben-Duval S.
      • Mesbah R.
      • Masy E.
      • Kyndt X.
      • et al.
      Elastase-ANCA-associated idiopathic necrotizing crescentic glomerulonephritis–a report of three cases.
      ] were detected in several samples with seronegativity for both MPO-ANCA and PR3-ANCA [
      • Tateyama K.
      • Kodama S.
      • Kishibe K.
      • Harabuchi Y.
      • Suzuki M.
      A novel strategy with combined assays for detection of anti-neutrophil cytoplasmic antibody (ANCA) in clinically ANCA-negative granulomatosis with polyangiitis patients.
      ]. These results suggest higher disease activity in the ANCA-negative phenotype.
      Neutrophil extracellular traps (NETs) are released as a result of the programmed neutrophil cell death mechanism known as NETosis. They are composed of extracellular DNA fibers decorated with various enzymes, including MPO, PR3, histones, and neutrophil elastase, and are involved in the pathogenesis of AAV [
      • Brinkmann V.
      • Reichard U.
      • Goosmann C.
      • Fauler B.
      • Uhlemann Y.
      • Weiss D.S.
      • et al.
      Neutrophil extracellular traps kill bacteria.
      ]. The formation of NETs induces inflammation of the vascular wall and produces pathogenic ANCA, resulting in a vicious cycle of neutrophil reactivation and widespread vasculitis [
      • Brinkmann V.
      • Reichard U.
      • Goosmann C.
      • Fauler B.
      • Uhlemann Y.
      • Weiss D.S.
      • et al.
      Neutrophil extracellular traps kill bacteria.
      ]. Recently, NETs (MPO-DNA complex) in the middle ear reservoir were reported to be very useful as biomarkers of OMAAV [
      • Morita S.
      • Nakamaru Y.
      • Nakazawa D.
      • Hattanda F.
      • Shida H.
      • Kusunoki Y.
      • et al.
      Elevated level of myeloperoxidase-deoxyribonucleic acid complex in the middle ear fluid obtained from patients with otitis media associated with antineutrophil cytoplasmic antibody-associated vasculitis.
      ,
      • Morita S.
      • Nakamaru Y.
      • Nakazawa D.
      • Suzuki M.
      • Hoshino K.
      • Fukuda A.
      • et al.
      The diagnostic and clinical utility of the myeloperoxidase-dna complex as a biomarker in otitis media with antineutrophil cytoplasmic antibody-associated vasculitis.
      . Even ANCA-negative patients and those receiving immunosuppressive therapy at the time of sampling showed high levels of the MPO–DNA complex [
      • Morita S.
      • Nakamaru Y.
      • Nakazawa D.
      • Hattanda F.
      • Shida H.
      • Kusunoki Y.
      • et al.
      Elevated level of myeloperoxidase-deoxyribonucleic acid complex in the middle ear fluid obtained from patients with otitis media associated with antineutrophil cytoplasmic antibody-associated vasculitis.
      ,
      • Morita S.
      • Nakamaru Y.
      • Nakazawa D.
      • Suzuki M.
      • Hoshino K.
      • Fukuda A.
      • et al.
      The diagnostic and clinical utility of the myeloperoxidase-dna complex as a biomarker in otitis media with antineutrophil cytoplasmic antibody-associated vasculitis.
      .

      5. Treatments

      5.1 Remission induction therapy

      Although there are several clinical practice guidelines for the treatment of systemic AAV [
      • Mukhtyar C.
      • Guillevin L.
      • Cid M.C.
      • Dasgupta B.
      • de Groot K.
      • Gross W.
      • et al.
      EULAR recommendations for the management of primary small and medium vessel vasculitis.
      ,
      • Ntatsaki E.
      • Carruthers D.
      • Chakravarty K.
      • D'Cruz D.
      • Harper L.
      • Jayne D.
      • et al.
      BSR and BHPR guideline for the management of adults with ANCA-associated vasculitis.
      ,
      • Yates M.
      • Watts R.A.
      • Bajema I.M.
      • Cid M.C.
      • Crestani B.
      • Hauser T.
      • et al.
      EULAR/ERA-EDTA recommendations for the management of ANCA-associated vasculitis.
      ,
      • Nagasaka K.
      • Harigai M.
      • Hagino N.
      • Hara A.
      • Horita T.
      • Hayashi T.
      • et al.
      Systematic review and meta-analysis for 2017 clinical practice guidelines of the Japan research committee of the ministry of health, labour, and welfare for intractable vasculitis for the management of ANCA-associated vasculitis.
      ,
      • Harigai M.
      • Nagasaka K.
      • Amano K.
      • Bando M.
      • Dobashi H.
      • Kawakami T.
      • et al.
      2017 clinical practice guidelines of the Japan research committee of the ministry of health, labour, and welfare for intractable vasculitis for the management of ANCA-associated vasculitis.
      ], therapies for AAV localized in the upper respiratory tract and OMAAV have not yet been standardized. As mentioned above, treatment of OMAAV with GCs and immunosuppressants can prevent disease relapse and the progression of hearing loss more effectively than can treatment with GCs alone [
      • Harabuchi Y.
      • Kishibe K.
      • Tateyama K.
      • Morita Y.
      • Yoshida N.
      • Kunimoto Y.
      • et al.
      Clinical features and treatment outcomes of otitis media with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (OMAAV): a retrospective analysis of 235 patients from a nationwide survey in Japan.
      ]. On the basis of the results of the nationwide survey, previous reports [
      • Akahoshi M.
      • Yoshimoto G.
      • Nakashima H.
      • Miyake K.
      • Inoue Y.
      • Tanaka Y.
      • et al.
      MPO-ANCA-positive Wegener's granulomatosis presenting with hypertrophic cranial pachymeningitis: case report and review of the literature.
      ,
      • Mukhtyar C.
      • Guillevin L.
      • Cid M.C.
      • Dasgupta B.
      • de Groot K.
      • Gross W.
      • et al.
      EULAR recommendations for the management of primary small and medium vessel vasculitis.
      ,
      • Sada K.E.
      • Yamamura M.
      • Harigai M.
      • Fujii T.
      • Takasaki Y.
      • Amano K.
      • et al.
      Different responses to treatment across classified diseases and severities in Japanese patients with microscopic polyangiitis and granulomatosis with polyangiitis: a nationwide prospective inception cohort study.
      , and recent treatment guidelines [
      • Nagasaka K.
      • Harigai M.
      • Hagino N.
      • Hara A.
      • Horita T.
      • Hayashi T.
      • et al.
      Systematic review and meta-analysis for 2017 clinical practice guidelines of the Japan research committee of the ministry of health, labour, and welfare for intractable vasculitis for the management of ANCA-associated vasculitis.
      ,
      • Harigai M.
      • Nagasaka K.
      • Amano K.
      • Bando M.
      • Dobashi H.
      • Kawakami T.
      • et al.
      2017 clinical practice guidelines of the Japan research committee of the ministry of health, labour, and welfare for intractable vasculitis for the management of ANCA-associated vasculitis.
      , combined administration of both GCs and immunosuppressants is recommended as remission induction therapy for OMAAV.
      For OMAAV with lesions localized to the ear, prednisolone (PSL; 0.3–1 mg/kg/day) and oral cyclophosphamide (CY; 25–75 mg/body/day) are recommended as drugs for remission induction therapy. As immunosuppressants, monthly CY pulse therapy (15 mg/kg/month) or oral azathioprine (AZA; 0.5–1.5 mg/kg/day), as recommended by recent clinical guidelines [
      • Nagasaka K.
      • Harigai M.
      • Hagino N.
      • Hara A.
      • Horita T.
      • Hayashi T.
      • et al.
      Systematic review and meta-analysis for 2017 clinical practice guidelines of the Japan research committee of the ministry of health, labour, and welfare for intractable vasculitis for the management of ANCA-associated vasculitis.
      ,
      • Harigai M.
      • Nagasaka K.
      • Amano K.
      • Bando M.
      • Dobashi H.
      • Kawakami T.
      • et al.
      2017 clinical practice guidelines of the Japan research committee of the ministry of health, labour, and welfare for intractable vasculitis for the management of ANCA-associated vasculitis.
      , and methotrexate (MTX; 15–25 mg/week) every alternate week, as recommended by JMHLW for disease limited to the upper respiratory tract [
      • Sada K.E.
      • Yamamura M.
      • Harigai M.
      • Fujii T.
      • Takasaki Y.
      • Amano K.
      • et al.
      Different responses to treatment across classified diseases and severities in Japanese patients with microscopic polyangiitis and granulomatosis with polyangiitis: a nationwide prospective inception cohort study.
      ], are also recommended. PSL dose reduction begins at 1–2 weeks after local and hearing levels exhibit remission, and the dose is tapered by 5–10 mg weekly up to 15–20 mg/day, which is maintained for at least 3 months.
      Rituximab (RTX), an anti-CD20 antibody, has been reported to be effective in inducing remission in cases of intractable MPA and GPA [
      • Nagasaka K.
      • Harigai M.
      • Hagino N.
      • Hara A.
      • Horita T.
      • Hayashi T.
      • et al.
      Systematic review and meta-analysis for 2017 clinical practice guidelines of the Japan research committee of the ministry of health, labour, and welfare for intractable vasculitis for the management of ANCA-associated vasculitis.
      ,
      • Harigai M.
      • Nagasaka K.
      • Amano K.
      • Bando M.
      • Dobashi H.
      • Kawakami T.
      • et al.
      2017 clinical practice guidelines of the Japan research committee of the ministry of health, labour, and welfare for intractable vasculitis for the management of ANCA-associated vasculitis.
      as well as cases of systemic AAV [
      • Jones R.B.
      • Tervaert J.W.
      • Hauser T.
      • Luqmani R.
      • Morgan M.D.
      • Peh C.A.
      • et al.
      Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis.
      ,
      • Stone J.H.
      • Merkel P.A.
      • Spiera R.
      • Seo P.
      • Langford C.A.
      • Hoffman G.S.
      • et al.
      Rituximab versus cyclophosphamide for ANCA-associated vasculitis.
      ,
      • Roll P.
      • Ostermeier E.
      • Haubitz M.
      • Lovric S.
      • Unger L.
      • Holle J.
      • et al.
      Efficacy and safety of rituximab treatment in patients with antineutrophil cytoplasmic antibody-associated vasculitides: results from a German registry (GRAID).
      ]. The European League Against Rhuematism (EULAR) recommends treatment with GC + RTX for achieving remission of organ-threatening or life-threatening AAV [
      • Yates M.
      • Watts R.A.
      • Bajema I.M.
      • Cid M.C.
      • Crestani B.
      • Hauser T.
      • et al.
      EULAR/ERA-EDTA recommendations for the management of ANCA-associated vasculitis.
      ]. In addition, GC + RTX (at a dose of 375 mg/m2 once a week for 2–4 weeks) is reported to be effective and safe for intractable OMAAV that does not exhibit remission with methylprednisolone pulse therapy and intravenous CY [
      • Okada M.
      • Suemori K.
      • Takagi D.
      • Teraoka M.
      • Yamada H.
      • Ishizaki J.
      • et al.
      The treatment outcomes of rituximab for intractable otitis media with ANCA-associated vasculitis.
      ].
      For patients with OMAAV accompanied by lesions in systemic organs such as the lungs and kidneys, treatments should be administered as per the severity, in accordance with clinical practice guidelines for systemic AAV in Japan [
      • Nagasaka K.
      • Harigai M.
      • Hagino N.
      • Hara A.
      • Horita T.
      • Hayashi T.
      • et al.
      Systematic review and meta-analysis for 2017 clinical practice guidelines of the Japan research committee of the ministry of health, labour, and welfare for intractable vasculitis for the management of ANCA-associated vasculitis.
      ,
      • Harigai M.
      • Nagasaka K.
      • Amano K.
      • Bando M.
      • Dobashi H.
      • Kawakami T.
      • et al.
      2017 clinical practice guidelines of the Japan research committee of the ministry of health, labour, and welfare for intractable vasculitis for the management of ANCA-associated vasculitis.
      ,
      • Sada K.E.
      • Yamamura M.
      • Harigai M.
      • Fujii T.
      • Takasaki Y.
      • Amano K.
      • et al.
      Different responses to treatment across classified diseases and severities in Japanese patients with microscopic polyangiitis and granulomatosis with polyangiitis: a nationwide prospective inception cohort study.
      ], EULAR guidelines [
      • Mukhtyar C.
      • Guillevin L.
      • Cid M.C.
      • Dasgupta B.
      • de Groot K.
      • Gross W.
      • et al.
      EULAR recommendations for the management of primary small and medium vessel vasculitis.
      ], and BSR/BHPR guidelines [
      • Ntatsaki E.
      • Carruthers D.
      • Chakravarty K.
      • D'Cruz D.
      • Harper L.
      • Jayne D.
      • et al.
      BSR and BHPR guideline for the management of adults with ANCA-associated vasculitis.
      ]. Patients with OMAAV and hypertrophic pachymeningitis receive methylprednisolone pulse therapy (500–1000 mg/body, 3 days), followed by remission induction therapy with PSL and immunosuppressants.

      5.2 Remission maintenance therapy

      Following maintenance PSL treatment at 15–20 mg/day for at least 3 months, remission maintenance therapy is initiated. PSL is reduced by 1.25 or 2.5 mg every 4–8 weeks and subsequently maintained at 10 mg/day for a certain duration. Subsequently, the dose should be carefully reduced by 1 mg or 10% every 4–8 weeks. Withdrawal of GCs within 12 months of treatment initiation significantly increases the risk of recurrence [
      • Walsh M.
      • Merkel P.A.
      • Mahr A.
      • Jayne D.
      Effects of duration of glucocorticoid therapy on relapse rate in antineutrophil cytoplasmic antibody-associated vasculitis: a meta-analysis.
      ].
      CY should be reduced by 5 mg every 4–8 weeks, following which it should be maintained at 12.5–25 mg/day for a certain duration. For further dose reduction, it is necessary to plan regimens such as administration every other day or administration for 2 days followed by a break for 1 day. PSL + CY therapy is effective, and remission can be achieved once in most patients with disease limited to the middle ear. However, long-term administration of CY can easily cause side effects such as infection, hematopoiesis, infertility, and bladder bleeding, and it also carries a risk of carcinogenesis (mainly bladder cancer). The incidence of these toxicities is proportional to the cumulative dose. Therefore, the duration of CY administration should not exceed 6 months, and recent practice guidelines recommend the replacement of CY with AZA (0.5–1.5 mg/kg/day) [
      • Nagasaka K.
      • Harigai M.
      • Hagino N.
      • Hara A.
      • Horita T.
      • Hayashi T.
      • et al.
      Systematic review and meta-analysis for 2017 clinical practice guidelines of the Japan research committee of the ministry of health, labour, and welfare for intractable vasculitis for the management of ANCA-associated vasculitis.
      ,
      • Harigai M.
      • Nagasaka K.
      • Amano K.
      • Bando M.
      • Dobashi H.
      • Kawakami T.
      • et al.
      2017 clinical practice guidelines of the Japan research committee of the ministry of health, labour, and welfare for intractable vasculitis for the management of ANCA-associated vasculitis.
      . Weekly administration of MTX (increased from 15 mg/week) is also an option for immunosuppression [
      • Nagasaka K.
      • Harigai M.
      • Hagino N.
      • Hara A.
      • Horita T.
      • Hayashi T.
      • et al.
      Systematic review and meta-analysis for 2017 clinical practice guidelines of the Japan research committee of the ministry of health, labour, and welfare for intractable vasculitis for the management of ANCA-associated vasculitis.
      ,
      • Harigai M.
      • Nagasaka K.
      • Amano K.
      • Bando M.
      • Dobashi H.
      • Kawakami T.
      • et al.
      2017 clinical practice guidelines of the Japan research committee of the ministry of health, labour, and welfare for intractable vasculitis for the management of ANCA-associated vasculitis.
      .

      5.3 Surgery

      Ear surgeries such as mastoidectomy and tympanoplasty for reducing inflammation and improving hearing loss should not be performed because they are not effective and may worsen the disease during the active phase of OMAAV. In addition, repeated biopsies with tympanostomy or experimental mastoidectomy to obtain histopathological evidence should be avoided. Histopathological evidence is present in the middle ear and mastoid cavity in extremely rare cases. A diagnosis can be established when the proposed diagnostic criteria, based on the clinical course, clinical features, and differential diagnoses, are fulfilled.
      Cochlear implantation should be considered as treatment for OMAAV that progresses to bilateral profound deafness [
      • Watanabe T.
      • Yoshida H.
      • Kishibe K.
      • Morita Y.
      • Yoshida N.
      • Takahashi H.
      • et al.
      Cochlear implantation in patients with bilateral deafness caused by otitis media with ANCA-associatedvasculitis (OMAAV): a report of four cases.
      ,
      • Abou-Elhmd K.A.
      • Hawthorne M.R.
      • Flood L.M.
      Cochlear implantation in a case of Wegener's granulomatosis.
      ,
      • Elmas F.
      • Shrestha B.L.
      • Linder T.E.
      Subtotal petrosectomy and cochlear implant placement in otologic presentation of ``Wegener's granulomatosis''.
      . Abou-Elhmd et al. [
      • Abou-Elhmd K.A.
      • Hawthorne M.R.
      • Flood L.M.
      Cochlear implantation in a case of Wegener's granulomatosis.
      ] reported that cochlear implantation in patients with GPA-associated OMAAV characterized by total hearing loss resulted in a free-field threshold of 40 dB and a score of 20% in the Bamford–Kowal–Bench (BKB) speech recognition test. Watanabe et al. [
      • Watanabe T.
      • Yoshida H.
      • Kishibe K.
      • Morita Y.
      • Yoshida N.
      • Takahashi H.
      • et al.
      Cochlear implantation in patients with bilateral deafness caused by otitis media with ANCA-associatedvasculitis (OMAAV): a report of four cases.
      ] reported that only one of four patients with OMAAV exhibited good receptive language after cochlear implantation; this patient had residual hearing and exhibited a longer interval from the onset of ear symptoms to deafness. The remaining three patients developed complete deafness shortly after the onset of ear symptoms, and MRI showed clear enhancement of the cochlea. This MRI finding may indicate massive bleeding within the cochlea and/or possible destruction of the cochlear structures, including the spiral ganglion. Thus, the time to deafness and contrast-enhanced MRI findings are important for predicting the prognosis of cochlear implantation for OMAAV with total hearing loss.

      6. Future perspective

      In summary, the nationwide survey revealed that OMAAV is a disease that occurs locally in the middle ear, with disease progression likely resulting in involvement of other organs such as the lungs and kidneys. In addition, it became clear that severe sequelae such as facial palsy, hypertrophic pachymeningitis, complete deafness, and even subarachnoid hemorrhage leading to death can occur. The treatment requires cooperation between ENT doctors and doctors specializing in vasculitis. In future, dissemination of the concept of OMAAV to worldwide will be necessary, with accumulation of evidence regarding the usefulness of the diagnostic criteria and treatment strategies proposed in this report. This will necessitate prospective follow-up studies based on the diagnostic criteria and treatment strategies. We are currently preparing for a nationwide, prospective follow-up study. Furthermore, early diagnosis and treatment through the development of more sensitive ANCA detection methods and the discovery of specific markers other than ANCA will be major challenges in the future.

      Declaration of Competing Interest

      All authors require neither any financial support nor other benefits from commercial sources for the work, nor any other financial interests that any of the authors may have, which could create a potential conflict of interest or the appearance of a conflict of interest with regard to the work.

      Acknowledgments

      We would like to thank 70 institutions of otolaryngology in Japan for providing detailed information regarding the patients and to thank Editage (www.editage.jp) also for English language editing.

      Disclosure state

      This study was performed as a work of the working group for a nationwide survey of OMAAV funded by the Japan Otological Society (JOS). The JOS is an independent academic organization that receives no sponsorship or funding from specific organizations or businesses. Furthermore, the JOS received no funding for the preparation of the present works, which includes businesses representing the pharmaceutical industry.

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