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Antineutrophil cytoplasmic antibody-associated interstitial lung disease: a review

Suha Kadura, Ganesh Raghu
European Respiratory Review 2021 30: 210123; DOI: 10.1183/16000617.0123-2021
Suha Kadura
Dept of Medicine, Center for Interstitial Lung Diseases, University of Washington, Seattle, WA, USA
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  • ORCID record for Suha Kadura
Ganesh Raghu
Dept of Medicine, Center for Interstitial Lung Diseases, University of Washington, Seattle, WA, USA
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  • For correspondence: graghu@uw.edu
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  • FIGURE 1
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    FIGURE 1

    Schematic illustration of proposed concepts of pathogenesis in antineutrophil cytoplasmic antibody (ANCA)-mediated lung disease including pulmonary capillaritis and interstitial lung disease (ILD). The pathogenesis of ANCA-ILD is thought to involve an interplay of factors (including environmental exposures such as silica or cigarette smoke, drugs including hydralazine, infection, immune dysregulation) and genetic predisposition (such as MUC5B, telomerase reverse transcriptase, desmoplakin and others). These factors lead to the generation of an aberrant autoimmune response including loss of T- and B-cell tolerance and ANCA production. ANCA induces neutrophils to secrete chemoattractants which lead to activation of the alternative complement pathway, with anaphylatoxin C5A as an important player, leading to amplification loops and further priming of neutrophils [19, 57]. ANCA-activated neutrophils locally release reactive oxygen species (ROS), proteolytic enzymes such as elastase or neutrophil extracellular trap (NET) formation, which injures vascular endothelial cells leading to pulmonary capillaritis. Furthermore, interleukin-17 (IL-17)-bearing NETs have been shown to trigger human lung fibroblast activation and differentiation into myofibroblasts [60]. Other proposed mechanisms for the development of ILD in AAV include repeated episodes of alveolar haemorrhage leading to pulmonary fibrosis.

  • FIGURE 2
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    FIGURE 2

    Suggested approach to diagnosis and treatment of antineutrophil cytoplasmic antibody (ANCA)-associated interstitial lung disease (ILD). HRCT: high-resolution computed tomography; AAV: ANCA-associated vasculitis; MDD: multidisciplinary discussion; UIP: usual interstitial pneumonia (the most common pattern of ANCA-ILD); NSIP: nonspecific interstitial pneumonia; OP: organising pneumonia, GCS: glucocorticoids; MMF: mycophenolate mofetil; #: Transbronchial biopsy (TBBx), cryobiopsy, or surgical lung biopsy (SLB), as per the treating clinician's discretion, local expertise and/or MDD; elective SLB in patients may be considered if TBBx and/or cryobiopsy is non-diagnostic in patients who are stable and are not at high risk for surgical complications. ¶: Pursue alternative diagnoses guided by appropriate clinical setting and guidelines (e.g., idiopathic pulmonary fibrosis, hypersensitivity pneumonitis, sarcoidosis, etc.).

Tables

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  • TABLE 1

    Published studies of anti-neutrophil cytoplasmic antibody associated interstitial lung disease

    Reference, year, countryStudy descriptionNumber of patientsMean age (years)Male (%)ILD (%)Systemic vasculitis (%)PF preceding AAV (%)Median follow-up period (months)ANCA specificity (%)HRCT pattern
    Nada et al. [2], 1990, USAPF in patients with pulmonary-renal vasculitis37333100100 MPA33 preceding, 67 concurrent12067 p-ANCAND
    Arimura et al. [3], 1995, JapanPulmonary involvement in patients with MPO-ANCA4661.1ND4328 MPANDND100 MPOND
    Hiromura et al. [4], 2000, JapanMPO+rapidly progressive GN during course of IPF46750100100 MPA100ND100 MPOND
    Eschun et al. [5], 2003, CanadaPF presenting manifestation of MPA669.8 (63–78)50100100 MPA10036100 p-ANCA3/6 UIP-like,
    2/6 fibrotic NSIP,
    1 ND
    Homma et al. [6], 2004, JapanPF in MPO-ANCA31695510025 MPA100120100 MPO84% UIP
    Foulon et al. [7], 2008, FranceANCA-associated PF17667110041 MPA86 preceding, 14 concurrent57±416/17 MPO,
    1/17 PR3
    100% UIP
    Nozu et al. [8], 2009, JapanComparison of ANCA-positive and -negative patients with PF19/53 with ANCA+ PF, 34/53 ANCA− PF69 (52–80)5810021 MPA100 preceding1–9017/19 MPO,
    2/19 PR3
    73.3% UIP
    Hervier et al. [9], 2009, FrancePF associated with AAV1270.77510083 MPA,
    17 GPA
    66 concurrent, 25 preceding, 8 following AAV49.2 (7–116)100 MPO 1006/12 UIP,
    1/12 NSIP,
    5/12 ND
    Tzelepis et al. [10], 2010, GreecePrevalence and outcome of PF in MPA36576939100 MPA92 concurrent, 8 following AAV38±3085 p-ANCA,
    8 p-ANCA+c-ANCA
    54% UIP,
    31% NSIP
    Arulkumaran et al. [11], 2011, UKILD and AAV1467.371100100 MPA14 preceding, 64 concurrent, 21 post90100 MPOND
    Tanaka et al. [12], 2012, JapanIP associated with MPO- ANCA962.166100NoneND39.1100 MPO66% UIP,
    11% NSIP,
    11% OP,
    11% DAD
    Ahn et al. [13], 2012, KoreaClinical features and outcomes of MPA55 patients with MPA, 13 with ILD (23.6%),59.29±13.60 MPA, ND in ILD patients60% MPA, ND in ILD patients24100 MPAND46.07 ±39.98100 MPO84.6% UIP,
    1 patient OP,
    2 patients NSIP
    Ando et al. [14], 2013, JapanIncidence of MPO-ANCA and MPA in course of IPF61 patients with initial dx IPF, 9/61 ANCA+69 (57–75)751522 (2/9) MPA100 preceding40 (1–121)100 MPO78% UIP,
    22% ND
    Comarmond et al. [15], 2014, FrancePF in AAV4966 (57–72)6110082 MPA,
    18 GPA
    45 preceding, 43 concurrent, 12 post48 (14–88)88 MPO, 4 PR343% “typical” UIP,
    14% “atypical” UIP,
    7% fibrotic NSIP,
    9.5% NSIP
    Huang et al. [16], 2014, ChinaMPA+PF1963.642100100 MPA68 preceding,
    32 concurrent
    29.9 (8–93)100 MPO100% UIP
    Yu et al. [17], 2014, ChinaCT image analysis before and after treatment of ANCA-ILD872.688100NDNDND75 MPO,
    12.5
    PR3+MPO, 12.5 PR3
    ND
    Fernandez Casares et al. [18], 2015, ArgentinaMPA associated with PF9 patients with PF out of 28 MPA patients60±14563210056 preceding, 44 concurrent76±60100 MPO89% UIP
    Flores-Suárez et al. [19], 2015, MexicoSurvival in MPA patients with PF40 patients, 17 (42.5%) with PF54.2 (total cohort including non-PF)5342.510082 preceding43 (11–213)90 MPO-ANCA,
    5 PR3,
    2.5 MPO+PR3
    88% UIP
    Ono et al. [20], 2015, JapanCharacteristics of MPO-positive GPA patients14 patients with ILD out of 41 MPA patients72.3 (total cohort)4434100ND38.6100 MPA (patients positive for MPO-ANCA)100% UIP
    Kagiyama et al. [21], 2015, JapanANCA positive conversion and MPA development in IPF patients504 PF, 36 ANCA+73611009/36 ANCA positive with MPA100 preceding2955 MPO,
    45 PR3
    ND
    Hosoda et al. [22], 2016, JapanClinical features of UIP with ANCA compared to IPF12 ANCA/UIP patients65.2 (48–74)6710025 MPA100 preceding72 (14–195)100 MPO100% UIP
    Hozumi et al. [23], 2016, JapanClinical implication of PR3 in patients with IIPs16 PR3+ of 360 IIP7275100NoneND22100 PR3 (MPO patients excluded)37.6% UIP/possible UIP, 31.3%
    NSIP, 31.3% “unclassifiable” CT pattern
    Tashiro et al. [24], 2017, JapanCharacteristics and prognosis of MPA with bronchiectasis23 patients with ILD out of 45 patients with MPA72±9.210051100 MPAND52.9 (1–125)100 MPOND
    Hozumi et al. [25], 2018, JapanClinical significance of MPO in patients with IIPs26 MPO+ of 305 patients707710024.3 MPA100 preceding69100 MPO100% UIP/possible UIP
    Juman et al. [26], 2019, UKILD associated with ANCA-positivity69 patients with ILD and 18 ANCA+675110025 coexisting AAV59 precedingND55 p-ANCA,
    45 c-ANCA,
    23 MPO,
    12 PR3
    ND
    Baqir et al. [27], 2019, USARadiologic and pathologic characteristics of MPO-ILD58 (43–75)5610061 MPA61 (11/18) of patients with existing MPA, 3/18 developed MPA on follow up52100 MPO22% UIP,
    29% NSIP,
    7% OP
    Liu et al. [28], 2019, USAPrevalence and significance of ANCA in IPF patients745 patients, 34 with ANCA+67.9±8.9531005/34 ANCA+ patients with MPA100 preceding18.353 MPO,
    26 PR3,
    18 ND
    75% UIP/possible UIP
    Watanbe et al. [29], 2019, JapanPrognosis of MPO-UIP in patients with AAV nephritis3174 (58–88)5210097 MPA,
    3 GPA
    All cases had pre-existing ANCA nephritisND100 MPO100% UIP
    Maillet et al. [30], 2020, FranceUIP in AAV62 AAV-ILD665510085 MPA,
    15 GPA
    52 preceding, 39 concurrent, 10 after40.5 (21–68)89 MPO,
    5 PR3
    63% UIP
    39% NSIP
    Kwon et al. [31], 2020, USAILD in AAV patients24 (14 with MPA, 8 with GPA, 2 EGPA)73 (19–94)45.810058 MPA,
    33 GPA,
    8 EGPA
    20.8 preceding, 45.8 concurrent, 33.3 after4266.7 MPO,
    33.3 PR3
    50% UIP/probable UIP, 41.7% alternative diagnosis (25% fibrotic HP pattern, 12.5% NSIP, 4.2% OP), 8.3% indeterminate
    Sun et al. [32], 2021, ChinaClinical features and long-term outcomes of ILD with ANCA antibody80604538.7 MPA-ILD
    61.25 isolated ANCA-IIP
    38.75
    MPA
    ND4056.25 MPO,
    86 p-ANCA,
    2.5 PR3,
    13.75 c-ANCA
    8.75% UIP,
    63.75% NSIP,
    27.5% “unclassifiable”

    AAV: ANCA-associated vasculitis; ANCA: anti-neutrophil cytoplasmic antibody; c-ANCA: cytoplasmic ANCA; AAV: ANCA-associated vasculitis; CT: computed tomography; DAD: diffuse alveolar damage; dx: diagnosis; EGPA: eosinophilic granulomatosis with polyangiitis; GN: glomerulonephritis; GPA: granulomatosis with polyangiitis; HP: hypersensitivity pneumonitis: HRCT: high-resolution computed tomography; IIP: idiopathic interstitial pneumonia; ILD: interstitial lung disease; IPF: idiopathic pulmonary fibrosis; MPA: microscopic polyangiitis; MPO: myeloperoxidase; ND: not described; NSIP: non-specific interstitial pneumonia, OP: organising pneumonia; p-ANCA: perinuclear ANCA; PF: pulmonary fibrosis; PR3: proteinase 3; UIP: usual interstitial pneumonia (the most common pattern of ANCA-ILD).

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    Antineutrophil cytoplasmic antibody-associated interstitial lung disease: a review
    Suha Kadura, Ganesh Raghu
    European Respiratory Review Dec 2021, 30 (162) 210123; DOI: 10.1183/16000617.0123-2021

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    Antineutrophil cytoplasmic antibody-associated interstitial lung disease: a review
    Suha Kadura, Ganesh Raghu
    European Respiratory Review Dec 2021, 30 (162) 210123; DOI: 10.1183/16000617.0123-2021
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