Figures
- 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
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
- TABLE 1
Published studies of anti-neutrophil cytoplasmic antibody associated interstitial lung disease
Reference, year, country Study description Number of patients Mean age (years) Male (%) ILD (%) Systemic vasculitis (%) PF preceding AAV (%) Median follow-up period (months) ANCA specificity (%) HRCT pattern Nada et al. [2], 1990, USA PF in patients with pulmonary-renal vasculitis 3 73 33 100 100 MPA 33 preceding, 67 concurrent 120 67 p-ANCA ND Arimura et al. [3], 1995, Japan Pulmonary involvement in patients with MPO-ANCA 46 61.1 ND 43 28 MPA ND ND 100 MPO ND Hiromura et al. [4], 2000, Japan MPO+rapidly progressive GN during course of IPF 4 67 50 100 100 MPA 100 ND 100 MPO ND Eschun et al. [5], 2003, Canada PF presenting manifestation of MPA 6 69.8 (63–78) 50 100 100 MPA 100 36 100 p-ANCA 3/6 UIP-like,
2/6 fibrotic NSIP,
1 NDHomma et al. [6], 2004, Japan PF in MPO-ANCA 31 69 55 100 25 MPA 100 120 100 MPO 84% UIP Foulon et al. [7], 2008, France ANCA-associated PF 17 66 71 100 41 MPA 86 preceding, 14 concurrent 57±41 6/17 MPO,
1/17 PR3100% UIP Nozu et al. [8], 2009, Japan Comparison of ANCA-positive and -negative patients with PF 19/53 with ANCA+ PF, 34/53 ANCA− PF 69 (52–80) 58 100 21 MPA 100 preceding 1–90 17/19 MPO,
2/19 PR373.3% UIP Hervier et al. [9], 2009, France PF associated with AAV 12 70.7 75 100 83 MPA,
17 GPA66 concurrent, 25 preceding, 8 following AAV 49.2 (7–116) 100 MPO 100 6/12 UIP,
1/12 NSIP,
5/12 NDTzelepis et al. [10], 2010, Greece Prevalence and outcome of PF in MPA 36 57 69 39 100 MPA 92 concurrent, 8 following AAV 38±30 85 p-ANCA,
8 p-ANCA+c-ANCA54% UIP,
31% NSIPArulkumaran et al. [11], 2011, UK ILD and AAV 14 67.3 71 100 100 MPA 14 preceding, 64 concurrent, 21 post 90 100 MPO ND Tanaka et al. [12], 2012, Japan IP associated with MPO- ANCA 9 62.1 66 100 None ND 39.1 100 MPO 66% UIP,
11% NSIP,
11% OP,
11% DADAhn et al. [13], 2012, Korea Clinical features and outcomes of MPA 55 patients with MPA, 13 with ILD (23.6%), 59.29±13.60 MPA, ND in ILD patients 60% MPA, ND in ILD patients 24 100 MPA ND 46.07 ±39.98 100 MPO 84.6% UIP,
1 patient OP,
2 patients NSIPAndo et al. [14], 2013, Japan Incidence of MPO-ANCA and MPA in course of IPF 61 patients with initial dx IPF, 9/61 ANCA+ 69 (57–75) 75 15 22 (2/9) MPA 100 preceding 40 (1–121) 100 MPO 78% UIP,
22% NDComarmond et al. [15], 2014, France PF in AAV 49 66 (57–72) 61 100 82 MPA,
18 GPA45 preceding, 43 concurrent, 12 post 48 (14–88) 88 MPO, 4 PR3 43% “typical” UIP,
14% “atypical” UIP,
7% fibrotic NSIP,
9.5% NSIPHuang et al. [16], 2014, China MPA+PF 19 63.6 42 100 100 MPA 68 preceding,
32 concurrent29.9 (8–93) 100 MPO 100% UIP Yu et al. [17], 2014, China CT image analysis before and after treatment of ANCA-ILD 8 72.6 88 100 ND ND ND 75 MPO,
12.5
PR3+MPO, 12.5 PR3ND Fernandez Casares et al. [18], 2015, Argentina MPA associated with PF 9 patients with PF out of 28 MPA patients 60±14 56 32 100 56 preceding, 44 concurrent 76±60 100 MPO 89% UIP Flores-Suárez et al. [19], 2015, Mexico Survival in MPA patients with PF 40 patients, 17 (42.5%) with PF 54.2 (total cohort including non-PF) 53 42.5 100 82 preceding 43 (11–213) 90 MPO-ANCA,
5 PR3,
2.5 MPO+PR388% UIP Ono et al. [20], 2015, Japan Characteristics of MPO-positive GPA patients 14 patients with ILD out of 41 MPA patients 72.3 (total cohort) 44 34 100 ND 38.6 100 MPA (patients positive for MPO-ANCA) 100% UIP Kagiyama et al. [21], 2015, Japan ANCA positive conversion and MPA development in IPF patients 504 PF, 36 ANCA+ 73 61 100 9/36 ANCA positive with MPA 100 preceding 29 55 MPO,
45 PR3ND Hosoda et al. [22], 2016, Japan Clinical features of UIP with ANCA compared to IPF 12 ANCA/UIP patients 65.2 (48–74) 67 100 25 MPA 100 preceding 72 (14–195) 100 MPO 100% UIP Hozumi et al. [23], 2016, Japan Clinical implication of PR3 in patients with IIPs 16 PR3+ of 360 IIP 72 75 100 None ND 22 100 PR3 (MPO patients excluded) 37.6% UIP/possible UIP, 31.3%
NSIP, 31.3% “unclassifiable” CT patternTashiro et al. [24], 2017, Japan Characteristics and prognosis of MPA with bronchiectasis 23 patients with ILD out of 45 patients with MPA 72±9.2 100 51 100 MPA ND 52.9 (1–125) 100 MPO ND Hozumi et al. [25], 2018, Japan Clinical significance of MPO in patients with IIPs 26 MPO+ of 305 patients 70 77 100 24.3 MPA 100 preceding 69 100 MPO 100% UIP/possible UIP Juman et al. [26], 2019, UK ILD associated with ANCA-positivity 69 patients with ILD and 18 ANCA+ 67 51 100 25 coexisting AAV 59 preceding ND 55 p-ANCA,
45 c-ANCA,
23 MPO,
12 PR3ND Baqir et al. [27], 2019, USA Radiologic and pathologic characteristics of MPO-ILD 58 (43–75) 56 100 61 MPA 61 (11/18) of patients with existing MPA, 3/18 developed MPA on follow up 52 100 MPO 22% UIP,
29% NSIP,
7% OPLiu et al. [28], 2019, USA Prevalence and significance of ANCA in IPF patients 745 patients, 34 with ANCA+ 67.9±8.9 53 100 5/34 ANCA+ patients with MPA 100 preceding 18.3 53 MPO,
26 PR3,
18 ND75% UIP/possible UIP Watanbe et al. [29], 2019, Japan Prognosis of MPO-UIP in patients with AAV nephritis 31 74 (58–88) 52 100 97 MPA,
3 GPAAll cases had pre-existing ANCA nephritis ND 100 MPO 100% UIP Maillet et al. [30], 2020, France UIP in AAV 62 AAV-ILD 66 55 100 85 MPA,
15 GPA52 preceding, 39 concurrent, 10 after 40.5 (21–68) 89 MPO,
5 PR363% UIP
39% NSIPKwon et al. [31], 2020, USA ILD in AAV patients 24 (14 with MPA, 8 with GPA, 2 EGPA) 73 (19–94) 45.8 100 58 MPA,
33 GPA,
8 EGPA20.8 preceding, 45.8 concurrent, 33.3 after 42 66.7 MPO,
33.3 PR350% 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, China Clinical features and long-term outcomes of ILD with ANCA antibody 80 60 45 38.7 MPA-ILD
61.25 isolated ANCA-IIP38.75
MPAND 40 56.25 MPO,
86 p-ANCA,
2.5 PR3,
13.75 c-ANCA8.75% 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).
