Background
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) includes three main types of diseases: microscopic polyangiitis (MPA), granulomatous polyangiitis (GPA), and eosinophilic granulomatous polyangiitis. GPA and MPA are frequently accompanied by glomerulonephritis within 2 years after the onset of vasculitis [
1,
2]. Pulmonary fibrosis develops less frequently than glomerulonephritis in patients with AAV. Among the three types of AAV, MPA, which is strongly associated with myeloperoxidase ANCA (MPO-ANCA), is most frequently accompanied by pulmonary fibrosis (15–47% of cases) [
3‐
6]. MPO-ANCA-associated vasculitis more frequently occurs in Japanese patients, whereas proteinase-3 ANCA-associated vasculitis is more common in Europe and the United States [
7]. Because both glomerulonephritis and pulmonary fibrosis are known to be unfavorable prognostic factors in patients with AAV, management of pulmonary fibrosis in patients with MPO-ANCA-related nephritis (MPO-ANCA nephritis) is a critical clinical problem [
8,
9]. In the real-world setting, nephrologists often consult with pulmonologists about the management of pulmonary fibrosis in patients with MPO-ANCA nephritis. Some previous studies have addressed the relationship between MPO-ANCA and pulmonary fibrosis, showing that MPO-ANCA positivity is associated with a poor prognosis of pulmonary fibrosis [
10]. However, because these studies focused mainly on pulmonary fibrosis, they may have included patients whose vasculitis activities were indolent or silent. Thus, the detailed clinical features of pulmonary fibrosis in patients with overt ANCA-related pathological conditions (i.e., those affecting other organs such as the kidney) have not been fully elucidated.
Previous studies have shown that a usual interstitial pneumonia (UIP) pattern is the most prevalent pattern on high-resolution computed tomography (HRCT) in patients with MPO-ANCA-associated interstitial pneumonia [
11]. A UIP pattern on HRCT is a distinct CT finding characterized by honeycombing, reticular shadows, and traction bronchiectasis [
12]. Idiopathic pulmonary fibrosis (IPF), which typically exhibits the UIP pattern on HRCT as well as the pathological pattern of UIP, has a significantly worse prognosis than chronic fibrotic idiopathic interstitial pneumonia [
12,
13]. The aim of this study was to compare the clinical features and prognosis of pulmonary fibrosis showing a UIP pattern in patients with MPO-ANCA nephritis versus IPF.
Discussion
Some excellent studies have addressed the clinical features, including the prognosis of pulmonary fibrosis, in patients with serum MPO-ANCA positivity [
10,
14]. These studies showed that the prognosis of MPO-ANCA-positive pulmonary fibrosis was worse than that of ANCA-negative pulmonary fibrosis associated with other collagen vascular diseases. However, few studies have focused on the development of pulmonary fibrosis in patients with MPO-ANCA nephritis. A previous review showed that pulmonary fibrosis in patients with MPA and GPA exhibits various HRCT patterns, including the typical UIP pattern with honeycombing in the basal lung (most common, 47%), a combined pulmonary fibrosis and emphysema pattern, and a fibrotic nonspecific interstitial pneumonia pattern [
15,
16]. Hosoda et al. [
17] reported that the clinical features of MPO-ANCA-positive UIP without any overt collagen diseases were distinguishable from the clinical features of IPF. Thus, the present study, which is the first study to elucidate the prognosis of a UIP pattern of pulmonary fibrosis in patients with MPO-ANCA nephritis, may have clinical relevance.
Tzelepis et al. [
18] reported that the overall survival of patients with MPO-ANCA nephritis with pulmonary fibrosis was 72 months, which is more favorable than in the present study. However, their study included pulmonary fibrosis with various chest CT patterns, not only a UIP pattern. In addition, they included younger patients than in our study. Conversely, the median survival time of patients with IPF in the present study was 55.8 months, which is more favorable than previously reported in Japan [
19] and Western countries [
20‐
23]. Notably, our patients with IPF had been treated with antifibrotic agents (nintedanib or pirfenidone). These previous articles were published before these antifibrotic agents had been introduced to daily clinical practice. Although there is no clear evidence that antifibrotic agents improve the survival of patients with IPF, some research has shown that pirfenidone might reduce mortality and improve life expectancy compared with best supportive care [
24,
25]. We speculate that our patients with IPF might have had a more favorable prognosis because they had all received either pirfenidone or nintedanib. Our study showed that MPO-ANCA nephritis with a UIP pattern might have a poor prognosis similar to that of IPF under the appropriate therapy for each type of disease (anti-inflammatory therapy for MPO-ANCA nephritis and antifibrotic therapy for IPF).
Although our study showed no significant difference in prognosis, we found a striking difference in the causes of death between MPO-ANCA nephritis with a UIP pattern and IPF. Among patients with IPF, 92% of deaths were respiratory-related. These results are consistent with those of an epidemiologic study of Japanese patients with IPF [
19]. In contrast, in patients with MPO-ANCA nephritis with a UIP pattern, deaths were more frequently related to anti-immune therapy (infectious complication) or vasculitis itself (alveolar hemorrhage and perhaps cardiovascular disease). Intriguingly, though the decline in lung volume and median survival time were similar between the two groups in this study, the causes of death were different. This might indicate that the respiratory impairment in patients with IPF may not be caused only by low vital capacity; other factors (impairment of diffusion capacity or acute exacerbation) may also have a significant prognostic influence.
In this study, we used 3D CT reconstruction data of the whole lung to evaluate the annual decline in lung volume. Because this study was a retrospective analysis of data from patients with nephritis (most patients were followed up mainly in the nephrology department), spirometry data obtained through regular follow-up were not available. Iwano et al. [
26] reported that lung volume calculated using 3D CT volumetry was well correlated with lung volume measured using spirometry. Because the decline of vital capacity in spirometry is an important prognostic factor in patients with IPF, we substituted the decline in lung volume calculated from 3D CT for the spirometric decline in vital capacity. Although further studies are needed to confirm the reliability, we believe that lung volume data calculated from CT images could be useful for evaluation of pulmonary restrictive impairment.
This study has some limitations. First, this was a single-center retrospective study involving a small number of patients. Second, we were unable to analyze pulmonary function test data. Thus, the decline in the true vital capacity and diffusion capacity could not be evaluated in this study. In addition, we cannot rule out the possibility that the decline in vital capacity calculated from reconstructed 3D lung images might have been influenced by timing or the time interval in which chest CT was performed. Finally, we selected patients with MPO-ANCA nephritis with a UIP pattern only by HRCT findings, not pathological findings. In addition, we did not include patients in whom pulmonary fibrosis preceded the onset of nephritis. The time interval between the nephritis diagnosis and initial consultation with the pulmonologist depended on the individual nephrologist, but the mean interval between diagnosis of nephritis and diagnosis of UIP (lung fibrosis) was 18 months. The patients with ANCA-nephritis UIP in our study might thus have had relatively advanced disease and we might have excluded more patients with mild or early-stage fibrosis with a UIP pattern from the patients with ANCA nephritis. Further multicenter prospective studies with large numbers of patients are needed to fully elucidate the clinical characteristics of MPO-ANCA nephritis with a UIP pattern.
Conclusions
The prognosis of MPO-ANCA nephritis with a UIP pattern is poor and equivalent to that of IPF treated with antifibrotic agents. The lung volume reduction rate might be equivalent in both diseases. However, according to the present study, non-respiratory events are the cause of death in nearly half of patients with MPO-ANCA nephritis with a UIP pattern, whereas respiratory events are the cause of death in most patients with IPF.
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