ReviewInterstital lung disease in ANCA vasculitis
Introduction
Anti-neutrophil cytoplasmic antibodies (ANCA) are autoantibodies specific for antigens located in the cytoplasmic granules of neutrophils and lysosomes of monocytes [1]. The two major autoantigen targets are myeloperoxidase (MPO-ANCA) and proteinase 3 (PR3-ANCA). ANCA vasculitides (ANCA-V) are multisystem diseases characterized by necrotizing vasculitis that predominantly affects small vessels [2]. The major clinicopathologic variants of ANCA-V are granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA), and single-organ ANCA-V, including renal-limited ANCA vasculitis (RLV). Pulmonary manifestations are a characteristic feature of ANCA-V [3], with the lung being involved in 85–90% of GPA patients during the course of their disease [4], [5], [6]. The frequency in MPA is slightly lower, with reported prevalence of 25–55% [7], [8], [9]. In both disorders, lung involvement has been associated with unfavorable outcomes [10], [11], [12].
During the last few years, an increasing number of publications have reported the association between interstitial lung disease (ILD) and ANCA vasculitis. The objectives of this review are 1) to describe the main clinical and radiologic manifestations of pulmonary fibrosis (PF) associated with ANCA, 2) to detail major histopathological findings and hypothesize physiopathogenic mechanisms involved in the development of this condition, and 3) to summarize the outcome and therapeutic options for affected patients.
We performed a MEDLINE search for English language articles published between January 1970 and September 2016. The search strategy combined the following terms: “vasculitis, ANCA, granulomatosis with polyangiitis, Wegener's granulomatosis, microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis, Churg-Strauss syndrome, myeloperoxidase or proteinase 3” and “interstitial lung disease, lung fibrosis, pulmonary fibrosis, lung manifestations, thoracic manifestations, interstitial pneumonia or computed tomography (CT)”. Full text of relevant articles were retrieved and reviewed. Additional references quoted in these publications were checked. Data of > 200 patients included in case series [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27] and case reports [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42] constitute the basis of this review.
Section snippets
Epidemiology
Interstitial lung disease associated with ANCA is usually observed in patients older than 65 years old. The average age at presentation seems to be higher in MPA patients with PF than in those with this systemic vasculitis described in general cohorts (66 vs 55 years, respectively) [7], [8], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], but similar to that reported in cases of idiopathic PF (IPF) [43], [44]. Regarding gender, some series have reported a
Clinical manifestations
Major symptoms of patients with ANCA-positive isolated pulmonary fibrosis are progressive dyspnea (50–73%) and nonproductive cough (21–60%) [16], [26], [49], [59]. Other manifestations such as pulmonary hemorrhage and hemoptysis (5%) or constitutional symptoms, i.e., fever (31%) and weight loss (5%) were observed less frequently [16], [49], [58]. In previous studies, ANCA titers did not correlate with the severity of PF [16]. In a small case series, clinical presentation of patients with PF and
Laboratory findings and pulmonary function test
In patients with MPA and ILD, ESR and C-reactive protein (CRP) were increased at disease onset in 95% and 73–79%, respectively [48], [51]. As expected, > 60% of these cases also have abnormal urinalysis [48], [50]. In contrast, marked elevations of ESR and CRP were not described in ANCA-positive PF. In this sense, most studies have found similar CRP levels in patients with initially isolated lung fibrosis irrespective of their ANCA status [16], [56], [58], [59].
Measurement of lung function is an
Imaging
Interstitial lung lesions are a frequent finding in radiologic studies of ANCA-V patients [64]. In a cohort of 150 MPA individuals, CT images obtained before treatment showed that 97% presented at least one lung abnormality, including interstitial lung changes in 66% [64]. Similarly, in another study that included 62 MPO-ANCA cases (51 with MPA), 82% had an abnormal CT scan, 94% of which displayed findings suggestive of interstitial involvement [65]. Most of these interstitial lesions are
Histopathology
The histologic features of pulmonary involvement associated with ANCA vasculitis have been described in detail in previous reports [45], [69]. In these studies, interstitial lesions were a common feature of C-ANCA (usually PR3-ANCA) and P-ANCA (usually MPO-ANCA) patients, observed in 100% and 57% of specimens, respectively [45]. In particular, interstitial fibrosis was documented in 16–48% of the reported patients, being focal in most of the analyzed samples [45], [69]. In 6% of cases,
Pathophysiology
In complex autoimmune diseases such as ANCA vasculitis, diverse mechanisms operate in leading to different disease features, such as glomerulonephritis or pulmonary involvement. Regarding ILD, there are several potential mediators that may contribute to the development of this complication in ANCA vasculitis. Pulmonary fibrosis might be the end result of iterative episodes of intra-alveolar hemorrhage [30], [36], [70]. In this sense, previous series have reported histologic evidence of acute or
Treatment
Treatment of ANCA-V involves induction of remission using highly potent immunosuppressive drugs, followed by a maintenance phase to prevent relapses and chronic damage [83]. Although regimen options for initial therapy of ANCA patients are well established [84], there is limited data on how to treat the particular subset of cases with ILD. In fact, this specific lung problem is not mentioned in recent publications providing recommendations for the management of ANCA-V [84], [85], [86].
Most of
Outcome
ILD has an adverse impact on the long-term prognosis of MPA patients. Most of the series that compare MPA patients with and without PF reported that ILD was associated with poor prognosis and reduced survival [13], [15], [17], [26], [96]. In two recent publications, mortality was 2 to 4 times higher in MPA patients with PF [7], [19]; although this has not been confirmed by others [18].
In the analyzed series of MPA patients with PF, one-third developed chronic respiratory insufficiency requiring
Conclusions
ILD is an uncommon complication of MPO-ANCA and PR3-ANCA vasculitis that is associated with poor prognosis. Most of the time, pulmonary fibrosis develops before or occurs simultaneously with onset of systemic vasculitis symptoms. ANCA vasculitis should be included in the differential diagnosis of “idiopathic” pulmonary fibrosis. ANCA testing should be included in the diagnostic workup of interstitial pneumonia and pulmonary fibrosis both at onset and periodically during the disease course.
Large
Take-home messages
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Diffuse interstitial lung disease and pulmonary fibrosis may be clinical manifestations of anti-neutrophil cytoplasmic antibodies (ANCA) vasculitis.
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The most common ANCA associated with ILD are those directed against myeloperoxidase (MPO-ANCA).
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Pulmonary fibrosis occurs concurrently or precedes to ANCA vasculitis in the majority of affected individuals.
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Usual interstitial pneumonia (UIP) is the most frequent radiological pattern in ANCA positive disease.
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Interstitial lung disease has an adverse
Declaration of interest
The authors declare no conflicts of interest.
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- 1
MA Alba was supported by Secretaria de Ciencia, Tecnología e Innovación (SECITI), Mexico City, Mexico.
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Kenneth M. Brinkhous Distinguished Professor and Chair. Department of Pathology and Laboratory Medicine, School of Medicine. Chief of Pathology and Laboratory Medicine Services, UNC Hospitals, Executive Director, UNC Nephropathology Division, University of North Carolina at Chapel Hill, 308 Brinkhous-Bullitt Building, CB#7525, Chapel Hill, NC 27599-7525.