Abstract
Objectives
This study describes the spectrum and initial impact of pulmonary manifestations in the primary systemic vasculitides.
Methods
Description and comparison of pulmonary manifestations in adults with Takayasu’s arteritis (TAK), GCA, granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic GPA (EGPA), polyarteritis nodosa (PAN) and IgA vasculitis (IgAV), using data collected within the Diagnostic and Classification Criteria in Vasculitis study.
Results
Data from 1952 patients with primary vasculitides were included: 170 TAK, 657 GCA, 555 GPA, 223 MPA, 146 EGPA, 153 IgAV and 48 PAN. Pulmonary manifestations were observed in patients with TAK (21.8%), GCA (15.8%), GPA (64.5%), MPA (65.9%), EGPA (89.0%), PAN (27.1%) and IgAV (5.9%). Dyspnoea occurred in patients with TAK (14.7%), GCA (7.8%), GPA (41.8%), MPA (43.5%), EGPA (65.8%), PAN (18.8%) and IgAV (2.6%). Cough was reported in TAK (7.6%), GCA (9.3%), GPA (34.8%), MPA (37.7%), EGPA (55.5%), PAN (16.7%) and IgAV (3.3%). Haemoptysis occurred mainly in patients with ANCA-associated vasculitis (AAV). Fibrosis on imaging at diagnosis was documented in GPA (1.9%), MPA (24.9%) and EGPA (6.3%). Only patients with AAV (GPA 2.7%, MPA 2.7% and EGPA 3.4%) required mechanical ventilation. At 6 months, the presence of at least one pulmonary item in the Vasculitis Damage Index was observed in TAK (4.1%), GCA (3.3%), GPA (15.4%), MPA (28.7%), EGPA (52.7%), PAN (6.2%) and IgAV (1.3%).
Conclusion
Pulmonary manifestations can occur in all primary systemic vasculitides, but are more frequent and more often associated with permanent damage in AAV.
Keywords: vasculitis, ANCA-associated vasculitis, interstitial lung disease, pulmonary
Rheumatology key messages
Pulmonary involvement may occur in all primary systemic vasculitides.
Pulmonary manifestations vary and may be useful to differentiate between different AAV.
Pulmonary manifestations are more frequent and more often associated with permanent damage in AAV.
Introduction
Pulmonary involvement in primary systemic vasculitides varies in its clinical presentation and frequency, depending on the type of vasculitis [1–3]. Because of the low prevalence of primary vasculitides, most information regarding pulmonary involvement comes from case reports or relatively small series.
Pulmonary manifestations have mainly been described in ANCA-associated vasculitides [AAV; granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic GPA (EGPA)]. Alveolar haemorrhage is frequent and can be seen in all AAV, although mostly in MPA. Patients with GPA can have pulmonary nodules, cavitating lesions, alveolar haemorrhage, endobronchial lesions or subglottic stenosis [4, 5]. Interstitial lung disease and pulmonary fibrosis is less frequent and mostly seen in MPA [6]. Adult-onset relapsing and/or refractory asthma is a hallmark of EGPA, but lung opacities with eosinophilia, nodules and alveolar haemorrhage have also been reported [7, 8].
Other small-, medium- and large-vessel vasculitides (LVVs) can also affect the lungs, pulmonary arteries and/or respiratory tract [3]. Takayasu’s arteritis (TAK) is a large-vessel vasculitis affecting the aorta and its branches, and pulmonary artery involvement has been reported with various frequencies [9–11]. GCA predominantly affects elderly patients. Although incompletely understood, it is estimated that up to 10% of patients with GCA will have respiratory symptoms such as cough, sore throat, and/or hoarseness [12, 13]. Polyarteritis nodosa (PAN) does not typically involve the lungs. There have been a few reports describing the presence of diffuse alveolar haemorrhage in PAN, which was more likely among patients who would now be classified as having a diagnosis of MPA [14–17]. IgA vasculitis (IgAV) is a small-vessel vasculitis most often affecting young patients, in which diffuse alveolar haemorrhage has been occasionally reported [18–20].
The objective of this study was to describe pulmonary involvement at diagnosis across multiple vasculitides, analyse its severity and its short-term prognostic value, using a recent, large international database of patients with primary vasculitis.
Methods
Study design and population
The Diagnostic and Classification Criteria in Vasculitis Study (DCVAS), initiated in 2010, is a large international cohort of well-characterized patients with different vasculitides. The purpose of DCVAS was to develop and validate diagnostic and classification criteria for systemic vasculitis for use in daily clinical practice and in clinical trials. A detailed description of the DCVAS study has been previously published [21].
The present study analysed data from patients enrolled in DCVAS between 2010 and 2016 with a definitive diagnosis of TAK, GCA, GPA, MPA, EGPA, PAN or IgAV. Patients were enrolled within the first 24 months after diagnosis of vasculitis was made, with data entered referent to the time of diagnosis and 6 months later. To improve feasibility of recruitment, an exception was made for patients with TAK and PAN by allowing recruitment within 5 years of diagnosis. The final diagnosis and confidence in the diagnosis were determined at the time of inclusion and month 6 by the investigator. Only patients with the seven types of vasculitis outlined above and for whom the investigator was very certain of the diagnosis by month 6 were included in this analysis.
Clinical data elements
Data from the time of diagnosis were analysed for the patients’ demographics, comorbidities, clinical manifestations and, when performed, results of pulmonary function tests [normal, restrictive or obstructive patterns, low diffusing capacity for carbon monoxide (DLCO)], lung imaging (chest radiograph, CT-scan or PET-CT study), bronchoscopy and lung biopsy. Laboratory test results included complete blood cell count, serum creatinine level and serum autoantibodies [ANCA, anti-glomerular basement membrane (anti-GBM), RF, anti-CCP antibodies and ANAs].
Data from the 6-month follow-up visits were also analysed including the Vasculitis Damage Index (VDI) total score and its seven individual items for lung damage (pulmonary hypertension; fibrosis; infarction; pleural fibrosis; chronic asthma; chronic breathlessness and impaired lung function), mortality and cause of death.
Statistical analysis
Chi-square test (or Fisher’s exact test when appropriate) and Student’s t-test were used to compare the qualitative and quantitative characteristics, respectively, among the seven studied primary vasculitides.
Ethics and approval committee
DCVAS was approved by institutional review boards at each participating institution. Written documentation of informed consent was obtained for each participant. Study procedures followed were in accordance with the 1983 revised Declaration of Helsinki. A specific research proposal for the use of DCVAS data for the present study was submitted and approved by the DCVAS Study Steering Committee.
Results
A total of 1952 patients with primary vasculitides were included in this analysis, including 170 patients with TAK, 657 with GCA, 555 with GPA, 223 with MPA, 146 with EGPA, 153 with IgAV and 48 with PAN. Their main disease and demographic characteristics are listed in Table 1.
Table 1.
Characteristics of vasculitis in the study cohort
| TAK | GCA | GPA | MPA | EGPA | PAN | IgAV | |
|---|---|---|---|---|---|---|---|
| Total number of patients | 170 | 657 | 555 | 223 | 146 | 48 | 153 |
| Gender, n (%) | |||||||
| Male | 28 (16.5) | 225 (34.2) | 287 (51.7) | 98 (44.0) | 78 (53.4) | 27 (56.2) | 85 (55.6) |
| Female | 142 (83.5) | 432 (65.8) | 268 (48.3) | 125 (56.0) | 68 (46.6) | 21 (43.8) | 68 (44.4) |
| Age at diagnosis, mean (s.d.) | 34.5 (12.1) | 72.0 (9.1) | 53.0 (16.5) | 64.2 (13.2) | 53.3 (15.2) | 46.2 (19.1) | 51.2 (21.0) |
| Ethnicity, no. of patients | |||||||
| African | 3 | 2 | 3 | 0 | 1 | 1 | 0 |
| African American | 0 | 3 | 1 | 2 | 2 | 0 | 0 |
| Asian | 13 | 7 | 20 | 49 | 10 | 2 | 14 |
| Caucasian | 10 | 56 | 76 | 29 | 32 | 9 | 13 |
| European | 38 | 554 | 314 | 104 | 72 | 21 | 107 |
| Indian | 40 | 2 | 38 | 5 | 9 | 3 | 3 |
| Latin American | 4 | 2 | 14 | 2 | 4 | 0 | 0 |
| Middle Eastern | 59 | 16 | 53 | 13 | 6 | 10 | 10 |
| Other | 8 | 20 | 48 | 22 | 13 | 2 | 6 |
| History of smoking, n (%) | 3 (1.8) | 17 (2.6) | 39 (7.0) | 28 (12.6) | 28 (19.2) | 1 (2.1) | 2 (1.3) |
| Comorbidities, n (%) | |||||||
| Asthma | 5 (2.9) | 39 (5.9) | 26 (4.7) | 4 (1.8) | 97 (66.4) | 4 (8.3) | 8 (5.2) |
| COPD | 1 (0.6) | 29 (4.4) | 11 (2.0) | 17 (7.6) | 5 (3.4) | 0 | 5 (3.3) |
| Serology, positive/available (%) | |||||||
| cANCA | 2/58 (3.4) | 7/311 (2.3) | 383/480 (79.8) | 17/178 (9.6) | 10/127 (7.9) | 1/39 (2.6) | 4/121 (3.3) |
| pANCA | 1/60 (1.7) | 20/301 (6.6) | 55/456 (12.1) | 163/183 (89.1) | 58/129 (45.0) | 3/41 (7.3) | 7/123 (5.7) |
| PR3-ANCA | 1/51 (1.9) | 3/281 (1.1) | 434/523 (83.0) | 11/212 (5.2) | 4/126 (3.2) | 1/32 (3.1) | 3/129 (2.3) |
| MPO-ANCA | 0/52 | 9/284 (3.2) | 47/503 (9.3) | 201/216 (93.1) | 65/129 (50.4) | 0/32 | 3/132 (2.2) |
| anti-GBM | 0/6 | 1/27 (3.7) | 3/182 (1.6) | 5/133 (3.8) | 0/21 | 0/7 | 0/15 |
| RF | 6/55 (10.9) | 22/264 (8.3) | 135/313 (43.1) | 56/144 (38.9) | 40/93 (43.0) | 6/28 (21.4) | 4/107 (3.7) |
| ACPA | 0/22 | 6/98 (6.1) | 9/141 (6.4) | 2/60 (3.3) | 1/31 (3.2) | 1/7 (14.3) | 0/23 |
| ANA | 20/95 (21.1) | 58/340 (17.1) | 54/417 (12.9) | 67/196 (34.2) | 21/122 (17.2) | 10/40 (25.0) | 14/139 (10.1) |
TAK: Takayasu’s arteritis; GPA: granulomatosis with polyangiitis; MPA: microscopic polyangiitis; EGPA: eosinophilic GPA; PAN: polyarteritis nodosa; IgAV, IgA vasculitis; COPD: chronic obstructive pulmonary disease; c: cytoplasmic; p: perinuclear; MPO: myeloperoxidase; anti-GBM: anti-glomerular basement membrane antibodies.
Respiratory symptoms
The frequencies of respiratory symptoms are presented in Table 2. Patients with AAV had more respiratory symptoms than patients with other vasculitides, with a frequency of 64.5, 65.9 and 89.0% for GPA, MPA and EGPA, respectively. Dyspnoea and cough were the most common respiratory symptoms. Wheezing was mostly reported in patients with EGPA.
Table 2.
Pulmonary manifestations in patients with different forms of vasculitis
| TAK | GCA | GPA | MPA | EGPA | PAN | IgAV | |
|---|---|---|---|---|---|---|---|
| Clinical features, patients (%) | |||||||
| Any respiratory symptom | 37 (21.8) | 104 (15.8) | 358 (64.5) | 147 (65.9) | 130 (89.0) | 13 (27.1) | 9 (5.9) |
| Dyspnoea | 25 (14.7) | 51 (7.8) | 232 (41.8) | 97 (43.5) | 96 (65.8) | 9 (18.8) | 4 (2.6) |
| Any cough | 13 (7.6) | 61 (9.3) | 193 (34.8) | 84 (37.7) | 81 (55.5) | 8 (16.7) | 5 (3.3) |
| Dry cough | 11 (6.5) | 54 (8.2) | 133 (24.0) | 48 (21.5) | 50 (34.2) | 5 (10.4) | 4 (2.6) |
| Productive cough | 2 (1.2) | 7 (1.1) | 60 (10.8) | 36 (16.1) | 31 (21.2) | 3 (6.3) | 1 (0.7) |
| Haemoptysis | 3 (1.8) a | 2 (0.3)a | 148 (26.7) | 52 (23.3) | 12 (8.2) | 2 (4.2) | 0 |
| Pleuritic chest pain | 3 (1.8) | 6 (0.9) | 43 (7.7) | 13 (5.8) | 7 (4.8) | 2 (4.2) | 0 |
| Chest wall tenderness | 1 (0.6) | 1 (0.2) | 10 (1.8) | 1 (0.4) | 3 (2.1) | 0 | 0 |
| Crackles on auscultation | 2 (1.2) | 10 (1.5)b | 89 (16.0) | 69 (30.9) | 21 (14.4) | 3 (6.3) | 1 (0.7) |
| Wheezing on auscultation | 2 (1.2) | 7 (1.1) | 24 (4.3) | 13 (5.8) | 79 (54.1) | 0 | 2 (1.3) |
| Oxygen administered | 2 (1.2) | 1 (0.2) | 44 (7.9) | 32 (14.3) | 14 (9.6) | 3 (6.3) | 1 (0.7) |
| Mechanical ventilation | 0 | 0 | 15 (2.7) | 6 (2.7) | 5 (3.4) | 0 | 0 |
| Imaging findings, patients (%) | |||||||
| Pulmonary imaging available | 73 (42.9) | 380 (57.8) | 476 (85.8) | 197 (88.3) | 127 (87.0) | 28 (58.3) | 82 (53.6) |
| Normal imaging | 64 (87.7) | 309 (81.3) | 197 (41.4) | 54 (27.4) | 38 (30.0) | 18 (64.3) | 73 (89.0) |
| Inflammation | 2 (2.8) | 12 (5.0) | 65 (13.7) | 46 (23.4) | 39 (30.7) | 0 | 1 (1.2) |
| Haemorrhage | 0 | 0 | 30 (6.3) | 19 (9.6) | 1 (0.8) | 1 (3.6) | 0 |
| Nodules | 2 (2.8) | 13 (3.4) | 119 (25.0)c | 23 (11.7) | 17 (13.4) | 0 | 1 (1.2) |
| Mass | 0 | 1 | 47 (9.9) | 0 | 0 | 0 | 0 |
| Abscess | 0 | 0 | 8 (1.7) | 0 | 0 | 0 | 1 (1.2) |
| Consolidation | 1 (1.4) | 1 | 76 (16.0) | 40 (20.3) | 33 (26.0) | 5 (17.9) | 3 (3.7) |
| Fibrosis | 0 | 6 (1.6) | 9 (1.9) | 49 (24.9) | 8 (6.3) | 0 | 1 (1.2) |
| Effusion | 0 | 9 (2.3) | 37 (7.8) | 27 (13.7) | 13 (10.2) | 3 (10.7) | 1 (1.2) |
In the 3 patients with TAK and 2 patients with GCA with haemoptysis, a previous history of COPD, smoking, congestive heart failure or productive cough was documented. bTen patients with GCA had crackles on lung auscultation, with 7 of them being current or previous smokers, 2 having chronic obstructive pulmonary disease (COPD) and 3 having a positive test for pANCA. Out of these 10 patients, 7 had normal lung imaging, while 3 patients had fibrosis or atelectasis. cClinical haemoptysis was reported by 36% of patients with GPA and pulmonary nodules. TAK: Takayasu’s arteritis; GPA: granulomatosis with polyangiitis; MPA: microscopic polyangiitis; EGPA: eosinophilic GPA; PAN: polyarteritis nodosa; IgAV: IgA vasculitis.
Haemoptysis was reported in 26.7, 23.3 and 8.2% of patients with GPA, MPA and EGPA, respectively. The need for mechanical ventilation was only reported in patients with AAV, with a frequency of 2.7% for GPA, 2.7% for MPA and 3.4% for EGPA (all these patients were still alive at month 6).
Lung imaging
Lung imaging (Table 2) was mostly performed and/or reported in patients with AAV: GPA (85.8%), MPA (88.3%) and EGPA (87.0%). Only 42.9, 57.8, 58.3 and 53.6% of patients with TAK, GCA, PAN and IgAV had documented lung imaging, respectively.
Lung imaging was normal in most patients with IgAV (89.0%) and PAN (64.3%), but only in 41.4% of patients with GPA, 27.4% in those with MPA and 30.0% in those with EGPA. Nodules were reported in 25.0, 11.7 and 13.4% of patients with GPA, MPA and EGPA who underwent lung imaging studies, respectively. Lung masses and/or cavitating lesions were exclusively documented in patients with GPA (11.8%). Pulmonary fibrosis on imaging at diagnosis was documented in 1.9, 24.9 and 6.3% of patients with GPA, MPA and EGPA, respectively.
Imaging of pulmonary arteries was rarely documented in patients with LVV. Two patients with GCA had available pulmonary vascular imaging: one was normal and the other showed an aneurysm of the right pulmonary artery. Out of the 11 patients with TAK and available pulmonary artery imaging results, 4 were normal, 6 showed arterial wall thickening (4 bilateral, 2 on the left side only) and 1 had an increased FDG uptake of pulmonary arteries seen on PET.
Other respiratory investigations
As shown in Table 3, PFTs were mostly performed in patients with GPA (30.4%), MPA (20.6%) and EGPA (59.6%). A restrictive pattern was observed in 16.6, 28.3 and 4.6%, respectively, and an obstructive pattern in 18.3, 19.6 and 70.1%. A low DLCO was mostly observed in patients with MPA (45.7%), compared with 16.0% and 9.2% of patients with GPA or EGPA.
Table 3.
Results of pulmonary function tests, bronchoscopy and lung biopsy in patients with ANCA-associated vasculitis
| GPA | MPA | EGPA | |
|---|---|---|---|
| Pulmonary function tests, patients (%) | |||
| PFT available | 169 (30.4) | 46 (20.6) | 87 (59.6) |
| Normal PFT | 86 (50.9) | 16 (34.8) | 19 (21.8) |
| Restrictive pattern | 28 (16.6) | 13 (28.3) | 4 (4.6) |
| Obstructive pattern | 31 (18.3) | 9 (19.6) | 61 (70.1) |
| Low DLCO | 27 (16.0) | 21 (45.7) | 8 (9.2) |
| Bronchoscopy findings, patients (%) | |||
| Bronchoscopy available | 144 (26.0) | 34 (15.2) | 31 (21.2) |
| Normal | 36 (25.0) | 9 (26.5) | 9 (29.0) |
| Mass | 6 (4.2) | 0 | 0 |
| Bronchial changes | 59 (40.9) | 6 (17.6) | 13 (41.9) |
| Alveolar haemorrhage | 61 (42.4) | 22 (64.7) | 3 (9.7) |
| Lung biopsy results, patients (%) | |||
| Lung biopsy available | 104 (18.9) | 6 (2.7) | 19 (13.0) |
| Normal | 4 (3.8) | 0 | 1 (5.3) |
| Non-diagnostic | 12 (11.5) | 2 (33.3) | 7 (36.8) |
| Vasculitis | 63 (60.6) | 0 | 12 (63.2) |
| Inflammation | 25 (24.0) | 3 (50.0) | 3 (15.8) |
| Fibrosis | 3 (2.9) | 1 (16.7) | 0 |
GPA: granulomatosis with polyangiitis; MPA: microscopic polyangiitis; EGPA: eosinophilic GPA; PFT: pulmonary function tests; DLCO: diffusion capacity for carbon monoxide.
Bronchoscopy was performed in patients with GPA (26.0%), MPA (15.2%), EGPA (21.2%), PAN (6.4%) and IgAV (1.3%); none with GCA or TAK. In patients with AAV, 75% of the bronchoscopies were abnormal; blood was found in 42.4, 64.7 and 9.7% of patients with GPA, MPA and EGPA. Airway stenosis, including subglottic stenosis, tracheal and/or bronchial stenosis, was found in 16 (11.1%) patients with GPA who underwent bronchoscopy, but in none with MPA or EGPA.
Lung biopsies were performed in 104 (18.9%), 6 (2.7%) and 19 (13.0%) patients with GPA, MPA and EGPA. Vasculitis was found on biopsy in 63 (60.6%) patients with GPA, 12 (63.2%) patients with EGPA and in no patient with MPA. Non-specific inflammation was present in 25 (24.0%) of patients with GPA, 3 (50.0%) patients with MPA and 3 (15.8%) patients with EGPA. Fibrosis was found on biopsy in only 3 (2.9%) patients with GPA, 1 (16.6%) with MPA and none with EGPA. Biopsies were non-diagnostic in 12 (11.5%), 2 (33.3%) and 7 (36.8%) patients, respectively.
Vasculitis Damage Index
Lung damage at 6 months post-diagnosis was more frequent in patients with AAV; at least one pulmonary-VDI item was present in 15.4, 28.7 and 52.7% of patients with GPA, MPA and EGPA, respectively. The frequency of each pulmonary VDI item is detailed in Table 4. In patients with AAV with at least one item of lung damage, pulmonary fibrosis was present in 22.3, 62.5 and 2.6% of those with GPA, MPA or EGPA. In patients with EGPA, persistent chronic asthma was recorded at 6 months in 63 (43.2%) patients.
Table 4.
Vasculitis Damage Index scores and individual items of pulmonary damage among patients with vasculitis
| TAK | GCA | GPA | MPA | EGPA | PAN | IgAV | |
|---|---|---|---|---|---|---|---|
| VDI score, mean (s.d.) | 1.9 (1.6) | 0.77 (1.1) | 1.9 (1.7) | 2.1 (1.7) | 2.4 (1.9) | 1.5 (1.4) | 0.5 (0.9) |
| VDI score in patients without pulmonary symptoms at baseline | 1.8 (1.5) | 0.8 (1.1) | 1.8 (1.4) | 1.5 (1.3) | 1.1 (1.0) | 1.3 (1.3) | 0.5 (0.9) |
| VDI score in patients with pulmonary symptoms at baseline | 2.49 (2.2) | 0.7 (1.1) | 1.9 (1.8) | 2.4 (1.8) | 2.6 (2.0) | 2.1 (1.9) | 1.1 (1.9) |
| Patients with ≥1 lung VDI item, n (%) | 7 (4.1) | 22 (3.3) | 85 (15.4) | 64 (28.7) | 77 (52.7) | 3 (6.2) | 2 (1.3) |
| VDI items, no. of patients | |||||||
| Pulmonary hypertension | 4 | 0 | 2 | 2 | 1 | 0 | 0 |
| Pulmonary fibrosis | 0 | 1 | 19 | 40 | 2 | 0 | 0 |
| Pulmonary infarction | 3 | 0 | 0 | 1 | 0 | 1 | 0 |
| Pleural fibrosis | 0 | 0 | 3 | 0 | 0 | 0 | 0 |
| Chronic asthma | 1 | 3 | 4 | 2 | 63 | 0 | 0 |
| Chronic dyspnoea | 3 | 17 | 55 | 23 | 24 | 2 | 2 |
| Abnormal pulmonary function tests | 1 | 2 | 30 | 18 | 17 | 0 | 0 |
TAK: Takayasu’s arteritis; GPA: granulomatosis with polyangiitis; MPA: microscopic polyangiitis; EGPA: eosinophilic GPA; PAN: polyarteritis nodosa; IgAV: IgA vasculitis; VDI: Vasculitis Damage Index.
Pulmonary manifestations and autoantibodies
In patients with GPA, haemoptysis at baseline was more frequent in patients with positive PR3-ANCA as opposed to those with negative PR3-ANCA (21.4% vs 6.7%). The frequency of lung fibrosis in GPA did not vary according to ANCA positivity. Pulmonary nodules were more frequently observed in patients with GPA and positive ANCA, irrespective of the type (P < 0.05): 31.6% in patients with c-ANCA had nodules vs 18.5% in c-ANCA negative patients; 42.4% in p-ANCA positive vs 26.2% in p-ANCA negative patients; 30.6% in PR3-ANCA positive vs 19.3% in PR3-ANCA negative patients and 48.4% in MPO-ANCA positive vs 25.7% in MPO-ANCA negative patients.
In patients with MPA, the frequency of haemoptysis, pulmonary fibrosis and nodules did not vary significantly according to ANCA positivity.
In patients with EGPA, positive p-ANCA (58/129 patients) and MPO-ANCA (65/129 patients) were more frequently observed than positive c-ANCA (10/127 patients) and PR3-ANCA (4/126 patients). Pulmonary nodules in the presence of PR3-ANCA (75.0% vs 11.1% in PR3-ANCA negative patients). The frequency of pulmonary fibrosis did not vary significantly according to ANCA positivity.
Of the 924 patients with AAV, 336 were tested for anti-GBM and 8 (2.4%) were positive (dual positive for ANCA and anti-GBM). In these patients, pulmonary haemorrhage was observed in 37.5% (3/8 patients) vs 7.3% in patients with AAV and negative anti-GBM (P < 0.001). Anti-GBM positivity did not influence the frequency of pulmonary VDI items at 6 months, including fibrosis, in patients with AAV.
Discussion
The DCVAS study was an international, collaborative effort to collect comprehensive clinical data on a large cohort of patients with various vasculitides, and offers detailed clinical, biological, radiological descriptions and short-term outcomes of patients with pulmonary manifestations. As expected, respiratory symptoms at baseline were more common in patients with AAV. Pulmonary involvement also led to more damage, mostly in AAV.
However, it is important to recognize that respiratory symptoms can also occur in patients with TAK, GCA, PAN or IgAV. In these patients, dyspnoea and cough were the two most common respiratory symptoms, as already reported in small series, and the pathophysiologic aetiologies of these findings are not always clear, especially in patients with LVV [22]. Therefore, clinicians should remain cautious as the differential diagnosis of respiratory symptoms is broad and may be unrelated to the underlying vasculitis. Vasculitis of the pulmonary artery has been reported more often in LVV, but was rarely observed in patients with TAK; however, only a few of them had documented imaging of these arteries.
The observed frequency of clinical haemoptysis in the DCVAS patients with AAV falls within the ranges previously described in smaller series (5–50%) [2–4, 8]. However, alveolar haemorrhage might be higher than reported since bronchoscopy was not performed in all patients with abnormal lung imaging, possibly missing subclinical alveolar haemorrhage. Haemoptysis was reported in all other forms of vasculitis, except in IgAV, despite existing cases in the literature [23]. However, one of the two patients with PAN and haemoptysis was p-ANCA positive (considered as having PAN by the investigator due to the presence of microaneurysms on vascular imaging) and the other had a normal bronchoscopy.
Pulmonary fibrosis was frequent in patients with MPA (24.6%), but much less in GPA (1.9%) or EGPA (6.3%). The longer-term incidence of lung fibrosis might be higher than reported here, as the follow-up duration was of only 6 months after the diagnosis of vasculitis. Lung imaging using CT-scan was not mandatory and plain chest radiograph may overlook or miss discrete, early changes of fibrosis. The occurrence of interstitial lung disease (with or without overt vasculitis) in patients with AAV, especially those with a positive MPO-ANCA, has been increasingly recognized and impacts survival [24–27]. In a series of 49 patients, the mortality rate in AAV with pulmonary fibrosis was as high as 37% after a median follow-up of 48 months, mainly due to respiratory insufficiency [6]. Similar data with other vasculitides is lacking.
At 6 months, only 43.2% of patients with EGPA had persistent chronic asthma recorded on the VDI. The short duration of follow-up, or the use of ongoing treatments, might explain this low rate. Discrepancies in how persistent asthma is interpreted (damage vs comorbidity), and recorded, between site investigators might also have contributed to this low reported percentage.
This study has several strengths. It is the largest, international study providing detailed information on pulmonary manifestations in systemic vasculitides. Data was collected in a standardized and systematic manner, providing valuable information on pulmonary symptoms, imaging, bronchoscopy, PFTs, biopsy and 6-month outcomes. Additionally, the DCVAS cohort provides ‘real-world’ data that is highly generalizable given the broad involvement of 136 centres in 32 countries and investigators from multiple specialties. Our study shows that pulmonary manifestations vary according to the type of vasculitis and may be useful to differentiate between different AAV [28].
There are several limitations to consider. This analysis included patients for whom the investigator was ‘very certain’ of the diagnosis, possibly reducing the generalizability of its findings. The DCVAS study had a short duration of follow-up, which may lead us to underestimate the cumulative pulmonary damage caused by the vasculitis. Investigations including imaging, PFTs, bronchoscopy and lung biopsy were not standardized in all patients; the frequency of findings must therefore be interpreted with caution as patients were more likely to be investigated if the clinician had a suspicion of pulmonary disease. Symptoms and investigation findings entered in the database had to be attributable to the vasculitis; however, there is a chance that some findings documented were unrelated and caused by another disease. Finally, data was entered either prospectively, at diagnosis, or retrospectively within the first 2–5 years after diagnosis of their vasculitis, which might be prone to recall bias or depend on the completeness of previous recordkeeping and prevented more analyses of short-term outcomes. Mortality was, for example, not analysed in detail in this study, because many patients were enrolled after month 6 post-diagnosis (possible ‘survivor bias’) [29].
Conclusion
Pulmonary manifestations occur in many primary systemic vasculitides, but at variable frequencies and with various presentations. In patients with AAV, pulmonary manifestations are frequent, often severe and the source of permanent damage. In patients with TAK, GCA, IgAV or PAN, pulmonary manifestations can occur but less commonly lead to lung damage. Clinicians caring for patients with vasculitis need to be aware of the full spectrum of potential pulmonary manifestations of these complex diseases.
Acknowledgements
The authors thank all participating patients and investigators for their contribution to this study. J.P.M. takes responsibility for the content of the manuscript, including data and analysis. J.P.M. and C.P. had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. J.P.M., P.G., C.P., J.R., R.S., R.A.W., R.L., A.C., P.A.M., C.P. contributed to the study design, data analysis and interpretation, and to the writing of the manuscript. The collaborators of DCVAS are Katerina Achilleos, Southend University Hospital NHS Foundation Trust, UK; Matthew Adler, Frimley Health NHS Foundation Trust, UK; Marco A. Alba, Hospital Clínic Barcelona, Spain; Marco A. Alba, Instituto Nacional de Enfermedades Respiratorias, Mexico; Daniel A. Albert, Dartmouth-Hitchcock Medical Center, USA; Fatma Alibaz-Oner, Marmara University Medical School, Turkey; Paul Allcoat, NHS Fife, UK; Koichi Amano, Saitama Medical University, Japan; Manishka Amarasuriya, University of Colombo Medical Unit, Sri Lanka; Naomi A. Amudala, Boston University, USA; Jacqueline Andrews, Leeds Teaching Hospitals & University of Leeds, UK; Amy M. Archer, University of Pennsylvania, USA; Yoshihiro Arimura, Kyorin University Hospital, Japan; Inoshi Atukorala, University of Colombo Medical Unit, Sri Lanka; Elsa Azevedo, Centro Hospitalar Sao João, Portugal; Shruti Bajad, Medanta Delhi, India; Corisande Baldwin, University of Calgary, Canada; Lillian J. Barra, St. Joseph’s Health Care London, Canada; Bo Baslund, Rigshospitalet, Denmark; Neil Basu, NHS Grampian, UK; Mahire Baykal, Hacettepe University, Turkey; Christoph Berger, Universität Basel, Switzerland; Ewa Berglin, Umeå University Hospital, Sweden; Emilio Besada, University Hospital of North Norway, Norway; Mamta Bhardwaj, Medanta Delhi, India; Antje Bischof, Universität Basel, Switzerland; Daniel Blockmans, University Hospital Leuven, Belgium; Janet Blood, Salford Royal NHS Foundation Trust, UK; Juliana Bordignon Draibe, Hospital Bellvitge, Spain; Sarah Brand, Nottingham University Hospitals NHS Trust, UK; Mariana Brandao, Centro Hospitalar do Porto, Portugal; Ian N. Bruce, Manchester University NHS Foundation Trust, UK; Amanda Butler, Nottingham University Hospitals NHS Trust, UK; Leonard H. Calabrese, Cleveland Clinic, USA; Daniel Camprubi Ferrer, Hospital Bellvitge, Spain; Simon Carette, University of Toronto, Canada; Diana Carmona, Santa Maria Hospital, Portugal; Helga Ceunen, University Hospital Leuven, Belgium; Kuntal Chakravarty, Barking, Havering and Redbridge University Hospitals NHS Trust, Queen’s Hospital, UK; Peter T. Chapman, Christchurch Hospital, University of Otago, Christchurch, New Zealand; Zdenka Chocova, General University Hospital, Prague, Czech Republic; Sharon A. Chung, University of California, San Francisco, USA; Weiping Ci, Anzhen Hospital, Capital Medical University, China; Maria C. Cid, Hospital Clínic Barcelona, Spain; Tiffany M. Clark, Cleveland Clinic, USA; Michael R. Clarkson, Cork University Hospital, Ireland; Felipe de Jesús Contreras Rodríguez, Instituto Nacional de Enfermedades Respiratorias, Mexico; Richard Conway, St. Vincent’s University Hospital, Ireland; Kelly Cooke, Staffordshire & Stoke on Trent Partnership NHS Trust, UK; Xavier Corbella Virós, Hospital Bellvitge, Spain; Ana Cordeiro, Hospital Garcia de Orta, Portugal; Andreia Costa, Centro Hospitalar Sao João, Portugal; Anthea Craven, Oxford University Hospitals NHS Foundation Trust, UK; Karen Culfear, Basildon and Thurrock University Hospitals NHS Foundation Trust, UK; Thomas Daikeler, Universität Basel, Switzerland; Debashish Danda, Christian Medical College & Hospital, India; Siddharth K. Das, CSM Medical Center, India; Bhaskar Dasgupta, Southend University Hospital NHS Foundation Trust, UK; Alice M. De Castro, Santa Maria Hospital, Portugal; Natasha Dehghan, University of Pennsylvania, USA; Roni Devassy, University of Pennsylvania, USA; Navjot Dhindsa, University of Manitoba, Canada; Andreas P. Diamantopoulos, Hospital of Southern Norway Trust, Kristiansand, Norway; Haner Direskeneli, Marmara University Medical School, Turkey; Hiroaki Dobashi, Kagawa University Hospital, Japan; Du Juan, Anzhen Hospital, Capital Medical University, China; Maumer Durrani, Epsom and St Helier University Hospitals NHS Trust, UK; Clive Edelsten, East Suffolk & North Essex NHS Foundation Trust, UK; Johanna Eifert, Universitätsklinikum Jena, Germany; Sallie Elhayek, St. Joseph’s Health Care London, Canada; Sunhoury Elsideeg, Southend University Hospital NHS Foundation Trust, UK; Tomomi Endo, Kitano Hospital, Japan; Abdulsamet Erden, Hacettepe University, Turkey; Burak Erer, Istanbul University, Faculty of Medicine, Turkey; Per Eriksson, Linköping University, Sweden; Zeynep Erturk, Marmara University Medical School, Turkey; Georgina Espígol-Frigolé, Hospital Clínic Barcelona, Spain; Mara Felicetti, Azienda Ospedaliera, University of Padua, Italy; Alaistair Ferraro, Nottingham University Hospitals NHS Trust, UK; José M. Ferro, Santa Maria Hospital, Portugal; Aurore Fifi-Mah, University of Calgary, Canada; Luis Felipe Flores-Suárez, Instituto Nacional de Enfermedades Respiratorias, Mexico; Oliver Flossmann, Royal Berkshire NHS Foundation Trust, UK; Deirdre Flynn, Cork University Hospital, Ireland; Joao Eurico Fonseca, Santa Maria Hospital, Portugal; Jayne Foot, Taunton and Somerset NHS Trust, UK; Michelle Foote, University of Ottawa, Canada; Lindsy Forbess, Cedars-Sinai Medical Center, USA; Shouichi Fujimoto, Miyazaki University Hospital, Japan; Kazuhito Fukuoka, Kyorin University Hospital, Japan; Carolina Furtado, Santa Maria Hospital, Portugal; Shunsuke Furuta, Chiba University, Japan; Angelo L. Gaffo, University of Alabama, Birmingham, USA; Phil Gallagher, St. Vincent’s University Hospital, Ireland; Na Gao, Anzhen Hospital, Capital Medical University, China; Paul Gatenby, Canberra Hospital, Australia; Nagui Gendi, Basildon and Thurrock University Hospitals NHS Foundation Trust, UK; Ruth Geraldes, Santa Maria Hospital, Portugal; Anneleen Gerits, University Hospital Leuven, Belgium; Andrea Gioffredi, University of Parma, Azienda Ospedaliero, Italy; Luke Gomples, Taunton and Somerset NHS Trust, UK; Maria Joao Gonçalves, Santa Maria Hospital, Portugal; Prisca Gondo, Southend University Hospital NHS Foundation Trust, UK; Anne Graham, North Cumbria University Hospitals, UK; Rebecca Grainger, University of Otago Wellington, New Zealand; David T. Gray, Oxford University Hospitals NHS Foundation Trust, UK; Peter C. Grayson, Boston University, USA; Laura Griffiths, York Teaching Hospitals NHS Foundation Trust, UK; Yanqiu Guo, Anzhen Hospital, Capital Medical University, China; Rajiva Gupta, Medanta Delhi, India; Micael Gylling, Linköping University, Sweden; Rula A. Hajj-Ali, Cleveland Clinic, USA; Nevin Hammam, Assiut University, Egypt; Masayoshi Harigai, Tokyo Medical and Dental University Hospital, Japan; Lorraine Hartley, Waikato District Health Board, New Zealand; Janine Haslett, Christchurch Hospital, University of Otago, Christchurch, New Zealand; Alaa Hassan, North Cumbria University Hospitals, UK; Gulen Hatemi, Istanbul University, Cerrahpasa Medical School, Turkey; Bernhard Hellmich, Kreiskliniken Esslingen, Germany; Liesbet Henckaerts, University Hospital Leuven, Belgium; Joerg C. Henes, University of Tuebingen, Germany; Joanna Hepburn, NHS Greater Glasgow & Clyde, UK; Vera Herd, NHS Grampian, UK; Christoph Hess, Universität Basel, Switzerland; Catherine Hill, Queen Elizabeth Hospital, Australia; Andrea Hinojosa-Azaola, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico; Junichi Hirahashi, University of Tokyo Hospital, Japan; Fumio Hirano, Tokyo Medical and Dental University Hospital, Japan; Alojzija Hocevar, University Medical Centre Ljubljana, Slovenia; Julia Holle, Klinikum Bad Bramstedt, Germany; Nicole Hollinger, Kreiskliniken Esslingen, Germany; Sakae Homma, Toho University Hospital, Japan; Theresa Howard, University of Kansas Medical Center Research Institute, USA; Rachel K. Hoyles, Oxford University Hospitals NHS Foundation Trust, UK; Zdenka Hruskova, General University Hospital, Prague, Czech Republic; Gayle Hutcheon, NHS Grampian, UK; Maria Ignacak, University of Jagiellonian, Poland; Annette Igney-Oertel, University of Tuebingen, Germany; Kei Ikeda, Chiba University, Japan; Noriko Ikegaya, Kyorin University Hospital, Japan; Samyukta Jagadeesh, Mount Sinai Hospital, Toronto, Canada; Jane Jaquith, Mayo Clinic, USA; David R. W. Jayne, Cambridge University Hospitals NHS Foundation Trust, UK; Teresa Jewell, Taunton and Somerset NHS Trust, UK; Colin Jones, York Teaching Hospitals NHS Foundation Trust, UK; Abhay Joshi, Wye Valley NHS Trust, UK; Umut Kalyoncu, Hacettepe University, Turkey; Sevil Kamalı, Istanbul University, Faculty of Medicine, Turkey; Sanjeet Kamath, Staffordshire & Stoke on Trent Partnership NHS Trust, Haywood UK; Kan Sow Lai, Penang General Hospital, Malaysia; Shinya Kaname, Kyorin University Hospital, Japan; Suresh Kanchinadham, Nizam’s Institute of Medical Sciences, India; Ömer Karadag, Hacettepe University, Turkey; Miho Karube, Kyorin University Hospital, Japan; Marek Kaszuba, University of Jagiellonian, Poland; Ramanjot Kaur, Medanta Delhi, India; Tamihiro Kawakami, St. Marianna University Hospital Dermatology, Japan; Soko Kawashima, Kyorin University Hospital, Japan; Nader Khalidi, St. Joseph’s Healthcare Hamilton, Canada; Asad Khan, Southend University Hospital NHS Foundation Trust, UK; Masao Kikuchi, Miyazaki University Hospital, Japan; Levent Kilic, Hacettepe University, Turkey; Makiko Kimura, Kameda Medical Centre, Japan; Maria J. King, Cambridge University Hospitals NHS Foundation Trust, UK; Sebastian Klapa, University of Lübeck, Germany; Rainer Klocke, Dudley Group NHS Foundation Trust, UK; Tatsuo Kobayashi, Kameda Medical Centre, Japan; Shigeto Kobayashi, Juntendo University Koshigaya Hospital, Japan; Yoshinori Komagata, Kyorin University Hospital, Japan; Andreas Kronbichler, Medical University Innsbruck, Austria; Pawel Kuczia, University of Jagiellonian, Poland; Mandal Santosh Kumar, Christian Medical College & Hospital, Vellore, India; Miho Kurosawa, University Tokyo Hospital, Japan; Peter Lamprecht, University of Lübeck, Germany; Carol A. Langford, Cleveland Clinic, USA; Peter Lanyon, Nottingham University Hospitals NHS Trust, UK; Catherine Laversuch, Taunton and Somerset NHS Trust, UK; Sang Jin Lee, Seoul National University Hospital, Korea; Simona Leoni, San Raffaele Scientific Institute, Italy; Jing Li, Peking Union Medical College Hospital, China; Kimberly Liang, University of Pittsburgh, USA; Patrick Liang, Centre Hospitalier Universitaire de Sherbrooke, Canada; Hua Liao, Anzhen Hospital, Capital Medical University, China; Lim Ai Lee, Penang General Hospital, Malaysia; Raashid A. Luqmani, Oxford University Hospitals NHS Foundation Trust, UK; Amanda Lyle, Mid Essex Hospital Services NHS Trust, UK; Matthew MacDonald, University of Pennsylvania, USA; Sarah L. Mackie, Leeds Teaching Hospitals & University of Leeds, UK; Leah Madden, University of Pennsylvania, USA; Malgorzata Magliano, Buckinghamshire Heathcare NHS Trust, Stoke Mandeville Hospital, UK; Hirofumi Makino, Okayama University Hospital, Japan; Ashima Makol, Mayo Clinic, USA; Ritu Malaiya, Epsom and St Helier University Hospitals NHS Trust, UK; Anshuman Malaviya, Mid Essex Hospital Services NHS Trust, UK; Ramesh Manthri, Nizam’s Institute of Medical Sciences, India; Federica Maritati, University of Parma, Italy; Ana Martins da Silva, Centro Hospitalar do Porto, Portugal; Justin C. Mason, Imperial College Healthcare NHS Trust, UK; Cecilia Matara, Cambridge University Hospitals NHS Foundation Trust, UK; Kazuo Matsui, Kameda Medical Centre, Japan; Eric L. Matteson, Mayo Clinic, USA; Dawn McBride, University of Pittsburgh, USA; Keith McCullough, York Teaching Hospitals NHS Foundation Trust, UK; Lucy McGeoch, NHS Greater Glasgow & Clyde, UK; John McLaren, NHS Fife, UK; Caitlin McMillian, University of Kansas Medical Center Research Institute, USA; Naval Mendiratta, Medanta Delhi, India; Ajit Menon, Staffordshire & Stoke on Trent Partnership NHS Trust, UK; Dimos Merinopoulos, Southend University Hospital NHS Foundation Trust, UK; Peter A. Merkel, Boston University, USA; Peter Merkel, University of Pennsylvania, USA; Sandra Messier, St. Joseph’s Healthcare Hamilton, Canada; Robert G. Micheletti, University of Pennsylvania, USA; Karen Mills, Norfolk and Norwich University Hospitals NHS Foundation Trust, UK; Nataliya Milman, University of Ottawa, Canada; Masahiro Minoda, Kameda Medical Centre, Japan; Ranjana Walker Minz, PGIMER, Chandigarh, India; Claudia Möck, Klinikum Bad Bramstedt, Germany; Aladdin J. Mohammad, Lund University, Sweden; Sergey Moiseev, Sechenov First Moscow State Medical University, Russia; Marta Moitinho, Santa Maria Hospital, Portugal; Eamonn Molloy, St. Vincent’s University Hospital, Ireland; Paul A. Monach, Boston University, USA; Marian Montgomery, Oxford University Hospitals NHS Foundation Trust, UK; Frank Moosig, Klinikum Bad Bramstedt, Germany; Manoosh Moradizadeh, St Joseph’s Health Care London, Canada; Matthew Morgan, University Hospitals Birmingham NHS Foundation Trust, UK; Ann W. Morgan, Leeds Teaching Hospitals & University of Leeds, UK; Ann-Marie Morgan, Oxford University Hospitals NHS Foundation Trust, UK; Alice Muir, Nottingham University Hospitals NHS Trust, UK; Chetan Mukhtyar, Norfolk and Norwich University Hospitals NHS Foundation Trust, UK; Antje Müller, University of Lübeck, Germany; Francesco Muratore, Azienda Ospedaliera di Reggio Emilia, Italy; Eri Muso, Kitano Hospital, Japan; Ritambhra Nada, PGIMER, Chandigarh, India; Hiroshi Nakajima, Chiba University, Japan; Toshiki Nakajima, Kyoto University Hospital, Japan; Hiroto Nakano, Kameda Medical Centre, Japan; Anupapama Nandagudi, Basildon and Thurrock University Hospitals NHS Foundation Trust, UK; Thomas Neumann, Universitätsklinikum Jena, Germany; Ying Fun Ng, Penang General Hospital, Malaysia; Kooi Heng Ng, Penang General Hospital, Malaysia; Estela L. Nogueira, Santa Maria Hospital, Portugal; Nilesh Nolkha, Royal Wolverhampton NHS Trust, UK; Dan Nordström, Helsinki University Central Hospital, Finland; Pavel Novikov, Sechenov First Moscow State Medical University, Russia; Asanka Nugaliyadde, Basildon and Thurrock University Hospitals NHS Foundation Trust, UK; John L. O’Donnell, Christchurch Hospital, University of Otago, Christchurch, New Zealand; Jennifer O’Donoghue, Oxford University Hospitals NHS Foundation Trust, UK; Lorraine O’Neill, St. Vincent’s University Hospital, Ireland; Edmond O’Riordan, Salford Royal NHS Foundation Trust, UK; Margaret Oatley, East Suffolk & North Essex NHS Foundation Trust, UK; Koshu Okubo, University Tokyo Hospital, Japan; Elena Oliva, University of Parma, Azienda Ospedaliero, Italy; Hideto Oshikawa, Kameda Medical Centre, Japan; Yuichiro Ota, Keio University Hospital, Japan; Roberto Padoan, Azienda Ospedaliera, University of Padua, Italy; Christian Pagnoux, University of Toronto, Mount Sinai Hospital, Canada; Lili Pan, Anzhen Hospital, Capital Medical University, China; Kalliopi Panaritis, McGill University Health Centre, Canada; Jin Kyun Park, Seoul National University Hospital, Korea; Sanjeev Patel, Epsom and St Helier University Hospitals NHS Trust, UK; Pravin Patil, Southend University Hospital NHS Foundation Trust, UK; Giulia Pazzola, Azienda Ospedaliera di Reggio Emilia, Italy; Adrian Peall, Wye Valley NHS Trust, UK; Fiona Pearce, Nottingham University Hospitals NHS Trust, UK; Seval Pehlevan, Fatih University, Turkey; Liliana Pereira, Hospital Garcia de Orta, Portugal; Tom Pettersson, Helsinki University Central Hospital, Finland; Christian A. Pineau, McGill University Health Centre, Canada; Laura Pirilä, Turku University Hospital, Finland; Bartlomiej Poglodek, University of Jagiellonian, Poland; Cristina Ponte, Santa Maria Hospital, Portugal; Sergio Prieto-González, Hospital Clínic Barcelona, Spain; Sangeetha R. Priya, Christian Medical College & Hospital, India; Bally Purewal, East Suffolk & North Essex NHS Foundation Trust, UK; Silke Purschke, Universität Basel, Switzerland; Jukka Putaala, Helsinki University Central Hospital, Finland; Stefanie Quickert, Universitätsklinikum Jena, Germany; Vicki Quincey, Waikato District Health Board, New Zealand; Subhra Raghuvanshi, Nottingham University Hospitals NHS Trust, UK; Liza Rajasekhar, Nizam’s Institute of Medical Sciences, India; Dwarakanathan Ranganathan, Royal Brisbane & Women’s Hospital, Australia; Manish Rathi, PGIMER, Chandigarh, India; David Rees, Wye Valley NHS Trust, UK; Frances Rees, Nottingham University Hospitals NHS Trust, UK; Ulrike Renken, Manchester University NHS Foundation Trust, UK; Giovanna Restuccia, Azienda Ospedaliera di Reggio Emilia, Italy; Rennie L. Rhee, University of Pennsylvania, USA; Brian Rice, University of Pennsylvania, USA; Diane Robins, St. Joseph’s Healthcare Hamilton, Canada; Joanna Robson, University Hospitals Bristol NHS Foundation Trust, UK; Joanna Robson, Oxford University Hospitals NHS Foundation Trust, UK; Miguel Rodrigues, Hospital Garcia de Orta, Portugal; Vasco C. Romao, Santa Maria Hospital, Portugal; Ziga Rotar, University Medical Centre Ljubljana, Slovenia; Carlee Ruediger, Queen Elizabeth Hospital, Australia; Abraham Rutgers, University Hospital Groningen UMCG, Netherlands; Ana C. Sá, Santa Maria Hospital, Portugal; Maria João Saavedra, Santa Maria Hospital, Portugal; Ken-ei Sada, Okayama University Hospital, Japan; Ilfita Sahbudin, Wye Valley NHS Trust, UK; Carlo Salvarani, Azienda Ospedaliera di Reggio Emilia, Italy; Namneet Sandhu, University of Calgary, Canada; Ernestina Santos, Centro Hospitalar do Porto, Portugal; Yuji Sato, Miyazaki University Hospital, Japan; Valentin S. Schäfer, Immanuel Krankhaus Berlin, Medical Center for Rheumatology Berlin Buch, Germany; Franco Schiavon, Azienda Ospedaliera, University of Padua, Italy; Wolfgang A. Schmidt, Immanuel Krankhaus Berlin, Medical Center for Rheumatology Berlin Buch, Germany; Mårten Segelmark, Linköping University, Sweden; Amira Shahin, Cairo University, Egypt; Aman Sharma, PGIMER, Chandigarh, India; Julie Shotton, NHS Grampian, UK; Cristiana Silva, Santa Maria Hospital, Portugal; Ora Gewurz Singer, University of Michigan, USA; Goutham Sivasuthan, Royal Brisbane & Women’s Hospital, Australia; Susan Smolen, Mid Essex Hospital Services NHS Trust, UK; Xavier Solanich-Moreno, Hospital Bellvitge, Spain; Laura Soldevila Boixader, Hospital Bellvitge, Spain; Yeong Wook Song, Seoul National University Hospital, Korea; Jason Springer, University of Kansas Medical Center Research Institute, USA; Antoine G. Sreih, University of Pennsylvania, USA; Antoine G. Sreih, Rush University Medical Center, USA; Ragini Srivastava, Department of Rheumatology, KG Medical University, India; Lisa K. Stamp, Christchurch Hospital, University of Otago, Christchurch, New Zealand; Robert Stevens, Doncaster and Bassetlaw Hospitals NHS Foundation Trust, UK; Daniel Strbian, Helsinki University Central Hospital, Finland; Keishi Sugino, Toho University Hospital, Japan; Cord Sunderkötter, Universitätsklinikum Münster, Germany; Ravi Suppiah, Auckland District Health Board, New Zealand; Katsuya Suzuki, Keio University Hospital, Japan; Kazuo Suzuki, Teikyo University Hospital, Japan; Zoltán Szekanecz, University of Debrecen Medical and Health Science Center, Hungary; Jan Sznajd, University of Jagiellonian, Poland; Kirsi Taimen, Turku University Hospital, Finland; Paul P. Tak, Academic Medical Centre, University of Amsterdam, Netherlands; Tsutomu Takeuchi, Keio University Hospital, Japan; Naoho Takizawa, Kameda Medical Centre, Japan; Lilian Tames, Manchester University NHS Foundation Trust, UK; Bee Eng Tan, Penang General Hospital, Malaysia; Mototsugu Tanaka, University Tokyo Hospital, Japan; Man Wai Tang, Academic Medical Centre, University of Amsterdam, Netherlands; Turgut Tatlisumak, Helsinki University Central Hospital, Finland; Vladimir Tesar, General University Hospital, Prague, Czech Republic; Alan Thomas, Nottingham University Hospitals NHS Trust, UK; Xinping Tian, Peking Union Medical College Hospital, China; Kenichiro Tokunaga, Kameda Medical Centre, Japan; Enrico Tombetti, San Raffaele Scientific Institute, Italy; Matija Tomsic, University Medical Centre Ljubljana, Slovenia; Bahtiyar Toz, Istanbul University, Faculty of Medicine, Turkey; Tatsuo Tsukamoto, Kyoto University Hospital, Japan; Shunya Uchida, Teikyo University Hospital, Japan; Ali Ugur Unal, Marmara University Medical School, Turkey; Maria L. Urban, University of Parma, Azienda Ospedaliero, Italy; Joichi Usui, Tsukuba University Hospital, Japan; Augusto Vaglio, University of Parma, Azienda Ospedaliero, Italy; Srinivasan Venkatachalam, Royal Wolverhampton NHS Trust, UK; Erin Vermaak, Staffordshire & Stoke on Trent Partnership NHS Trust, UK; Vishad Viswanath, Christian Medical College & Hospital, India; Takashi Wada, Kanazawa University Hospital, Japan; Shrikant Wagh, Jehangir Clinical Development Centre, India; Daniel J. Wallace, Cedars-Sinai Medical Center, USA; Giles Walters, Canberra Hospital, Australia; Bastian Walz, Kreiskliniken Esslingen, Germany; Jin Wan, Anzhen Hospital, Capital Medical University, China; Tian Wang, Anzhen Hospital, Capital Medical University, China; Guochun Wang, China–Japan Friendship Hospital, China; Kenneth J. Warrington, Mayo Clinic, USA; Richard A. Watts, East Suffolk & North Essex NHS Foundation Trust, UK; Katarzyna Wawrzycka-Adamczyk, University of Jagiellonian, Poland; Praveen Weeratunga, University of Colombo Medical Unit, Sri Lanka; Michael H. Weisman, Cedars-Sinai Medical Center, USA; Sugeesha Wickramasinghe, University of Colombo Medical Unit, Sri Lanka; Mark Williams, Southend University Hospital NHS Foundation Trust, UK; Megan Williams, Auckland District Health Board, New Zealand; Krzysztof Wojcik, University of Jagiellonian, Poland; Laticia Woodruff, University of Alabama, Birmingham, USA; Theodoros Xenitidis, University of Tuebingen, Germany; Hidehiro Yamada, St. Marianna University Hospital Internal Medicine, Japan; Kunihiro Yamagata, Tsukuba University Hospital, Japan; Chee-Seng Yee, Doncaster and Bassetlaw Hospitals NHS Foundation Trust, UK; Myeongjae Yoon, Seoul National University Hospital, Korea; Kazuki Yoshida, Kameda Medical Centre, Japan; Hajime Yoshifuji, Kyoto University Hospital, Japan; Steven R. Ytterberg, Mayo Clinic, USA; Wako Yumura, IUHW Hospital (Jichi Medical University Hospital), Japan; Hania Zayed, Cairo University, Egypt; Xiaofeng Zeng, Peking Union Medical College Hospital, China; Ming-Hui Zhao, Peking University First Hospital, China; Anna Zugaj, University of Jagiellonian, Poland; Joanna Zuk, University of Jagiellonian, Poland.
Funding: This work was supported in part by University of Oxford, the American College of Rheumatology, the EULAR, the Vasculitis Foundation and the University of Pennsylvania.
Disclosure statement: P.A.M. reports receiving funds for consulting from AbbVie, AstraZeneca, Biogen, Boeringher-Ingelheim, Bristol-Myers Squibb, Celgene, ChemoCentryx, CSL Behring, Genentech/Roche, Genzyme/Sanofi, GlaxoSmithKline, InflaRx, Insmed, Jannsen, Kiniksa and Sparrow; for research support from AstraZeneca, Boeringher-Ingelheim, Bristol-Myers Squibb, Celgene, ChemoCentryx, Genentech/Roche, GlaxoSmithKline, Kypha, TerumoBCT and royalties: UpToDate. All other authors have declared no conflicts of interest.
Data availability statement
Data from the DCVAS study used for analysis of this study are available from the corresponding author after consultation with the DCVAS steering committee on reasonable request. The data are not publicly available because of ethical restrictions.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Data from the DCVAS study used for analysis of this study are available from the corresponding author after consultation with the DCVAS steering committee on reasonable request. The data are not publicly available because of ethical restrictions.