Abstract
Background
Patients with anti-neutrophil cytoplasmic antibody (ANCA)-positive interstitial lung disease (ILD) but without evidence of systemic vasculitis have been reported in studies and are classified as isolated ANCA-positive idiopathic interstitial pneumonia (IIP). However, the clinical significance of ANCA, particularly myeloperoxidase (MPO) -ANCA in IIP remains poorly understood. This study aims to investigate the differences between ANCA-positive and ANCA-negative IIP patients and further explore the impact of MPO-ANCA on clinical manifestations and prognostic outcomes.
Methods
We reviewed 408 ILD patients with available ANCA results from January 2012 to September 2021. 61 patients diagnosed with microscopic polyangiitis-associated ILD were not included in the analysis. A comparative analysis was performed between 61 isolated ANCA-positive IIP patients (ANCA-IIP group) and 286 ANCA-negative IIP patients (IIP group). We further conducted subgroup analyses based on the status of MPO-ANCA.
Results
Baseline clinical characteristics, pulmonary function tests, radiological features and all-cause mortality were similar between ANCA-IIP and IIP groups. When comparing the MPO-ANCA-IIP group with the IIP group and the non-MPO-ANCA-IIP group separately, a higher proportion of fibrotic features was observed on imaging (P = 0.004 vs IIP group; P = 0.031 vs non-MPO-ANCA-IIP group). After one year of treatment, the MPO-ANCA-IIP group showed a significantly greater decline in pulmonary function parameters compared to both the IIP group and the non-MPO-ANCA-IIP group. The frequency of pulmonary function decline was significantly higher in the MPO-ANCA-IIP group compared to the non-MPO-ANCA-IIP group (P = 0.026). Additionally, MPO-ANCA was not found to be statistically associated with mortality among patients with IIP.
Conclusion
ANCA-IIP patients had similar clinical characteristics and prognoses with IIP patients. MPO-ANCA-IIP patients had more prominent fibrosis on imaging and a greater decline in pulmonary function following treatment. Special attention should be paid to MPO-ANCA positivity during the diagnosis and treatment of IIP patients.
Trial registration
ClinicalTrials.gov: NCT04413149, May 2020.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12890-025-03736-4.
Keywords: Idiopathic interstitial pneumonia, ANCA, MPO-ANCA, Pulmonary function progression
Background
Anti-neutrophil cytoplasmic antibodies (ANCAs) are a family of autoantibodies that target antigens within the cytoplasmic granules of neutrophils and the lysosomes of monocytes [1]. ANCA-associated vasculitis (AAV) refers to a category of systemic, necrotising vasculitides that predominantly affect small vessels [2]. Since at least 1990, interstitial lung disease (ILD) has been increasingly recognised as a significant pulmonary manifestation of AAV, particularly in microscopic polyangiitis (MPA) [3–6]. Over the past two decades, cases have been reported about patients with ILD and ANCA positivity without extrapulmonary manifestations or histopathological evidence of vasculitis. Anti-myeloperoxidase (MPO)-ANCA is the most prevalent subtype in these cases [7–16].
Several hypotheses have been proposed to explain the association between ANCA, particularly MPO-ANCA, and ILD. For instance, MPO-ANCA may directly contribute to the pathogenesis of lung fibrosis. Specifically, oxidative products generated by MPO activation, as well as proteolytic enzymes and neutrophil extracellular traps (NETs) released from ANCA-activated neutrophils, can promote fibroblast proliferation, differentiation and extracellular matrix deposition [17–19]. Conversely, ANCA might be induced by various pathological stimuli such as tobacco smoke exposure, infections, and other chronic inflammation processes [20–22]. This could explain the emergence of ANCA following the onset of ILD in predisposed individuals, where localized production of MPO-ANCA could lead to the development of AAV.
Most studies about isolated ANCA-positive ILD patients focused on idiopathic pulmonary fibrosis (IPF) patients. Previous large cohort studies have shown that the prevalence of ANCA positivity in patients initially diagnosed with IPF ranges between 4–36% for MPO-ANCA and 2–4% for proteinase 3 (PR3)-ANCA [7–13]. During follow-up, 13.8 to 25% of ANCA-positive IPF patients subsequently developed clinical manifestations of systemic vasculitis [7, 8, 12, 13]. ANCA-positive IPF without evidence of systemic involvement is predominantly observed in patients older than 65 years and is frequently accompanied by nonspecific symptoms such as cough, dyspnea, and fever. Studies by Nozu et al. [10] and Liu et al. [11] reported no significant difference in survival between ANCA-positive IPF and ANCA-negative IPF, whereas Kagiyama et al. [12] observed a higher mortality rate among patients with ANCA-positive IPF compared to those with ANCA-negative IPF. Additional evidence also supports that p-ANCA/MPO-ANCA positivity may serve as an important predictor for the progression of usual interstitial pneumonia towards systemic vasculitis in IPF patients [23, 24].
Previous studies have also identified isolated ANCA-positive patients in non-IPF types of idiopathic interstitial pneumonia (IIP) [14–16, 25, 26]. Our prior data [15] demonstrated that patients with isolated ANCA-positive IIP exhibit lower erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels, as well as a more favourable prognosis compared to patients with MPA-associated ILD. ANCA-positive IIP patients differ from those with interstitial pneumonia with autoimmune features (IPAF), as our findings indicated a more pronounced decline in lung function and a higher mortality rate among ANCA-positive IIP patients [27, 28]. However, ANCA-positive IIP patients are still classified as IIP based on the current criteria [29], and no studies have directly compared the clinical and prognostic differences between ANCA-positive IIP and ANCA-negative IIP. Additionally, due to limitations in sample size, studies comparing MPO-ANCA positivity with other types of ANCA positivity in IIP patients are scarce. To address these gaps, our study aimed to investigate the distinctions between ANCA-positive IIP and ANCA-negative IIP patients and further assess the impact of MPO-ANCA on clinical and prognostic characteristics.
Methods
Study population
We retrospectively reviewed consecutive patients who had been diagnosed with ILD at Peking Union Medical College Hospital (PUMCH) between January 2012 and September 2021. To be included in this study, patients were required to 1. have a diagnosis of ILD based on clinical symptoms and radiologic features, with or without histopathologic results [30]. Radiological features in chest high-resolution computed tomography (HRCT) include diffuse ground-glass opacities, reticular opacities or consolidation, with or without honeycombing and traction bronchiectasis. 2. have available ANCA testing results during the first visit and follow-up period. Patients with ILD secondary to connective tissue disease (CTD), IPAF, drug, environment, or occupational exposure, hypersensitivity pneumonitis, and sarcoidosis were excluded from the study. ANCA tests were performed at the central laboratory of PUMCH and ANCA was assessed by indirect immunofluorescence (IIF), while MPO-ANCA and PR3-ANCA titers were measured by ELISA [31]. According to the laboratory testing standards of our hospital, pANCA and cANCA were defined as positive if their titers were equal to or greater than 1:10. MPO-ANCA or PR3-ANCA titers greater than 20RU/ml were defined as positive. Patients were classified into different groups based on their diagnoses: (1) Patients who were ANCA-positive (either by IIP or ELISA) and diagnosed with MPA according to 2022 ACR/EULAR classification criteria were defined as the MPA-ILD group [32], which were not included in this analysis according to our study objectives. (2) ILD patients with isolated ANCA positivity (either by IIP or ELISA) were classified into the ANCA-IIP group. (3) Patients who did not meet any of these criteria were classified into the IIP group. In the ANCA-IIP group, patients were further divided into the MPO-ANCA-IIP and the non-MPO-ANCA-IIP groups based on whether they were positive for MPO-ANCA. Figure 1 presents the flowchart of patient screening and classification for this study.
Fig. 1.
Flowchart of the study. Flowchart illustrating the selection of patients with ANCA-IIP and IIP. ILD, interstitial lung disease; HP, Hypersensitivity pneumonitis; CTD, connective tissue disease; ANCA, anti-neutrophil cytoplasmic antibody; IIP, idiopathic interstitial pneumonia; IPAF, interstitial pneumonia with autoimmune features; MPA, microscopic polyangiitis
Data collection
Baseline information at the time of initial diagnosis was obtained, and the following items were analysed: demographic information (age, gender), clinical course, clinical symptoms and signs, laboratory findings (routine blood and urine, liver and renal function tests, ESR, CRP, rheumatoid factor and serologic anti-cyclic citrullinated peptides [anti-CCP]), pulmonary function tests (PFTs), and chest HRCT scans.
Chest HRCT images were evaluated by at least two pulmonologists and radiologists. The HRCT scans were analysed for the following characteristics: ground-glass opacities, reticular patterns, honeycombing and traction bronchiectasis. Fibrosis was described as the presence of honeycombing and traction bronchiectasis; honeycombing and reticular patterns; or traction bronchiectasis and reticular patterns [33].
PFTs were performed according to standardised guidelines. Results of the PFTs were expressed as percentages of the predicted values and were adjusted for age, gender, and body weight. The baseline PFT was performed at the time of diagnosis and a follow-up PFT was performed within 12 ± 3 months post-treatment. Patients were therefore divided into three groups based on absolute changes in forced vital capacity (FVC)% predicted and diffusing capacity of lung for carbon monoxide (DLco)% predicted (corrected for haemoglobin): pulmonary function progression (either FVC decline ≧5% predicted or DLco decline ≧10% predicted) [30]; pulmonary function improvement (FVC improvement ≧5% predicted and DLco improvement ≧10% predicted); pulmonary function stable (FVC decline or improvement < 5% predicted or DLco decline or improvement < 10% predicted).
Treatment regimens were recorded. Corticosteroids were graded according to the dose administered at the time of diagnosis. The medium dose was defined as ≥ 0.5 mg/kg prednisone equivalent per day but < 1 mg/kg prednisone equivalent per day; the high dose was defined as ≥ 1 mg/kg prednisone equivalent a day, and if it exceeded ≥ 250 mg prednisone equivalent a day for one or a few days, it was considered pulse therapy [34–36].
Patients were scheduled for outpatient follow-up visits at Month 3, Month 6, and Month 12 post-diagnosis according to the follow-up protocol established in PUMCH. During these follow-up visits, routine laboratory tests, ANCA tests, assessment of extrapulmonary involvement, PFTs and chest HRCT were performed. For patients who achieve disease stability, follow-up intervals were gradually extended to once per year. The follow-up period ended in September 2022, and the outcomes were defined as death from any cause.
The informed consent for the utilisation of medical records was obtained from each patient and/or their legal guardian upon admission to the hospital. This study was approved by the Peking Union Medical College Hospital Institutional Review Board (Reference number: S-634).
Statistical analysis
All data were analysed using SPSS software version 26.0 and GraphPad Prism software version 8. Normally distributed variables are presented as the means ± SDs, and Student’s t-test was used for comparisons. Continuous, non-normally distributed data are presented as medians with interquartile ranges (IQRs), and the Mann–Whitney U test was used for comparisons. Categorical variables are expressed as numbers (%), and the χ2 test or Fisher’s exact test was used for comparisons. Survival analysis was performed by Kaplan–Meier analysis using the log-rank test. P values are two-sided, and P < 0.05 was considered statistically significant.
Results
A total of 999 patients were diagnosed with ILD, among whom 408 had available ANCA testing results. At first diagnosis, 104 patients were ANCA-positive, composed of 58 patients in MPA-ILD group and 46 patients in ANCA-IIP group. 304 patients with ANCA-negative IIP were included in the IIP group. During follow-up, 18/304 (5.9%) patients with IIP converted to ANCA positive. 3 patients in the ANCA-IIP group developed MPA and were reclassified into the MPA-ILD group. By September 2022, 61 patients with ANCA-IIP and 286 patients with IIP were analysed. Among the 61 ANCA-IIP patients, 25 were MPO-ANCA positive, which were classified as the MPO-ANCA-IIP group. The other 36 patients were classified as the non-MPO-ANCA-IIP group (Fig. 1).
Comparison between ANCA-IIP and IIP patients
Baseline characteristics were compared between the ANCA-IIP and IIP groups (Table 1 and Table 2). There were no significant differences in age or gender between the two groups. ANCA-IIP group had a significantly lower frequency of smoke (16.4% vs 35.0%, P = 0.005), but a higher frequency of arthralgia compared with the IIP group (19.7% vs 7.7%, P = 0.004). There were no differences in other symptoms, signs, and laboratory tests. The major HRCT features of ANCA-IIP patients included ground-glass opacities (90.2%), reticular patterns (59.0%) and traction bronchiectasis (34.4%). The frequencies of ground-glass opacities (90.2% vs 73.1%, P = 0.005) and traction bronchiectasis (34.4% vs 21.7%, P = 0.034) tended to be higher in the ANCA-IIP group. Non-usual interstitial pneumonia (UIP) was the most common radiologic pattern in ANCA-IIP group. There were no significant differences in baseline PFTs or PFT changes during follow-up between the groups (Table 2, Fig. 2a).
Table 1.
Demographic, Clinical, and Serologic Characteristics of ANCA-IIP and IIP
| Characteristic | ANCA-IIP (n = 61) | IIP(n = 286) | P -value |
|---|---|---|---|
| Age, y | 60.00 (50.00,68.00) | 58.50 (50.00,66.00) | 0.328 |
| Sex, male | 29 (47.5) | 156 (54.5) | 0.319 |
| Former or current smoker | 10 (16.4) | 100 (35.0) | 0.005 |
| Follow-up time, months | 64.00 (43.00,83.50) | 62.50 (37.75,87.00) | 0.923 |
| Symptoms | |||
| Fever | 14 (23.0) | 78 (27.3) | 0.488 |
| Cough | 46 (75.4) | 215 (75.2) | 0.969 |
| Fatigue | 8 (13.1) | 44 (15.4) | 0.652 |
| Arthralgia | 12 (19.7) | 22 (7.7) | 0.004 |
| Signs | |||
| Rash | 7 (11.5) | 19 (6.6) | 0.188 |
| Mechanics hand | 5 (8.2) | 9 (3.1) | 0.079 |
| Gottron’s sign | 3 (4.9) | 12 (4.2) | 0.734 |
| Laboratory findings | |||
| WBC,109/L | 6.68 (5.90,9.04) | 7.33 (6.01,9.21) | 0.516 |
| NE,109/L | 4.54 (3.40,6.43) | 4.61 (3.55,6.18) | 0.780 |
| PLT,109/L | 237.00 (175.50,287.00) | 225.00 (185.50,295.25) | 0.976 |
| ESR, mm/h | 19.00 (8.00,44.00) | 16.00 (8.00,37.25) | 0.397 |
| Hs-CRP, mg/dL | 2.22 (0.85,7.87) | 3.85 (1.23,11.91) | 0.085 |
| ANCA | |||
| c-ANCA | 9 (14.8) | - | - |
| p-ANCA | 47 (77.0) | - | - |
| MPO-ANCA | 25 (41.0) | - | - |
| PR3-ANCA | 8 (13.1) | - | - |
| anti-CCP positive | 1 (1.6) | 4 (1.4) | 1.000 |
| RF positive | 10 (16.4) | 27 (9.4) | 0.080 |
Data are presented as the medians (IQRs), means ± SDs or No. (%)
ANCA anti-neutrophil cytoplasmic antibody, IIP idiopathic interstitial pneumonia, WBC white blood cell, PLT platelet, ESR erythrocyte sedimentation rate, Hs-CRP hypersensitivity-C reactive protein, MPO myeloperoxidase, PR3 proteinase 3, anti-CCP anti-cyclic citrullinated peptide antibody, RF rheumatoid factor
Table 2.
Radiologic features and Pulmonary function test of ANCA-IIP and IIP
| Characteristic | ANCA-IIP (n = 61) | IIP(n = 286) | P -value |
|---|---|---|---|
| HRCT Abnormalities | |||
| Ground-glass opacity | 55 (90.2) | 209 (73.1) | 0.005 |
| Traction bronchiectasis | 21 (34.4) | 62 (21.7) | 0.034 |
| Honeycombing | 10 (16.4) | 48 (16.8) | 0.941 |
| Reticular pattern | 36 (59.0) | 169 (59.1) | 0.991 |
| Fibrosisa | 22 (36.1) | 72 (25.2) | 0.082 |
| HRCT patterns | |||
| UIP | 9 (14.8) | 41 (14.3) | 0.933 |
| Non-UIP | |||
| NSIP | 36 (59.0) | 112 (39.2) | 0.004 |
| OP | 1 (1.6) | 31 (10.8) | 0.024 |
| NSIP with OP overlap | 0 (0) | 3 (1.0) | 1.000 |
| Unclassifiable | 15 (24.6) | 99 (34.6) | 0.130 |
| Pulmonary function tests | |||
| Baseline FEV1, % predicted | 80.60 (6.10,94.00) | 78.00 (64.40,90.90) | 0.209 |
| Baseline FVC, % predicted | 82.50 (68.30,93.80) | 77.10 (62.30,91.10) | 0.129 |
| Baseline TLC, % predicted | 73.80 (65.80,85.25) | 73.30 (59.20,83.50) | 0.293 |
| Baseline DLCO, % predicted | 60.00 (47.20,69.40) | 56.30 (43.00,70.25) | 0.317 |
| ΔFEV1, % predicted b | −0.61 ± 8.82 | 1.81 ± 10.92 | 0.243 |
| ΔFVC, % predicted b | 0.28 ± 11.01 | 3.87 ± 12.74 | 0.143 |
| ΔTLC, % predicted b | 0.33 ± 10.9 | 1.32 ± 11.34 | 0.675 |
| ΔDLCO, % predicted b | −0.89 ± 11.89 | 1.33 ± 12.99 | 0.390 |
| pulmonary function progression b | 11 (32.3) | 32 (29.3) | 0.740 |
| Pulmonary function stable b | 19 (55.9) | 56 (51.4) | 0.646 |
| Pulmonary function improvement b | 4 (11.8) | 21 (19.3) | 0.315 |
| Treatment | |||
| Corticosteroids | 52 (85.2) | 205 (71.7) | 0.028 |
| Medium dose | 17 (27.9) | 59 (20.6) | 0.191 |
| High dose | 34 (55.7) | 144 (50.3) | 0.445 |
| Cyclophosphamide | 14 (23.0) | 31 (10.8) | 0.011 |
| Other immunosuppressants c | 3 (4.9) | 22 (7.7) | 0.591 |
| Anti-fibrosis d | 6 (9.8) | 36 (12.6) | 0.550 |
| None e | 10 (16.4) | 25 (8.7) | 0.068 |
| Death of all cause | 11 (18.0) | 60 (21.0) | 0.605 |
Data are presented as the medians (IQRs), means ± SDs or No. (%)
ANCA anti-neutrophil cytoplasmic antibody, IIP idiopathic interstitial pneumonia, HRCT high resolution computed tomography, UIP usual interstitial pneumonia, NSIP nonspecific interstitial pneumonia, OP organizing pneumonia, FEV1 forced expiratory volume in 1 s, FVC forced vital capacity, TLC total lung capacity, DLCO diffusing capacity of lung for carbon monoxide
aFibrosis was radiologically defined as the presence of honeycombing and traction bronchiectasis; honeycombing and reticular patterns; or traction bronchiectasis and reticular patterns
bANCA-IIP: n = 34; IIP: n = 109
cOther immunosuppressants include tacrolimus, azathioprine, mycophenolate mofetil, methotrexate, hydroxychloroquine, and tripterygium wilfordii
dAnti-fibrosis include nintedanib and pirfenidone
eNone represents not receiving anti-inflammatory and anti-fibrotic therapy
Fig. 2.
Changes in pulmonary function and incident of pulmonary function decline after 1 year of treatment. a A greater decline in %FEV1, %FVC, %TLC and %DLCO was observed in MPO-ANCA-IIP group than non-MPO-ANCA-IIP group and IIP group. No statistical differences were observed between non-MPO-ANCA-IIP group and IIP groups. b The proportion of pulmonary function progression at 1-year follow-up in MPO-ANCA-IIP group was higher than non-MPO-ANCA-IIP group and IIP group. The proportion of pulmonary function improvement was lower in the MPO-ANCA-IIP group. ANCA, anti-neutrophil cytoplasmic antibody; IIP, idiopathic interstitial pneumonia; MPO, myeloperoxidase; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; TLC, total lung capacity; DLCO, diffusing capacity of lung for carbon monoxide. * P < 0.05 ** P < 0.01 ns, not significant
Patients in ANCA-IIP group received individual-based treatment involving rheumatologists and respirologists. Compared with IIP group, the proportions of glucocorticoids (85.2% vs 71.7%, P = 0.028) and cyclophosphamide (23.0% vs 10.8%, P = 0.011) administration were significantly higher in ANCA-IIP group. Only 9.8% of the patients in ANCA-IIP group received anti-fibrotic therapy. During the follow-up period, all-cause mortality was 18.0% in the ANCA-IIP group and 21.0% in the IIP group, with no statistically significant difference (Table 2).
Comparison between MPO-ANCA-IIP and IIP patients
Patients in ANCA-IIP group were further divided into the MPO-ANCA-IIP group and the non-MPO-ANCA-IIP group based on the presence of MPO-ANCA positivity. Comparisons between the MPO-ANCA-IIP and IIP groups are summarised in sTable 1 and sTable 2, Additional file 1. No significant differences were observed in clinical symptoms, signs, and laboratory tests. Traction bronchiectasis (44.0% vs 21.7%, P = 0.012) and fibrotic features (52.0% vs 25.2%, P = 0.004) were more frequently seen in patients in MPO-ANCA-IIP group. As for PFTs, MPO-ANCA-IIP patients had significantly higher levels of baseline %FEV1 (87.40% vs 78.00%, P = 0.017) and %FVC (87.40% vs 77.10%, P = 0.031) than IIP patients. 48.0% (12/25) of MPO-ANCA-IIP patients and 38.1% (109/286) of IIP patients had follow-up PFTs. The follow-up PFTs showed that the pulmonary functions in the IIP group were improved after one year of treatment, while the pulmonary functions in the MPO-ANCA-IIP groups continually deteriorated compared to the baseline data. Accordingly, we found a significant decline of ΔFEV1% (−5.43 vs 1.81, P = 0.027), ΔFVC% (−6.71 vs 3.87, P = 0.006), ΔTLC% (−6.13 vs 1.32, P = 0.047) and ΔDLCO% (−8.77 vs 1.33, P = 0.015) in the MPO-ANCA-IIP group (sTable 2, Fig. 2a).
Comparison between MPO-ANCA-IIP and Non-MPO-ANCA-IIP patients
To further assess the impact of MPO-ANCA in IIP patients, we compared the MPO-ANCA-IIP group with the non-MPO-ANCA-IIP group (Table 3 and Table 4). Median age (64.00 vs 60.00, P = 0.533) and the proportion of males (52.0% vs 44.4%, P = 0.561) were not significantly different between the two groups. The frequency of cough was higher in the non-MPO-ANCA-IIP group (86.1% vs 60.0%, P = 0.020).
Table 3.
Comparision of Clinical Characteristics MPO-ANCA-IIP and non-MPO-ANCA-IIP
| Characteristic | MPO-ANCA-IIP(n = 25) | Non-MPO-ANCA-IIP(n = 36) | P -value |
|---|---|---|---|
| Age, y | 64.00 (46.00,70.50) | 60.00 (53.25,64.00) | 0.533 |
| Sex, male | 13 (52.0) | 16 (44.4) | 0.561 |
| Former or current smoker | 5 (20.0) | 5 (13.9) | 0.526 |
| Follow-up time, months | 62.00 (29.00,83.00) | 65.50 (49.00,85.75) | 0.486 |
| Symptoms | |||
| Fever | 6 (24.0) | 8 (22.2) | 0.871 |
| Cough | 15 (60.0) | 31 (86.1) | 0.020 |
| Fatigue | 3 (12.0) | 5 (13.9) | 1.000 |
| Arthralgia | 5 (20.0) | 7 (19.4) | 1.000 |
| Signs | |||
| Rash | 3 (12.0) | 4 (11.1) | 1.000 |
| Mechanics hand | 0 | 5 (13.9) | 0.072 |
| Gottron’s sign | 0 | 3 (8.3) | 0.262 |
| Laboratory findings | |||
| WBC,109/L | 7.20 (5.65,9.01) | 6.65 (5.94,9.09) | 1.000 |
| NE,109/L | 4.71 (3.22,6.10) | 4.51 (3.42,6.93) | 0.747 |
| PLT,109/L | 226.00 (173.50,277.50) | 252.50 (178.25,290.50) | 0.472 |
| ESR, mm/h | 16.50 (8.00,58.50) | 20.50 (8.00,42.25) | 0.780 |
| Hs-CRP, mg/dL | 3.79 (0.64,13.09) | 1.98 (0.99,4.14) | 0.342 |
| ANCA | |||
| c-ANCA | 0 | 9 (22.0) | - |
| p-ANCA | 23 (92.0) | 24 (66.7) | - |
| MPO-ANCA | 25 (100) | 0 | - |
| PR3-ANCA | 3 (12.0) | 5 (13.9) | - |
| anti-CCP positive | 1 (4.0) | 0 | 0.400 |
| RF positive | 3 (12.0) | 7 (19.4) | 0.727 |
Data are presented as the medians (IQRs), means ± SDs or No. (%)
ANCA anti-neutrophil cytoplasmic antibody, IIP idiopathic interstitial pneumonia, WBC white blood cell, PLT platelet, ESR erythrocyte sedimentation rate, Hs-CRP hypersensitivity-C reactive protein, MPO myeloperoxidase, PR3 proteinase 3, anti-CCP anti-cyclic citrullinated peptide antibody, RF rheumatoid factor
Table 4.
Comparision of Radiologic and Pulmonary function features between MPO-ANCA-IIP and non-MPO-ANCA-IIP
| Characteristic | MPO-ANCA-IIP(n = 25) | Non-MPO-ANCA-IIP(n = 36) | P -value |
|---|---|---|---|
| HRCT Abnormalities | |||
| Ground-glass opacity | 22 (88.0) | 33 (91.7) | 0.682 |
| Traction bronchiectasis | 11 (44.0) | 10 (27.8) | 0.190 |
| Honeycombing | 5 (20.0) | 5 (13.9) | 0.526 |
| Reticular pattern | 16 (64.0) | 20 (55.6) | 0.510 |
| Fibrosisa | 13 (52.0) | 9 (22.0) | 0.031 |
| HRCT patterns | |||
| UIP | 5 (20.0) | 4 (11.1) | 0.336 |
| Non-UIP | |||
| NSIP | 13 (52.0) | 23 (63.9) | 0.353 |
| OP | 0 (0.0) | 1 (2.8) | 1.000 |
| NSIP with OP overlap | 0 (0.0) | 0 (0.0) | 1.000 |
| Unclassifiable | 7 (28.0) | 8 (22.2) | 0.606 |
| Pulmonary function tests | |||
| Baseline FEV1, % predicted | 87.40 (77.80,95.00) | 75.75 (66.23,89.15) | 0.034 |
| Baseline FVC, % predicted | 84.40 (71.80,92.60) | 77.10 (61.83,96.30) | 0.276 |
| Baseline TLC, % predicted | 80.10 (66.25,87.20) | 73.10 (64.30,82.03) | 0.267 |
| Baseline DLCO, % predicted | 62.10 (57.30,76.65) | 55.55 (44.33,67.75) | 0.098 |
| ΔFEV1, % predicted b | −5.43 ± 6.41 | 2.02 ± 8.96 | 0.016 |
| ΔFVC, % predicted b | −6.71 ± 8.79 | 4.09 ± 10.33 | 0.004 |
| ΔTLC, % predicted b | −6.13 ± 9.44 | 3.57 ± 10.42 | 0.020 |
| ΔDLCO, % predicted b | −8.77 ± 12.07 | 3.24 ± 9.70 | 0.005 |
| Pulmonary function progression b | 7 (58.3) | 4 (18.2) | 0.026 |
| Pulmonary function stable b | 5 (41.7) | 14 (63.6) | 0.218 |
| Pulmonary function improvement b | 0 (0) | 4 (18.2) | 0.273 |
| Treatment | |||
| Corticosteroids | 22 (88.0) | 30 (83.3) | 0.725 |
| Medium dose | 8 (32.0) | 9 (25.0) | 0.549 |
| High dose | 13 (52.0) | 21 (58.3) | 0.624 |
| Cyclophosphamide | 6 (24.0) | 8 (22.2) | 0.871 |
| Other immunosuppressants c | 2 (8.0) | 1 (2.8) | 0.562 |
| Anti-fibrosis d | 3 (12.0) | 3 (8.3) | 0.682 |
| None e | 3 (12.1) | 7 (19.4) | 0.727 |
| Death of all cause | 6 (24.0) | 5 (13.9) | 0.747 |
Data are presented as the medians (IQRs), means ± SDs or No. (%)
MPO myeloperoxidase, ANCA anti-neutrophil cytoplasmic antibody, IIP idiopathic interstitial pneumonia, HRCT high resolution computed tomography, UIP usual interstitial pneumonia, NSIP nonspecific interstitial pneumonia, OP organizing pneumonia, FEV1 forced expiratory volume in 1 s, FVC forced vital capacity, TLC total lung capacity, DLCO diffusing capacity of lung for carbon monoxide
aFibrosis was radiologically defined as the presence of honeycombing and traction bronchiectasis; honeycombing and reticular patterns; or traction bronchiectasis and reticular patterns
bMPO-ANCA-IIP: n = 12; Non-MPO-ANCA-IIP: n = 22
cOther immunosuppressants include tacrolimus, azathioprine, mycophenolate mofetil, methotrexate, hydroxychloroquine, and tripterygium wilfordii
dAnti-fibrosis include nintedanib and pirfenidone
eNone represents not receiving anti-inflammatory and anti-fibrotic therapy
On imaging, 52.0% of the patients in MPO-ANCA-IIP group had fibrosis characteristics on HRCT, which was higher than that of non-MPO-ANCA-IIP group. Comparative analysis of PFTs revealed significantly higher levels of %FEV1 (87.40% vs 75.75%, P = 0.034) in the MPO-ANCA-IIP group. Treatment regimens were comparable between groups. Again, after 1-year of follow-up, we found significantly lower levels of ΔFEV1% (−5.43 vs 2.02, P = 0.016), ΔFVC% (−6.71 vs 4.09, P = 0.004), ΔTLC% (−6.13 vs 3.57, P = 0.020) and ΔDLCO% (−8.77 vs 3.24, P = 0.005) in the MPO-ANCA-IIP group compared with that in the non-MPO-ANCA-IIP group (Table 4, Fig. 2a). Additionally, the incidence of pulmonary function progression was significantly higher in the MPO-ANCA-IIP group than in the non-MPO-ANCA-IIP group (58.3% vs 18.2%, P = 0.026), whereas the proportion of pulmonary function improvement was lower than that in the non-MPO-ANCA-IIP group (0% vs 18.2%, P = 0.273) (Table 4, Fig. 2b).
Outcomes
The survival time during the follow-up period was analysed using the Kaplan–Meier curve. We observed no statistical difference in the overall survival rate in the comparison between ANCA-IIP and IIP groups (p = 0.592 by log-rank test) (Fig. 3a). Patients in the non-MPO-ANCA-IIP group tended to have better survival rates than those in the MPO-ANCA-IIP group, with no statistical difference in log-rank test (Fig. 3b).
Fig. 3.
Kaplan–Meier survival curves. a Kaplan–Meier curves comparing survival time in patients with ANCA-IIP versus patients with IIP. P = 0.592 by log-rank test. b The prognosis of Non-MPO-ANCA-IIP was better than MPO-ANCA-IIP. P = 0.567 by log-rank test. ANCA, anti-neutrophil cytoplasmic antibody; IIP, idiopathic interstitial pneumonia; MPO, myeloperoxidase
Discussion
This study analysed the differences in clinical and prognostic characteristics between ANCA-IIP and IIP patients and focused on the significance of MPO-ANCA positivity in IIP by comparing MPO-ANCA-IIP with non-MPO-ANCA-IIP. Key findings include: (1) Most baseline characteristics, including demographic, radiologic and pulmonary function features, were similar between the ANCA-IIP and IIP groups. However, a higher proportion of patients in ANCA-IIP received immunosuppressive therapy. In terms of outcomes, we found no statistically significant differences in the incidence of pulmonary function progression or all-cause mortality between the two groups. (2) When comparing the MPO-ANCA-IIP group with both IIP and non-MPO-ANCA-IIP groups, more pronounced fibrotic HRCT features and a greater decline in pulmonary function following treatment were observed in MPO-ANCA-IIP patients.
Based on the classification of IIP published by the American Thoracic Society (ATS) and the European Respiratory Society (ERS) in 2013 [29], ANCA-IIP is categorised within the IIP population. A limited number of studies have described and compared the characteristics of ANCA-IIP patients [14–16, 27]. Consistent with prior studies, our data indicated that ANCA-IIP predominantly affects elderly patients presenting with nonspecific symptoms such as cough, fever, and fatigue, along with restrictive ventilatory dysfunction. Non-UIP was the predominant pattern on HRCT. Our current study further investigated the differences between ANCA-positive IIP and ANCA-negative IIP, revealing that demographic and clinical features were mostly similar between the two groups.
The prognostic implications of ANCA positivity on ILD, particularly IPF, have yielded conflicting results. Previous studies predominantly focused on IPF, with the majority of studies reporting similar outcomes between ANCA-positive and ANCA-negative groups [8, 10, 11]. However, some studies have reported a higher mortality rate among ANCA-positive IPF patients [12]. The impact of ANCA positivity on the prognosis of IIP patients has been less extensively examined. In our study, we found no significant differences in all-cause mortality, which is consistent with previously reported findings in IPF.
Pulmonary function progression is a critical indicator of disease progression and poor prognosis in patients with IPF and can also be observed in various forms of ILDs beyond IPF [37–39]. In our study, 11 out of 34 (32.4%) ANCA-IIP patients exhibited pulmonary function deterioration following one year of treatment. This finding is consistent with a recent retrospective study from Japan, which reported that 35.3% of ANCA-IIP patients experienced pulmonary function decline [40]. No statistically significant differences were noted in PFT changes between the ANCA-IIP and IIP groups. However, among patients with MPO-ANCA positivity, a more pronounced deterioration of pulmonary function was observed compared to the IIP group despite a higher proportion of patients receiving immunosuppressive therapy.
Accumulating evidence from animal models and in vitro studies has demonstrated the direct involvement of MPO-ANCA in the pathogenesis of pulmonary fibrosis. Several hypotheses have been proposed to elucidate the mechanisms [41, 42]. For example, Guilpain et al. [17] introduced the oxidative stress hypothesis, positing that MPO interacts with anti-MPO antibody in vitro to generate oxidation products such as hypochlorous acid. These products subsequently promote fibroblast proliferation and extracellular matrix deposition. Furthermore, neutrophils activated by MPO-ANCA can locally release elastase or form neutrophil extracellular traps, which play a crucial role in the activation and differentiation of lung fibroblasts into myofibroblasts, ultimately leading to lung tissue damage and fibrosis [42–45]. To further elucidate the differences between MPO-ANCA and non-MPO-ANCA, our study conducted subgroup analyses among 25 MPO-ANCA-IIP patients and 36 non-MPO-ANCA-IIP patients. Our analyses revealed comparable baseline characteristics between the two groups in terms of demographic, symptoms, and laboratory tests results. However, fibrosis features and the proportion of UIP patterns were more prominent in MPO-ANCA-IIP patients. Notably, despite receiving similar treatment, a more significant decline in pulmonary functions was observed in the MPO-ANCA-IIP group. Pulmonary function progression was noted in over 50% of MPO-ANCA-IIP patients, while no patients showed improvement, which is lower than in the non-MPO-ANCA-IIP group. Our results are consistent with previous findings and indicate that MPO-ANCA may play a pathogenic role in the progression of pulmonary fibrosis, which could potentially result in a more rapid decline in pulmonary function.
Currently, there is no international consensus on the management of isolated ANCA-positive IIP patients [46], and reported therapeutic regimens vary across studies, ranging from the use of glucocorticoids alone to combination regimens with immunosuppressants such as cyclophosphamide or azathioprine [7, 13, 40]. Several studies have indicated that immunosuppressive therapy may reduce the risk of MPA progression in MPO-ANCA-positive patients initially diagnosed with IPF [8, 12, 13]. Anti-fibrotic agents have been administered to some ANCA-IIP patients with UIP patterns. However, their efficacy remains uncertain. In our study, approximately 85.2% of ANCA-IIP patients received glucocorticoids and cyclophosphamide, while only 9.8% were treated with anti-fibrotic therapy. Nintedanib and pirfenidone, two FDA-approved drugs, have demonstrated the ability to slow the decline in lung function in IPF patients [47], as well as in patients with other progressing fibrosing ILD [30, 48–50]. The INBUILD trial confirmed that nintedanib could slow the rate of FVC decline in patients with progressive fibrosing autoimmune disease related ILDs [48]; however, most of the patients enrolled were diagnosed with rheumatoid arthritis and scleroderma. Our study found that patients with MPO-ANCA-IIP had more prominent fibrotic features on imaging and experienced a significantly greater decline in pulmonary function parameters compared to patients with IIP and Non-MPO-ANCA-IIP. This suggests importance of implementing more proactive therapeutic strategies to mitigate disease progression. Based on the treatment recommendations for ANCA-IIP patients proposed by Thompson et al. and Yamakawa et al. [51, 52], monotherapy with antifibrotic agents (without immunosuppression) may be appropriate for ANCA-IIP patients with UIP pattern, while combination therapy with both immunosuppressants and antifibrotic agents could be potentially beneficial for ANCA-IIP patients with NSIP pattern. In the future, a multidisciplinary approach will be pivotal in managing these patients effectively, and high-quality randomized controlled clinical trials will play an essential role in validating the efficacy of these treatments.
Our study had several limitations. Firstly, this was a single-centre retrospective study. Although our cohort size was relatively large compared to the published literature, it remains limited for drawing a definitive conclusion. Larger, multi-centre studies are necessary to validate our findings. Secondly, variations in treatment regimens may have influenced the survival analyses between groups. Finally, our study did not include histological data to fully assess the extent of lung fibrosis. However, given the ANCA positivity and clinal features indicative of ILD, a lung biopsy may not be essential for histopathological diagnosis.
Conclusions
In conclusion, patients with ANCA-IIP exhibited comparable baseline characteristics and prognosis to those with IIP. However, compared to ANCA-negative IIP patients and non-MPO-ANCA IIP patients, MPO-ANCA-IIP patients had more prominent fibrotic features on imaging and were more likely to experience a decline in pulmonary function following treatment. Therefore, particular attention should be given to MPO-ANCA positivity during the diagnosis and management of IIP patients.
Supplementary Information
Acknowledgements
The authors express their appreciation to all staff and physicians in the Department of Respiratory and Critical Care Medicine PUMCH who cared for these patients between 2012 and 2022.
Clinical trial registration
This retrospective observational study was first registered in ClinicalTrials.gov in May 2020 and the trial registration number was NCT04413149.
Abbreviations
- AAV
Anti-neutrophil cytoplasmic antibody-associated vasculitis
- ANCA
Anti-neutrophil cytoplasmic antibody
- CCP
Cyclic citrullinated peptide antibody
- CRP
C-reactive protein
- CTD
Connective tissue disease
- DLCO
Diffusing capacity of lung for carbon monoxide
- ESR
Erythrocyte sedimentation rate
- FEV1
Forced expiratory volume in 1 s
- FVC
Forced vital capacity
- HRCT
High-resolution computed tomography
- IIP
Idiopathic interstitial pneumonia
- ILD
Interstitial lung disease
- IPAF
Interstitial pneumonia with autoimmune features
- IPF
Idiopathic pulmonary fibrosis
- MPA
Microscopic polyangiitis
- MPO
Myeloperoxidase
- NSIP
Nonspecific interstitial pneumonia
- OP
Organizing pneumonia
- PFT
Pulmonary function test
- PR3
Proteinase 3
- TLC
Total lung capacity
- UIP
Usual interstitial pneumonia
Authors’ contributions
Conceptualization, J. Shi, M. Peng; Data curation, X. Sun, W. Zhu, Z. Li, W. Zhang; Formal analysis, X. Sun, W. Zhu, C. Zhou; Funding acquisition, J. Shi; Investigation, X. Sun, W. Zhu, C. Zhou, P. Xue; Methodology, X. Sun, C. Zhou; Project administration, J. Shi; Resources, J. Shi; Software, X. Sun, C. Zhou; Supervision, J. Shi, M. Peng, T. Zhang; Validation, J. Shi; Visualization, X. Sun, C. Zhou, W. Zhu, J. Shi; Writing—original draft, X. Sun, W. Zhu;—Writing—review & editing, C. Zhou, J. Zhao, J. Shi, T. Zhang, M. Peng, C. Wang.
Funding
This research was funded by National High Level Hospital Clinical Research Funding (Grant No.2022-PUMCH-C-017), National Key Research and Development Program of China (Grant No.2023YFC2507204). The funders had no role in study design, data collection, and analysis, the decision to publish, or preparation of the manuscript.
Data availability
This retrospective observational study was first registered in ClinicalTrials.gov in May 2020 and the trial registration number was NCT04413149. The datasets generated and analysed during the current study are available in the ClinicalTrials repository [https://clinicaltrials.gov/ct2/show/NCT04413149?term = NCT04413149&draw = 2&rank = 1].
Declarations
Ethics approval and consent to participate
The study was conducted in accordance with the Declaration of Helsinki and was approved by the Peking Union Medical College Hospital Institutional Review Board (Reference number: S-634). Written informed consent from study subjects was waived because of the retrospective design.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Xin Sun, Wenyan Zhu and Chunsheng Zhou contributed equally to this work.
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Associated Data
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Supplementary Materials
Data Availability Statement
This retrospective observational study was first registered in ClinicalTrials.gov in May 2020 and the trial registration number was NCT04413149. The datasets generated and analysed during the current study are available in the ClinicalTrials repository [https://clinicaltrials.gov/ct2/show/NCT04413149?term = NCT04413149&draw = 2&rank = 1].