Results
Patient Characteristics and ANCA Positivity at IPF Diagnosis
Of the 504 patients, 20 (4%) were MPO-ANCA positive and 16 (3.2%) were PR3-ANCA positive (Table 1) at diagnoses. All of these patients were Asian. The ANCA-positive patients were older than the ANCA-negative patients. ESR and C reactive protein values were higher and FVC was lower in the ANCA-positive versus ANCA-negative patients. Rheumatoid factor positivity and antinuclear antibody positivity were more likely to be seen in the ANCA-positive patients than in the ANCA-negative patients.
Incidence Density of ANCA-positive Conversion
During the disease course, MPO-ANCA or PR3-ANCA-positive conversion occurred in 15 (5.7%) and 14 (5.3%), respectively, of the 264 patients in whom ANCA was repeatedly measured over a median follow-up period of 5.03 years (IQR, 3.11–8.07 years). Thus, the incidence density of MPO-ANCA and PR3-ANCA-positive conversion was 13.10 and 12.23 cases per 1000 person-years, respectively (figure 2).
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Figure 2.
Kaplan–Meier curves for the time until myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA)-positive conversion (A: MPO-ANCA, B: proteinase 3 [PR3]-ANCA) in patients with idiopathic pulmonary fibrosis.
Risk Factors for MPO- or PR3-ANCA-positive Conversion
In a multivariate Cox regression hazard model, rheumatoid factor positivity was associated with MPO-ANCA-positive conversion (adjusted HR 3.435, 95% CI 1.032 to 11.440, p=0.044), as was an ESR of ≥40 mm/h (adjusted HR 3.361, 95% CI 1.100 to 10.271, p=0.033).
Incidence Density of MPA Development According to ANCA Positivity
Ten patients with MPA at IPF diagnosis were excluded from this analysis. Among these 10 patients (5 men, 5 women) with MPA at IPF diagnosis, the median age was 69 (range, 62–79) years, 7 had rapidly progressive glomerulonephritis, 10 had diffuse alveolar haemorrhage, 3 had acute respiratory failure, 4 had fever, 5 had mononeuritis multiplex and 2 had purpuric rash. In total, 9 patients in the cohort of 504 developed MPA. Among these 9 patients (5 men, 4 women), the median age was 73 (range, 60–76) years, 7 had rapidly progressive glomerulonephritis, 3 had diffuse alveolar haemorrhage, 3 had acute respiratory failure, 8 had fever, and 1 patient each had mononeuritis multiplex, gastrointestinal bleeding and purpuric rash (Table 2). Three of the 20 patients with MPO positivity and none of the 16 patients with PR3-ANCA positivity at IPF diagnosis developed MPA over a median follow-up period of 2.42 years (IQR 1.38–4.92 years) (incidence density of 39.4 cases per 1000 MPO-ANCA-positive IPF person-years and 0.00 cases per 1000 PR3-ANCA-positive IPF person-years, respectively; figure 3). Of the 468 patients with ANCA negativity at IPF diagnosis, 6 developed MPA over a median follow-up period of 4.02 years (IQR 1.92–6.73 years) (incidence density of 2.75 cases per 1000 ANCA-negative IPF person-years), MPO-ANCA converted to positive in 5 patients at MPA diagnosis and 1 patient developed MPA 19 months after ANCA converted to positive. MPO-ANCA-positive patients developed MPA more frequently than did ANCA-negative patients (p<0.001).
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Figure 3.
Kaplan–Meier curves for the time until development of microscopic polyangiitis (MPA) in patients with idiopathic pulmonary fibrosis according to antineutrophil cytoplasmic antibody (ANCA) positivity at diagnosis. The log-rank test showed the difference between ANCA-negative patients and myeloperoxidase (MPO)-ANCA-positive patients to be significant (p<0.001). PR3, proteinase 3.
Mortality According to ANCA Positivity at IPF Diagnosis
Of the 504 patients with IPF, death from any cause occurred in 245 (48.6%) patients over a median follow-up period of 3.95 years (IQR, 1.84–6.64 years). Patients died from progression of the IPF (35.9%), acute exacerbation of IPF (21.0%), pneumonia (10.1%), lung cancer (9.3%), other pulmonary diseases (2.4%), MPA (1.2%), non-pulmonary diseases (10.9%) and unknown causes (9.2%). Five-year and 10-year mortality rates were, respectively, 61.3% and 85.7% for ANCA-positive patients, and 37.6% and 70.5% for ANCA-negative patients at IPF diagnosis. The log-rank test showed the difference between survival curves of ANCA-positive and ANCA-negative patients to be significant (p=0.001) (figure 4). Five-year mortality rates of MPO-ANCA and PR3-ANCA positive patients were 51.3% and 81.7%, respectively. In a multivariate Cox proportional hazard model, older age, PR3-ANCA positivity, %FVC predicted <70%, FEV1/FVC ≥70% and DLCO <70% were found to be negative prognostic factors (Table 3). Since FEV1/FVC ≥70% was an independent risk factor of IPF mortality, we compared baseline parameters of patients with IPF whose FEV1/FVC ratio was ≥70% and <70%. In comparison with patients with an FEV1/FVC ≥70%, patients with an FEV1/FVC <70% were significantly more frequently male (90.2% vs 72.5%, p=0.006), smokers (94.1% vs 75.3%, p<0.001), had emphysema (70.6% vs 21.7%, p<0.001) and had higher %FVC predicted (89.00±18.43 vs 72.74±18.97 mL, p<0.001).
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Figure 4.
Kaplan–Meier survival curves of all-cause mortality according to antineutrophil cytoplasmic antibody (ANCA) positivity. The log-rank test showed the difference between ANCA-positive and ANCA-negative survival curves to be significant (p<0.001).
MPA Development and Mortality in Patients With Positive and Positively-converted MPO-ANCA According to Corticosteroid Therapy Before MPA Onset
In this cohort of patients with IPF, a total of 35 patients were positive for MPO-ANCA (20 at IPF diagnosis and 15 subsequent seroconversion). Among this retrospective cohort of patients with IPF from 1998 to 2013, some patients received corticosteroid treatment, although this is no longer recommended in the international guidance published in 2012. Among the 35 MPO-ANCA-positive patients, 8 had received systemic corticosteroids and none developed MPA. Among the remaining 27 MPO-ANCA-positive patients who never received steroids, 9 developed MPA. Accordingly, the incidence of developing MPA tended to be lower in patients treated with corticosteroids than in patients not treated with corticosteroids (p=0.063). There was no significant difference in survival between patients treated or not treated with corticosteroids (p=0.323) (figure 5).
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Figure 5.
Kaplan–Meier curves for the time until development of microscopic polyangiitis (MPA) (A) and for survival (B) in myeroperoxidase-antineutrophil cytoplasmic antibody-positive or antibody-positively converted patients with idiopathic pulmonary fibrosis according to corticosteroid treatment. The incidence of the development of MPA tended to be lower in patients treated than not treated with corticosteroids (log-rank test: p=0.063). The difference in survival curves between patients treated and not treated with corticosteroids was not significant (log-rank test: p=0.323).