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Clinical Significance of MPO-ANCA
in Eosinophilic Granulomatosis With
Polyangiitis: Experience From a
Longitudinal Chinese Cohort
Suying Liu
1†
, Linna Han
2†
, Yanhui Liu
3
, Jun Yang
1
, Yu Zhang
4
, Mengtao Li
1
,
Xinping Tian
1
, Xiaofeng Zeng
1
, Li Wang
1
*and Fengchun Zhang
1
*
1
Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of
Medical Sciences and Peking Union Medical College, The Ministry of Education Key Laboratory, National Clinical Research
Center for Dermatologic and Immunologic Diseases, Beijing, China,
2
Department of Rheumatology and Clinical Immunology,
the Third Affiliated Hospital of Chongqing Medical University, Chongqing, China,
3
Department of Rheumatology and Clinical
Immunology, Affiliated Hospital of Chifeng University, Chifeng, China,
4
Division of Nephrology, Nanfang Hospital, Southern
Medical University, Guangzhou, China
Objectives: The aim of this study is to investigate the clinical significance of
myeloperoxidase (MPO)–antineutrophil cytoplasmic antibody (ANCA) on eosinophilic
granulomatosis with polyangiitis (EGPA) from a longitudinal Chinese cohort.
Methods: A total of 120 patients with EGPA were consecutively enrolled and followed up.
Two patients with PR3 ANCA was excluded and our analysis focused on the 118 patients
with EGPA. On the basis of MPO-ANCA status, baseline clinical manifestations,
treatment, and outcomes were analyzed. Logistic regression analysis was performed to
analyze the independently associated factors for renal involvement.
Results: ANCA positivity was observed in 24.2% of patients with EGPA. Patients with
MPO-ANCA accounted for 20.8%. Patients with positive MPO-ANCA had higher levels of
erythrocyte sedimentation rate (ESR), C-reactive protein, Birmingham Vasculitis Activity
Score (BVAS), higher ratios of fever, myalgia, renal involvement, and biopsy-proven
vasculitis. Heart manifestations and asthma were more common in patients with
negative ANCA. Baseline MPO-ANCA titers positively correlated with ESR, eosinophil
count, and BVAS and were higher in patients with methylprednisolone pulse. Among
patients with renal involvement, patients with positive MPO-ANCA had higher proportions
of female, fever, biopsy-proven vasculitis, and faster ESR; patients with negative ANCA
developed more skin and cardiac involvement. MPO-ANCA positivity, male, and ear
involvement were the independent factors associated with renal involvement. Intravenous
cyclophosphamide and immunoglobulins were prescribed more frequently in patients with
positive MPO-ANCA.
Frontiers in Immunology | www.frontiersin.org June 2022 | Volume 13 | Article 8851981
Edited by:
Janine Lamb,
The University of Manchester,
United Kingdom
Reviewed by:
Hans-Hartmut Peter,
University of Freiburg Medical
Center, Germany
Philippe Guilpain,
Universite
´de Montpellier, France
*Correspondence:
Li Wang
wangli2221@sina.com
Fengchun Zhang
zhangfch@pumch.cn
†
These authors have contributed
equally to this work
Specialty section:
This article was submitted to
Autoimmune and
Autoinflammatory Disorders,
a section of the journal
Frontiers in Immunology
Received: 27 February 2022
Accepted: 25 May 2022
Published: 27 June 2022
Citation:
Liu S, Han L, Liu Y, Yang J,
Zhang Y, Li M, Tian X, Zeng X,
Wang L and Zhang F (2022) Clinical
Significance of MPO-ANCA in
Eosinophilic Granulomatosis With
Polyangiitis: Experience From a
Longitudinal Chinese Cohort.
Front. Immunol. 13:885198.
doi: 10.3389/fimmu.2022.885198
ORIGINAL RESEARCH
published: 27 June 2022
doi: 10.3389/fimmu.2022.885198
Conclusion: In this cohort, patients with positive MPO-ANCA and negative ANCA
displayed distinct clinical features, suggesting that MPO-ANCA might be a valuable
biomarker for EGPA stratification. Baseline MPO-ANCA level correlated positively with
disease activity of EGPA. MPO-ANCA was a significant independent factor associated
with renal involvement.
Keywords: myeloperoxidase, antineutrophil cytoplasmic antibody, eosinophilic granulomatosis with polyangiitis,
stratification, renal involvement
INTRODUCTION
Eosinophilic granulomatosis with polyangiitis (EGPA), previously
called Churg–Strauss syndrome, is a rare type of antineutrophil
cytoplasmic antibody (ANCA)–associated systemic vasculitis
(AAV) characterized by blood and tissue eosinophilia, necrotizing
vasculitis, and granulomatous inflammation (1).Frequently, EGPA
affects the respiratory tract, peripheral nervous system (PNS),
cardiovascular system, kidney, gastrointestinal tract, and ENT
(ear, nose, and throat) (2).
In the diagnosis of AAV, ANCA plays an important role,
which displays perinuclear or cytoplasmic distribution on
immunofluorescence with specificity against myeloperoxidase
(MPO) or protease 3 (PR3) antigen (3). Although EGPA is a
member of AAV, MPO-ANCA can only be detected in 30%–40%
of patients with EGPA (4). The 1984 Lanham diagnosis criteria
(5) and 1990 American College of Rheumatology criteria (6)do
not include ANCA in the items, possibly due to the low detection
rate. Previous studies from different cohorts suggest that ANCA
is associated with clinical manifestations of EGPA (7–10). Large-
scale retrospective studies on the relationship between EGPA
and ANCA were conducted in Europe. However, among the
Chinese population, the role of specific MPO-ANCA in the
clinical spectrum of EGPA remains unclear. In this study, we
aimed to investigate the significance of MPO-ANCA in the
clinical characteristics, treatment, and outcomes of patients
with EGPA from a longitudinal Chinese cohort.
PATIENTS AND METHODS
Patients
A total of 120 patients with EGPA were identified by at least two
rheumatologists in Peking Union Medical College Hospital
(PUMCH) between January 2010 and December 2020. The
patients were enrolled according to the 1990 American College
of Rheumatology classification criteria for EGPA (6). Other
causes of eosinophilia were carefully excluded from this cohort,
such as parasite infection, eosinophilic pneumonia, eosinophilic
gastroenteritis, asthma with hypereosinophilia, other allergic
diseases, primary or neoplastic hypereosinophilic syndrome,
and other neoplastic diseases. Written informed consent was
obtained from all the patients. The ethical committee of PUMCH
approved this study (approval number: S-K1385; Beijing, China).
The study was performed in accordance with the ethical
standards of the Declaration of Helsinki.
ANCA Detection
The indirect immunofluorescence was used to test the cytoplastic
ANCA (cANCA) and perinuclear ANCA (pANCA). Enzyme-
linked immunosorbent assay or chemiluminescence was
performed to identify the titer of target antigens, including
MPO and PR3. ANCA was considered positive when the
testing result using indirect immunofluorescence was positive,
or the titer of MPO-ANCA and/or PR3-ANCA was higher than
the reference value. ANCA was tested mainly at baseline, and
continuous testing was lacking.
Clinical Assessment at Baseline
Medical records were retrieved and reviewed to extract the clinical
data, including the affected organs,laboratory testing, and histological
findings. Organ involvement was assessed on the basis of medical
history, laboratory tests, imaging, and biopsies. Each system
involvement was defined on the basis of our previous descriptions
with slight modifications (11). Asthma was defined as the active
condition that required continuous glucocorticoids (GC; including
inhaled, oral, or intravenous form) or with persistent dyspnea. Skin
involvement included palpable purpura, reticulata, maculopapular
rash, skin ulcers, or gangrene of the extremities. The definition of
arthritis was swelling and pain in multiple joints with morning
stiffness. Renal involvement was defined as abnormal urine test or
serum creatinine beyond the upper limit of the normal range, and the
former included hematuria, proteinuria (urine protein>0.5 g/24 h),
and cylindruria. Gastrointestinal involvement included bleeding,
obstruction, perforation of digestive tract, or abdominal symptoms
that could not be explained by other disorders. PNS involvement was
defined as mononeuritis multiplex and multiple peripheral
neuropathy based on paresthesia or motion abnormality,
electromyogram, and muscle biopsies. EGPA-associated central
nervous system (CNS) involvement was diagnosed according to the
clinical manifestations, physical examinations, and imaging, which
included intracranial ischemia or hemorrhages, spinal cord or
medulla oblongata involvement, and hypertrophic cranial
pachymeningitis and precluded the CNS lesions caused by related
risk factors, such as hypertension, hyperlipidemia, hyperglycemia,
smoking, infection, and genetic factors. Cardiac involvement
presented with myocardial involvement, heart failure, pericardial
effusion, coronary lesions, moderate to severe valve involvement, and
arrhythmia, which could not be explained by other reasons.
Biopsy findings were recorded as normal or showing evidence
of eosinophilic infiltrates, vasculitis, and/or granuloma. Biopsy-
proven vasculitis presented with inflammatory cell infiltration or
fibrinoid necrosis in the wall of vessels, thickening of vessel walls,
Liu et al. Significance of MPO-ANCA in EGPA
Frontiers in Immunology | www.frontiersin.org June 2022 | Volume 13 | Article 8851982
and/or internal elastic lamina rupture. The original 1994
Birmingham Vasculitis Activity Score (BVAS) was used to
assess the disease activity at diagnosis (12). Disease features
were only scored if they were attributable to active vasculitis.
The prognosis was assessed according to the 2011 revised five
factor score (FFS), which includes age over 65 years, cardiac
symptoms, gastrointestinal involvement, renal insufficiency
(peak serum creatinine ≥150 mmol/L), and the absence of ENT
manifestations (13).
Treatment Strategy
Patients were treated with therapy that was considered the most
appropriate regimen at that time. The drugs used to induce and
maintain remission were recorded in detail. For GCs, initial pulse
of methylprednisolone (MP) was defined as 0.5~1.0 g/d for 3~5
days, high-dose prednisone was 1~2 mg kg
−1
d
−1
, and medium-
dose prednisone was 0.5~0.8 mg kg
−1
d
−1
.
Follow-Up and Outcomes
Long-term follow-up and outcomes were established after the
patient’s last visit or death. Complete remission was achieved if
the BVAS became zero, and partial relief was defined as a ≥50%
decrease of BVAS from baseline for at least six months. Mortality
analysis was based on all-cause mortality.
Statistical Analysis
Clinical characteristics of patients are presented as numbers and
percentages for categorical variables and as mean ± standard
deviation (SD) or median (first and third quartiles) for
continuous variables. All analysis was performed using SPSS 25.0.
Differences between the patients with positive MPO-ANCA and
negative ANCA regarding the continuous variables were tested
using t-test or Mann–Whitney U-test, and differences in categorical
variables were assessed with Fisher’s exact or Chi-square tests, as
appropriate. Two-sided P-values of <0.05 were considered
statistically significant. Survival analysis was conducted using
Kaplan–Meier survival curves and log-rank tests (Prism 7;
GraphPad, San Diego, CA, USA). Univariate and multivariate
logistic regression analyses were performed to find out the
independently associated factors for renal involvement in EGPA.
Correlations were calculated using Pearson correlation analysis.
RESULTS
Clinical Features of Patients With EGPA
With MPO-ANCA and Without ANCA
at Baseline
A total of 120 patients with EGPA were enrolled in our cohort.
Positive ANCA was observed in 29 patients (24.2%), including
25 with MPO-ANCA (20.8%), 5 with PR3-ANCA (4.2%), 25
with pANCA (20.8%), and 7 with cANCA (5.8%). Three patients
showedquadruplepositiveforMPO-ANCA,PR3-ANCA,
pANCA, and cANCA.
We first explored the association between MPO-ANCA and
the clinical spectrum in this cohort (Table 1). We removed two
patients with only PR3-ANCA to ensure the data clarity. Patients
with MPO-ANCA were relatively older than those without
ANCA (50.6 ± 13.8 vs. 44.0 ± 15.0, p = 0.05), and the gender
was not significantly different. Laboratory tests revealed that ESR
[53 (40, 79) vs. 26 (9, 44) mm/1 h, p < 0.0001] and CRP [36.5
(22.4, 70.0) vs. 13.8 (5.2, 55.7) mg/L, p = 0.02] were significantly
higher in the MPO-ANCA–positive group than in the ANCA-
negative group. The eosinophil count and ratio were comparable
between groups. Compared with the ANCA-negative group, the
MPO-ANCA–positive group had higher percentages of patients
with fever (84.0% vs. 40.9%, p = 0.0001) and myalgia (40.0% vs.
17.2%, p = 0.02). In terms of the systemic manifestations, renal
involvement occurred more frequently in the MPO-ANCA–
positive group (80.0% vs. 35.5%, p < 0.0001), whereas cardiac
lesions (38.7% vs. 12.0%, p = 0.01) and asthma (76.3% vs. 56.0%,
p = 0.04) presented more commonly in the ANCA-negative
group. A total of 64.0% of patients with EGPA with MPO-ANCA
developed PNS involvement compared with 43.0% in the
ANCA-negative group, which was close to the statistical
significance (p = 0.06).
The disease activity and prognosis were also assessed for the
patients. BVAS in patients with positive MPO-ANCA was higher
than that in controls [21 (17, 24) vs. 15 (10, 20), p = 0.004], and
the MPO-ANCA–positive group had a higher percentage of
patients with active disease condition (76.0% vs. 45.2%, p =
0.006), which was defined as BVAS > 15. Overall FFS was similar
between the groups, although the ratio of FFS = 3 in the MPO-
ANCA–positive group was relatively higher than that in the
control group (16.0% vs. 8.6%).
Correlation of MPO-ANCA Titers at Onset
and Other Parameters
Among the MPO-ANCA–positive patients with EGPA at baseline,
we analyzed the correlation of MPO-ANCA titers and ESR, CRP,
eosinophil count, and BVAS(Fi gures 1A–D). The results suggested
that MPO-ANCA titers positively correlated with ESR (r = 0.492, p
= 0.027 eosinophil count (r = 0.483,p = 0.036),and BVAS (r = 0.535,
p = 0.015). Moreover, the patients with EGPA who were given MP
pulse had higher MPO-ANCA titers at onset than those who never
experienced MP pulse (Figure 1E).
Relationship Between Renal Involvement
and MPO-ANCA
The analysis above emphasized that the ratio of renal involvement
in the MPO-ANCA–positive group was significantly higher
compared with the ANCA-negative group. However, a large
proportion of patients with renal lesions were ANCA-negative
(33 of 53). Therefore, we further investigated the differences
between patients with postive MPO-ANCA and negative ANCA
with renal lesions (Table 2). The results indicated that female
percentage was higher in the MPO-ANCA–positive group than in
the ANCA-negative group (45% vs. 18%, p = 0.04). ESR was faster
in the MPO-ANCA–positive group compared with the negative
group [61 (40, 85) vs. 24 (10, 45) mm/1 h, p < 0.001]. The biopsy-
proven vasculitis (44.4% vs. 8.7%, p = 0.04) and fever (85.0% vs.
42.4%, p = 0.002) in patients with MPO-ANCA were more
common than in patients without ANCA. On the other hand,
the patients with negative ANCA with renal involvement had
Liu et al. Significance of MPO-ANCA in EGPA
Frontiers in Immunology | www.frontiersin.org June 2022 | Volume 13 | Article 8851983
higher percentages of skin lesions (60.6% vs. 25.0%, p = 0.01) and
cardiac involvement (42.4% vs. 15.0%, p = 0.04). Gastrointestinal
involvement showed a higher tendency in the patients with
negative ANCA with renal involvement (39.4% vs. 15.0%,
p=0.06).
We further analyzed the independent factors associated with
renal lesions in EGPA. We first screened out the possible related
factors through univariate logistic regression analysis
(Figure 2A). Then, after adjustment for age using multivariate
logistic regression analysis, three independent associated factors
were finally revealed which were male (OR = 4.041, 95% CI:
1.582–10.324, p = 0.004), ear involvement (OR = 4.157, 95% CI:
1.022–16.918, p = 0.047), and MPO-ANCA positivity (OR =
9.528, 95% CI: 2.708–33.526, p < 0.001) (Figure 2B).
Pathologic Characteristics
A total of 77 patientsunderwent one or more biopsies from different
tissues or organs. Extravascular eosinophilic infiltration was present
in 70.1% (54 of 77) of the patients, but there was no difference
between the groups. Biopsy-proven vasculitis was seen in 23.4% (18
of 77) of all the patients with EGPA and frequently occurred in
kidneys and peripheral nerves. Granulomas were relatively rare
(14.3%, 11 of77), occasionally observed in lungs and skin. Detailed
records of renal pathology were from three patients and all of them
were males. Two of the patients were MPO-ANCA–positive, which
both showed crescentic glomerulonephritis, accompanied by
glomerular necrosis in different ranges without obvious immune
complex deposition. Another patient was MPO-ANCA–negative
and developed mesangial proliferative glomerulonephritis. In this
study, the patients with positive MPO-ANCA showed a
significantly higher ratio of biopsy-proven vasculitis than the
patients with negative ANCA (53.8% vs. 17.7%, p = 0.01;
Table 1), but eosinophilic infiltration and granulomas were both
comparable between the groups.
Treatment
The GC therapy was administered to 117 patients, and three
patients selected other therapies because their conditions were
TABLE 1 | Clinical features of patients with EGPA with MPO-ANCA and without ANCA at baseline.
Characteristics All patientsn = 118
a
MPO-ANCA–positive, n = 25 ANCA-negative, n = 93 P-value
Age, years, mean ± SD 45.4 ± 15.0 50.6 ± 13.8 44.0 ± 15.0 0.05
Gender, male/female, number 69/49 13/12 56/37 0.46
Time from allergy to EGPA diagnosis (month), median (IQR) 31 (0, 77) 48 (7,72) 28 (0, 73) 0.50
Time from initial symptoms to EGPA diagnosis (month), median (IQR) 18 (3,53) 13 (6, 56) 18 (3,50) 0.83
Eosinophil count, median (IQR) 3.2 (1.5, 8.5) 4.2 (1.3, 8.7) 3.2 (1.6, 7.2) 0.72
Eosinophil ratio, median (IQR) 28.6 (16.9, 45.9) 31.9 (13.4, 44.1) 28.5 (18.3, 45.8) 0.91
ESR, mm/1 h, median (IQR) 34 (11, 53) 53 (40, 79) 26 (9, 44) <0.0001
CRP, mg/L, median (IQR) 21.3 (6.1, 64.9) 36.5 (22.4, 70.0) 13.8 (5.2, 55.7) 0.02
RF, IU/ml, median (IQR) 15 (7, 72) 39 (6, 180) 13 (8, 58) 0.32
Eosinophilic infiltration, n (%) 52/75 (69.3) 10/13 (76.9) 42/62 (67.7) 0.74
Biopsy-proven vasculitis, n (%) 18/75 (24.0) 7/13 (53.8) 11/62 (17.7) 0.01
Granuloma, n (%) 11/75 (14.7) 3/13 (23.1) 8/62 (12.9) 0.39
Clinical manifestations, n (%)
Fever 59 (50.0) 21 (84.0) 38 (40.9) 0.0001
Weight loss 45 (38.1) 12 (48.0) 33 (35.5) 0.26
Arthritis 17 (14.4) 3 (12.0) 14 (15.1) 1.00
Myalgia 26 (22.0) 10 (40.0) 16 (17.2) 0.02
Allergic rhinitis 50 (42.4) 8 (32.0) 42 (45.2) 0.23
Asthma 85 (72.0) 14 (56.0) 71 (76.3) 0.04
Gastrointestinal involvement 38 (32.2) 6 (24.0) 32 (34.4) 0.32
Renal involvement 53 (44.9) 20 (80.0) 33 (35.5) <0.0001
Abnormal urine test 51 (43.2) 19 (76) 32 (34.4) 0.0002
Increased serum creatinine 15 (12.7) 8 (32.0) 7 (7.5) 0.003
Skin involvement 59 (50.0) 9 (36.0) 50 (53.8) 0.11
PNS involvement 56 (47.5) 16 (64.0) 40 (43.0) 0.06
CNS involvement 18 (15.4) 4 (16.0) 14 (15.2) 1.00
Cardiac involvement 39 (33.1) 3 (12.0) 36 (38.7) 0.01
Ear involvement 15 (12.7) 4 (16.0) 11 (11.8) 0.52
Sinusitis 72 (61.0) 12 (48.0) 60 (64.5) 0.13
Thrombotic event 25 (21.2) 5 (20) 20 (21.5) 0.87
BVAS>15 61 (51.7) 19 (76.0) 42 (45.2) 0.006
BVAS, median (IQR) 16 (10, 22) 21 (17, 24) 15 (10, 20) 0.004
Five factor score 0.35
0 29 (24.6) 7 (28.0) 22 (23.7) –
1 49 (41.5) 11 (44.0) 38 (40.9) –
2 28 (23.7) 3 (12.0) 25 (26.9) –
3 12 (10.2) 4 (16.0) 8 (8.6) –
a
Two patients with only PR3-ANCA positivity were removed. ANCA, antineutrophil cytoplasmic antibody; BVAS, Birmingham Vasculitis Activity Score; CNS, central nervous system; CRP,
C-reactive protein; EGPA, eosinophilic granulomatosis with polyangiitis; ESR, erythrocyte sedimentation rate; IQR, interquartile range; MPO, myeloperoxidase; PNS, peripheral nervous
system; RF, rheumatoid factor. The bold values indicate statistically significant differences.
Liu et al. Significance of MPO-ANCA in EGPA
Frontiers in Immunology | www.frontiersin.org June 2022 | Volume 13 | Article 8851984
relatively good and they were too concerned about the adverse
effects of GC. MP pulse was prescribed to 36.0% (nine) of
patients with positive MPO-ANCA and 24.7% (twenty-three)
of patients with negative ANCA, which did not reach the
statistical difference. Intravenous cyclophosphamide (CYC) was
more commonly administered in the MPO-ANCA–positive
group than in the ANCA-negative group (80.0% vs.
58.1%; Figure 3A).
Patients with positive MPO-ANCA were used a relatively
higher ratio of intravenous immunoglobulin (IVIG) therapy than
the patients with negative ANCA (32.0% vs. 14.0%; Figure 3B).
We retrospectively analyzed the outcomes between patients who
had used IVIG at least once and those who had never used IVIG
(Supplementary Table 1). The result showed that all death cases
occurred in the group without IVIG therapy. The details of
patients who had used IVIG were presented in Supplementary
Table 2. A total of 21 patients with EGPA were administered
IVIG, most of whom were prescribed IVIG together with GC and
CYC for inducing remission. IVIG was generally prescribed 20 g
per day for 3–5 days. Most of the patients who used IVIG therapy
had FFS of ≥1 (18 of 21) or had cardiac manifestations or
peripheral neuropathy (17 of 21). The median of BVAS for
them was 18. Finally, they got complete remission (17 of 21) or
partial relief (4 of 21) under the treatment strategy.
Outcomes
The median follow-up duration was 26 months (range: 1–120
months). Of all the patients with EGPA, 77.3% and 17.6%
achieved complete remission and partial relief, respectively.
The overall outcomes were not significantly different between
the two groups (Figure 3C). We also summarized the clinical
features of death cases in this cohort (Supplementary Table 3).
Six patients died, including one with MPO-ANCA (Case 1, 4.0%)
and five without ANCA (5.4%). Among them, two patients died
due to cancers which were chronic myelomonocytic leukemia
and lung cancer; one was due to digestive tract perforation; one
was diagnosed as intestinal perforation combined with infection
and myocardial involvement; one died of multiple organ failure
combined with severe infection; and the last one died of a sudden
aneurysm rupture. Of note, most of the death events (five of six)
occurred within 6 months, and most patients had used GC and
CYC (only one patient used hydroxychloroquine and
tripterygium) but none had tried IVIG.
We further performed the survival analysis and found that the
cumulative survival rates were comparable in the two
groups (Figure 3D).
DISCUSSION
The critical role of ANCA in AAV remains to be a focus. Many
studies have explored it extensively, mainly in GPA and MPA. In
EGPA, the clinical significance of specificMPO-ANCA,
particularly in Chinese patients, was elusive. In this study, we
retrospectively investigated the impact of MPO-ANCA on
EGPA. The patients with positive MPO-ANCA had higher
disease activity and rates of renal involvement, biopsy-proven
vasculitis, fever, and myalgia. The patients with negative ANCA
A
B
DE
C
FIGURE 1 | Correlation of MPO-ANCA titers at baseline with other parameters in the patients with MPO-ANCA-positive EGPA. (A–D) Correlation of MPO-ANCA
titers with ESR, CRP, EOS count, and BVAS. Pearson correlation was used for the analysis. (E) Comparison of MPO-ANCA titers between patients with and without
MP pulse. ANCA, antineutrophil cytoplasmic antibody; BVAS, Birmingham Vasculitis Activity Score; CRP, C-reactive protein; EGPA, eosinophilic granulomatosis with
polyangiitis; EOS, eosinophil; ESR, erythrocyte sedimentation rate; MP, methylprednisolone; MPO, myeloperoxidase.
Liu et al. Significance of MPO-ANCA in EGPA
Frontiers in Immunology | www.frontiersin.org June 2022 | Volume 13 | Article 8851985
developed more cardiac involvement and asthma. The baseline
MPO-ANCA titers correlated positively with disease activity.
MPO-ANCA was the most significant independent factor
associated with renal involvement. Patients with positive
MPO-ANCA were administered intravenous CYC and IVIG
more frequently than patients with negative ANCA.
In the published papers about EGPA, patients were almost
from the cohort of the French Vasculitis Study Group or the
United States (7,8,14–19), and comprehensive data from Asia,
especially from China, were scarce. Therefore, we established
such an EGPA cohort to provide more information from China
in the field of EGPA. The French Vasculitis Study Group
published their findings 20 years ago (14) and subsequently
updated many contents from the same cohort in 2013 and 2021
(8,17), which may be because the disease process and outcomes
have been changed with the development of EGPA diagnosis and
treatment. For instance, one study from Rodriguez-Pla et al.
revealed that, since 1999, the mortality rates of patients with
primary systemic vasculitis have progressively decreased in the
United States, and they demonstrated the mortality trends of
vasculitis in gender, racial, and geographic disparities (19).
Therefore, studies from different regions, races, and year
ranges are warranted.
We described some similar results with publications of Sable-
Fourtassou et al. or Sinico et al. from European EGPA cohorts
(14,15). However, our study had distinct findings, which
provided more evidence for the clinical significance of MPO-
ANCA. Notably, ANCA includes MPO-ANCA, PR3-ANCA,
and ANCAs without specificity according to target
autoantigens. The French cohort in 2013 reported that only
63% of ANCA positivity was positive for MPO-ANCA (8). Many
previous studies have just selected total ANCAs detected by
immunofluorescence as the stratification marker (7–9).
However, our preliminary analysis found that the clinical
phenotypic differences of EGPA were more significant based
on MPO-ANCA grouping than ANCA grouping. Therefore, this
TABLE 2 | Clinical characteristics of patients with EGPA with renal involvement at baseline.
Characteristics MPO-ANCA–positive, n = 20 ANCA-negative, n = 33 P-value
Demographics
Age, years, mean ± SD 51.3 ± 14.5 45.3 ± 15.3 0.17
Gender, male/female, number 11/9 27/6 0.04
Time from allergy to EGPA diagnosis
(month), median (IQR)
48 (12, 72) 6 (0, 60) 0.16
Time from initial symptoms to
EGPA diagnosis (month), median (IQR)
13 (5, 54) 12 (2, 55) 0.90
Laboratory tests
Eosinophil count, median (IQR) 3.0 (1.3, 7.6) 3.6 (2.4, 8.3) 0.62
Eosinophil ratio, median (IQR) 28.5 (12.2, 40.8) 30.9 (19.7, 45.8) 0.45
ESR, mm/1 h, median (IQR) 61 (40, 85) 24 (10, 45) <0.001
CRP, mg/L, median (IQR) 36.8 (24.4, 84.4) 19.6 (7.2, 81.0) 0.13
RF, IU/ml, median (IQR) 39 (16, 135) 14 (10, 51) 0.35
Extravascular eosinophilic infiltration, n (%) 7/9 (77.8) 16/23 (69.6) 1.00
Biopsy-proven vasculitis, n (%) 4/9 (44.4) 2/23 (8.7) 0.04
Granuloma, n (%) 2/9 (22.2) 2/23 (8.7) 0.56
Clinical manifestations, n (%)
Fever 17 (85.0) 14 (42.4) 0.002
Weight loss 10 (50.0) 14 (42.4) 0.59
Arthritis 2 (10.0) 6 (18.2) 0.70
Myalgia 8 (40.0) 7 (21.2) 0.14
Allergic rhinitis 6 (30.0) 12 (36.4) 0.64
Asthma 11 (55.0) 23 (69.7) 0.28
Gastrointestinal involvement 3 (15.0) 13 (39.4) 0.06
Skin involvement 5 (25.0) 20 (60.6) 0.01
PNS involvement 13 (65.0) 15 (45.5) 0.17
CNS involvement 3 (15.0) 8 (24.2) 0.50
Cardiac involvement 3 (15.0) 14 (42.4) 0.04
Ear involvement 4 (20.0) 7 (21.2) 1.00
Sinusitis 11 (55.0) 23 (69.7) 0.28
Thrombotic event 3 (15.0) 10 (30.3) 0.33
BVAS>15 17 (85.0) 21 (63.6) 0.09
BVAS, median (IQR) 22 (18, 25) 18 (13, 28) 0.50
Five factor score, n (%) 0.37
0 6 (30.0) 7 (21.2) –
1 9 (45.0) 13 (39.4) –
2 1 (5.0) 8 (24.2) –
3 4 (20.0) 5 (15.2) –
ANCA, antineutrophil cytoplasmic antibody; BVAS, Birmingham Vasculitis Activity Score; CNS, central nervous system; CRP, C-reactive protein; EGPA, eosinophilic granulomatosis with
polyangiitis; ESR, erythrocyte sedimentation rate; IQR, interquartile range; MPO, myeloperoxidase; PNS, peripheral nervous system; RF, rheumatoid factor. The bold values mean
statistical differences.
Liu et al. Significance of MPO-ANCA in EGPA
Frontiers in Immunology | www.frontiersin.org June 2022 | Volume 13 | Article 8851986
A
B
FIGURE 2 | Forest plots of univariate and multivariate logistic regression analysis of renal involvement of patients with EGPA. Forest plots of (A) univariate and
(B) multivariate logistic regression analysis of patients with EGPA with renal involvement. ANCA, antineutrophil cytoplasmic antibody; CRP, C-reactive protein;
EGPA, eosinophilic granulomatosis with polyangiitis; ESR, erythrocyte sedimentation rate; MPO, myeloperoxidase; OR, odds ratio. *P< 0.05.
A
B
C D
FIGURE 3 | Treatment and outcomes in patients with EGPA with MPO-ANCA and without ANCA. (A, B) Comparisons of CYC-IV and IVIG used in patients with
MPO-ANCA and without ANCA. (C, D) Comparisons of outcomes and cumulative survival rates between the two groups. ANCA, antineutrophil cytoplasmic
antibody; CYC-IV, intravenous cyclophosphamide; EGPA, eosinophilic granulomatosis with polyangiitis; IVIG, intravenous immunoglobulin; MPO, myeloperoxidase.
Liu et al. Significance of MPO-ANCA in EGPA
Frontiers in Immunology | www.frontiersin.org June 2022 | Volume 13 | Article 8851987
study specifically explored the clinical significance of MPO-
ANCA. We compared two European EGPA cohorts with ours
as a representative Asian cohort and found some disparities
(Table 3). First, our study indicated that fever was more
common, and the proportion of fever and myalgia in the
MPO-ANCA–positive group was significantly higher than that
in the ANCA-negative group. Second, the percentage of asthma
at baseline was relatively lower in our cohort, and the ANCA-
negative group had a higher proportion of asthma than the
MPO-ANCA–positive group. Therefore, it should be aware that
not all patients with EGPA would develop asthma in clinical
practice especially for the respiratory physician. Third, we
demonstrated that BVAS, ESR, and CRP in MPO-ANCA–
positive group were significantly higher, and baseline MPO-
ANCA titers positively correlated with ESR, eosinophil count,
and BVAS, implying the possible pathogenic role of MPO-
ANCA and the necessity of repeated MPO-ANCA detection.
Moreover, EGPA-associated CNS involvement occurred more
commonly in our cohort. Regarding the prognosis and
treatment, the European cohort from Papo et al. had a higher
proportion of patients with FFS of ≥2 in the MPO-ANCA–
positive group than the control group, and MP pulse and
immunosuppressants for induction were used more in the
patients with positive MPO-ANCA (17). Concerning the
mortality, the 2013 French cohort grouped by ANCA revealed
that the ANCA-negative group had a higher mortality than the
ANCA-positive group at 10 years (8). We found that the
proportion of FFS of ≥2 in ANCA-negative group was higher
(ANCA
+
vs. ANCA
−
: 33% vs. 46%), but the usage percentage of
immunosuppressants for induction was comparable between the
two groups and the total usage ratio of immunosuppressants was
significantly lower than that in ours and the study of Papo et al.
Therefore, we speculated that, at that time, the treatment might
be inadequate for patients with negative ANCA in this early
EGPA cohort. Together, this cohort from China might reflect
some discrepancies between different regions, ethnicities, and
year ranges in EGPA.
MPO-ANCA can activate neutrophils in many ways, releasing
reactive oxygen species, granule proteins, and cytokines, which
damages tissues (20). In our study, the patients with positive MPO-
ANCA suffered more fever and myalgia and had higher ESR, CRP,
and BVAS, suggesting MPO-ANCA as an inflammatory mediator.
The renal histology implied pauci-immune necrotizing crescentic
glomerulonephritis in the patients with positive MPO-ANCA. A
recent study with 63-biopsy-proven renal involvement also revealed
necrotizing pauci-immune glomerulonephritis as the most common
presentation in ANCA-positive patients with EGPA (21). Animal
studies have confirmed that the anti-MPO antibody alone can cause
necrotizing crescentic glomerulonephritis (22,23). Together, MPO-
ANCA plays an essential role in the pathogenesis of EGPA.
TABLE 3 | Comparison of EGPA cohorts from different regions.
Our study, 2022 Papo et al., 2021 (17) Comarmond et al., 2013
a
(8)
Country/Region China European France
Patients number 120 734 348
ANCA+, n (%) 29 (24.2) 226 (30.8) 108 (31.0)
MPO-ANCA+, n (%) 25 (20.8) 210 (28.6) 68 (19.5)
PR3-ANCA+, n (%) 5 (4.2) 16 (2.2) 4 (1.1)
MPO-ANCA+ vs. ANCA-
Female gender, % 48 vs. 40 48 vs. 58 44 vs. 48
Age, years, mean 51 vs. 44 57 vs. 51 53 vs. 50
CRP, median, mg/L 37 vs. 14 66 vs. 18 79 vs. 59
Eosinophils, median,/mm
3
4.2 vs. 3.2 5.4 vs. 3.2 7.8 vs. 7.3
Fever, % 84 vs. 41 36 vs 27 41 vs. 35
Myalgia, % 40 vs. 17 31 vs. 28 41 vs. 38
Arthralgia, % 12 vs. 15 38 vs. 25 34 vs. 27
Asthma, % 56 vs. 76 91 vs. 93 93 vs. 91
Skin involvement, % 36 vs. 54 38 vs. 34 45 vs. 36
PNS involvement, % 64 vs. 43 71 vs. 47 63 vs. 44
CNS involvement, % 16 vs. 15 5 vs. 3 7 vs. 4
Renal involvement, % 80 vs. 36 29 vs. 5 27 vs. 16
Gastrointestinal involvement, % 24 vs. 34 15 vs. 16 22 vs. 23
Cardiac involvement, % 12 vs. 39 21 vs. 33 8 vs. 19
b
ENT manifestations, % 60 vs. 65 84 vs. 83 59 vs. 44
BVAS, median 21 vs. 15 16 vs. 13 21 vs. 18
Five factor score, %
FFS = 0 28 vs. 24 59 vs. 63
c
33 vs. 22
FFS = 1 44 vs. 41 22 vs. 30
c
34 vs. 32
FFS ≥2 28 vs. 35 19 vs. 7
c
33 vs. 46
Pulses of methylprednisolone, % 36 vs. 25 58 vs. 46 ——
Immunosuppressant for induction, % 92 vs. 85 72 vs. 62 50 vs. 56
Death, % 4 vs. 5 6 vs. 5 6 vs. 13
a
This cohort study was based on ANCA grouping, not MPO-ANCA.
b
Only cardiomyopathy was included in this analysis.
c
The 1996 Five Factor Score system was used here. Numbers
shown in bold are statistically significant. ANCA, antineutrophil cytoplasmic antibody; BVAS, Birmingham Vasculitis Activity Score; CNS, central nervous system; CRP, C-reactive protein;
EGPA, eosinophilic granulomatosis with polyangiitis; ENT, ear, nose, throat; FFS, five factor score; MPO, myeloperoxidase; PNS, peripheral nervous system; PR3, protease 3.
Liu et al. Significance of MPO-ANCA in EGPA
Frontiers in Immunology | www.frontiersin.org June 2022 | Volume 13 | Article 8851988
We further explored the correlation of MPO-ANCA level with
disease activity in EGPA. The analysis was basedon baseline ANCA
testing results because repeat ANCA testingwas not a routine in our
hospital. For patients with positive MPO-ANCA at baseline, MPO-
ANCA titers positively correlated with parameters suggestive of
diseaseactivity and were associated withthe ratio of MP pulse in this
cohort. A study from Mayo Clinic reported that 75% of patients
with EGPA were ANCA positive during the disease flare, whereas
only 16% during remission. ANCA prevalence was 73% before and
36% after treatment. Serial measurements indicated a correlation of
MPO-ANCA titers with disease status (24). A prospective AAV
cohort study from Japan in 2018 revealed that reappearance of
MPO-ANCA may be useful for predicting relapse in the patients
with MPO-ANCA–positive AAV in remission.MPO-ANCA could
convert to negative after treatment (25). Therefore, for patients who
were positive for MPO-ANCA at baseline, monitoring MPO-
ANCA levels may be meaningful in terms of observing disease
activity and predicting relapse.
Whether EGPA can be divided into two subtypes based on the
ANCA status remains controversial. According to our cohort, the
MPO-ANCA–positive group had more severe inflammation,
higher disease activity and frequencies of renal involvement and
biopsy-proven vasculitis, and the ANCA-negative group developed
more cardiac manifestations and asthma. The large European
cohort reported some similar findings (17). Conversely, the 2020
international consensus on ANCA testing in EGPA suggested that
the MPO-ANCA is neither sensitive nor specific enough to identify
“vasculitic”or “eosinophilic”EGPA, although patients with MPO-
ANCA have more features of vasculitis (26). Even so, it did not
mean that MPO-ANCA is not suitable for subclassification, if not
simply limited to classify as “vasculitic”and “eosinophilic”.
Furthermore, a recent genome-wide association study of EGPA
stratified by MPO-ANCA suggests that EGPA may comprise two
clinicallyand genetically distinct syndromes. MPO+ EGPA shares a
strongHLA-DQ associationwith anti-MPO AAV, whereas ANCA-
negative EGPA presents with mucosal/barrier dysfunction.
Variants with IRF1/IL5 are associated with ANCA-negative
EGPA, suggesting that anti-IL5 therapy might be more specific
for this subset (27). Although functional studies are needed, this
study suggests that patientswith positive MPO-ANCA and negative
ANCA have fundamentally different genetic background in
pathogenesis, which supports MPO-ANCA as a potential
biomarker of EGPA stratification.
More specifically, a recent study investigated the
clinicopathologic features of EGPA-associated neuropathy with
and without MPO-ANCA (10). Compared with the ANCA-
negative group, the MPO-ANCA–positive group had higher CRP
and percentage of vasculitis suggested by sural nerve biopsy but
lower eosinophil infiltration in affected tissues. Furthermore, rare
PR3+ EGPA also showed distinct features compared with patients
with positive MPO-ANCA and negative ANCA. French Vasculitis
and EGPA European Study Group in 2021 reported that PR3+
patients with EGPA shared more clinical features with GPA.
Compared with patients with positive MPO-ANCA and negative
ANCA, patients with PR3+ ANCA less frequently developed active
asthma and peripheral neuropathy and more frequently had
cutaneous manifestations and pulmonary nodules and lower
eosinophil count (17). Taken together, MPO-ANCA may be an
effective stratification biomarker for EGPA.
Recently, the newly revised classification criteria of AAV have
incorporated the MPO-ANCA and PR3-ANCA into the system for
the first time, highlighting the significance of specificANCA(28–
30). Positive cANCA or PR3-ANCA in GPA and pANCA or MPO-
ANCA in MPA are weighted largely in the new criteria, because
these antibodies are very commonly seen in GPA or MPA. In
EGPA, cANCA orPR3-ANCA is a deduction item, and pANCA or
MPO-ANCA isnot included in the criteria, possibly because MPO-
ANCA positivity is relatively low in patients with EGPA. Therefore,
MPO-ANCA may be not appropriate for EGPA classification, but
be meaningful for subtype stratification as MPO-ANCA–positive,
PR3-ANCA–positive, and ANCA-negative EGPA.
The therapy of CYC combined with GC induced long-term
remission in more than 90% of patients with AAV (31), which was
the core treatment in our cohort. IVIG was more commonly
prescribed in the MPO-ANCA–positive group. More importantly,
we found that for patients who were ever administered IVIG therapy,
the outcomes might be better, in particular, all deaths occurred in the
group without IVIG therapy. Most of the death cases were recorded
within 6 months. Therefore, early combination with IVIG on basis of
GC and CYC might yield better outcomes for these patients.
However, this result is only a rough analysis with confounding
factors because it was based on a retrospective cohort. Interestingly,
we noted that IVIG is a mainstay in the treatment of Kawasaki
disease which is a form of acute vasculitis that mainly occurred in
children. If not intervened in the early stage, about 25% of patients
will develop serious coronary artery aneurysms (32,33). Newburger
et al. in 2016 reviewed that the risk of coronary artery aneurysms was
reduced five-fold if IVIG was used within 10 days offever onset (34).
In our cohort, one patient with EGPA died from a sudden aneurysm
rupture, implying the potential benefitofearlyIVIGusagetoprevent
serious artery aneurysms in EGPA. A meta-analysis suggested that
IVIG potentially reduced levels of ANCA, BVAS, and CRP in
patients with active AAV (35). In theory, IVIG preparations might
be implicated in neutralizing pathogenic ANCAs by anti-idiotype
antibodies (36,37). One review in 2013 indicated that IVIG had
broad immunosuppression in autoimmune diseases such as the
expansion of regulatory T cells, modulation of dendritic cells, and
blocking cellular receptors (38). Crickx et al. in 2016 reported a
retrospective study with 92 patients with AAV using IVIG including
20 patients with EGPA, and the result supports the use of IVIG in
AAV as adjunctive therapy, particularly in relapsing or refractory
disease (39). The high-dose IVIG might be effective for patients with
heart failure or peripheral neuropathy not responsive to standard
immunosuppressive therapy (40–42). A recent study suggested that
earlier add-on combination administration of IVIG and
mepolizumab might be efficient adjunct treatment to induce
clinical remission and decrease relapse risk for patients with
EGPA (43).
IVIG does have a certain position in the treatment of EGPA;
however, in fact, IVIG is mainly used for critically severe patients
in our hospital. First, the cost of IVIG for each course of
treatment is 20,000–30,000 yuan and is not covered by public
Liu et al. Significance of MPO-ANCA in EGPA
Frontiers in Immunology | www.frontiersin.org June 2022 | Volume 13 | Article 8851989
insurance, which is hardly affordable for many patients in China.
Second, as a blood product, IVIG sometimes is in a state of
insufficient supply. Thus, only patients who have severe heart,
CNS, or kidney involvements, or are complicated by severe
infection could be administered IVIG. All the above factors
may partly explain why IVIG was sometimes not given as the
first line in a real-world situation. Hoffmann and Enk in 2019
summarized that although IVIG is generally used as a second- or
third-line treatment in autoimmune disease including systemic
vasculitis; however, the first-line treatment may be warranted in
special conditions like concomitant malignancy, foudroyant
clinical courses, and contraindications against alternative
treatments (32). For these conditions in EGPA, early IVIG
usage might be also beneficial as the first-line therapy, which
deserves more trials, especially for those at a high risk of death.
This study has limitations. First, as a tertiary referral center in
China, most of enrolled hospitalized patients were relatively
complicated or severe cases, and the ANCA-negative patients
with EGPA were more likely to be hospitalized, causing the
ANCA-positive rate to be relatively lower. Second, considering
that the sample size was not large enough, some of the findings
did not reach statistical difference but have suggested valuable
tendencies. Therefore, we are consecutively enrolling more
patients to establish a lager EGPA cohort and the prospective
multicenter study is warranted.
In summary, this EGPA cohort from China revealed that the
patients with positive MPO-ANCA showed an increased disease
activity, higher proportions of renal lesions, and biopsy-proven
vasculitis, whereas the patients with negative ANCA had more
cardiac involvement and asthma. The titers of MPO-ANCA at
baseline correlated positively with disease activity. MPO-ANCA
positivity was the most significantly independent factor
associated with renal involvement in EGPA.
DATA AVAILABILITY STATEMENT
The original contributions presented in the study are included in
the article/Supplementary Material. Further inquiries can be
directed to the corresponding authors.
ETHICS STATEMENT
The studies involving human participants were reviewed and
approved by ethical committee of Peking Union Medical College
Hospital. The patients/participants provided their written
informed consent to participate in this study.
AUTHOR CONTRIBUTIONS
LW and FZ designed the study.SL analyzed the data and wrote the
manuscript. LW revised the manuscript. LH, YL, JY, YZ, and SL
collected the data. ML, XT, XZ, LW, and FZ enrolled and managed
the patients. All authors contributed to the article and approved
the submitted version.
FUNDING
The study was supported by the Non-profit Central Research
Institute Fund of Chinese Academy of Medical Science
(2019XK320022), National Key Research and Development
Program (2016YFA0101003 and 2016YFC0903901), National
Natural Science Foundation of China (81501414, 81771764, and
81571594), CAMS Innovation Fund for Medical Sciences (2017-
I2M-3–008 and 2016-I2M-1–003), and Graduate Innovation Fund
of Peking Union Medical College (2019-1002-01).
ACKNOWLEDGMENTS
We would like to thank all the patients enrolled in our study and
all the professional staff in our hospital.
SUPPLEMENTARY MATERIAL
The Supplementary Material for this article can be found online at:
https://www.frontiersin.org/articles/10.3389/fimmu.2022.885198/
full#supplementary-material
Supplementary Table 1 | IVIG usage and outcomes. IVIG, intravenous immunoglobulin.
Supplementary Table 2 | Clinical features of EGPA patientswho used IVIG. EGPA,
eosinophilic granulomatosiswith polyangiitis; IVIG, intravenous immunoglobulin;BVAS,
Birmingham Vasculitis Activity Score; FFS, five factor score; PNS, peripheral nervous
system; Y, yes, means the patients had heart or PNS involvement; N, no, means the
patients did not have heartor PNS involvement in thefourth column and means no
biologics were used in the “Biologics”column; MP, methylprednisolone; CYC,
cyclophosphamide; Pred, prednisone; LEF, leflunomide; MTX, methotrexate; NA, the
information was not clear; AZA, azathioprine; MMF, mycophenolate mofetil; CR,
complete remission; PR, partial relief. #, the exact dose is unknown.
Supplementary Table 3 | Clinical features of deaths in the cohort. BVAS,
eosinophilic granulomatosiswith polyangiitis; FFS, five factor score;GC, glucocorticoid;
CYC, cyclophosphamide; FU, follow-up; Y, yes,means the patientswere administered
the corresponding drugs; N, no, means the patients were not administered the
corresponding drugs; HCQ, hydroxychloroquine; T2, Tripterygium.
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