Main text;
To the editor,
Eosinophilic granulomatosis with polyangiitis (EGPA) is anti-neutrophil
cytoplasmic antibody (ANCA)-associated vasculitis with
eosinophilia1. Mepolizumab, an anti-IL-5 antibody, has
been shown to maintain remission in EGPA patients, contribute to reduced
use of oral steroids, and reduce the frequency of
relapses2. However, the effect of mepolizumab on ANCA
remains unclear, as only case reports have been published so far.
Herein, we present a case series where the effect of mepolizumab on ANCA
values in EGPA is evaluated and a synthesis report of the published
cases.
We conducted a retrospective cohort study at Sagamihara Hospital and
Shonan Kamakura General Hospital.
From April 2004 to March 2022,
710 cases with EGPA disease insurance coverage at these hospitals were
identified, and 166 cases diagnosed as EGPA according to the American
College of Rheumatology 1990 criteria and the International Chapel Hill
Consensus Conference Nomenclature of Vasculitides (CHSS) were extracted
using medical records (Figure 1). Of the 61 patients treated with
mepolizumab, 44 cases who were ANCA-negative at onset and 6 cases whose
ANCA levels were negative due to use of systemic steroids or
immunosuppressants were excluded. The remaining 11 patients (nine with
Myeloperoxidase anti-neutrophil cytoplasmic antibodies (MPO-ANCA), and
two with Proteinase 3 anti-neutrophil cytoplasmic antibodies) were
included in the study (Tables S1, S2).
The blood eosinophil count was significantly lower after treatment, and
many cases showed low values even before mepolizumab treatment (Figure
2A). On the other hand, ANCA (median and interquartile range U/mL)
showed a clear decrease (p = 0.0014) after mepolizumab treatment (4.0
[1.0-7.1] U/mL) compared to ANCA levels before treatment (11.0
[6.3-28.7] U/mL) (Figures 2B-1 and 2B-2). Corticosteroid doses and
Birmingham Vasculitis Activity Score (BVAS) decreased after mepolizumab
treatment (Figure 2C, D), suggesting that mepolizumab improved EGPA
activity and decreased ANCA levels, despite reduced corticosteroid
levels (median and interquartile range mg/day before mepolizumab; 7.0
[4.0-10.0] U/mL, after mepolizumab; 4.0 [2.0-5.0] U/mL).
Next, we created a synthesis report of the published cases
(Supplementary Material). Of the 90 relevant articles, 16 articles that
used biologics preparations other than mepolizumab, 58 articles in which
ANCA was negative, and 12 articles in which ANCA was not measured before
and after antibiotic treatment were excluded; 4 articles were included
(Figure S1). All 12 eligible cases were MPO-ANCA-positive, and ANCA
reduction was confirmed with mepolizumab in 10 patients (Table S1).
There have been no large-scale reports that mepolizumab reducing ANCA
levels, and the reason why mepolizumab lowered ANCA levels is unknown.
Based on reports, B cell-activating factor and a proliferation-inducing
ligand produced by eosinophils act on B cells3, and
IL-5 promotes antibody production from B cells in
mice4. It is also possible that blocking IL-5
suppressed antibody production in B cells directly. However, in the
present study, serum IgG and IgE levels were not decreased by
mepolizumab (Figures E and F), suggesting that the suppression of B cell
function cannot explain the decrease in ANCA levels. On the other hand,
neutrophil extracellular trap (NET) has been reported as an ANCA
production mechanism in granulomatosis with polyangiitis and microscopic
polyangiitis5, and we recently reported the
relationship between severe EGPA and eosinophil
ETosis6. It is also possible that mepolizumab reduced
ETosis, resulting in decreased ANCA production. However, further studies
are required in the future. In addition, since mepolizumab
simultaneously improves EGPA disease activity and reduces ANCA levels,
elucidation of the mechanism of action of mepolizumab on EGPA pathology
will lead to elucidation of EGPA pathology itself.
Thus, we concluded from case series and literature that mepolizumab
significantly reduced ANCA in ANCA-positive EGPA.