Galactosylation and Sialylation Levels of IgG Predict Relapse in Patients With PR3-ANCA Associated Vasculitis.
OBJECTIVE
The objective of our study is to investigate the Fc glycosylation profiles of both antigen-specific IgG targeted against proteinase 3 (PR3-ANCA) and total IgG as prognostic markers of relapse in patients with Granulomatosis with Polyangiitis (GPA).


METHODS
Seventy-five patients with GPA and a PR3-ANCA rise during follow-up were included, of whom 43 patients relapsed within a median period of 8 (2-16) months. The N-glycan at Asn297 of affinity-purified and denatured total IgG and PR3-ANCA was determined by mass spectrometry of glycopeptides in samples obtained at the time of the PR3-ANCA rise and at the time of the relapse or time-matched during remission.


RESULTS
Patients with total IgG1 exhibiting low galactosylation or low sialylation were highly prone to relapse after an ANCA rise (HR 3.46 [95%-CI 1.73-6.96], p<0.0001 and HR 3.22 [95%-CI 1.52-6.83], p=0.002, respectively). In relapsing patients, total IgG1 galactosylation, sialylation and bisection significantly decreased and fucosylation significantly increased from the time of the PR3-ANCA rise to the relapse (p<0.0001, p=0.0087, p<0.0001 and p=0.0025), while the glycosylation profile remained similar in non-relapsing patients. PR3-ANCA IgG1 galactosylation, sialylation and fucosylation of PR3-ANCA IgG1 decreased in relapsing patients (p=0.0073, p=0.0049 and p=0.0205), but also in non-relapsing patients (p=0.0007, p=0.0114 and p=0.0002), while bisection increased only in non-relapsing patients (p<0.0001).


CONCLUSIONS
While Fc glycosylation profiles have been associated with clinically manifest autoimmune diseases, in the present study we show that low galactosylation and sialyation in total IgG1 but not PR3-ANCA IgG1 predicts disease reactivation in patients with GPA who experience an ANCA rise during follow-up. We postulate that glycosylation profiles may be useful in pre-emptive therapy studies using ANCA rises as guideline.
Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands; Department of Internal Medicine, Division of Nephrology and Clinical Immunology, Maastricht University Medical Center, Maastricht, The Netherlands.
Michael J
MJ
Kemna
Central Diagnostic Laboratory, Maastricht University Medical Center, Maastricht, The Netherlands.
Rosina
R
Plomp
Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands; Department of Internal Medicine, Division of Nephrology and Clinical Immunology, Maastricht University Medical Center, Maastricht, The Netherlands.
Pieter
P
van Paassen
Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands.
Carolien A M
CAM
Koeleman
Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands.
Bas C
BC
Jansen
Central Diagnostic Laboratory, Maastricht University Medical Center, Maastricht, The Netherlands.
Jan G M C
JGMC
Damoiseaux
Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands. Electronic address: jw.cohentervaert@maastrichtuniversity.nl.
Jan Willem
JW
Cohen Tervaert
Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands.
Manfred
M
Wuhrer
D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D005260:Female; D005690:Galactose / Q000378:metabolism; D014890:Granulomatosis with Polyangiitis / Q000097:blood* / Q000473:pathology; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D053146:Myeloblastin / Q000276:immunology; D012794:Sialic Acids / Q000378:metabolism; D006023:Glycoproteins
D015415:Biomarkers; D005690:Galactose; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D053146:Myeloblastin; D012794:Sialic Acids; C046179:glycosylated IgG; D006023:Glycoproteins
Glycopeptide; Glycosylation; Granulomatosis with Polyangiitis; Immunoglobulin; Mass spectrometry; PR3-ANCA associated vasculitis