Michael J. Kemna

ANCA as a Predictor of Relapse: Useful in Patients with Renal Involvement But Not in Patients with Nonrenal Disease

The value of measuring ANCA during follow-up to predict a relapse is controversial. On the basis of recently obtained pathophysiologic insights, we postulated that measuring ANCA is useful in patients with renal involvement but is less valuable in patients with nonrenal disease. One hundred sixty-six consecutive patients with ANCA-associated vasculitis, positive for either proteinase 3 (PR3)-ANCA or myeloperoxidase (MPO)-ANCA, were included in our study, followed at regular intervals, and tested for PR3-ANCA and MPO-ANCA. In this cohort, 104 patients had renal involvement (72 with PR3-ANCA, 32 with MPO-ANCA) and 62 patients had nonrenal disease (36 with PR3-ANCA, 26 with MPO-ANCA). During an average (±SD) follow-up of 49±33 months and 18±14 ANCA measurements, 89 ANCA rises and 74 relapses were recorded. ANCA rises correlated with relapses in patients who presented with renal involvement (hazard ratio [HR], 11.09; 95% confidence interval [95% CI], 5.01 to 24.55), but in comparison, associated only weakly with relapses in patients who presented with nonrenal disease (HR, 2.79; 95% CI, 1.30 to 5.98). In conclusion, longitudinal ANCA measurements may be useful in patients with renal involvement but is less valuable in patients with nonrenal disease.

Prevalence and prognostic relevance of cardiac involvement in ANCA-associated vasculitis: Eosinophilic granulomatosis with polyangiitis and granulomatosis with polyangiitis

BACKGROUND To investigate the prevalence and prognostic relevance of cardiac involvement in an ANCA-associated vasculitis (AAV) population of eosinophilic granulomatosis with polyangiitis (EGPA) and granulomatosis with polyangiitis (GPA) patients. METHODS Prospective cohort study of fifty EGPA and forty-one GPA patients in sustained remission without previous in-depth cardiac screening attending our clinical immunology outpatient department. Cardiac screening included clinical evaluation, ECG, 24-hour Holter registration, echocardiography and cardiac magnetic resonance imaging (CMR) with coronary angiography and endomyocardial biopsy upon indication. Fifty age-, sex- and cardiovascular risk factor-matched control subjects were randomly selected from a population study. Long-term outcome was assessed using all-cause and cardiovascular mortality. RESULTS A total of 91 AAV-patients (age 60±11, range 63-87years) were compared to 50-matched control subjects (age 60±9years, range 46-78years). ECG and echocardiography demonstrated cardiac abnormalities in 62% EGPA and 46% GPA patients vs 20% controls (P<0.001 and P=0.014, respectively). A total of 69 AAV-patients underwent additional CMR, slightly increasing the prevalence of cardiac involvement to 66% in EGPA and 61% in GPA patients. After a mean follow-up of 53±18months, presence of cardiac involvement using ECG and echocardiography in AAV-patients showed increased all-cause and cardiovascular mortality (Log-rank P=0.015 and Log-rank P=0.021, respectively). CONCLUSION Cardiac involvement in EGPA and GPA patients with sustained remission is high, even if symptoms are absent and ECG is normal. Moreover, cardiac involvement is a strong predictor of (cardiovascular) mortality. Therefore, risk stratification using cardiac imaging is recommended in all AAV-patients, irrespective of symptoms or ECG abnormalities.

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). Conclusion 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.

HLA-DPB1 as a Risk Factor for Relapse in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: A Cohort Study.

The antineutrophil cytoplasmic antibody (ANCA)–associated vasculitides (AAVs) form a group of small‐vessel vasculitides with systemic involvement. Although the etiology of AAVs remains largely unknown, both genetic and environmental factors have been implicated. Recently, certain alleles in the HLA–DPB1 region on chromosome 6 were shown to be associated with proteinase 3 (PR3)–ANCA–positive AAV but not with myeloperoxidase (MPO)–ANCA–positive AAV. The aim of this study was to investigate whether different alleles in the HLA–DPB1 region have clinical and/or prognostic implications in AAV.

Positron emission tomography scanning in anti-neutrophil cytoplasmic antibodies-associated vasculitis

AbstractTools for evaluation of disease activity in patients with anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) include scoring clinical manifestations, determination of biochemical parameters of inflammation, and obtaining tissue biopsies. These tools, however, are sometimes inconclusive. 2-deoxy-2-[18F]-fluoro-D-glucose (FDG) positron emission tomography (PET) scans are commonly used to detect inflammatory or malignant lesions. Our objective is to explore the ability of PET scanning to assess the extent of disease activity in patients with AAV.Consecutive PET scans made between December 2006 and March 2014 in Maastricht (MUMC) and between July 2008 and June 2013 in Brussels (EUH) to assess disease activity in patients with AAV were retrospectively included. Scans were re-examined and quantitatively scored using maximum standard uptake values (SUVmax). PET findings were compared with C-reactive protein (CRP) and ANCA positivity at the time of scanning.Forty-four scans were performed in 33 patients during a period of suspected active disease. All but 2 scans showed PET-positive sites, most commonly the nasopharynx (n = 22) and the lung (n = 22). Forty-one clinically occult lesions were found, including the thyroid gland (n = 4 patients), aorta (n = 8), and bone marrow (n = 7). The amount of hotspots, but not the highest observed SUVmax value, was higher if CRP levels were elevated. Seventeen follow-up scans were made in 13 patients and showed decreased SUVmax values.FDG PET scans in AAV patients with active disease show positive findings in multiple sites of the body even when biochemical parameters are inconclusive, including sites clinically unsuspected and difficult to assess otherwise.

Passive Immunization with Hypochlorite-oxLDL Specific Antibodies Reduces Plaque Volume in LDL Receptor-Deficient Mice

Aims New strategies to overcome complications of cardiovascular diseases are needed. Since it has been demonstrated that atherosclerosis is an inflammatory disease, modulation of the immune system may be a promising approach. Previously, it was suggested that antibodies may confer protective effects on the development of atherosclerosis. In this study, we hypothesised that passive immunization with anti-oxLDL IgM antibodies specific for hypochlorite (HOCl) may be athero-protective in mice. Methods and Results Monoclonal mouse IgM antibodies were produced and the antibody with specificity for hypochlorite-oxLDL (HOCl-oxLDL) (Moab A7S8) was selected. VH sequence determination revealed that Moab A7S8 is a natural IgM antibody. Atherosclerosis in LDLr−/− mice was induced by a perivascular collar placement around the right carotid artery in combination with feeding a high-fat diet. Subsequently, the mice were treated every six days with 500 µg Moab A7S8, non-relevant IgM or with PBS and the carotid arteries and aortic roots were studied for atherosclerosis. Passive immunization with this Moab A7S8 resulted in a significant reduced plaque volume formation in LDLr−/− mice when compared with PBS treatment (P = 0.002 and P = 0.035). Cholesterol levels decreased by 20% when mice were treated with Moab A7S8 compared to PBS. Furthermore, anti-oxLDL specific IgM and IgG antibody production increased significantly in the Moab A7S8 treated mice in comparison with PBS treated mice. Conclusion Our data show that passive immunization with a natural IgM antibody, directed to HOCl-oxLDL, can reduce atherosclerotic plaque development. We postulate that specific antibody therapy may be developed for use in human cardiovascular diseases.

HLA‐DPB1 as a risk factor for relapse in ANCA‐associated vasculitis – a cohort study

The antineutrophil cytoplasmic antibody (ANCA)–associated vasculitides (AAVs) form a group of small‐vessel vasculitides with systemic involvement. Although the etiology of AAVs remains largely unknown, both genetic and environmental factors have been implicated. Recently, certain alleles in the HLA–DPB1 region on chromosome 6 were shown to be associated with proteinase 3 (PR3)–ANCA–positive AAV but not with myeloperoxidase (MPO)–ANCA–positive AAV. The aim of this study was to investigate whether different alleles in the HLA–DPB1 region have clinical and/or prognostic implications in AAV.

The avidity of PR3-ANCA in patients with granulomatosis with polyangiitis during follow-up.

The objective of this study is to investigate whether the avidity of proteinase‐3‐anti‐neutrophil cytoplasmic antibody (PR3‐ANCA) changes during follow‐up in different subgroups of patients with granulomatosis with polyangiitis (GPA). We selected 10 patients with renal relapsing GPA, 10 patients with renal non‐relapsing GPA and 10 patients with non‐renal relapsing GPA. In all patients, an ANCA rise occurred during remission. The avidity was measured using a chaotropic approach at the time of an ANCA rise and at the time of a relapse in relapsing patients or time‐matched during remission in non‐relapsing patients. No difference was observed in the avidity at the ANCA rise between renal relapsing patients [26·2% (15·5–47·5)], renal patients without a relapse [39·6% (21·2–63·4)] and non‐renal relapsing patients [34·2% (21·6–59·5)]. In renal relapsing patients, the avidity increased significantly from the moment of the ANCA rise to the relapse [difference 6·4% (0·0–17·1), P = 0·0273]. The avidity did not increase after an ANCA rise in renal non‐relapsing patients [difference 3·5 (−6·0 to 10·1), P = 0·6250] or in non‐renal relapsing patients [difference −3·1% (−8·0 to 5·0), P = 0·5703]. The avidity of PR3‐ANCA increases after an ANCA rise during follow‐up in renal relapsing patients, but not after an ANCA rise in renal patients who remain in remission or in non‐renal relapsing patients.

Editorial: Can an Increase in Antineutrophil Cytoplasmic Autoantibody Titer Predict Relapses in Antineutrophil Cytoplasmic Antibody–Associated Vasculitis?

Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV) is a rare disease, but one which occurs worldwide and affects all ethnic groups with varying incidence and clinical characteristics. The pathology of AAV is characterized by inflammation and necrosis of small blood vessels with or without granuloma in such diverse organs as the skin, respiratory tract, and kidneys. Over the last decade, there have been significant advances in our understanding of the pathogenesis, diagnosis, and treatments of AAV. One historical advance is the discovery of ANCAs. ANCAs are autoantibodies directed against myeloperoxidase (MPO), proteinase 3 (PR3), or other granular constituents of neutrophils and monocytes. PR3-ANCA is associated with a cytoplasmic granular fluorescence pattern and is seen in 85–95% of individuals with granulomatosis with polyangiitis (Wegener’s). MPOANCA has a perinuclear neutrophil fluorescence pattern and is predominantly seen in patients with microscopic polyangiitis (70% of cases) and eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (40–50% of cases) (1). The diagnostic utility of serial ANCA testing for predicting AAV relapse was demonstrated shortly after the discovery of ANCAs (2). However, this could not be confirmed in several other studies, possibly due to considerable methodologic heterogeneity. Despite numerous studies, there has been an ongoing debate as to whether an increase in ANCA titer predicts disease reactivation in patients with AAV. Therefore, there is uncertainty as to whether rheumatologists should serially check serum ANCA titers in clinical settings. If an increase in ANCA levels is indeed frequently followed by a relapse, it may be beneficial to preemptively treat the patient at the time of the increase in ANCA levels in order to prevent a subsequent relapse. However, the benefits of preemptive treatment should be balanced against unnecessary exposure to immunosuppressive therapy and treatment-related side effects. Beyond its utility for the diagnosis of AAV, ANCA targeting PR3 or MPO is thought to play a direct role in the pathogenesis of AAV. It has been demonstrated in vitro that PR3-ANCA and MPO-ANCA activate neutrophils by binding cell surface–expressed PR3 and MPO via both F(ab)2 and Fcg receptors (3). PR3 and MPO are then internalized by endothelial cells and exert distinct effects, culminating in neutrophil activation and endothelial injury. Whereas PR3 induces apoptosis of the endothelial cells, MPO promotes the production of intracellular oxidants (4). The direct pathogenic role of MPO-ANCA is also supported by in vivo studies demonstrating that MPO-deficient mice immunized with purified murine MPO develop glomerulonephritis and pulmonary capillaritis as in human AAV (5). Interestingly, injection of human PR3-ANCA into humanized mice fails to induce granulomatous inflammation while promoting glomerulonephritis and pulmonary capillaritis (6), suggesting that mechanisms (perhaps cellular response) other than ANCA response are required for granuloma formation in AAV. These observations have previously led to the hypothesis that increases in ANCA levels may be highly associated with a relapse of capillaritis but not with a relapse of granulomatous disease. Indeed, a previous study showed that increases in ANCA levels are highly associated with a relapse in Supported by grants from the National Research Foundation of Korea funded by the Ministry of Education, Science, and Technology (grants 2014R1A2A1A11049812 and 2015R1A3A2032927). Jung Hee Koh, MD, Wan-Uk Kim, MD, PhD: The Catholic University of Korea, Seoul, Republic of Korea; Michael Joseph Kemna, MD, Jan Willem Cohen Tervaert, MD, PhD: Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands. Drs. Koh and Kemna contributed equally to this work. Address correspondence to Wan-Uk Kim, MD, Department of Internal Medicine, Division of Rheumatology, The Catholic University of Korea, School of Medicine, Seoul 137-701, Republic of Korea. E-mail: wan725@catholic.ac.kr. Submitted for publication February 1, 2016; accepted in revised form February 9, 2016.

Aortic 18F-FDG uptake in patients suffering from granulomatosis with polyangiitis

PurposeThe objective of the study was to systematically assess aortic inflammation in patients with granulomatosis with polyangiitis (GPA) using 18F-2-deoxy-2-[18F]fluoro-D-glucose (FDG) positron emission tomography (PET)/CT.MethodsAortic inflammation was studied in PET/CT scans obtained from 21 patients with GPA; 14 patients with sarcoidosis were included as disease controls, 7 patients with stage I or II head and neck carcinoma ascertained during routine clinical practice were used as healthy controls (HC) and 5 patients with large vessel vasculitis (LVV) were used as positive controls. Aortic 18F-FDG uptake was expressed as the blood-normalized maximum standardized uptake value (SUVmax), known as the target to background ratio (mean TBRmax).ResultsThe mean TBRmax (interquartile range) of the aorta in patients with GPA, sarcoidosis, HC and LVV were 1.75 (1.32–2.05), 1.62 (1.54–1.74), 1.29 (1.22–1.52) and 2.03 (1.67–2.45), respectively. The mean TBRmax was significantly higher in patients suffering from GPA or LVV compared to HC (p < 0.05 and p < 0.005, respectively) and tended to be higher in patients suffering from sarcoidosis, but this did not reach statistical significance (p = 0.098). The mean TBRmax of the most diseased segment was significantly higher compared to HC [1.57 (1.39–1.81)] in LVV patients [2.55 (2.22–2.82), p < 0.005], GPA patients [2.17 (1.89–2.83), p < 0.005] and patients suffering from sarcoidosis [2.04 (1.88–2.20), p < 0.05]. In GPA patients, the mean TBRmax of the aorta was significantly higher in patients with previous renal involvement [2.01 (1.69–2.53)] compared to patients without renal involvement in the past [1.60 (1.51–1.80), p < 0.05]. Interrater reproducibility with a second reader was high (all intraclass correlation coefficients >0.9).ConclusionPatients suffering from GPA show marked aortic FDG uptake.