Publications by authors named "Pieter van Paassen"

82 Publications

Adult-onset autoinflammation caused by somatic mutations in UBA1: A Dutch case series of VEXAS patients.

J Allergy Clin Immunol 2021 May 25. Epub 2021 May 25.

Department of Rheumatology and Clinical Immunology, University Medical Center Groningen, University of Groningen, The Netherlands. Electronic address:

Background: A novel autoinflammatory syndrome was described recently in male patients who harboured somatic mutations in the X-chromosomal UBA1 gene. These patients were characterized by adult-onset, treatment-refractory inflammation with fever, cytopenias, dysplastic bone marrow, vacuoles in myeloid and erythroid progenitor cells, cutaneous and pulmonary inflammation, chondritis and vasculitis, abbreviated as VEXAS.

Objective: This study aimed to (retrospectively) diagnose VEXAS in patients that had been previously registered with unclassified autoinflammation. We furthermore aimed to describe clinical experiences with this multifaceted, complex disease.

Methods: A systematic re-analysis of whole-exome sequencing data from a cohort of undiagnosed patients with autoinflammation from academic hospitals in the Netherlands was performed. When no sequencing data was available, targeted Sanger sequencing was applied in cases with high clinical suspicion of VEXAS.

Results: A total of 12 male patients were identified that carried mutations in UBA1. These patients presented with adult-onset (mean age 67 years, range 47-79) autoinflammation with systemic symptoms, elevated inflammatory parameters, and multiorgan involvement, most typically involving the skin and bone marrow. Novel features of VEXAS included interstitial nephritis, cardiac involvement, stroke, and intestinal perforation related to treatment with tocilizumab. Although many types of treatment were initiated, most patients became treatment-refractory with a high mortality rate of 50%.

Conclusion: VEXAS should be considered in the differential diagnosis of males with adult-onset autoinflammation, characterized by systemic symptoms and multiorgan involvement. Early diagnosis can prevent unnecessary diagnostic procedures, and provide better prognostic information and more suitable treatment options, including stem cell transplantation.
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http://dx.doi.org/10.1016/j.jaci.2021.05.014DOI Listing
May 2021

Functional and Genetic Landscape of Complement Dysregulation Along the Spectrum of Thrombotic Microangiopathy and its Potential Implications on Clinical Outcomes.

Kidney Int Rep 2021 Apr 3;6(4):1099-1109. Epub 2021 Feb 3.

Department of Nephrology and Clinical Immunology.

Introduction: The syndromes of thrombotic microangiopathy (TMA) are diverse and represent severe endothelial damage caused by various mechanisms. The complement system plays a major role in a subset of patients with TMA, and its recognition is of clinical importance because it guides choice and duration of treatment.

Methods: We studied a well-defined cohort of patients with TMA and hypothesized that assessment of serum-induced   C5b9 formation on the endothelium and screening for rare variants in complement genes can better categorize TMA.

Results: Massive C5b9 formation was found in all patients with primary atypical hemolytic uremic syndrome (/ = 11/11) and in 59% of patients with TMA and coexisting conditions (/ = 30/51). Massive C5b9 formation was associated with rare genetic variants (45% [/ = 20/44] vs. 0% [/ = 0/21] patients with normal C5b9 formation;  < 0.001). Massive C5b9 formation was associated with favorable renal response to therapeutic complement inhibition in patients with TMA and coexisting conditions (86% [/ = 12/14] vs. 31% [/ = 5/16] of untreated patients;  < 0.001), indicating complement-mediated TMA rather than secondary disease. Among treated patients, the odds ratio for 1-year kidney survival was 12.0 (95% confidence interval 1.2-115.4). TMA recurrence was linked to rare genetic variants in all cases. Patients with normal C5b9 formation had an acute, nonrelapsing form of TMA.

Conclusions: C5b9 formation and genetic testing appears to categorize TMAs into different groups because it identifies complement as a driving factor of disease, with potential therapeutic and prognostic implications.
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http://dx.doi.org/10.1016/j.ekir.2021.01.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071658PMC
April 2021

Severe thrombotic microangiopathy after autologous stem cell transplantation in systemic sclerosis: a case report.

Rheumatology (Oxford) 2021 Mar 12. Epub 2021 Mar 12.

Department of Rheumatology and Clinical Immunology, University Medical Centre Utrecht, The Netherlands.

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http://dx.doi.org/10.1093/rheumatology/keab239DOI Listing
March 2021

Intravenous immunoglobulin therapy in adult patients with idiopathic chronic cardiomyopathy and cardiac parvovirus B19 persistence: a prospective, double-blind, randomized, placebo-controlled clinical trial.

Eur J Heart Fail 2021 Feb 7;23(2):302-309. Epub 2021 Jan 7.

Department of Cardiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, The Netherlands.

Aims: Previous uncontrolled studies suggested a possible benefit of intravenous immunoglobulin (IVIg) in parvovirus B19 (B19V)-related dilated cardiomyopathy (DCM). This randomized, double-blind, placebo-controlled, single-centre trial investigated the benefits of IVIg beyond conventional therapy in idiopathic chronic DCM patients with B19V persistence.

Methods And Results: Fifty patients (39 men; mean age 54 ± 11 years) with idiopathic chronic (>6 months) DCM on optimal medical therapy, left ventricular ejection fraction (LVEF) <45%, and endomyocardial biopsy (EMB) B19V load of >200 copies/µg DNA were blindly randomized to either IVIg (n = 26, 2 g/kg over 4 days) or placebo (n = 24). The primary outcome was change in LVEF at 6 months after randomization. Secondary outcomes were change in functional capacity assessed by 6-min walk test (6MWT), quality of life [Minnesota Living with Heart Failure Questionnaire (MLHFQ)], left ventricular end-diastolic volume (LVEDV), and EMB B19V load at 6 months after randomization. LVEF significantly improved in both IVIg and placebo groups (absolute mean increase 5 ± 9%, P = 0.011 and 6 ± 10%, P = 0.008, respectively), without a significant difference between groups (P = 0.609). Additionally, change in 6MWT [median (interquartile range) IVIg 36 (13;82) vs. placebo 32 (5;80) m; P = 0.573], MLHFQ [IVIg 0 (-7;5) vs. placebo -2 (-6;6), P = 0.904] and LVEDV (IVIg -16 ± 49 mL/m vs. placebo -29 ± 40 mL/m ; P = 0.334) did not significantly differ between groups. Moreover, despite increased circulating B19V antibodies upon IVIg administration, reduction in cardiac B19V did not significantly differ between groups.

Conclusion: Intravenous immunoglobulin therapy does not significantly improve cardiac systolic function or functional capacity beyond standard medical therapy in patients with idiopathic chronic DCM and cardiac B19V persistence.

Clinical Trial Registration: ClinicalTrials.gov ID NCT00892112.
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http://dx.doi.org/10.1002/ejhf.2082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048650PMC
February 2021

Spondylitis as a Rare Manifestation of Granulomatosis With Polyangiitis.

Arthritis Rheumatol 2021 02 16;73(2):294. Epub 2020 Dec 16.

Maastricht University Medical Center, Maastricht, The Netherlands.

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http://dx.doi.org/10.1002/art.41565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898716PMC
February 2021

Evaluation of the diagnostic performance of an immunoblot for ANCA and anti-GBM antibody detection.

Autoimmunity 2021 02 20;54(1):45-50. Epub 2020 Nov 20.

Central Diagnostic Laboratory, Maastricht University Medical Center, Maastricht, The Netherlands.

The use of high-quality antigen-specific immunoassays for detecting anti-neutrophil cytoplasmic antibodies (ANCA) and anti-glomerular basement membrane (GBM) autoantibodies is recommended in patients with suspected ANCA vasculitis and/or anti-GBM disease. We analysed the diagnostic performance of a semi-quantitative and rapid immunoblot (EUROIMMUN AG, Lübeck, Germany) in two settings. Patient sera from different cohorts (ANCA vasculitis  = 187, anti-GBM disease  = 19, and disease controls  = 51) were used. The diagnostic performance of the immunoblot was assessed when used as a confirmatory test for the presence of ANCA in suspected ANCA vasculitis and when evaluating the presence of ANCA and/or anti-GBM antibodies in AAV and/or anti-GBM disease patients with a rapidly progressive glomerulonephritis (RPGN). In a confirmatory test setting, the immunoblot had an optimal sensitivity and specificity of 97.4 and 98.1% for PR3-ANCA and 98.5 and 96.4% for MPO-ANCA, respectively. With increasing test result ranges, a higher interval likelihood ratio (LR) was found for both ANCA entities. When evaluating for ANCA in patients with RPGN, the highest diagnostic accuracy (sensitivity 92.9% and specificity 100%) was obtained by using different cut-off values of positivity for PR3- (>5) and MPO-ANCA (>10). Also, the diagnostic performance for detecting anti-GBM was good (sensitivity 100% and specificity 100%). There are advantages over other assays in terms of time, costs, and interpretation of results. The immunoblot is a useful addition to current guidelines, particularly when a rapid diagnosis is necessary.
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http://dx.doi.org/10.1080/08916934.2020.1846185DOI Listing
February 2021

Urinary Soluble CD163 and Disease Activity in Biopsy-Proven ANCA-Associated Glomerulonephritis.

Clin J Am Soc Nephrol 2020 12 17;15(12):1740-1748. Epub 2020 Nov 17.

Department of Nephrology and Clinical Immunology, Maastricht University Medical Center, Maastricht, The Netherlands

Background And Objectives: ANCA-associated GN is a common cause of rapidly progressive GN, with high relapse rates. The early recognition of an ANCA-associated GN relapse is of importance to prevent loss of kidney function. Urinary soluble CD163 has been identified as a promising marker of active ANCA-associated GN. Previous studies, however, are limited by the lack of histologic data.

Design, Setting, Participants, & Measurements: We analyzed urinary soluble CD163 in 95 patients with ANCA-associated vasculitis who underwent a kidney biopsy. In total, 125 kidney tissue sections (first kidney biopsy, =67; repeated biopsy, =58) with concurrent 24-hour urine samples were studied. Correlation analyses comparing urinary soluble CD163 levels and morphologic features of ANCA-associated GN were performed using Spearman rank correlation analysis. The diagnostic performance of biomarkers to detect relapsing ANCA-associated GN was evaluated using receiver operating characteristics curve analysis.

Results: High levels of urinary soluble CD163 were found in 96 (87%) of 110 biopsies with active ANCA-associated GN compared with one (7%) of 15 biopsies without active ANCA-associated GN and one (6%) of 17 healthy controls. Urinary soluble CD163 correlated with fibrinoid necrosis (Rho=0.48, <0.001) and cellular crescents (Rho=0.70, <0.001) on kidney biopsy. In repeated biopsies, urinary soluble CD163's sensitivity of 0.94 and specificity of 0.91 for the recognition of relapsing ANCA-associated GN appeared better than routine clinical measures. The presence of CD163 cells in affected glomeruli confirmed urinary soluble CD163's origin.

Conclusions: Urinary soluble CD163 is associated with active ANCA-associated GN and correlates with histologic features as seen in ANCA-associated GN.

Podcast: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2020_11_17_CJN07210520_final.mp3.
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http://dx.doi.org/10.2215/CJN.07210520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769013PMC
December 2020

Anti-C5a antibody IFX-1 (vilobelimab) treatment versus best supportive care for patients with severe COVID-19 (PANAMO): an exploratory, open-label, phase 2 randomised controlled trial.

Lancet Rheumatol 2020 Dec 28;2(12):e764-e773. Epub 2020 Sep 28.

Department of Neurology, Amsterdam Neuroscience, University of Amsterdam, Amsterdam UMC, Amsterdam, Netherlands.

Background: Severe COVID-19 is characterised by inflammation and coagulation in the presence of complement system activation. We aimed to explore the potential benefit and safety of selectively blocking the anaphylatoxin and complement protein C5a with the monoclonal antibody IFX-1 (vilobelimab), in patients with severe COVID-19.

Methods: We did an exploratory, open-label, randomised phase 2 trial (part of the adaptive phase 2/3 PANAMO trial) of intravenous IFX-1 in adults with severe COVID-19 at three academic hospitals in the Netherlands. Eligibility criteria were age 18 years or older; severe pneumonia with pulmonary infiltrates consistent with pneumonia, a clinical history of severe shortness of breath within the past 14 days, or a need for non-invasive or invasive ventilation; severe disease defined as a ratio of partial pressure of arterial oxygen to fractional concentration of oxygen in inspired air (PaO/FiO) between 100 mm Hg and 250 mm Hg in the supine position; and severe acute respiratory syndrome coronavirus 2 infection confirmed by RT-PCR. Patients were randomly assigned 1:1 to receive IFX-1 (up to seven doses of 800 mg intravenously) plus best supportive care (IFX-1 group) or best supportive care only (control group). The primary outcome was the percentage change in PaO/FiO in the supine position between baseline and day 5. Mortality at 28 days and treatment-emergent and serious adverse events were key secondary outcomes. The primary analysis was done in the intention-to-treat population and safety analyses were done in all patients according to treatment received. This trial is registered at ClinicalTrials.gov (NCT04333420).

Findings: Between March 31 and April 24, 2020, 30 patients were enrolled and randomly assigned to the IFX-1 group (n=15) or the control group (n=15). During the study it became clear that several patients could not be assessed regularly in the supine position because of severe hypoxaemia. It was therefore decided to focus on all PaO/FiO assessments (irrespective of position). At day 5 after randomisation, the mean PaO/FiO (irrespective of position) was 158 mm Hg (SD 63; range 84-265) in the IFX-1 group and 189 mm Hg (89; 71-329) in the control group. Analyses of the least squares mean relative change in PaO/FiO at day 5 showed no differences between treatment groups (17% change in the IFX-1 group 41% in the control group; difference -24% [95% CI -58 to 9], p=0·15. Kaplan-Meier estimates of mortality by 28 days were 13% (95% CI 0-31) for the IFX-1 group and 27% (4-49) for the control group (adjusted hazard ratio for death 0·65 [95% CI 0·10-4·14]). The frequency of serious adverse events were similar between groups (nine [60%] in the IFX-1 group seven [47%] in the control group) and no deaths were considered related to treatment assignment. However, a smaller proportion of patients had pulmonary embolisms classed as serious in the IFX-1 group (two [13%]) than in the control group (six [40%]). Infections classed as serious were reported in three (20%) patients in the IFX-1 group versus five (33%) patients in the control group.

Interpretation: In this small exploratory phase 2 part of the PANAMO trial, C5a inhibition with IFX-1 appears to be safe in patients with severe COVID-19. The secondary outcome results in favour of IFX-1 are preliminary because the study was not powered on these endpoints, but they support the investigation of C5a inhibition with IFX-1 in a phase 3 trial using 28-day mortality as the primary endpoint.

Funding: InflaRx.
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http://dx.doi.org/10.1016/S2665-9913(20)30341-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521913PMC
December 2020

Cardiac Inflammation Impedes Response to Cardiac Resynchronization Therapy in Patients With Idiopathic Dilated Cardiomyopathy.

Circ Arrhythm Electrophysiol 2020 11 30;13(11):e008727. Epub 2020 Sep 30.

Cardiovascular Research Institute (CARIM), Departments of Cardiology (J.A.J.V., J.J.M., A.M.W.v.S., M.T.H.M.H., V.P.M.v.E., C.K., J.G.L.M.L., H.J.G.M.C., H.-P.B.-L.R., K.V., S.R.B.H., M.R.H.), Maastricht University Medical Center, the Netherlands.

Background: Cardiac resynchronization therapy (CRT) is an established therapy in patients with dilated cardiomyopathy (DCM) and conduction disorders. Still, one-third of the patients with DCM do not respond to CRT. This study aims to depict the underlying cardiac pathophysiological processes of nonresponse to CRT in patients with DCM using endomyocardial biopsies.

Methods: Within the Maastricht and Innsbruck registries of patients with DCM, 99 patients underwent endomyocardial biopsies before CRT implantation, with histological quantification of fibrosis and inflammation, where inflammation was defined as >14 infiltrating cells/mm. Echocardiographic left ventricular end-systolic volume reduction ≥15% after 6 months was defined as response to CRT. RNA was isolated from cardiac biopsies of a representative subset of responders and nonresponders.

Results: Sixty-seven patients responded (68%), whereas 32 (32%) did not respond to CRT. Cardiac inflammation before implantation was negatively associated with response to CRT (25% of responders, 47% of nonresponders; odds ratio 0.3 [0.12-0.76]; =0.01). Endomyocardial biopsies fibrosis did not relate to CRT response. Cardiac inflammation improved the robustness of prediction beyond well-known clinical predictors of CRT response (likelihood ratio test <0.001). Cardiac transcriptomic profiling of endomyocardial biopsies reveals a strong proinflammatory and profibrotic signature in the hearts of nonresponders compared with responders. In particular, , and were significantly higher expressed in the hearts of nonresponders.

Conclusions: Cardiac inflammation along with a transcriptomic profile of high expression of combined proinflammatory and profibrotic genes are associated with a poor response to CRT in patients with DCM.
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http://dx.doi.org/10.1161/CIRCEP.120.008727DOI Listing
November 2020

More about complement in the antiphospholipid syndrome.

Blood 2020 09;136(12):1456-1459

Department of Nephrology and Clinical Immunology, Maastricht University Medical Center, Maastricht, The Netherlands; and.

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http://dx.doi.org/10.1182/blood.2020005171DOI Listing
September 2020

The natural course of pregnancies in women with primary atypical haemolytic uraemic syndrome and asymptomatic relatives.

Br J Haematol 2020 08 27;190(3):442-449. Epub 2020 Apr 27.

Department of Nephrology and Clinical Immunology, Maastricht University Medical Center, Maastricht, the Netherlands.

Pregnancy has been linked to various microangiopathies, including primary atypical haemolytic uraemic syndrome (aHUS). Complement dysregulation, often linked to rare variants in complement genes, is key for primary aHUS to manifest and may play a role in pregnancy complications of the mother and fetus. The burden of such complications is unknown, making counselling of women with primary aHUS and asymptomatic relatives difficult. We analyzed the maternal and fetal outcomes of 39 pregnancies from 17 women with primary aHUS and two asymptomatic relatives. Seven out of 39 pregnancies were complicated by pregnancy-associated aHUS. Five out of 32 pregnancies not linked to pregnancy-associated aHUS were complicated by pre-eclampsia or HELLP. Rare genetic variants were identified in 10 women (asymptomatic relatives, n = 2) who had a total of 14 pregnancies, including 10 uncomplicated pregnancies. Thirty-five out of 39 pregnancies resulted in live birth. Eight out of 19 women had progressed to end-stage kidney disease, with an incidence of 2·95 (95% confidence interval, 1·37-5·61) per 100 person-years after the first pregnancy. Thus, we emphasized the frequency of successful pregnancies in women with primary aHUS and asymptomatic relatives. Pregnancies should be monitored closely. Rare genetic variants cannot predict the risk of a given pregnancy.
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http://dx.doi.org/10.1111/bjh.16626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496636PMC
August 2020

Chronic thrombotic microangiopathy in patients with a C3 gain of function protein.

Nephrol Dial Transplant 2020 08;35(8):1449-1451

Department of Nephrology and Clinical Immunology, Maastricht University Medical Center, Maastricht, The Netherlands.

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http://dx.doi.org/10.1093/ndt/gfaa050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462720PMC
August 2020

Use of recombinant human hyaluronidase-facilitated subcutaneous immunoglobulin in elderly patients.

Immunotherapy 2020 02 18;12(2):131-139. Epub 2020 Feb 18.

Division of Internal Medicine & Dermatology, Department of Infectious Diseases, University Medical Center, Utrecht, The Netherlands.

Data on the real-world use of hyaluronidase-facilitated subcutaneous 10% immunoglobulin (fSCIG; HyQvia) in elderly patients with primary or secondary immunodeficiencies (PID or SID) are unreported. This study determined real-world patterns from one administration of fSCIG. In this retrospective, multicenter study, medical records of patients aged ≥65 years with PID or SID were reviewed. The majority of patients (mean age: 69.9 years) with PID (n = 10) or SID (n = 6) self-administered fSCIG (200-350 ml) at home every 3-4 weeks using a single infusion site by infusion pump at rates up to 300 ml/h. This study provides initial real-world evidence supporting home-based, self-administration of large volumes of fSCIG in elderly patients with PID or SID.
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http://dx.doi.org/10.2217/imt-2019-0175DOI Listing
February 2020

Rituximab for the Treatment of Pediatric Double-Positive Small-Vessel Vasculitis.

Kidney Int Rep 2020 Feb 26;5(2):235-238. Epub 2019 Nov 26.

Department of Pediatrics, Zuyderland Medical Center, Sittard-Geleen, The Netherlands.

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http://dx.doi.org/10.1016/j.ekir.2019.11.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000840PMC
February 2020

The Co-inhibitor BTLA Is Functional in ANCA-Associated Vasculitis and Suppresses Th17 Cells.

Front Immunol 2019 10;10:2843. Epub 2019 Dec 10.

Department of Nephrology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.

The activation and inhibition of T-cells has been well-studied under physiological conditions. Co-inhibition is an important mechanism to keep effector T-cells in check. Co-inhibitors mediate peripheral self-tolerance and limit the immune response. Dysfunctional co-inhibition is associated with loss of T-cell regulation and induction of autoimmunity. Therefore, we investigated the co-inhibitor B- and T-Lymphocyte attenuator (BTLA) in ANCA-associated vasculitis (AAV). Fifty-six AAV patients and 32 healthy controls (HC) were recruited. Flow cytometry was performed to investigate the expression of BTLA on T-cells. Double negative T-cells were defined as CD3CD4CD8. To assess the functionality of BTLA, CFSE-labeled T-cells were stimulated in presence or absence of an agonistic anti-BTLA antibody. In addition, impact of BTLA-mediated co-inhibition on Th17 cells was studied. AAV patients in remission had a decreased expression of BTLA on double negative T-cells (CD3CD4CD8). On all other subtypes of T-cells, expression of BTLA was comparable to healthy controls. TCR-independent stimulation of T-cells resulted in down-regulation of BTLA on Th cells in AAV and HC, being significantly lower in HC. Co-inhibition via BTLA led to suppression of T-cell proliferation in AAV as well as in HC. As a result of BTLA mediated co-inhibition, Th17 cells were suppressed to the same extent in AAV and HC. BTLA expression is altered on double negative T-cells but not on other T-cell subsets in quiescent AAV. BTLA-induced co-inhibition has the capacity to suppress Th17 cells and is functional in AAV. Thus, BTLA-mediated co-inhibition might be exploited for future targeted therapies in AAV.
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http://dx.doi.org/10.3389/fimmu.2019.02843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6914808PMC
November 2020

Diagnostic and Risk Factors for Complement Defects in Hypertensive Emergency and Thrombotic Microangiopathy.

Hypertension 2020 02 23;75(2):422-430. Epub 2019 Dec 23.

From the Department of Nephrology and Clinical Immunology (S.A.M.E.G.T., P.v.P.), Cardiovascular Research Institute Maastricht, the Netherlands.

Hypertensive emergency can cause thrombotic microangiopathy (TMA) in the kidneys with high rates of end-stage renal disease (ESRD) and vice versa. The conundrum of hypertension as the cause of TMA or consequence of TMA on the background of defects in complement regulation remains difficult. Patients with hypertensive emergency and TMA on kidney biopsy were tested for ex vivo C5b9 formation on the endothelium and rare variants in complement genes to identify complement-mediated TMA. We identified factors associated with defects in complement regulation and poor renal outcomes. Massive ex vivo C5b9 formation was found on resting endothelial cells in 18 (69%) out of 26 cases at the presentation, including the 9 patients who carried at least one rare genetic variant. Thirteen (72%, =18) and 3 (38%, =8) patients with massive and normal ex vivo complement activation, respectively, progressed to ESRD (=0.03). In contrast to BP control, inhibition of C5 activation prevented ESRD to occur in 5 (83%, =6) patients with massive ex vivo complement activation. TMA-related graft failure occurred in 7 (47%, =15) donor kidneys and was linked to genetic variants. The assessment of both ex vivo C5b9 formation and screening for rare variants in complement genes may categorize patients with hypertensive emergency and TMA into different groups with potential therapeutic and prognostic implications. We propose an algorithm to recognize patients at the highest risk for defects in complement regulation.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.13714DOI Listing
February 2020

Defects in complement and "secondary" hemolytic uremic syndrome.

Kidney Int 2019 08;96(2):517

Department of Nephrology and Clinical Immunology, Maastricht University Medical Center, Maastricht, the Netherlands; Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht, the Netherlands.

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http://dx.doi.org/10.1016/j.kint.2019.04.011DOI Listing
August 2019

Mycophenolate Mofetil Versus Cyclophosphamide for the Induction of Remission in Nonlife-Threatening Relapses of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: Randomized, Controlled Trial.

Clin J Am Soc Nephrol 2019 07 28;14(7):1021-1028. Epub 2019 Jun 28.

Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Background And Objectives: Cyclophosphamide has been the mainstay of treatment of ANCA-associated vasculitis. However, cyclophosphamide has unfavorable side effects and alternatives are needed. Evidence suggests that mycophenolate mofetil can induce sustained remission in nonlife-threatening disease. The purpose of this study was to compare the efficacy and safety of mycophenolate mofetil versus cyclophosphamide for the induction treatment of nonlife-threatening relapses of proteinase 3-ANCA- and myeloperoxidase-ANCA-associated vasculitis.

Design, Setting, Participants, & Measurements: We conducted a multicenter randomized, controlled trial. Participants with a first or second relapse of ANCA-associated vasculitis were randomized to induction treatment with cyclophosphamide or mycophenolate mofetil both in combination with glucocorticoids. Maintenance therapy consisted of azathioprine in both arms. Primary outcome was remission at 6 months, and secondary outcomes included disease-free survival at 2 and 4 years.

Results: Eighty-four participants were enrolled, of whom 41 received mycophenolate mofetil and 43 received cyclophosphamide. Eighty-nine percent of participants were proteinase 3-ANCA positive. At 6 months, 27 (66%) mycophenolate mofetil-treated participants versus 35 (81%) cyclophosphamide-treated participants were in remission (=0.11). Disease-free survival rates at 2 and 4 years were 61% and 39% for cyclophosphamide, respectively, and 43% and 32% for mycophenolate mofetil, respectively (at 4 years, log rank test, =0.17).

Conclusions: We did not demonstrate mycophenolate mofetil to be similarly effective as cyclophosphamide in inducing remission of relapsed ANCA-associated vasculitis. However, mycophenolate mofetil might be an alternative to cyclophosphamide for the treatment of selected patients with nonlife-threatening relapses.
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http://dx.doi.org/10.2215/CJN.11801018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6625631PMC
July 2019

Exome sequencing in routine diagnostics: a generic test for 254 patients with primary immunodeficiencies.

Genome Med 2019 06 17;11(1):38. Epub 2019 Jun 17.

Department of Pediatrics, Children's specialist Hospital, King Fahad Medical City, Riyadh, Saudi Arabia.

Background: Diagnosis of primary immunodeficiencies (PIDs) is complex and cumbersome yet important for the clinical management of the disease. Exome sequencing may provide a genetic diagnosis in a significant number of patients in a single genetic test.

Methods: In May 2013, we implemented exome sequencing in routine diagnostics for patients suffering from PIDs. This study reports the clinical utility and diagnostic yield for a heterogeneous group of 254 consecutively referred PID patients from 249 families. For the majority of patients, the clinical diagnosis was based on clinical criteria including rare and/or unusual severe bacterial, viral, or fungal infections, sometimes accompanied by autoimmune manifestations. Functional immune defects were interpreted in the context of aberrant immune cell populations, aberrant antibody levels, or combinations of these factors.

Results: For 62 patients (24%), exome sequencing identified pathogenic variants in well-established PID genes. An exome-wide analysis diagnosed 10 additional patients (4%), providing diagnoses for 72 patients (28%) from 68 families altogether. The genetic diagnosis directly indicated novel treatment options for 25 patients that received a diagnosis (34%).

Conclusion: Exome sequencing as a first-tier test for PIDs granted a diagnosis for 28% of patients. Importantly, molecularly defined diagnoses indicated altered therapeutic options in 34% of cases. In addition, exome sequencing harbors advantages over gene panels as a truly generic test for all genetic diseases, including in silico extension of existing gene lists and re-analysis of existing data.
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http://dx.doi.org/10.1186/s13073-019-0649-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6572765PMC
June 2019

Mother and Child Reunion in "Hypertensive" End-Stage Renal Disease: Will They Complement Each Other?

Nephron 2019 14;142(3):253-257. Epub 2019 Mar 14.

Department of Nephrology and Clinical Immunology, Maastricht University Medical Center, Maastricht, The Netherlands,

Severe hypertension can lead to irreversible kidney failure and end-stage renal disease (ESRD) and vice versa. Patients are often classified as hypertensive ESRD with no confirmative proof and the true cause of disease can therefore be missed, affecting outcomes. We present a case of chronic thrombotic microangiopathy (TMA) after kidney transplantation in a recipient who had been classified as hypertensive ESRD and found to have a genetic defect in CD46, a transmembrane protein that regulates complement activation, indicating atypical hemolytic uremic syndrome (HUS). The pathogenic variant in CD46 was also found in the mother who donated the kidney, indicating that the TMA occurred on the background of atypical HUS instead of severe hypertension. The patient died from disseminated cancer originated in the mother's kidney. Knowledge of the genetic background would have prevented recurrent disease and the cancer to occur. Patients classified as hypertensive ESRD suspect for TMA should therefore be screened for variants in complement genes to make informed decisions and save kidneys.
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http://dx.doi.org/10.1159/000497779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6690409PMC
June 2020

Effect of Plasmapheresis on Cholestatic Pruritus and Autotaxin Activity During Pregnancy.

Hepatology 2019 06 14;69(6):2707-2710. Epub 2019 Feb 14.

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, the Netherlands.

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http://dx.doi.org/10.1002/hep.30496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6593664PMC
June 2019

Impact of MPO-ANCA-mediated oxidative imbalance on renal vasculitis.

Am J Physiol Renal Physiol 2018 12 12;315(6):F1769-F1776. Epub 2018 Sep 12.

Department of Internal Medicine and Multi-Organic Diseases, University Hospital , Montpellier , France.

Glomerulonephritis is a severe complication of microscopic polyangiitis (MPA), a small-vessel vasculitis associated with anti-myeloperoxidase antibodies (MPO-ANCA). We previously showed the pathogenic effects of MPO-ANCA that activate MPO to trigger an oxidative burst mainly through HOCl production, contributing to endothelial injury and lung fibrosis. The aim of this study was to investigate the relationship between MPO-induced oxidative stress, anti-oxidant defenses and renal histological lesions in MPA patients. We therefore analyzed histological data from a prospective cohort of ANCA-associated glomerulonephritis. Serum-mediated HOCl production, advanced oxidation protein products (AOPP), and thiol concentration in sera were determined. From 38 patients included, histological classification noted 50% focal glomerulonephritis, 15.8% crescentic-glomerulonephritis, and 34.2% mixed-glomerulonephritis. MPA patients' sera displayed higher HOCl production by MPO ( P < 0.001), higher AOPP ( P < 0.001) and thiol ( P < 0.01) levels, compared with healthy subjects. The presence of cellular crescents was associated with higher serum-mediated HOCl production ( P = 0.049) and lower thiol levels ( P = 0.022) at disease onset. Higher thiol concentrations were associated with focal glomerulonephritis ( P = 0.042), less interstitial fibrosis ( P = 0.039) and hyalinosis ( P = 0.066). In remission, HOCl production was decreased ( P < 0.01), and thiol concentration remained high ( P = 0.39). Our findings suggest that HOCl production by activated MPO could contribute to the very early stage of glomerulonephritis, whereas thiol may exert a protective effect against the development of renal vasculitis and glomerulosclerosis. This study highlights the importance of oxidative defenses to counteract the process of MPO-ANCA associated glomerulonephritis.
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http://dx.doi.org/10.1152/ajprenal.00111.2018DOI Listing
December 2018

Conservative treatment for C3 glomerulopathy and monoclonal Ig.

Kidney Int 2018 09;94(3):632

Department of Nephrology and Clinical Immunology, Maastricht University Medical Center, Maastricht, The Netherlands. Electronic address:

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http://dx.doi.org/10.1016/j.kint.2018.05.027DOI Listing
September 2018

C5b9 Formation on Endothelial Cells Reflects Complement Defects among Patients with Renal Thrombotic Microangiopathy and Severe Hypertension.

J Am Soc Nephrol 2018 08 1;29(8):2234-2243. Epub 2018 Jun 1.

Departments of Nephrology and Clinical Immunology and

Severe hypertension can induce thrombotic microangiopathy (TMA) in the renal vasculature, the occurrence of which has been linked to mechanical stress to the endothelium. Complement defects may be the culprit of disease in patients who present with severe renal disease and often progress to ESRD, despite BP control. We studied a well defined cohort of 17 patients with hypertension-associated TMA to define the prevalence of complement defects by a specific serum-based microvascular endothelial cell assay. Compared with normal human serum and samples from patients with hypertensive arterionephrosclerosis, 14 of 16 (87.5%) serum samples collected at presentation from 16 patients with hypertension-associated TMA induced abnormal C5b9 formation on microvascular endothelial cells. We detected rare variants in complement genes in eight of 17 (47%) patients. ESRD occurred in 14 of 17 (82%) patients, and recurrent TMA after transplant occurred in seven of 11 (64%) donor kidneys. Eculizumab improved the renal function in three patients and prevented TMA recurrence in an allograft recipient. These observations point to complement defects as the key causative factor of ESRD and recurrent TMA after transplant in patients presenting with severe hypertension. Complement defects can be identified by measurements of complement activation on microvascular endothelial cells, which should substantially influence treatment and prognosis.
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http://dx.doi.org/10.1681/ASN.2018020184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6065094PMC
August 2018

Immunosuppressive Therapy Improves Both Short- and Long-Term Prognosis in Patients With Virus-Negative Nonfulminant Inflammatory Cardiomyopathy.

Circ Heart Fail 2018 02;11(2):e004228

From the Cardiology Department (J.M., M.H., J.V., V.V.E., C.K., H.-P.B.-L.R., S.H.), Immunology Department (P.V.P.), and Pathology Department (M.A.H.), Maastricht University Medical Center, The Netherlands; and Clinical Division of Cardiology and Angiology (M.S., J.K., P.H., G.P.) and Institute of Pathology (C.E.), Innsbruck Medical University, Austria.

Background: Inflammatory cardiomyopathy (infl-CMP) is characterized by increased cardiac inflammation in the absence of viruses, ischemia, valvular disease, or other apparent causes. Studies addressing the efficacy of immunosuppressive therapy in patients with infl-CMP are sparse. This study retrospectively investigates whether immunosuppressive agents on top of heart failure therapy according to current guidelines improves cardiac function and long-term outcome in patients with infl-CMP.

Methods And Results: Within the Innsbruck and Maastricht Cardiomyopathy Registry, a total of 209 patients fulfilled the criteria for infl-CMP using endomyocardial biopsy (≥14 infiltrating inflammatory cells/mm). A total of 110 (53%) patients received immunosuppressive therapy and 99 (47%) did not. To correct for potential selection bias, 1:1 propensity score matching was used on all significant baseline parameters, resulting in a total of 90 patients per group. Baseline characteristics did not significantly differ between both patient groups, reflecting optimal propensity score matching. After a median follow-up of 31 (15-47) months, immunosuppressive therapy resulted in an improved long-term outcome (eg, heart transplantation-free survival) as compared with standard heart failure therapy alone (Log-rank =0.043; hazard ratio, 0.34 [95% CI, 0.17-0.92]) and in a significant larger increase of left ventricular ejection fraction after a mean of 12 months follow-up, as compared with patients receiving standard heart failure treatment only (12.2% versus 7.3%, respectively; =0.036).

Conclusions: To conclude, this study suggests that immunosuppressive therapy in infl-CMP patients results in an improved heart transplantation-free survival as compared with standard heart failure therapy alone, underscoring the urgent need for a large prospective multicenter trial.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.117.004228DOI Listing
February 2018

Position paper: Revised 2017 international consensus on testing of ANCAs in granulomatosis with polyangiitis and microscopic polyangiitis.

Nat Rev Rheumatol 2017 Nov 14;13(11):683-692. Epub 2017 Sep 14.

Department of Internal Medicine, Rheumatology and Immunology, Vasculitis-Centre Tübingen-Kirchheim, Medius Klinik Kirchheim, University of Tübingen, Eugenstrasse 3, 73230 Kirchheim unter Teck, Germany.

Anti-neutrophil cytoplasmic antibodies (ANCAs) are valuable laboratory markers used for the diagnosis of well-defined types of small-vessel vasculitis, including granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). According to the 1999 international consensus on ANCA testing, indirect immunofluorescence (IIF) should be used to screen for ANCAs, and samples containing ANCAs should then be tested by immunoassays for proteinase 3 (PR3)-ANCAs and myeloperoxidase (MPO)-ANCAs. The distinction between PR3-ANCAs and MPO-ANCAs has important clinical and pathogenic implications. As dependable immunoassays for PR3-ANCAs and MPO-ANCAs have become broadly available, there is increasing international agreement that high-quality immunoassays are the preferred screening method for the diagnosis of ANCA-associated vasculitis. The present Consensus Statement proposes that high-quality immunoassays can be used as the primary screening method for patients suspected of having the ANCA-associated vaculitides GPA and MPA without the categorical need for IIF, and presents and discusses evidence to support this recommendation.
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http://dx.doi.org/10.1038/nrrheum.2017.140DOI Listing
November 2017

Individual values of antineutrophil cytoplasmic antibodies do not correspond between antigen-specific assays.

Clin Chem Lab Med 2018 01;56(2):e39-e42

Department of Laboratory Medicine, University Hospitals Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium, Phone: +32 16 347009, Fax: +32 16 34 79 31.

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http://dx.doi.org/10.1515/cclm-2017-0362DOI Listing
January 2018

The Authors Reply.

Kidney Int 2017 07;92(1):267-268

Department of Nephrology and Clinical Immunology, Maastricht University Medical Center, Maastricht, the Netherlands. Electronic address:

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http://dx.doi.org/10.1016/j.kint.2017.03.048DOI Listing
July 2017