Karina de Leeuw

University Medical Center Groningen

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Johanna Westra

University Medical Center Groningen

Hendrika Bootsma

University of Groningen

Marc Bijl

Martini Ziekenhuis

Barbara Horváth

University Medical Center Groningen

Pieter van Paassen

Maastricht University

Wietske M. Lambers

Geneeskundige en Gezondheidsdienst

Abraham Rutgers

University Medical Center Groningen

Alexandre E. Voskuyl

Amsterdam UMC Location VUmc

Y.K. Onno Teng

Leiden University Medical Center

Theo Rispens

University of Amsterdam

Cooperative Institutions

University Medical Center Groningen

188

Center for Rheumatology

180

University of Groningen

179

University of Amsterdam

160

Misgav Ladach

147

Universidad de Salamanca

145

Amsterdam University Medical Centers

135

Istituti di Ricovero e Cura a Carattere Scientifico

118

Istituto Giannina Gaslini

115

Academic Medical Center

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Biomarkers of Oxidative Stress in Systemic Lupus Erythematosus Patients with Active Nephritis

Antioxidants (2023)

Lu Liu Karina de Leeuw Suzanne Arends Berber Doornbos‐van der Meer Marian Bulthuis

Oxidative stress plays an important role in systemic lupus erythematosus (SLE) and especially in lupus nephritis (LN). The aim of this study was to compare redox-related biomarkers between patients with active LN, quiescent SLE (Q-SLE) and healthy controls (HC) and to explore their association with clinical characteristics such as disease activity in patients. We investigated levels of plasma free thiols (R-SH, sulfhydryl groups), levels of soluble receptor for advanced glycation end products (sRAGE) and levels of malondialdehyde (MDA) in SLE patients with active LN (n = 23), patients with quiescent SLE (n = 47) and HC (n = 23). Data of LN patients who previously participated in Dutch lupus nephritis studies and longitudinal samples up to 36 months were analyzed. Thiol levels were lower in active LN at baseline and Q-SLE patients compared to HC. In generalized estimating equation (GEE) modelling, free thiol levels were negatively correlated with the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) over time (p < 0.001). sRAGE and MDA were positively correlated with the SLEDAI over time (p = 0.035 and p = 0.016, respectively). These results indicate that oxidative stress levels in LN patients are increased compared to HC and associated with SLE disease activity. Therefore, interventional therapy to restore redox homeostasis may be useful as an adjunctive therapy in the treatment of oxidative damage in SLE.

Nephritis

10.3390/antiox12081627

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Citations (7)

Pharmacokinetics of Monoclonal Antibodies Throughout Pregnancy: A Systematic Literature Review

Clinical Pharmacokinetics (2024)

Jip van Gendt R. Emaus Marijn C. Visschedijk Daan J. Touw D G Bouwknegt

Although little information is available on the pharmacokinetics (PK) of monoclonal antibodies (mAbs) during pregnancy, multiple mAbs are being used during pregnancy for various indications. The aim of this systematic literature review was to characterize the PK of mAbs throughout pregnancy. A systematic literature search was carried out in PubMed and Embase on 21 April 2023. Articles were included when information on PK or exposure parameters of mAbs in pregnant women was available. A total of 42 relevant articles were included, of which eight discussed adalimumab, three certolizumab pegol, five eculizumab, one golimumab, 12 infliximab (IFX), two natalizumab, one canakinumab, one omalizumab, five tocilizumab, eight ustekinumab, and five vedolizumab. One of the 42 studies reported information on clearance (CL) and volume of distribution (VD) of IFX; all other studies only reported on serum concentrations in the pre-pregnancy state, different trimesters, and the postpartum period. For all of the assessed mAbs except IFX, serum concentrations were similar to concentrations in the pre-pregnancy state or modestly decreased. In contrast, IFX trough concentrations generally increased in the second and third trimesters in comparison to the non-pregnant state. Available information suggests that the anatomical and physiological changes throughout pregnancy may have meaningful effects on the PK of mAbs. For most mAbs (not IFX), modestly higher dosing (per mg) maybe needed during pregnancy to sustain a similar serum exposure compared to pre-pregnancy.

Certolizumab pegol

Golimumab

10.1007/s40262-024-01370-7

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Superior mesenteric artery aneurysm in a 9‐year‐old boy with classical Ehlers–Danlos syndrome

American Journal of Medical Genetics Part A (2012)

Karina de Leeuw J. Goorhuis Ignace F.J. Tielliu Sofie Symoens Fransiska Malfait

Abstract A 9‐year‐old boy with the classical type of Ehlers–Danlos syndrome (EDS) developed a symptomatic aneurysm of the superior mesenteric artery. His EDS diagnosis had been confirmed biochemically and genetically. Vascular complications are known to be associated with the vascular type of EDS, but this is the first report of a child with classical EDS who developed a major vascular complication. Clinicians should be aware that severe vascular complications albeit rare, can also occur in classical EDS. © 2012 Wiley Periodicals, Inc.

Ehlers–Danlos syndrome

10.1002/ajmg.a.34420

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Citations (36)

Autoantibodies Against High Mobility Group Box 1 (HMGB1) in Patients with SLE

Fleur Schaper Gerda Horst Daan van Beijeren Bergenen Henegouwen Johan Bijzet Karina de Leeuw

Background/Purpose: High mobility group box 1 (HMGB1) is a damage-associated molecular pattern and can be divided in three separate domains: the A Box, B Box and the acidic tail. Box A by itself serves as a competitive antagonist for HMGB1 and inhibits HMGB1 activity. In an earlier study we showed that anti-HMGB1 antibodies are present in Systemic Lupus Erythematosus (SLE) patients and may play a role in the pathogenesis of the disease, but are not present in patients with systemic vasculitis. In this study we investigate the relation between anti-HMGB1 antibodies and disease activity, renal involvement, anti-dsDNA antibodies and medication use. We performed cross-sectional and longitudinal analyses. Methods: Seventy-one SLE patients, 25 age and sex matched healthy controls (HC), and 15 disease control patients with incomplete lupus (fulfilled less than 4 of the ACR criteria), were included in this study. All 71 SLE patients were measured during quiescent or mild (SLEDAI ≤ 4) disease, and 28 were also measured during an exacerbation (SLEDAI ≥ 5). Furthermore, in a subgroup of patients (n=11) longitudinal levels of HMGB1 were determined over a period of three years. Serum levels of anti-HMGB1 IgG and IgM were measured using an in house ELISA. Epitope recognition was measured by ELISA against Box A and B IgG. Data are presented as arbitrary units (AU). Results: Quiescent as well as active SLE patients showed a significant increase in anti-HMGB1 IgG compared to HC (median 236 vs 339 vs 46 AU respectively). Incomplete lupus patients also had an increased anti-HMGB1 level compared to HC (p=0.03), but lower compared to SLE patients (ns). Patients recognized both Box A and Box B epitopes of the molecule. Anti-HMGB1 IgM levels were not different in patients versus controls. We did find an association with disease activity, as there was a significant decrease in Box A recognition after exacerbation (p=0.028). No differences were found comparing active patients with renal involvement to patients without for anti-HMGB1 IgG, IgM, Box A and Box B. There was also no effect of immunosuppressive medication, including hydroxychloroquine, on anti-HMGB1 levels. Finally, longitudinal values of anti-HMGB1 IgG showed similar patterns compared to anti-dsDNA and might even increase shortly before an increase in anti-ds DNA levels are seen. Conclusion: Anti-HMGB1 antibodies seem specific for SLE, as they were significantly increased compared to HC. Interestingly, also incomplete lupus patients showed already a minor increase of anti-HMGB1 antibodies. Antibodies directed to Box A decreased after an exacerbation, indicating a correlation with disease activity. Furthermore, longitudinally levels of anti- HMGB1 seemed to increase before an increase in anti-dsDNA levels occurred, which might indicate an interesting new biomarker in the follow-up of SLE patients.

HMGB1

Pathogenesis

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THU0276 Interferon-related chemokine IP-10 is a potential biomarker in incomplete systemic lupus erythematosus

Annals of the Rheumatic Diseases (2017)

Wietske M. Lambers Karina de Leeuw M. F. Jonkman Hendrika Bootsma Johanna Westra

Background

Incomplete SLE (iSLE) is the designation of patients who display symptoms that are typical for SLE, but with insufficient criteria to fulfil the diagnosis. Unfortunately, predictive biomarkers for SLE development are lacking. Increased IFN-type I production is an important factor in the pathogenesis of SLE. Interferon-regulated chemokines therefore could possibly be useful as biomarkers for disease progression to SLE. Candidate biomarkers IFN-γ induced protein 10 (IP-10) and monocyte chemo attractant protein (MCP-1) have shown to be increased in SLE and to correlate with disease activity.

Objectives

To determine possible candidate biomarkers IFN-γ induced protein 10 (IP-10) and monocyte chemo attractant protein (MCP-1) in patients with iSLE.

Methods

Serum samples were collected of 30 iSLE patients, 29 SLE patients, and 17 ANA-negative patients with histologically proven cutaneous lupus erythematosus (ANCLE). Outcomes were compared with 25 age- and gender-matched controls (CTL) and 31 rheumatoid arthritis (RA) patients as disease control group. Levels of IP-10 and MCP-1 were measured using ELISA.

Results

IP-10 was significantly increased in SLE and RA patients compared with CTL and ANCLE. IP-10 levels were increased in 23% of iSLE patients. These patients had higher SLE disease activity index (SLEDAI) and more frequently decreased C3 level and joint involvement compared to those with normal IP-10 levels. Regarding MCP-1 levels, no significant differences were found between any of the groups and no correlations with clinical markers was found.

Conclusions

Levels of IP-10, but not MCP-1, might be useful as a predictive biomarker for progression to SLE in patients with iSLE, although future prospective longitudinal analyses are needed to confirm this hypothesis.

Disclosure of Interest

None declared

Pathogenesis

CTL*

10.1136/annrheumdis-2017-eular.4016

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Efficacy of belimumab combined with rituximab in severe systemic lupus erythematosus: study protocol for the phase 3, multicenter, randomized, open-label Synbiose 2 trial

Trials (2022)

Mieke van Schaik Eline J. Arends Darius Soonawala Ellen van Ommen Karina de Leeuw

Belimumab, an anti-B-cell activating factor antibody, is approved for the treatment of auto-antibody positive systemic lupus erythematosus with a high degree of disease activity. Anti-CD20 B cell depletion with rituximab is used in refractory SLE as well, although with variable responses. We hypothesized that incomplete B cell depletion, related to a surge in BAFF levels following rituximab treatment, can cause ongoing disease activity and flares. The Synbiose 1 study primarily focused on immunological effects and shows the preliminary clinical benefit of combined rituximab and belimumab in SLE. The Synbiose 2 study will evaluate the clinical efficacy of combining belimumab with rituximab in patients with severe SLE, allowing the tapering of prednisolone and mycophenolate.Synbiose 2 is a phase 3, multicenter, randomized, controlled, open-label 2-year clinical trial. Seventy adults with severe SLE including lupus nephritis will be randomized 1:1 to receive either standard of care consisting of prednisolone and mycophenolate as induction and maintenance treatment, or belimumab and rituximab combined with standard of care as induction treatment, followed by prednisolone and belimumab as maintenance treatment. The primary objective is to assess whether combined B cell therapy will lead to a reduction of treatment failure. Secondary endpoints are complete and partial clinical and renal response and the improvement of SLE-specific autoimmune phenomena. Safety endpoints include the incidence of adverse events, with a special interest in infections.The Synbiose 2 trial is the first multicenter phase 3 clinical trial investigating combined B cell targeted therapy in SLE, including lupus nephritis. The outcome of this study will provide further evidence for the clinical efficacy of this new treatment strategy in severe SLE.ClinicalTrials.gov NCT03747159 . Registered on 20 November 2018.

Belimumab

Open label

10.1186/s13063-022-06874-w

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Citations (17)

HIBISCUS: Hydroxychloroquine for the secondary prevention of thrombotic and obstetrical events in primary antiphospholipid syndrome

Autoimmunity Reviews (2018)

C. Belizna Francesca Pregnolato S. Abad Jaume Alijotas‐Reig Howard Amital

Hydroxychloroquine

10.1016/j.autrev.2018.05.012

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Citations (68)

Diagnosing and treating antiphospholipid syndrome: a consensus paper.

PubMed (2019)

Maarten Limper Karina de Leeuw A. Titia Lely Jan Westerink Y.K. Onno Teng

Catastrophic antiphospholipid syndrome

Gold standard (test)

Source

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Citations (34)

Dr. van Roon, et al reply

The Journal of Rheumatology (2020)

A.M. van Roon Karina de Leeuw Douwe J. Mulder

To the Editor: We thank Dr. Lambova for her interesting comment1 on our recent article published in The Journal 2. We reported that a systemic sclerosis (SSc) or scleroderma-like capillaroscopic pattern is common in patients with Raynaud phenomenon, and can be frequently observed in patients with connective tissue diseases (CTD) other than SSc. Dr. Lambova underlines the interesting point that a scleroderma-like capillaroscopic pattern could also be associated with presence of cutaneous digital vasculitis, which can be observed in a subset of patients with systemic lupus erythematodes (SLE)1. In a previous study from Dr. … Address correspondence to Dr. D.J. Mulder, Department of Internal Medicine, Division of Vascular Medicine, University Medical Center Groningen, Huispostcode AA41, Hanzeplein 1, Postbus 30 001, Groningen, the Netherlands. E-mail: d.j.mulder{at}umcg.nl

Scleroderma (fungus)

CTD

10.3899/jrheum.200136

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P5 Recognizing the disease, treating the patient: a mixed-method evaluation of care for the antiphospholipid syndrome (APS) in the Netherlands

Poster presentations (2020)

Mirthe J Klein Haneveld Caro H C Lemmen Tammo E. Brunekreef Marc Bijl A.J. Gerard Jansen

Purpose

This study aims to gain insight into the care provided to patients with antiphospholipid syndrome (APS) in The Netherlands and to identify areas for improvement from the perspective of both patients and clinicians.

Methods

APS care was evaluated using qualitative and quantitative methods. Perspectives on APS care were identified using semi-structured interviews with medical specialists, patient focus groups and a cross-sectional, online patient survey. In order to examine differences in medical practice, medical records were reviewed retrospectively regarding clinical and laboratory manifestations, pharmacological treatment and management of disease in six hospitals throughout The Netherlands.

Results

Fourteen interviewed medical specialists, fourteen focus group participants and 79 survey respondents participated in the study. 237 patients were included in medical record review. Only one-third of patients were diagnosed with APS within three months after entering specialist care. Diagnosis and management varied between centres and specialists. Almost 10% of triple positive patients did not receive any treatment at the time of medical record review. Major challenges according to specialists and patients were poor recognition of APS by health care professionals, fragmentation of care and lack of accessible, reliable patient education and psychosocial support.

Conclusion

This study describes delayed diagnosis, variability in management strategies and a burden placed on patients to orchestrate their own care in APS care in The Netherlands. Of note, almost 10% of triple positive patients did not receive any treatment, despite this group of patients being at the highest risk of recurrent thrombosis.

Acknowledgements

This work was supported by the Arthritis Research and Collaboration Hub (ARCH) Foundation.

Medical record

10.1136/lupus-2020-eurolupus.54

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