Tom W J Huizinga

Leiden University, Leyden, South Holland, Netherlands

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Publications (586)3944.85 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective Mast cells (MCs) have been implicated in the pathogenesis of Rheumatoid Arthritis (RA). In particular, their activation by IL-33 has been linked to the development of arthritis in animal models. Aim of this study was to evaluate the functional responses of human mast cells to IL-33 in the context of RA. Methods Human MCs were stimulated with IL-33 combined with plate-bound IgG (pbIgG) or Anti-Citrullinated Protein Antibody (ACPA)-IgG and their effects on monocyte activation were evaluated. Cellular interactions of MCs in RA synovia were assessed by immunofluorescence and the mRNA expression of MC-specific genes in synovial biopsies of early RA patients naïve to therapy was evaluated. Results IL-33 induced the upregulation of the FcγRIIa and enhanced the activation of MCs by IgG, including ACPA-IgG, as measured by CXCL8/IL-8 production. Intriguingly, MCs triggered with IL-33 and IgG released mediators, such as histamine and IL-10, which inhibited monocyte activation. Synovial MCs were found in contact with CD14(+) monocytes/macrophages. Finally, mRNA levels of MC-specific genes were inversely associated with disease severity, and IL-33 mRNA expression showed an inverse correlation with pro-inflammatory markers. Conclusion Human MCs triggered with IL-33 acquire an immunomodulatory phenotype, gaining the ability to suppress monocyte activation via the release of IL-10 and histamine. These findings, together with the presence of synovial MC-monocytes interactions and the inverse association between the expression of MC genes at the synovial level and disease activity suggest that these newly described MC-mediated inhibitory pathways might have a functional relevance in the pathogenesis of RA. This article is protected by copyright. All rights reserved. © 2015, American College of Rheumatology.
    05/2015; DOI:10.1002/art.39192
  • Journal of managed care pharmacy: JMCP 05/2015; 21(5):409. · 2.68 Impact Factor
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    ABSTRACT: Objective. To test the feasibility of collecting, storing, retrieving and analysing necessary information to fulfil a preliminary set of quality indicators (QIs) that have been proposed by an international task force in a large multinational clinical practice database of patients with RA. Methods. Data from all 12 487 patients with 46 005 visits in the Measurement of Efficacy of Treatment in the Era of Outcome in Rheumatology database from January 2008 until January 2012 were analysed to test the feasibility of collecting information on 10 QIs: time to diagnosis; frequency of visits; assessment of autoantibodies and radiographs, disease activity and function; disease remission, low disease activity, normal function; time to first DMARD and type of first DMARD. For each QI, two aspects were assessed: information availability and target achievement. Results. Information was available for <50% of patients regarding the following QIs: time to diagnosis, assessment of ACPAs or radiographs, time to first DMARD and type of first DMARD. Information was available for function assessment in 49% of visits and 67% of patients and for disease activity assessment in 85% of visits and 86% of patients. Information relevant to the QI frequency of visits was available for all patients. Relevant information to calculate the proportion of patients who achieved a defined target could be obtained for all QIs. Conclusion. Collecting storing, retrieving and analysing the core data necessary to meaningfully assess quality of care is feasible in a multinational, practice-based electronic database.
    Rheumatology (Oxford, England) 04/2015; DOI:10.1093/rheumatology/kev108 · 4.44 Impact Factor
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    ABSTRACT: Objectives. To evaluate the efficacy and safety of sarilumab in combination with methotrexate (MTX) for treatment of rheumatoid arthritis (RA). Methods. Adults with moderate-to-severe RA and inadequate response to MTX were randomized (1:1:1) to sarilumab 150mg, 200 mg, or placebo every 2 weeks (q2w) with MTX for 52 weeks. Results. Baseline characteristics were similar among groups. For all three co-primary endpoints, sarilumab 150mg and 200mg groups demonstrated statistically significant improvements vs placebo: ACR20 response at Week 24 (58.0%, 66.4% vs 33.4%; p<0.0001), HAQ-DI at Week 16 (-0.53, -0.55, vs -0.29; p<0.0001) and mTSS at Week 52 (0.90, 0.25 vs 2.78; p<0.0001). The most common treatment-emergent adverse event was infection; serious infections incidence was 2.6%, 4.0%, and 2.3% (sarilumab 150mg, 200 mg, and placebo, respectively). Elevations in alanine aminotransferase >3-fold the upper limit of normal in 9.5%, 8.0%, and 2.1% of patients led to discontinuation of 24 patients. Elevated total cholesterol levels were observed in 36.8%, 43.0% and 18.3% of sarilumab 150mg, 200 mg and placebo patients, respectively. Neutrophil counts 500-<1000 Giga/L occurred in 5.1% and 7.8%, <500 Giga/L in 0.9% and 0.7% of sarilumab 150mg and 200mg patients, respectively, and none receiving placebo. Conclusions: In RA patients treated with sarilumab (150mg and 200mg q2w) in combination with MTX, both doses provided sustained clinical efficacy, significantly improving symptomatic, functional, and radiographic outcomes. Sarilumab was generally well tolerated. The adverse events observed in this study were consistent with IL-6 signaling blockade. This article is protected by copyright. All rights reserved. © 2015 American College of Rheumatology.
    03/2015; 67(6). DOI:10.1002/art.39093
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    ABSTRACT: The aim of this study was to assess whether baseline characteristics in patients with undifferentiated arthritis or early RA affect the possibility of achieving drug-free remission after 1 year (DFR1 year) of early remission induction therapy. We included 375 patients participating in the IMPROVED study who achieved remission (DAS < 1.6) after 4 months (early remission) and were by protocol able to achieve DFR1 year. Having started with MTX plus prednisone, patients tapered prednisone to zero; after 8 months, those still in remission tapered MTX to zero, while those not in remission restarted prednisone. Characteristics of patients achieving and not achieving DFR1 year were compared. Logistic regression was performed to identify predictors of DFR1 year. After 1 year, 119 patients (32%) were in DFR. Presence of RF, fulfilling the 2010 criteria for RA, and a low tender joint count were associated with achieving DFR1 year, whereas presence of ACPA was not. None of the baseline characteristics was independently associated with DFR1 year. DFR1 year was sustained for 4 months in 65% of the patients. ACPA-positive patients less often had sustained DFR than ACPA-negative patients (58% vs 80%, P = 0.013). After 1 year of remission-steered treatment, 32% of the patients who had achieved early remission after 4 months were able to taper medication and achieved DFR. Neither the presence of ACPA nor any other baseline characteristics were independently associated with achieving DFR1 year, but in ACPA-positive patients DFR was less often sustained. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email:
    Rheumatology (Oxford, England) 02/2015; DOI:10.1093/rheumatology/keu477 · 4.44 Impact Factor
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    ABSTRACT: Background Mast cells are mainly present in strategic locations, where they may have a role in defense against parasites and bacteria. These pathogens can be recognized by mast cells via toll-like receptors (TLR). Allergic symptoms are often increased in the presence of pathogens at the site of allergen exposure, but it is unknown which cytokines can mediate such an effect.Objective To study whether an interaction between IgE- and TLR-mediated activation of human mast cells can contribute to exacerbated inflammatory responses.Methods Peripheral blood-derived mast cells were stimulated with TLR ligands, in presence or absence of anti-IgE triggering, after which degranulation was measured using flow cytometry and cytokine production was evaluated by multiplex assays, ELISA and intracellular flow cytometry. For evaluation of allergen-specific responses, mast cells were sensitized with serum of allergic individuals or controls, after which they were stimulated using allergens in combination with TLR ligands.ResultsSimultaneous triggering of mast cells via IgE and TLR ligands greatly enhanced cytokine production but not IgE-induced degranulation. Different TLR ligands specifically enhanced the differential production of cytokines in conjunction with FcεRI triggering. Importantly, only TLR-4 and -6 were able to induce robust production of IL-13, an important molecule in allergic reactions.Conclusions & clinical relevanceThese results indicate that the simultaneous presence of pathogen- or danger-associated signals and FcεRI triggering via specific IgE can significantly modify mast cell-mediated allergic reactions via synergistic production of cytokines and inflammatory mediators and provide an explanation of augmented allergic symptoms during infection.This article is protected by copyright. All rights reserved.
    Clinical & Experimental Allergy 02/2015; 45(4). DOI:10.1111/cea.12509 · 4.32 Impact Factor
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    ABSTRACT: To evaluate whether intravenous gadolinium (Gd) contrast administration can be eliminated when evaluating synovitis and tenosynovitis in early arthritis patients, thereby decreasing imaging time, cost, and invasiveness. Wrist MRIs of 93 early arthritis patients were evaluated by two readers for synovitis of the radioulnar, radiocarpal, and intercarpal joints, according to the Rheumatoid Arthritis MRI Scoring method (RAMRIS), and for tenosynovitis in ten compartments. Scores of MRI images without Gd contrast enhancement were compared to scores obtained when evaluating all, including contrast-enhanced, MRI images as reference. Subsequently, a literature review and pooled analysis of data from the present and two previous studies were performed. At the individual joint/tendon level, sensitivity to detect synovitis without Gd contrast was 91 % and 72 % for the two readers, respectively, with a specificity of 51 % and 81 %. For tenosynovitis, the sensitivity was 67 % and 54 %, respectively, with a specificity of 87 % and 91 %. Pooled data analysis revealed an overall sensitivity of 81 % and specificity of 50 % for evaluation of synovitis. Variations in tenosynovitis scoring systems hindered pooled analyses. Eliminating Gd contrast administration resulted in low specificity for synovitis and low sensitivity for tenosynovitis, indicating that Gd contrast administration remains essential for an optimal assessment. • Eliminating gadolinium contrast administration results in low specificity for synovitis • For tenosynovitis, sensitivity is low without gadolinium contrast administration • Gadolinium contrast administration remains essential for evaluating synovitis and tenosynovitis in early arthritis.
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    ABSTRACT: Anti-carbamylated protein (anti-CarP) antibodies could further elucidate early rheumatoid arthritis (RA) pathogenesis and predict clinical disease. We compared the diagnostic accuracy of anti-CarP antibodies for future RA to other RA-related antibodies in military personnel. Stored pre-RA diagnosis serum samples from 76 RA cases were tested for anti-CarP fetal calf serum (FCS), anti-CarP fibrinogen (Fib), anticyclic citrullinated peptide antibodies version 2 (anti-CCP2), rheumatoid factor-nephelometry (RF-Neph), and RF isotypes [immunoglobulin M (IgM), IgG, and IgA]. Positivity for all antibodies was determined as ≥ 2 SD of log-transformed means from controls. Relationships between autoantibodies and future RA were assessed in prediagnosis serum for all RA cases compared to controls using sensitivity, specificity, and logistic regression. Differences in diagnostic accuracy between antibody combinations were assessed using comparisons of area under the curves (AUC). Anti-CarP-FCS was 26% sensitive and 95% specific for future RA, whereas anti-CarP-Fib was 16% sensitive and 95% specific for future RA. Anti-CarP-FCS positivity was associated with future RA, while anti-CarP-Fib trended toward association. The antibody combination of anti-CCP2 and/or ≥ 2 RF (RF-Neph and/or RF-isotypes) resulted in an AUC of 0.72 for future RA, where the AUC was 0.71 with the addition of anti-CarP-FCS to this prior combination. Adding anti-CarP-FCS to antibody combinations did not improve AUC. However, anti-CarP-FCS was associated with future onset of RA, and was present in prediagnosis serum in ~10% of RA cases negative for anti-CCP2 but positive for RF.
    The Journal of Rheumatology 01/2015; 42(4). DOI:10.3899/jrheum.140767 · 3.17 Impact Factor
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    ABSTRACT: To understand the molecular features distinguishing anti-citrullinated protein antibodies (ACPA) from 'conventional' antibodies in rheumatoid arthritis (RA). Serum of ACPA-positive RA patients was fractionated by size exclusion chromatography and analysed for the presence of ACPA-IgG by ELISA. ACPA-IgG and non-citrulline-specific IgG were affinity purified from serum, plasma and/or synovial fluid and analysed by gel electrophoresis. Electrophoresis bands were excised, enzymatically digested and analysed by mass spectrometry. Binding affinity to citrullinated antigens was measured by ELISA and imaging surface plasmon resonance using recombinant monoclonal ACPA with molecular modifications. In all donor samples studied (n=24), ACPA-IgG exhibited a 10-20 kDa higher molecular weight compared with non-autoreactive IgG. This feature also distinguished ACPA-IgG from antibodies against recall antigens or other disease-specific autoantibodies. Structural analysis revealed that a high frequency of N-glycans in the (hyper)variable domains of ACPA is responsible for this observation. In line with their localisation, these N-glycans were found to modulate binding avidity of ACPA to citrullinated antigens. The vast majority of ACPA-IgG harbour N-glycans in their variable domains. As N-linked glycosylation requires glycosylation consensus sites in the protein sequence and as these are lacking in the 'germline-counterparts' of identified variable domains, our data indicate that the N-glycosylation sites in ACPA variable domains have been introduced by somatic hypermutation. This finding also suggests that ACPA-hyperglycosylation confers a selective advantage to ACPA-producing B cells. This unique and completely novel feature of the citrulline-specific immune response in RA elucidates our understanding of the underlying B cell response. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to
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    ABSTRACT: Objective For decades it has been known that the HLA-DRB1 Shared Epitope (SE) alleles are associated with an increased risk on development and progression of rheumatoid arthritis (RA). Recently, new insights into variations in the peptide-binding grooves of HLA-molecules that predispose to RA-development are obtained: position 11 in HLA-DRβ1 (Valine and Leucine), position 9 in HLA-B (Aspartic acid) and position 9 in HLA-DPβ1 (Phenylalanine). This study investigated whether these variants also associate with radiographic progression within RA, independent of SE-status and ACPA. Methods In total 4,911 radiograph-sets of 1,878 RA-patients, included in the Leiden-EAC (Netherlands), Umeå (Sweden), HCSC-RAC (Spain) and NDB (USA) cohorts, were studied. HLA was imputed using SNP-data of the Immunochip and the mentioned amino acids were tested in relation to radiographic progression per cohort using an additive model. Results of the four cohorts were combined in inverse-variance weighted meta-analyses using a fixed effects model. Analyses were conditioned on SE-status and anti-citrullinated-peptide antibodies (ACPA). Results Valine and Leucine at HLA-DRβ1 position 11 associated with more radiographic progression (meta-analysis p=5.11x10(-7) ); this effect was independent of SE-status (meta-analysis p=0.022) but not independent of ACPA. Aspartic acid at HLA-DPβ1 position 9 associated with more severe radiographic progression (meta-analysis p=0.024), though not independent of SE-status. Phenylalanine at HLA-B position 9 was not associated with radiographic progression. Conclusion Valine and Leucine at HLA-DRβ1 position 11 conferred risk to a higher rate of radiographic progression independent of SE-status but not independent of ACPA. This supports the relevance of these amino acids at position 11. This article is protected by copyright. All rights reserved. Copyright © 2015 American College of Rheumatology.
    01/2015; DOI:10.1002/art.39018
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    ABSTRACT: Objectives: MRI is a sensitive method to detect inflammation in rheumatoid arthritis (RA), visualizing synovitis, bone marrow edema and tenosynovitis. The prevalence of MRI-detected tenosynovitis and the diagnostic value in early arthritis are unclear. This study aimed to identify the frequency of MRI-detectable tenosynovitis at the metacarpophalangeal (MCP) and wrist joints in early arthritis and the association of these with RA and severity features within RA. Methods: 178 early arthritis patients underwent unilateral 1.5T extremity-MRI at baseline. The MCP and wrist-joints were scored using the RAMRIS system extended with Haavardsholms tenosynovitis score. 69 patients fulfilled the 2010 RA classification criteria during the first year and were compared with the other patients. Within RA-patients comparisons were made for anti-citrullinated-peptide-antibody (ACPA)-positivity and for radiographic progression during year-1. Results: 65% of all patients had MRI-detected tenosynovitis. RA-patients had tenosynovitis more often than non-RA patients (75% versus 59%, p=0.023). The flexor tendons at MCP-5, the extensor tendons at MCP-2 and MCP-4 and extensor compartment-I of the wrist were more frequently affected in RA than in other patients (odds ratio's 2.8 (95%CI 1.2-7.0), 9.1 (95%CI 1.9-42.8), 14.2 (95%CI 1.7-115.9), 4.0 (95%CI 1.4-11.1) respectively). These associations were independent of local MRI synovitis. Specificities were all ≥82%. Within RA, tenosynovitis-scores were not associated with ACPA-positivity or radiographic progression. Conclusions: MRI-detected tenosynovitis is commonly seen in early arthritis. The flexor tendons at MCP-5, the extensor tendons at MCP-2 and MCP-4 and the first extensor compartment of the wrist are more often affected in RA, independent of local synovitis. This article is protected by copyright. All rights reserved. Copyright © 2014 American College of Rheumatology.
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    ABSTRACT: Objective To identify risk factors for early study termination and motivators for adherence to a long-term followup trial and to improve completeness of long-term studies.Methods Risk factors for early termination in 508 included patients were identified through Cox regression analysis. Patients completing the 10-year followup filled in a questionnaire on possible motives for continued study participation.ResultsRisk factors for early termination were higher age (hazard ratio [HR] 1.03, 95% confidence interval [95% CI] 1.02-1.04), functional disability during the preceding year (HR 1.54, 95% CI 1.20-1.99), having achieved drug-free remission (HR 6.62, 95% CI 2.07-21.14), limited joint damage (HR 0.98, 95% CI 0.97-0.995 for actual damage; HR 0.83, 95% CI 0.73-0.94 for damage progression), and few adverse events (HR 0.35, 95% CI 0.26-0.47). A total of 288 of 313 patients (92%) attending the last visit answered the questionnaire. The majority mentioned contributing to scientific research (97% agreed), helping other patients (91%), and learning about new treatment strategies (84%) and their disease (85%) as reasons to continue participation. Next, patients mentioned tight control (202 of 278 patients), good treatment strategy (128 of 278), good medication (117 of 278), and good half-term results (102 of 278) as motivators. More than 95% of patients experienced participation “as expected” or “better than expected.” Additional examinations during yearly visits (extra questionnaires, imaging) were mentioned as “worse than expected” (10%), as was answering routine questionnaires (7%).Conclusion Continued participation was relatively high in the Treatment Strategies for Rheumatoid Arthritis (BeSt) Study. Higher age, functional disability, drug-free remission, little joint damage, and few adverse events predicted early study termination. Main motives for continued participation were a willingness to contribute to research, help future patients, and because patients had good experiences with the study protocol.
    12/2014; 67(6). DOI:10.1002/acr.22540
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    ABSTRACT: The aim of this study is to test the performance of a matrix model to predict rapid radiological progression (RRP) in a study population of early rheumatoid arthritis (RA) or undifferentiated arthritis (UA) patients. A matrix model using baseline CRP, erosion score, autoantibody status, and initial treatment choice to predict RRP (increase ≥5 points in Sharp-van der Heijde score (SHS) in 1 year) was derived from the BeSt study where patients with active RA (1987-criteria) were treated with initial monotherapy or combination therapy, aiming at low disease activity. In the IMPROVED study, patients with early RA (2010 criteria) and UA were initially treated with methotrexate and prednisone aiming at remission. A receiver operating characteristics (ROC) curve was used to assess the discriminative value of the model to predict damage progression in the IMPROVED population. Four hundred thirty-one out of 479 patients with RA and 106/122 with UA could be categorized as high, intermediate, low, or very low risk for RRP. One patient, with a very low risk profile, showed RRP. Thirty-two other patients (5 %) showed radiological progression ≥0.5 point SHS; none had a high risk profile and 22 had a very low risk profile. The area under the curve (AUC) of the ROC curve was 0.56 (95% CI 0.45; 0.68). A matrix model predicting RRP based on risk factors identified in recent onset active RA according to the 1987-criteria performed poorly in recent onset RA (2010 criteria) and UA. It appears that known risk factors for damage progression lose their impact with early remission steered treatment, so that RRP might be considered a phenomenon of the past.
    Clinical Rheumatology 11/2014; DOI:10.1007/s10067-014-2815-8 · 1.77 Impact Factor
  • Sofia Ajeganova, Tom W J Huizinga
    Nature Reviews Rheumatology 11/2014; DOI:10.1038/nrrheum.2014.194 · 10.25 Impact Factor
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    ABSTRACT: To evaluate clinical remission with subcutaneous abatacept plus methotrexate (MTX) and abatacept monotherapy at 12 months in patients with early rheumatoid arthritis (RA), and maintenance of remission following the rapid withdrawal of all RA treatment.
    Annals of the Rheumatic Diseases 11/2014; 74(1). DOI:10.1136/annrheumdis-2014-206106 · 9.27 Impact Factor
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    ABSTRACT: The METEOR (Measurement of Efficacy of Treatment in the 'Era of Outcome' in Rheumatology) initiative aims at improving care for RA patients by assisting rheumatologists in strict monitoring and tight control of disease activity. The state of the art of the METEOR initiative, the technical organisation of the database and future perspectives are described.
    Clinical and experimental rheumatology 11/2014; 32 Suppl 85(5):135-140. · 2.97 Impact Factor
  • Frans G.M. Kroese, Dominique Baeten, Tom W.J. Huizinga
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    ABSTRACT: The study of fundamental mechanisms of autoimmunity has been instrumental to clinical progress in the diagnosis and treatment of a range of immune-mediated inflammatory disorders. Dutch immunology has made major contributions to these developments, ranging from fundamental studies on immune cells, antibodies and cytokines to translational and clinical studies with targeted therapies in patients. In this paper we illustrate the progress made in our understanding of autoimmunity and the translational implications for human disease management by focusing on three areas: the autoantibody response in rheumatoid arthritis (RA), T-B cell interactions in Sjögren's syndrome (SS), and cytokine targeting in spondylarthritis (SpA).
    Immunology Letters 10/2014; 162(2). DOI:10.1016/j.imlet.2014.10.013 · 2.37 Impact Factor
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    ABSTRACT: Introduction C1q deficiency is a rare genetic disorder that is strongly associated with development of Systemic Lupus Erythematosus (SLE). Several mutations in the coding regions of the C1q genes have been described that result in stop-codons or other genetic abnormalities ultimately leading to C1q deficiency. Here we report on a Dutch boy suffering from recurrent infections with a complete C1q deficiency, without any SLE symptoms. Methods The presence of C1q in serum was assessed using ELISA and hemolytic assay. By western blot we examined the different C1q chains in cell lysates. We identified the mutation using deep-sequencing. By qPCR we studied the mRNA expression of C1qA, C1qB and C1qC in the PBMCs of the patient. Results Deep-sequencing revealed a homozygous mutation in the non-coding region of C1qB in the patient, whereas both parents were heterozygous. The mutation is located two nucleotides before the splice site of the second exon. In-silico analyses predict a complete abrogation of this natural splice site. Analyses of in vitro cultured cells from the patient revealed a lack of production of C1q and intracellular absence of C1qB in the presence of C1qA and C1qC peptides. Quantitative PCR analysis revealed total absence of C1qB mRNA, a reduced level of C1qA mRNA and normal levels of C1qC mRNA. Conclusion In this study we report a new mutation in the non-coding region of C1qB that is associated with C1q deficiency.
    Immunobiology 10/2014; 220(3). DOI:10.1016/j.imbio.2014.10.005 · 3.18 Impact Factor
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    ABSTRACT: Objective. Increased numbers of IL-17-producing CD4+ T cells have been observed in AS. However, it is not known whether these CD4+ T cells are already present in early disease or if this is a late disease phenomenon only. Therefore we aimed to investigate whether IL-17-producing CD4+ T cells are involved in early active axial SpA, including patients without imaging abnormalities, by determining the frequency and phenotype of IL-17-producing CD4+ T cells in these patients. Methods. Flow cytometry was used to analyse cytokine production and surface marker expression of peripheral blood mononuclear cells from 31 patients suffering from early active HLA-B27-positive axial SpA fulfilling the Assessment of SpondyloArthritis International Society criteria with or without MRI abnormalities and 21 healthy controls. Results. Patients with early active axial SpA showed an increased percentage of IL-17-producing CD4+ T cells compared with healthy controls (mean 1.1% vs 0.4%, respectively; P = 0.013). The percentage of IL-17-producing CD4+ T cells was equally increased in patients with and without MRI abnormalities (1.2% vs 1.1%, respectively; P = 0.81). These IL-17-producing CD4+T cells expressed the αβ T cell receptor but not the γδ T cell receptor, exhibited a memory phenotype and expressed CD161, but only sporadically expressed killer cell immunoglobulin-like receptor 3DL2 (KIR3DL2). Conclusion. IL-17-producing CD4+ T cells are increased in patients with early active axial SpA both with and without MRI abnormalities. This finding shows that the frequency of IL-17-producing CD4+ T cells is enhanced in the early stages of disease.
    Rheumatology (Oxford, England) 10/2014; 54(4). DOI:10.1093/rheumatology/keu382 · 4.44 Impact Factor
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    ABSTRACT: Introduction: Macrophage migration inhibitory factor (MIF) has been shown to be a key regulator in innate and adaptive immune responses. A single nucleotide polymorphism in the 5′ region of the MIF gene, MIF -173∗G/C, is associated with increased MIF protein production, in vivo and in vitro. Associations have been shown between the minor MIF -173C allele and sarcoidosis patients with erythema nodosum (EN). Löfgren’s syndrome is an acute and usually self-remitting phenotype of sarcoidosis. It is defined as having an acute onset with bilateral hilar lymphadenopathy (BHL), fever, erythema nodosum (EN) and/or arthritis. The aim of this study was to investigate whether MIF -173G/C associates with the susceptibility to and the clinical manifestations, i.e. arthritis or EN, of Löfgren’s syndrome. A total of 171 patients with Löfgren’s syndrome and 313 controls were genotyped for a single nucleotide polymorphism at position -173 of the MIF gene (SNP rs755622), using a PCR and a restriction enzyme technique. Results: There were no significant differences found in the MIF -173C allele frequencies between patients with Löfgren’s syndrome and controls. In patients with Löfgren’s syndrome with only EN, a significantly increased frequency of the C minor allele was observed compared to patients with arthritis only (p = 0.0095; OR 3.08, CI: 1.28–7.39). Patients with only EN compared to patients with EN and arthritis showed a significantly increased frequency of the minor C allele (p = 0.044; OR 1.97, CI: 1.01–3.85). But patients with only arthritis compared to patients with EN and arthritis did not show a significant difference in C allele frequency (p = 0.270; OR 0.64, CI: 0.29–1.42). Conclusions: The MIF -173C allele is associated with erythema nodosum in Löfgren’s syndrome, but not with susceptibility to sarcoidosis. This indicates a role for MIF after antigen presenting to the T cell has taken place and the sarcoid inflammatory response has begun.
    Cytokine 10/2014; 69(2). DOI:10.1016/j.cyto.2014.05.020 · 2.87 Impact Factor

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20k Citations
3,944.85 Total Impact Points


  • 1999–2015
    • Leiden University
      Leyden, South Holland, Netherlands
  • 1996–2015
    • Leiden University Medical Centre
      • • Department of Rheumatology
      • • Department of Nephrology
      • • Department of Clinical Epidemiology
      Leyden, South Holland, Netherlands
  • 2013
    • TNO
      Delft, South Holland, Netherlands
    • Bronovo Hospital
      's-Gravenhage, South Holland, Netherlands
    • Harvard Medical School
      Boston, Massachusetts, United States
  • 2011
    • Stichting Kwaliteitsbewaking Medische Laboratoriumdiagnostiek
      Nymegen, Gelderland, Netherlands
    • Karolinska Institutet
      • Institutet för miljömedicin - IMM
      Solna, Stockholm, Sweden
  • 2009
    • University Medical Center Utrecht
      Utrecht, Utrecht, Netherlands
  • 2003–2009
    • VU University Medical Center
      • • Department of Pathology
      • • Department of Molecular Cell Biology and Immunology
      Amsterdam, North Holland, Netherlands
  • 2008
    • University of Coimbra
      Coímbra, Coimbra, Portugal
  • 2004
    • VU University Amsterdam
      Amsterdamo, North Holland, Netherlands
  • 1990–1998
    • University of Amsterdam
      • Central Laboratory of the Netherlands Red Cross Blood Transfusion Service
      Amsterdam, North Holland, Netherlands