Tom W J Huizinga

Leiden University, Leyden, South Holland, Netherlands

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Publications (543)3594.16 Total impact

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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; · 4.32 Impact Factor
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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;
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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.
    Arthritis & rheumatology (Hoboken, N.J.). 01/2015;
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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.
    Arthritis & rheumatology (Hoboken, N.J.). 12/2014;
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    ABSTRACT: Objective: Identifying risk factors for early study termination and motivators for adherence to a long-term follow-up trial and improving completeness of long-term studies.Methods: Risk factors for early termination in 508 included patients were identified through cox regression analysis. Patients completing ten-year follow-up filled in a questionnaire on possible motives for continued study participation.Results: Risk factors for early termination were higher age (HR 1.03, 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 progression) and few adverse events (HR 0.35, 95% CI 0.26-0.47). 288/313 patients attending the last visit (92%) answered the questionnaire. The majority mentioned contributing to scientific research (97% agreed), helping other patients (91%), learning about new treatment strategies (84%) and their disease (85%) as reasons to continue participation. Next, patients mentioned tight control (202/278 patients), good treatment strategy (128/278), good medication (117/278) and good half-term results (102/278) as motivators. Over 95% of patients experienced participation ‘as expected’ or ‘better than expected’. Additional examinations during yearly visits (extra questionnaires, imaging) were mentioned ‘worse than expected’ (10%) as was answering routine questionnaires (7%).Conclusion: Continued participation was relatively high in the 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. This article is protected by copyright. All rights reserved.
    Arthritis Care & Research. 12/2014;
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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; · 1.77 Impact Factor
  • Sofia Ajeganova, Tom W J Huizinga
    Nature Reviews Rheumatology 11/2014; · 9.75 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; · 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; · 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). · 2.81 Impact Factor
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    ABSTRACT: 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.
    Rheumatology (Oxford, England) 10/2014; · 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; · 2.87 Impact Factor
  • Rheumatology (Oxford, England) 09/2014; · 4.44 Impact Factor
  • Annie Yarwood, Tom W J Huizinga, Jane Worthington
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    ABSTRACT: There is now a general consensus that RA has a spectrum of disease stages that can begin many years before the onset of clinical symptoms. It is widely thought that understanding the complex interplay between genetics and environment, and their role in pathogenesis, is essential in gaining further insight into the mechanisms that drive disease development and progression. More than 100 genetic susceptibility loci have now been identified for RA through studies that have focused on patients with established RA compared with healthy controls. Studying the early preclinical phases of disease will provide valuable insights into the biological events that precede disease and could potentially identify biomarkers to predict disease onset and future therapeutic targets. In this review we will cover recent advances in the knowledge of genetic and environmental risk factors and speculate on how these factors may influence the transition from one stage of disease to another.
    Rheumatology (Oxford, England) 09/2014; · 4.44 Impact Factor
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    Rheumatology (Oxford, England) 09/2014; · 4.44 Impact Factor
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    ABSTRACT: To assess the efficacy and safety of tocilizumab (TCZ) plus methotrexate/placebo (MTX/PBO) over 2 years and the course of disease activity in patients who discontinued TCZ due to sustained remission.
    Annals of the Rheumatic Diseases 08/2014; · 9.27 Impact Factor
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    ABSTRACT: Treatment of patients with rheumatoid arthritis (RA) is rarely personalized, since predictors of disease course are lacking. The severity of RA can be measured objectively by radiographic progression. The most reliable way to measure radiographic progression is in a longitudinal cohort with serial time points, scoring on a quantitative scale, with a validated scoring method and trained readers. Current models used to predict radiographic progression are based on C-reactive protein and anti-citrullinated protein antibodies. Other biomarkers could increase the prognostic ability of these models. In this review, we evaluated the published (and partly nonpublished) data on genetic, serologic, and imaging biomarkers for the severity of joint destruction in RA. We evaluated variants in 10 genes (CD40, IL2RA, IL4R, IL15, OPG, DKK1, SOST, GRZB, MMP9, and SPAG16). In 5 variants (IL2RA, DKK1, GRZB, MMP9, and SPAG16), we found evidence of an association at the functional level. We evaluated several serological biomarkers, namely, autoantibodies (RF, ACPA, anti-CarP), markers related to inflammation (ESR, CRP), and proteinases or components of the extracellular matrix of bone and cartilage (MMP3, CTX-I, CTX-II, COMP, TIMP1, PYD, RANKL/OPG, CXCL13). Finally, we evaluated markers that can be visualized by ultrasound or MRI, including erosions, bone marrow edema, synovitis, and tenosynovitis. Several studies showed that bone marrow edema and synovitis on MRI are robust predictors of radiographic progression. Some studies showed that inflammation detected with ultrasound predicted radiographic progression. Future studies will reveal whether adding and combining all these different biomarkers will increase the accuracy of risk models predicting radiographic progression in RA.
    Current Pharmaceutical Design 08/2014; · 3.29 Impact Factor
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    ABSTRACT: To determine whether a multibiomarker disease activity (MBDA) score predicts radiographic damage progression in the subsequent year in patients with early rheumatoid arthritis.
    The Journal of Rheumatology 08/2014; · 3.17 Impact Factor

Publication Stats

16k Citations
3,594.16 Total Impact Points


  • 2006–2015
    • Leiden University
      Leyden, South Holland, Netherlands
    • Revmatologicky Ustav
      Praha, Praha, Czech Republic
  • 1996–2014
    • Leiden University Medical Centre
      • • Department of Rheumatology
      • • Department of Nephrology
      • • Department of Clinical Epidemiology
      Leyden, South Holland, Netherlands
  • 2013
    • University of Leeds
      • Division of Rheumatic and Musculoskeletal Disease
      Leeds, ENG, United Kingdom
    • Harvard Medical School
      Boston, Massachusetts, United States
    • TNO
      Delft, South Holland, Netherlands
    • Bronovo Hospital
      's-Gravenhage, South Holland, Netherlands
  • 2009–2013
    • University Medical Center Utrecht
      • Department of Orthopedics
      Utrecht, Provincie Utrecht, Netherlands
    • Massachusetts Institute of Technology
      Cambridge, Massachusetts, United States
    • Medical University of Vienna
      Wien, Vienna, Austria
  • 2012
    • University of Amsterdam
      • Faculty of Medicine AMC
      Amsterdamo, North Holland, Netherlands
    • Maasstad Ziekenhuis
      Rotterdam, South Holland, Netherlands
  • 2011
    • The Bracton Centre, Oxleas NHS Trust
      Дартфорде, England, United Kingdom
    • Stichting Kwaliteitsbewaking Medische Laboratoriumdiagnostiek
      Nymegen, Gelderland, Netherlands
  • 2010–2011
    • Karolinska Institutet
      • • Institutet för miljömedicin - IMM
      • • Institutionen för medicin, Huddinge
      Solna, Stockholm, Sweden
    • King's College London
      • Department of Academic Rheumatology
      London, ENG, United Kingdom
    • Brigham and Women's Hospital
      • Division of Rheumatology, Immunology, and Allergy
      Boston, MA, United States
    • University of Crete
      Retimo, Crete, Greece
  • 2008
    • Broad Institute of MIT and Harvard
      • Program in Medical and Population Genetics
      Cambridge, MA, United States
    • University of Birmingham
      • School of Immunity and Infection
      Birmingham, ENG, United Kingdom
    • University of Coimbra
      Coímbra, Coimbra, Portugal
  • 2005–2008
    • VU University Medical Center
      • • Department of Rheumatology
      • • Department of Molecular Cell Biology and Immunology
      Amsterdamo, North Holland, Netherlands
  • 2004
    • Erasmus MC
      • Department of Obstetrics and Gynaecology
      Rotterdam, South Holland, Netherlands
    • Ghent University
      • Rheumatology
      Gent, VLG, Belgium
  • 2003
    • Fundação Oswaldo Cruz
      • Laboratório de Hanseníase (IOC)
      Rio de Janeiro, Rio de Janeiro, Brazil