Anouk L Feitsma

Publications (5)41.15 Total impact

• Article: Protection against anti-citrullinated protein antibody-positive rheumatoid arthritis is predominantly associated with HLA-DRB1*1301: a meta-analysis of HLA-DRB1 associations with anti-citrullinated protein antibody-positive and anti-citrullinated protein antibody-negative rheumatoid arthritis in four European populations.

  Diane van der Woude, Benedicte A Lie, Emeli Lundström, Alejandro Balsa, Anouk L Feitsma, Jeanine J Houwing-Duistermaat, Willem Verduijn, Gry B N Nordang, Lars Alfredsson, Lars Klareskog, [......], Miguel A Gonzalez-Gay, Miguel A Lopez-Nevot, Fernando Valero, Bart O Roep, Tom W J Huizinga, Tore K Kvien, Javier Martín, Leonid Padyukov, René R P de Vries, René E M Toes
  [show abstract] [hide abstract]
  ABSTRACT: The protective effect of HLA-DRB1 alleles on the development of rheumatoid arthritis (RA) is poorly understood. The aim of this study was to perform a meta-analysis of 4 European populations to investigate which HLA-DRB1 alleles are associated with protection in anti-citrullinated protein antibody (ACPA)-positive RA and ACPA-negative RA. Data for >2,800 patients and >3,000 control subjects for whom information on HLA-DRB1 typing and ACPA status was available were collected from 4 European countries: Norway, Sweden, The Netherlands, and Spain. The odds ratios (ORs) and 95% confidence intervals (95% CIs) associated with the different HLA-DRB1 alleles were analyzed in a combined meta-analysis focused on protective alleles and classifications. The analysis of ACPA-positive RA was stratified for the shared epitope (SE) alleles, to correct for skewing due to this association. In ACPA-positive RA, the only alleles that conveyed protection after stratification for SE were HLA-DRB1*13 alleles (OR 0.54 [95% CI 0.38-0.77]). The protective effect of the allele classifications based on the DERAA and D70 sequences was no longer present after exclusion of DRB1*13 (for D70, OR 0.97 [95% CI 0.75-1.25]), indicating that DRB1*13, rather than the DERAA or D70 sequence as such, is associated with protection. Among the DRB1*13 alleles, only DRB1*1301 was associated with protection (OR 0.24 [95% CI 0.09-0.59]). Protection appeared to follow a north-to-south gradient, with the strongest association in northern European countries. In ACPA-negative RA, there were no robust associations with HLA-DRB1 alleles. Our data do not support any of the classifications of protective alleles and indicate that protection against ACPA-positive RA is predominantly associated with HLA-DRB1*1301.
  Arthritis & Rheumatism 05/2010; 62(5):1236-45. · 7.87 Impact Factor
• Article: Protection against anti–citrullinated protein antibody–positive rheumatoid arthritis is predominantly associated with HLA–DRB1*1301: A meta‐analysis of HLA–DRB1 associations with anti–citrullinated protein antibody–positive and anti–citrullinated protein antibody–negative rheumatoid arthritis in four European populations

  Diane van der Woude, Benedicte A. Lie, Emeli Lundström, Alejandro Balsa, Anouk L. Feitsma, Jeanine J. Houwing-Duistermaat, Willem Verduijn, Gry B. N. Nordang, Lars Alfredsson, Lars Klareskog, [......], Miguel A. Gonzalez-Gay, Miguel A. Lopez-Nevot, Fernando Valero, Bart O. Roep, Tom W. J. Huizinga, Tore K. Kvien, Javier Martín, Leonid Padyukov, René R. P. de Vries, René E. M. Toes
  [show abstract] [hide abstract]
  ABSTRACT: Objective The protective effect of HLA–DRB1 alleles on the development of rheumatoid arthritis (RA) is poorly understood. The aim of this study was to perform a meta-analysis of 4 European populations to investigate which HLA–DRB1 alleles are associated with protection in anti–citrullinated protein antibody (ACPA)–positive RA and ACPA-negative RA.Methods Data for >2,800 patients and >3,000 control subjects for whom information on HLA–DRB1 typing and ACPA status was available were collected from 4 European countries: Norway, Sweden, The Netherlands, and Spain. The odds ratios (ORs) and 95% confidence intervals (95% CIs) associated with the different HLA–DRB1 alleles were analyzed in a combined meta-analysis focused on protective alleles and classifications. The analysis of ACPA-positive RA was stratified for the shared epitope (SE) alleles, to correct for skewing due to this association.ResultsIn ACPA-positive RA, the only alleles that conveyed protection after stratification for SE were HLA–DRB1*13 alleles (OR 0.54 [95% CI 0.38–0.77]). The protective effect of the allele classifications based on the DERAA and D70 sequences was no longer present after exclusion of DRB1*13 (for D70, OR 0.97 [95% CI 0.75–1.25]), indicating that DRB1*13, rather than the DERAA or D70 sequence as such, is associated with protection. Among the DRB1*13 alleles, only DRB1*1301 was associated with protection (OR 0.24 [95% CI 0.09–0.59]). Protection appeared to follow a north-to-south gradient, with the strongest association in northern European countries. In ACPA-negative RA, there were no robust associations with HLA–DRB1 alleles.Conclusion Our data do not support any of the classifications of protective alleles and indicate that protection against ACPA-positive RA is predominantly associated with HLA–DRB1*1301.
  Arthritis & Rheumatism 01/2010; 62(5):1236 - 1245. · 7.87 Impact Factor
• Article: Identification of citrullinated vimentin peptides as T cell epitopes in HLA-DR4-positive patients with rheumatoid arthritis.

  Anouk L Feitsma, Ellen I H van der Voort, Kees L M C Franken, Hanane el Bannoudi, Berendina G Elferink, Jan W Drijfhout, Tom W J Huizinga, René R P de Vries, René E M Toes, A Ioan-Facsinay
  [show abstract] [hide abstract]
  ABSTRACT: Antibodies directed against citrullinated proteins (ACPAs) are highly specific for rheumatoid arthritis (RA). The production of ACPAs is most likely dependent on the presence of T cells, since ACPAs undergo isotype switching and are associated with the shared epitope (SE)-containing HLA-DRB1 alleles. Vimentin is a likely candidate protein for T cell recognition, since >90% of patients positive for ACPAs that are reactive with (peptides derived from) citrullinated vimentin carry SE-containing HLA-DRB1 alleles. The aim of this study was to identify citrullinated vimentin peptides that are presented to HLA-DRB1*0401-restricted T cells. HLA-DR4-transgenic mice were immunized with all possible citrulline-containing peptides derived from vimentin, and T cell reactivity was analyzed. Peptides recognized in a citrulline-specific manner by T cells were selected and analyzed for their ability to be processed from the entire vimentin protein. A first inventory of the selected epitopes recognized by T cells was performed using peripheral blood mononuclear cells (PBMCs) from ACPA+, HLA-DR4+ patients with RA. A citrulline-specific response was observed for 2 of the peptides analyzed in DR4-transgenic mice. These peptides were found to be naturally processed from the vimentin protein, since citrullinated vimentin was recognized by peptide-specific T cells. T cell reactivity against these peptides was also observed in cultures of PBMCs from RA patients. This study identifies, for the first time, 2 naturally processed peptides from vimentin that are recognized by HLA-DRB1*0401-restricted T cells in a citrulline-specific manner. These peptides can be recognized by T cells in ACPA+, HLA-DR4+ patients with RA, as shown in a first inventory.
  Arthritis & Rheumatism 01/2010; 62(1):117-25. · 7.87 Impact Factor
• Source

  Available from: Lina M Olsson

  Article: Association of a single-nucleotide polymorphism in CD40 with the rate of joint destruction in rheumatoid arthritis.

  Michael P M van der Linden, Anouk L Feitsma, Saskia le Cessie, Marlena Kern, Lina M Olsson, Soumya Raychaudhuri, Ann B Begovich, Monica Chang, Joseph J Catanese, Fina A S Kurreeman, Jessica van Nies, Désirée M van der Heijde, Peter K Gregersen, Tom W J Huizinga, René E M Toes, Annette H M van der Helm-Van Mil
  [show abstract] [hide abstract]
  ABSTRACT: The severity of joint destruction in rheumatoid arthritis (RA) is highly variable from patient to patient and is influenced by genetic factors. Genome-wide association studies have enormously boosted the field of the genetics of RA susceptibility, but risk loci for RA severity remain poorly defined. A recent meta-analysis of genome-wide association studies identified 6 genetic regions for susceptibility to autoantibody-positive RA: CD40, KIF5A/PIP4K2C, CDK6, CCL21, PRKCQ, and MMEL1/TNFRSF14. The purpose of this study was to investigate whether these newly described genetic regions are associated with the rate of joint destruction. RA patients enrolled in the Leiden Early Arthritis Clinic were studied (n=563). Yearly radiographs were scored using the Sharp/van der Heijde method (median followup 5 years; maximum followup 9 years). The rate of joint destruction between genotype groups was compared using a linear mixed model, correcting for age, sex, and treatment strategies. A total of 393 anti-citrullinated protein antibody (ACPA)-positive RA patients from the North American Rheumatoid Arthritis Consortium (NARAC) who had radiographic data available were used for the replication study. The TT and CC/CG genotypes of 2 single-nucleotide polymorphisms, rs4810485 (CD40) and rs42041 (CDK6), respectively, were associated with a higher rate of joint destruction in ACPA-positive RA patients (P=0.003 and P=0.012, respectively), with rs4810485 being significant after Bonferroni correction for multiple testing. The association of the CD40 minor allele with the rate of radiographic progression was replicated in the NARAC cohort (P=0.021). A polymorphism in the CD40 locus is associated with the rate of joint destruction in patients with ACPA-positive RA. Our findings provide one of the first non-HLA-related genetic severity factors that has been replicated.
  Arthritis & Rheumatism 08/2009; 60(8):2242-7. · 7.87 Impact Factor
• Source

  Available from: Jon van Rood

  Article: Protective effect of noninherited maternal HLA-DR antigens on rheumatoid arthritis development.

  Anouk L Feitsma, Jane Worthington, Annette H M van der Helm-van Mil, Darren Plant, Wendy Thomson, Jennie Ursum, Dirkjan van Schaardenburg, Irene E van der Horst-Bruinsma, Jon J van Rood, Tom W J Huizinga, René E M Toes, René R P de Vries
  [show abstract] [hide abstract]
  ABSTRACT: Rheumatoid arthritis (RA) is a complex genetic disorder in which the HLA-region contributes most to the genetic risk. HLA-DRB1-molecules containing the amino acid sequence DERAA (i.e., HLA-DRB1*0103, *0402, *1102, *1103, *1301, *1302, and *1304) are associated with protection from RA. It has been proposed that not only inherited but also noninherited HLA-antigens from the mother (NIMA) can influence RA-susceptibility. Up to now, no protective NIMAs were described. Here, we studied whether DERAA-containing HLA-DRB1-alleles as NIMA are associated with a protective effect. One hundred seventy-nine families were studied, 88 from the Netherlands and 91 from the United Kingdom. The frequency of DERAA-containing HLA-DRB1-alleles of the Dutch mothers (16.1%), but not of the fathers (26.2%), was lower compared with the general Dutch population (29.3%; P = 0.02). This was replicated in the English set of patients and controls (P = 0.01). Further, of all families, 45 contained at least one DERAA-negative child with RA and at least one DERAA-positive parent. The odds for the DERAA-negative RA patients of having a DERAA-positive mother was significantly lower compared with having a DERAA-positive father (OR 0.25; P = 0.003). These data show a protective NIMA-effect in a human autoimmune disease and indicate that a DERAA-positive mother can transfer protection against RA to her DERAA-negative child.
  Proceedings of the National Academy of Sciences 01/2008; 104(50):19966-70. · 9.68 Impact Factor