Rheumatoid Arthritis: Toes RE

Wenink MH, Han W, Toes RE, Radstake TR. · Department of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. · Handb Exp Pharmacol. · Pubmed #19031022 No free full text.

Abstract: Dendritic cells (DC) are the professional antigen presenting cells that protect us against invading organisms. On the other hand, they uphold tolerance thereby avoiding the initiation of autoimmunity. In performing these contrasting but essential tasks DC are unique and divide these processes in time and space. It is often thought that a loss of separation of these tasks underlies the breakthrough of tolerance leading to autoimmune conditions such as rheumatoid arthritis. In this review, we will focus on the evidence which points towards the implication of DC in the inflammatory process observed in RA and in experimental models of arthritis. Finally, we will conclude on future programs exploiting the capacity of DC to cure conditions such as RA.

Feitsma AL, van der Helm-van Mil AH, Huizinga TW, de Vries RR, Toes RE. · Department of Rheumatology, LUMC, Leiden, The Netherlands. · Ann Rheum Dis. · Pubmed #19022816 No free full text.

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 QKRAA/QRRAA/RRRAA (ie, HLA-DRB1*0101, *0102, *0401, *0404, *0405, *0408, *0410, *1001 and *1402) at position 70-74 in the third hypervariable region of the DRB1 chain are associated with susceptibility to RA. HLA-DRB1 molecules containing the amino acids "DERAA" (ie, HLA-DRB1*0103, *0402, *1102, *1103, *1301, *1302 and *1304) at the same position are associated with protection from RA. Interestingly, not only inherited but also non-inherited HLA-antigens from the mother can influence RA susceptibility. A protective effect of "DERAA"-containing HLA-DRB1 alleles as non-inherited maternal antigen (NIMA) has recently been described. The underlying mechanism of this protective effect is currently unknown, although a possible explanation is covered below. In this review, an overview of the current knowledge on protection against RA is given and the inherited and NIMA effect of "DERAA"-containing HLA-DRB1 alleles are compared.

van der Helm-van Mil AH, Huizinga TW, de Vries RR, Toes RE. · Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands. · Arthritis Rheum. · Pubmed #17534941 links to  free full text

This publication has no abstract.

van Duivenvoorde LM, van Mierlo GJ, Boonman ZF, Toes RE. · Department of Rheumatology, Leiden University Medical Center, The Netherlands. · Immunobiology. · Pubmed #16920501 No free full text.

Abstract: Adaptive immune responses are orchestrated by specialized professional antigen-presenting cells (APCs), the dendritic cells (DCs), which play crucial roles as initiators and modulators of adaptive immune responses. A main feature of DCs is their phenotypic and functional plasticity. In the absence of any inflammation or pathogenic elements, most DCs in peripheral tissues and lymphoid organs have a resting, immature phenotype characterized by high endocytic capacity and low surface expression of MHC- and costimulatory molecules. However, upon interaction with microbial ligands, pro-inflammatory cytokines or CD40Ligand, DCs rapidly acquire an activated phenotype. These mature DCs have a very efficient T cell-priming ability as a consequence of upregulation of MHC- and costimulatory molecules on their cell surface. For this reason, DC-based vaccines have been used successfully to combat infections and malignancies. Nonetheless, evidence is accumulating that, especially immature, or semi-matured, DCs also have a potent ability to tolerize T cells or prevent undesired immune reactions. Therefore, current and prospective strategies to promote the inherent tolerogenic potential of DCs are a rational approach for the therapy of autoimmune diseases such as rheumatoid arthritis (RA). This review summarizes some aspects of the intriguing ability of DCs to steer the outcome of immunity and their potency to modulate the outcome of various pathological conditions.

de Vries RR, Huizinga TW, Toes RE. · Department of Immunohematology/Bloodtransfusion, Leiden University Medical Center, The Netherlands. · Hum Immunol. · Pubmed #16728269 No free full text.

Abstract: An obvious way to unravel the apparently complex association between human leukocyte antigen (HLA) and rheumatoid arthritis (RA) is to reduce the heterogeneity of this multifactorial disease. Recently we have discovered that shared epitope (SE)-positive HLA-DRB1 alleles are exclusively associated with a subgroup of RA patients that test positive for auto-antibodies against cyclic citrullinated peptides. Further studies suggested that SE-positive alleles are classical immune response genes for the development of these antibodies. On the basis of these and other data we formulated a two-hit model for the pathogenesis of RA which incorporates a novel "citrullinated" SE hypothesis. About 5 years ago Zanelli et al. reported that HLA-DR6 (*1301 and *1302) and some other DR alleles that share the DERAA-sequence on amino acids 70-74 of their third hypervariable region are associated with protection from (severe) RA. Recently we corroborated these data in a large prospective cohort study and demonstrated that protection was observed both in the presence and in the absence of a SE susceptibility allele on the other haplotype. Finally we review the state of the art of the association of noninherited maternal HLA antigens with both susceptibility to and protection from RA.

de Vries RR, Huizinga TW, Toes RE. · Department of Immunohematology and Bloodtransfusion, Leiden University Medical Center, Building 1, E3-Q, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands. · J Autoimmun. · Pubmed #16257178 No free full text.

Abstract: Rheumatoid Arthritis (RA) is the most common chronic inflammatory joint disease. The overall prevalence is 1% and in people older than 60 it is more than 2%. RA has auto-immune features: auto-antibodies against the Fc part of IgG, so-called Rheumatoid Factor (RF) are found more often in RA patients and more recently RA-specific auto-antibodies directed against Cyclic Citrunilated Peptides (CCP) have been discovered. Based on twin studies the contribution of genetic factors to the pathogenesis has been estimated to be about 60%. The main genetic contribution (about 40%) comes from the HLA complex. An association between HLA-DR4 and RA was already documented almost 30 years ago. This association was more prominent for severe forms of the disease. Because more HLA-DRB1 alleles appeared to be associated with RA and the products of these alleles shared a 5AA sequence in a peptide-binding pocket the so-called Shared Epitope (SE) hypothesis was formulated, the prediction being that these DRB1 molecules would bind an RA inducing peptide(s). Thus far however such (a) peptides remain elusive. Because the risk for RA associated with different but SE-identical DRB1 alleles varies considerably this SE can also not be the whole explanation for the HLA contribution to RA susceptibility/severity. A modified SE has been postulated and a role for DQ has been postulated. There is also evidence for a contribution of non-class II genes to susceptibility. About 5 years ago we have reported that certain HLA-DRB1 alleles are associated with protection from (severe) RA. The products of these alleles carry instead of the SE sequence another peptide anchor region consisting of the amino acid DERAA. In a large prospective cohort study we showed recently that these alleles indeed confer (dominant) protection both against developing RA and a severe course of the disease. This protection was observed both in the presence and the absence of SE susceptibility alleles. We are presently exploring the hypothesis that this protection is mediated by regulatory T cells reactive with the DERAA epitope. An obvious way to unravel the apparently complex association between HLA and RA is to reduce the heterogeneity of this multifactorial disease. Recently, we have discovered that SE positive DRB1 alleles are exclusively associated with CCP positive RA. The previously reported association with RF positive RA appeared to be secondary to the association with anti-CCP pos. RA. This was the case both for the association found for susceptibility and severity. Interestingly, DRB1*03 was exclusively associated with anti-CCP neg. RA. Because recent evidence puts the immune response against citrunilated proteins (CCP) as prime suspect for disease induction and progression in this subgroup of RA these observations are a big leap forwards in solving the HLA-RA puzzle.

van Gaalen F, Ioan-Facsinay A, Huizinga TW, Toes RE. · Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands. · J Immunol. · Pubmed #16237041 links to  free full text

Abstract: Rheumatoid arthritis is a chronic inflammatory autoimmune disease of unknown cause. The immune response against citrullinated Ags has recently become the prime suspect for disease pathogenesis. Immunity against citrullinated Ags is thought to play a pivotal role in the disease for several reasons: 1) citrullinated Ags are expressed in the target organ, the inflamed joint; 2) anti-citrullinated protein Abs are present before the disease becomes manifest; and 3) these Abs are highly specific for rheumatoid arthritis. In this review, data from clinical, genetic, biochemical, and animal studies is combined to create a profile of this remarkable autoantibody response. Moreover, a model is proposed of how the anti-citrullinated proteins response is generated and how it could eventually lead to chronic inflammation.

Verpoort KN, van Dongen H, Allaart CF, Toes RE, Breedveld FC, Huizinga TW. · Department of Rheumatology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands. · Clin Exp Rheumatol. · Pubmed #15552509 No free full text.

Abstract: The prognosis of patients with undifferentiated arthritis (UA) may vary from self-limited to severe destructive rheumatoid arthritis (RA). Because early aggressive treatment might offer an effective means to slow disease progression in RA, it is important to identify UA patients who will develop RA and treat them as early as possible. At the same time, inappropriate treatment of patients with a more benign disease course should be avoided. Here, an overview is given of the characteristics and numbers of patients with UA who evolve into RA. UA is defined as any arthritis that has the potential for a persistent course, without fulfilling the classification criteria for specific rheumatic disorders. To compare endpoints in the different databases, the 1987 ACR criteria for RA were used. In the nine databases employing a similar definition for undifferentiated arthritis, the proportion of patients with UA that evolved into RA within 1 year varied from 6% to 55%. These differences arise in large part from differences in the inclusion criteria and in the definitions used for UA and RA. The data from the various cohorts support a hypothesis that a considerable proportion of UA patients are actually patients with RA in a very early stage. Controlled intervention studies with early antirheumatic treatment in these patients are mandatory in order to provide further insight into the natural course of UA and to define a treatment strategy that will successfully slow or prevent disease progression.

Verburg RJ, Toes RE, Fibbe WE, Breedveld FC, van Laar JM. · Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands. · Hum Immunol. · Pubmed #12121670 No free full text.

Abstract: A new treatment approach, involving intense immunosuppression and autologous hematopoietic stem cell transplantation (SCT), has emerged in recent years for the treatment of severe, refractory rheumatic autoimmune diseases including rheumatoid arthritis (RA). The rationale of this strategy is based on the concept of immunoablation by intense immunosuppression with subsequent regeneration of naïve T lymphocytes derived from reinfused hematopoietic progenitor cells. Patients with a therapy-refractory, progressively erosive disease who are at risk of functional disability and early mortality are considered eligible for treatment with autologous SCT. The goal is long-term improvement of disease activity and quality of life. However, when offering SCT to RA patients these benefits should be balanced against toxicities and treatment-related mortality. In several patients with intractable RA, long-term remissions were observed with this strategy, but failures have been reported as well. Only small numbers of RA patients have been treated thus far. Although different treatment protocols have been used, high dose chemotherapy as a means to achieve immunoablation has been invariably used in all studies. In this review we discuss background, clinical results, protocols, and future prospects of high dose chemotherapy and autologous SCT for RA.

Zanelli E, Toes RE. · No affiliation provided · Nat Med. · Pubmed #10835673 No free full text.

This publication has no abstract.

Verburg RJ, Flierman R, Sont JK, Ponchel F, van Dreunen L, Levarht EW, Welling MM, Toes RE, Isaacs JD, van Laar JM. · Department of Rheumatology, Division of Nuclear Medicine, Leiden University Medical Centre, PO Box 9600, 2300 RC Leiden, The Netherlands. · Ann Rheum Dis. · Pubmed #15829573 links to  free full text

Abstract: OBJECTIVE: To determine clinical and immunological correlates of high dose chemotherapy (HDC) + autologous stem cell transplantation (ASCT) in patients with severe rheumatoid arthritis (RA), refractory to conventional treatment. METHODS: Serial samples of peripheral blood and synovial tissue were obtained from seven patients with RA treated with HDC and autologous peripheral blood grafts enriched for CD34+ cells. Disease activity was assessed with the Disease Activity Score (DAS), serum concentrations of C reactive protein (CRP), and human immunoglobulin (HIg) scans, and the extent of immunoablation was determined by immunophenotyping of peripheral blood mononuclear cells, and immunohistochemistry and double immunofluorescence of synovium. RESULTS: Clinical responders (n = 5) had a larger number of cells at baseline expressing CD3, CD4, CD27, CD45RA, CD45RB, and CD45RO in synovium (p < 0.05), higher activity on HIg scans (p = 0.08), and a trend towards higher concentrations of CRP in serum than non-responders (n = 2). Subsequent remissions and relapses in responders paralleled reduction and re-expression, respectively, of T cell markers. A relatively increased expression of CD45RB and CD45RO on synovial CD3+ T cells was seen after HDC + ASCT. No correlations were found between DAS and changes in B cells or macrophage infiltration or synoviocytes. CONCLUSIONS: HDC + ASCT results in profound but incomplete immunoablation of both the memory and naïve T cell compartment, which is associated with longlasting clinical responses in most patients. The findings provide strong circumstantial evidence for a role of T cells in established RA, and demonstrate a role for the synovium in post-transplantation T cell reconstitution.

van Oosterhout M, Levarht EW, Sont JK, Huizinga TW, Toes RE, van Laar JM. · Leiden University Medical Centre, Department of Rheumatology, PO Box 9600, 2300 RC Leiden, Netherlands. · Ann Rheum Dis. · Pubmed #15769913 links to  free full text

Abstract: BACKGROUND: Tumour necrosis alpha (TNF alpha) blocking agents lead to pronounced clinical effects and reduced synovial infiltrate in rheumatoid arthritis. Laboratory and clinical studies suggest that TNF alpha independent pathways play a role in the disease. OBJECTIVES: To evaluate the immunopathological effects of combination therapy on rheumatoid synovial tissue in order to identify TNF alpha independent mechanisms. METHODS: 12 rheumatoid patients, including four DMARD (disease modifying antirheumatic drug) naive patients with early disease, were studied for the effect of combination therapy with infliximab and methotrexate on the synovial infiltrate. Biopsies and clinical assessments (DAS28) were carried out before the first and after the third infusion of infliximab. Synovial inflammation was scored semiquantitatively. Co-expression of CD38(+) cells was studied by an immunofluorescent double labelling technique. RESULTS: Marked clinical responses were associated with a global reduction in the synovial infiltrate and expression of cytokines, notably interleukin 18 and TNF alpha, but low grade disease activity persisted. There was no effect on the expression of CXC chemokine ligand (CXCL12), and germinal centre-like structures were still detectable in synovial tissue in two patients after treatment. CD38(+) activated T cells were more resistant to treatment than CD38(+) plasma cells. No differences in clinical response or effects on synovial infiltrate were observed between DMARD refractory and DMARD naive patients. CONCLUSIONS: Persistent expression of CXCL12 and incomplete resolution of lymphocytic infiltrates after infliximab plus methotrexate indicates that TNF alpha independent mechanisms are operative in rheumatoid arthritis. This may contribute to low grade disease activity, even in DMARD naive patients with early disease.

Trouw LA, Haisma EM, Levarht EW, van der Woude D, Ioan-Facsinay A, Daha MR, Huizinga TW, Toes RE. · Leiden University Medical Center, Leiden, The Netherlands. · Arthritis Rheum. · Pubmed #19565507 No free full text.

Abstract: OBJECTIVE: It has been suggested that anti-citrullinated protein antibodies (ACPAs) play an important role in the pathogenesis of rheumatoid arthritis (RA). To exert their pathologic effects, ACPAs must recruit immune effector mechanisms such as activation of the complement system. Mouse models of RA have shown that, surprisingly, arthritogenic antibodies activate the alternative pathway of complement rather than the expected classical pathway. This study was undertaken to investigate whether human anti-cyclic citrullinated peptide (anti-CCP) antibodies activate the complement system in vitro and, if so, which pathways of complement activation are used. METHODS: We set up novel assays to analyze complement activation by anti-CCP antibodies, using cyclic citrullinated peptide-coated plates, specific buffers, and normal and complement-deficient sera as a source of complement. RESULTS: Anti-CCP antibodies activated complement in a dose-dependent manner via the classical pathway of complement, and, surprisingly, via the alternative pathway of complement. The lectin pathway was not activated by anti-CCP antibodies. Complement activation proceeded in vitro up to the formation of the membrane attack complex, indicating that all activation steps, including the release of C5a, took place. CONCLUSION: Our findings indicate that anti-CCP antibodies activate the complement system in vitro via the classical and alternative pathways but not via the lectin pathway. These findings are relevant for the design of interventions aimed at inhibition of complement-mediated damage in RA.

Daha NA, Kurreeman FA, Marques RB, Stoeken-Rijsbergen G, Verduijn W, Huizinga TW, Toes RE. · Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands. · Arthritis Rheum. · Pubmed #19404967 No free full text.

Abstract: OBJECTIVE: Recent advances have led to novel identification of genetic polymorphisms that are associated with susceptibility to rheumatoid arthritis (RA). Currently, 5 loci (HLA, PTPN22, TRAF1/C5, TNFAIP3, and STAT4) have been consistently reported, whereas others have been observed less systematically. The aim of the present study was to independently replicate 3 recently described RA susceptibility loci, STAT4, IL2/IL21, and CTLA4, in a large Dutch case-control cohort, and to perform a meta-analysis of all published studies to date and investigate the relevance of the findings in clinically well-defined subgroups of RA patients with or without autoantibodies. METHODS: The STAT4, IL2/IL21, and CTLA4 gene polymorphisms (rs7574865, rs6822844, and rs3087243, respectively) were genotyped in 877 RA patients and 866 healthy individuals. A meta-analysis of all published studies of disease association with these polymorphisms was performed using the Mantel-Haenszel fixed-effects method. RESULTS: An association of STAT4, IL2/IL21, and CTLA4 with RA was detected in Dutch patients (odds ratio [OR] 1.19 [P=0.031], OR 0.84 [P=0.051], and OR 0.87 [P=0.041], respectively). Results from the meta-analysis confirmed an association of all 3 polymorphisms with RA in Caucasians (OR 1.24 [P=1.66x10(-11)], OR 0.78 [P=5.6x10(-5)], and OR 0.91 [P=1.8x10(-3)], respectively). The meta-analysis also revealed that STAT4 predisposed to disease development equally in patients with autoantibodies and those without autoantibodies, and that CTLA4 enhanced the development of anti-citrullinated protein antibody (ACPA)-positive RA as compared with ACPA-negative RA. CONCLUSION: Our results replicate and firmly establish the association of STAT4 and CTLA4 with RA and provide highly suggestive evidence for IL2/IL21 loci as a risk factor for RA. Given the strong statistical power of our meta-analysis to confirm a true-positive association, these findings provide considerable support for the involvement of CTLA4 in distinct subsets of RA patients.

van der Woude D, Houwing-Duistermaat JJ, Toes RE, Huizinga TW, Thomson W, Worthington J, van der Helm-van Mil AH, de Vries RR. · Leiden University Medical Center, Leiden, The Netherlands. · Arthritis Rheum. · Pubmed #19333951 No free full text.

Abstract: OBJECTIVE: The majority of genetic risk factors for rheumatoid arthritis (RA) are associated with anti-citrullinated protein antibody (ACPA)-positive RA, while far fewer genetic risk factors have been identified for ACPA-negative RA. This study was undertaken to quantify the contribution of genetic risk factors in general, and of the predisposing HLA-DRB1 shared epitope (SE) alleles in particular, to the ACPA-positive and ACPA-negative subsets of RA, by computing their heritability and assessing the contribution of the HLA SE alleles. METHODS: One hundred forty-eight RA twin pairs, in which at least 1 twin of each pair had RA, were tested for ACPAs and typed for HLA-DRB1 genotypes. Heritability was assessed in a logistic regression model including a bivariate, normally distributed random effect, representing the contribution of unobserved genetic factors to RA susceptibility, with the correlation of the random effects fixed according to twin zygosity. The contribution of the HLA SE alleles to genetic variance was assessed using a similar model, except that estimates were based on genotype-specific population prevalences. RESULTS: The heritability of RA among the twin pairs was 66% (95% confidence interval [95% CI] 44-75%). For ACPA-positive RA, the heritability was 68% (95% CI 55-79%), and for ACPA-negative RA it was 66% (95% CI 21-82%). Presence of the HLA SE alleles explained 18% (95% CI 16-19%) of the genetic variance of ACPA-positive RA but only 2.4% (95% CI 1.6-10%) of the genetic variance of ACPA-negative RA. CONCLUSION: The heritability of ACPA-positive RA is comparable with that of ACPA-negative RA. These data indicate that genetic predisposition plays an important role in the pathogenesis of ACPA-negative RA, for which most individual genetic risk factors remain to be identified.

van Bergen J, Kooy-Winkelaar EM, van Dongen H, van Gaalen FA, Thompson A, Huizinga TW, Feltkamp MC, Toes RE, Koning F. · Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, the Netherlands. · J Immunol. · Pubmed #19299715 No free full text.

Abstract: Although very few CD4(+) T cells express killer Ig receptors (KIR), a large proportion of CD4(+) T cells with a late memory phenotype, characterized by the absence of CD28, does express KIR. Here, we show that KIR expression on CD4(+) T cells is also associated with memory T cell function, by showing that the frequency of CMV-specific cells is higher in CD4(+)KIR(+) than CD4(+)KIR(-) T cells. In addition, engagement of an inhibitory KIR inhibited the CMV-specific proliferation of these CD4(+)KIR(+) memory T cells, but had no detectable effect on cytokine production. Our data reveal that, in marked contrast with CD8(+) T cells, the activity of a subset of CMV-specific CD4(+) T cells is modulated by HLA class I-specific KIR. Thus, the CMV-induced down-regulation of HLA class I may in fact enhance memory CMV-specific CD4(+) T cell responses restricted by HLA class II.

Albers HM, Kurreeman FA, Stoeken-Rijsbergen G, Brinkman DM, Kamphuis SS, van Rossum MA, Girschick HJ, Wouters C, Saurenmann RK, Hoppenreijs E, Slagboom P, Houwing-Duistermaat JJ, Verduijn W, Huizinga TW, Ten Cate R, Toes RE, Schilham MW. · Leiden University Medical Center, Leiden, The Netherlands. · Arthritis Rheum. · Pubmed #19248117 No free full text.

Abstract: OBJECTIVE: Juvenile idiopathic arthritis (JIA) is characterized by chronic arthritis and an autoimmune etiology. In several autoimmune diseases, including rheumatoid arthritis (RA), an association with the 4q27 locus has been reported. We undertook this study to investigate the possible role of the 4q27 locus in JIA. METHODS: A case-control association study was conducted, with a total of 655 Caucasian JIA patients and 791 healthy controls divided into 2 independent sample sets. The rs6822844 marker in the 4q27 locus was genotyped. RESULTS: In the first and larger sample set, a 5% decrease in T allele frequency was observed in patients compared with controls (allelic odds ratio [OR] 0.72 [95% confidence interval 0.55-0.95], P = 0.019), and in the second set, a 3% decrease was observed (allelic OR 0.81 [95% confidence interval 0.61-1.09], P = 0.169). The combined data set generated an OR of 0.76 (95% confidence interval 0.62-0.93, P = 7.08 x 10(-3)). When the different JIA subtypes were analyzed individually, significant decreases were seen in the subtypes with a polyarticular course of disease (extended oligoarthritis [P = 0.019] and rheumatoid factor-negative polyarthritis [P = 0.038]). CONCLUSION: Our findings suggest that the 4q27 locus, previously reported to be associated with RA, type 1 diabetes mellitus, celiac disease, and psoriatic arthritis, is also associated with susceptibility to JIA.

Toes RE, Huizinga TW. · Department of Rheumatology, Leiden UniversityMedical Center, Leiden, The Netherlands. · PLoS Med. · Pubmed #19143469 links to  free full text

This publication has no abstract.

Ioan-Facsinay A, Willemze A, Robinson DB, Peschken CA, Markland J, van der Woude D, Elias B, Ménard HA, Newkirk M, Fritzler MJ, Toes RE, Huizinga TW, El-Gabalawy HS. · Leiden University Medical Center, Leiden, The Netherlands. · Arthritis Rheum. · Pubmed #18821680 No free full text.

Abstract: OBJECTIVE: Anti-citrullinated protein antibodies (ACPAs) display high association with rheumatoid arthritis (RA) and are implicated in its pathogenesis. The presence of ACPAs is known to precede the onset of RA. In order to identify the features that could confer its pathogenicity, we extensively characterized this antibody response in a unique North American native population of patients with RA and their unaffected relatives. METHODS: The levels of IgA, IgM, and IgG ACPAs, as well as IgM and IgA rheumatoid factor (RF), were measured in serum samples obtained from 81 patients with RA and 195 of their unaffected relatives. The isotype distribution, the fine specificity of the ACPA response, and its association with RF were compared in health and disease. RESULTS: ACPA positivity was observed in 19% of the healthy relatives and approximately 91% of the patients with RA. ACPA isotype usage was strikingly lower in unaffected relatives than in patients with RA (1-2 versus 5-6 isotypes). Fine specificity studies showed that reactivity to citrullinated fibrinogen and vimentin was present in sera from patients with RA, while it was virtually absent in their unaffected relatives. Finally, the ACPA and RF responses were associated in patients with RA but were discordant in their healthy relatives. Extended analyses revealed that the presence of ACPAs was associated with RA irrespective of RF status, while the association of RF with disease relied on its interaction with ACPAs. CONCLUSION: The fine specificity and isotype usage of the ACPA response are qualitatively different in health and disease. Epitope spreading and expansion of the isotype repertoire might be necessary for development of RA, and this could be facilitated by the presence of RF antibodies.

Raychaudhuri S, Remmers EF, Lee AT, Hackett R, Guiducci C, Burtt NP, Gianniny L, Korman BD, Padyukov L, Kurreeman FA, Chang M, Catanese JJ, Ding B, Wong S, van der Helm-van Mil AH, Neale BM, Coblyn J, Cui J, Tak PP, Wolbink GJ, Crusius JB, van der Horst-Bruinsma IE, Criswell LA, Amos CI, Seldin MF, Kastner DL, Ardlie KG, Alfredsson L, Costenbader KH, Altshuler D, Huizinga TW, Shadick NA, Weinblatt ME, de Vries N, Worthington J, Seielstad M, Toes RE, Karlson EW, Begovich AB, Klareskog L, Gregersen PK, Daly MJ, Plenge RM. · Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA. · Nat Genet. · Pubmed #18794853 No free full text.

Abstract: To identify rheumatoid arthritis risk loci in European populations, we conducted a meta-analysis of two published genome-wide association (GWA) studies totaling 3,393 cases and 12,462 controls. We genotyped 31 top-ranked SNPs not previously associated with rheumatoid arthritis in an independent replication of 3,929 autoantibody-positive rheumatoid arthritis cases and 5,807 matched controls from eight separate collections. We identified a common variant at the CD40 gene locus (rs4810485, P = 0.0032 replication, P = 8.2 x 10(-9) overall, OR = 0.87). Along with other associations near TRAF1 (refs. 2,3) and TNFAIP3 (refs. 4,5), this implies a central role for the CD40 signaling pathway in rheumatoid arthritis pathogenesis. We also identified association at the CCL21 gene locus (rs2812378, P = 0.00097 replication, P = 2.8 x 10(-7) overall), a gene involved in lymphocyte trafficking. Finally, we identified evidence of association at four additional gene loci: MMEL1-TNFRSF14 (rs3890745, P = 0.0035 replication, P = 1.1 x 10(-7) overall), CDK6 (rs42041, P = 0.010 replication, P = 4.0 x 10(-6) overall), PRKCQ (rs4750316, P = 0.0078 replication, P = 4.4 x 10(-6) overall), and KIF5A-PIP4K2C (rs1678542, P = 0.0026 replication, P = 8.8 x 10(-8) overall).

Kurreeman FA, Rocha D, Houwing-Duistermaat J, Vrijmoet S, Teixeira VH, Migliorini P, Balsa A, Westhovens R, Barrera P, Alves H, Vaz C, Fernandes M, Pascual-Salcedo D, Michou L, Bombardieri S, Radstake T, van Riel P, van de Putte L, Lopes-Vaz A, Prum B, Bardin T, Gut I, Cornelis F, Huizinga TW, Petit-Teixeira E, Toes RE, Anonymous00030. · Leiden University Medical Center, Leiden, The Netherlands. · Arthritis Rheum. · Pubmed #18759306 No free full text.

Abstract: OBJECTIVE: We recently showed, using a candidate gene approach in a case-control association study, that a 65-kb block encompassing tumor necrosis factor receptor-associated factor 1 (TRAF1) and C5 is strongly associated with rheumatoid arthritis (RA). Compared with case-control association studies, family-based studies have the added advantage of controlling potential differences in population structure and are not likely to be hampered by variation in population allele frequencies, as is seen for many genetic polymorphisms, including the TRAF1/C5 locus. The aim of this study was to confirm this association in populations of European origin by using a family-based approach. METHODS: A total of 1,356 western European white individuals from 452 "trio" families were genotyped for the rs10818488 polymorphism, using the TaqMan allelic discrimination assay. RESULTS: We observed evidence for association, demonstrating departure from Mendel's law, with an overtransmission of the rs10818488 A allele (A = 55%; P = 0.036). By taking into consideration parental phenotypes, we also observed an increased A allele frequency in affected versus unaffected parents (A = 64%; combined P = 0.015). Individuals carrying the A allele had a 1.2-fold increased risk of developing RA (allelic odds ratio 1.24, 95% confidence interval 1.04-1.50). CONCLUSION: Using a family-based study that is robust against population stratification, we provide evidence for the association of the TRAF1/C5 rs10818488 A allele and RA in populations of European descent, further substantiating our previous findings. Future functional studies should yield insight into the biologic relevance of this locus to the pathways involved in RA.

Chang M, Rowland CM, Garcia VE, Schrodi SJ, Catanese JJ, van der Helm-van Mil AH, Ardlie KG, Amos CI, Criswell LA, Kastner DL, Gregersen PK, Kurreeman FA, Toes RE, Huizinga TW, Seldin MF, Begovich AB. · Celera, Alameda, California, United States of America. · PLoS Genet. · Pubmed #18648537 links to  free full text

Abstract: Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease affecting both joints and extra-articular tissues. Although some genetic risk factors for RA are well-established, most notably HLA-DRB1 and PTPN22, these markers do not fully account for the observed heritability. To identify additional susceptibility loci, we carried out a multi-tiered, case-control association study, genotyping 25,966 putative functional SNPs in 475 white North American RA patients and 475 matched controls. Significant markers were genotyped in two additional, independent, white case-control sample sets (661 cases/1322 controls from North America and 596 cases/705 controls from The Netherlands) identifying a SNP, rs1953126, on chromosome 9q33.2 that was significantly associated with RA (OR(common) = 1.28, trend P(comb) = 1.45E-06). Through a comprehensive fine-scale-mapping SNP-selection procedure, 137 additional SNPs in a 668 kb region from MEGF9 to STOM on 9q33.2 were chosen for follow-up genotyping in a staged-approach. Significant single marker results (P(comb)<0.01) spanned a large 525 kb region from FBXW2 to GSN. However, a variety of analyses identified SNPs in a 70 kb region extending from the third intron of PHF19 across TRAF1 into the TRAF1-C5 intergenic region, but excluding the C5 coding region, as the most interesting (trend P(comb): 1.45E-06 --> 5.41E-09). The observed association patterns for these SNPs had heightened statistical significance and a higher degree of consistency across sample sets. In addition, the allele frequencies for these SNPs displayed reduced variability between control groups when compared to other SNPs. Lastly, in combination with the other two known genetic risk factors, HLA-DRB1 and PTPN22, the variants reported here generate more than a 45-fold RA-risk differential.

Teng YK, Levarht EW, Toes RE, Huizinga TW, van Laar JM. · Department of Rheumatology, Leiden University Medical Center, The Netherlands. · Ann Rheum Dis. · Pubmed #18647852 No free full text.

Abstract: OBJECTIVE: To investigate the clinical effects of rituximab treatment in relation to immunological effects of rituximab on tissue-derived B lineage cells and repopulation of circulating B cells. METHODS: A total of 24 patients with rheumatoid arthritis (RA) were treated with 2x1000 mg rituximab and assessed clinically at 4, 12, 18 and 24 weeks using a 44-joint Disease Activity Score (DAS(44)). Synovial biopsies were analysed with immunohistochemistry at baseline and 12 weeks after treatment. Peripheral blood mononuclear cells were analysed by high sensitivity flow cytometry at all timepoints. RESULTS: In this study, a cohort of patients was dichotomised according to those who achieved a low disease activity score (DAS(44)<2.4: LoA group) and those with persistent disease activity (DAS(44)>2.4: HiA group) at any time after rituximab treatment. At baseline, the low activity (LoA) group had significantly lower DAS(44) scores (median 3.33, range 2.84 to 4.23) than the high activity (HiA) group (median 3.73, range 3.03 to 5.23; p = 0.022) and significantly less histological inflammation in synovium (median 6.7, range 1 to 15 vs 16.6, range 4 to 22; p = 0.036). DAS(44) scores before and after rituximab treatment were associated with synovial infiltration of CD79a+ CD20- B cells, morphologically resembling plasma cells. Following treatment with rituximab, the LoA group had significantly reduced repopulation of circulating pre-switched IgD+ B cells (median 0.044%, range 0.002 to 0.66 vs 0.45%, range 0.07 to 9.47; p = 0.006) and post-switched CD27+ B cells (median 0.17%, range 0.04 to 0.39 vs 0.67, range 0.08 to 2.05; p = 0.005) compared to the HiA group. CONCLUSION: The present study demonstrated that a low disease activity state following rituximab was associated with reduced infiltration of CD79a+ CD20- plasma cells in synovium and reduced B cell repopulation.

Albers HM, Kurreeman FA, Houwing-Duistermaat JJ, Brinkman DM, Kamphuis SS, Girschick HJ, Wouters C, Van Rossum MA, Verduijn W, Toes RE, Huizinga TW, Schilham MW, ten Cate R. · Department of Paediatrics, Leiden University Medical Centre, Leiden, The Netherlands. · Ann Rheum Dis. · Pubmed #18593758 No free full text.

Abstract: OBJECTIVE: Juvenile idiopathic arthritis (JIA) is a chronic disorder in which both genetic and environmental factors are involved. Recently, we identified the TRAF1/C5 region (located on chromosome 9q33-34) as a risk factor for rheumatoid arthritis (RA) (p(combined) = 1.4 x 10(-8)). In the present study the association of the TRAF1/C5 region with the susceptibility to JIA was investigated. METHODS: A case-control association study was performed in 338 Caucasian patients with JIA and 511 healthy individuals. We genotyped the single nucleotide polymorphism rs10818488 as a marker for the TRAF1/C5 region. RESULTS: The A allele was associated with the susceptibility to rheumatoid factor-negative polyarthritis with an 11% increase in allele frequency (OR 1.54, 95% CI 1.09 to 2.18; p = 0.012). This association was stronger when combining subtypes with a polyarticular phenotype (OR 1.46, 95% CI 1.12 to 1.90; p = 0.004). In addition, we observed a trend towards an increase in A allele frequency in patients with extended oligoarthritis versus persistent oligoarthritis (49%, 38% respectively); p = 0.055. CONCLUSIONS: Apart from being a well replicated risk factor for RA, TRAF1/C5 also appears to be a risk factor for the rheumatoid factor-negative polyarthritis subtype of JIA and, more generally, seems to be associated with subtypes of JIA characterised by a polyarticular course.

Chang M, Saiki RK, Cantanese JJ, Lew D, van der Helm-van Mil AH, Toes RE, Huizinga TW, Ardlie KG, Criswell LA, Seldin MF, Amos CI, Kastner DL, Gregersen PK, Schrodi SJ, Begovich AB. · Celera, Alameda, CA, USA. · Arthritis Rheum. · Pubmed #18512797 links to  free full text

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