Rheumatoid Arthritis: van der Helm-van Mil AH

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. · Department of Rheumatology, Leiden University Medical Center, PO Box 9600, 2300RC Leiden, The Netherlands. · Arthritis Res Ther. · Pubmed #18394179 links to  free full text

Abstract: In the past few years considerable advances have been made in the genetics of susceptibility to rheumatoid arthritis (RA). For decades the HLA-DRB1 alleles were the only extensively replicated genetic factor, but more genetic risk factors have now been identified that predispose to RA. Interestingly, several of the observed genetic variants conferred risk to anticitrulline-peptide antibody (ACPA)-positive RA and two variants may be restricted to ACPA-negative RA, pointing to the need for subclassification of RA. The current manuscript reviews recently identified genetic factors predisposing to ACPA-positive RA and ACPA-negative RA. Additionally, although being scarcely explored, genetic variants affecting the severity of disease course are discussed.

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

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van der Helm-van Mil AH, Breedveld FC, Huizinga TW. · Department of Rheumatology, Leiden University Medical Center, The Netherlands. · Arthritis Res Ther. · Pubmed #16879719 links to  free full text

Abstract: With regard to rheumatoid arthritis, remission as currently used in the literature can have two meanings: either a state with persistent absence of clinical and radiological signs of disease activity without being treated for a specific time period, or it may point to a disease state with minimal disease activity during antirheumatic treatment. A risk factor for the first is absence of autoantibodies, with the anti-CCP-antibodies as best predictors, whereas risk factors for achieving a drug-induced state of minimal disease activity are not well defined. These definitions of remission refer to different disease states; therefore, we propose that the term remission is reserved for patients that are not treated with antirheumatic drugs.

van der Helm-van Mil AH, Wesoly JZ, Huizinga TW. · Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands. · Curr Opin Rheumatol. · Pubmed #15838240 No free full text.

Abstract: PURPOSE OF REVIEW: The identification of the genetic variants that mediate the risk for susceptibility and severity of rheumatoid arthritis will allow the development of new drug targets and also increase the ability to predict disease course. Technical and methodologic progress has fueled the advances in this field. RECENT FINDINGS: The second risk factor for rheumatoid arthritis, the PTPN22 polymorphism, has been identified. This genetic variant regulates the threshold of T cell activation. Intriguingly, this variant is a risk factor for diabetes as well. Moreover, it has been shown that multiple genetic variants in one pathway (both in a transcription factor, RUNX-1, as in the transcription factor binding site of RUNX1 in the SLC22A4 gene) can each confer very small risks but by gene-gene interactions can confer a ninefold risk for rheumatoid arthritis. These genetic risk factors have been found to confer risk for multiple autoimmune diseases. Phenotype-genotype interactions were described by the enhanced prevalence of a rheumatoid arthritis-specific autoantibody (anti-cyclic citrullinated peptide antibodies) in rheumatoid arthritis patients that harbor the rheumatoid arthritis-associated human leukocyte antigen class II genes, the shared epitope alleles. An environmental factor, smoking was demonstrated to confer risk for rheumatoid arthritis, especially in patients positive for both shared epitope and rheumatoid arthritis-specific anti-cyclic citrullinated peptide antibodies. SUMMARY: Two new pathways, T cell receptor signaling and a hematopoietic-specific signal transduction pathway, have been discovered that allow future pharmacologic interventions. The description of the new genetic risk factors and the interaction with environmental triggers as well as phenotypic features are gradually expanding the ability to predict disease susceptibility and course.

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.

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).

van der Helm-van Mil AH, Detert J, le Cessie S, Filer A, Bastian H, Burmester GR, Huizinga TW, Raza K. · Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands. <> · Arthritis Rheum. · Pubmed #18668546 links to  free full text

Abstract: OBJECTIVE: The decision to start disease-modifying antirheumatic drugs in patients with recent-onset undifferentiated arthritis (UA) is complicated by a varied natural disease course in which the disease in one-third of patients progresses to rheumatoid arthritis (RA), whereas 40-50% of patients experience spontaneous remission. Recently, a prediction rule was developed to estimate the chance of progression to RA in individual patients presenting with UA. This study investigates the accuracy of this prediction rule in independent cohorts of patients with UA. METHODS: In 3 cohorts of patients with recent-onset UA, from the UK, Germany, and The Netherlands, the prediction score and the corresponding chance of developing RA were calculated. These data were compared with the observed disease outcome after > or =1 year of followup. Positive predictive values (PPVs) and negative predictive values (NPVs) were calculated and the overall discriminative ability of the prediction rule was assessed using area under the receiver operating characteristic curves (AUCs). RESULTS: Since data on the severity of morning stiffness were not available in all validation cohorts, the prediction rule was rederived with the duration of morning stiffness as a substitute. The AUC for this rule was 0.88 (SEM 0.015). For each validation cohort, the AUC was 0.83 (SEM 0.041), 0.82 (SEM 0.037), and 0.95 (SEM 0.031) in the British, German, and Dutch cohorts, respectively. The NPV (for a prediction score < or =6) in these 3 cohorts was 83%, 83%, and 86%, respectively; the PPV (for a prediction score > or =8) was 100%, 93%, and 100%, respectively. CONCLUSION: The recently derived prediction rule, when applied to 3 independent cohorts of patients with UA, has an excellent discriminative ability for assessing the likelihood of progression to RA. Application of this rule will allow individualized treatment decision-making for patients with UA.

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.

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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Feitsma AL, Worthington J, van der Helm-van Mil AH, Plant D, Thomson W, Ursum J, van Schaardenburg D, van der Horst-Bruinsma IE, van Rood JJ, Huizinga TW, Toes RE, de Vries RR. · Departments of Immunohematology and Blood Transfusion and Rheumatology, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands. · Proc Natl Acad Sci U S A. · Pubmed #18077428 links to  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 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.

Verpoort KN, Cheung K, Ioan-Facsinay A, van der Helm-van Mil AH, de Vries-Bouwstra JK, Allaart CF, Drijfhout JW, de Vries RR, Breedveld FC, Huizinga TW, Pruijn GJ, Toes RE. · Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands. · Arthritis Rheum. · Pubmed #18050209 links to  free full text

Abstract: OBJECTIVE: In classic studies on the genetic background of antibody production, the major histocompatibility complex (MHC) has been shown to act as the most prominent immune response gene that controls the magnitude and the specificity of antibody production. The strongest genetic risk factor for rheumatoid arthritis (RA), the human MHC HLA-DRB1 shared epitope (SE) alleles, predisposes for antibodies against citrullinated proteins (ACPAs). ACPA levels are higher in SE-positive patients with RA than in SE-negative patients with RA. The aim of the present study was to determine whether SE influences not only the magnitude but also the specificity of the ACPA response. METHODS: In 2 cohorts of anti-citrullinated peptide 2-positive patients with RA, one from a study of recent-onset arthritis (n = 206) and the other from a treatment strategy study (n = 141), serum antibodies against a citrullinated peptide derived from vimentin (cVim) and antibodies against a citrullinated fibrinogen peptide (cFibr) were determined by enzyme-linked immunosorbent assay. HLA-DRB1 genotyping was performed. RESULTS: In the first cohort, SE alleles were significantly associated with the presence of antibodies against cVim (odds ratio [OR] 4.95, 95% confidence interval [95% CI] 1.87-15.3) and were not significantly associated with the presence of antibodies against cFibr (OR 1.71, 95% CI 0.70-4.14). These results were replicated in the second cohort (OR 5.05, 95% CI 1.92-13.6 and OR 1.19, 95% CI 0.30-3.97, respectively). CONCLUSION: In 2 cohorts of ACPA-positive patients with RA, SE alleles predisposed for the development of antibodies against cVim but not for the development of antibodies against cFibr. These data indicate that SE alleles act as "classic" immune response genes in the ACPA response, because they influence both the magnitude and the specificity of this RA-specific antibody response.

van der Helm-van Mil AH, van der Kooij SM, Allaart CF, Toes RE, Huizinga TW. · Department of Rheumatology, Leiden University Medical Centre, PO Box 9600, 2300RC Leiden, The Netherlands. · Ann Rheum Dis. · Pubmed #17965124 No free full text.

Abstract: BACKGROUND: Obesity is a state of chronic low-grade inflammation that predisposes people to several diseases and that is increasingly prevalent. Rheumatoid arthritis (RA) is marked by the presence of proinflammatory cytokines and, in general, the presence of high levels of inflammatory markers is associated with a severe disease course and joint damage. OBJECTIVES: To evaluate prospectively (a) whether obesity is a risk factor for the development of RA and (b) whether the body mass index (BMI) is associated with the amount of joint destruction in early RA after 3 years' follow-up. METHODS: In a cohort of 570 patients with undifferentiated arthritis, the relation between the BMI and the development of RA during 1 year of follow-up was assessed. In a cohort of 488 patients with early RA the correlation between the BMI and degree of radiological joint destruction (Sharp-van der Heijde score) after 3 years of follow-up was determined. The findings were replicated in an independent cohort of 247 patients with early RA. RESULTS: Obesity did not influence the likelihood of developing RA. In both RA cohorts, the BMI was inversely correlated with the Sharp-van der Heijde score after 3 years' follow-up (r = -0.15, p = 0.025 for the Leiden EAC and r = -0.27, p<0.001 for the replication cohort). Linear regression analyses in both cohorts showed that the BMI was independently and inversely associated with the level of joint destruction in anti-CCP-positive patients with RA, but not in anti-CCP-negative patients. CONCLUSIONS: A high BMI is associated with a less severe disease outcome in anti-CCP-positive patients with RA.

Kurreeman FA, Padyukov L, Marques RB, Schrodi SJ, Seddighzadeh M, Stoeken-Rijsbergen G, van der Helm-van Mil AH, Allaart CF, Verduyn W, Houwing-Duistermaat J, Alfredsson L, Begovich AB, Klareskog L, Huizinga TW, Toes RE. · Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands. · PLoS Med. · Pubmed #17880261 links to  free full text

Abstract: BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disorder affecting approximately 1% of the population. The disease results from the interplay between an individual's genetic background and unknown environmental triggers. Although human leukocyte antigens (HLAs) account for approximately 30% of the heritable risk, the identities of non-HLA genes explaining the remainder of the genetic component are largely unknown. Based on functional data in mice, we hypothesized that the immune-related genes complement component 5 (C5) and/or TNF receptor-associated factor 1 (TRAF1), located on Chromosome 9q33-34, would represent relevant candidate genes for RA. We therefore aimed to investigate whether this locus would play a role in RA. METHODS AND FINDINGS: We performed a multitiered case-control study using 40 single-nucleotide polymorphisms (SNPs) from the TRAF1 and C5 (TRAF1/C5) region in a set of 290 RA patients and 254 unaffected participants (controls) of Dutch origin. Stepwise replication of significant SNPs was performed in three independent sample sets from the Netherlands (ncases/controls = 454/270), Sweden (ncases/controls = 1,500/1,000) and US (ncases/controls = 475/475). We observed a significant association (p < 0.05) of SNPs located in a haplotype block that encompasses a 65 kb region including the 3' end of C5 as well as TRAF1. A sliding window analysis revealed an association peak at an intergenic region located approximately 10 kb from both C5 and TRAF1. This peak, defined by SNP14/rs10818488, was confirmed in a total of 2,719 RA patients and 1,999 controls (odds ratiocommon = 1.28, 95% confidence interval 1.17-1.39, pcombined = 1.40 x 10(-8)) with a population-attributable risk of 6.1%. The A (minor susceptibility) allele of this SNP also significantly correlates with increased disease progression as determined by radiographic damage over time in RA patients (p = 0.008). CONCLUSIONS: Using a candidate-gene approach we have identified a novel genetic risk factor for RA. Our findings indicate that a polymorphism in the TRAF1/C5 region increases the susceptibility to and severity of RA, possibly by influencing the structure, function, and/or expression levels of TRAF1 and/or C5.

Verpoort KN, Papendrecht-van der Voort EA, van der Helm-van Mil AH, Jol-van der Zijde CM, van Tol MJ, Drijfhout JW, Breedveld FC, de Vries RR, Huizinga TW, Toes RE. · Leiden University Medical Center, Leiden, The Netherlands. · Arthritis Rheum. · Pubmed #17763436 links to  free full text

Abstract: OBJECTIVE: Smoking is a risk factor for anti-cyclic citrullinated peptide (anti-CCP) antibody-positive rheumatoid arthritis (RA) in patients with HLA-DRB1 shared epitope (SE) alleles. It is unknown whether smoking influences not only the presence of these antibodies, but also other characteristics of the anti-CCP response, such as isotype usage. The aim of this study was to determine the influence of smoking on anti-CCP isotypes in RA patients, and to determine whether this influence is observed in the presence and/or absence of SE alleles. METHODS: IgA, IgM, and IgG subclasses of anti-CCP antibodies were measured by enzyme-linked immunosorbent assay in serum obtained at the first visit to the Leiden Early Arthritis Clinic from 216 patients with anti-CCP-positive RA whose smoking habits were also assessed. HLA genotyping data were available for 202 of these patients. RESULTS: IgA and IgM anti-CCP were more frequent in RA patients who were smokers than in those who were nonsmokers (odds ratio 2.8 and 1.8, respectively). In addition, levels of all isotypes of anti-CCP, except IgG3, were significantly higher (P < 0.05) in smokers. The number of anti-CCP isotypes was higher in smokers compared with nonsmokers, both in SE-negative RA (P = 0.04) and in SE-positive RA (P = 0.07). CONCLUSION: Patients with anti-CCP-positive RA who have a current or former tobacco exposure display a more extensive anti-CCP isotype usage in general, and IgA and IgM in particular, compared with patients with anti-CCP-positive RA who have never smoked. In contrast to its influence on the incidence of anti-CCP positivity, the influence of tobacco exposure on the constitution of the anti-CCP response is significant in SE-negative RA. These findings suggest a differential effect of tobacco exposure on the induction as compared with the propagation of the anti-CCP antibody response.

Kallberg H, Padyukov L, Plenge RM, Ronnelid J, Gregersen PK, van der Helm-van Mil AH, Toes RE, Huizinga TW, Klareskog L, Alfredsson L, Anonymous00205. · Institute for Environmental Medicine, Karolinska Institutet, Stockholm, Sweden. · Am J Hum Genet. · Pubmed #17436241 links to  free full text

Abstract: Gene-gene and gene-environment interactions are key features in the development of rheumatoid arthritis (RA) and other complex diseases. The aim of this study was to use and compare three different definitions of interaction between the two major genetic risk factors of RA--the HLA-DRB1 shared epitope (SE) alleles and the PTPN22 R620W allele--in three large case-control studies: the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA) study, the North American RA Consortium (NARAC) study, and the Dutch Leiden Early Arthritis Clinic study (in total, 1,977 cases and 2,405 controls). The EIRA study was also used to analyze interactions between smoking and the two genes. "Interaction" was defined either as a departure from additivity, as interaction in a multiplicative model, or in terms of linkage disequilibrium--for example, deviation from independence of penetrance of two unlinked loci. Consistent interaction, defined as departure from additivity, between HLA-DRB1 SE alleles and the A allele of PTPN22 R620W was seen in all three studies regarding anti-CCP-positive RA. Testing for multiplicative interactions demonstrated an interaction between the two genes only when the three studies were pooled. The linkage disequilibrium approach indicated a gene-gene interaction in EIRA and NARAC, as well as in the pooled analysis. No interaction was seen between smoking and PTPN22 R620W. A new pattern of interactions is described between the two major known genetic risk factors and the major environmental risk factor concerning the risk of developing anti-CCP-positive RA. The data extend the basis for a pathogenetic hypothesis for RA involving genetic and environmental factors. The study also raises and illustrates principal questions concerning ways to define interactions in complex diseases.

Feitsma AL, Toes RE, Begovich AB, Chokkalingam AP, de Vries RR, Huizinga TW, van der Helm-van Mil AH. · Departments of Rheumatology, University Medical Center, Leiden, The Netherlands. · Rheumatology (Oxford). · Pubmed #17341507 links to  free full text

Abstract: OBJECTIVES: Anti-citrullinated peptide antibodies (ACPA) and the C1858T missense single-nucleotide polymorphism (SNP) in the PTPN22 gene are both associated with the development of rheumatoid arthritis (RA). We investigated whether the combination of these two biomarkers yielded better test characteristics to predict progression from undifferentiated arthritis (UA) to RA compared with ACPA alone. METHODS: A total of 394 individuals with UA from a Dutch population-based inception cohort were included in this study. At baseline, ACPA were measured and the PTPN22 C1858T and HLA-DRB1 genotypes determined. Progression to RA was monitored at 1 yr after entry into the cohort. RESULTS: A priori, UA patients had a 35% (95% CI 30-40%) risk of developing RA, which increased to 66% (95% CI 57-75%) in patients who were ACPA-positive. There was an additional, although non-significant (P = 0.34), increase in RA risk to 76% (95% CI 57-90%) when patients were positive for both ACPA and the PTPN22 1858T-allele. The area under the receiver operator characteristic curve increased from 0.68 for ACPA-status alone to 0.70 for the combination of ACPA-status and the PTPN22 C1858T polymorphism. In logistic regression analysis, ACPA predicted RA-development independent of PTPN22, while the PTPN22 polymorphism had no independent effect. In HLA-DRB1 shared epitope positive, ACPA-positive UA patients, ACPA-levels were significantly increased in PTPN22 1858T allele carriers compared with non-1858T carriers. CONCLUSIONS: In this Dutch cohort of UA-patients, the PTPN22 1858T allele does not markedly improve individual decision-making to predict RA-development over ACPA alone, but it is associated with higher ACPA-levels.

van der Helm-van Mil AH, le Cessie S, van Dongen H, Breedveld FC, Toes RE, Huizinga TW. · Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands. · Arthritis Rheum. · Pubmed #17265478 links to  free full text

Abstract: OBJECTIVE: In patients with undifferentiated arthritis (UA), methotrexate is effective for inhibiting symptoms, structural damage, and progression to rheumatoid arthritis (RA). However, 40-50% of patients with UA experience spontaneous remission. Thus, adequate decision-making regarding treatment of patients with early UA requires identification of those patients in whom RA will develop. METHODS: A prediction rule was developed using data from the Leiden Early Arthritis Clinic, an inception cohort of patients with recent-onset arthritis (n = 1,700). The patients who presented with UA were selected (n = 570), and progression to RA or another diagnosis in this group was monitored for 1 year of followup. The clinical characteristics with independent predictive value for the development of RA were selected using logistic regression analysis. The diagnostic performance of the prediction rule was evaluated using the area under the curve (AUC). Cross-validation controlled for overfitting of the data (internal validation). An independent cohort of patients with UA was used for external validation. RESULTS: The prediction rule consisted of 9 clinical variables: sex, age, localization of symptoms, morning stiffness, the tender joint count, the swollen joint count, the C-reactive protein level, rheumatoid factor positivity, and the presence of anti-cyclic citrullinated peptide antibodies. Each prediction score varied from 0 to 14 and corresponded to the percent chance of RA developing. For several cutoff values, the positive and negative predictive values were determined. The AUC values for the prediction rule, the prediction model after cross-validation, and the external validation cohort were 0.89, 0.87, and 0.97, respectively. CONCLUSION: In patients who present with UA, the risk of developing RA can be predicted, thereby allowing individualized decisions regarding the initiation of treatment with disease-modifying antirheumatic drugs in such patients.

van der Helm-van Mil AH, Verpoort KN, le Cessie S, Huizinga TW, de Vries RR, Toes RE. · Leiden University Medical Center, Leiden, The Netherlands. · Arthritis Rheum. · Pubmed #17265477 links to  free full text

Abstract: OBJECTIVE: The HLA shared epitope (SE) alleles are primarily a risk factor for the presence of antibodies to cyclic citrullinated peptide (anti-CCP antibodies) rather than for the development of rheumatoid arthritis (RA). The SE alleles interact with the environmental risk factor tobacco exposure (TE) for predisposition to anti-CCP+ RA. The objectives of this study were to determine 1) whether different SE subtypes contribute differently to the presence of anti-CCP antibodies, 2) whether different SE subtypes all interact with TE for the development of anti-CCP antibodies, and 3) the effect of TE in relation to the SE alleles and anti-CCP antibodies on the risk of progression from undifferentiated arthritis (UA) to RA. METHODS: We assessed the effect of SE subtypes and TE on the presence and level of anti-CCP antibodies and on the risk of progression from UA to RA in 977 patients with early arthritis who were included in the Leiden Early Arthritis Clinic. RESULTS: The HLA-DRB1*0401, *0404, *0405, or *0408 SE alleles conferred the highest risk of developing anti-CCP antibodies (odds ratio [OR] 5.0, compared with an OR of 2.0 for the HLA-DRB1*0101 or *0102 SE alleles and an OR of 1.7 for the HLA-DRB1*1001 SE allele). Conversely, the TE-SE allele interaction was the strongest for the HLA-DRB1*0101 or *0102 SE alleles and the HLA-DRB1*1001 SE allele. TE in SE+, anti-CCP+ patients correlated with higher levels of anti-CCP antibodies and with progression from UA to RA. In logistic regression analysis, only the presence and level of anti-CCP antibodies were associated independently with RA development. CONCLUSION: The HLA-DRB1 SE subtypes differ in their interaction with smoking and in their predisposition to anti-CCP antibodies. TE contributes to the development of RA in SE+, anti-CCP+ patients, which is explained by its effect on the level of anti-CCP antibodies.

Linn-Rasker SP, van der Helm-van Mil AH, Breedveld FC, Huizinga TW. · Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands. · Ann Rheum Dis. · Pubmed #17142384 No free full text.

Abstract: OBJECTIVE: To investigate the predictive value of the distribution of inflamed joints at first presentation for the severity of the disease course in rheumatoid arthritis (RA). METHODS: Of the 1009 consecutive patients included in the Leiden Early Arthritis Clinic (Leiden, The Netherlands), 285 patients fulfilled the American College of Rheumatology criteria for RA within 1 year of follow-up. Of these, 28 patients achieved remission. Radiographs of hands and feet were scored according to the Sharp-van der Heijde method, and the 28 patients with the most destructive disease were selected. The distribution of inflamed joints of the patients with the extreme disease courses was compared. The association between the distribution of inflamed joints and the level of destruction of the joints of hands and feet in the whole group of patients with RA was assessed using regression analysis. RESULTS: Comparison of patients with extreme disease courses using univariate and logistic regression analyses showed that arthritis of the large joints - in particular, the knee - was associated with severe RA. In the whole group of patients with RA, the total number of swollen joints and the presence of knee arthritis were associated independently with the level of destruction of the small joints. Patients with RA with knee arthritis had higher C reactive protein (CRP) levels than patients without knee arthritis, and investigating the distribution of inflamed joints together with other variables yielded the number of swollen joints, CRP, presence of anti-cyclic citrullinated peptide antibodies and symptom duration as predictors for severity of RA. CONCLUSION: Arthritis of large joints - in particular, the knee - at first presentation is associated with a destructive course of RA.

van der Helm-van Mil AH, Kern M, Gregersen PK, Huizinga TW. · Leiden University Medical Center, Leiden, The Netherlands. · Arthritis Rheum. · Pubmed #16732568 links to  free full text

This publication has no abstract.

van der Helm-van Mil AH, Verpoort KN, Breedveld FC, Huizinga TW, Toes RE, de Vries RR. · Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands. · Arthritis Rheum. · Pubmed #16572446 links to  free full text

Abstract: OBJECTIVE: The shared epitope (SE)-containing HLA-DRB1 alleles represent the most significant genetic risk factor for rheumatoid arthritis (RA). Recent studies indicate that the SE alleles are associated with only RA that is characterized by the presence of anti-cyclic citrullinated peptide (anti-CCP) antibodies, and not with anti-CCP-negative disease. In this study we investigated whether the SE alleles contribute to the development of anti-CCP-positive RA, or whether they are associated solely with the presence of anti-CCP antibodies. We therefore determined the influence of the SE alleles and anti-CCP antibodies on the progression from recent-onset undifferentiated arthritis (UA) to RA. METHODS: Patients with recent-onset UA at the 2-week visit (n=570) were selected from the Leiden Early Arthritis Cohort. SE alleles, rheumatoid factor (RF) status, and anti-CCP antibody levels were determined. Progression to RA or other diagnoses was monitored. RESULTS: One hundred seventy-seven patients with UA developed RA during the 1-year followup, whereas the disease in 393 patients remained unclassified or was given other diagnoses. The SE alleles correlated with the presence of anti-CCP antibodies, but not with the presence of RF. Both in SE-positive and in SE-negative patients with UA, the presence of anti-CCP antibodies was significantly associated with the development of RA. More intriguingly, however, no apparent contribution of the SE alleles to the progression to RA was found when analyses were stratified according to the presence of anti-CCP antibodies. In patients with anti-CCP-positive disease, the presence of SE alleles was associated with significantly higher levels of anti-CCP antibodies, suggesting that the SE alleles act as classic immune response genes. CONCLUSION: The SE alleles do not independently contribute to the progression to RA from UA, but rather contribute to the development of anti-CCP antibodies.

Huizinga TW, Amos CI, van der Helm-van Mil AH, Chen W, van Gaalen FA, Jawaheer D, Schreuder GM, Wener M, Breedveld FC, Ahmad N, Lum RF, de Vries RR, Gregersen PK, Toes RE, Criswell LA. · Department of Rheumatology-C4R, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands. · Arthritis Rheum. · Pubmed #16255021 links to  free full text

Abstract: OBJECTIVE: The main genetic risk factor for rheumatoid arthritis (RA), the HLA region, has been known for 25 years. Previous research has demonstrated, within the RA population, an association between HLA-DRB1 alleles carrying the shared epitope (SE) and antibodies directed against cyclic citrullinated peptides (anti-CCP antibodies). We undertook this study to make the first comparison of SE allele frequencies in the healthy population with those in RA patients who do or do not harbor anti-CCP antibodies. METHODS: HLA-DRB1 typing was performed in 408 RA patients from the Leiden Early Arthritis Clinic (the Leiden EAC; a Dutch population-based inception cohort in which disease course was followed up over time), in 423 healthy Dutch controls, and in 720 affected members of 341 US multiplex (sibpair) families of Caucasian origin from the North American RA Consortium (NARAC) with well-established disease and fulfilling the American College of Rheumatology classification criteria for RA. The presence of anti-CCP antibodies was determined by enzyme-linked immunosorbent assay. RESULTS: For the Leiden EAC, the odds ratio (OR) describing the association of 2 copies of the SE allele with anti-CCP positivity (using no copies of the SE allele in the healthy control group as the referent) was 11.79 (P < 0.0001), while the OR for 1 SE allele was 4.37 (P < 0.0001). No association with the SE was observed in the Dutch anti-CCP-negative RA patients. For the NARAC families, linkage and association analysis revealed the SE to be associated only with anti-CCP-positive disease and not with anti-CCP-negative disease. Stratified analyses indicated that anti-CCP antibodies primarily mediated association of the SE with joint damage or disease persistence. CONCLUSION: HLA-DRB1 alleles encoding the SE are specific for disease characterized by antibodies to citrullinated peptides, indicating that these alleles do not associate with RA as such, but rather with a particular phenotype.

van der Helm-van Mil AH, Verpoort KN, Breedveld FC, Toes RE, Huizinga TW. · Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands. · Arthritis Res Ther. · Pubmed #16207336 links to  free full text

Abstract: Antibodies to citrullinated proteins (anti-cyclic-citrullinated peptide [anti-CCP] antibodies) are highly specific for rheumatoid arthritis (RA) and precede the onset of disease symptoms, indicating a pathogenetic role for these antibodies in RA. We recently showed that distinct genetic risk factors are associated with either anti-CCP-positive disease or anti-CCP-negative disease. These data are important as they indicate that distinct pathogenic mechanisms are underlying anti-CCP-positive disease or anti-CCP-negative disease. Likewise, these observations raise the question of whether anti-CCP-positive RA and anti-CCP-negative RA are clinically different disease entities. We therefore investigated whether RA patients with anti-CCP antibodies have a different clinical presentation and disease course compared with patients without these autoantibodies. In a cohort of 454 incident patients with RA, 228 patients were anti-CCP-positive and 226 patients were anti-CCP-negative. The early symptoms, tender and swollen joint count, and C-reactive protein level at inclusion, as well as the swollen joint count and radiological destruction during 4 years of follow-up, were compared for the two groups. There were no differences in morning stiffness, type, location and distribution of early symptoms, patients' rated disease activity and C-reactive protein at inclusion between RA patients with and without anti-CCP antibodies. The mean tender and swollen joint count for the different joints at inclusion was similar. At follow-up, patients with anti-CCP antibodies had more swollen joints and more severe radiological destruction. Nevertheless, the distribution of affected joints, for swelling, bone erosions and joint space narrowing, was similar. In conclusion, the phenotype of RA patients with or without anti-CCP antibodies is similar with respect to clinical presentation but differs with respect to disease course.

Verpoort KN, van Gaalen FA, van der Helm-van Mil AH, Schreuder GM, Breedveld FC, Huizinga TW, de Vries RR, Toes RE. · Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands. · Arthritis Rheum. · Pubmed #16200610 links to  free full text

Abstract: OBJECTIVE: Recent data have shown that the most prominent and longest known genetic risk factors for rheumatoid arthritis (RA), HLA-DRB1 shared epitope alleles, are only associated with RA that is characterized by the presence of antibodies against cyclic citrullinated peptide (anti-CCP antibodies) and not with anti-CCP-negative RA. We undertook this study to investigate whether anti-CCP-negative RA is associated with other HLA-DRB1 alleles. METHODS: HLA typing was performed for 377 patients from the Leiden Early Arthritis Clinic who were diagnosed as having RA within the first year of followup (206 anti-CCP-positive patients and 171 anti-CCP-negative patients), 235 patients who, after 1 year, had undifferentiated arthritis (UA) (28 anti-CCP-positive patients and 207 anti-CCP-negative patients), and 423 healthy control subjects. Odds ratios (ORs) with 95% confidence intervals (95% CIs) for HLA-DRB1 allele frequencies were determined for all patient groups compared with the healthy control group. RESULTS: HLA-DR3 was more frequently present in the anti-CCP-negative RA group than in the control group (OR 1.84, 95% CI 1.26-2.67). This was not the case for anti-CCP-positive RA (OR 0.92, 95% CI 0.60-1.40). HLA-DR3 was also more frequently present in anti-CCP-negative UA patients (OR 1.59, 95% CI 1.10-2.28), but not in anti-CCP-positive UA patients (OR 0.68, 95% CI 0.17-1.92). CONCLUSION: HLA-DR3 is associated with anti-CCP-negative arthritis and not with anti-CCP-positive arthritis. These data show that distinct genetic risk factors are associated with the presence of anti-CCP antibodies in RA and indicate that different pathogenetic mechanisms underlie anti-CCP-positive and anti-CCP-negative RA.