Lars Klareskog

Karolinska Institutet, Solna, Stockholm, Sweden

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Publications (233)2035.55 Total impact

  • Annals of the rheumatic diseases. 09/2014;
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    ABSTRACT: IntroductionGenetic susceptibility to complex diseases has been intensively studied during the last decade, yet only signals with small effect have been found leaving open the possibility that subgroups within complex traits show stronger association signals. In rheumatoid arthritis (RA), autoantibody production serves as a helpful discriminator in genetic studies and today anti-citrullinated cyclic peptide (anti-CCP) antibody positivity is employed for diagnosis of disease. The HLA-DRB1 locus is known as the most important genetic contributor for the risk of RA, but is not sufficient to drive autoimmunity and additional genetic and environmental factors are involved. Hence, we addressed the association of previously discovered RA loci with disease-specific autoantibody responses in RA patients stratified by HLA-DRB1*04.Methods We investigated 2178 patients from three RA cohorts from Sweden and Spain for 41 genetic variants and four autoantibodies, including the generic anti-CCP as well as specific responses towards citrullinated peptides from vimentin, alpha-enolase and type II collagen.ResultsOur data demonstrated different genetic associations of autoantibody-positive disease subgroups in relation to the presence of DRB1*04. Two specific subgroups of autoantibody-positive RA were identified. The SNP in PTPN22 was associated with presence of anti-citrullinated enolase peptide antibodies in carriers of HLA-DRB1*04 (Cochran-Mantel-Haenszel test P¿=¿0.0001, P corrected <0.05), whereas SNPs in CDK6 and PADI4 were associated with anti-CCP status in DRB1*04 negative patients (Cochran-Mantel-Haenszel test P¿=¿0.0004, P corrected <0.05 for both markers). Additionally we see allelic correlation with autoantibody titers for PTPN22 SNP rs2476601 and anti-citrullinated enolase peptide antibodies in carriers of HLA-DRB1*04 (Mann Whitney test P¿=¿0.02) and between CDK6 SNP rs42041 and anti-CCP in non-carriers of HLA-DRB1*04 (Mann Whitney test P¿=¿0.02).Conclusion These data point to alternative pathways for disease development in clinically similar RA subgroups and suggest an approach for study of genetic complexity of disease with strong contribution of HLA.
    Arthritis research & therapy. 08/2014; 16(5):414.
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    ABSTRACT: Rheumatoid arthritis (RA) is a prototype for a criterion-defined inflammatory disease, for which the aetiology and initial molecular pathogenesis has been elusive for a long time. We describe in this Review how studies on the interplay between specific immunity, alongside genetic and environmental predisposing factors, provide new tools to understand the molecular basis of distinct subsets of the disease. A particular emphasis is on the possibility that pathogenic immune reactions might be initiated at other sites than the joints, and that the lungs could harbour such sites. New data strengthen this concept, showing that local immunity towards citrullinated proteins and accompanying inflammation might be present in the lungs early during disease development. This progress makes RA an interesting case for the future development of therapies that might be directed against disease-inducing immunity even before inflammation and destruction of joints has begun.
    Nature Reviews Rheumatology 07/2014; · 9.75 Impact Factor
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    ABSTRACT: Introduction A major subset of patients with rheumatoid arthritis (RA) is characterised by the presence of circulating autoantibodies directed to citrullinated proteins/peptides (ACPA). These autoantibodies, which are commonly detected using an ELISA assay based on synthetic cyclic citrullinated peptides (CCP), predict clinical onset and a destructive disease course. In the present study, we have utilised plasma and synovial fluids from patients with RA, for the affinity purification and characterisation of anti-CCP2 reactive antibodies, with an aim to generate molecular tools that can be utilized in vitro and in vivo for future investigations into the pathobiology of the ACPA response. Specifically, this study aims to demonstrate that the surrogate marker CCP2 can capture ACPA that bind to autoantigens expressed in vivo, in the major inflammatory lesions of RA, i.e. in the rheumatoid joint. Methods Plasma (n = 16) and synovial fluid (n = 26) samples were collected from RA patients with anti-CCP2 IgG levels above 300 AU/ml. Total IgG was isolated on Protein G columns, and subsequently applied to CCP2 affinity columns. Purified anti-CCP2 IgG was analysed for reactivity and specificity using the CCPlus® ELISA assay, in-house peptide-ELISAs, western blot and immunohisto-/immunocytochemistry. Results Approximately 2 % of the total IgG pool in both plasma and synovial fluid was CCP2-reactive. Purified anti-CCP2 reactive antibodies from different patients showed differences in binding to CCP2 and differences in binding to citrullinated peptides from α-enolase, −vimentin, −fibrinogen, and -collagen type II, illustrating different ACPA fine-specificity profiles. Furthermore, the purified ACPA bound not only in vitro citrullinated proteins but more importantly, in vivo-generated epitopes on synovial fluid cells and synovial tissues from RA patients. Conclusions We have isolated ACPA from plasma and synovial fluid, and demonstrated that the CCP2 peptides, frequently used in diagnostic ELISA assays, de facto act as surrogate antigens for at least four different, well-characterised, largely non cross-reactive, ACPA fine-specificities. Moreover, we have determined the concentration and proportion of CCP2-reactive IgG molecules in rheumatoid plasma and synovial fluid, and we have shown that the purified ACPA can be used to detect both in vitro- and in vivo-generated citrullinated epitopes by various techniques. We anticipate that these antibodies will provide us with new opportunities to investigate the potential pathogenic effects of human ACPAs.
    Arthritis research & therapy 07/2014; · 4.27 Impact Factor
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    ABSTRACT: Objective To investigate the association between life events and the risk for rheumatoid arthritis (RA) with and without antibodies to citrullinated protein (ACPAs).Methods We used data from a population-based case–control study of individuals ages 18–70 years living in geographically defined parts of Sweden between May 1996 and November 2009. We included incident cases (n = 2,774) diagnosed by rheumatologists according to the American College of Rheumatology 1987 criteria for RA and randomly selected controls (n = 3,911) matched to the cases by age, sex, and area of residence. All of the participants answered a questionnaire consisting of questions about 15 life events. We calculated odds ratios (ORs) and 95% confidence intervals (95% CIs) from unconditional logistic regression models adjusted for matching variables and confounding factors.ResultsHaving experienced a life event was weakly associated with ACPA-positive RA as well as ACPA-negative RA (OR 1.1, 95% CI 1.0–1.2 and OR 1.2, 95% CI 1.0–1.4, respectively). The association with ACPA-negative RA was stronger with an increasing number of events (OR 1.4, 95% CI 1.1–1.7 for having experienced ≥3 events versus none). Several particular life events were associated with RA (e.g., “conflict at work,” “change of residence,” “change of work place,” and “increased responsibility at work”). The results were more consistent in women than in men.Conclusion Our study lends support to the concept that certain stressful conditions, here measured as life events, are associated with an increased risk of developing RA.
    Arthritis Care & Research. 06/2014; 66(6).
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    ABSTRACT: To investigate whether overweight/obesity at diagnosis affects the chances of decrease in disease activity and pain in early rheumatoid arthritis (RA). We investigated incident RA cases from the population-based Epidemiological Investigation of risk factors for Rheumatoid Arthritis (EIRA) study (2006-2009, N=495) with clinical follow-up in the Swedish Rheumatology Quality Register. At diagnosis, 93% received disease-modifying antirheumatic drugs (DMARDs) (86% methotrexate). The odds of achieving a good response according to the DAS28-based European League Against Rheumatism (EULAR) criteria, low disease activity (DAS28<3.2), remission (DAS28<2.6) or pain remission (visual analogue scale ≤20 mm) at 3-months and 6-months follow-up, were calculated using logistic regression, adjusting for potential confounders. Significant dose-response relationships were found between Body Mass Index (BMI) and change of disease activity as well as pain at both time points. Patients with BMI ≥25 had 51% lower odds of achieving low disease activity (odds ratio (OR=0.49 (95% CI 0.31 to 0.78)) and 42% lower odds of remission (OR=0.58 (95% CI 0.37 to 0.92)) at the 6-months visit, compared to normal-weight patients. This effect was also present at 3 months, where we also found a 43% decreased odds of pain remission (OR=0.57 (95% CI 0.37 to 0.88)). No effect modification was found for anti-citrullinated protein antibody (CCP)-status, sex, prednisolone treatment or DAS28 at diagnosis. Overweight at diagnosis significantly decreases the chance of achieving good disease control during the early phase of RA.
    Annals of the rheumatic diseases 05/2014; · 8.11 Impact Factor
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    ABSTRACT: Immunological events in the lungs might trigger production of anti-citrullinated protein antibodies during early rheumatoid arthritis (RA). We investigated the presence of shared immunological citrullinated targets in joints and lungs of patients with RA. Proteins extracted from bronchial (n=6) and synovial (n=7) biopsy specimens from patients with RA were investigated by mass spectrometry-based proteomics. One candidate peptide was synthesised and used to investigate by ELISA the presence of antibodies in patients with RA (n=393), healthy controls (n=152) and disease controls (n=236). HLA-DRB1 shared epitope (SE) alleles were detected in patients with RA. Ten citrullinated peptides belonging to seven proteins were identified, with two peptides shared between the synovial and bronchial biopsy samples. Further analysis, using accurate mass and retention time, enabled detection of eight citrullinated peptides in synovial and seven in bronchial biopsy specimens, with five peptides shared between the synovial and bronchial biopsy specimens. Two citrullinated vimentin (cit-vim) peptides were detected in the majority of synovial and lung tissues. Antibodies to a synthesised cit-vim peptide candidate (covering both cit-vim peptides identified in vivo) were present in 1.8% of healthy controls, 15% of patients with RA, and 3.4% of disease controls. Antibodies to cit-vim peptide were associated with the presence of the SE alleles in RA. Identical citrullinated peptides are present in bronchial and synovial tissues, which may be used as immunological targets for antibodies of patients with RA. The data provide further support for a link between lungs and joints in RA and identify potential targets for immunity that may mediate this link.
    Annals of the rheumatic diseases 05/2014; · 8.11 Impact Factor
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    ABSTRACT: In rheumatoid arthritis (RA), several genetic risk factors and smoking are strongly associated with the presence of anticitrullinated protein antibodies (ACPA), while much less is known about risk factors for ACPA-negative RA. Antibodies against carbamylated proteins (anti-CarP) have been described in both ACPA-positive and ACPA-negative RA patients. In this study, we have analysed the relationships among anti-CarP antibodies, ACPA, genetic risk factors (HLA-DRB1 alleles and PTPN22) and smoking in RA. Presence of antibodies to carbamylated fetal calf serum (CarP-FCS) and fibrinogen (CarP-Fib) was determined by inhouse ELISAs among RA cases in the Leiden Early Arthritis Clinic (n=846) and in the Swedish Epidemiological Investigation of Rheumatoid Arthritis (n=1985) cohorts. ORs for associations with different HLA-DRB1 alleles, PTPN22 genotypes and smoking were calculated separately for each cohort as well as in meta-analysis in RA subsets defined by the presence/absence of anti-CarP and anticyclic citrullinated peptide (anti-CCP) antibodies. In both cohorts, anti-CarP antibody positivity was mainly detected in the anti-CCP-positive population (49%-73%), but also in the anti-CCP-negative population (8%-14%). No associations between anti-CarP antibodies and HLA-DRB1 shared epitope alleles could be identified, while there were data to support an association between anti-CarP-FCS and HLA-DRB1*03. Further analyses did not reveal any specific associations of anti-CarP antibodies with other HLA-DRB1 alleles, PTPN22 genotypes or smoking. Anti-CarP antibodies were present in both ACPA-positive and ACPA-negative RA. There were no significant associations among anti-CarP antibodies and HLA-DRB1 alleles, PTPN22 or smoking. These data suggest that different biological mechanisms may underlie anti-CarP versus anti-CCP antibody formation.
    Annals of the rheumatic diseases 05/2014; · 8.11 Impact Factor
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    ABSTRACT: To develop and validate rheumatoid arthritis (RA) risk models based on family history, epidemiologic factors and known genetic risk factors. We developed and validated models for RA based on known RA risk factors, among women in two cohorts: the Nurses' Health Study (NHS, 521 RA cases and 517 controls) and the Epidemiological Investigation of RA (EIRA, 1244 RA cases and 971 controls). Model discrimination was evaluated using the area under the receiver operating characteristic curve (AUC) in logistic regression models for the study population and for those with positive family history. The joint effect of family history with genetics, smoking and body mass index (BMI) was evaluated using logistic regression models to estimate ORs for RA. The complete model including family history, epidemiologic risk factors and genetics demonstrated AUCs of 0.70 for seropositive RA in NHS and 0.77 for anti-citrullinated protein antibody (ACPA)-positive RA in EIRA. Among women with positive family history, discrimination was excellent for complete models for seropositive RA in NHS (AUC 0.83) and ACPA-positive RA in EIRA (AUC 0.83). Positive family history, high genetic susceptibility, smoking and increased BMI had an OR of 21.73 for ACPA-positive RA. We developed models for seropositive and seronegative RA phenotypes based on family history, epidemiological and genetic factors. Among those with positive family history, models using epidemiologic and genetic factors were highly discriminatory for seropositive and seronegative RA. Assessing epidemiological and genetic factors among those with positive family history may identify individuals suitable for RA prevention strategies.
    Annals of the rheumatic diseases 03/2014; · 8.11 Impact Factor
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    ABSTRACT: In a broad attempt to improve the understanding of the genetic regulation of serum IgA levels, the heritability was estimated in over 12,000 Swedish twins and a genome-wide association study was conducted in a subsample of 9,617. Using the classical twin-model the heritability was found to be significantly larger among females (51%) compared to males (22%), while contribution from shared environment (18%) was only seen for males. By modeling the genetic relationship matrix with IgA levels, we estimate that a substantial proportion (31%) of variance in IgA levels can ultimately be explained by the investigated SNPs. The genome-wide association study revealed significant association to two loci; 1) rs6928791 located on chromosome 6, 22Kb upstream of the gene SAM and SH3 domain containing 1 (SASH1) and 2) rs13300483 on chromosome 9, situated 12kb downstream the CD30 ligand (CD30 L) encoding gene. The association to rs13300483 was replicated in two additional independent Swedish materials. The heritability of IgA levels is moderate and can partly be attributable to common variation in the CD30 L locus.
    Human Molecular Genetics 03/2014; · 7.69 Impact Factor
  • Annals of the rheumatic diseases 03/2014; · 8.11 Impact Factor
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    ABSTRACT: Despite progress in defining human leukocyte antigen (HLA) alleles for anti-citrullinated-protein-autoantibody-positive (ACPA(+)) rheumatoid arthritis (RA), identifying HLA alleles for ACPA-negative (ACPA(-)) RA has been challenging because of clinical heterogeneity within clinical cohorts. We imputed 8,961 classical HLA alleles, amino acids, and SNPs from Immunochip data in a discovery set of 2,406 ACPA(-) RA case and 13,930 control individuals. We developed a statistical approach to identify and adjust for clinical heterogeneity within ACPA(-) RA and observed independent associations for serine and leucine at position 11 in HLA-DRβ1 (p = 1.4 × 10(-13), odds ratio [OR] = 1.30) and for aspartate at position 9 in HLA-B (p = 2.7 × 10(-12), OR = 1.39) within the peptide binding grooves. These amino acid positions induced associations at HLA-DRB1(∗)03 (encoding serine at 11) and HLA-B(∗)08 (encoding aspartate at 9). We validated these findings in an independent set of 427 ACPA(-) case subjects, carefully phenotyped with a highly sensitive ACPA assay, and 1,691 control subjects (HLA-DRβ1 Ser11+Leu11: p = 5.8 × 10(-4), OR = 1.28; HLA-B Asp9: p = 2.6 × 10(-3), OR = 1.34). Although both amino acid sites drove risk of ACPA(+) and ACPA(-) disease, the effects of individual residues at HLA-DRβ1 position 11 were distinct (p < 2.9 × 10(-107)). We also identified an association with ACPA(+) RA at HLA-A position 77 (p = 2.7 × 10(-8), OR = 0.85) in 7,279 ACPA(+) RA case and 15,870 control subjects. These results contribute to mounting evidence that ACPA(+) and ACPA(-) RA are genetically distinct and potentially have separate autoantigens contributing to pathogenesis. We expect that our approach might have broad applications in analyzing clinical conditions with heterogeneity at both major histocompatibility complex (MHC) and non-MHC regions.
    The American Journal of Human Genetics 03/2014; · 11.20 Impact Factor
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    ABSTRACT: Physical activity has been shown to decrease inflammatory markers; here we investigate the effect on the clinical presentation of rheumatoid arthritis (RA). We used the cases from the population-based EIRA study (N=617), followed in the Swedish Rheumatology Quality Register, calculating the odds of having above median level of 28-joint disease activity score (DAS28), physician assessment, pain (visual-analogue scale (VAS), VAS-pain) and activity limitation (health assessment questionnaire (HAQ)) at diagnosis, as an effect of physical activity 5 years before diagnosis, investigated both in categories and dichotomised. Dose-response relationships were seen for all measures; the higher the level of physical activity, the lower the likelihood of having outcome measure above median. Further, regular physical activity associated with 42% reduced odds of having DAS28 above median (OR=0.58 (95% CI 0.42 to 0.81)). Effects were similar for VAS-pain (OR=0.62 (95%CI 0.45 to 0.86)) and physician assessment (OR=0.67 (95%CI 0.47 to 0.95)) but not for HAQ. Statistically significant effects were also found both for the combined objective components and the combined subjective components of DAS28. Physically active individuals seem to present with milder RA, which adds to the evidence of beneficial effects of physical activity on inflammatory diseases. The observation should be important for both health professionals and individuals seeking to reduce their risk.
    Annals of the rheumatic diseases 03/2014; · 8.11 Impact Factor
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    ABSTRACT: Epigenetic marks such as DNA methylation have generated great interest in the study of human disease. However, studies of DNA methylation have not established population-epigenetics principles to guide design, efficient statistics, or interpretation. Here, we show that the clustering of correlated DNA methylation at CpGs was similar to that of linkage-disequilibrium (LD) correlation in genetic SNP variation but for much shorter distances. Some clustering of methylated CpGs appeared to be genetically driven. Further, a set of correlated methylated CpGs related to a single SNP-based LD block was not always physically contiguous-segments of uncorrelated methylation as long as 300 kb could be interspersed in the cluster. Thus, we denoted these sets of correlated CpGs as GeMes, defined as potentially noncontiguous methylation clusters under the control of one or more methylation quantitative trait loci. This type of correlated methylation structure has implications for both biological functions of DNA methylation and for the design, analysis, and interpretation of epigenome-wide association studies.
    The American Journal of Human Genetics 03/2014; · 11.20 Impact Factor
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    ABSTRACT: Objective: Rheumatoid arthritis is thought to be a T cell mediated disease, based on its strong association with HLA class II alleles, clinical responsiveness to T cell directed therapies and the presence of CD4 T cells in rheumatoid joints. The presence of ACPA in RA serum and the association of these antibodies with HLA-DR4 alleles implicates citrullinated specific autoreactive T cells in the development and progression of RA. The goal of this study was to determine the character and specificity of auto-reactive T cell responses in RA.Methods: We developed a panel of HLA-DRB1*04:01 tetramers, selecting citrullinated peptides from synovial antigens and verifying their immunogenicity in DRB1*04:01 transgenic mice. Seven tetramers were used to examine the ex vivo frequency and surface phenotype of cit-specific T cells in RA and healthy subjects with DRB1*04:01 haplotypes using a magnetic enrichment procedure.Results: Cit-specific T cells were detectable in peripheral blood samples from both healthy subjects and RA patients. In comparison to healthy subjects, RA patients had significantly higher frequencies of cit-specific T cells and a greater proportion of these cells displayed a Th1 memory phenotype. Among RA subjects the frequency of cit-specific T cells was highest within the first 5 years after diagnosis of RA and was decreased in patients taking biologic therapies irrespective of disease duration.Conclusion: These findings link the presence of ACPA in RA with Th1 cells specific to citrullinated epitopes and provide tools for disease-specific immunomonitoring of autoreactive T cells. © 2014 American College of Rheumatology.
    Arthritis & Rheumatology. 03/2014;
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    ABSTRACT: To investigate if changes in the lungs are present in rheumatoid arthritis (RA) patients early in the disease process and to address the contribution of these changes to the initiation of the disease. 24 RA patients with patient-reported symptom duration less than one year and naive to DMARD treatment and 15 healthy individuals were subjected to bronchoscopy and mucosal bronchial biopsies were retrieved. Histological analysis for identification of inducible bronchia associated lymphoid tissues (iBALT) and lymphocyte infiltration, as well as immunohistochemistry (IHC) for PAD enzymes, CD3, HLA-DQ and HLA-DR were performed. Presence of citrullinated targets were detected by IHC using biotinylated ACPA isolated from synovial fluid of RA patients. Mass spectrometry was used for identification of citrullinated epitopes in 6 lung and 8 synovial biopsies from RA patients. An in-house ELISA was setup to measure reactivity against new identified citrullinated targets in the serum of RA patients in two distinct early RA cohorts (n = 393) and a cohort of non-RA patients (n = 236) as disease controls. Bronchial lymphocyte infiltration and iBALT formation was observed in 55% of the ACPA+ RA patients but only 17% of ACPA- patients and 7% of healthy volunteers. Higher expression of CD3, HLA-DQ, HLA-DR and citrullinated targets was observed in bronchial biopsies of ACPA+ as compare to ACPA- RA patients. BAL fluids were enriched in both IgG and IgA ACPA as compared to paired serum samples. Mass spectrometry identified 5 proteins in the synovium (in total 8 sites) and 4 in the lungs (in total 6 sites) containing citrullinated residues. Two vimentin derived citrullinated peptides were present in a majority of both synovial and lung biopsies with slightly higher citrullinated/unmodified peptides ratios in the smokers as compared to non-smokers.14.5% of the RA patients tested by ELISA showed antibody reactivity against the new identified citrullinated target compared to 3.4% in the disease controls. Signs of inflammation and local ACPA enrichment are present early in bronchial tissues of ACPA+ RA patients. Shared citrullinated targets in the lung and joints as well as systemic reactivity against these targets are present in RA patients. Our findings support the notion that early inflammatory events in the lungs may represent a critical initiating factor in the development of ACPA+ RA.
    Annals of the rheumatic diseases 03/2014; 73 Suppl 1:A4-5. · 8.11 Impact Factor
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    ABSTRACT: Objectives: To investigate the association between snuff use (smokeless tobacco containing nicotine) and the risk of anti-citrullinated protein/peptide antibody (ACPA)-positive and ACPA-negative rheumatoid arthritis (RA).Methods: Data from EIRA, a population-based case-control study including 1998 incident cases and 2252 randomly selected controls (matched on age, sex and residential area) aged 18-70 years, was analysed. Ever, current and past moist snuff users were compared with never users. We calculated odds ratios (OR) with 95% confidence intervals (CI) by means of unconditional logistic regression models. All analyses were adjusted for cigarette smoking, alcohol consumption and the matching variables.Results: In total, 254 (13%) cases were ever moist snuff users compared with 290 (13%) controls, resulting in an OR of 1.0 (95% CI: 0.8-1.2) of RA overall. When exposure to moist snuff was analysed in relation to ACPA-positive and ACPA-negative disease, no associations were observed. Neither current nor past moist snuff use was related to the risk of any of the two RA subgroups. Analyses restricted to never smokers provided similar results.Conclusions: The use of moist snuff was not associated with the risk of neither ACPA-positive nor ACPA-negative RA. The increased risk of RA associated with smoking is most probably not due to nicotine. © 2014 American College of Rheumatology.
    Arthritis Care & Research. 03/2014;
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    ABSTRACT: In rheumatoid arthritis (RA), the presence of antibodies to citrullinated proteins (ACPA) is strongly associated with certain genetic risk factors and smoking. The recently identified antibodies against carbamylated proteins (anti-CarP) are present in part of ACPA-positive, but also ACPA-negative RA patients. This raised the question whether the presence of anti-CarP may be associated with specific risk factors, which could provide clues about the pathogenesis of ACPA-negative RA. In this study we have therefore analysed the relationship between anti-CarP antibodies, ACPA, genetic risk factors (HLA-DRB1 alleles and PTPN22) and smoking in RA. Presence of antibodies to carbamylated fetal calf serum (CarP-FCS) and fibrinogen (CarP-Fib) was determined by in-house ELISAs in the Leiden Early Arthritis Cohort (EAC) and in the Swedish Epidemiological Investigation of RA (EIRA) cohort. Odds ratios for associations with different HLA-DRB1 alleles, PTPN22 genotypes and smoking were calculated separately for each cohort as well as in a combined meta-analysis, in RA subsets defined by anti-CarP and anti-cyclic citrullinated peptide (CCP) antibody status. In both cohorts,anti-CarP antibodies were mainly detected in the anti-CCP-positive population, but also in the anti-CCP-negative population. No strong associations between anti-CarP antibodies and specific HLA-DRB1 alleles, including shared epitope alleles, could be identified, with the exception of a consistent association between anti-CarP FCS and HLA-DRB1*03. Further analyses did not reveal any specific associations between anti-CarP antibodies and PTPN22 genotypes or smoking. Anti-CarP antibodies were present in both ACPA-positive and ACPA-negative RA patients in the two separate cohorts. Except for a modest association with HLA-DRB1*03, there were no strong associations between anti-CarP antibodies and other HLA-DRB1 alleles, PTPN22 or smoking. Although it cannot be excluded that risk factors not investigated here may be importance for anti-CarP-positive disease, the lack of association found here suggests a possible fundamentally different biological mechanism for anti-CarP antibody formation compared with anti-CCP antibody formation.
    Annals of the rheumatic diseases 03/2014; 73 Suppl 1:A11-2. · 8.11 Impact Factor
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    ABSTRACT: A highly polygenic aetiology and high degree of allele-sharing between ancestries have been well elucidated in genetic studies of rheumatoid arthritis. Recently, the high-density genotyping array Immunochip for immune disease loci identified 14 new rheumatoid arthritis risk loci among individuals of European ancestry. Here, we aimed to identify new rheumatoid arthritis risk loci using Korean-specific Immunochip data. We analysed Korean rheumatoid arthritis case-control samples using the Immunochip and genome-wide association studies (GWAS) array to search for new risk alleles of rheumatoid arthritis with anticitrullinated peptide antibodies. To increase power, we performed a meta-analysis of Korean data with previously published European Immunochip and GWAS data for a total sample size of 9299 Korean and 45 790 European case-control samples. We identified eight new rheumatoid arthritis susceptibility loci (TNFSF4, LBH, EOMES, ETS1-FLI1, COG6, RAD51B, UBASH3A and SYNGR1) that passed a genome-wide significance threshold (p<5×10(-8)), with evidence for three independent risk alleles at 1q25/TNFSF4. The risk alleles from the seven new loci except for the TNFSF4 locus (monomorphic in Koreans), together with risk alleles from previously established RA risk loci, exhibited a high correlation of effect sizes between ancestries. Further, we refined the number of single nucleotide polymorphisms (SNPs) that represent potentially causal variants through a trans-ethnic comparison of densely genotyped SNPs. This study demonstrates the advantage of dense-mapping and trans-ancestral analysis for identification of potentially causal SNPs. In addition, our findings support the importance of T cells in the pathogenesis and the fact of frequent overlap of risk loci among diverse autoimmune diseases.
    Annals of the rheumatic diseases 02/2014; · 8.11 Impact Factor
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    ABSTRACT: Translational medicine is becoming increasingly dependent upon data generated from health care, clinical research, and molecular investigations. This increasing rate of production and diversity in data has brought about several challenges, including the need to integrate fragmented databases, enable secondary use of patient clinical data from health care in clinical research, and to create information systems that clinicians and biomedical researchers can readily use. Our case study effectively integrates requirements from the clinical and biomedical researcher perspectives in a translational medicine setting. Our three principal achievements are (a) a design of a user-friendly web-based system for management and integration of clinical and molecular databases, while adhering to proper de-identification and security measures; (b) providing a real-world test of the system functionalities using clinical cohorts; and (c) system integration with a clinical decision support system to demonstrate system interoperability. We engaged two active clinical cohorts, 747 psoriasis patients and 2001 rheumatoid arthritis patients, to demonstrate efficient query possibilities across the data sources, enable cohort stratification, extract variation in antibody patterns, study biomarker predictors of treatment response in RA patients, and to explore metabolic profiles of psoriasis patients. Finally, we demonstrated system interoperability by enabling integration with an established clinical decision support system in health care. To assure the usefulness and usability of the system, we followed two approaches. First, we created a graphical user interface supporting all user interactions. Secondly we carried out a system performance evaluation study where we measured the average response time in seconds for active users, http errors, and kilobits per second received and sent. The maximum response time was found to be 0.12 seconds; no server or client errors of any kind were detected. In conclusion, the system can readily be used by clinicians and biomedical researchers in a translational medicine setting.
    PLoS ONE 01/2014; 9(9):e104382. · 3.53 Impact Factor

Publication Stats

12k Citations
2,035.55 Total Impact Points


  • 2001–2014
    • Karolinska Institutet
      • • Institutet för miljömedicin - IMM
      • • Institutionen för medicin, Huddinge
      • • Department of Rheumatology
      Solna, Stockholm, Sweden
  • 1999–2014
    • Karolinska University Hospital
      • Department of Rheumatology
      Tukholma, Stockholm, Sweden
  • 2010–2013
    • The University of Manchester
      Manchester, England, United Kingdom
    • KTH Royal Institute of Technology
      • School of Biotechnology (BIO)
      Stockholm, Stockholm, Sweden
    • Partners HealthCare
      Boston, Massachusetts, United States
  • 2009–2013
    • Brigham and Women's Hospital
      • • Department of Medicine
      • • Division of Rheumatology, Immunology, and Allergy
      Boston, MA, United States
  • 2004–2013
    • Umeå University
      • Department of Public Health and Clinical Medicine
      Umeå, Vaesterbotten, Sweden
  • 2011–2012
    • University of Amsterdam
      • Faculty of Medicine AMC
      Amsterdam, North Holland, Netherlands
  • 2003–2012
    • Harvard Medical School
      • Department of Medicine
      Boston, Massachusetts, United States
  • 1986–2012
    • Uppsala University
      • • Department of Immunology, Genetics and Pathology
      • • Department of Medical Sciences
      Uppsala, Uppsala, Sweden
  • 2007–2011
    • Leiden University Medical Centre
      • Department of Rheumatology
      Leiden, South Holland, Netherlands
    • National Institute of Arthritis and Musculoskeletal and Skin Diseases
      Maryland, United States
  • 2008
    • Broad Institute of MIT and Harvard
      • Program in Medical and Population Genetics
      Cambridge, MA, United States
  • 2000–2008
    • Uppsala University Hospital
      • Department of Rheumatology
      Uppsala, Uppsala, Sweden
  • 2006
    • University of California, Davis
      Davis, California, United States
    • Akademiska Sjukhuset
      Uppsala, Uppsala, Sweden
  • 2005–2006
    • Maastricht Universitair Medisch Centrum
      Maestricht, Limburg, Netherlands