TY  - JOUR
AB  - OBJECTIVES: CD4+CD8+ T cells are increased in patients with rheumatoid arthritis (RA). They are not only associated with joint erosions in established disease, but are also present in the pre-clinical stages of RA. This study aims to further investigate their expansion in the context of T cell clonality in patients with RA, as well as their responsiveness to T cell targeted treatment. METHODS: Single-cell-(sc)RNA- and scTCR-sequencing data were used to determine co-receptor expression and T cell receptor sequences to assess clonality of CD4+CD8+ T cells in RA (n=3) patients and healthy controls (n=2). Peripheral CD4+CD8+ T cells and their subpopulations were measured in patients with RA (n=53), PsA (n=52) and healthy donors (n=50) using flow cytometry. In addition, changes in CD4+CD8+ T cell frequency were prospectively followed in RA patients receiving therapy with abatacept for 12 weeks. RESULTS: We observed an increase of CD4+ T cells expressing CD8α in RA patients, both in comparison to PsA patients and to healthy controls. Clonality analysis revealed, that these CD4+CD8αlow T cells are part of large T cell clones, which cluster separately from CD4+CD8- T cell clones in the scRNA-seq gene expression analysis. Treatment with abatacept significantly reduced the frequency of peripheral CD4+CD8αlow T cells, and this was linked to reduction in disease activity. CONCLUSION: In RA, clonal expansion of CD4+ T cell clones culminates in the emergence of peripheral CD4+CD8αlow T cells, which are associated with disease activity and diminished upon abatacept treatment, and which could contribute to disease pathogenesis.
AU  - Beck, F.*
AU  - Nguyen, P.*
AU  - Hoffmann, A.
AU  - Loyal, L.*
AU  - Thiel, A.*
AU  - Melzer, M.*
AU  - Apel, H.*
AU  - Pierer, M.*
AU  - Krasselt, M.*
AU  - Seifert, O.*
AU  - Glimm, A.M.*
AU  - Hagemann, T.
AU  - Rothe, K.*
AU  - Wagner, U.*
C1  - 71295
C2  - 56027
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 1719-1729
TI  - CD4+CD8αlow T cells in rheumatoid arthritis are clonally expanded and dependent on co-stimulation.
JO  - Arthritis Rheum.
VL  - 76
IS  - 12
PB  - Wiley
PY  - 2024
SN  - 0004-3591
ER  - 

TY  - JOUR
AB  - OBJECTIVES: To examine the genetic architecture of cam morphology, using alpha angle (AA) as a proxy measure, we conducted an AA genome wide association study (GWAS), followed by Mendelian randomisation (MR) to evaluate its causal relationship with hip osteoarthritis (HOA). METHODS: Observational analyses examined associations between AA derived from hip DXA scans in UK Biobank (UKB), and radiographic HOA (rHOA) and subsequent total hip replacement (THR). Afterwards, an AA GWAS meta-analysis was performed (n=44,214), using AA previously derived in the Rotterdam Study (RS). Linkage disequilibrium score regression assessed the genetic correlation between AA and HOA. Genetic associations with P<5x10-8 instrumented AA for two-sample MR. RESULTS: DXA-derived AA showed expected associations between AA and rHOA (OR 1.63 [95% CI 1.58-1.67]) and THR (HR 1.45 [1.33-1.59]) in UKB. The heritability of AA was 10% and AA had a moderate genetic correlation with HOA (rg =0.26 [0.10-0.43]). Eight independent genetic signals were associated with AA. Two-sample MR provided weak evidence of causal effects of AA on HOA risk (inverse variance weighted (IVW): OR=1.84 [1.14-2.96], P 0.01). In contrast, genetic predisposition for HOA had stronger evidence of a causal effect on increased AA (IVW: β=0.09 [0.04-0.13], P 4.58 x 10-05 ). CONCLUSIONS: Expected observational associations between AA and related clinical outcomes provided face-validity for the DXA-derived AA measures. Evidence of bidirectional associations between AA and HOA, particularly in the reverse direction, suggests that hip shape modelling secondary to a genetic predisposition to HOA contributes to the well-established relationship between HOA and cam morphology in older adults.
AU  - Faber, B.G.*
AU  - Frysz, M.*
AU  - Hartley, A.E.*
AU  - Ebsim, R.*
AU  - Boer, C.G.*
AU  - Saunders, F.R.*
AU  - Gregory, J.S.*
AU  - Aspden, R.M.*
AU  - Harvey, N.C.*
AU  - Southam, L.
AU  - Giles, W.*
AU  - Le Maitre, C.L.*
AU  - Wilkinson, J.M.*
AU  - van Meurs, J.B.J.*
AU  - Zeggini, E.
AU  - Cootes, T.*
AU  - Lindner, C.*
AU  - Kemp, J.P.*
AU  - Davey Smith, G.*
AU  - Tobias, J.H.*
C1  - 67268
C2  - 54204
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 900-909
TI  - A GWAS meta-analysis of alpha angle suggests cam-type morphology may be a specific feature of hip osteoarthritis in older adults.
JO  - Arthritis Rheum.
VL  - 75
IS  - 6
PB  - Wiley
PY  - 2023
SN  - 0004-3591
ER  - 

TY  - JOUR
AB  - OBJECTIVE: In this study, we aimed to establish the causal effects of lowering sclerostin, target of the antiosteoporosis drug romosozumab, on atherosclerosis and its risk factors. METHODS: A genome-wide association study meta-analysis was performed of circulating sclerostin levels in 33,961 European individuals. Mendelian randomization (MR) was used to predict the causal effects of sclerostin lowering on 15 atherosclerosis-related diseases and risk factors. RESULTS: We found that 18 conditionally independent variants were associated with circulating sclerostin. Of these, 1 cis signal in SOST and 3 trans signals in B4GALNT3, RIN3, and SERPINA1 regions showed directionally opposite signals for sclerostin levels and estimated bone mineral density. Variants with these 4 regions were selected as genetic instruments. MR using 5 correlated cis-SNPs suggested that lower sclerostin increased the risk of type 2 diabetes mellitus (DM) (odds ratio [OR] 1.32 [95% confidence interval (95% CI) 1.03-1.69]) and myocardial infarction (MI) (OR 1.35 [95% CI 1.01-1.79]); sclerostin lowering was also suggested to increase the extent of coronary artery calcification (CAC) (β = 0.24 [95% CI 0.02-0.45]). MR using both cis and trans instruments suggested that lower sclerostin increased hypertension risk (OR 1.09 [95% CI 1.04-1.15]), but otherwise had attenuated effects. CONCLUSION: This study provides genetic evidence to suggest that lower levels of sclerostin may increase the risk of hypertension, type 2 DM, MI, and the extent of CAC. Taken together, these findings underscore the requirement for strategies to mitigate potential adverse effects of romosozumab treatment on atherosclerosis and its related risk factors.
AU  - Zheng, J.*
AU  - Wheeler, E.*
AU  - Pietzner, M.*
AU  - Andlauer, T.F.M.*
AU  - Yau, M.S.*
AU  - Hartley, A.E.*
AU  - Brumpton, B.M.*
AU  - Rasheed, H.*
AU  - Kemp, J.P.*
AU  - Frysz, M.*
AU  - Robinson, J.*
AU  - Reppe, S.*
AU  - Prijatelj, V.*
AU  - Gautvik, K.M.*
AU  - Falk, L.*
AU  - Maerz, W.*
AU  - Gergei, I.*
AU  - Peyser, P.A.*
AU  - Kavousi, M.*
AU  - de Vries, P.S.*
AU  - Miller, C.L.*
AU  - Bos, M.*
AU  - van der Laan, S.W.*
AU  - Malhotra, R.*
AU  - Herrmann, M.*
AU  - Scharnagl, H.*
AU  - Kleber, M.*
AU  - Dedoussis, G.*
AU  - Zeggini, E.
AU  - Nethander, M.*
AU  - Ohlsson, C.*
AU  - Lorentzon, M.*
AU  - Wareham, N.*
AU  - Langenberg, C.*
AU  - Holmes, M.V.*
AU  - Davey Smith, G.*
AU  - Tobias, J.H.*
C1  - 67667
C2  - 53974
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 1781-1792
TI  - Lowering
       of circulating sclerostin may increase risk of atherosclerosis and its 
      risk factors: Evidence from a genome-wide association meta-analysis 
      followed by Mendelian randomization.
JO  - Arthritis Rheum.
VL  - 75
IS  - 10
PB  - Wiley
PY  - 2023
SN  - 0004-3591
ER  - 

TY  - JOUR
AB  - OBJECTIVES: Polygenic risk scores (PRS) allow risk-stratification using common SNPs, and clinical applications are currently explored for several diseases. This study used PRS to assess the risk for hip- and knee-Osteoarthritis (OA). METHODS: We analyzed 12,732 individuals from a population-based cohort of the Rotterdam Study (RS;n=11,496), a clinical cohort (CHECK;n=908), and a high-risk cohort of overweight women (PROOF;n=328), for the association of the PRSs with prevalence/incidence of radiographic-OA, of clinical-OA, and of total hip- or knee-replacement (THR/TKR). The hip-PRS and knee-PRS contained 44 and 24 independent SNPs, respectively, and were derived from a recent GWAS meta-analysis. Standardized PRSs (Z-transformation) were used in all analyses. RESULTS: We found a stronger association of the PRSs for clinically-defined OA compared to radiographic-OA phenotypes. We observed the highest PRS risk-stratification for TKR/THR. The odds ratio (OR) per SD was 1.3 for incident-THR (95% confidence interval (CI) [1.1-1.5]) and 1.6[1.3-1.9] for incident TKR in RS. The knee-PRS was associated with incident clinical-knee-OA in CHECK 1.3[1.1-1.5], but not for PROOF 1.2[0.8-1.7]. The OR for OA increased gradually across the PRSs distribution, up to 2.1[1.4-3.2] for individuals with the 10% highest PRS compared to the middle 50% of the PRSs distribution. CONCLUSIONS: The findings validated the association of PRSs across OA-definitions. Since OA is becoming frequent and primary-prevention is not commonly applicable, PRS-based risk assessment could play a role in OA-prevention. However, the PRSs utility is dependent on the setting. Further studies are needed to test the integration of genetic risk assessment in diverse health care settings. This article is protected by copyright. All rights reserved.
AU  - Sedaghati-Khayat, B.*
AU  - Boer, C.G.*
AU  - Runhaar, J.*
AU  - Bierma-Zeinstra, S.M.A.*
AU  - Broer, L.*
AU  - Ikram, M.A.*
AU  - Zeggini, E.
AU  - Uitterlinden, A.G.*
AU  - van Rooij, J.G.J.*
AU  - van Meurs, J.B.J.*
C1  - 65474
C2  - 52701
SP  - 1488-1496
TI  - Risk assessment for hip and knee osteoarthritis using polygenic risk scores.
JO  - Arthritis Rheum.
VL  - 74
IS  - 9
PY  - 2022
SN  - 0004-3591
ER  - 

TY  - JOUR
AB  - Objective: To identify single-cell transcriptional signatures of dendritic cells (DCs) that are associated with autoimmunity, and determine whether those DC signatures are correlated with the clinical heterogeneity of autoimmune disease. Methods: Blood-derived DCs were single-cell sorted from the peripheral blood of patients with rheumatoid arthritis, systemic lupus erythematosus, or type 1 diabetes as well as healthy individuals. DCs were analyzed using single-cell gene expression assays, performed immediately after isolation or after in vitro stimulation of the cells. In addition, protein expression was measured using fluorescence-activated cell sorting. Results: CD1c+ conventional DCs and plasmacytoid DCs from healthy individuals exhibited diverse transcriptional signatures, while the DC transcriptional signatures in patients with autoimmune disease were altered. In particular, distinct DC clusters, characterized by up-regulation of TAP1, IRF7, and IFNAR1, were abundant in patients with systemic autoimmune disease, whereas DCs from patients with type 1 diabetes had decreased expression of the regulatory genes PTPN6, TGFB, and TYROBP. The frequency of CD1c+ conventional DCs that expressed a systemic autoimmune profile directly correlated with the extent of disease activity in patients with rheumatoid arthritis (Spearman's r = 0.60, P = 0.03). Conclusion: DC transcriptional signatures are altered in patients with autoimmune disease and are associated with the level of disease activity, suggesting that immune cell transcriptional profiling could improve our ability to detect and understand the heterogeneity of these diseases, and could guide treatment choices in patients with a complex autoimmune disease.
AU  - Ashton, M.P.*
AU  - Eugster, A.*
AU  - Dietz, S.*
AU  - Loebel, D.*
AU  - Lindner, A.*
AU  - Kuehn, D.*
AU  - Taranko, A.E.*
AU  - Heschel, B.*
AU  - Gavrisan, A.*
AU  - Ziegler, A.-G.
AU  - Aringer, M.*
AU  - Bonifacio, E.*
C1  - 55874
C2  - 46644
SP  - 817-828
TI  - Association of dendritic cell signatures with autoimmune inflammation revealed by single-cell profiling.
JO  - Arthritis Rheum.
VL  - 71
IS  - 5
PY  - 2019
SN  - 0004-3591
ER  - 

TY  - JOUR
AU  - Thompson, G.A.*
AU  - Moura, M.C.*
AU  - Nelson, D.*
AU  - Hummel, A.M.*
AU  - Jenne, D.
AU  - Fervenza, F.*
AU  - Hoffman, G.S.*
AU  - Kallenberg, C.G.M.*
AU  - Langford, C.*
AU  - McCune, J.W.*
AU  - Merkel, P.A.*
AU  - Monach, P.A.*
AU  - Seo, P.*
AU  - Spiera, R.F.*
AU  - St Clair, E.W.*
AU  - Ytterberg, S.R.*
AU  - Stone, J.H.*
AU  - Robinson, W.H.*
AU  - Pang, Y.*
AU  - Specks, U.*
C1  - 54619
C2  - 45712
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Characterization of preferential recognition of a chimeric recombinant proteinase 3 variant by anti-neutrophil cytoplasmic antibodies.
JO  - Arthritis Rheum.
VL  - 70
PB  - Wiley
PY  - 2018
SN  - 0004-3591
ER  - 

TY  - JOUR
AB  - Objective. Inclusion body myositis (IBM) is characterized by a combination of inflammatory and degenerative changes affecting muscle. While the primary cause of IBMis unknown, genetic factors may influence disease susceptibility. To determine genetic factors contributing to the etiology of IBM, we conducted the largest genetic association study of the disease to date, investigating immune-related genes using the Immunochip. Methods. A total of 252 Caucasian patients with IBM were recruited from 11 countries through the Myositis Genetics Consortium and compared with 1,008 ethnically matched controls. Classic HLA alleles and amino acids were imputed using SNP2HLA. Results. The HLA region was confirmed as the most strongly associated region in IBM (p=3.58 x 10(-33)). HLA imputation identified 3 independent associations (with HLA-DRB1*03: 01, DRB1*01: 01, and DRB1*13: 01), although the strongest association was with amino acid positions 26 and 11 of the HLA-DRB1 molecule. No association with anti-cytosolic 50-nucleotidase 1A-positive status was found independent ofHLA-DRB1*03: 01. There was no association of HLA genotypes with age at onset of IBM. Three non-HLA regions reached suggestive significance, including the chromosome 3 p21.31 region, an established risk locus for autoimmune disease, where a frameshift mutation in CCR5 is thought to be the causal variant. Conclusion. This is the largest, most comprehensive genetic association study to date in IBM. The data confirm that HLA is the most strongly associated region and identifies novel amino acid associations that may explain the risk in this locus. These amino acid associations differentiate IBM from polymyositis and dermatomyositis and may determine properties of the peptide-binding groove, allowing it to preferentially bind autoantigenic peptides. A novel suggestive association within the chromosome 3 p21.31 region suggests a role for CCR5.
AU  - Rothwell, S.*
AU  - Cooper, R.G.*
AU  - Lundberg, I.E.*
AU  - Gregersen, P.K.*
AU  - Hanna, M.G.*
AU  - Machado, P.M.*
AU  - Herbert, M.K.*
AU  - Pruijn, G.J.M.*
AU  - Lilleker, J.B.*
AU  - Roberts, M.*
AU  - Bowes, J.*
AU  - Seldin, M.F.*
AU  - Vencovsky, J.*
AU  - Danko, K.*
AU  - Limaye, V.*
AU  - Selva-O'Callaghan, A.*
AU  - Platt, H.*
AU  - Molberg, O.*
AU  - Benveniste, O.*
AU  - Radstake, T.R.D.J.*
AU  - Doria, A.*
AU  - de Bleecker, J.*
AU  - de Paepe, B.*
AU  - Gieger, C.
AU  - Meitinger, T.
AU  - Winkelmann, J.
AU  - Amos, C.I.*
AU  - Ollier, W.E.*
AU  - Padyukov, L.*
AU  - Lee, A.T.*
AU  - Lamb, J.A.*
AU  - Chinoy, H.*
C1  - 51131
C2  - 42695
CY  - Hoboken
SP  - 1090-1099
TI  - Immune-array analysis in sporadic inclusion body myositis reveals HLA-DRB1 amino acid heterogeneity across the myositis spectrum.
JO  - Arthritis Rheum.
VL  - 69
IS  - 5
PB  - Wiley
PY  - 2017
SN  - 0004-3591
ER  - 

TY  - JOUR
AU  - Stutzer, K.*
AU  - Pirronello, F.*
AU  - Wahl, S.
AU  - Schulze-Koops, H.*
AU  - Skapenko, A.*
AU  - Leipe, J.*
C1  - 48123
C2  - 39925
CY  - Hoboken
TI  - Genome-wide association study of DNA methylation in Th1 and Th17 cells in rheumatoid arthritis.
JO  - Arthritis Rheum.
VL  - 67
PB  - Wiley-blackwell
PY  - 2015
SN  - 0004-3591
ER  - 

TY  - JOUR
AB  - Objectives Rheumatoid Arthritis (RA) is one of the most frequent inflammatory diseases, causing pain and disability in the affected joints. Early diagnosis is essential for the efficiency of symptomatic treatment, and relies on careful clinical, serologic and imaging examinations, such as Magnetic Resonance Imaging (MRI), which is both expensive and time consuming. In an effort to provide the biomedical community with a more accessible way to assess arthritis advancement, we investigated the use of multispectral optoacoustic tomography (MSOT) in a murine model to visualize the extent of the inflammation in vivo through a L- and P-selectin targeting contrast agent. Methods Collagen induced arthritis mice were used as a rheumatoid arthritis model of the limb. MSOT was performed using a L- and P-selectin targeting contrast agent (dPGS-NIR provided by Mivenion, Germany) to increase contrast of the arthritic joint, and signal intensity ratios between healthy and arthritic legs were calculated. Contrast enhanced MR imaging as well as clinical observation, lymphocyte/granulocyte ratio and histology served as references. Results MSOT using an inflammation targeting contrast agent allowed for accurate diagnosis of inflammation in the mouse joints and for significant differentiation of inflamed to healthy joints (P = 0.023). The arthritis findings on the MSOT images were confirmed by clinical observation, blood analysis, contrast enhanced MRI and ex vivo histological examinations. Conclusion This study demonstrates that the combination of inflammation targeting contrast agent and optoacoustic tomographic imaging present a promising mean for diagnosis and staging of arthritic inflammation.
AU  - Bézière, N.
AU  - von Schacky, C.*
AU  - Kosanke, Y.*
AU  - Kimm, M.*
AU  - Nunes, A.
AU  - Licha, K.*
AU  - Aichler, M.
AU  - Walch, A.K.
AU  - Rummeny, E.J.*
AU  - Ntziachristos, V.
AU  - Meier, R.*
C1  - 30992
C2  - 34067
CY  - Hoboken
SP  - 2071-2078
TI  - Optoacoustic imaging and staging of arthritic inflammation.
JO  - Arthritis Rheum.
VL  - 66
IS  - 8
PB  - Wiley-blackwell
PY  - 2014
SN  - 0004-3591
ER  - 

TY  - JOUR
AB  - Objective Psoriatic arthritis (PsA) is a common inflammatory joint disease distinct from other chronic arthritides and frequently accompanied by psoriasis vulgaris. In a first genome-wide association study (GWAS), we were able to identify several genetic risk factors. However, even combined with previously identified factors, the genetic contribution to disease was not fully explained. Therefore, we undertook this study to investigate further 17 loci from our GWAS that did not reach genome-wide significance levels of association in the initial analysis. Methods Twenty-one of 22 single-nucleotide polymorphisms were successfully genotyped in independent cohorts of 1,398 PsA patients and 6,389 controls and in a group of 964 German patients with psoriasis vulgaris. Results Association with a RUNX3 variant, rs4649038, was replicated in independent patients and controls and resulted in a combined P value of 1.40 x 108 by Cochran-Mantel-Haenszel test and an odds ratio (OR) of 1.24 (95% confidence interval [95% CI] 1.151.33). Further analyses based on linkage disequilibrium (LD) at RUNX3 refined the most significant association to an LD block located in the first intron of one isoform. Weaker evidence for association was detected in German patients with psoriasis vulgaris (P = 5.89 x 102; OR 1.13 [95% CI 1.001.28]), indicating a role in the skin manifestations of psoriasis. Conclusion Our analyses identified variants in RUNX3 as susceptibility factors for PsA. RUNX3 has already been implicated in susceptibility to ankylosing spondylitis, another spondyloarthritis, although its risk allele is independent from the one for PsA. RUNX-3 is involved in CD8+ T lymphocyte differentiation and is therefore a good candidate for involvement in PsA and psoriasis vulgaris as T cellmediated diseases.
AU  - Apel, M.*
AU  - Uebe, S.*
AU  - Bowes, J.*
AU  - Giardina, E.*
AU  - Korendowych, E.*
AU  - Juneblad, K.*
AU  - Pasutto, F.*
AU  - Ekici, A.B.*
AU  - McManus, R.*
AU  - Ho, P.*
AU  - Bruce, I.N.*
AU  - Ryan, A.W.*
AU  - Behrens, F.*
AU  - Bohm, B.*
AU  - Traupe, H.*
AU  - Lohmann, J.*
AU  - Gieger, C.
AU  - Wichmann, H.-E.
AU  - Padyukov, L.*
AU  - FitzGerald, O.*
AU  - Alenius, G.M.*
AU  - McHugh, N.J.*
AU  - Novelli, G.*
AU  - Burkhardt, H.*
AU  - Barton, A.*
AU  - Reis, A.*
AU  - Hüffmeier, U.*
C1  - 24679
C2  - 31644
SP  - 1224-1231
TI  - Variants in RUNX3 contribute to susceptibility to psoriatic arthritis, exhibiting further common ground with ankylosing spondylitis.
JO  - Arthritis Rheum.
VL  - 65
IS  - 5
PB  - Wiley-Blackwell
PY  - 2013
SN  - 0004-3591
ER  - 

TY  - JOUR
AB  - OBJECTIVE: Recognition of the well-known pleiotropism of autoimmune genes supports the concept of a shared pathogenesis across autoimmune diseases such as rheumatoid arthritis (RA) and systemic sclerosis (SSc). Studies have reproducibly demonstrated an association between susceptibility to RA and polymorphisms of the CCR6 gene, a surface marker for Th17 cells, and the causal variant was recently identified. The present study was thus undertaken to investigate whether CCR6 polymorphisms could also be associated with susceptibility to SSc. METHODS: Twelve tag single-nucleotide polymorphisms (SNPs) of CCR6, including the known RA-associated SNP rs3093023, were genotyped in a total of 2,411 SSc patients and 7,084 healthy individuals from 3 European populations (France, Italy, and Germany). Meta-analyses of the data were performed to assess whether an association exists between CCR6 polymorphisms and susceptibility to SSc or its main subtypes. Direct sequencing of DNA was performed to ascertain whether the functional dinucleotide polymorphism of CCR6 previously identified in RA (CCR6DNP) was also present in SSc. RESULTS: Combined analyses revealed an association between the rs10946216 SNP and SSc susceptibility (odds ratio [OR] 1.13, 95% confidence interval [95% CI] 1.05-1.21, adjusted P [Padj ] = 0.026). The rs3093023 A allele and rs10946216 T allele were in high linkage disequilibrium, and both were found to confer disease susceptibility in the antitopoisomerase-positive subset of SSc patients (OR 1.27, 95% CI 1.13-1.42, Padj = 1.5 × 10(-3) and OR 1.32, 95% CI 1.17-1.48, Padj = 9.0 × 10(-5) , respectively, relative to healthy controls). Direct sequencing of the DNA of 78 individuals supported the hypothesis that the regulatory dinucleotide CCR6DNP could be the causal variant in SSc. CONCLUSION: The results of this study establish CCR6 as a new susceptibility factor for antitopoisomerase-positive SSc, as demonstrated in 3 European Caucasian populations, confirming the notion that SSc and RA could conceivably share autoimmune risk alleles. The results also suggest a potential role of the interleukin-17 pathway in SSc.
AU  - Koumakis, E.*
AU  - Bouaziz, M.*
AU  - Dieudé, P.*
AU  - Ruiz, B.*
AU  - Riemekasten, G.*
AU  - Airo, P.*
AU  - Müller-Nurasyid, M.
AU  - Cusi, D.*
AU  - Matucci-Cerinic, M.*
AU  - Melchers, I.*
AU  - Salvi, E.*
AU  - Strauch, K.
AU  - Peters, A.
AU  - Cuomo, G.*
AU  - Hachulla, E.*
AU  - Diot, E.*
AU  - Hunzelmann, N.*
AU  - Caramaschi, P.*
AU  - Riccieri, V.*
AU  - Distler, J.H.*
AU  - Tarner, I.*
AU  - Avouac, J.*
AU  - Letenneur, L.*
AU  - Amouyel, P.*
AU  - Lambert, J.C.*
AU  - Chiocchia, G.*
AU  - Boileau, C.*
AU  - Allanore, Y.*
C1  - 28742
C2  - 33537
SP  - 3202-3208
TI  - Brief report: A regulatory variant in CCR6 is associated with susceptibility to antitopoisomerase-positive systemic sclerosis.
JO  - Arthritis Rheum.
VL  - 65
IS  - 12
PB  - Wiley-Blackwell
PY  - 2013
SN  - 0004-3591
ER  - 

TY  - JOUR
AB  - OBJECTIVE: It is difficult to identify a single causative factor for inflammatory arthritis because of the multifactorial nature of the disease. This study was undertaken to dissect the molecular complexity of systemic inflammatory disease, utilizing a combined approach of mutagenesis and systematic phenotype screening in a murine model. METHODS: In a large-scale N-ethyl-N-nitrosourea mutagenesis project, the Ali14 mutant mouse strain was established because of dominant inheritance of spontaneous swelling and inflammation of the hind paws. Genetic mapping and subsequent candidate gene sequencing were conducted to find the causative gene, and systematic phenotyping of Ali14/+ mice was performed in the German Mouse Clinic. RESULTS: A novel missense mutation in the phospholipase Cγ2 gene (Plcg2) was identified in Ali14/+ mice. Because of the hyperreactive external entry of calcium observed in cultured B cells and other in vitro experiments, the Ali14 mutation is thought to be a novel gain-of-function allele of Plcg2. Findings from systematic screening of Ali14/+ mice demonstrated various phenotypic changes: an abnormally high T cell:B cell ratio, up-regulation of Ig, alterations in body composition, and a reduction in cholesterol and triglyceride levels in peripheral blood. In addition, spermatozoa from Ali14/+ mice failed to fertilize eggs in vitro, despite the normal fertility of the Ali14/+ male mice in vivo. CONCLUSION: These results suggest that the Plcg2-mediated pathways play a crucial role in various metabolic and sperm functions, in addition to initiating and maintaining the immune system. These findings may indicate the importance of the Ali14/+ mouse strain as a model for systemic inflammatory diseases and inflammation-related metabolic changes in humans.
AU  - Abe, K.
AU  - Fuchs, H.
AU  - Boersma, A.
AU  - Hans, W.
AU  - Yu, P.
AU  - Kalaydjiev, S.
AU  - Klaften, M.
AU  - Adler, T.
AU  - Calzada-Wack, J.
AU  - Mossbrugger, I.
AU  - Rathkolb, B.
AU  - Rozman, J.*
AU  - Prehn, C.
AU  - Maraslioglu, M.*
AU  - Kametani, Y.*
AU  - Shimada, S.*
AU  - Adamski, J.
AU  - Busch, D.H.
AU  - Esposito, I.
AU  - Klingenspor, M.*
AU  - Wolf, E.
AU  - Wurst, W.
AU  - Gailus-Durner, V.
AU  - Katan, M.*
AU  - Marschall, S.
AU  - Soewarto, D.
AU  - Wagner, S.
AU  - Hrabě de Angelis, M.
C1  - 3755
C2  - 28497
SP  - 1301-1311
TI  - A novel N-ethyl-N-nitrosourea-induced mutation in phospholipase Cγ2 causes inflammatory arthritis, metabolic defects, and male infertility in vitro in a murine model.
JO  - Arthritis Rheum.
VL  - 63
IS  - 5
PB  - Wiley-Blackwell
PY  - 2011
SN  - 0004-3591
ER  - 

TY  - JOUR
AB  - Several autoimmune disorders, including systemic sclerosis (SSc), are characterized by a strong sex bias. To date, it is not known whether genes on the sex chromosomes influence SSc susceptibility. Recently, an IRAK1 haplotype that contains the 196Phe functional variant (rs1059702), located on Xq28, was found to confer susceptibility to systemic lupus erythematosus (SLE). This study was undertaken to test for an association between SSc and the IRAK1 SLE risk haplotype. We tested for an association with the IRAK1 SLE risk haplotype in a discovery set of 849 SSc patients and 625 controls. IRAK1 rs1059702 was further genotyped in a replication set, which included Caucasian women from Italy (493 SSc patients and 509 controls) and Germany (466 SSc patients and 1,083 controls. An association between the IRAK1 haplotype and SSc was detected in the discovery set. In both the discovery and replication sets, the rs1059702 TT genotype was found to be associated with specific SSc subsets, highlighting a potential contribution to disease severity. A meta-analysis provided evidence of an association of both the T allele and TT genotype with the overall disease, with an odds ratio (OR) of 1.20 and 95% confidence interval (95% CI) of 1.06-1.35 for the T allele (P = 0.003) and an OR of 1.49 and 95% CI of 1.06-2.10 for the TT genotype (P = 0.023). However, the most notable associations were observed with the diffuse cutaneous, anti-topoisomerase I antibody positive, and SSc-related fibrosing alveolitis subsets (OR 2.35 [95% CI 1.51-3.66], P = 1.56 × 10(-4), OR 2.84 [95% CI 1.87-4.32], P = 1.07 × 10(-6), and OR 2.09 [95% CI 1.35-3.24], P = 9.05 × 10(-4), respectively). Our study provides the first evidence of an association between IRAK1 and SSc, demonstrating that a sex chromosome gene directly influences SSc susceptibility and its phenotypic heterogeneity.
AU  - Dieudé, P.*
AU  - Bouaziz, M.*
AU  - Guedj, M.*
AU  - Riemekasten, G.*
AU  - Airo, P.*
AU  - Müller, M.
AU  - Cusi, D.*
AU  - Matucci-Cerinic, M.*
AU  - Melchers, I.*
AU  - Koenig, W.*
AU  - Salvi, E.*
AU  - Wichmann, H.-E.
AU  - Cuomo, G.*
AU  - Hachulla, E.*
AU  - Diot, E.*
AU  - Hunzelmann, N.*
AU  - Caramaschi, P.*
AU  - Mouthon, L.*
AU  - Riccieri, V.*
AU  - Distler, J.*
AU  - Tarner, I.*
AU  - Avouac, J.*
AU  - Meyer, O.*
AU  - Kahan, A.*
AU  - Chiocchia, G.*
AU  - Boileau, C.*
AU  - Allanore, Y.*
C1  - 6911
C2  - 29446
CY  - Atlanta, USA
SP  - 3979-3987
TI  - Evidence of the contribution of the X chromosome to systemic sclerosis susceptibility: Association with the functional IRAK1 196Phe/532Ser haplotype.
JO  - Arthritis Rheum.
VL  - 63
IS  - 12
PB  - Arthritis Foundation
PY  - 2011
SN  - 0004-3591
ER  - 

TY  - JOUR
AB  - Induction of arthritis with autoantibodies against glucose-6-phosphate isomerase (GPI) is entirely independent of T cells and B cells but is strictly dependent on the presence of mast cells. Here, we used this disease model to analyze whether exclusive intraarticular mast cell reconstitution is sufficient for disease induction and whether targeted mast cell silencing can prevent neoangiogenesis and joint destruction, 2 hallmarks of rheumatoid arthritis. METHODS: Ankle swelling and clinical index scores were determined after injection of either K/BxN mouse-derived serum or control serum in wild-type Kit(+)/Kit(+) mice, congenic mast cell-deficient Kit(W)/Kit(W-v) mice, or mast cell-deficient Kit(W)/Kit(W-v) mice reconstituted with mast cells, either by intraperitoneal or selective intraarticular injection. Angiogenesis was quantified in vivo by measuring activated alphavbeta3 integrin using (18)F-galacto-RGD and positron emission tomography. In addition, staining of joint tissue with hematoxylin and eosin, Giemsa, beta3, and alpha-actin was performed. The effect of mast cell stabilization by treatment with cromolyn or salbutamol was investigated in C57BL/6 or BALB/c mice. RESULTS: Comparing wild-type mice, mast cell-deficient Kit(W)/Kit(W-v) mice, and mast cell-reconstituted Kit(W)/Kit(W-v) mice, we first showed that intraarticular and intraperitoneal mast cell engraftment fully restores susceptibility to antibody-induced arthritis, angiogenesis, and alphavbeta3 integrin activation. Importantly, selective mast cell silencing with either salbutamol or cromolyn prevented alphavbeta3 integrin activation, angiogenesis, and joint destruction. CONCLUSION: Mast cell engraftment fully restores susceptibility to alphavbeta3 integrin activation, angiogenesis, and joint destruction in GPI antibody-induced arthritis. Importantly, selective mast cell stabilization prevents alphavbeta3 integrin activation, angiogenesis, and joint destruction.
AU  - Kneilling, M.*
AU  - Hültner, L.
AU  - Pichler, B.J.*
AU  - Mailhammer, R.
AU  - Morawietz, L.*
AU  - Solomon, S.*
AU  - Eichner, M.*
AU  - Sabatino, J.
AU  - Biedermann, T.*
AU  - Krenn, V.*
AU  - Weber, W.A.*
AU  - Illges, H.*
AU  - Haubner, R.*
AU  - Röcken, M.*
C1  - 3768
C2  - 24654
SP  - 1806-1816
TI  - Targeted mast cell silencing protects against joint destruction and angiogenesis in experimental arthritis in mice.
JO  - Arthritis Rheum.
VL  - 56
IS  - 6
PB  - Wiley-Blackwell
PY  - 2007
SN  - 0004-3591
ER  - 

TY  - JOUR
AB  - Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is an inherited autosomal-dominant autoinflammatory condition caused by mutations in the ectodomain of the 55-kd tumor necrosis factor (TNF) receptor superfamily 1A. Proinflammatory blood monocytes with the phenotype CD14+,CD16+,HLA-DR++ are a major source of TNF, and the number of such monocytes is increased during infection and inflammation. The aim of this study was to investigate whether the expression of circulating CD16+ monocytes is affected in patients with TRAPS. METHODS: Peripheral blood obtained from patients with TRAPS and healthy control subjects was stained with monoclonal antibodies to detect CD14++,CD16- monocytes and CD14+,CD16+ monocytes, using flow cytometry. Lipopolysaccharide-induced TNF production was measured by intracellular cytokine staining. Activation-induced shedding of CD16 was investigated by treating blood samples with phorbol myristate acetate. RESULTS: The level of CD16 expression by CD14+,CD16+ monocytes, but not their absolute number, was significantly elevated in patients with TRAPS, even though the patients were not experiencing clinically overt episodes of autoinflammation at the time of sampling. These findings are similar to those for the C-reactive protein levels and erythrocyte sedimentation rates in the same patients. The enhanced level of CD16 expression by monocytes from patients with TRAPS was not attributable to a defect in activation-induced shedding of CD16. The CD14+,CD16+ monocytes were the predominant source of TNF in both patients and healthy control subjects. CONCLUSION: The level of CD16 expression by monocytes was elevated in patients with TRAPS, as a feature of the underlying constitutive inflammation status.
AU  - Todd, I.*
AU  - Radford, P.M.*
AU  - Ziegler-Heitbrock, L.
AU  - Ghaemmaghami, A.M.*
AU  - Powell, R.J.*
AU  - Tighe, P.J.*
C1  - 2048
C2  - 24977
SP  - 4182-4188
TI  - Elevated CD16 expression by monocytes from patients with tumor necrosis factor receptor-associated periodic syndrome.
JO  - Arthritis Rheum.
VL  - 56
IS  - 12
PB  - Wiley-Blackwell
PY  - 2007
SN  - 0004-3591
ER  - 

TY  - JOUR
AB  - Objective
      	
      		
      			Quantitative diagnostic tools for osteoarthritis (OA) are important for evaluating the treatment response to structure-modifying drugs. This study was undertaken to test the technical validity (accuracy) of quantitative magnetic resonance imaging (qMRI) for reliable determination of the total bone interface area, percentage of cartilaginous (denuded) joint surface area, and cartilage thickness in OA.
      	
      
      
      	
      		Methods
      	
      		
      			High-resolution MRIs of femorotibial and patellar cartilage were acquired in 21 patients prior to total knee arthroplasty, using a T1-weighted gradient-echo sequence with water excitation. After segmentation of original bone interface areas (before disease onset) and the actual cartilage layer, the percentages of cartilaginous joint surface area, cartilage thickness, and cartilage volume were determined using proprietary software. During surgery, the patella and the medial and lateral tibia were resected. Results obtained with qMRI were compared with those obtained by direct image analysis of surface area, cartilage thickness, and cartilage volume of the surgically removed tissue.
      	
      
      
      	
      		Results
      	
      		
      			Pairwise differences between results obtained with qMRI and morphologic analysis were ±4.6% for percentage of cartilaginous surface area, ±8.9% for cartilage thickness, and ±9.1% for cartilage volume. Correlation coefficients ranged from 0.92 (thickness) to 0.98 (volume).
      	
      
      
      	
      		Conclusion
      	
      		
      			Quantitative MRI permits technically accurate and differential assessment of increases in eroded joint surface area and reductions in cartilage thickness in OA. The surrogate validity of these parameters requires testing in longitudinal studies. These parameters may be advantageous over determination of cartilage volume alone when diagnosing OA, exploring its progression, or testing responsiveness to new therapies.
      	
      
      
      	 
AU  - Graichen, H.*
AU  - von Eisenhart-Rothe, R.*
AU  - Vogl, T.*
AU  - Englmeier, K.-H.
AU  - Eckstein, F.*
C1  - 3343
C2  - 21913
SP  - 811-816
TI  - Quantitative assessment of cartilage status in osteoarthritis by quantitative magnetic resonance imaging: Technical validation for use in analysis of cartilage volume and further morphologic parameters.
JO  - Arthritis Rheum.
VL  - 50
IS  - 3
PY  - 2004
SN  - 0004-3591
ER  - 

TY  - JOUR
AB  - Objective
      	
      		
      			T scores (an indicator of the difference between patients and young healthy subjects) and Z scores (an indicator of the difference between patients and age-matched healthy subjects) are used in the diagnosis of osteoporosis and form the current basis for the definition of osteoporosis by the World Health Organization. We tested the feasibility of using T and Z scores derived from quantitative cartilage imaging with magnetic resonance imaging (MRI) for the diagnosis of osteoarthritis (OA).
      	
      
      
      	
      		Methods
      	
      		
      			High-resolution MR images of tibial cartilage were acquired from 126 young healthy adults (ages 20–35 years), 24 age-matched elderly healthy adults (ages 50–75 years), 7 OA patients prior to tibial osteotomy, and 7 OA patients prior to knee arthroplasty. Cartilage volume, thickness, surface area, and original joint surface area (before onset of disease) were determined in the medial and lateral tibia.
      	
      
      
      	
      		Results
      	
      		
      			The cartilage volume of the medial tibia of osteotomy patients with varus malalignment displayed moderate T scores (−1.0), and more negative T scores (−3.8) were observed in knee arthroplasty patients with varus malalignment. Normalization of the cartilage volume to the original joint surface area substantially enhanced the scores in patients undergoing osteotomy (−2.3) and in patients undergoing knee arthroplasty (−5.5), and this was superior to the normalization ratios of cartilage volume to body height and cartilage volume to body weight, in terms of distinguishing the loss of articular cartilage.
      	
      
      
      	
      		Conclusion
      	
      		
      			Quantitative analysis of OA by MRI is feasible using T and Z scores. However, cartilage volume should be normalized to the individual joint surface area in order to maximize the discriminatory power of this technique for the diagnosis of OA.
      	
      
      
      	 
AU  - Burgkart, R.*
AU  - Glaser, C.*
AU  - Hinterwimmer, S.*
AU  - Hudelmaier, M.*
AU  - Englmeier, K.-H.
AU  - Reiser, M.*
AU  - Eckstein, F.*
C1  - 22384
C2  - 21301
SP  - 2829-2835
TI  - Feasibility of T and Z Scores from Magnetic Resonance Imaging Data for Quantification of Cartilage Loss in Osteoarthritis.
JO  - Arthritis Rheum.
VL  - 48
IS  - 10
PY  - 2003
SN  - 0004-3591
ER  - 

TY  - JOUR
AU  - Burgkart, R.*
AU  - Glaser, C.*
AU  - Hyhlik-Dürr, A.*
AU  - Englmeier, K.-H.
AU  - Reiser, M.*
AU  - Eckstein, F.*
C1  - 22171
C2  - 20871
SP  - 2072-2077
TI  - Magnetic resonance imaging-based assessment of cartilage loss in severe osteoarthritis: accuracy, precision, and diagnostic value.
JO  - Arthritis Rheum.
VL  - 44
PY  - 2001
SN  - 0004-3591
ER  - 

TY  - JOUR
AB  - OBJECTIVE: To examine the in vivo accuracy and precision of magnetic resonance imaging (MRI)-based assessment of cartilage loss in patients with severe osteoarthritis (OA) of the knee. METHODS: High-resolution MRI images of the tibial cartilage were obtained in 8 patients prior to total knee arthroplasty, using a water-excitation gradient-echo MRI sequence (acquisition time 6 minutes 19 seconds; spatial resolution 1.2 x 0.31 x 0.31 mm3). The MRI measurements were repeated after joint repositioning. The precision of the cartilage volume and thickness computations was determined after 3-dimensional reconstruction. During surgery, the tibial plateaus were resected, and the MRI data were compared with water displacement of surgically retrieved cartilage. RESULTS: The standard deviation (coefficient of variation) of repeated tibial cartilage volume measurements was 56 mm3 (5.5%) medially and 59 mm3 (3.8%) laterally. The deviation from surgically removed tissue was -13%, on average, with a high linear correlation between both methods (r = 0.98). In patients with varus OA, the tissue loss was estimated to be 1,290 mm3 in the medial tibia and 1,150 mm3 in the lateral tibia, compared with the data in healthy volunteers. CONCLUSION: Noninvasive quantitative MRI-based analysis of cartilage morphometry in severe OA is accurate, precise, and displays high potential diagnostic value.
AU  - Burgkart, R.*
AU  - Glaser, C.*
AU  - Hyhlik-Dürr, A.*
AU  - Englmeier, K.-H.
AU  - Reiser, M.*
AU  - Eckstein, F.*
C1  - 22507
C2  - 31107
SP  - 2072-2077
TI  - Magnetic resonance imaging-based assessment of cartilage loss in severe osteoarthritis: Accuracy, precision, and diagnostic value.
JO  - Arthritis Rheum.
VL  - 44
IS  - 9
PB  - Wiley
PY  - 2001
SN  - 0004-3591
ER  - 

TY  - JOUR
AB  - Objective
      	
      		
      			Alterations of cartilage morphology and mechanical properties occur in osteoarthritis, but it is unclear whether similar changes also take place physiologically during aging, in the absence of disease. In this in vivo study, we tested the hypothesis that thinning of knee joint cartilage occurs with aging and that elderly subjects display a different amount of cartilage deformation than do young subjects.
      	
      
      
      	
      		Methods
      	
      		
      			We evaluated 30 asymptomatic subjects ages 50–78 years. Morphologic parameters for the knee cartilage (mean and maximum thickness, surface area) were computed from magnetic resonance imaging data. Results were compared with those in 95 young asymptomatic subjects ages 20–30 years. Deformation of the patellar cartilage was determined after the subjects performed 30 knee bends.
      	
      
      
      	
      		Results
      	
      		
      			There was a significant reduction of patellar cartilage thickness in elderly women (−12%; P < 0.05), but not in elderly men (−6%). Femoral cartilage was significantly thinner in both sexes (−21% in women, −13% in men; P < 0.01), whereas tibial cartilage thickness displayed only nonsignificant trends (−10% in women, −7% in men). Patellar cartilage deformation was −2.6% in elderly women and −2.2% in elderly men. These values were significantly lower (P < 0.05) than those in young subjects.
      	
      
      
      	
      		Conclusion
      	
      		
      			We confirmed the hypothesis that knee cartilage becomes thinner during aging, in the absence of cartilage disease, but that the amount of reduction differs between sexes and between compartments of the knee joint. We show that under in vivo loading conditions, elderly subjects display a lower level of cartilage deformation than do healthy young subjects.
      	
      
      
      	 
AU  - Hudelmaier, M.*
AU  - Glaser, C.*
AU  - Hohe, J.*
AU  - Englmeier, K.-H.
AU  - Reiser, M.*
AU  - Putz, R.*
AU  - Eckstein, F.*
C1  - 21893
C2  - 20134
SP  - 2556-2561
TI  - Age-Related Changes in the Morphology and Deformational Behavior of Knee Joint Cartilage.
JO  - Arthritis Rheum.
VL  - 44
IS  - 11
PY  - 2001
SN  - 0004-3591
ER  -