ABSTRACT
Rheumatoid arthritis (RA) risk has a large genetic component (~60%) that is still not fully understood. This has hampered the design of effective treatments that could promise lifelong remission. RA is a polygenic disease with 106 known genome-wide significant associated loci and thousands of small effect causal variants. Our current understanding of RA risk has suggested cell-type-specific contexts for causal variants, implicating CD4 + effector memory T cells, as well as monocytes, B cells and stromal fibroblasts. While these cellular states and categories are still mechanistically broad, future studies may identify causal cell subpopulations. These efforts are propelled by advances in single cell profiling. Identification of causal cell subpopulations may accelerate therapeutic intervention to achieve lifelong remission.
Subject(s)
Arthritis, Rheumatoid/genetics , B-Lymphocytes/physiology , CD4-Positive T-Lymphocytes/physiology , Fibroblasts/physiology , Monocytes/physiology , Animals , Genetic Association Studies , Genetic Predisposition to Disease , Humans , Immunologic Memory , RiskABSTRACT
With the worldwide digitalisation of medical records, electronic health records (EHRs) have become an increasingly important source of real-world data (RWD). RWD can complement traditional study designs because it captures almost the complete variety of patients, leading to more generalisable results. For rheumatology, these data are particularly interesting as our diseases are uncommon and often take years to develop. In this review, we discuss the following concepts related to the use of EHR for research and considerations for translation into clinical care: EHR data contain a broad collection of healthcare data covering the multitude of real-life patients and the healthcare processes related to their care. Machine learning (ML) is a powerful method that allows us to leverage a large amount of heterogeneous clinical data for clinical algorithms, but requires extensive training, testing, and validation. Patterns discovered in EHR data using ML are applicable to real life settings, however, are also prone to capturing the local EHR structure and limiting generalisability outside the EHR(s) from which they were developed. Population studies on EHR necessitates knowledge on the factors influencing the data available in the EHR to circumvent biases, for example, access to medical care, insurance status. In summary, EHR data represent a rapidly growing and key resource for real-world studies. However, transforming RWD EHR data for research and for real-world evidence using ML requires knowledge of the EHR system and their differences from existing observational data to ensure that studies incorporate rigorous methods that acknowledge or address factors such as access to care, noise in the data, missingness and indication bias.
Subject(s)
Artificial Intelligence , Electronic Health Records , Humans , Algorithms , Machine Learning , Research DesignABSTRACT
OBJECTIVES: The human leukocyte antigen-shared epitope (HLA-SE) alleles and smoking are the most prominent genetic and environmental risk factors for rheumatoid arthritis (RA). However, at which pre-arthritis stage (asymptomatic/symptomatic) they exert their effect is unknown. We aimed to determine whether HLA-SE and smoking are involved in the onset of autoantibody positivity, symptoms (clinically suspect arthralgia (CSA)) and/or progression to clinical arthritis. METHODS: We performed meta-analyses on results from the literature on associations of HLA-SE and smoking with anti-citrullinated protein antibodies (ACPAs) in the asymptomatic population. Next, we studied associations of HLA-SE and smoking with autoantibody positivity at CSA onset and with progression to clinical inflammatory arthritis (IA) during follow-up. Associations in ACPA-positive patients with CSA were validated in meta-analyses with other arthralgia cohorts. Analyses were repeated for rheumatoid factor (RF), anti-carbamylated protein antibodies (anti-CarP) and anti-acetylated protein antibodies (AAPA). RESULTS: Meta-analyses showed that HLA-SE is not associated with ACPA positivity in the asymptomatic population (OR 1.06 (95% CI:0.69 to 1.64)), whereas smoking was associated (OR 1.37 (95% CI: 1.15 to 1.63)). At CSA onset, both HLA-SE and smoking associated with ACPA positivity (OR 2.08 (95% CI: 1.24 to 3.49), OR 2.41 (95% CI: 1.31 to 4.43)). During follow-up, HLA-SE associated with IA development (HR 1.86 (95% CI: 1.23 to 2.82)), in contrast to smoking. This was confirmed in meta-analyses in ACPA-positive arthralgia (HR 1.52 (95% CI: 1.08 to 2.15)). HLA-SE and smoking were not associated with RF, anti-CarP or AAPA-positivity at CSA onset. Longitudinally, AAPA associated with IA development independent from ACPA and RF (HR 1.79 (95% CI: 1.02 to 3.16)), anti-CarP did not. CONCLUSIONS: HLA-SE and smoking act at different stages: smoking confers risk for ACPA and symptom development, whereas HLA-SE mediates symptom and IA development. These data enhance the understanding of the timing of the key risk factors in the development of RA.
Subject(s)
Anti-Citrullinated Protein Antibodies/blood , Arthralgia/blood , Arthritis, Rheumatoid/blood , Arthritis, Rheumatoid/etiology , HLA Antigens/genetics , Tobacco Smoking , Alleles , Arthritis, Rheumatoid/genetics , Arthritis, Rheumatoid/immunology , Asymptomatic Diseases , Disease Progression , Epitopes/genetics , Humans , Rheumatoid Factor/blood , Risk FactorsABSTRACT
BACKGROUND: Genetic variants in complement genes have been associated with a wide range of human disease states, but well-powered genetic association studies of complement activation have not been performed in large multiethnic cohorts. METHODS: We performed medical records-based genome-wide and phenome-wide association studies for plasma C3 and C4 levels among participants of the Electronic Medical Records and Genomics (eMERGE) network. RESULTS: In a GWAS for C3 levels in 3949 individuals, we detected two genome-wide significant loci: chr.1q31.3 (CFH locus; rs3753396-A; ß=0.20; 95% CI, 0.14 to 0.25; P=1.52x10-11) and chr.19p13.3 (C3 locus; rs11569470-G; ß=0.19; 95% CI, 0.13 to 0.24; P=1.29x10-8). These two loci explained approximately 2% of variance in C3 levels. GWAS for C4 levels involved 3998 individuals and revealed a genome-wide significant locus at chr.6p21.32 (C4 locus; rs3135353-C; ß=0.40; 95% CI, 0.34 to 0.45; P=4.58x10-35). This locus explained approximately 13% of variance in C4 levels. The multiallelic copy number variant analysis defined two structural genomic C4 variants with large effect on blood C4 levels: C4-BS (ß=-0.36; 95% CI, -0.42 to -0.30; P=2.98x10-22) and C4-AL-BS (ß=0.25; 95% CI, 0.21 to 0.29; P=8.11x10-23). Overall, C4 levels were strongly correlated with copy numbers of C4A and C4B genes. In comprehensive phenome-wide association studies involving 102,138 eMERGE participants, we cataloged a full spectrum of autoimmune, cardiometabolic, and kidney diseases genetically related to systemic complement activation. CONCLUSIONS: We discovered genetic determinants of plasma C3 and C4 levels using eMERGE genomic data linked to electronic medical records. Genetic variants regulating C3 and C4 levels have large effects and multiple clinical correlations across the spectrum of complement-related diseases in humans.
Subject(s)
Complement C3/genetics , Complement C3/metabolism , Complement C4/genetics , Complement C4/metabolism , Genetic Variation , Medical Records , Adult , Aged , Alleles , Complement Activation/genetics , Databases, Genetic , Epidemiologic Studies , Female , Gene Dosage , Genetic Loci , Genome-Wide Association Study , Humans , Male , Medical Record Linkage , Middle Aged , Young AdultABSTRACT
The Electronic Medical Records and Genomics (eMERGE) network is a network of medical centers with electronic medical records linked to existing biorepository samples for genomic discovery and genomic medicine research. The network sought to unify the genetic results from 78 Illumina and Affymetrix genotype array batches from 12 contributing medical centers for joint association analysis of 83,717 human participants. In this report, we describe the imputation of eMERGE results and methods to create the unified imputed merged set of genome-wide variant genotype data. We imputed the data using the Michigan Imputation Server, which provides a missing single-nucleotide variant genotype imputation service using the minimac3 imputation algorithm with the Haplotype Reference Consortium genotype reference set. We describe the quality control and filtering steps used in the generation of this data set and suggest generalizable quality thresholds for imputation and phenotype association studies. To test the merged imputed genotype set, we replicated a previously reported chromosome 6 HLA-B herpes zoster (shingles) association and discovered a novel zoster-associated loci in an epigenetic binding site near the terminus of chromosome 3 (3p29).
Subject(s)
Electronic Health Records , Genetic Predisposition to Disease , Genome-Wide Association Study , Herpes Zoster/genetics , Algorithms , Black People/genetics , Chromosomes, Human/genetics , Female , Haplotypes/genetics , Homozygote , Humans , Male , Phenotype , Polymorphism, Single Nucleotide/genetics , Principal Component Analysis , White People/geneticsSubject(s)
Scleroderma, Systemic/pathology , Disease Progression , Female , Humans , Male , Middle Aged , Time FactorsABSTRACT
OBJECTIVES: Anticitrullinated protein antibodies (ACPA) are specific for rheumatoid arthritis (RA) and have been implicated in disease pathogenesis. Previously we have shown that ACPA display a considerably lower avidity as compared with antibodies against recall antigens. Nonetheless, ACPA-avidity did vary between patients. As antibody mediated effects are influenced by antibody-avidity, we now investigated ACPA-avidity in relation to biological activity and clinical outcome. METHODS: We determined the avidity of ACPA and related this with severity of joint damage in two Dutch early-RA cohorts containing 199 and 132 patients respectively. Differences in effector functions of low- and high-avidity ACPA were studied. RESULTS: Extensive variation in ACPA-avidity between patients was observed. This allowed the analysis of the relationship between avidity and severity. The presence of low-avidity ACPA is associated with a higher rate of joint destruction. This finding was replicated in an independent cohort. Analysis of the properties of low-versus high-avidity ACPA revealed that low-avidity ACPA are less hampered in their ability to bind 'new' citrullinated antigens. Although no differences could be observed regarding cellular activation via Fc-γ receptors, low-avidity ACPA were more potent in activating the complement system. CONCLUSIONS: Patients with low-avidity ACPA display a higher rate of joint destruction. Low-avidity ACPA display a higher potency to interact with more citrullinated antigens in time and show that low-avidity ACPA are more potent in complement activation. These data indicate that (low) avidity impacts on the biological activity of ACPA and associates with a worse radiological outcome.
Subject(s)
Arthritis, Rheumatoid/diagnostic imaging , Arthritis, Rheumatoid/immunology , Joints/immunology , Peptides, Cyclic/immunology , Severity of Illness Index , Adolescent , Adult , Aged , Aged, 80 and over , Antibody Affinity/immunology , Antigens/immunology , Arthrography , Cohort Studies , Complement System Proteins/immunology , Epitopes/immunology , Female , Follow-Up Studies , Humans , Male , Middle Aged , Young AdultABSTRACT
BACKGROUND: Joint destruction is a hallmark of autoantibody-positive rheumatoid arthritis (RA), though the severity is highly variable between patients. The processes underlying these interindividual differences are incompletely understood. METHODS: We performed a genome-wide association study on the radiological progression rate in 384 autoantibody-positive patients with RA. In stage-II 1557 X-rays of 301 Dutch autoantibody-positive patients with RA were studied and in stage-III 861 X-rays of 742 North American autoantibody-positive patients with RA. Sperm-Associated Antigen 16 (SPAG16) expression in RA synovium and fibroblast-like synoviocytes (FLS) was examined using Real-Time Quantitative Polymerase Chain Reaction (RT-qPCR) and immunohistochemistry. FLS secrete metalloproteinases that degrade cartilage and bone. SPAG16 genotypes were related to matrix metalloproteinase (MMP)-3 and MMP-1 expression by FLS in vitro and MMP-3 production ex vivo. RESULTS: A cluster of single nucleotide polymorphisms (SNPs) at 2q34, located at SPAG16, associated with the radiological progression rate; rs7607479 reached genome-wide significance. A protective role of rs7607479 was replicated in European and North American patients with RA. Per minor allele, patients had a 0.78-fold (95% CI 0.67 to 0.91) progression rate over 7 years. mRNA and protein expression of SPAG16 in RA synovium and FLS was verified. FLS carrying the minor allele secreted less MMP-3 (p=1.60×10(-2)). Furthermore, patients with RA carrying the minor allele had lower serum levels of MMP-3 (p=4.28×10(-2)). In a multivariate analysis on rs7607479 and MMP-3, only MMP-3 associated with progression (p=2.77×10(-4)), suggesting that the association between SPAG16-rs7607479 and joint damage is mediated via an effect on MMP-3 secretion. CONCLUSIONS: Genetic and functional analyses indicate that SPAG16 influences MMP-3 regulation and protects against joint destruction in autoantibody-positive RA. These findings could enhance risk stratification in autoantibody-positive RA.
Subject(s)
Arthritis, Rheumatoid/genetics , Autoantibodies/analysis , Adult , Aged , Arthritis, Rheumatoid/immunology , Arthritis, Rheumatoid/metabolism , Disease Progression , Female , Genome-Wide Association Study , Genotype , Humans , Male , Matrix Metalloproteinase 3/biosynthesis , Matrix Metalloproteinase 3/blood , Microtubule-Associated Proteins/genetics , Microtubule-Associated Proteins/metabolism , Middle Aged , Polymorphism, Single Nucleotide , Synovial Membrane/metabolismABSTRACT
OBJECTIVE: There is increasing evidence to indicate that genetic factors contribute significantly to radiologic joint damage in rheumatoid arthritis (RA). The aim of the present study was to determine whether genotypes of 10 recently identified RA susceptibility loci are associated with radiologic severity. METHODS: A 2-stage study was performed using 3 Northern European RA populations: a British cross-sectional population (discovery cohort; n=885) and the Leiden Early Arthritis Clinic (EAC) cohort (n=581) and Yorkshire Early Arthritis Register (YEAR) cohort (n=418) (validation cohorts). Radiologic damage was assessed using a modified Larsen method for scoring radiographs (in the discovery cohort) or modified Sharp/van der Heijde score (in the 2 validation cohorts). A meta-analysis was performed to bring together the evidence from the 3 studies, using data on radiologic severity of joint damage from a single time point. RESULTS: An allele-dose association of rs26232 was present in the discovery population (P=4×10(-4)); the median modified Larsen scores of radiologic joint damage per genotype were 31 (for those with CC), 27 (for those with CT), and 16 (for those with TT). The allele-dose association of rs26232 was replicated in both the Leiden EAC cohort during the initial 7 years of RA (P=0.04) and the YEAR cohort (P=0.039). In a fixed-effects meta-analysis of all 3 studies, the per T allele effect on the ratio of radiologic severity scores was 0.90 (95% confidence interval 0.84, 0.96; P=0.004). CONCLUSION: The variant rs26232, in the first intron of the C5orf30 locus, is associated with the severity of radiologic damage in RA and is independent of established prognostic biomarkers. The biologic activities of C5orf30 are unknown, but our genetic data suggest that it is involved in mediating joint damage in RA.
Subject(s)
Alleles , Arthritis, Rheumatoid/diagnostic imaging , Arthritis, Rheumatoid/genetics , Genetic Variation/genetics , Mitochondrial Proteins/genetics , Adult , Aged , Aged, 80 and over , Carrier Proteins/genetics , Cohort Studies , Cross-Sectional Studies , Europe , Female , Foot Joints/diagnostic imaging , Foot Joints/pathology , Genetic Predisposition to Disease/genetics , Genotype , Hand Joints/diagnostic imaging , Hand Joints/pathology , Humans , Male , Middle Aged , Phosphoproteins , Radiography , Severity of Illness Index , United KingdomABSTRACT
Autoimmune responses against posttranslationally modified antigens are a hallmark of several autoimmune diseases. For example, antibodies against citrullinated protein antigens (ACPA) have shown their relevance for the prognosis and diagnosis of rheumatoid arthritis (RA), and have been implicated in disease pathogenesis. It is conceivable that other autoantibody systems, recognizing other posttranslationally modified proteins, are also present in RA. Here, we describe the presence of an autoantibody system that discriminates between citrulline- and homocitrulline-containing antigens in the sera of RA-patients. IgG antibodies recognizing carbamylated (homocitrulline-containing) antigens were present in sera of over 45% of RA-patients. Likewise, anticarbamylated protein (anti-CarP) IgA antibodies were observed in 43% of RA-sera. ACPA and anti-CarP antibodies are distinct autoantibodies because, in selected double-positive patients, the anti-CarP antibody binding to carbamylated antigens could be inhibited by carbamylated antigens, but not by control or citrullinated antigens. Similarly, ACPA-binding to citrullinated antigens could only be inhibited by citrullinated antigens. In line with this observation, 16% of ACPA-negative RA-patients, as measured by a standard ACPA assay, harbored IgG anti-CarP antibodies, whereas 30% of these patients tested positive for IgA anti-CarP antibodies. The presence of anti-CarP antibodies was predictive for a more severe disease course in ACPA-negative patients as measured by radiological progression. Taken together, these data show the presence of a unique autoantibody system recognizing carbamylated, but not citrullinated, protein antigens. These antibodies are predictive for a more severe clinical course in ACPA-negative RA-patients, indicating that anti-CarP antibodies are a unique and relevant serological marker for ACPA-negative RA.
Subject(s)
Arthritis, Rheumatoid/immunology , Autoantibodies/blood , Blood Proteins/immunology , Arthritis, Rheumatoid/pathology , Autoantigens/blood , Autoantigens/chemistry , Biomarkers/blood , Blood Proteins/chemistry , Case-Control Studies , Citrulline/analogs & derivatives , Citrulline/chemistry , Humans , Immunoglobulin A/blood , Immunoglobulin G/blood , Joints/pathologyABSTRACT
BACKGROUND: Because anti-neutrophil cytoplasmatic antibody (ANCA)-associated vasculitis (AAV) is a rare, life-threatening, auto-immune disease, conducting research is difficult but essential. A long-lasting challenge is to identify rare AAV patients within the electronic-health-record (EHR)-system to facilitate real-world research. Artificial intelligence (AI)-search tools using natural language processing (NLP) for text-mining are increasingly postulated as a solution. METHODS: We employed an AI-tool that combined text-mining with NLP-based exclusion, to accurately identify rare AAV patients within large EHR-systems (>2.000.000 records). We developed an identification method in an academic center with an established AAV-training set (n = 203) and validated the method in a non-academic center with an AAV-validation set (n = 84). To assess accuracy anonymized patient records were manually reviewed. RESULTS: Based on an iterative process, a text-mining search was developed on disease description, laboratory measurements, medication and specialisms. In the training center, 608 patients were identified with a sensitivity of 97.0 % (95%CI [93.7, 98.9]) and positive predictive value (PPV) of 56.9 % (95%CI [52.9, 60.1]). NLP-based exclusion resulted in 444 patients increasing PPV to 77.9 % (95%CI [73.7, 81.7]) while sensitivity remained 96.3 % (95%CI [93.8, 98.0]). In the validation center, text-mining identified 333 patients (sensitivity 97.6 % (95%CI [91.6, 99.7]), PPV 58.2 % (95%CI [52.8, 63.6])) and NLP-based exclusion resulted in 223 patients, increasing PPV to 86.1 % (95%CI [80.9, 90.4]) with 98.0 % (95%CI [94.9, 99.4]) sensitivity. Our identification method outperformed ICD-10-coding predominantly in identifying MPO+ and organ-limited AAV patients. CONCLUSIONS: Our study highlights the advantages of implementing AI, notably NLP, to accurately identify rare AAV patients within large EHR-systems and demonstrates the applicability and transportability. Therefore, this method can reduce efforts to identify AAV patients and accelerate real-world research, while avoiding bias by ICD-10-coding.
Subject(s)
Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis , Artificial Intelligence , Humans , Natural Language Processing , Electronic Health Records , Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/diagnosis , SoftwareABSTRACT
Objective: Recently, a genome-wide association study identified an association between RA-associated interstitial lung disease (ILD) and RPA3-UMAD1 rs12702634 in the Japanese population, especially for patients with a usual interstitial pneumonia (UIP) pattern. We aimed to replicate this association in a European population and test for interaction with MUC5B rs35705950. Methods: In this genetic case-control association study, patients with RA and ILD and controls with RA and no ILD were included from France, the USA and the Netherlands. Only cases and controls from European genetic ancestries determined by principal components analysis were included in the analyses. RA was defined by the 1987 ACR or 2010 ACR/EULAR criteria and ILD by chest high-resolution CT scan, except in the control dataset from the Netherlands, where the absence of ILD was determined by chart review. Patients were genotyped for RPA3-UMAD1 rs12702634 and MUC5B rs35705950. Associations were tested using logistic regression adjusted for sex, age at RA onset, age at ILD onset or at certified absence of ILD, tobacco smoking status and country of origin. Results: Among the 883 patients included, 322 were RA-ILD cases (36.5%). MUC5B rs35705950 was strongly associated with RA-ILD in all datasets {combined adjusted odds ratio [OR] 2.9 [95% CI 2.1, 3.9], P = 1.1 × 10-11. No association between RPA3-UMAD1 rs12702634 and RA-ILD was observed [combined OR 1.2 (95% CI 0.8, 1.6), P = 0.31. No interaction was found between RPA3-UMAD1 rs12702634 and MUC5B rs35705950 (P = 0.70). Conclusion: Our findings did not support a contribution of RPA3-UMAD1 rs12702634 to the overall RA-ILD susceptibility in the European population.
ABSTRACT
BACKGROUND: According to the 2010 criteria, rheumatoid arthritis (RA) can be classified in the presence of ≥6 points on the criteria or 'typical' erosive disease. RA-specific erosiveness however has not been defined yet. This study reports the results of the data driven phase of a European League Against Rheumatism (EULAR) taskforce aiming to define RA-specific erosiveness. METHODS: Baseline radiographs of hands and feet of 980 Dutch and 811 French early arthritis patients were studied on the number and site of erosive joints. Test characteristics were determined, with the outcome measures being initiation of methotrexate (MTX) therapy or any disease modifying antirheumatic drug (DMARD) therapy within the first year of disease and arthritis persistency over 5 years. Analyses were repeated in the patients with <6 points on the American College of Rheumatology/EULAR 2010 criteria. RESULTS: In both cohorts comparable test characteristics were observed for the outcomes MTX therapy, any DMARD therapy and arthritis persistency. Test characteristics were not influenced by the site of erosiveness. The specificity observed was >50% for ≥1 erosive joint, >80% for ≥3 erosive joints and >90% for ≥5 erosive joints. When analysing the patients not fulfilling the 2010 criteria (n=308 and 149), specificity was >60% for ≥1 erosive joint, >90% for ≥3 erosive joints and >95% for ≥5 erosive joints. Few of these patients fulfilled the radiological criterion; 27-36 patients had ≥3 erosive joints and 13-14 patients had ≥5 erosive joints. CONCLUSIONS: RA-specific erosiveness can be defined with high specificity at several cut-offs for the number of erosive joints in two independent cohorts with multiple different outcomes. The final radiological criterion will be established in the next phase.
Subject(s)
Arthritis, Rheumatoid/classification , Arthritis, Rheumatoid/diagnostic imaging , Arthrography/standards , Joints/pathology , Severity of Illness Index , Adult , Aged , Antirheumatic Agents/therapeutic use , Arthritis, Rheumatoid/drug therapy , Diagnosis-Related Groups/standards , Disease Progression , Europe , Female , Humans , Male , Methotrexate/therapeutic use , Middle Aged , Predictive Value of Tests , Prognosis , Rheumatology/standards , Sensitivity and Specificity , Treatment OutcomeABSTRACT
BACKGROUND: Progression of joint destruction in rheumatoid arthritis (RA) is partly heritable; knowledge of genetic factors may increase our understanding of the mechanisms underlying joint destruction. The activity of the Wnt/ß-catenin pathway influences osteoblast differentiation. Dickkopf-1 (Dkk-1) and sclerostin (Sost) are negative regulators and lipoprotein receptor-related protein-5 (LRP-5) and Kremen-1 are transmembrane receptors involved in this pathway. OBJECTIVE: To study variants in the genes encoding these proteins in relation to progression of joint destruction. METHODS: 1418 patients with RA of four cohorts with 4885 sets of hands and feet x-rays were studied. Explorative analyses were performed on 600 patients with RA from Leiden on single nucleotide polymorphisms (SNPs) tagging Dkk-1, Sost, Kremen-1 and LRP-5. SNPs significantly associating with joint damage progression were subsequently genotyped in cohorts from Groningen (NL), Sheffield (UK) and Lund (Sweden). Data were summarised in meta-analyses. Serum levels of functional Dkk-1 and sclerostin were measured and studied in relation to genotypes. RESULTS: In the first cohort, six Dkk-1, three Sost, one Kremen-1 and 10 LRP-5 SNPs were significantly associated with radiological progression of joint destruction. Three Dkk-1 SNPs were associated significantly with progression of joint damage in the meta-analysis, also after correction for multiple testing (rs1896368, rs1896367 and rs1528873). Two Sost SNPs tended to significance (rs4792909 and rs6503475, p=0.07 after false discovery rate correction). Gene-gene interactions between SNPs on Dkk-1 and Sost were seen. Serum levels of Dkk-1 were significantly correlated with the genotypes in rs1896368 (p=0.02). CONCLUSIONS: Patients with RA carrying risk alleles of genetic variants in Dkk-1 have higher serum levels of functional Dkk-1 and more progressive joint destruction over time.
Subject(s)
Arthritis, Rheumatoid/genetics , Arthritis, Rheumatoid/metabolism , Bone Morphogenetic Proteins/genetics , Genetic Markers/genetics , Intercellular Signaling Peptides and Proteins/genetics , Low Density Lipoprotein Receptor-Related Protein-5/genetics , Membrane Proteins/genetics , Adaptor Proteins, Signal Transducing , Adult , Aged , Arthritis, Rheumatoid/epidemiology , Arthritis, Rheumatoid/pathology , Bone Morphogenetic Proteins/metabolism , Endonucleases/physiology , Female , Follow-Up Studies , Genetic Predisposition to Disease/epidemiology , Genetic Predisposition to Disease/genetics , Genotype , Humans , Intercellular Signaling Peptides and Proteins/metabolism , Joints/metabolism , Joints/pathology , Low Density Lipoprotein Receptor-Related Protein-5/metabolism , Male , Membrane Proteins/metabolism , Middle Aged , Osteoblasts/cytology , Osteoblasts/physiology , Polymorphism, Single Nucleotide/genetics , Risk Factors , Severity of Illness Index , Wnt Signaling Pathway/genetics , beta Catenin/genetics , beta Catenin/metabolismABSTRACT
The aim of this report was to propose a definition for erosive disease in the context of inflammatory arthritis in light of the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) rheumatoid arthritis (RA) criteria for use in clinical practice and studies. A EULAR task force was formed including 16 rheumatologists and one rheumatology fellow. The process was both evidence based and consensus based, and included, between March 2010 and April 2012, analyses of data from two cohorts, two face-to-face meetings, one online voting and one teleconference. The Leiden Early Arthritis Cohort and the French ESPOIR cohort were used for the evidence-based part. The outcome measures, which were initiation of methotrexate therapy, or any disease-modifying antirheumatic drug therapy within the first year of disease and arthritis persistency over 5 years, were studied with the aim to give the best definition of erosive disease. A decision was made to select a definition with a high specificity and focus on patients who did not otherwise fulfil the 2010 ACR/EULAR RA criteria (<6 points). By a unanimous vote the following definition was selected: erosive disease for use in the 2010 ACR/EULAR RA classification criteria is defined when an erosion (defined as a cortical break) is seen in at least three separate joints at any of the following sites: the proximal interphalangeal, the metacarpophalangeal, the wrist (counted as one joint) and the metatarsophalangeal joints on radiographs of both hands and feet. A highly specific definition for erosive disease has thus been formulated.
Subject(s)
Arthritis, Rheumatoid/classification , Arthritis, Rheumatoid/pathology , Evidence-Based Medicine/standards , Joints/pathology , Rheumatology/standards , Antirheumatic Agents/therapeutic use , Arthritis, Rheumatoid/drug therapy , Europe , HumansABSTRACT
OBJECTIVES: To determine whether molecular remission defined by a multi-biomarker disease activity (MBDA) score predicts a reduced risk of joint damage progression, and whether the MBDA score can augment existing classifications of remission. METHODS: The study examined 271 visits for 163 RA patients in the Leiden Early Arthritis Cohort. The MBDA score and other variables from each visit were evaluated for prediction of progression [change in Sharp-van der Heijde Score (ΔSHS) >3] over the ensuing 12 months. Positive likelihood ratios (PLRs) for non-progression were calculated for remission based upon DAS based on 28-joint counts and CRP (DAS28-CRP <2.32), EULAR/ACR Boolean criteria and MBDA score (≤25). RESULTS: Ninety-three per cent of patients in MBDA-defined remission did not experience progression, compared with 70% of patients not in MBDA remission (P = 0.001). There were no significant differences in the fraction of non-progressers between patients in remission and those not in remission using either DAS28-CRP or EULAR/ACR criteria. The PLR for non-progression over 12 months for MBDA remission was 4.73 (95% CI 1.67, 15.0). Among patients in DAS28-CRP remission, those with a high MBDA score were 2.3 times as likely (95% CI 1.1, 3.7) to have joint damage progression during the next year. CONCLUSION: MBDA-defined remission was an indicator of limited radiographic progression over the following 12 months. For patients in DAS28-CRP remission, high MBDA scores were a significant indicator of elevated risk of progression. MBDA results may provide a useful adjunct to clinical assessment to identify progression-free remission and assess subclinical disease.
Subject(s)
Arthritis, Rheumatoid/blood , Arthritis, Rheumatoid/diagnostic imaging , Biomarkers/blood , Disease Progression , Inflammation Mediators/blood , Adult , Aged , Ambulatory Care , Ambulatory Care Facilities , Antirheumatic Agents/therapeutic use , Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/physiopathology , Biomarkers/metabolism , Cohort Studies , Female , Humans , Male , Middle Aged , Monitoring, Physiologic/methods , Netherlands , Prognosis , Radiography , Risk Assessment , Sensitivity and Specificity , Severity of Illness Index , Treatment OutcomeABSTRACT
OBJECTIVES: There are conflicting reports concerning the association between alcohol consumption and RA. We performed a case-control study to investigate the association of alcohol consumption with RA as well as with other forms of arthritis. To assess whether alcohol consumption affects long-term disease outcome, we also investigated its association with radiographic progression and sustained drug-free remission in RA. METHODS: Patients with arthritis and various diagnoses including RA, OA, ReA, SpA and PsA were compared with 5868 controls from the general population. The association of disease with alcohol consumption was analysed by logistic regression analysis. RESULTS: Alcohol consumption was inversely associated with not only RA [odds ratio (OR) 0.28, 95% CI 0.23, 0.35] but also OA (OR 0.31, 95% CI 0.16, 0.62) and other forms of arthritis (OR 0.34, 95% CI 0.24, 0.48). A higher degree of systemic inflammation, reflected by the ESR and CRP level, was associated with a smaller proportion of patients consuming alcohol. There was no dose-response relationship between the amount of alcohol consumed and the presence of arthritis. The extent of joint destruction and the rate of sustained drug-free remission were not affected by alcohol consumption. CONCLUSION: Arthritis patients report less alcohol consumption than controls, regardless of the type of arthritis. This suggests that alcohol may either protect against different kinds of arthritis or that the inverse association between alcohol and arthritis may be secondary to disease development, with arthritis patients being less inclined to consume alcohol due to their decreased general well-being.
Subject(s)
Alcohol Drinking/epidemiology , Arthritis, Psoriatic/epidemiology , Arthritis, Rheumatoid/epidemiology , Osteoarthritis/epidemiology , Spondylarthritis/epidemiology , Adult , Aged , Arthritis, Psoriatic/diagnostic imaging , Arthritis, Rheumatoid/diagnostic imaging , Case-Control Studies , Disease Progression , Female , Humans , Male , Middle Aged , Osteoarthritis/diagnostic imaging , Prohibitins , Radiography , Severity of Illness Index , Spondylarthritis/diagnostic imagingABSTRACT
OBJECTIVE: One of the disease hallmarks of RA is progressive cartilage and bone destruction in the joints. The exact mechanism underlying this disease process is largely unknown. Nod1, an intracellular pattern recognition receptor expressed by the innate immune system, has been previously shown to display anti-inflammatory effects in experimental arthritis. Furthermore, an insertion/deletion polymorphism in NOD1 has been demonstrated to modulate cytokine responses of immune cells. In this study, the effect of the insertion/deletion polymorphism in NOD1 on RA susceptibility and severity was assessed. METHODS: Ex vivo stimulation of primary immune cells and osteoclasts with microbial triggers was performed to measure cytokine responses and osteoclast-specific gene expression in relation to the NOD1 genotype. In total, 1047 RA patients from two centres were genotyped for the NOD1 polymorphism and compared with 431 healthy controls. Clinical scores of joint inflammation and destruction were correlated with the NOD1 genotype. RESULTS: Functional analysis revealed increased production of pro-inflammatory cytokines in cells from individuals bearing the NOD1 +32656 insertion allele. Furthermore, osteoclast bone resorption activity was elevated, as reflected by increased expression of the lysosomal protease cathepsin K. However, the insertion allele of the NOD1 +32656 polymorphism was not associated with either susceptibility to, or clinical parameters of, inflammation or bone destruction in RA patients. CONCLUSION: These findings demonstrate that the NOD1 polymorphism modulates pro-inflammatory cytokine responses induced through Toll-like receptor or Nod-like receptor ligands. Nevertheless, these effects of genetic variation in NOD1 appear to be redundant in RA susceptibility and severity.
Subject(s)
Arthritis, Rheumatoid/genetics , Cytokines/metabolism , Genetic Predisposition to Disease , Nod1 Signaling Adaptor Protein/genetics , Polymorphism, Genetic , Adult , Arthritis, Rheumatoid/physiopathology , Bone Resorption/genetics , Bone Resorption/physiopathology , Case-Control Studies , Disease Progression , Female , Gene Expression Regulation , Genotype , Humans , Male , Middle Aged , Netherlands , Reference Values , Risk AssessmentABSTRACT
Remote patient monitoring (RPM) leverages advanced technology to monitor and manage patients' health remotely and continuously. In 2022 European Alliance of Associations for Rheumatology (EULAR) points-to-consider for remote care were published to foster adoption of RPM, providing guidelines on where to position RPM in our practices. Sample papers and studies describe the value of RPM. But for many rheumatologists, the unanswered question remains the 'how to?' implement RPM.Using the successful, though not frictionless example of the Southmead rheumatology department, we address three types of barriers for the implementation of RPM: service, clinician and patients, with subsequent learning points that could be helpful for new teams planning to implement RPM. These address, but are not limited to, data governance, selecting high quality cost-effective solutions and ensuring compliance with data protection regulations. In addition, we describe five lacunas that could further improve RPM when addressed: establishing quality standards, creating a comprehensive database of available RPM tools, integrating data with electronic patient records, addressing reimbursement uncertainties and improving digital literacy among patients and healthcare professionals.