New classification of HLA-DRB1 alleles in rheumatoid arthritis susceptibility: a combined analysis of worldwide samples

IntroductionRheumatoid arthritis (RA) is a complex polygenic disease of unknown etiology. HLA-DRB1 alleles encoding the shared epitope (SE) (RAA amino acid pattern in positions 72 to 74 of the third hypervariable region of the DRbeta1 chain) are associated with RA susceptibility. A new classification of HLA-DRB1 SE alleles has been developed by Tezenas du Montcel and colleagues to refine the association between HLA-DRB1 and RA. In the present study, we used RA samples collected worldwide to investigate the relevance of this new HLA-DRB1 classification in terms of RA susceptibility across various Caucasoid and non-Caucasoid patients.MethodsEighteen subsamples were defined from a total number of 759 cases and 789 controls and grouped in 10 samples on the basis of their ethnic origin. HLA-DRB1 alleles were divided into five groups (S1, S2, S3D, S3P, and X) according to the new HLA-DRB1 allele classification. The whole analysis was performed by comparing carrier frequencies for the five HLA-DRB1 allele groups between RA patients and controls across the 10 Caucasoid and non-Caucasoid samples. The Mantel-Haenszel method of meta-analysis provided a global odds ratio (OR) estimate with 95% confidence interval (CI).ResultsA positive association with RA susceptibility was found for S2 allele carriers (OR 2.15, 95% CI 1.54 to 3.00; p < 10(-5)) and S3P allele carriers (OR 2.74, 95% CI 2.01 to 3.74; p < 10(-5)). A negative association was found for S1 alleles (OR 0.60, 95% CI 0.48 to 0.76; p < 10(-4)) and X alleles (OR 0.58, 95% CI 0.39 to 0.84; p = 4 x 10(-3)). No significant association was highlighted for the S3D group of alleles (OR 0.89, 95% CI 0.69 to 1.14; p = 0.89). The complementary genotype analysis fit with the genotype risk hierarchy previously reported in Caucasoid RA patients.ConclusionSo far, the present study is the first attempt to investigate the relevance of this new HLA-DRB1 classification in terms of RA susceptibility on both Caucasoid and non-Caucasoid samples. Our results support the hypothesis of a differential role played by different HLA-DRB1 allele groups in RA susceptibility across different ethnic backgrounds and confirm the interest of such an HLA-DRB1 classification in differentiating predisposing and protective alleles

Results From the Global Rheumatology Alliance Registry

Funding Information: We acknowledge financial support from the ACR and EULAR. The ACR and EULAR were not involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Publisher Copyright: © 2022 The Authors. ACR Open Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.Objective: Some patients with rheumatic diseases might be at higher risk for coronavirus disease 2019 (COVID-19) acute respiratory distress syndrome (ARDS). We aimed to develop a prediction model for COVID-19 ARDS in this population and to create a simple risk score calculator for use in clinical settings. Methods: Data were derived from the COVID-19 Global Rheumatology Alliance Registry from March 24, 2020, to May 12, 2021. Seven machine learning classifiers were trained on ARDS outcomes using 83 variables obtained at COVID-19 diagnosis. Predictive performance was assessed in a US test set and was validated in patients from four countries with independent registries using area under the curve (AUC), accuracy, sensitivity, and specificity. A simple risk score calculator was developed using a regression model incorporating the most influential predictors from the best performing classifier. Results: The study included 8633 patients from 74 countries, of whom 523 (6%) had ARDS. Gradient boosting had the highest mean AUC (0.78; 95% confidence interval [CI]: 0.67-0.88) and was considered the top performing classifier. Ten predictors were identified as key risk factors and were included in a regression model. The regression model that predicted ARDS with 71% (95% CI: 61%-83%) sensitivity in the test set, and with sensitivities ranging from 61% to 80% in countries with independent registries, was used to develop the risk score calculator. Conclusion: We were able to predict ARDS with good sensitivity using information readily available at COVID-19 diagnosis. The proposed risk score calculator has the potential to guide risk stratification for treatments, such as monoclonal antibodies, that have potential to reduce COVID-19 disease progression.publishersversionepub_ahead_of_prin

What has GWAS done for HLA and disease associations?

The major histocompatibility complex (MHC) is located in chromosome 6p21 and contains crucial regulators of immune response, including human leucocyte antigen (HLA) genes, alongside other genes with nonimmunological roles. More recently, a repertoire of noncoding RNA genes, including expressed pseudogenes, has also been identified. The MHC is the most gene dense and most polymorphic part of the human genome. The region exhibits haplotype-specific linkage disequilibrium patterns, contains the strongest cis- and trans-eQTLs/meQTLs in the genome and is known as a hot spot for disease associations. Another layer of complexity is provided to the region by the extreme structural variation and copy number variations. While the HLA-B gene has the highest number of alleles, the HLA-DR/DQ subregion is structurally most variable and shows the highest number of disease associations. Reliance on a single reference sequence has complicated the design, execution and analysis of GWAS for the MHC region and not infrequently, the MHC region has even been excluded from the analysis of GWAS data. Here, we contrast features of the MHC region with the rest of the genome and highlight its complexities, including its functional polymorphisms beyond those determined by single nucleotide polymorphisms or single amino acid residues. One of the several issues with customary GWAS analysis is that it does not address this additional layer of polymorphisms unique to the MHC region. We highlight alternative approaches that may assist with the analysis of GWAS data from the MHC region and unravel associations with all functional polymorphisms beyond single SNPs. We suggest that despite already showing the highest number of disease associations, the true extent of the involvement of the MHC region in disease genetics may not have been uncovered

Enjeux méthodologiques de l'analyse de marqueurs génétiques dans les études d'association de maladies multifactorielles (application à la polyarthrite rhumatoïde)

TOULOUSE3-BU Sciences (315552104) / SudocSudocFranceF

Enjeux méthodologiques de l'analyse de marqueurs génétiques dans les études d'association de maladies multifactorielles (application à la polyarthrite rhumatoïde)

TOULOUSE3-BU Sciences (315552104) / SudocSudocFranceF

Diagnostic value of ultrasound in calcium pyrophosphate deposition disease: a systematic review and meta-analysis

International audienceA systematic review and meta-analysis of data from cohort studies to analyse the diagnostic performances (ie, sensitivity and specificity) of ultrasound (US) for diagnosis of calcium pyrophosphate deposition (CPPD) disease with microscopic crystal detection used as a gold standard

Short-term Risk of Total Malignancy and Nonmelanoma Skin Cancers with Certolizumab and Golimumab in Patients with Rheumatoid Arthritis: Metaanalysis of Randomized Controlled Trials

International audienceObjective. To assess the risk of total malignancy and nonmelanoma skin cancers (NMSC) in patients with rheumatoid arthritis (RA) receiving certolizumab and golimumab through a metaanalysis of data from randomized control trials (RCT). Methods. We systematically reviewed the literature up to May 2011 in Medline databases, as well as abstracts from the 2009 and 2010 annual meetings of the European League Against Rheumatism and the American College of Rheumatology. Mantel-Haenszel method was used to determine a common odds ratio (OR). Statistical heterogeneity was assessed by chi-square Q test. We selected only RCT including more than 30 RA subjects randomly assigned to an anti-tumor necrosis factor (TNF) or a nonbiological disease-modifying antirheumatic drug (DMARD) control group. Results. The literature search identified 793 articles; 6 (2 with certolizumab and 4 with golimumab) were selected for metaanalysis. A total of 2710 patients received at least 1 dose of certolizumab or golimumab. For anti-TNF-treated patients, 18 cancers (excluding NMSC) and 9 NMSC were observed versus 4 cases of total malignancy and 3 NMSC in control groups. Metaanalysis revealed a pooled OR of 1.06 (95% CI 0.39–2.85) for risk of total malignancy and 0.69 (95% CI 0.23–2.11) for risk of NMSC with certolizumab and golimumab versus DMARD. Heterogeneity was not significant. Conclusion. Metaanalysis of RCT of golimumab and certolizumab did not find an increased risk of total malignancy and NMSC. These results must be confirmed with longterm extension studies and registry studies, and careful monitoring remains mandatory

Association of Body Mass Index Categories with Disease Activity and Radiographic Joint Damage in Rheumatoid Arthritis: A Systematic Review and Metaanalysis

International audienceOBJECTIVE:Obesity and overweight are increasing conditions. Adipose tissue with proinflammatory properties could be involved in rheumatoid arthritis (RA) activity and radiographic progression. This study aims to investigate the influence of overweight and obesity on RA activity and severity.METHODS:We conducted a systematic review and metaanalysis to assess the association of body mass index (BMI) categories with the Disease Activity Score in 28 joints (DAS28), functional disability [Health Assessment Questionnaire (HAQ)], and radiographic joint damage in patients with RA. We searched Medline through PubMed, EMBASE, and the Cochrane Database of Systematic Reviews for all studies assessing DAS28, HAQ, or/and radiographic damage according to predefined BMI groups.RESULTS:Among the 737 citations retrieved, 58 articles met the inclusion criteria and 7 were included in the metaanalysis. DAS28 was higher in obese (BMI > 30 kg/m(2)) than non-obese (BMI ≤ 30 kg/m(2)) patients (mean difference 0.14, 95% CI 0.01-0.27, p = 0.04, I(2) = 0%). HAQ score was also higher among obese patients (mean difference 0.10, 95% CI 0.01-0.19, p = 0.03, I(2) = 0%). Radiographic joint damage was negatively associated with obesity (standardized mean difference -0.15, 95% CI -0.29 to -0.02, p = 0.03, I(2) = 38%).CONCLUSION:Obesity in RA is associated with increased DAS28 and HAQ score and with lower radiographic joint damage. These associations mainly result from an increase of subjective components of the DAS28 (total joint count and global health assessment) in obese patients. Conflicting results were reported concerning inflammation markers (C-reactive protein and erythrocyte sedimentation rate)