The systemic lupus erythematosus IRF5 risk haplotype is associated with systemic sclerosis

Systemic sclerosis (SSc) is a fibrotic autoimmune disease in which the genetic component plays an important role. One of the strongest SSc association signals outside the human leukocyte antigen (HLA) region corresponds to interferon (IFN) regulatory factor 5 (IRF5), a major regulator of the type I IFN pathway. In this study we aimed to evaluate whether three different haplotypic blocks within this locus, which have been shown to alter the protein function influencing systemic lupus erythematosus (SLE) susceptibility, are involved in SSc susceptibility and clinical phenotypes. For that purpose, we genotyped one representative single-nucleotide polymorphism (SNP) of each block (rs10488631, rs2004640, and rs4728142) in a total of 3,361 SSc patients and 4,012 unaffected controls of Caucasian origin from Spain, Germany, The Netherlands, Italy and United Kingdom. A meta-analysis of the allele frequencies was performed to analyse the overall effect of these IRF5 genetic variants on SSc. Allelic combination and dependency tests were also carried out. The three SNPs showed strong associations with the global disease (rs4728142: P = 1.34×10<sup>−8</sup>, OR = 1.22, CI 95% = 1.14–1.30; rs2004640: P = 4.60×10<sup>−7</sup>, OR = 0.84, CI 95% = 0.78–0.90; rs10488631: P = 7.53×10<sup>−20</sup>, OR = 1.63, CI 95% = 1.47–1.81). However, the association of rs2004640 with SSc was not independent of rs4728142 (conditioned P = 0.598). The haplotype containing the risk alleles (rs4728142*A-rs2004640*T-rs10488631*C: P = 9.04×10<sup>−22</sup>, OR = 1.75, CI 95% = 1.56–1.97) better explained the observed association (likelihood P-value = 1.48×10<sup>−4</sup>), suggesting an additive effect of the three haplotypic blocks. No statistical significance was observed in the comparisons amongst SSc patients with and without the main clinical characteristics. Our data clearly indicate that the SLE risk haplotype also influences SSc predisposition, and that this association is not sub-phenotype-specific

IgA Anti-β2-Glycoprotein I Autoantibodies Are Associated with an Increased Risk of Thromboembolic Events in Patients with Systemic Lupus Erythematosus

The clinical utility of testing for antiphospholipid antibodies (aPL) of IgA isotype remains controversial.To address this issue, we reasoned that if IgA aPL contribute to the clinical manifestations of the antiphospholipid syndrome, then an association with thromboembolic events should manifest in patients whose only aPL is of IgA isotype. We performed a retrospective chart review of 56 patients (31 with systemic lupus erythematosus [SLE] and 25 without SLE) whose only positive aPL was IgA anti-beta2-glycoprotein I (isolated IgA anti-beta2GPI) and compared their clinical features with 56 individually matched control patients without any aPL. Patients with isolated IgA anti-beta2GPI had a significantly increased number of thromboembolic events, as compared to controls. When patients were stratified into those with and without SLE, the association between isolated IgA anti-beta2GPI and thromboembolic events persisted for patients with SLE, but was lost for those without SLE. Titers of IgA anti-beta2GPI were significantly higher in SLE patients who suffered a thromboembolic event. Among patients with isolated IgA anti-beta2GPI, there was an increased prevalence of diseases or morbidities involving organs of mucosal immunity (i.e., gastrointestinal system, pulmonary system, and skin).The presence of isolated IgA anti-beta2GPI is associated with an increased risk of thromboembolic events, especially among patients with SLE. IgA anti-beta2GPI is associated with an increased prevalence of morbidities involving organs of mucosal immunity

Investigation of potential non-HLA rheumatoid arthritis susceptibility loci in a European cohort increases the evidence for nine markers

BACKGROUND: Genetic factors have a substantial role in determining development of rheumatoid arthritis (RA), and are likely to account for 50-60% of disease susceptibility. Genome-wide association studies have identified non-human leucocyte antigen RA susceptibility loci which associate with RA with low-to-moderate risk. OBJECTIVES: To investigate recently identified RA susceptibility markers using cohorts from six European countries, and perform a meta-analysis including previously published results. METHODS: 3311 DNA samples were collected from patients from six countries (UK, Germany, France, Greece, Sweden and Denmark). Genotype data or DNA samples for 3709 controls were collected from four countries (not Sweden or Denmark). Eighteen single nucleotide polymorphisms (SNPs) were genotyped using Sequenom MassArray technology. Samples with a >95% success rate and only those SNPs with a genotype success rate of >95% were included in the analysis. Scandinavian patient data were pooled and previously published Swedish control data were accessed as a comparison group. Meta-analysis was used to combine results from this study with all previously published data. RESULTS: After quality control, 3209 patients and 3692 controls were included in the study. Eight markers (ie, rs1160542 (AFF3), rs1678542 (KIF5A), rs2476601 (PTPN22), rs3087243 (CTLA4), rs4810485 (CD40), rs5029937 (6q23), rs10760130 (TRAF1/C5) and rs7574865 (STAT4)) were significantly associated with RA by meta-analysis. All 18 markers were associated with RA when previously published studies were incorporated in the analysis. Data from this study increased the significance for association with RA and nine markers. CONCLUSIONS: In a large European RA cohort further evidence for the association of 18 markers with RA development has been obtained

Associations of baseline use of biologic or targeted synthetic DMARDs with COVID-19 severity in rheumatoid arthritis: Results from the COVID-19 Global Rheumatology Alliance physician registry.

OBJECTIVE: To investigate baseline use of biologic or targeted synthetic (b/ts) disease-modifying antirheumatic drugs (DMARDs) and COVID-19 outcomes in rheumatoid arthritis (RA). METHODS: We analysed the COVID-19 Global Rheumatology Alliance physician registry (from 24 March 2020 to 12 April 2021). We investigated b/tsDMARD use for RA at the clinical onset of COVID-19 (baseline): abatacept (ABA), rituximab (RTX), Janus kinase inhibitors (JAKi), interleukin 6 inhibitors (IL-6i) or tumour necrosis factor inhibitors (TNFi, reference group). The ordinal COVID-19 severity outcome was (1) no hospitalisation, (2) hospitalisation without oxygen, (3) hospitalisation with oxygen/ventilation or (4) death. We used ordinal logistic regression to estimate the OR (odds of being one level higher on the ordinal outcome) for each drug class compared with TNFi, adjusting for potential baseline confounders. RESULTS: Of 2869 people with RA (mean age 56.7 years, 80.8% female) on b/tsDMARD at the onset of COVID-19, there were 237 on ABA, 364 on RTX, 317 on IL-6i, 563 on JAKi and 1388 on TNFi. Overall, 613 (21%) were hospitalised and 157 (5.5%) died. RTX (OR 4.15, 95% CI 3.16 to 5.44) and JAKi (OR 2.06, 95% CI 1.60 to 2.65) were each associated with worse COVID-19 severity compared with TNFi. There were no associations between ABA or IL6i and COVID-19 severity. CONCLUSIONS: People with RA treated with RTX or JAKi had worse COVID-19 severity than those on TNFi. The strong association of RTX and JAKi use with poor COVID-19 outcomes highlights prioritisation of risk mitigation strategies for these people

Associations of baseline use of biologic or targeted synthetic DMARDs with COVID-19 severity in rheumatoid arthritis : Results from the COVID-19 Global Rheumatology Alliance physician registry

Funding Information: Competing interests JAS is supported by the National Institute of Arthritis and Funding Information: Musculoskeletal and Skin Diseases (grant numbers K23 AR069688, R03 AR075886, L30 AR066953, P30 AR070253 and P30 AR072577), the Rheumatology Research Foundation (K Supplement Award and R Bridge Award), the Brigham Research Institute, and the R Bruce and Joan M Mickey Research Scholar Fund. JAS has received research support from Amgen and Bristol-Myers Squibb and performed consultancy for Bristol-Myers Squibb, Gilead, Inova, Janssen and Optum, unrelated to this work. ZSW reports grant support from Bristol-Myers Squibb and Principia/ Sanofi and performed consultancy for Viela Bio and MedPace, outside the submitted work. His work is supported by grants from the National Institutes of Health. MG is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (grant numbers K01 AR070585 and K24 AR074534; JY). KLH reports she has received speaker’s fees from AbbVie and grant income from BMS, UCB and Pfizer, all unrelated to this study. KLH is also supported by the NIHR Manchester Biomedical Research Centre. LC has not received fees or personal grants from any laboratory, but her institute works by contract for laboratories such as, among other institutions, AbbVie Spain, Eisai, Gebro Pharma, Merck Sharp & Dohme España, Novartis Farmaceutica, Pfizer, Roche Farma, Sanofi Aventis, Astellas Pharma, Actelion Pharmaceuticals España, Grünenthal and UCB Pharma. LG reports research grants from Amgen, Galapagos, Janssen, Lilly, Pfizer, Sandoz and Sanofi; consulting fees from AbbVie, Amgen, BMS, Biogen, Celgene, Galapagos, Gilead, Janssen, Lilly, Novartis, Pfizer, Samsung Bioepis, Sanofi Aventis and UCB, all unrelated to this study. EFM reports that LPCDR received support for specific activities: grants from AbbVie, Novartis, Janssen-Cilag, Lilly Portugal, Sanofi, Grünenthal, MSD, Celgene, Medac, Pharma Kern and GAfPA; grants and non-financial support from Pfizer; and non-financial support from Grünenthal, outside the submitted work. AS reports grants from a consortium of 13 companies (among them AbbVie, BMS, Celltrion, Fresenius Kabi, Lilly, Mylan, Hexal, MSD, Pfizer, Roche, Samsung, Sanofi Aventis and UCB) supporting the German RABBIT register, and personal fees from lectures for AbbVie, MSD, Roche, BMS and Pfizer, outside the submitted work. AD-G has no disclosures relevant to this study. His work is supported by grants from the Centers for Disease Control and Prevention and the Rheumatology Research Foundation. KMD is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (T32-AR-007258) and the Rheumatology Research Foundation. NJP is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (T32-AR-007258). PD has received research support from Bristol-Myers Squibb, Chugai and Pfizer, and performed consultancy for Boehringer Ingelheim, Bristol-Myers Squibb, Lilly, Sanofi, Pfizer, Chugai, Roche and Janssen, unrelated to this work. NS is supported by the RRF Investigator Award and the American Heart Association. MFU-G reports grant support from Janssen and Pfizer. SB reports no competing interests related to this work. He reports non-branded consulting fees for AbbVie, Horizon, Novartis and Pfizer (all <$10 000). RG reports no competing interests related to this work. Outside of this work she reports personal and/or speaking fees from AbbVie, Janssen, Novartis, Pfizer and Cornerstones, and travel assistance from Pfizer (all <$10 000). JH reports no competing interests related to this work. He is supported by grants from the Rheumatology Research Foundation and the Childhood Arthritis and Rheumatology Research Alliance. He has performed consulting for Novartis, Sobi and Biogen, all unrelated to this work (<$10 000). JL has received research funding from Pfizer, outside the submitted work. ES is a Board Member of the Canadian Arthritis Patient Alliance, a patient-run, volunteer-based organisation whose activities are largely supported by independent grants from pharmaceutical companies. PS reports no competing interests related to this work. He reports honorarium for doing social media for American College of Rheumatology journals (<$10 000). PMM has received consulting/speaker’s fees from AbbVie, BMS, Celgene, Eli Lilly, Janssen, MSD, Novartis, Pfizer, Roche and UCB, all unrelated to this study (all <$10 000). PMM is supported by the National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre (BRC). PCR reports no competing interests related to this work. Outside of this work he reports personal consulting and/or speaking fees from AbbVie, Eli Lilly, Janssen, Novartis, Pfizer and UCB, and travel assistance from Roche (all <$10 000). JY reports no competing interests related to this work. Her work is supported by grants from the National Institutes of Health, Centers for Disease Control, and the Agency for Healthcare Research and Quality. She has performed consulting for Eli Lilly and AstraZeneca, unrelated to this project. Publisher Copyright: © Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.Objective To investigate baseline use of biologic or targeted synthetic (b/ts) disease-modifying antirheumatic drugs (DMARDs) and COVID-19 outcomes in rheumatoid arthritis (RA). Methods We analysed the COVID-19 Global Rheumatology Alliance physician registry (from 24 March 2020 to 12 April 2021). We investigated b/tsDMARD use for RA at the clinical onset of COVID-19 (baseline): abatacept (ABA), rituximab (RTX), Janus kinase inhibitors (JAKi), interleukin 6 inhibitors (IL-6i) or tumour necrosis factor inhibitors (TNFi, reference group). The ordinal COVID-19 severity outcome was (1) no hospitalisation, (2) hospitalisation without oxygen, (3) hospitalisation with oxygen/ventilation or (4) death. We used ordinal logistic regression to estimate the OR (odds of being one level higher on the ordinal outcome) for each drug class compared with TNFi, adjusting for potential baseline confounders. Results Of 2869 people with RA (mean age 56.7 years, 80.8% female) on b/tsDMARD at the onset of COVID-19, there were 237 on ABA, 364 on RTX, 317 on IL-6i, 563 on JAKi and 1388 on TNFi. Overall, 613 (21%) were hospitalised and 157 (5.5%) died. RTX (OR 4.15, 95% CI 3.16 to 5.44) and JAKi (OR 2.06, 95% CI 1.60 to 2.65) were each associated with worse COVID-19 severity compared with TNFi. There were no associations between ABA or IL6i and COVID-19 severity. Conclusions People with RA treated with RTX or JAKi had worse COVID-19 severity than those on TNFi. The strong association of RTX and JAKi use with poor COVID-19 outcomes highlights prioritisation of risk mitigation strategies for these people.publishersversionPeer reviewe

Integration of sequence data from a consanguineous family with genetic data from an outbred population identifies PLB1 as a candidate rheumatoid arthritis risk gene

Integrating genetic data from families with highly penetrant forms of disease together with genetic data from outbred populations represents a promising strategy to uncover the complete frequency spectrum of risk alleles for complex traits such as rheumatoid arthritis (RA). Here, we demonstrate that rare, low-frequency and common alleles at one gene locus, phospholipase B1 (PLB1), might contribute to risk of RA in a 4-generation consanguineous pedigree (Middle Eastern ancestry) and also in unrelated individuals from the general population (European ancestry). Through identity-by-descent (IBD) mapping and whole-exome sequencing, we identified a non-synonymous c.2263G>C (p.G755R) mutation at the PLB1 gene on 2q23, which significantly co-segregated with RA in family members with a dominant mode of inheritance (P = 0.009). We further evaluated PLB1 variants and risk of RA using a GWAS meta-analysis of 8,875 RA cases and 29,367 controls of European ancestry. We identified significant contributions of two independent non-coding variants near PLB1 with risk of RA (rs116018341 [MAF = 0.042] and rs116541814 [MAF = 0.021], combined P = 3.2×10-6). Finally, we performed deep exon sequencing of PLB1 in 1,088 RA cases and 1,088 controls (European ancestry), and identified suggestive dispersion of rare protein-coding variant frequencies between cases and controls (P = 0.049 for C-alpha test and P = 0.055 for SKAT). Together, these data suggest that PLB1 is a candidate risk gene for RA. Future studies to characterize the full spectrum of genetic risk in the PLB1 genetic locus are warranted. © 2014 Plenge et al

Genetics of rheumatoid arthritis contributes to biology and drug discovery

A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological datasets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA)1. Here, we performed a genome-wide association study (GWAS) meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating ~10 million single nucleotide polymorphisms (SNPs). We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 1012–4. We devised an in-silico pipeline using established bioinformatics methods based on functional annotation5, cis-acting expression quantitative trait loci (cis-eQTL)6, and pathway analyses7–9 – as well as novel methods based on genetic overlap with human primary immunodeficiency (PID), hematological cancer somatic mutations and knock-out mouse phenotypes – to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field