Legal obstacles jeopardise research in personalised medicine - experiences from a Nordic collaboration within rheumatology.

Aims: Personalised medicine in chronic complex diseases such as rheumatoid arthritis (RA) is within reach but requires international multi-stakeholder collaboration. We exemplify how national implementations of the General Data Protection Regulation (GDPR) have introduced administrative delays and created disincentives for data sharing and collaborative research.

Methods: Our Danish/Swedish/Norwegian research collaboration (the 3-year NordForsk-funded "NORA" project) aims to develop a personalised medicine approach for the management of RA, built on the exploitation of unique existing data sources: longitudinal data from clinical rheumatology registries, research cohorts, nationwide health care registries, and biobank material from >20 sample collections.

Revisiting the Link Between HLA-DRB1 Alleles and Autoantibodies in Rheumatoid Arthritis: Association of non-Shared Epitope Alleles *09 and *15 With High Levels of Anti-Citrullinated Peptide/Protein Antibodies.

Objective: Autoantibodies serve as essential clinical biomarkers and may indicate etiological mechanisms in rheumatic diseases. In light of the increasing knowledge concerning the diversity and biologic implications of anti-citrullinated peptide/protein antibodies (ACPAs), we have re-evaluated the association between the ACPA response and the HLA-DRB1 allelic groups, known to represent a major genetic risk factor for rheumatoid arthritis (RA).

Methods: We explored a collection of 4,392 well-characterized incident patients with RA of White European descent from the Epidemiological Investigation of Rheumatoid Arthritis (EIRA) new-onset RA study, as well as 1,199 cases of patients with RA of Southeast Asian origin from the Malaysian EIRA study.

The peculiar features, diversity and impact of citrulline-reactive autoantibodies.

Since entering the stage 25 years ago as a highly specific serological biomarker for rheumatoid arthritis, anti-citrullinated protein antibodies (ACPAs) have been a topic of extensive research. This hallmark B cell response arises years before disease onset, displays interpatient autoantigen variability, and is associated with poor clinical outcomes. Technological and scientific advances have revealed broad clonal diversity and intriguing features including high levels of somatic hypermutation, variable-domain N-linked glycosylation, hapten-like peptide interactions, and clone-specific multireactivity to citrullinated, carbamylated and acetylated epitopes.

Minor Genetic Overlap Among Rheumatoid Arthritis, Myocardial Infarction, and Myocardial Infarction Risk Determinants.

Objective: The aim of this study was to investigate whether a shared genetic susceptibility exists between individuals with rheumatoid arthritis (RA) and individuals with myocardial infarction (MI)-including major MI risk factors-and to quantify the degree of any such overlap.

Methods: Genome-wide association study (GWAS) data for individuals with RA were constructed from a sample of 26,637 Swedish patients with RA and controls without RA. For patients with MI, GWAS data were obtained from a previously published meta-analysis.

The serological immunogenicity of the third and fourth doses of COVID-19 vaccine in patients with inflammatory rheumatic diseases on different biologic or targeted DMARDs: a Swedish nationwide study (COVID-19-REUMA).

Unlabelled: Studies investigating the immunogenicity of additional COVID-19 vaccine doses in immunosuppressed patients with inflammatory rheumatic diseases (IRD) are still limited. The objective was to explore the antibody response including response to omicron virus subvariants (sBA.1 and sBS.

Identification of circulating autoantibodies to non-modified proteins associated with ACPA status in early rheumatoid arthritis.

Objective: The objective of this study was to discover autoantibodies to non-modified proteins associated with the presence/absence of ACPAs in RA.

Methods: The autoantibody repertoire of 80 ACPA-negative and 80 ACPA-positive RA subjects from the Swedish population-based Epidemiological Investigation of RA (EIRA) cohort was screened using a suspension bead array built on protein fragments earlier described as autoimmunity targets. Four autoantibodies positive in the initial screening were validated in another set of EIRA samples containing 317 ACPA-positive, 302 ACPA-negative and 372 age- and sex-matched controls.

In early rheumatoid arthritis, anticitrullinated peptide antibodies associate with low number of affected joints and rheumatoid factor associates with systemic inflammation.

Objectives: To investigate how individual rheumatoid arthritis (RA) autoantibodies associate with individual signs and symptoms at the time of RA diagnosis.

Methods: IgA, IgG, IgM rheumatoid factor (RF), antibodies against cyclic citrullinated peptide version 2 (anti-CCP2) and 16 individual antibodies against citrullinated protein (ACPA) reactivities were analysed centrally in baseline sera from 1600 patients with RA classified according to the 1987 American College of Rheumatology (ACR) criteria. These results were related to C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), number of swollen and tender joints (SJC and TJC), 28-joint disease activity scores (DAS28 and DAS28CRP), global disease activity evaluated by the patients and Health Assessment Questionnaire, all obtained at baseline.

Rheumatology tolerance for cure (RTCure) - an IMI project aimed at prevention and cure of RA.

The RT Cure project, supported from the Innovative Medicines Initiative (IMI) has been active for 6 years and involved several European and one Australian rheumatology institutions, six major pharma companies and a few small companies. The present report describes the major aims and results of the project which include new understanding of specificity and regulation a of adaptive immunity that precedes RA and is active in established disease. use this understanding to predict risk for RA and establish registers of at risk for RA cohorts.

Autoreactive B cells against malondialdehyde-induced protein cross-links are present in the joint, lung, and bone marrow of rheumatoid arthritis patients.

Autoantibodies to malondialdehyde (MDA) proteins constitute a subset of anti-modified protein autoantibodies in rheumatoid arthritis (RA), which is distinct from citrulline reactivity. Serum anti-MDA IgG levels are commonly elevated in RA and correlate with disease activity, CRP, IL6, and TNF-α. MDA is an oxidation-associated reactive aldehyde that together with acetaldehyde mediates formation of various immunogenic amino acid adducts including linear MDA-lysine, fluorescent malondialdehyde acetaldehyde (MAA)-lysine, and intramolecular cross-linking.

Prevention vs treatment of rheumatoid arthritis.

Whether a yet chronic and not curable disease like rheumatoid arthritis (RA) can be subject to prevention or whether available resources should be focused on treatment is a classical dilemma. Similar to the case in most other chronic diseases, the focus in research as well as in clinical practice has been on the treatment of established diseases, resulting in drugs that are efficient in eliminating most joint damage but not able to cure the disease or stop needs for continuous treatment of the disease. Less effort has been spent on identifying and implementing ways to prevent the disease.

A genome-wide cross-trait analysis identifies genomic correlation, pleiotropic loci, and causal relationship between sex hormone-binding globulin and rheumatoid arthritis.

Background: Our study aims to investigate an intrinsic link underlying sex hormone-binding globulin (SHBG) and rheumatoid arthritis (RA), which remains inconclusive in observational settings.

Methods: Summary statistics were collected from the largest GWAS(s) on SHBG adjusted for BMI (SHBGBMI; N = 368,929; N = 180,094; N = 188,908), crude SHBG (N = 370,125; N = 180,726; N = 189,473), and RA (N = 22,350; N = 74,823). A genome-wide cross-trait design was performed to quantify global and local genetic correlation, identify pleiotropic loci, and infer a causal relationship.

Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets.

Circulating proteins have important functions in inflammation and a broad range of diseases. To identify genetic influences on inflammation-related proteins, we conducted a genome-wide protein quantitative trait locus (pQTL) study of 91 plasma proteins measured using the Olink Target platform in 14,824 participants. We identified 180 pQTLs (59 cis, 121 trans).

Insights into FcγR involvement in pain-like behavior induced by an RA-derived anti-modified protein autoantibody.

Joint pain is one of the most debilitating symptoms of rheumatoid arthritis (RA) and patients frequently rate improvements in pain management as their priority. RA is hallmarked by the presence of anti-modified protein autoantibodies (AMPA) against post-translationally modified citrullinated, carbamylated and acetylated proteins. It has been suggested that autoantibody-mediated processes represent distinct mechanisms contributing to pain in RA.

Peripheral blood cellular dynamics of rheumatoid arthritis treatment informs about efficacy of response to disease modifying drugs.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by systemic inflammation and is mediated by multiple immune cell types. In this work, we aimed to determine the relevance of changes in cell proportions in peripheral blood mononuclear cells (PBMCs) during the development of disease and following treatment. Samples from healthy blood donors, newly diagnosed RA patients, and established RA patients that had an inadequate response to MTX and were about to start tumor necrosis factor inhibitors (TNFi) treatment were collected before and after 3 months of treatment.

Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality.

Genotypes causing pregnancy loss and perinatal mortality are depleted among living individuals and are therefore difficult to find. To explore genetic causes of recessive lethality, we searched for sequence variants with deficit of homozygosity among 1.52 million individuals from six European populations.

Rheumatoid Arthritis-Specific Autoimmunity in the Lung Before and at the Onset of Disease.

Objective: The lung is implicated as a site for breach of tolerance prior to onset of seropositive rheumatoid arthritis (RA). To substantiate this, we investigated lung-resident B cells in bronchoalveolar lavage (BAL) samples from untreated early RA patients and anti-citrullinated protein antibody (ACPA)-positive individuals at risk for developing RA.

Methods: Single B cells (n = 7,680) were phenotyped and isolated from BAL samples from individuals at risk of RA (n = 3) and at RA diagnosis (n = 9).

Anti-Citrullinated Protein Antibody Reactivity towards Neutrophil-Derived Antigens: Clonal Diversity and Inter-Individual Variation.

Background: Why the adaptive immune system turns against citrullinated antigens in rheumatoid arthritis (RA) and whether anti-citrullinated protein antibodies (ACPAs) contribute to pathogenesis are questions that have triggered intense research, but still are not fully answered. Neutrophils may be crucial in this context, both as sources of citrullinated antigens and also as targets of ACPAs. To better understand how ACPAs and neutrophils contribute to RA, we studied the reactivity of a broad spectrum of RA patient-derived ACPA clones to activated or resting neutrophils, and we also compared neutrophil binding using polyclonal ACPAs from different patients.

The impact of immunomodulating treatment on the immunogenicity of COVID-19 vaccines in patients with immune-mediated inflammatory rheumatic diseases compared to healthy controls. A Swedish nationwide study (COVID19-REUMA).

Objectives: To elucidate antibody responses after the second and third dose of COVID-19 vaccine in patients with inflammatory rheumatic diseases (IRD) treated with biologic/targeted disease modifying anti-rheumatic drugs (b/ts DMARDs).

Methods: Antibody levels to antigens representing spike full length protein and spike S1 were measured before vaccination, 2-12 weeks after the second dose, before and after the third dose using multiplex bead-based serology assay. Positive antibody response was defined as antibody levels over cut off (seropositivity) in seronegative individuals or ≥ 4-fold increase in antibodies in individuals seropositive for both spike proteins.

Molecular signature of methotrexate response among rheumatoid arthritis patients.

Background: Methotrexate (MTX) is the first line treatment for rheumatoid arthritis (RA), but failure of satisfying treatment response occurs in a significant proportion of patients. Here we present a longitudinal multi-omics study aimed at detecting molecular and cellular processes in peripheral blood associated with a successful methotrexate treatment of rheumatoid arthritis.

Methods: Eighty newly diagnosed patients with RA underwent clinical assessment and donated blood before initiation of MTX, and 3 months into treatment.