Multi-omic Biomarkers Distinguish Rheumatoid Arthritis in Discordant Monozygotic Twins.

Background: Although genetic factors have been identified in the pathogenesis of rheumatoid arthritis (RA), the concordance rate in monozygotic (MZ) twins is low, suggesting that other features contribute to disease development. Further, the relative contribution of such non-genetic elements in identical twins have not been characterized. Here, we aimed to measure differentiating host and microbial biomarkers of RA by studying MZ twins discordant for disease using a multi-omics approach.

Autoantibodies against citrullinated and native proteins and prediction of rheumatoid arthritis-associated interstitial lung disease: A nested case-control study.

Background: To identify fine specificity anti-citrullinated protein antibodies (ACPA) associated with incident rheumatoid arthritis-associated interstitial lung disease (RA-ILD).

Methods: This nested case-control study within the Brigham RA Sequential Study matched incident RA-ILD cases to RA-noILD controls on time of blood collection, age, sex, RA duration, and rheumatoid factor status. A multiplex assay measured ACPA and anti-native protein antibodies from stored serum prior to RA-ILD onset.

Neutralizing anti-IL-1 receptor antagonist autoantibodies induce inflammatory and fibrotic mediators in IgG4-related disease.

Background: IgG4-related disease (IgG4-RD) is a fibroinflammatory condition involving loss of B-cell tolerance and production of autoantibodies. However, the relevant targets and role of these aberrant humoral immune responses are not defined.

Objective: Our aim was to identify novel autoantibodies and autoantigen targets that promote pathogenic responses in IgG4-RD.

Associations of serum cytokines and chemokines with the risk of incident cancer in a prospective rheumatoid arthritis cohort.

Objectives: We aimed to assess whether serum cytokine/chemokine concentrations predict incident cancer in RA patients.

Methods: Data from cancer-free enrollees in the Veterans Affairs Rheumatoid Arthritis (VARA) Registry were linked to a national VA oncology database and the National Death Index (NDI) to identify incident cancers. Seventeen serum cytokines/chemokines were measured from enrollment serum and an overall weighted cytokine/chemokine score (CK score) was calculated.

Elevated Anti-Citrullinated Protein Antibodies Prior to Rheumatoid Arthritis Diagnosis and Risks for Chronic Obstructive Pulmonary Disease or Asthma.

Objective: To investigate elevation of anti-citrullinated protein antibodies (ACPAs) before diagnosis of rheumatoid arthritis (RA) and risks for chronic obstructive pulmonary disease (COPD) or asthma.

Methods: We performed a matched cohort study nested within the Nurses' Health Studies among women who donated blood. Women with incident RA after blood draw (self-reported, then confirmed by medical records) were each matched to 3 controls by age, cohort, year, and menopausal factors.

Fibroblast-like synovial cell production of extra domain A fibronectin associates with inflammation in osteoarthritis.

Background: The pathophysiology of osteoarthritis (OA) involves wear and tear, and a state of low-grade inflammation. Tissue repair responses include transforming growth factor beta (TGFβ)-induced myofibroblast production of extracellular matrix. Fibronectins are an essential part of the extracellular matrix, and injection of fibronectin fragments into rabbit joints is a previously established animal model of OA.

Asthma and elevation of anti-citrullinated protein antibodies prior to the onset of rheumatoid arthritis.

Background: Anti-citrullinated protein antibodies (ACPA) are central to rheumatoid arthritis (RA) pathogenesis and may develop at inflamed mucosa. We investigated whether asthma, a disease of airway mucosal inflammation, was associated with elevated ACPA before RA diagnosis.

Methods: We performed a nested case-control study among women in two prospective cohorts, the Nurses' Health Study (NHS; 1976-2014) and NHSII (1989-2015).

Dysregulated integrin αVβ3 and CD47 signaling promotes joint inflammation, cartilage breakdown, and progression of osteoarthritis.

Osteoarthritis (OA) is the leading cause of joint failure, yet the underlying mechanisms remain elusive, and no approved therapies that slow progression exist. Dysregulated integrin function was previously implicated in OA pathogenesis. However, the roles of integrin αVβ3 and the integrin-associated receptor CD47 in OA remain largely unknown.

IgE-mediated mast cell activation promotes inflammation and cartilage destruction in osteoarthritis.

Unlabelled: Osteoarthritis is characterized by articular cartilage breakdown, and emerging evidence suggests that dysregulated innate immunity is likely involved. Here, we performed proteomic, transcriptomic, and electron microscopic analyses to demonstrate that mast cells are aberrantly activated in human and murine osteoarthritic joint tissues. Using genetic models of mast cell deficiency, we demonstrate that lack of mast cells attenuates osteoarthritis in mice.

A Prospective Study of the Development of Inflammatory Arthritis in the Family Members of Indigenous North American People With Rheumatoid Arthritis.

Objective: To determine the incidence of inflammatory arthritis and autoantibody prevalence in Indigenous North American people.

Methods: Unaffected relatives of Indigenous North Americans with rheumatoid arthritis (RA) from central Canada and Alaska were systematically monitored from 2005 to 2017. Rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPAs) were tested at every visit, and a subset was tested for ACPA fine specificity using a custom multiplex assay.

Post-traumatic stress disorder and serum cytokine and chemokine concentrations in patients with rheumatoid arthritis.

Objective: Although post-traumatic stress disorder (PTSD) is identified as a risk factor in the development of rheumatoid arthritis (RA), associations of PTSD with disease progression are less clear. To explore whether PTSD might influence disease-related measures of systemic inflammation in RA, we compared serum cytokine/chemokine (cytokine) concentrations in RA patients with and without PTSD.

Methods: Participants were U.

Plasma adiponectin levels are associated with circulating inflammatory cytokines in autoantibody positive first-degree relatives of rheumatoid arthritis patients.

Background: Extra-articular manifestations of rheumatoid arthritis (RA), potentially due to systemic inflammation, include cardiovascular disease and sarcopenic obesity. Adiponectin, an adipose-derived cytokine, has been implicated in inflammatory processes in RA, but little is known regarding its association with inflammation in a pre-clinical period. Therefore, we investigated whether adiponectin was associated with inflammatory markers in individuals at risk for RA, and whether RA-related autoimmunity modifies these associations.

Combination of anti-citrullinated protein antibodies and rheumatoid factor is associated with increased systemic inflammatory mediators and more rapid progression from preclinical to clinical rheumatoid arthritis.

The development of rheumatoid factor (RF) and/or anti-citrullinated protein antibodies (ACPAs) can be observed years prior to clinical diagnosis of rheumatoid arthritis (RA). Nevertheless, the interaction between these two autoantibodies and their combined effect on development of RA is unclear. We measured RF, cytokines, and ACPA subtypes in serial pre-clinical serum samples collected from 83 US veterans who all developed RA.

Antibody Responses to Citrullinated and Noncitrullinated Antigens in the Sputum of Subjects With Rheumatoid Arthritis and Subjects at Risk for Development of Rheumatoid Arthritis.

Objective: The location and mechanisms involved in the initial generation of autoantibodies to citrullinated and noncitrullinated proteins/peptides during the natural history of rheumatoid arthritis (RA) development is incompletely understood. This study sought to explore individual antibody responses to citrullinated and noncitrullinated proteins/peptides in the sputum and associations with neutrophil extracellular traps (NETs) in subjects at risk for the future development of RA.

Methods: Serum and sputum samples were obtained from 41 RA-free subjects who were considered at risk for the development of RA based on familial or serologic risk factors, from 20 subjects classified as having RA, and from 22 healthy control subjects.

Association of Antibodies to Citrullinated Protein Antigens with Blood Pressure in First-Degree Relatives of Rheumatoid Arthritis Patients: The Studies of the Etiology of Rheumatoid Arthritis.

Background: Hypertension is more common in patients with rheumatoid arthritis (RA) than in the general population. It is unknown whether hypertension is due to RA-related medications or the disease itself. Therefore, we sought to investigate associations between RA-related autoantibodies, specifically antibodies to citrullinated protein antigens (ACPA) and systolic blood pressure (SBP) and diastolic blood pressure (DBP) in first-degree relatives of RA patients, who were free of RA and RA-related medications.

Non-progressing cancer patients have persistent B cell responses expressing shared antibody paratopes that target public tumor antigens.

There is significant debate regarding whether B cells and their antibodies contribute to effective anti-cancer immune responses. Here we show that patients with metastatic but non-progressing melanoma, lung adenocarcinoma, or renal cell carcinoma exhibited increased levels of blood plasmablasts. We used a cell-barcoding technology to sequence their plasmablast antibody repertoires, revealing clonal families of affinity matured B cells that exhibit progressive class switching and persistence over time.

Association Between Anti-Citrullinated Fibrinogen Antibodies and Coronary Artery Disease in Rheumatoid Arthritis.

Objective: Antibodies against citrullinated fibrinogen (anti-Cit-fibrinogen) have been implicated in rheumatoid arthritis (RA) and associated with cardiovascular risk in RA. The objective of this study was to examine the association between anti-Cit-fibrinogens and coronary artery disease (CAD) outcomes.

Methods: We performed the study in an RA cohort based in a large academic institution linked with electronic medical record data containing information on CAD outcomes from medical record review.

The tyrosine kinase inhibitor imatinib mesylate suppresses uric acid crystal-induced acute gouty arthritis in mice.

Gouty arthritis is caused by the deposition of monosodium urate (MSU) crystals in joints. Despite many treatment options for gout, there is a substantial need for alternative treatments for patients unresponsive to current therapies. Tyrosine kinase inhibitors have demonstrated therapeutic benefit in experimental models of antibody-dependent arthritis and in rheumatoid arthritis in humans, but to date, the potential effects of such inhibitors on gouty arthritis has not been evaluated.

Enrichment of malondialdehyde-acetaldehyde antibody in the rheumatoid arthritis joint.

Objective: To characterize the expression of malondialdehdye-acetaldehyde (MAA) adducts and anti-MAA antibody in articular tissues and serum of patients with RA.

Methods: Paired sera and SF were examined from 29 RA and 13 OA patients. Anti-MAA antibody, RF, ACPA and total immunoglobulin were quantified.

Molecular basis for increased susceptibility of Indigenous North Americans to seropositive rheumatoid arthritis.

Objective: The pathogenetic mechanisms by which alleles are associated with anticitrullinated peptide antibody (ACPA)-positive rheumatoid arthritis (RA) are incompletely understood. RA high-risk alleles are known to share a common motif, the 'shared susceptibility epitope (SE)'. Here, the electropositive P4 pocket of HLA-DRB1 accommodates self-peptide residues containing citrulline but not arginine.

Nicotine drives neutrophil extracellular traps formation and accelerates collagen-induced arthritis.

Objectives: The aim was to investigate the effects of nicotine on neutrophil extracellular traps (NETs) formation in current and non-smokers and on a murine model of RA.

Methods: We compared spontaneous and phorbol 12-myristate 13-acetate-induced NETosis between current and non-smokers by DNA release binding. Nicotine-induced NETosis from non-smokers was assessed by DNA release binding, NET-specific (myeloperoxidase (MPO)-DNA complex) ELISA and real-time fluorescence microscopy.