M. Kristen Demoruelle

Brief report: airways abnormalities and rheumatoid arthritis-related autoantibodies in subjects without arthritis: early injury or initiating site of autoimmunity?

OBJECTIVE To evaluate the presence of pulmonary abnormalities in rheumatoid arthritis (RA)-related autoantibody-positive subjects without inflammatory arthritis. METHODS Forty-two subjects who did not have inflammatory arthritis but were positive for anti-cyclic citrullinated peptide antibodies and/or ≥2 rheumatoid factor isotypes (a profile that is 96% specific for RA), 15 autoantibody-negative controls, and 12 patients with established seropositive early RA (<1-year duration) underwent spirometry and high-resolution computed tomography (HRCT) lung imaging. RESULTS The median age of autoantibody-positive subjects was 54 years, 52% were female, and 38% were ever-smokers; these characteristics were not significantly different from those of autoantibody-negative control subjects. No autoantibody-positive subject had inflammatory arthritis based on joint examination. HRCT revealed that 76% of autoantibody-positive subjects had airways abnormalities including bronchial wall thickening, bronchiectasis, centrilobular opacities, and air trapping, compared with 33% of autoantibody-negative controls (P = 0.005). The prevalence and type of lung abnormalities among autoantibody-positive subjects were similar to those among patients with early RA. In 2 autoantibody-positive subjects with airways disease, inflammatory arthritis classifiable as articular RA developed ∼13 months after the lung evaluation. CONCLUSION Airways abnormalities that are consistent with inflammation are common in autoantibody-positive subjects without inflammatory arthritis and are similar to airways abnormalities seen in patients with early RA. These findings suggest that the lung may be an early site of autoimmune-related injury and potentially a site of generation of RA-related autoimmunity. Further studies are needed to define the mechanistic role of lung inflammation in the development of RA.

Sputum Autoantibodies in Patients With Established Rheumatoid Arthritis and Subjects at Risk of Future Clinically Apparent Disease

OBJECTIVE To evaluate the generation of rheumatoid arthritis (RA)-related autoantibodies in the lung. METHODS Simultaneous collection of serum and induced sputum was performed in 21 healthy controls, 49 at-risk subjects without inflammatory arthritis but at risk of RA due to family history or seropositivity for anti-citrullinated protein antibodies, and 14 subjects with early RA. Samples were tested for anti-cyclic citrullinated peptide 2 (anti-CCP2), anti-CCP3, anti-CCP3.1, rheumatoid factor isotypes IgM, IgG, and IgA, and total IgM, IgG, and IgA. RESULTS One or more autoantibodies were present in sputum of 39% of at-risk seronegative subjects, 65% of at-risk seropositive subjects, and 86% of subjects with early RA. In at-risk seronegative subjects, the rate of anti-CCP3.1 positivity and the median number of autoantibodies were elevated in sputum versus serum. In subjects with early RA, the rate of positivity for several individual autoantibodies and the median number of autoantibodies were higher in serum than in sputum. Results in at-risk seropositive subjects were intermediate between these groups. In at-risk subjects with autoantibody positivity in sputum, the ratios of autoantibody to total Ig were higher in sputum than in serum, suggesting that these autoantibodies are generated or sequestered in the lung. CONCLUSION RA-related autoantibodies are detectable in sputum in subjects at risk of RA and in subjects with early RA. In a subset of at-risk subjects, the presence of sputum autoantibodies in the absence of seropositivity, and the increased autoantibody-to-total Ig ratios in sputum, suggest that the lung may be a site of autoantibody generation in the early development of RA. These findings suggest an important role of the lung in the pathogenesis of RA.

When and where does inflammation begin in rheumatoid arthritis

Purpose of reviewThe cause of rheumatoid arthritis (RA), as well as the timing and anatomic site at which RA-related autoimmunity is initiated, is currently unknown. An improved understanding of the initial steps in the development of RA would provide insights into disease pathogenesis that could ultimately lead to more effective treatments and/or novel preventive strategies in RA. Recent findingsSystemic inflammation and autoimmunity in RA begin long before the onset of detectable joint inflammation. Emerging data suggest that RA-related autoimmunity may be initiated at a mucosal site years before the onset of joint symptoms. The candidate sites of origin include the oral, lung and gastrointestinal mucosa, as data consistent with this hypothesis have been generated for each location. Individual patients may undergo initiation events at unique sites, but still converge on similar joint findings as the disease process evolves. SummaryInvestigations are needed to determine when and where RA begins, including comprehensive prospective studies of individuals in the preclinical period of RA that can provide insight into the relationship between mucosal inflammation, RA-related autoantibody generation and subsequent joint inflammation in RA.

Antibodies to Citrullinated Protein Antigens (ACPAs): Clinical and Pathophysiologic Significance

Antibodies to citrullinated protein antigens (ACPAs) are highly specific for rheumatoid arthritis (RA) and are useful in the diagnosis of RA as well as the prediction of the course and outcomes of disease. Multiple methodologies exist for measuring ACPAs, including the widely available tests for anticyclic citrullinated peptide antibodies and for antibodies to mutated/modified citrullinated vimentin. These methodologies overall have similar diagnostic accuracies for RA, although there is some variability. The discovery of ACPAs and the biology of citrullination have also led to important advances in the understanding of the pathophysiology and development of RA, especially regarding the relationship between potential genetic and environmental risk factors for RA. Going forward, research into autoimmunity to citrullinated proteins may help identify the specific etiology of RA and provide approaches for the prediction of future risk of disease, and ultimately prevention of RA.

Performance of anti-cyclic citrullinated peptide assays differs in subjects at increased risk of rheumatoid arthritis and subjects with established disease

OBJECTIVE To compare the diagnostic accuracy and agreement of commonly available assays for anti-citrullinated protein antibodies in patients with established rheumatoid arthritis (RA) and subjects at increased risk of RA. METHODS Tests for anti-cyclic citrullinated peptide (anti-CCP) antibodies were performed using CCP2 IgG and CCP3.1 IgA/IgG enzyme-linked immunosorbent assays in the following groups: probands with established RA (n = 340) from the Studies of the Etiology of Rheumatoid Arthritis (SERA) cohort and their first-degree relatives (FDRs) without inflammatory arthritis (n = 681), Department of Defense Serum Repository (DoDSR) RA cases with pre-RA diagnosis samples (n = 83; 47 cases also had post-RA diagnosis samples), and blood donor and DoDSR control subjects (n = 283). RESULTS In patients with established RA, the CCP2 assay was more specific (99.2% versus 93.1%; P < 0.01) but less sensitive (58.7% versus 67.4%; P = 0.01) than the CCP3.1 assay; the specificity of the CCP3.1 assay increased to 97.2% when cutoff levels ≥3-fold the standard level were considered. In all subjects, CCP3.1 assay positivity (using standard cutoff levels) was more prevalent. Among DoDSR cases, the CCP2 assay was more specific than the CCP3.1 for predicting a future diagnosis of RA, and higher CCP levels trended toward increasing specificity for the development of RA within 2 years. At standard cutoff levels, assay agreement was good in patients with established RA (κ = 0.76) but poor in FDRs without inflammatory arthritis (κ = 0.25). CONCLUSION Anti-CCP assays differ to an extent that may be meaningful for diagnosing RA in patients with inflammatory arthritis and evaluating the natural history of RA development in subjects at risk of RA. The mechanisms underlying these differences in test performance need further investigation.

Elevated IgA Plasmablast Levels in Subjects at Risk of Developing Rheumatoid Arthritis.

The disease process in rheumatoid arthritis (RA) starts years before the clinical diagnosis is made, and elevated levels of disease‐specific autoantibodies can be detected during this period. Early responses to known or novel autoantigens likely drive the eventual production of pathogenic autoimmunity. Importantly, the presence of disease‐specific autoantibodies can identify individuals who are at high risk of developing RA but who do not currently have arthritis. The goal of the current study was to characterize plasmablasts from individuals at risk of developing RA.

Relationship between air pollution and positivity of RA-related autoantibodies in individuals without established RA: a report on SERA

Introduction Studies suggest that respiratory exposures including smoking, proximity to traffic and air pollution might be associated with development of rheumatoid arthritis (RA). RA-related autoantibodies are predictive of the development of RA. Objective We evaluated the relationship between RA-related autoantibodies and exposure to particulate matter (PM), a measure of air pollution of interest to health, in individuals without RA. Methods The Studies of the Etiology of Rheumatoid Arthritis (SERA) is a multicentre study following first-degree relatives (FDRs) of a proband with RA. FDRs are without the 1987 ACR (American College of Rheumatology) classifiable RA at enrolment and are followed for the development of RA-related autoimmunity. RA-related autoantibody outcomes as well as tender and swollen joint outcomes were assessed. Exposure to PM was assigned using ambient air pollution monitoring data and interpolated with inverse distance weighting spatial analyses using Geographic Information Systems. PM exposures were linked to FDRs residential zip codes. Results RA-related autoantibodies as well as tender or swollen joints are not associated with ambient PM concentrations. Discussion While other respiratory exposures may be associated with increased risk of RA, our data suggest that ambient PM is not associated with autoantibodies and joint signs among individuals without RA, but at increased risk of developing RA.

IgA Plasmablasts are Elevated in Subjects At Risk for Future Rheumatoid Arthritis

The disease process in rheumatoid arthritis (RA) starts years before the clinical diagnosis is made, and elevated levels of disease‐specific autoantibodies can be detected during this period. Early responses to known or novel autoantigens likely drive the eventual production of pathogenic autoimmunity. Importantly, the presence of disease‐specific autoantibodies can identify individuals who are at high risk of developing RA but who do not currently have arthritis. The goal of the current study was to characterize plasmablasts from individuals at risk of developing RA.

Omega-3 fatty acids are associated with a lower prevalence of autoantibodies in shared epitope-positive subjects at risk for rheumatoid arthritis

Objectives Previously, we found that omega-3 fatty acids (n-3 FAs) were inversely associated with anti-cyclic citrullinated peptide (anti-CCP) positivity in participants at risk for future rheumatoid arthritis (RA). We investigated whether n-3 FAs were also associated with rheumatoid factor (RF) positivity and whether these associations were modified by shared epitope (SE) positivity. Methods The Studies of the Etiology of RA (SERA) cohort includes RA-free participants who are at increased risk for RA. We conducted a nested case–control study (n=136) to determine the association between RF and anti-CCP2 positivity and n-3 FA percentage in erythrocyte membranes (n-3 FA% in red blood cells (RBCs)). Additionally, in the baseline visit of the SERA cohort (n=2166), we evaluated the association between reported n-3 FA supplement use and prevalence of RF and anti-CCP2. We assessed SE positivity as an effect modifier. Results In the case–control study, increasing n-3 FA% in RBCs was inversely associated with RF positivity in SE-positive participants (OR 0.27, 95% CI 0.10 to 0.79), but not SE-negative participants. Similar associations were seen with anti-CCP positivity in SE-positive participants (OR 0.42, 95% CI 0.20 to 0.89), but not SE-negative participants. In the SERA cohort at baseline, n-3 FA supplement use was associated with a lower prevalence of RF positivity in SE-positive participants (OR 0.32, 95% CI 0.12 to 0.82), but not SE-negative participants; similar but non-significant trends were observed with anti-CCP2. Conclusions The potential protective effect of n-3 FAs on RA-related autoimmunity may be most pronounced in those who exhibit HLA class II genetic susceptibility to RA.

Lower omega-3 fatty acids are associated with the presence of anti-cyclic citrullinated peptide autoantibodies in a population at risk for future rheumatoid arthritis: a nested case-control study

OBJECTIVE The aim of this study was to investigate omega-3 fatty acid (FA) supplement use and omega-3 FAs in erythrocyte membranes [omega-3 FA % in erythrocyte membranes (RBC)] and their association with anti-CCP autoantibodies in a population without RA, but who are at genetic risk for RA. METHODS The multicentre Studies of the Etiology of RA (SERA) cohort includes RA-free subjects who are first-degree relatives of RA probands or are enriched with the HLA-DR4 allele. In a nested case-control study, 30 SERA cases were identified who were anti-CCP2 antibody positive. We further identified 47 autoantibody negative controls, frequency matched to cases on age at study visit, sex, race and study site. Anti-CCP2 status, self-reported omega-3 FA supplement use and omega-3 FA % in RBCs were obtained from a single visit. RESULTS Anti-CCP2 positive cases were less likely than controls to report omega-3 FA supplement use (odds ratio: 0.14; 95% CI 0.03, 0.68). In addition, the likelihood of anti-CCP2 positivity was inversely associated with total omega-3 FA % in RBCs (odds ratio: 0.47; 95% CI 0.24, 0.92, for a s.d. increase). CONCLUSION The inverse association between anti-CCP2 positivity and self-reported omega-3 FA supplement use and omega-3 FA % in RBCs suggests that omega-3 FAs may protect against the development of RA-related autoimmunity in pre-clinical RA.