Factors associated with progression to inflammatory arthritis in first-degree relatives of individuals with RA following autoantibody positive screening in a non-clinical setting.

OBJECTIVES: Little is known about the likelihood of developing inflammatory arthritis (IA) in individuals who screen autoantibody positive (aAb+) in a non-clinical research setting. METHODS: We screened for serum cyclic citrullinated peptide antibody (anti-CCP) and rheumatoid factor isotype aAbs in subjects who were at increased risk for rheumatoid arthritis (RA) because they are a first-degree relative of an individual with classified RA (n=1780). We evaluated combinations of aAbs and high titre aAbs, as defined by 2-times (2 x) the standard cut-off and an optimal cut-off, as predictors of our two outcomes, aAb+ persistence and incident IA. RESULTS: 304 subjects (17.1%) tested aAb+; of those, 131 were IA-free and had at least one follow-up visit. Sixty-four per cent of these tested aAb+ again on their next visit. Anti-CCP+ at levels ≥2 x the standard cut-off was associated with 13-fold higher likelihood of aAb +persistence. During a median of 4.4 years (IQR: 2.2-7.2), 20 subjects (15.3%) developed IA. Among subjects that screened anti-CCP+ at ≥ 2 x or ≥an optimal cut-off, 32% and 26% had developed IA within 5 years, respectively. Both anti-CCP cut-offs conferred an approximate fourfold increased risk of future IA (HR 4.09 and HR 3.95, p<0.01). CONCLUSIONS: These findings support that aAb screening in a non-clinical setting can identify RA-related aAb+ individuals, as well as levels and combinations of aAbs that are associated with higher risk for future IA. Monitoring for the development of IA in aAb+ individuals and similar aAb testing approaches in at-risk populations may identify candidates for prevention studies in RA.

A double-blind, placebo-controlled, phase II, randomized study of lovastatin therapy in the treatment of mildly active rheumatoid arthritis.

OBJECTIVES: 3-hydroxy-3-methylglutaryl coenzyme-A (HMG Co-A) reductase inhibitors (statins) are standard treatment for hyperlipidaemia. In addition to lipid-lowering abilities, statins exhibit multiple anti-inflammatory effects. The objectives of this study were to determine whether treatment of patients with RA with lovastatin decreased CRP or reduced disease activity. METHODS: We conducted a randomized double-blind placebo-controlled 12 week trial of lovastatin vs placebo in 64 RA patients with mild clinical disease activity but an elevated CRP. The primary efficacy end point was the reduction in mean log CRP. Secondary end points included disease activity, RF and anti-CCP antibody titres. Mechanistic end points included levels of serum cytokines. Safety was assessed; hepatic and muscle toxicities were of particular interest. RESULTS: Baseline features were similar between groups. No significant difference in mean log CRP reduction between the two groups was observed, and disease activity did not change from baseline in either treatment group. Mechanistic analyses did not reveal significant changes in any biomarkers. A post hoc analysis of subjects not using biologic therapy demonstrated a significantly greater proportion achieving ⩾20% reduction in CRP from baseline in the lovastatin group compared with placebo (P-value = 0.007). No difference was observed in subjects receiving biologics. Lovastatin was well tolerated with no serious safety concerns. CONCLUSION: This study showed no anti-inflammatory or clinical effects on RA disease activity after 12 weeks of treatment with lovastatin. Lovastatin had a modest effect on CRP in subjects not using biologics, suggesting statins may be anti-inflammatory in selected patients. TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov, NCT00302952.

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.

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.

Relatives without rheumatoid arthritis show reactivity to anti-citrullinated protein/peptide antibodies that are associated with arthritis-related traits: studies of the etiology of rheumatoid arthritis.

OBJECTIVE: To examine reactivity to anti-citrullinated protein/peptide antibodies (ACPAs) and determine associations between ACPAs and other rheumatoid arthritis (RA)-related autoantibodies and clinically assessed swollen or tender joints in unaffected first-degree relatives of RA patients. METHODS: Serum samples were obtained from first-degree relatives without RA according to the 1987 American College of Rheumatology (ACR) and the 2010 ACR/European League Against Rheumatism classification criteria. A bead-based assay was used to measure 16 separate ACPAs in sera from 111 antibody-positive first-degree relatives who were positive on at least 1 visit for any of 5 RA-related autoantibodies (rheumatoid factor [RF], anti-cyclic citrullinated peptide 2 [anti-CCP-2], and RF isotypes), and sera from 99 antibody-negative first-degree relatives who were never autoantibody positive. Cutoffs for positivity for each ACPA were determined using receiver operating characteristic curves derived from data on 200 RA patients and 98 blood donor controls, in which positivity for ≥9 ACPAs had 92% specificity and 62% sensitivity for RA. In first-degree relatives, ACPA reactivity was assessed, and associations between ACPAs (number positive, and positivity for ≥9 ACPAs) and RA-related characteristics were examined. RESULTS: Fifty-seven percent of anti-CCP-2-positive first-degree relatives and 8% of anti-CCP-2- negative first-degree relatives were positive for ≥9 ACPAs. After adjusting for age, sex, ethnicity, and pack-years of smoking, an increasing number of ACPAs was directly associated with the presence of ≥1 tender joint on examination (odds ratio [OR] 1.18, 95% confidence interval [95% CI] 1.04-1.34), with the greatest risk of having ≥1 tender joint seen in first-degree relatives positive for ≥9 ACPAs (OR 5.00, 95% CI 1.37-18.18). CONCLUSION: RA-free first-degree relatives (even those negative for RF and anti-CCP-2) demonstrate reactivity to multiple ACPAs, and the presence of an increasing number of ACPAs may be associated with signs of joint inflammation. Prospective evaluation of the relationship between these findings and the progression of classifiable RA is warranted.

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 FDR's 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.

Multiple cytokines and chemokines are associated with rheumatoid arthritis-related autoimmunity in first-degree relatives without rheumatoid arthritis: Studies of the Aetiology of Rheumatoid Arthritis (SERA).

OBJECTIVE: We investigated whether rheumatoid arthritis (RA)-related autoantibodies were associated with systemic inflammation in a prospective cohort of first-degree relatives (FDRs) of RA probands, a population without RA but at increased risk for its future development. METHODS: We studied 44 autoantibody positive FDRs, of whom 29 were rheumatoid factor (RF) positive, 25 were positive for the high risk autoantibody profile (HRP), that is, positive for anti-cyclic citrullinated peptide and/or for at least two RF IgM, IgG or IgA isotypes, and nine FDRs who were positive for both; and 62 FDRs who were never autoantibody positive. Twenty-five cytokines/chemokines were measured using a bead-based assay in serum. As a comprehensive measure of inflammation, we calculated a Cytokine Score by summing all cytokine/chemokine levels, weighted by their regression coefficients for RA-autoantibody association. We compared C-reactive protein, individual cytokines/chemokines and Cytokine Score to the outcomes: positivity for RF and for the HRP using logistic regression. RESULTS: Adjusting for age, sex, ethnicity and ever smoking, the Cytokine Score and levels of IL-6 and IL-9 were associated with both RF and HRP. IL-2, granulocyte macrophage-colony stimulating factor (GM-CSF), and interferon (IFN)-γ were associated with HRP only. Associations between the Cytokine Score and RF and HRP positivity were replicated in an independent military personnel cohort. CONCLUSIONS: In first-degree relatives of patients with RA, RA-related autoimmunity is associated with inflammation, as evidenced by associations with multiple cytokines and chemokines.

Porphyromonas gingivalis and disease-related autoantibodies in individuals at increased risk of rheumatoid arthritis.

OBJECTIVE: To examine the relationship of Porphyromonas gingivalis to the presence of autoantibodies in individuals at risk of rheumatoid arthritis (RA). METHODS: Study participants included the following: 1) a cohort enriched in subjects with HLA-DR4 and 2) subjects at risk of RA by virtue of having a first-degree relative with RA. None of the study subjects satisfied the American College of Rheumatology 1987 classification criteria for RA. Autoantibodies measured included anti-citrullinated protein antibody (ACPA; by second-generation anti-cyclic citrullinated peptide antibody enzyme-linked immunosorbent assay [ELISA]) and rheumatoid factor (RF; by nephelometry or ELISA for IgA, IgM, or IgG isotype). Individuals were considered autoantibody positive (n = 113) if they had ≥1 RA-related autoantibody; individuals were further categorized as high risk (n = 38) if they had ACPA or positive findings ≥2 assays for RF. Autoantibody-negative individuals (n = 171) served as a comparator group. Antibody to P gingivalis, P intermedia, and F nucleatum were measured. Associations of bacterial antibodies with group status were examined using logistic regression. RESULTS: Anti-P gingivalis concentrations were higher in high-risk (P = 0.011) and autoantibody positive group (P = 0.010) than in the autoantibody negative group. There were no group differences in anti-P intermedia or anti-F nucleatum concentrations. After multivariable adjustment, anti-P gingivalis concentrations (but not anti-P intermedia or anti-F nucleatum) were significantly associated with autoantibody-positive and high-risk status (P < 0.05). CONCLUSION: Immunity to P gingivalis, but not P intermedia or F nucleatum, is significantly associated with the presence of RA-related autoantibodies in individuals at risk of RA. These results support the hypothesis that infection with P gingivalis may play a central role in the early loss of tolerance to self antigens that occurs in the pathogenesis of RA.

Association of Antibodies to Prevotella copri in Anti-Cyclic Citrullinated Peptide-Positive Individuals At Risk of Developing Rheumatoid Arthritis and in Patients With Early or Established Rheumatoid Arthritis.

OBJECTIVE: Prevotella copri (P copri), a gut commensal, has been reported to be an immune-relevant organism in individuals with rheumatoid arthritis (RA). This study sought to evaluate anti-P copri (anti-Pc) antibody responses in our participant cohorts and to determine when in the natural history of RA such responses develop. METHODS: We analyzed serum levels of immunoglobulin A (IgA) and IgG antibodies from a 27-kd protein of P copri (anti-Pc-p27), an immunogenic P copri protein, in study participants at risk of developing RA, participants who transitioned to RA, participants with early RA (<1 year of disease), and participants with established RA, with comparisons made to their matched controls. We also evaluated anti-Pc-p27 antibody levels in individuals stratified by RA-related autoantibody status. RESULTS: Overall, participants with RA had significantly higher IgA anti-Pc-p27 antibody levels and trended toward higher IgG anti-Pc-p27 antibody levels compared with matched controls. When stratified by early versus established RA, participants with early RA had median IgG anti-Pc-p27 antibody levels that were overall higher, whereas median IgA anti-Pc-p27 antibody levels were statistically significantly higher in participants with established RA compared with their matched controls. In the autoantibody-specific analyses, the at-risk population with anti-cyclic citrullinated peptide (anti-CCP) antibodies, but not rheumatoid factor (RF), trended toward increased levels of IgG anti-Pc-p27. Additionally, RA participants who were seropositive for both CCP and RF had significantly increased levels of IgA anti-Pc-p27 antibodies and trended toward higher levels of IgG anti-Pc-p27 antibodies compared with matched controls. CONCLUSION: Our findings support a potential etiologic role for P copri in both RA preclinical evolution and the subsequent pathogenesis of synovitis.

Activated Peripheral Blood B Cells in Rheumatoid Arthritis and Their Relationship to Anti-Tumor Necrosis Factor Treatment and Response: A Randomized Clinical Trial of the Effects of Anti-Tumor Necrosis Factor on B Cells.

OBJECTIVE: B cells can become activated in germinal center (GC) reactions in secondary lymphoid tissue and in ectopic GCs in rheumatoid arthritis (RA) synovium that may be tumor necrosis factor (TNF) and lymphotoxin (LT) dependent. This study was undertaken to characterize the peripheral B cell compartment longitudinally during anti-TNF therapy in RA. METHODS: Participants were randomized in a 2:1 ratio to receive standard dosing regimens of etanercept (n = 43) or adalimumab (n = 20) for 24 weeks. Eligible participants met the American College of Rheumatology 1987 criteria for RA, had clinically active disease (Disease Activity Score in 28 joints >4.4), and were receiving stable doses of methotrexate. The primary mechanistic end point was the change in switched memory B cell fraction from baseline to week 12 in each treatment group. RESULTS: B cell subsets remained surprisingly stable over the course of the study regardless of treatment group, with no significant change in memory B cells. Blockade of TNF and LT with etanercept compared to blockade of TNF alone with adalimumab did not translate into significant differences in clinical response. The frequencies of multiple activated B cell populations, including CD21- double-negative memory and activated naive B cells, were higher in RA nonresponders at all time points, and CD95+ activated B cell frequencies were increased in patients receiving anti-TNF treatment in the nonresponder group. In contrast, frequencies of transitional B cells-a putative regulatory subset-were lower in the nonresponders. CONCLUSION: Overall, our results support the notion that peripheral blood B cell subsets are remarkably stable in RA and not differentially impacted by dual blockade of TNF and LT with etanercept or single blockade of TNF with adalimumab. Activated B cells do associate with a less robust response.

Relationship Between a Vitamin D Genetic Risk Score and Autoantibodies Among First-Degree Relatives of Probands With Rheumatoid Arthritis and Systemic Lupus Erythematosus.

Objective: Higher 25-hydroxyvitamin D (25(OH)D) levels have been associated with reduced risk for autoimmune diseases and are influenced by vitamin D metabolism genes. We estimated genetically-determined vitamin D levels by calculating a genetic risk score (GRS) and investigated whether the vitamin D GRS was associated with the presence of autoantibodies related to rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) in those at increased risk for developing RA and SLE, respectively. Methods: In this cross-sectional study, we selected autoantibody positive (aAb+) and autoantibody negative (aAb-) individuals from the Studies of the Etiologies of Rheumatoid Arthritis (SERA), a cohort study of first-degree relatives (FDRs) of individuals with RA (189 RA aAb+, 181 RA aAb-), and the Lupus Family Registry and Repository (LFRR), a cohort study of FDRs of individuals with SLE (157 SLE aAb+, 185 SLE aAb-). Five SNPs known to be associated with serum 25(OH)D levels were analyzed individually as well as in a GRS: rs4588 (GC), rs12785878 (NADSYN1), rs10741657 (CYP2R1), rs6538691 (AMDHD1), and rs8018720 (SEC23A). Results: Both cohorts had similar demographic characteristics, with significantly older and a higher proportion of males in the aAb+ FDRs. The vitamin D GRS was inversely associated with RA aAb+ (OR = 0.85, 95% CI = 0.74-0.99), suggesting a possible protective factor for RA aAb positivity in FDRs of RA probands. The vitamin D GRS was not associated with SLE aAb+ in the LFRR (OR = 1.09, 95% CI = 0.94-1.27). The SEC23A SNP was associated with RA aAb+ in SERA (OR = 0.65, 95% CI = 0.43-0.99); this SNP was not associated with SLE aAb+ in LFRR (OR = 1.41, 95% CI = 0.90 - 2.19). Conclusion: Genes associated with vitamin D levels may play a protective role in the development of RA aAbs in FDRs of RA probands, perhaps through affecting lifelong vitamin D status. The GRS and the SEC23A SNP may be of interest for future investigation in pre-clinical RA. In contrast, these results do not support a similar association in SLE FDRs, suggesting other mechanisms involved in the relationship between vitamin D and SLE aAbs not assessed in this study.

Relationships within the Araceae: comparison of morphological patterns with molecular phylogenies.

PREMISE OF THE STUDY: The first family-wide molecular phylogeny of the Araceae, a family of about 3800 published species in 120 genera, became available in 1995, followed by a cladistic analysis of morpho-anatomical data in 1997. The most recent and comprehensive family-wide molecular phylogeny was published in 2008 and included species from 102 genera. We reanalyzed the molecular data with a more complete genus sampling and compared the resulting phylogeny with morphological and anatomical data, with a view to contributing to a new formal classification of the Araceae. METHODS: We analyzed 113 aroid genera and 4494 aligned nucleotides that resulted from adding 11 genera to the 2008 molecular matrix. We also analyzed 81 morphological characters in the context of the molecular phylogeny, using an extended version of the 1997 morpho-anatomical data set. KEY RESULTS: The resulting maximum-likelihood phylogeny is well resolved and supported, and most of the 44 larger clades also have morphological or anatomical synapomorphies as well as ecological or geographic cohesion. Of the 44 clades, 16 are here newly circumscribed and informally named. However, some relationships remain poorly supported within the Aroideae subfamily. The most problematic placement is Calla within Aroideae, which conflicts with the distribution of morphological, anatomical, and palynological character states. CONCLUSIONS: The comparison of the molecular analysis with morphological and anatomical data presented here represents an important basis for a new formal classification for the Araceae and for the understanding of the evolution of this ancient family, a monocot group known in the fossil record from the early Cretaceous.

Evaluating associations of joint swelling, joint stiffness and joint pain with physical activity in first-degree relatives of patients with rheumatoid arthritis: Studies of the Aetiology of Rheumatoid Arthritis (SERA), a prospective cohort study.

OBJECTIVE: Physical activity (PA) in preclinical rheumatoid arthritis (RA) is associated with lower RA risk and disease severity. As joint signs and symptoms of inflammatory arthritis serve as a barrier to PA in RA, it is important to consider whether they affect PA in the time prior to RA. Therefore, we investigated whether joint swelling, stiffness or pain were associated with PA in first-degree relatives (FDRs) of patients with RA, a population at higher risk for future RA. DESIGN: Prospective study design. SETTING: We recruited FDRs of patients with RA from academic centres, Veterans' hospitals and rheumatology clinics or through responses to advertising from six sites across the USA. PARTICIPANTS: We evaluated associations of joint stiffness, joint swelling and joint pain with PA time in 268 FDRs with ≥2 visits over an average 1.2 years. Clinicians confirmed joint swelling. Participants self-reported joint stiffness and/or pain. PRIMARY OUTCOME MEASURES: PA during a typical 24-hour day was quantified via questionnaire, weighted to reflect metabolic expenditure, where 24 hours was the minimum PA time. Linear mixed models evaluated associations between symptoms and change in PA over time, adjusting for age, sex, race, body mass index, smoking and RA-related autoantibodies. RESULTS: Average weighted PA time was 37±7 hours. In the cross-sectional analysis, PA time was 1.3±0.9 hours higher in FDRs reporting joint pain (p=0.15); and 0.8±1.6 and 0.4±1 hours lower in FDRs with joint swelling (p=0.60) and stiffness (p=0.69), respectively. Longitudinally, adjusting for baseline PA time, baseline symptoms were not significantly associated with changes in PA time. However, on average over time, joint stiffness and pain were associated with lower PA time (pinteraction=0.0002, pinteraction=0.002), and joint swelling was associated with higher PA time (pinteraction <0.0001). CONCLUSION: Baseline symptoms did not predict future PA time, but on average over time, joint symptoms influenced PA time.

Association of Lipid Mediators With Development of Future Incident Inflammatory Arthritis in an Anti-Citrullinated Protein Antibody-Positive Population.

OBJECTIVE: To determine the association of polyunsaturated fatty acid (PUFA)-derived lipid mediators with progression from rheumatoid arthritis (RA)-related autoimmunity to inflammatory arthritis (IA). METHODS: We conducted a prospective cohort study using data from the Studies of the Etiology of Rheumatoid Arthritis (SERA). SERA enrolled first-degree relatives (FDRs) of individuals with RA (FDR cohort) and individuals who screened positive for RA-related autoantibodies at health fairs (screened cohort). We followed up 133 anti-cyclic citrullinated peptide 3.1 (anti-CCP3.1)-positive participants, 29 of whom developed IA. Lipid mediators selected a priori were quantified from stored plasma samples using liquid chromatography tandem mass spectrometry. We fit multivariable Cox proportional hazards models for each lipid mediator as a time-varying variable. For lipid mediators found to be significantly associated with IA, we then examined interleukin-1ß (IL-1ß), IL-6, IL-8, and tumor necrosis factor (TNF) as potential statistical mediators. RESULTS: For every 1 natural log pg/ml increase in the circulating plasma levels of proinflammatory 5-HETE, the risk of developing IA increased by 241% (hazard ratio 2.41 [95% confidence interval 1.43-4.07]) after adjusting for age at baseline, cohort (FDR or screened), and shared epitope status. The models examining 15-HETE and 17-HDHA had the same trend but did not reach significance. We did not find evidence that the association between 5-HETE and IA risk was influenced by the proinflammatory cytokines tested. CONCLUSION: In a prospective cohort of anti-CCP-positive individuals, higher levels of 5-HETE, an important precursor to proinflammatory leukotrienes, is associated with subsequent IA. Our findings highlight the potential significance of these PUFA metabolites in pre-RA populations.

Perceived Stress and Inflammatory Arthritis: A Prospective Investigation in the Studies of the Etiologies of Rheumatoid Arthritis Cohort.

OBJECTIVE: The aim of this study was to determine the association of perceived stress with incident inflammatory arthritis (IA) defined as having at least 1 joint consistent with rheumatoid arthritis (RA)-like synovitis based on examination. METHODS: We conducted a prospective cohort study in the Studies of the Etiologies of Rheumatoid Arthritis cohort. Participants without IA were recruited if they were a first-degree relative of an RA proband or screened positive for anti-citrullinated protein antibody. Perceived stress was measured using the Perceived Stress Scale-14 (PSS-14), in which scores can range from 0 to 56, and a higher score indicates greater perceived stress. The total PSS-14 score, as well as 2 subscores indicative of perceived distress and self-efficacy, were averaged across all study visits until development of IA or the last follow-up. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) of IA associated with average PSS-14 scores were obtained using Cox proportional hazards models. RESULTS: The mean total PSS-14 score was 20.4. We found that a 1-point increase in the perceived distress score was significantly associated with a 10-percent increase in the risk of IA (adjusted HR 1.10 [95% CI 1.02-1.19]). Total PSS-14 and self-efficacy were not associated with IA risk (adjusted HR 1.05 [95% CI 0.99-1.10] and 1.04 [95% CI 0.91-1.18], respectively). CONCLUSION: An association between perceived distress and incident IA was observed in this at-risk cohort. Replication of this finding in other preclinical and at-risk RA populations is needed.

Anticyclic Citrullinated Peptide Antibodies 3.1 and Anti-CCP-IgA Are Associated with Increasing Age in Individuals Without Rheumatoid Arthritis.

OBJECTIVE: We investigated the association of age and anticyclic citrullinated peptide antibodies (anti-CCP) in subjects without rheumatoid arthritis (RA). METHODS: Serum was tested for anti-CCP3.1 (IgG/IgA) in 678 first-degree relatives (FDR) of patients with RA and 330 patients with osteoarthritis (OA). Individual isotypes (anti-CCP-IgA and anti-CCP-IgG) were also tested in all FDR. RESULTS: In FDR, increasing age was significantly associated with positivity for anti-CCP3.1 (per year, OR 1.03) and anti-CCP-IgA (per year, OR 1.05) but not anti-CCP-IgG. In FDR and OA subjects, anti-CCP3.1 prevalence was significantly increased after age 50 years. CONCLUSION: Increasing age in individuals without RA should be considered in the interpretation of anti-CCP3.1 positivity.

Latent autoimmunity across disease-specific boundaries in at-risk first-degree relatives of SLE and RA patients.

BACKGROUND: Autoimmune disease prevention requires tools to assess an individual's risk of developing a specific disease. One tool is disease-associated autoantibodies, which accumulate in an asymptomatic preclinical period. However, patients sometimes exhibit autoantibodies associated with a different disease classification. When and how these alternative autoantibodies first appear remain unknown. This cross-sectional study characterizes alternative autoimmunity, and associated genetic and environmental factors, in unaffected first-degree relatives (FDRs) of patients, who exhibit increased future risk for the same disease. METHODS: Samples (n = 1321) from disease-specific autoantibody-positive (aAb+) systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and type 1 diabetes (T1D) patients; and unaffected aAb+ and autoantibody-negative (aAb-) SLE and RA FDRs were tested for SLE, RA, and T1D aAbs, as well as anti-tissue transglutaminase, anti-cardiolipin and anti-thyroperoxidase. FDR SLE and RA genetic risk scores (GRS) were calculated. FINDINGS: Alternative autoimmunity occurred in SLE patients (56%) and FDRs (57·4%), RA patients (32·6%) and FDRs (34·8%), and T1D patients (43%). Expanded autoimmunity, defined as autoantibodies spanning at least two other diseases, occurred in 18·5% of SLE patients, 16·4% of SLE FDRs, 7·8% of RA patients, 5·3% of RA FDRs, and 10·8% of T1D patients. SLE FDRs were more likely to have alternative (odds ratio [OR] 2·44) and expanded (OR 3·27) autoimmunity than RA FDRs. Alternative and expanded autoimmunity were associated with several environmental exposures. Alternative autoimmunity was associated with a higher RA GRS in RA FDRs (OR 1·41), and a higher SLE GRS in aAb+ RA FDRs (OR 1·87), but not in SLE FDRs. INTERPRETATION: Autoimmunity commonly crosses disease-specific boundaries in systemic (RA, SLE) and organ-specific (T1D) autoimmune diseases. Alternative autoimmunity is more common in SLE FDRs than RA FDRs, and is influenced by genetic and environmental factors. These findings have substantial implications for preclinical disease pathogenesis and autoimmune disease prevention studies. FUND: NIH U01AI101981, R01AR051394, U19AI082714, P30AR053483, P30GM103510, U54GM104938, U01AI101934, R01AI024717, U01AI130830, I01BX001834, & U01HG008666.

Newly detected atrial fibrillation following dual chamber pacemaker implantation.

INTRODUCTION: Pacemaker (PPM)-detected atrial high-rate episodes (AHREs) of even 5-minute duration may identify patients at increased risk for stroke and death. In this study, we sought to determine the incidence of newly detected atrial fibrillation (AF defined as an AHRE > or = 5 minutes) in patients following dual-chamber PPM implantation and to define the clinical predictors of developing AF. METHODS AND RESULTS: We evaluated 262 patients (142 male; age 74 +/- 12 years) without documented AF who underwent PPM implantation for sinus node dysfunction (n = 122) or atrioventricular block (n = 140). Information regarding patient demographics, cardiovascular diseases, and medication history was obtained. The cumulative percentages of ventricular pacing as well as the frequency, duration, and time to first episode of an AHRE were also determined. During follow-up of 596 +/- 344 days, an AHRE > or = 5 minutes was detected in 77 (29%) patients. Of these, 47 (61%) patients had an AHRE > or = 1 hour, 22 (29%) patients had an AHRE > or = 1 day, and 12 (16%) patients had an AHRE > or = 1 week. An AHRE > or = 5 minutes was seen in 24% and 34% of patients at 1 year and 2 years, respectively. Among patients with sinus node dysfunction, > or = 50% cumulative ventricular pacing was the only significant predictor of an AHRE > or = 5 minutes (HR 2.2; CI 1.0-4.7; P = 0.04). CONCLUSIONS: Within 1 year of PPM implantation, AF is detected in 24% of patients without history of AF. In patients with sinus node dysfunction, > or = 50% cumulative right ventricular pacing is associated with a 2-fold increase in risk of developing AF.