Addressing cardiovascular risk factors and therapy effects in rheumatoid arthritis: implications for atherosclerosis and cardiovascular disease

Rheumatoid arthritis (RA) is the prototype of chronic inflammatory disease associated with a 1.5-2 fold increased risk of cardiovascular disease (CVD) and premature mortality. Though traditional CVD risk factors are important in the pathogenesis of atherosclerosis in patients with RA, they do not fully explain the increased risk of CVD events observed in RA. This thesis aimed to explore further the mechanisms that could account for accelerated atherogenesis and CVD in RA. In the study of established RA disease, which included patients treated during one year with TNF-α inhibitors, n=162, or the anti-CD20 agent rituximab, n=53, anti-atherogenic apolipoprotein A1 increased after commencement of therapy; this increase was not agent-specific and paralleled a reduction in RA disease activity. At the same time, apolipoprotein B and the atherogenic index did not change significantly. These favorable effects may have a potential for at least short-term improvement in cardiovascular risk in RA. On the other hand, the biologic agents caused differential effect on serum levels of anti-phosphorylcholine (anti-PC) IgM, a promising atheroprotective biomarker. Thus, these antibodies increased on TNF-α inhibitors in contrast to treatment with rituximab. The contribution of biologic agents to beneficial or harmful CVD effects needs to be elucidated in future studies. In studies incorporating 114 participants with early RA, examined with high-resolution B-mode ultrasonography after five years of disease, the proatherogenic apoB and apoB/apoA1-ratio were independently associated with unfavorable carotid outcomes, while a profitable effect was associated with the antiatherogenic, anti-inflammatory apoA1. Also, low anti-PC IgM levels longitudinally had an unfavorable association with the plaque presence at the end of observation. These results suggest that apolipoproteins and anti-PC antibodies may have independent roles in subclinical atherosclerosis in patients with RA. Further analysis, over a prolonged observation period more than 10 years, showed that the bilateral carotid plaques occurrence was associated with a subsequent CVD event. Early improvement of inflammation, pain and disability, measured as reductions in DAS28, VAS pain and the HAQ score the first year after RA diagnosis, as well as use of methotrexate were associated with a better CVD outcome. Longitudinal approach confirmed the association of low anti-PC IgM levels and, also, increasing oxidized LDL over first five years of RA disease with an adverse CVD outcome. In a large observational early RA cohort of 741 patients followed more than 10 years, we examined the relationships of inflammatory and novel biomarkers with incident CVD morbidity and all-cause mortality. The study outcomes were tracked through the Swedish Hospital Discharge and the National Cause of Death Registries. The factors associated with adverse outcomes differed in patients with disease onset before 65 years of old and those 65 years and older. The cumulative burden of inflammation over the first two years and the presence of RA disease related autoantibodies had a value for CVD and mortality prognosis in the younger patients, while a change in inflammatory markers the first year after diagnosis had a stronger effect in the older patients. Low-dose glucocorticoids increased but use of methotrexate decreased risk of poor outcomes in the elderly. These findings imply that age stratification could add to identification of patient-at-risk, and highlight the need to treat RA early and more aggressively to improve long-term outcomes. Taken together, these results emphasize the complexity of the associations between inflammation, anti-rheumatic therapies, atherosclerotic burden and CVD in RA. Further studies addressing indicators for cardiovascular prognosis are unmet needed

Is Anti-Citrullinated Protein Antibody-Positive Rheumatoid Arthritis Still a More Severe Disease Than Anti-Citrullinated Protein Antibody-Negative Rheumatoid Arthritis? A Longitudinal Cohort Study in Rheumatoid Arthritis Patients Diagnosed From 2000 Onward

ObjectiveBecause of its association with joint destruction, anti-citrullinated protein antibody (ACPA)-positive rheumatoid arthritis (RA) is considered to be more severe than ACPA-negative RA. Clinically relevant joint destruction is now infrequent thanks to adequate disease suppression. According to patients, important outcomes are pain, fatigue, and independence. We evaluated whether ACPA-positive RA patients diagnosed during or after 2000 have more severe self-reported limitations and impairments, including restrictions at work, than ACPA-negative RA patients. MethodsA total of 492 ACPA-positive and 450 ACPA-negative RA patients who fulfilled the 2010 criteria and were included in the Leiden Early Arthritis Clinic cohort during or after 2000 were compared for self-reported pain, fatigue, disease activity, general well-being (measured by numerical rating scales), physical function (measured by the Health Assessment Questionnaire), and work restrictions, including absenteeism at baseline and during the 4-year followup. Linear mixed models were used. ResultsAt disease presentation, ACPA-negative patients had more severe pain, fatigue, self-reported disease activity scores, and functional disability (P < 0.05), although absolute differences were small. During followup, ACPA-negative patients remained somewhat more fatigued (P = 0.002), whereas other patient-reported impairments and limitations were similar. Thirty-eight percent of ACPA-negative and 48% of ACPA-positive patients reported absenteeism (P = 0.30), with median 4 days missed in both groups in the last 3 months. Also, restrictions at work among employed patients and restrictions with household work were not statistically different at baseline and during followup. ConclusionIn current rheumatology practice, ACPA-positive RA is not more severe than ACPA-negative RA in terms of patients' relevant outcomes, including physical functioning and restrictions at work. This implies that efforts to further improve the disease course should be proportional to both disease subsets

Smoking is associated with the concurrent presence of multiple autoantibodies in rheumatoid arthritis rather than with anti-citrullinated protein antibodies per se:a multicenter cohort study

BACKGROUND: The contribution of smoking to rheumatoid arthritis (RA) is hypothesized to be mediated through formation of anti-citrullinated protein antibodies (ACPA). In RA, however, autoantibodies such as ACPA, rheumatoid factor (RF), and anti-carbamylated protein antibodies (anti-CarP) often occur together, and it is thus unclear whether smoking is specifically associated with some autoantibodies rather than others. We therefore investigated whether smoking is only associated with ACPA or with the presence of multiple RA-related autoantibodies. METHODS: A population-based Japanese cohort (n = 9575) was used to investigate the association of smoking with RF and anti-cyclic citrullinated peptide antibodies (anti-CCP2) in individuals without RA. Furthermore, RA patients fulfilling the 1987 criteria from three early arthritis cohorts from the Netherlands (n = 678), the United Kingdom (n = 761), and Sweden (n = 795) were used. Data on smoking, RF, anti-CCP2, and anti-CarP were available. A total score of autoantibodies was calculated, and odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated by logistic regression. RESULTS: In the population-based non-RA cohort, no association was found between smoking and one autoantibody (RF or anti-CCP2), but smoking was associated with double-autoantibody positivity (OR 2.95, 95% CI 1.32-6.58). In RA patients, there was no association between smoking and the presence of one autoantibody (OR 0.99, 95% CI 0.78-1.26), but smoking was associated with double-autoantibody positivity (OR 1.32, 95% CI 1.04-1.68) and triple-autoantibody positivity (OR 2.05, 95% CI 1.53-2.73). CONCLUSIONS: Smoking is associated with the concurrent presence of multiple RA-associated autoantibodies rather than just ACPA. This indicates that smoking is a risk factor for breaking tolerance to multiple autoantigens in RA

2016 update of the EULAR recommendations for the management of early arthritis

Objectives: Since the 2007 recommendations for the management of early arthritis have been presented, considerable research has been published in the field of early arthritis, mandating an update of the 2007 EULAR recommendations for management of early arthritis. Methods: In accordance with the 2014 EULAR Standardised Operating Procedures, the expert committee pursued an approach that was based on evidence in the literature and on expert opinion. The committee involved 20 rheumatologists, 2 patients and 1 health professional representing 12 European countries. The group defined the focus of the expert committee and target population, formulated a definition of “management” and selected the research questions. A systematic literature research (SLR) was performed by 2 fellows with the help of a skilled librarian. A set of draft recommendations was proposed on the basis of the research questions and the results of the SLR. For each recommendation the categories of evidence were identified, the strength of recommendations was derived and the level of agreement was determined through a voting process. Results: The updated recommendations comprise 3 overarching principles and 12 recommendations for managing early arthritis. The selected statements involve the recognition of arthritis, referral, diagnosis, prognostication, treatment (information, education, pharmacological and non-pharmacological interventions), monitoring and strategy. Eighteen items were identified as relevant for future research. Conclusion: These recommendations provide rheumatologists, general practitioners, health professionals, patients and other stakeholders with an updated EULAR consensus on the entire management of early arthritis

Obesity, Fat Mass and Immune System: Role for Leptin

Obesity is an epidemic disease characterized by chronic low-grade inflammation associated with a dysfunctional fat mass. Adipose tissue is now considered an extremely active endocrine organ that secretes cytokine-like hormones, called adipokines, either pro- or anti-inflammatory factors bridging metabolism to the immune system. Leptin is historically one of most relevant adipokines, with important physiological roles in the central control of energy metabolism and in the regulation of metabolism-immune system interplay, being a cornerstone of the emerging field of immunometabolism. Indeed, leptin receptor is expressed throughout the immune system and leptin has been shown to regulate both innate and adaptive immune responses. This review discusses the latest data regarding the role of leptin as a mediator of immune system and metabolism, with particular emphasis on its effects on obesity-associated metabolic disorders and autoimmune and/or inflammatory rheumatic diseases.OG is Staff Personnel of Xunta de Galicia (Servizo Galego de Saude, SERGAS) through a research-staff stabilization contract (ISCIII/SERGAS). VF is a “Sara Borrell” Researcher funded by ISCIII and FEDER. RG is a “Miguel Servet” Researcher funded by Instituto de Salud Carlos III (ISCIII) and FEDER. OG, MG-G, and RG are members of RETICS Program, RD16/0012/0014 (RIER: Red de Investigación en Inflamación y Enfermedades Reumáticas) via Instituto de Salud Carlos III (ISCIII) and FEDER. The work of OG and JP (PIE13/00024 and PI14/00016, PI17/00409), and RG (PI16/01870 and CP15/00007) was funded by Instituto de Salud Carlos III and FEDER. OG is a beneficiary of a project funded by Research Executive Agency of the European Union in the framework of MSCA-RISE Action of the H2020 Program (Project No. 734899). The funders had no role in study design, data collection, and analysis, decision to publish, or preparation of the manuscript