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

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

Disease Factors in Early Rheumatoid Arthritis Are Associated with Differential Risks for Cardiovascular Events and Mortality Depending on Age at Onset: A 10-year Observational Cohort Study.

To investigate, within the first 2 years of diagnosis with rheumatoid arthritis (RA), associations between disease-related measures and cardiovascular disease (CVD) and mortality in patients with RA onset before and after 65 years of age

Anti-citrullinated protein antibodies are associated with osteopenia but not with pain at diagnosis of rheumatoid arthritis : Data from the BARFOT cohort

Background: Anti-citrullinated protein antibodies (ACPA) have been suggested to have a potential role in both bone loss and pain in rheumatoid arthritis (RA), based on studies in vitro and in animal models. Here we addressed if anti-cyclic citrullinated (anti-CCP) antibodies were associated with osteopenia or pain in patients with RA, at the time for diagnosis. Methods: Baseline data from the BARFOT (Better Anti-Rheumatic PharmacOTherapy) cohort, which consists of patients with RA with a disease duration of 1 year or less, were analyzed. To be included, they should have been assessed by anti-CCP, dual-energy X-ray absorptiometry (DEXA) of lumbar spine and hip, and/or digital X-ray radiogrammetry (DXR) of the metacarpal bones. Osteopenia was defined as a z-score 40 mm, was defined as patient unacceptable pain. Multiple logistic regression analyses were performed to assess whether anti-CCP was independently associated with osteopenia or unacceptable pain. Results: Of the 657 patients, 65% were women, 58% were anti-CCP positive, 37% had osteopenia in the lumbar spine, and 29% had osteopenia in the hip. Sixty-one percent had unacceptable pain at diagnosis. Patients positive for anti-CCP had significantly more frequently osteopenia in the femoral neck and Ward's triangle compared with anti-CCP-negative patients (p = 0.016 and 0.003, respectively). This difference was found in men at any anti-CCP titer, but in women, osteopenia in these hip locations was found only in those with high anti-CCP titers (> 500 IU/ml). Anti-CCP was not associated with osteopenia in the lumbar spine or the metacarpal bones. In multiple logistic regression analyses, anti-CCP was independently associated with osteopenia in the femoral neck and/or Ward's triangle but not with unacceptable pain. Instead, inflammatory variables were independently associated with unacceptable pain. Conclusion: These data show that in patients with early RA, anti-CCP positivity was independently associated with osteopenia in the femoral neck and/or Ward, but not in the lumbar spine. In our patients, we could not confirm a recently suggested association between anti-CCP antibodies and pain. Further studies are necessary to explore the possible clinical relevance of interactions between ACPA, bone, and pain found in vitro and in animal models

Higher levels of anti-phosphorylcholine autoantibodies in early rheumatoid arthritis indicate lower risk of incident cardiovascular events

Background: The increased risk of cardiovascular events (CVE) in rheumatoid arthritis (RA) is not fully explained by traditional risk factors. Immuno-inflammatory mechanisms and autoantibodies could be involved in the pathogenesis of atherosclerotic disease. It has been suggested that anti-phosphorylcholine antibodies (anti-PC) of the IgM subclass may have atheroprotective effects. Here, we aimed to investigate the association between levels of IgM anti-PC antibodies with CVE in patients with early RA. Methods: The study population was derived from the BARFOT early RA cohort, recruited in 1994–1999. The outcome of incident CVE (AMI, angina pectoris, coronary intervention, ischemic stroke, TIA) was tracked through the Swedish Hospital Discharge and the National Cause of Death Registries. Sera collected at inclusion and the 2-year visit were analyzed with ELISA to determine levels of anti-PC IgM. The Kaplan-Meier estimates and Cox proportional hazards regression models were used to compare CV outcome in the groups categorized by baseline median level of IgM anti-PC. Results: In all, 653 patients with early RA, 68% women, mean (SD) age 54.8 (14.7) years, DAS28 5.2 (1.3), 68% seropositive, and without prevalent CVD, were included. During the follow-up of mean 11.7 years, 141 incident CVE were recorded. Baseline IgM anti-PC above median was associated with a reduction in risk of incident CVE in patients aged below 55 years at inclusion, HR 0.360 (95% CI, 0.142–0.916); in males, HR 0.558 (0.325–0.958); in patients with BMI above 30 kg/m2, HR 0.235 (0.065–0.842); and in those who did not achieve DAS28 remission at 1 year, HR 0.592 (0.379–0.924). The pattern of associations was confirmed in the models with AUC IgM anti-PC over 2 years. Conclusion: Protective effects of higher levels of innate IgM anti-PC autoantibodies on CVE were detected in younger patients with RA and those at high risk of CVE: males, presence of obesity, and non-remission at 1 year

Variation in pain related to systemic lupus erythematosus (SLE) : a 7-year follow-up study

We have previously shown that most patients with systemic lupus erythematosus (SLE) reported low degree of SLE-related pain. However, 24% of the patients reported high degree of SLE-related pain, more fatigue, anxiety and depression, and worse health-related quality of life (HRQoL). To explore SLE-related pain, the presence of long-standing widespread pain, and patient-reported outcomes (PROs) after 7 years. Sixty-four out of 84 patients participated in a 7-year follow-up of the original survey and completed the same questionnaires answered at inclusion: pain (VAS 100 mm), fatigue (MAF), HRQoL (SF-36), anxiety and depression (HADS), and, if appropriate, a pain-drawing. Differences between inclusion and follow-up (change) were calculated. The patients with a low degree of SLE-related pain at inclusion reported no changes at follow-up in pain and PROs except for worsening in physical function in SF-36, median change (IQR) 0 (− 10 to 5), p = 0.024. Half of the patients with high degree of pain at inclusion reported decreased pain at follow-up, median change (IQR) 45 (35 to 65), p = 0.021; fatigue, 8 (8 to 17), p = 0.018; anxiety, 4 (1 to 4), p = 0.035; and depression, 4 (2 to 5), p = 0.018 and improvements in most dimensions of SF-36. The remaining half of the patients reported no changes regarding pain and PROs except for a worsening in vitality in SF-36, 20 (15 to 35), p = 0.0018. All patients with remaining high level of pain indicated long-standing widespread pain. After 7 years, a subgroup of patients with SLE reported remaining high level of SLE-related pain and a high symptom burden, including long-standing widespread pain. Such patients require more observant attention to receive appropriate treatment

Erosion-free rheumatoid arthritis: clinical and conceptional implications—a BARFOT study

Abstract Background Bone erosions may appear early or later during rheumatoid arthritis (RA), causing joint damage and functional impairment. However, in some patients erosions do not occur, even after several years of disease. This study evaluates the prevalence, clinical relevance and possible predictors of erosion-free RA. Methods Six hundred and eight patients from an early RA cohort (BARFOT) having radiographs of hands and feet at inclusion and after 1, 2, 5 and 8 years were studied. Clinical and functional assessments were performed on all these time-points. Results In all, 144 patients (24%) did not develop erosions up to 8 years follow-up (Never erosive group), while 464 patients (76%) had erosions on one or more assessments (Ever erosive group). At diagnosis, the patients in the Never erosive group were significantly younger, satisfied fewer ACR criteria, and were less frequently RF- and/or anti-CCP- positive compared with those in the Ever erosive group. The Never erosive patients had consistently more tender joints, lower erythrocyte sedimentation rate (ESR) and, from two years and onwards, fewer swollen joints. Absence of rheumatoid factor (RF) and/or anti-CCP were strong independent predictors for erosion-free disease. The erosion-free patients were less frequently treated with DMARDs and/or prednisolone. Conclusions One-quarter of the patients was erosion-free during eight years in this early RA cohort. Erosion-free patients had a less severe disease course as to disease activity and were more often seronegative compared with those with erosive disease. The results suggest that non-erosive RA represents a milder form of RA

Effect of FCGR polymorphism on the occurrence of late-onset neutropenia and flare-free survival in rheumatic patients treated with rituximab

Background: The causes and mechanisms of late-onset neutropenia (LON) following rituximab treatment in patients with rheumatic diseases are not known. In this study, we aimed to investigate the role of established Fc gamma receptor gene (FCGR) polymorphisms and B-cell-activating factor (BAFF) gene promoter polymorphisms for the development of LON and for the efficacy of rituximab in patients with rheumatic diseases. Methods: A single-center case-control retrospective study was nested in a cohort of 214 consecutive patients with rheumatic diseases treated with rituximab. Eleven patients presented with LON. Fifty non-LON control subjects were matched by diagnosis, age, sex, and treatments. Single-nucleotide polymorphisms of FCGR (FCGR2A 131H/R, FCGR2B 232I/T, FCGR3A 158V/F) and BAFF promoter polymorphism -871C/T were analyzed with polymerase chain reaction-based techniques, and serum immunoglobulin M (IgM) and BAFF levels were analyzed by enzyme-linked immunosorbent assay. Flare-free survival was related to LON occurrence and polymorphisms. Results: The FCGR3A V allele, but not other FCGR polymorphisms, correlated with the occurrence of LON; each V allele conferred a fourfold increased OR for LON (p = 0.017). FCGR3A 158V/V and presentation with LON were associated with a longer flare-free survival (p = 0.023 and p = 0.031, respectively). FCGR3A 158V/V was related to lower IgM levels (p = 0.016). Serum BAFF levels showed no relationship with LON and BAFF -871C/T promoter polymorphism. There was a tendency toward longer flare-free survival in patients with the BAFF -871T/T allotype compared with the C/T or C/C allotypes (p = 0.096). Conclusions: The results of the present study suggest that presentation with LON may be a result of the intrinsic efficacy of rituximab in patients with rheumatic diseases. LON could indicate a longer biological and therapeutic activity of rituximab modulated by a certain genotypic polymorphism: the high-affinity FCGR3A V allele. This genotype and the occurrence of LON are both related to longer flare-free survival, suggestive of common mechanisms for LON and duration of response to rituximab. The role of the BAFF -871C/T promoter polymorphism in LON occurrence is unclear