Effect of TNF inhibitors on arterial stiffness and intima media thickness in rheumatoid arthritis: a systematic review and meta-analysis.

Controlling inflammation with tumor necrosis factor (TNF) inhibitors in rheumatoid arthritis (RA) patients is hypothesized to reduce their cardiovascular risk. We performed a systematic review and meta-analysis on the effects of TNF inhibitors on arterial stiffness and carotid intima media thickness (IMT) in RA. MEDLINE, EMBASE, clinicaltrials.gov , and WHO Clinical Trials Registry were searched up to September 2021 for randomized controlled trials, prospective cohort studies, and nonrandomized clinical trials evaluating the effects of TNF inhibitors on pulse wave velocity (PWV), augmentation index (AIx), and IMT in RA. A meta-analysis was performed to assess changes of these measures after therapy during different follow-up periods. Risk of bias assessment was performed using an adjusted Downs and Black checklist (INPLASY: 2022-1-0131). Thirty studies were identified from 1436 records, of which 23 were included in the meta-analysis. PWV and AIx showed a decrease after treatment (PWV: mean difference (MD) -0.51 m/s (95% CI: -0.96, -0.06), p=0.027; AIx: MD -0.57% (95% CI: -2.11, 0.96), p=0.463, sensitivity analysis AIx: MD -1.21% (95% CI: -2.60, 0.19), p=0.089). For IMT, there was a slight increase in the first months of follow-up, but this disappeared on the long-term (overall timepoints MD -0.01 mm (95% CI: -0.04, 0.02), p=0.615). Heterogeneity was high in the overall analyses and subgroups with long follow-up periods (≥12 months). The included studies showed mixed results of the effects of TNF inhibitors on the surrogate markers. The pooled results suggest that PWV and AIx decrease over time, while IMT remains stable. This indicates a favorable effect of TNF inhibitors on the cardiovascular disease risk, all the more since these markers also increase with age.

Effect of anti-inflammatory therapy on vascular biomarkers for subclinical cardiovascular disease in rheumatoid arthritis patients.

OBJECTIVE: To assess the effect of 4 years of anti-inflammatory therapy on markers of subclinical vascular disease in rheumatoid arthritis patients. METHODS: Carotid intima media thickness (IMT), augmentation index (AIx@75) and pulse wave velocity (PWV) measurements were performed repeatedly in 61 RA patients (30 early RA starting with csDMARDs and 31 established RA starting with adalimumab) for 4 years. These markers were also measured in 29 controls with osteoarthritis at baseline (BL). RESULTS: IMT and AIx@75 at BL were higher in RA compared to OA, while PWV was higher in OA. In RA patients, AIx@75 and PWV decreased in the first 6 months after starting anti-inflammatory therapy. At 48 M, the level of AIx@75 remained lower than before therapy, while PWV at 48 M was comparable to BL (AIx@75: BL 28% (95% confidence interval 25-30%), 6 M 23% (20-26%), 48 M 25% (22-28%); PWV: BL 8.5 (7.8-9.2), 6 M 8.0 (7.1-8.9), 48 M 8.6 (7.6-9.6) m/s). IMT remained stable. There was an effect of disease activity (longitudinally, adjusted for changes over time) on IMT, AIx@75 and PWV. CONCLUSION: This study suggests modest beneficial changes in some surrogate markers of subclinical vascular disease after anti-inflammatory therapy. These changes were associated with improvement in disease activity markers. Whether or not these beneficial changes ultimately predict a reduction in clinicalcardiovascular endpoints remains to be established in prospective studies.

18F-FDG PET-CT in rheumatoid arthritis patients tapering TNFi: reliability, validity and predictive value.

OBJECTIVES: To investigate the reliability and validity of fluorine-18 fluorodeoxyglucose (18F-FDG) PET-CT scanning (FDG-PET) in RA patients with low disease activity tapering TNF inhibitors (TNFis) and its predictive value for successful tapering or discontinuation. METHODS: Patients in the tapering arm of the Dose REduction Strategies of Subcutaneous TNFi study, a randomized controlled trial of TNFi tapering in RA, underwent FDG-PET before tapering (baseline) and after maximal tapering. A total of 48 joints per scan were scored both visually [FDG-avid joint (FAJ), yes/no] and quantitatively [maximal and mean standardized uptake values (SUVmax and SUVmean)]. Interobserver agreement was calculated in 10 patients at baseline. Quantitative and visual FDG-PET scores were investigated for (multilevel) association with clinical parameters both on a joint and patient level and for the predictive value at baseline and the change between baseline and maximal tapering (Δ) for successful tapering and discontinuation at 18 months. RESULTS: A total of 79 patients underwent FDG-PET. For performance of identification of FAJs on PET, Cohen's κ was 0.49 (range 0.35-0.63). For SUVmax and SUVmean, intraclass correlation coefficients were 0.80 (range 0.77-0.83) and 0.96 (0.9-1.0), respectively. On a joint level, swelling was significantly associated with SUVmax and SUVmean [B coefficients 1.0 (95% CI 0.73, 1.35) and 0.2 (0.08, 0.32), respectively]. On a patient level, only correlation with acute phase reactants was found. FDG-PET scores were not predictive of successful tapering or discontinuation. CONCLUSIONS: Quantitative FDG-PET arthritis scoring in RA patients with low disease activity is reliable and has some construct validity. However, no predictive values were found for FDG-PET parameters for successful tapering and/or discontinuation of TNFi.

Arterial wall inflammation in rheumatoid arthritis is reduced by anti-inflammatory treatment.

BACKGROUND: Rheumatoid arthritis (RA) patients have an increased risk of cardiovascular disease (CVD), partly due to an increased prevalence of cardiovascular risk factors, but also due to chronic systemic inflammation inducing atherosclerotic changes of the arterial wall. The aim of this study was to determine whether anti-inflammatory therapy for the treatment of RA has favorable effects on arterial wall inflammation in RA patients. METHODS: Arterial wall inflammation before and after 6 months of anti-inflammatory treatment was assessed in 49 early and established RA patients using 18F-fluorodeoxyglucose-positron emission tomography with computed tomography (18F-FDG-PET/CT). Arterial 18F-FDG uptake was quantified as maximum standardized uptake value (SUVmax) in the thoracic aorta, abdominal aorta, carotid, iliac and femoral arteries. Early RA patients (n = 26) were treated with conventional synthetic disease modifying anti-rheumatic drugs with or without corticosteroids, whereas established RA patients (n = 23) were treated with adalimumab. RESULTS: In RA patients, overall SUVmax was over time reduced by 4% (difference -0.06, 95%CI -0.12 to -0.01, p = 0.02), with largest reductions in carotid (-8%, p = 0.001) and femoral arteries (-7%, p = 0.005). There was no difference in arterial wall inflammation change between early and established RA patients (SUVmax difference 0.003, 95%CI -0.11 to 0.12, p = 0.95). Change in arterial wall inflammation significantly correlated with change in serological inflammatory markers (erythrocyte sedimentation rate and C-reactive protein). CONCLUSION: Arterial wall inflammation in RA patients is reduced by anti-inflammatory treatment and this reduction correlates with reductions of serological inflammatory markers. These results suggest that anti-inflammatory treatment of RA has favorable effects on the risk of cardiovascular events in RA patients.

Arterial wall inflammation is increased in rheumatoid arthritis compared with osteoarthritis, as a marker of early atherosclerosis.

OBJECTIVE: RA is associated with higher risk of cardiovascular (CV) disease. Ongoing systemic inflammation is presumed to accelerate atherosclerosis by increasing inflammation in the arterial wall. However, evidence supporting this hypothesis is limited. We aimed to investigate arterial wall inflammation in RA vs OA, and its association with markers of inflammation and CV risk factors. METHODS: 18-fluorodeoxyglucose PET combined with CT (18F-FDG-PET/CT) was performed in RA (n = 61) and OA (n = 28) to investigate inflammatory activity in the wall of large arteries. Secondary analyses were performed in patients with early untreated RA (n = 30), and established RA, active under DMARD treatment (n = 31) vs OA. RESULTS: Patients with RA had significantly higher 18F-FDG uptake in the wall of the carotid arteries (beta 0.27, 95%CI 0.11-0.44, P <0.01) and the aorta (beta 0.47, 95%CI 0.17-0.76, P <0.01) when compared with OA, which persisted after adjustment for traditional CV risk factors. Patients with early RA had the highest 18F-FDG uptake, followed by patients with established RA and OA respectively. Higher ESR and DAS of 28 joints values were associated with higher 18F-FDG uptake in all arterial segments. CONCLUSION: Patients with RA have increased 18F-FDG uptake in the arterial wall compared with patients with OA, as a possible marker of early atherosclerosis. Furthermore, a higher level of clinical disease activity and circulating inflammatory markers was associated with higher arterial 18F-FDG uptake, which may support a role of arterial wall inflammation in the pathogenesis of vascular complications in patients with RA.

The value of joint ultrasonography in predicting arthritis in seropositive patients with arthralgia: a prospective cohort study.

BACKGROUND: The value of joint ultrasonography (US) in the prediction of clinical arthritis in individuals at risk of developing rheumatoid arthritis (RA) is still a point of debate, due to varying scanning protocols and different populations. We investigated whether US abnormalities assessed with a standard joint protocol can predict development of arthritis in seropositive patients with arthralgia. METHODS: Anti-citrullinated protein antibodies and/or rheumatoid factor positive patients with arthralgia, but without clinical arthritis were included. US was performed at baseline in 16 joints: bilateral metacarpophalangeal 2-3, proximal interphalangeal 2-3, wrist and metatarsophalangeal (MTP) joints 2-3 and 5. Images were scored semi-quantitatively for synovial thickening and for positive signs on power Doppler (PD). Association between US abnormalities and arthritis development at the joint and at the patient level was evaluated. Also, we investigated the added value of US over clinical parameters. RESULTS: Out of 163 patients who underwent US examination, 51 (31%) developed clinical arthritis after a median follow-up time of 12 (interquartile range 5-24) months, of which 44 (86%) satisfied the 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for RA. US revealed synovial thickening and PD in at least one joint in 49 patients (30%) and 7 patients (4%), respectively. Synovial thickening was associated with both development and timing of clinical arthritis in any joint (patient level) when MTP joints were excluded from the US assessment (odds ratio 6.6, confidence interval (CI) 1.9-22), and hazard ratio 3.4, CI 1.6-6.8, respectively, with a mean time to arthritis of 23 versus 45 months when synovial thickening was present versus not present). There was no association between US and arthritis development at the joint level. Predictive capacity was highest in the groups with an intermediate and high risk of developing arthritis based on a prediction rule with clinical parameters. CONCLUSIONS: Synovial thickening on US predicted clinical arthritis development at the patient level in seropositive patients with arthralgia when MTPs were excluded from the US assessment. Positive PD signs were infrequently seen in these at-risk individuals and was not predictive. In patients at intermediate risk of RA, US may help to identify those at higher risk of developing arthritis.

The effect of biological DMARDs on the risk of congestive heart failure in rheumatoid arthritis: a systematic review.

INTRODUCTION: A common cardiovascular manifestation in rheumatoid arthritis (RA) is congestive heart failure (CHF) in which inflammation is considered to play a pivotal role. Although anti-inflammatory therapy such as biological disease-modifying anti-rheumatic drugs (bDMARDs) have the potential of improving the cardiac function and reducing the risk of CHF, the published studies showed contrasting results. This review aims to systematically summarize and analyze literature regarding the effect of bDMARDs on the cardiac function and on the risk of CHF in RA. AREAS COVERED: Observational cohort, randomized controlled trials and case-controlled studies were included. The systematic literature search was conducted in PubMed, Wiley/Embase, Cochrane, Web of Science and clinicaltrials.gov (up to 2017). Two authors assessed abstracts for inclusion and methodological quality was assessed by one reviewer. EXPERT OPINION: RA patients have a clinically relevant increased risk of developing CHF needing further attention. However, we found a lack of high quality studies. Future studies should focus on distinguishing the effect of myocardial inflammation reduction versus antibody-specific myocardial cellular effects of bDMARDs to improve the understanding of the effects of bDMARDs in RA patients and the relation with the development of CHF.