• No results found

Extent of atherosclerosis after 11-year prospective follow-up in patients with early rheumatoid arthritis was affected by disease severity at diagnosis

N/A
N/A
Protected

Academic year: 2021

Share "Extent of atherosclerosis after 11-year prospective follow-up in patients with early rheumatoid arthritis was affected by disease severity at diagnosis"

Copied!
10
0
0

Loading.... (view fulltext now)

Full text

(1)

Full Terms & Conditions of access and use can be found at

https://www.tandfonline.com/action/journalInformation?journalCode=irhe20

Scandinavian Journal of Rheumatology

ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/irhe20

Extent of atherosclerosis after 11-year prospective follow-up in patients with early rheumatoid

arthritis was affected by disease severity at diagnosis

I Björsenius , S Rantapää-Dahlqvist , E Berglin & A Södergren

To cite this article: I Björsenius , S Rantapää-Dahlqvist , E Berglin & A Södergren (2020) Extent of atherosclerosis after 11-year prospective follow-up in patients with early rheumatoid arthritis was affected by disease severity at diagnosis, Scandinavian Journal of Rheumatology, 49:6, 443-451, DOI: 10.1080/03009742.2020.1767200

To link to this article: https://doi.org/10.1080/03009742.2020.1767200

© 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

View supplementary material

Published online: 21 Jul 2020. Submit your article to this journal

Article views: 367 View related articles

View Crossmark data

(2)

Extent of atherosclerosis after 11-year prospective follow-up in patients with early rheumatoid arthritis was affected by disease severity at diagnosis

I Björsenius

1

, S Rantapää-Dahlqvist

1

, E Berglin

1

, A Södergren

1,2

1Department of Public Health and Clinical Medicine/Rheumatology, Umeå University, Umeå, Sweden

2Wallenberg Centre for Molecular Medicine (WCMM), Umeå University, Umeå, Sweden

Objective: Cardiovascular disease (CVD) is increased among patients with rheumatoid arthritis (RA). The underlying cause is not clear. In this prospective study, patients with early RA were investigated for associations between subclinical atherosclerosis and CVD risk factors as well as inflammation.

Method: At diagnosis, RA patients were recruited into a prospective study. A subgroup was included (n = 55) for ultrasound measurements of intima–media thickness (IMT) at inclusion (T0), and after 5 years (T5) and 11 years (T11). Thirty-one age and gender-matched controls were also included for comparison.

Results: IMT increased significantly between T0 and T11 among patients and controls (p < 0.0001). No statistically significant differences in IMT between patients and controls were detected at T11, T5, or T0 (p > 0.05 for all). In simple regression models, IMT at T11 was significantly associated with age (p < 0.0001), as well as systolic blood pressure at T0 (p < 0.01) and T11 (p < 0.01) among RA patients. Furthermore, the composite Systematic COronary Risk Evaluation (SCORE) measurements (p < 0.0001) and Reynolds risk score (p < 0.01) and the radiographic Larsen score (p < 0.05) at T0 were all significantly associated with IMT at T11. Results from conditional logistic regression analysis showed an increased progression rate between T0 and T11 in the RA group compared with controls (p < 0.05).

Conclusion: We found increased atherosclerotic development among patients with RA compared with controls 11 years after diagnosis. The atherosclerotic burden was associated with disease severity at baseline.

Rheumatoid arthritis (RA) is the most common rheumatic disease, with a prevalence of 0.5–1%. It is a chronic sys- temic autoimmune disease in which destruction of joints is accompanied by extra-articular organ manifestations (1).

Compared to the general population, patients with RA have increased mortality and morbidity due to cardiovascu- lar disease (CVD) (2–5). Previous studies have shown that patients with manifest RA have an increased subclinical atherosclerosis in comparison with controls (6). Ultrasound measurement of intima–media thickness (IMT) of the com- mon carotid artery is known to be an early indicator of generalized atherosclerosis (7), and relationships between an increased IMT and a future cardiovascular event have been observed in the general population (8–10) as well as among patients with RA (11–13).

This study was launched to identify risk factors at the time of diagnosis of the RA disease that could predict

future atherosclerotic development among RA patients. In this way, patients at risk could be identified and treated accordingly. The cohort was followed prospectively for 11 years from the time of diagnosis with regard to tradi- tional CVD risk factors, disease activity, and IMT. Our hypothesis was that the level of atherosclerosis was increased in the RA patients compared with controls. The primary aim was to investigate whether the atherosclerotic progression rate over 11 years among the RA patients was related to disease activity and/or traditional CVD risk factors identified at the time of disease onset. The second aim was to relate the presence of atherosclerosis in the RA patients, 11 years after diagnosis, to disease activity, dis- ease severity, and/or traditional CVD risk factors at that time-point.

Method

Study design and inclusion

For this study inception cohort as part of a continuing structured program, including patients with early RA included for the analysis of disease development, using the Swedish Rheumatoid Arthritis Quality Registry (SRQ) was

Anna Södergren, Department of Rheumatology, University Hospital, 901 85 Umeå, Sweden.

E-mail: anna.sodergren@umu.se Accepted 6 May 2020

© 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits

(3)

used. All eligible patients with newly diagnosed RA (14) and who have been symptomatic for less than 12 months are continuously enrolled in the register. From this cohort, a subgroup of patients, aged ≤ 60 years, was included con- secutively in this study. The inclusion of patients with RA and controls has been described in detail previously (15).

Seventy-nine patients with early RA, and 44 age- and gender-matched controls were investigated at baseline (T0), and 55 patients with RA and 31 controls were avail- able for a re-evaluation after 11 years (T11). Of the pre- viously included patients with RA, one had died, three had been found not to have RA, one declined because of dementia, one had moved, and 18 declined follow-up for personal reasons. Among the controls, four had moved and the remaining nine declined follow-up for personal reasons.

All patients were examined clinically at inclusion and regularly thereafter. Pharmacological treatment, comorbid- ities including earlier CVD, markers of inflammation [erythrocyte sedimentation rate (ESR), C-reactive protein (CRP)], lipid status [cholesterol, triglycerides, high- density lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol], rheumatoid factor (RF), anti-citrullinated peptide antibodies (ACPAs), number of swollen and tender joints, and measurements of disease activity were registered. The Disease Activity Score based on 28-joint count (DAS28) was calculated (16). All patients were treated and followed up according to clinical guide- lines, and no treatment interventions were made as part of this study. Among the RA patients, 39/55 (71%) had a positive RF and 35/55 (64%) were ACPA positive. All participants were requested to complete a survey on comor- bidity, and a survey of CVD risk factors and lifestyle, as previously described (17). Smoking was recorded as ever smoking, i.e. current as well as previous smoking, or pre- vious smoking, i.e. not including current smokers. Any previous cardiovascular events, i.e. acute myocardial infarc- tion, stroke, coronary artery bypass graft operation, or diag- nosed peripheral atherosclerotic disease, were verified in the medical records. All blood pressure measurements were taken once in each patient after 5 min rest at the time of the ultrasound measurements with the cuff applied on the right arm and with the individual in the supine position. Body mass index (BMI), European Systematic COronary Risk Evaluation (SCORE) (range 0–23%) (18), and Reynolds risk score (range 0 to > 20%) (19) were calculated. Larsen score (range 0–120) (20) was calculated in individuals with accessible radiographs of the hands and feet (n = 44).

All individuals gave their written consent in accor- dance with the Declaration of Helsinki. The study was approved by the Regional Ethics Committee of Umeå University, Umeå, Sweden.

Ultrasound

Ultrasound examinations of the IMT of the right carotid artery were performed as soon as possible after the

diagnosis of RA at T0. New measurements were carried out after 5 and 11 years of follow-up, as previously described (15,

17). All examinations were performed

by the same investigator. Unfortunately, seven IMT measurements from the patients at T11 were lost owing to technical issues.

Statistical analysis

IMT progression rate (ΔT11–T0) was calculated by subtracting baseline values from 11 year follow-up values. Data were analysed using parametric and non- parametric tests. Comparisons between the RA group and controls were performed using the Mann–Whitney U-test, and for comparisons over time, within each group, the Wilcoxon’s signed-rank test was used.

When analysing the matched case–control sample, we used conditional logistic regression with IMT values (IMT T0, IMT T5, IMT T11) or IMT progression rates (ΔT11–T0, ΔT11–T5) as covariates. Since we matched patients with RA and controls with respect to age and gender, we considered the analyses to be adjusted for age and gender. With atherosclerosis as the outcome, simple and multiple linear regressions were used for analysing data within the RA group as well as in controls. Variables with p-value < 0.08 in simple regression models, together with clinical assumptions, determined which covariates were included in the mul- tiple regression models. All analyses, unless otherwise stated, were adjusted for age and gender. Collinearity statistics for the multiple regression models resulted in variance inflation factors < 3 for all variables in each model. Results from previous publications showed that a sample size of 26 in each group would render 95%

power to detect a difference in IMT of 0.1 mm and sd of 0.1 mm (21). There are some missing data in most of the variables collected during clinical follow-up, e.g. X-rays and cardiovascular risk factors. Those missing data can be regarded as random.

Results

Five of the RA patients had experienced a cardiovascular event (Table 1); in the control group, two had ever experienced a cardiovascular event (Table 1).

Progression rate of IMT

When comparing groups, ΔIMT T11–T0 in the RA group was significantly higher than in controls (ΔIMT T11–T0 mean ± sd = 0.16 ± 0.1 in patients with RA and 0.086 ± 0.08 in controls) and was, in the conditional logistic regression, associated with being an RA patient (p = 0.023) (Supplementary table S1). Furthermore, ΔIMT T11–T5 was significantly higher among patients

444 I Björsenius et al

www.scandjrheumatol.se

(4)

Table 1. Descriptive statistics in rheumatoid arthritis (RA) patients and controls at baseline (T0), and after 5 years (T5) and 11 years (T11) of follow-up. RA Controls Variable T0 T5 T11 T0 T5 T11 p, T11 Female, n (%) 48 (87) 25 (81) – Age (years) 46.9 ± 10.2 (n = 55) 51.9 ± 10.2 (n = 55) 57.9 ± 10.2 (n = 55) 49.1 ± 10.8 (n = 31) 54.1 ± 10.8 (n = 31) 60.0 ± 10.8 (n = 31) – IMT (mm) 0.51 ± 0.12 (n = 55) 0.59 ± 0.14 (n = 55) 0.68 ± 0.16***†††§ (n = 54) 0.54 ± 0.12 (n = 30) 0.61 ± 0.11 (n = 31) 0.63 ± 0.13*†††§ (n = 31) 0.265 Systolic BP (mmHg) 122.3 ± 14.2 (n = 51) 125.5 ± 14.0 (n = 55) 130.3 ± 13.9**††† (n = 51) 117.6 ± 10.9 (n = 31) 125.2 ± 12.2 (n = 31) 123.1 ± 11.3† (n = 31) 0.029‡§ Diastolic BP (mmHg) 76.4 ± 8.0 (n = 51) 75.8 ± 7.4 (n = 55) 78.4 ± 6.9*§ (n = 51) 76.7 ± 7.4 (n = 31) 78.1 ± 6.8 (n = 31) 75.5 ± 6.8 (n = 31) 0.048‡§ Cholesterol (mmol/L) 5.5 ± 0.9 (n = 48) 5.3 ± 1.0 (n = 54) 5.4 ± 1.1 (n = 55) 5.4 ± 1.1 (n = 30) 5.6 ± 1.0 (n = 31) 5.5 ± 1.2 (n = 31) 0.906 HDL (mmol/L) 1.5 ± 0.4 (n = 46) 1.6 ± 0.5 (n = 54) 1.7 ± 0.6† (n = 53) 1.5 ± 0.4 (n = 30) 1.7 ± 0.5 (n = 31) 1.8 ± 0.6††† (n = 31) 0.592 Triglycerides (mmol/L) 1.3 ± 0.5 (n = 34) 1.2 ± 0.5 (n = 54) 1.3 ± 0.6 (n = 54) 1.1 ± 0.3 (n = 30) 1.1 ± 0.5 (n = 31) 1.1 ± 0.5 (n = 31) 0.141 BMI (kg/m2 ) 25.7 ± 4.1 (n = 39) 25.5 ± 4.2 (n = 54) 25.9 ± 4.7 (n = 54) 25.8 ± 5.0 (n = 29) 25.6 ± 4.0 (n = 28) 26.9 ± 4.9*†§ (n = 30) 0.259 SCORE (18) 0.89 ± 1.30 (n = 45) – – 0.73 ± 0.74 (n = 30) – – – Reynolds risk score (19) 2.31 ± 3.50 (n = 33) – – – – – – ESR (mm/h) 18.2 ± 17.8 (n = 55) 14.0 ± 10.3 (n = 39) 18.5 ± 15.8 (n = 48) – – – – CRP (mg/L) 13.3 ± 1.3 (n = 52) 8.1 ± 7.7 (n = 36) 7.4 ± 10.5††§ (n = 46) – – – – Previous CVD event, n 3 (n = 55) 5 (n = 55) 5 (n = 55) 0 (n = 31) 1 (n = 31) 2 (n = 31) 0.420 Diabetes mellitus, n (%) 1 (2) (n = 55) 2 (4) (n = 54) 2 (4) (n = 55) 1 (3) (n = 31) 0 (0) (n = 31) 1 (3) (n = 30) 0.879 Statin use, ever, n (%) 1 (2) (n = 55) 4 (7) (n = 55) 9 (17)† (n = 53) 0 (0) (n = 31) 4 (13) (n = 31) 7 (23)†† (n = 31) 0.681 Antihypertensive use, n (%) 7 (13) (n = 55) 9 (16) (n = 55) 18 (33)†† (n = 55) 4 (13) (n = 31) 8 (3) (n = 31) 11 (36)†† (n = 31) 0.943 NSAID use, ever, n (%) – – 47 (89) (n = 53) – – 24 (77) (n = 31) – DAS28 (16) 3.5 ± 1.5 (n = 51) 2.9 ± 1.5 (n = 31) 3.0 ± 1.4† (n = 46) – – – – Larsen score (20) 4.09 ± 4.31 (n = 44) – – – – – – (Continued)

(5)

with RA compared with controls (ΔIMT T11–T5 mean ± sd = 0.089 ± 0.1 in patients with RA and 0.024 ± 0.07 in controls) and was associated with RA (p = 0.041) (Supplementary table S1).

T11 compared to T0

The IMT at T11 increased significantly among RA patients in comparison to the measurement at T0 (Table 1,

Figure 1). Systolic blood pressure, HDL,

and frequency of ever use of statins or of anti-hyper- tensive drugs, also increased significantly, while CRP and DAS28 decreased significantly, among RA patients after 11 years compared with baseline (Table 1). Similar results were found in the controls, with significant increases in IMT, systolic blood pres- sure, HDL, and ever use of statins compared with T0 (Table 1). There were six patients (11%) with RA and two controls (6%) with current smoking at T11. The corresponding numbers with previous smoking were 21 (41%) and 12 (39%), respectively.

T11 compared to T5

In comparison to T5, both systolic and diastolic blood pressure increased significantly in the RA group (Table 1). Controls had significant increases in IMT and BMI compared to T5 (Table 1).

Patients with RA compared with controls

No statistically significant differences in IMT between patients and controls were detected at T11, T5, or T0 (p > 0.05 for all) (Supplementary table S1).

At T11, the RA patients had significantly higher systolic and diastolic blood pressure compared with controls (Table 1).

Table 1. (Continued). RA Controls Variable T0 T5 T11 T0 T5 T11 p, T11 Previous smoking (years) 7.3 ± 10.8 (n = 55) – 13.4 ± 16.2 (n = 45) 4.7 ± 7.2 (n = 31) – 5.3 ± 8.3 (n = 29) 0.053 Smoking ever (years) 14.2 ± 14.0 (n = 55) – 27 (n = 54) 6.9 ± 10.0 (n = 31) – 14.0 (n = 31) – Data are presented as mean ± sd unless otherwise specified. IMT, intima–media thickness; BP, blood pressure; HDL, high-density cholesterol; BMI, body mass index; SCORE, Systematic COronary Risk Evaluation; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; CVD, cardiovascular disease; NSAID, non-steroidal anti-inflammatory drug; DAS28, Disease Activity Score based on 28-joint count. *p < 0.05, **p < 0.01, ***p < 0.001 (compared to data at T5); †p < 0.05, ††p < 0.01, †††p < 0.001 (compared to data at T0). The p-values at T11 are obtained by comparing RA patients with controls. ‡Significant values (p < 0.05). §p > 0.05 after correction for number of analyses (n = 105) according to Bonferroni.

T0 T5

T11

T0 T5

T11 0.0

0.2 0.4 0.6 0.8

mm

T0 T5

Controls RA

T11

Figure 1. Mean intima–media thickness in 55 patients with rheu- matoid arthritis (RA) and 31 controls at baseline (T0), and after 5 years (T5) and 11 years (T11) of follow-up.

446 I Björsenius et al

www.scandjrheumatol.se

(6)

Simple regression models

Among the RA patients, there were significant associa- tions between IMT at T11 and age, as well as systolic blood pressure, at both T11 and T0 (Table 2). SCORE, Reynolds risk score, and Larsen score, all measured at T0, were significantly associated with IMT at T11 (Table 2). Sensitivity analyses were performed and showed no difference in DAS28 or IMT at T0 between those with and those without data on Larsen score, SCORE, or Reynolds risk score (data not shown).

Among the controls, only age and SCORE, measured at T0, were significantly associated with IMT at T11 (Table 2). Among the RA patients, there were signifi- cant associations between ΔIMT T11–T0 and age and Larsen score at T0 (Table 2). Sensitivity analyses were performed excluding individuals with previous CVD, without significant changes in the results (data not shown).

Multiple regression models for the ultrasound measurements

A multiple regression model analysis applied in the RA group, with Larsen score at baseline, being a previous smoker, and cholesterol level at T0 as independent variables, explained 39% of the variance in ΔIMT T11–T0 (Table 3A). In that model, ΔIMT T11–T0 was significantly associated with Larsen score at T0. When the model was further adjusted for age, it explained 46% of the variance in ΔIMT T11–T0. Larsen score was still significantly associated with ΔIMT T11–T0.

A second multiple regression model including some of the variables from SCORE and Reynolds risk score, respectively, explained 32% of the variance in ΔIMT T11–T0 (Table 3B). When adjusting for Larsen score, this model explained 50% of the variance in ΔIMT T11–T0. Only Larsen score and age were significantly associated with ΔIMT T11–T0 in that model (Table 3B,

Table 2. Simple regression models among 55 patients with early rheumatoid arthritis (RA), with intima–media thickness (IMT) at T11 and ΔIMT T11–T0 as the dependent variables.

IMT T11 ΔT11–T0

Variable Β 95% CI p β 95% CI p

Age, T0 0.104/year

(n = 54)

0.071; 0.136 < 0.001* 0.035

(n = 54)

0.010; 0.061 0.008*

Systolic BP, T0 0.035/mmHg

(n = 50)

0.009; 0.061 0.009†* 0.012

(n = 50)

−0.008; 0.033 0.239

Diastolic BP, T0 0.050/mmHg

(n = 50)

0.003; 0.097 0.039* 0.014

(n = 50)

−0.023; 0.051 0.449

SCORE, T0 0.534/unit

(n = 44)

0.261; 0.807 < 0.001* 0.137

(n = 44)

−0.086; 0.360 0.221

Reynolds risk score, T0 0.182/unit

(n = 32)

0.048; 0.315 0.009* −0.012

(n = 32)

−0.104; 0.079 0.784

Larsen score, T0 0.122/unit

(n = 43)

0.004; 0.239 0.043* 0.106

(n = 43)

0.043; 0.170 0.002‡*

Cholesterol, T0 0.090/mmol L−1

(n = 47)

−0.411; 0.591 0.719 −0.271

(n = 47)

−0.558; 0.016 0.064

HDL, T0 −0.264/mmol L−1

(n = 45)

−1.364; 0.835 0.630 −0.332

(n = 45)

−0.976; 0.311 0.304

Triglycerides, T0 1.185/mmol L−1

(n = 33)

−0.106; 2.477 0.071 0.051

(n = 33)

−0.808; 0.910 0.904

Previous smoking, T0 (years) 0.017/year

(n = 54)

−0.024; 0.057 0.409 0.023

(n = 54)

−0.001; 0.048 0.065

Smoking ever, T0 (years) 0.014/year

(n = 54)

−0.017; 0.045 0.384 0.000

(n = 54)

−0.020; 0.020 0.989

DAS28, T0 −0.236/unit

(n = 19)

−0.771; 0.298 0.364 0.039

(n = 19)

−0.427; 0.505 0.861

Age, T11 0.104/year

(n = 54)

0.071; 0.136 < 0.001* – – –

Systolic BP, T11 0.041/mmHg

(n = 54)

0.012; 0.070 0.006§* – – –

BP, blood pressure; SCORE, Systematic COronary Risk Evaluation; HDL, high-density lipoprotein; DAS28, Disease Activity Score based on 28-joint count; T0, baseline; T11, 11 year follow-up; CI, confidence interval.

†Age-adjusted at T0, p = 0.323; ‡age-adjusted at T0, p = 0.008; §age-adjusted at T11, p = 0.160.

*Significant values (p < 0.05).

(7)

Table 3. Multiple regression models among 54 patients with rheumatoid arthritis (RA), with intima–media thickness (IMT) ΔT11–T0 as the dependent variable. A. Independent variables included where a p-value < 0.08 was found in the simple regression models Model I Model II Variable B 95% CI p β 95% CI p Larsen score, T0 0.11/unit 0.053; 0.161 < 0.001* 0.09/unit 0.037; 0.145 0.002* Previous smoking, T0 0.017/year −0.006; 0.040 0.134 0.009/year −0.014; 0.032 0.447 Cholesterol, T0 −0.14/mmol L−1 −0.429; 0.140 0.310 −0.25/mmol L−1 −0.543; 0.043 0.092 Age, T0 – – – 0.025/year 0.000; 0.050 0.054 B. Independent variables based on traditional CVD risk scores and Larsen score Model III Model IV Model V Variable B 95% CI p β 95% CI p β 95% CI p Systolic BP, T0 −0.002/mmHg −0.022; 0.018 0.822 −0.002/mmHg −0.024; 0.019 0.819 −0.006/mmHg −0.026; 0.014 0.524 Cholesterol, T0 −0.41/mmol L−1 −0.694; (−0.119) 0.007* −0.44/mmol L−1 −0.746; (−0.141) 0.005* −0.34/mmol L−1 −0.680; 0.001 0.051 Smoking ever, T0 −0.59/year −1.222; 0.051 0.070 −0.47/year −1.169; 0.227 0.180 −0.53/year −1.368; 0.302 0.201 Age, T0 0.05/year 0.018; 0.075 0.002* 0.04/year 0.013; 0.074 0.006* 0.03/year 0.002; 0.060 0.035* CRP, T0 – – – −0.003/mg L−1 −0.026; 0.020 0.817 0.002/mg L−1 −0.018; 0.023 0.826 Larsen score, T0 – – – – – – 0.10/unit 0.038; 0.164 0.003* Model I, R2 = 0.388; Model II, R2 = 0.456; Model III, R2 = 0.319; Model IV, R2 = 0.318; Model V, R2 = 0.50. CVD, cardiovascular disease; BP, blood pressure; CRP, C-reactive protein; T0, baseline; T11, 11 year follow-up; CI, confidence interval. *Significant values (p < 0.05).

448 I Björsenius et al

www.scandjrheumatol.se

(8)

Model V). When also including IMT at T0 in that model, there were no significant changes in the results, with ΔIMT T11–T0 being significantly associated with Larsen score (p = 0.004) and age (p = 0.002), but also with IMT at T0 (β = −4.4, p = 0.1, R

2

for that model = 0.60).

Discussion

In this study, we found that there was an increase in atherosclerotic progression in RA patients compared with controls, and that this increase was associated with disease severity, i.e. radiological signs of increased joint destruction, adjusted for age at baseline. Larsen score at baseline proved to be the best predictor of IMT progression rate in the RA group, in both simple and multiple regression models. The association was stron- ger than those of several traditional CVD risk factors, including age. Kumeda et al previously demonstrated a cross-sectional relationship between disease severity, as measured by Larsen score for the metacarpophalan- geal joints, and increased IMT in RA patients (22). The prospective design of this study enabled us to point towards a predictive relationship. Apart from methodo- logical aspects, patients in our study were slightly older than in the previous study and no exclusion criteria were applied at inclusion. Furthermore, vascular calci- fication, such as intimal atherosclerosis, has displayed similar molecular mechanisms to those of bone remo- delling (23). These findings are in line with the results presented here, suggesting that disease severity as mea- sured by radiographic changes is related to increased atherosclerosis among RA patients.

It is widely established that atherosclerosis increases with age in the general population, and the association between age and increased IMT among RA patients has been documented previously (6, 13). In a multiple regres- sion model, some of the variables from the CVD risk scores, e.g. SCORE and Reynolds risk score, were related to IMT progression rate. When Larsen score was intro- duced into the model, R

2

increased from 32% to 50%.

In the cross-sectional study, after 11 years of follow- up, traditional CVD risk factors at baseline, such as systolic and diastolic blood pressure and age, were significantly associated with IMT at T11 in simple regression models. When taking traditional CVD risk factors at T11 into account, the same associations to IMT at T11 was found, except for diastolic blood pressure, when measured at T11. In a 2015 report, RA patients with hypertension had an 84% increased risk of myocardial infarction compared with non- hypertensive RA patients (24). SCORE and Reynolds risk score at T0 were also significantly associated with IMT at T11 in simple regression models. SCORE is designed to be applied in the general population and indicates the risk of CVD mortality in the following

10 years, taking systolic blood pressure, gender, cho- lesterol level, smoking habits, and age into account.

Reynolds risk score, also applied in the general popu- lation, indicates the risk of a CVD event in the next 10 years. It is calculated similarly to SCORE, but with the addition of inflammation, as measured by CRP. To date, risk tools developed for the general population do not seem to predict CVD risk in RA patients in a satisfactory way (25, 26). Moreover, previous studies have demonstrated that existing RA-specific CVD predicting scores do not predict CVD more accurately than those developed for the general population (26,

27). Although SCORE and Reynolds risk score

were significantly associated with IMT at T11 in sim- ple regression models, only age remained significant in the multiple regression models. This underlines age as the major contributory factor to the progression of IMT in RA patients in the observed CVD risk management score systems.

With progression rate of IMT at 11 years as the dependent variable, previous smoking at baseline showed a possible trend towards significance. Although a relationship between smoking and increased cardiovascular morbidity is present in the general population (28), the same associations have not been as evidently established among patients with RA. It has been reported that this lack of statistically significant associations is likely to be due to index event bias. This is a phenomenon that could be explained by how, for example, smoking leads to the development of the disease (RA) as well as its sequelae (cardiovascular morbidity) (24, 29, 30).

Others have linked smoking to radiographic progression in RA (24).

While results from this study indicated that disease severity was related to IMT progression rate, others have suggested that ESR and the number of traditional cardio- vascular risk factors play an important role (3). Further- more, it has been shown that inflammation potentiates traditional CVD risk factors in an almost exponential way (31). Although the above-mentioned findings empha- size the activity of the disease rather than its severity, they are unarguably related clinically (1).

The introduction of biological medication has chan- ged the progression of RA disease, in terms of both disease activity and disease severity. Even though conventional disease-modifying anti-rheumatic drugs (e.g. methotrexate or salazopyrine) were predomi- nantly used by patients in this study from baseline, DAS28 decreased significantly between T0 and T5 and decreased numerically between T5 and T11.

Thus, despite the patients with RA being well con- trolled regarding inflammation, the IMT increased in comparison with controls.

In our multiple regression models, R

2

ranged from 0.32

to 0.50, suggesting that other risk factors, not studied here,

may contribute towards the increased IMT progression in

RA patients. The models could have been improved if

other risk factors such as alcohol consumption, insulin

(9)

resistance, adipokines, and other biomarkers, and/or body composition had been included. Furthermore, physical activity was not measured in this study. This factor has become increasingly noticed as being important for the development for CVD, including in patients with RA (32) This study has some limitations. First, in relation to the previous studies during this follow-up (15, 17), the number of controls was diminished further at this study point. To the best of our knowledge, all measure- ments were taken in the same way as at baseline, e.g.

measuring IMT only in the right common artery.

Owing to the small number of individuals, this study was not able to provide enough power to yield signifi- cant associations between IMT progression and tradi- tional risk factors among the controls. Although parameters of inflammation were unavailable in the control group, this study was designed to explore associations between these variables and IMT in the RA group. Furthermore, to avoid diminishing the power among both patients with RA and controls, no individuals were excluded because of previous CVD.

However, sensitivity analyses were performed exclud- ing individuals with a previous CVD, without signifi- cant changes in the results. Secondly, seven IMT measurements from the patients at T11 were lost owing to technical issues. Thirdly, for logistical rea- sons, the IMT measurements were analysed in the same order as the examinations, and thus were not blinded to chronology. Still, the investigator was una- ware of the values of the IMT at the previous measure- ments at the time-points of the follow-ups.

The prospective design is the main strength of the study. Data have been collected from disease onset and thereafter continuously for 11 years. Prospective studies within this field are few and have been in demand by the European League Against Rheumatism working group (33). Secondly, the inclusion of matched controls, also followed prospectively, is another strength. It is hard to give normal values for progression rate in the general population (34), which is why it is important to include controls for each study. The third strength of our study is that all ultrasound measurements were performed by the same investigator at all time-points, hence limiting confounding assessment.

Conclusion

This study indicates the necessity for early diagnosis of RA. It suggests disease severity at baseline as a contributory factor to the development of athero- sclerosis among RA patients. Furthermore, traditional CVD risk factors should be detected early and inter- vened with whenever possible. The results from this study, and from the limited numbers of other studies, show the need for further studies analysing disease severity and atherosclerosis in RA patients.

Acknowledgements

We thank Elisabet Lundström at the Department of Surgical and Perioperative Sciences, University of Umeå, who carried out all of the ultrasound measurements. We also thank Gun-Britt Johansson, Ann-Chatrin Kallin, Sonja Odeblom, and Viktoria von Zweigbergk at the Department for Rheumatology, University Hospital, Umeå, for their excellent help with the collection of patient data, and Marie Eriksson, Department of Statistics, as well as Fredrik Jonsson and Simon Wallin, Department of Medicine, University Hospital, Umeå, for valuable statistical discussions.

This study received funding from the Swedish Research Council;

Knut and Alice Wallenberg Foundation; the Swedish Rheumatism Association; the Swedish Rheumatism Association in the Västerbotten County; Visare Norr, Norrlandstingens regionförbund (Northern County Councils); the Swedish Heart–Lung Foundation; the King Gustaf V’s 80-Year Fund, Sweden; and the Swedish Society for Medical Research (SSMF). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Disclosure statement

No potential conflict of interest was reported by the authors.

References

1. Aletaha D, Smolen JS. Diagnosis and management of rheumatoid arthritis: a review. JAMA 2018;320:1360–72.

2. Wallberg-Jonsson S, Johansson H, Ohman ML, Rantapaa- Dahlqvist S. Extent of inflammation predicts cardiovascular dis- ease and overall mortality in seropositive rheumatoid arthritis.

A retrospective cohort study from disease onset. J Rheumatol 1999;26:2562–71.

3. Del Rincon I, Freeman GL, Haas RW, O’Leary DH, Escalante A.

Relative contribution of cardiovascular risk factors and rheuma- toid arthritis clinical manifestations to atherosclerosis. Arthritis Rheum 2005;52:3413–23.

4. Avina-Zubieta JA, Choi HK, Sadatsafavi M, Etminan M, Esdaile JM, Lacaille D. Risk of cardiovascular mortality in patients with rheumatoid arthritis: a meta-analysis of observa- tional studies. Arthritis Rheum 2008;59:1690–7.

5. Avina-Zubieta JA, Thomas J, Sadatsafavi M, Lehman AJ, Lacaille D. Risk of incident cardiovascular events in patients with rheumatoid arthritis: a meta-analysis of observational studies. Ann Rheum Dis 2012;71:1524–9.

6. van Sijl AM, Peters MJ, Knol DK, de Vet HC, Gonzalez- Gay MA, Smulders YM, et al. Carotid intima media thickness in rheumatoid arthritis as compared to control subjects: a meta-analysis. Semin Arthritis Rheum 2011;40:389–97.

7. Wendelhag I, Wiklund O, Wikstrand J. Atherosclerotic changes in the femoral and carotid arteries in familial hypercholesterolemia.

Ultrasonographic assessment of intima-media thickness and pla- que occurrence. Arterioscler Thromb 1993;13:1404–11.

8. O’Leary DH, Bots ML. Imaging of atherosclerosis: carotid intima-media thickness. Eur Heart J 2010;31:1682–9.

9. Lorenz MW, Markus HS, Bots ML, Rosvall M, Sitzer M. Predic- tion of clinical cardiovascular events with carotid intima-media thickness: a systematic review and meta-analysis. Circulation 2007;115:459–67.

10. Polak JF, Szklo M, Kronmal RA, Burke GL, Shea S, Zavodni AE, et al. The value of carotid artery plaque and intima-media thick- ness for incident cardiovascular disease: the multi-ethnic study of atherosclerosis. J Am Heart Assoc 2013;2:e000087.

11. Gonzalez-Juanatey C, Llorca J, Martin J, Gonzalez-Gay MA.

Carotid intima-media thickness predicts the development of car- diovascular events in patients with rheumatoid arthritis. Semin Arthritis Rheum 2009;38:366–71.

450 I Björsenius et al

www.scandjrheumatol.se

(10)

12. Evans MR, Escalante A, Battafarano DF, Freeman GL, O’Leary DH, Del Rincon I. Carotid atherosclerosis predicts inci- dent acute coronary syndromes in rheumatoid arthritis. Arthritis Rheum 2011;63:1211–20.

13. Ambrosino P, Lupoli R, Di Minno A, Tasso M, Peluso R, Di Minno MN. Subclinical atherosclerosis in patients with rheuma- toid arthritis. A meta-analysis of literature studies. Thromb Hae- most 2015;113:916–30.

14. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis.

Arthritis Rheum 1988;31:315–24.

15. Södergren A, Karp K, Boman K, Eriksson C, Lundstrom E, Smedby T, et al. Atherosclerosis in early rheumatoid arthritis:

very early endothelial activation and rapid progression of intima media thickness. Arthritis Res Ther 2010;12:R158.

16. Prevoo ML, van ‘T Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van Riel PL. Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum 1995;38:44–8.

17. Södergren A, Karp K, Bengtsson C, Möller B, Rantapää- Dahlqvist S, Wållberg-Jonsson S. The extent of subclinical ather- osclerosis is partially predicted by the inflammatory load:

a prospective study over 5 years in patients with rheumatoid arthritis and matched controls. J Rheumatol 2015;42:935–42.

18. Conroy RM, Pyorala K, Fitzgerald AP, Sans S, Menotti A, De Backer G, et al. Estimation of ten-year risk of fatal cardiovascular disease in Europe: the SCORE project. Eur Heart J 2003;24:987–1003.

19. Ridker PM, Buring JE, Rifai N, Cook NR. Development and validation of improved algorithms for the assessment of global cardiovascular risk in women: the Reynolds risk score. JAMA 2007;297:611–19.

20. Larsen A, Dale K, Eek M. Radiographic evaluation of rheumatoid arthritis and related conditions by standard reference films. Acta Radiol Diagn (Stockh) 1977;18:481–91.

21. Södergren A Epidemiological and pathogenic aspects on cardio- vascular disease in rheumatoid arthritis. PhD thesis, Umeå Uni- versity, 2008.

22. Kumeda Y, Inaba M, Goto H, Nagata M, Henmi Y, Furumitsu Y, et al. Increased thickness of the arterial intima-media detected by ultrasonography in patients with rheumatoid arthritis. Arthritis Rheum 2002;46:1489–97.

23. Fuery MA, Liang L, Kaplan FS, Mohler ER 3rd. Vascular ossifi- cation: pathology, mechanisms, and clinical implications. Bone 2018;109:28–34.

24. Baghdadi LR, Woodman RJ, Shanahan EM, Mangoni AA. The impact of traditional cardiovascular risk factors on cardiovascular outcomes in patients with rheumatoid arthritis: a systematic review and meta-analysis. PLoS One 2015;10:e0117952.

25. Arts EE, Popa CD, Den Broeder AA, Donders R, Sandoo A, Toms T, et al. Prediction of cardiovascular risk in rheumatoid arthritis: performance of original and adapted SCORE algorithms.

Ann Rheum Dis 2016;75:674–80.

26. Crowson CS, Gabriel SE, Semb AG, van Riel P, Karpouzas G, Dessein PH, et al. Rheumatoid arthritis-specific cardiovascular risk scores are not superior to general risk scores: a validation analysis of patients from seven countries. Rheumatology (Oxford) 2017;56:1102–10.

27. Wahlin B, Innala L, Magnusson S, Moller B, Smedby T, Rantapaa- Dahlqvist S, et al. Performance of the expanded cardiovascular risk prediction score for rheumatoid arthritis is not superior to the ACC/

AHA risk calculator. J Rheumatol 2019;46:130–7.

28. Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study):

case-control study. Lancet 2004;364:937–52.

29. Ruiz-Esquide V, Gomez-Puerta JA, Canete JD, Graell E, Vazquez I, Ercilla MG, et al. Effects of smoking on disease activity and radiographic progression in early rheumatoid arthritis. J Rheumatol 2011;38:2536–9.

30. Kallberg H, Ding B, Padyukov L, Bengtsson C, Ronnelid J, Klareskog L, et al. Smoking is a major preventable risk factor for rheumatoid arthritis: estimations of risks after various expo- sures to cigarette smoke. Ann Rheum Dis 2011;70:508–11.

31. Innala L, Möller B, Ljung L, Magnusson S, Smedby T, Södergren A, et al. Cardiovascular events in early RA are a result of inflammatory burden and traditional risk factors: a five year prospective study.

Arthritis Res Ther 2011;13:R131.

32. Hörnberg K, Pomeroy J, Sandberg C, Södergren A, Ångström L, Sundström B, et al. Physical activity in rheumatoid arthritis: rela- tionship to cardiovascular risk factors, subclinical atherosclerosis, and disease activity. Scand J Rheumatol 2020;49:112–21.

33. Agca R, Heslinga SC, Rollefstad S, Heslinga M, McInnes IB, Peters MJ, et al. EULAR recommendations for cardiovascular disease risk management in patients with rheumatoid arthritis and other forms of inflammatory joint disorders: 2015/2016 update. Ann Rheum Dis 2017;76:17–28.

34. Liao X, Norata GD, Polak JF, Stehouwer CD, Catapano A, Rundek T, et al. Normative values for carotid intima media thickness and its progression: are they transferrable outside of their cohort of origin? Eur J Prev Cardiol 2016;23:1165–73.

Supporting information

Additional Supporting Information may be found in the online version of this article.

Supplementary table S1. Data on analyses of the matched case-control sample including 54 patients with RA and 31 controls matched for age and sex.

Please note that the editors are not responsible for the content or functionality of any supplementary material supplied by the authors. Any queries should be directed to the corresponding author.

References

Related documents

The presence of a higher number of different ACPA reactivities, and different ACPA subtypes could provide prognostic information of disease activity and radiological destruction.

TIRA = Swedish acronym for Early Interventions in Rheumatoid Arthritis; ICF = International Classification of Functioning Disability and Health; ESR = erythrocyte sedimentation

Center for Medical Technology Assessment, Department of Health and Society, Linköping University, SE-581 83 Linköping, Sweden.

After 3 years, almost 25% of the TIRA patients were in remission, but approximately 15% had sustained high or moderate disease activity during all 3 years, indicating that this

Assessments related to work (MEI and physical workload), and shoulder function (shoulder-arm movement, activity-induced shoulder pain, shoulder muscle strength), hand-grip

Impaired work ability is common among patients with early RA and associated with impaired shoulder function, mechanical exposure and activity limitations related to the shoulder,

Ek, Amanda: Physical activity among patients with cardiovascular disease: a predictor of hospital care utilisation and mortality in clinical work.. Avhandlingsserie för Gymnastik-

In total, 17.6% of respondents reported hand eczema after the age of 15 years and there was no statistically significant difference in the occurrence of hand