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Abstract
Objectives To elucidate the association between different disease activity levels over time on long-term vascular outcomes in patients with early rheumatoid arthritis (ERA).
Methods This was a 5-year prospective study. Patients with consecutive ERA without overt cardiovascular disease (CVD) were recruited to receive 1 year of tight-control treatment followed by standard-of-care management. High-resolution carotid ultrasound was assessed at baseline and year 5. The primary outcome was subclinical atherosclerosis progression (AP+), defined as the occurrence of incident plaque, increased region harbouring plaques and/or maximum carotid intima-media thickness progression ≥0.9 mm at year 5. Inflammatory burden during the follow-up period was represented by the cumulative average Disease Activity Score 28-erythrocyte sedimentation rate (ca-DAS28-ESR). Persistent low disease activity (LDA) or remission state was defined as ca-DAS28-ESR≤3.2.
Results One-hundred and four patients with ERA (age: 52±11 years, 81 (77.9%) female) were included in this analysis. Fifty-two (50%) patients achieved persistent LDA or remission and 42 patients (40.4%) had AP+. Patients in the AP+ group were older and had more traditional cardiovascular risk factors at baseline. Multivariate logistic regression analysis revealed that patients with persistent moderate or high disease activity (ca-DAS28-ESR>3.2) had a significantly increased risk of AP+ (OR 5.05, 95% CI 1.53, 16.64, p=0.008) compared with those who achieved persistent remission. The risk of AP+ was similar in patients who achieved persistent LDA and remission.
Conclusions Achieving persistent LDA or remission may prevent progression of atherosclerosis in ERA. A treat-to-target approach aiming at sustained LDA or remission may reduce the risk of CVD by preventing AP+.
- Atherosclerosis
- Inflammation
- Arthritis, Rheumatoid
- Therapeutics
Data availability statement
No data are available.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Systemic inflammation appears to contribute to excess risk of cardiovascular disease (CVD) in rheumatoid arthritis (RA) due to accelerated atherosclerosis. Nonetheless, the impact of different levels of disease activity over time on subclinical atherosclerosis progression (AP+) in patients with early RA (ERA) remained uncertain.
WHAT THIS STUDY ADDS
Persistent inflammation in patients with moderate and high disease activity levels was associated with higher risk of AP+ compared with those who achieved persistent remission. Conversely, AP+ was similar in patients who achieved persistent low disease activity (LDA) and remission.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
Treat-to-target strategies aiming at persistent LDA or remission may reduce the risk of CVD by preventing progression of atherosclerosis in patients with ERA.
Introduction
Rheumatoid arthritis (RA) is associated with increased risk of cardiovascular disease (CVD), which accounts for more than 50% of premature deaths in RA.1 2 The augmented risk is believed to be associated with inflammation, as supported by a recent cohort study indicating that Disease Activity Score 28 (DAS28) accounted for approximately 12.6% of the overall CVD risk, a proportion similar to that of total cholesterol level (12.2%).3 Another study revealed that higher cumulative disease activity and an increased number of disease flares (HR 1.07 per 6-week flare, 95% CI 1.01, 1.15 vs remission) were associated with a higher CVD risk in RA.4
Evaluation of CVD risk by screening for asymptomatic carotid atherosclerosis is recommended by EULAR.1 The progression of an atherosclerotic plaque to the development of a cardiovascular event (CVE) can vary widely among individuals. Based on an inception cohort of 105 patients without prior CVEs before the onset of RA, 17 CVEs occurred after a mean follow-up of 12 years, resulting in an incidence rate of 1.35 events per 100 person-years (95% CI 0.71, 2.0). The presence of bilateral carotid plaques is associated with a lower likelihood of CVD-free survival, with a clear separation between the two groups at 10 years.5 Furthermore, the presence of carotid plaques was linked to an HR of 1.83 (95% CI 1.27, 2.62) for cardiovascular (CV) mortality and non-fatal myocardial infarction6 and in psoriatic arthritis (PsA), the HR was 1.04 (95% CI 1.01, 1.08, p=0.009).7 Increased carotid intima-media thickness (cIMT) was also predictive of CVD after 5 years of follow-up in patients with RA.8 On the other hand, arterial stiffness is also a surrogate marker for CV risk. A 1.0 m/s increase in brachial-ankle pulse wave velocity (ba-PWV) was associated with a 12% increase in total CVEs after adjusting for age, sex and traditional risk factors. Patients with RA with a high ba-PWV at baseline experienced more CVEs.9
The treat-to-target (T2T) approach has been widely adopted in the past decade.10 By implementing a tight-control treatment strategy, it is possible to halt structural joint damage in a majority of patients regardless of the type of disease-modifying antirheumatic drugs (DMARDs) used.11 12 In addition, it has been hypothesised that suppression of inflammation might also ameliorate the excess CV risk.13 We have reported that patients with early RA (ERA) managed by a T2T strategy did not develop excess CVE compared with CV risk factor-matched controls over a period of 5 years.14 The incidence of CVE in the ERA cohort was significantly lower than that of the historical RA cohort, and the difference became insignificant after adjusting for inflammation, the use of methotrexate and traditional CV risk factors.14 Nonetheless, the low CVE rate precluded the investigation of how different disease activity levels over time affected CVD risk in these patients. The presence of carotid plaque was found to be associated with an HR of 1.83 for CV mortality and non-fatal myocardial infarction. Additionally, each 0.1 mm increase in cIMT was associated with an HR of 1.65 for the development of CVEs. Using a surrogate marker, we have reported that after 1 year of T2T management, achieving sustained DAS28 remission was associated with a significant improvement in arterial stiffness in patients with ERA.15 It would be worth studying whether different levels of disease activity over time, particularly low disease activity (LDA) and remission, may be associated with beneficial long-term vascular outcomes in patients with ERA.
The objective of this study was to elucidate the relationship between different levels of disease activity and the progression of atherosclerosis and arterial stiffness in patients with ERA.
Methods
Subjects
This was a 5-year prospective, longitudinal cohort study. One hundred and twenty patients were recruited from the rheumatology clinic of the Prince of Wales Hospital from December 2012 to December 2015. Details of these patients have been reported before.15 Briefly, patients were included if they met the following criteria: (1) 2010 American College of Rheumatology (ACR)/EULAR classification criteria for RA16; (2) had symptoms onset <2 years; (3) had active disease (DAS28≥3.2); and (4) were ≥18 years of age. Patients with a CVD history, severe renal impairment or malignancy at baseline were excluded. The patients received tight-control treatment in the first year, followed by standard-of-care management subsequently. The predefined intensive treatment protocol is developed according to the ACR recommendation and the details of the tight control were shown in online supplemental figure 1.17 One hundred and four patients completed a fifth-year follow-up assessment (mean±SD interval of 5.4±1.2 years from baseline). All patients provided informed consent according to the Declaration of Helsinki.
Supplemental material
Sample size estimation
Using a two-sided significance level (α) of 0.05, an OR of 5.05 and R2 indicating that 66% of the variance is unexplained by the model, the logistic regression analysis examining the progression of atherosclerosis, while accounting for persistent LDA achievement and adjusting for covariates, yielded a power of 92% (G*Power 3.1).
Predictive covariates
Traditional CV risk factors at baseline, including age, sex, body mass index, smoking and drinking habits, and history of diabetes mellitus, hypertension and dyslipidaemia, were retrieved from the Clinical Data Analysis and Reporting System (CDARS), an electronic public healthcare database in Hong Kong. Clinical assessments performed at each visit included blood pressure, patient’s pain score, physician and patient global assessment, tender joint count (28 joints assessed), swollen joint count (28 joints assessed) and the number of irreversibly damaged joints (at baseline and annually). The irreversibly damaged joints were defined as joints with a limitation of range of movement of more than 20% of the range not related to the presence of joint effusion, the presence of joint deformities, subluxation, flail joints or ankylosis. Laboratory assessments included rheumatoid factor and anti-cyclic citrullinated peptide antibody levels at baseline; fasting glucose and lipid profile at least once a year; inflammatory marker (erythrocyte sedimentation rate (ESR) and C reactive protein (CRP)) levels were measured at each clinic visit. Disease activity was evaluated using the DAS28 with ESR (DAS28-ESR) at every clinic visit. The cumulative inflammatory burden was calculated based on (1) cumulative average DAS28-ESR (ca-DAS28-ESR) and (2) cumulative average ESR (ca-ESR) level.18 To indicate the disease activity control over time, persistent moderate or high disease activity (Mo/HDA) and persistent LDA were defined as ca-DAS28-ESR>3.2 and ca-DAS28-ESR≤3.2, respectively. Data on the diagnosis of diabetes mellitus, hypertension and dyslipidaemia at baseline or during subsequent follow-up were retrieved from CDARS or from the dispensed prescription records of relevant medications.
Medication exposures
Medication use at every clinic visit, including conventional synthetic DMARDs (csDMARDs), biological/targeted synthetic DMARDs (b/tsDMARDs), non-steroidal anti-inflammatory drugs (NSAIDs)—divided into cyclo-oxygenase-2 inhibitor and non-selective NSAID categories—glucocorticoids, antihypertensive drugs, antidiabetic drugs and lipid-lowering drugs, was retrieved using the CDARS. Patients were reminded at each visit to take their medications and inquire about any potential side effects.
Subclinical atherosclerosis and arterial stiffness assessment
The cIMT and plaque were recorded and measured at baseline and the fifth year using the B-mode EPIQ7 ultrasound machine (Philips) by an experienced sonographer who was blinded to the clinical information of patients.19 The cIMT was measured as previously described, and a carotid plaque was defined as a localised thickness of ≥1.2 mm.19 Atherosclerosis progression (AP+) was defined as the maximum cIMT of six arterial segments progressed to ≥0.9 mm, or incident plaque, or an increased region harbouring plaques at year 5. The intraobserver intraclass correlation coefficient for IMT was 0.97.
Arterial stiffness was measured using ba-PWV at baseline and at year 5 while the subjects were in the supine position. A dedicated tonometry system (VP-2000; Omron Healthcare) was used by the same skilled operator as in a previous study.15
Statistical analysis
Data were presented as mean and SD or median and IQR for continuous variables and frequency or percentage for categorical variables. Student’s t-test or Mann-Whitney U test; or χ2 or Fisher’s exact test was used for the comparison of the baseline characteristics between the patients with (AP+) and without (AP−) plaque progression where appropriate. The area under the curve of all available measurements was divided by the total number of months of follow-up to calculate the cumulative average of inflammatory burden, traditional CV risk factors and medication use parameters. Cumulative exposure to DAS28-ESR (take DAS28-ESR for example) was calculated as the weighted sum of the average DAS28-ESR level for each: (DAS28-ESR baseline+DAS28-ESR year 1)/2×duration between baseline-year 1+(DAS28-ESR year 1+DAS28-ESR year 2)/2×time year 1-year 2, …(DAS28-ESR year 4+DAS28-ESR year 5)/2×time year 4-year 5, where DAS28-ESR baseline indicates DAS28-ESR at baseline, etc. The time intervals between consecutive examinations, specified as time year 2-year 1 and time year 3-year 2, represent the duration in years for each participant.18 Univariate analysis was performed to determine the association between plaque and ba-PWV progression and baseline clinical characteristics, cumulative average inflammatory markers, traditional CV risk factors and medication exposure. The independent predictors for AP+ were determined using multivariable logistic regression analysis and ba-PWV progression at year 5 was analysed using multivariable linear regression. All variables with p<0.05 in the univariate analysis were included in the multivariate analysis. A minimal level of significance of p<0.05 was used. All statistical analyses were conducted using IBM SPSS Statistics V.24 (IBM). A minimal level of significance of p<0.05 is used.
Results
This analysis included 104 patients (81 female (77.9%), with a mean age of 52±11 years at baseline, and a disease duration of 3 (0, 6) months) who completed 5 years of follow-up with carotid ultrasound and ba-PWV assessment. No major adverse CVEs were reported during the follow-up period. After 5 years of treatment, there was a significant improvement in disease activity, with a decrease in DAS28-ESR from 5.8±0.9 at baseline to 3.2±1.2 at year 5 (p<0.001). At year 5, nearly 40% of patients had moderate disease activity (MoDA) or HDA (figure 1 A; online supplemental table 1).
(A) Disease activity state according to Disease Activity Score 28-erythrocyte sedimentation rate (DAS28-ESR) and (B) mean DAS-ESR changes across the study. LDA, low disease activity.
Disease activity states and inflammatory burden over time
At baseline, 1%, 20.2% and 79.8% of patients had LDA, MoDA and HDA, respectively. After a year of intensive treatment, the proportion of patients achieving remission, LDA and MoDA increased significantly to 26.0%, 26.0% and 44.2%, respectively, and only 3.8% had HDA. By year 5, the proportion of patients achieving remission further increased to 33.7%, while LDA and HDA remained stable at 26.3% and 6.3%, respectively, and MoDA decreased to 33.7% (figure 1A). A total of 18 patients achieved over 3 years of sustained remission and 29 patients achieved over 2 years of sustained remission. A total of 14 patients achieved over 3 years of sustained LDA and 23 patients achieved over 2 years of sustained LDA.
The mean DAS-ESR decreased from 5.8 at baseline to 3.3 at year 1 and remained stable at 3.2 at year 5 (figure 1B). The mean ESR level also decreased from 36 mm/hour at baseline to 33 mm/hour at year 1, and 25 mm/hour at year 5. According to the ca-DAS-ESR, 17.3%, 32.7%, 48.1% and 1.9% of patients achieved persistent remission, LDA, MoDA and HDA, respectively.
Treatments administered during the 5-year follow-up period
The proportion of patients using csDMARDs increased from 15.4% at baseline to 92.3% at year 1, and then decreased to 81.5% at year 5. The use of b/tsDMARDs increased from none at baseline to 8.7% at year 1, and then decreasing to 6.3% at year 5. A total of five patients at year 5 changed to biologics monotherapy instead of csDMARDs compared with year 4. In contrast, the use of NSAIDs decreased steadily from 79.8% at baseline to 55.8% at year 1 and further to 35.8% at year 5 (figure 2A).
Medication regimens of the patients during the follow-up period. (A) Overall drug use during the study period. (B) Details of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). (C) Details of non-steroidal anti-inflammatory drugs (NSAIDs). (D) Details of biological DMARDs (bDMARDs). caDAS28-ESR, cumulative average Disease Activity Score 28-erythrocyte sedimentation rate.
The use of csDMARDs was comparable between the persistent Mo/HDA and LDA/remission groups (figure 2). However, a higher prevalence of NSAIDs and bDMARDs use was observed in the persistent Mo/HDA group throughout the 5-year follow-up period (figure 2C,D).
Subclinical atherosclerosis and arterial stiffness progression
Over a period of 5 years, an increase in Framingham Risk Score (FRS) (8.6±9.8 at baseline vs 10.7±9.8 at the last visit, p=0.003) (online supplemental table 1), mean cIMT and ba-PWV (mean IMT: 0.60±0.11 mm at baseline vs 0.62±0.10 mm at follow-up, p<0.001; ba-PWV: 1461±285 cm/s at baseline vs 1559±309 cm/s at year 5, p<0.001) (online supplemental table 1) was observed. Out of the total 104 patients, 42 (40.4%) experienced AP+ (AP+ group). These patients were older and had a higher prevalence of traditional CV risk factors at baseline (table 1). The use of cs/bDMARDs, NSAIDs and glucocorticoids was comparable between the patients with AP+ and AP− (tables 1 and 2).
Baseline clinical characteristics, traditional CV risk profile and medication use between AP+ group and AP−
Inflammatory burden, traditional CV risk profile, medication use and treat to target between AP+ group and AP− group over the 5-year follow-up period
Vascular effects of patients who attained different inflammatory states
The proportion of patients having persistent active disease activity (ca-DAS-ESR>3.2) in the AP+ group was higher when compared with the AP− group (57.0% vs 45.2%, p=0.318) (table 2). Univariate analysis revealed that patients with a higher baseline FRS (online supplemental table 2) and persistent Mo/HDA had a significantly higher risk of AP+ compared with those who had achieved persistent remission, while the risk of AP+ was similar in patients who achieved persistent LDA and remission (online supplemental table 3).
In the multivariate analysis, patients with persistent Mo/HDA had a significantly higher risk of AP+ compared with those who achieved persistent remission (OR 5.05, 95% CI 1.53, 16.64, p=0.008), after adjusting for baseline FRS, duration of leflunomide (LEF) use (overall duration of LEF usage in each patient) and cumulative average plasma low-density lipoprotein cholesterol (ca-LDL-C). In contrast, the risk of AP+ in patients who achieved persistent LDA and remission was similar (OR 0.35, 95% CI 0.09, 2.32, p=0.345). Other independent predictors for AP+ included higher baseline FRS and ca-LDL-C, and longer duration of LEF use (table 3).
Multivariable analysis on cumulative inflammatory burden and AP+
On the other hand, ca-ESR was significantly associated with ba-PWV progression after adjustment for sex and baseline ba-PWV (β=3.41, 95% CI 1.31, 5.52, p=0.002) (table 4).
Multivariable analysis on cumulative inflammatory burden and progression of arterial stiffness
Discussion
This is the first longitudinal study to demonstrate that patients with ERA who have persistent MoDA or HDA are independently associated with a higher risk of AP+ compared with those who achieved remission. Patients who achieved persistent LDA and remission have a similar risk of AP+. The current study provided important evidence supporting the hypothesis that the primary mechanism that accelerates AP+ in patients with RA is through activated inflammatory pathways and immune dysregulation.20 In patients with RA who are exposed to the inflammatory milieu, elevated levels of circulating proinflammatory cytokines, including tumour necrosis factor-alpha (TNF-α) and interleukin-1 (IL-1), IL-6 and IL-8, lead to the initiation of the atherosclerotic progress by activating endothelial cells, upregulating the expression of adhesion molecules and recruitment of T cells and monocytes to the endothelium and the media, resulting in the formation of foam cells and progression of atherosclerotic plaques.21 22 During the late stages of atherosclerosis, TH1, TH17 and cytotoxic responses could cause plaque destabilisation by promoting the secretion of matrix metalloproteinases by macrophages and other immune cells, which promote the erosion of the plaque fibrous cap, exposing its thrombogenic content and leading to thrombi formation.23 Clinical evidence also supported the notion that higher inflammatory burden, as reflected by elevated disease activity levels over time (measured by time-averaged DAS28 or Clinical Disease Activity Index (CDAI)), is associated with an increased risk of CVEs which further suggest the critical role of inflammation in the development of CVEs.24–26 In contrast, patients with ERA who achieved lower mean DAS28 and longer remission duration had a similar CVE rate compared with CV risk factor-matched controls over a period of 5 years, suggesting that effective control of inflammation may ameliorate excess CV risk in these patients.14
The clinical significance of subclinical AP+ has been addressed by a meta-analysis. A reduction of cIMT progression by 10 µm/year would yield relative risk (RR) of CVD of 0.84 (0.75–0.93).27 In a study involving 873 patients with ERA with a median (IQR) follow-up time of 5 (3–9) years (totalling 4560 patient-years), low DAS28 (≤3.2) was significantly associated with a reduced risk of CVD (HR 0.65, 95% CI 0.43, 0.99) compared with DAS28>3.2.28 In our study, the average change in cIMT over 5 years was 0.016±0.082 mm in the remission or LDA group, and 0.025±0.080 mm in the MoDA or HDA group, with a difference of 9 μm, which aligns with an RR of 0.84. However, a much larger sample size would be required to demonstrate differences in CVEs as an outcome. By using AP+ and cIMT as surrogate markers, we are able to observe an increase in CV risk, thereby enabling us to take proactive measures in preventing CVEs in patients at an earlier stage. Our study found that patients who are able to achieve sustained LDA over time have a similar risk of developing AP+ compared with those who achieved sustained remission which may suggest that achieving persistent remission may not offer additional benefits in terms of reducing the risk of developing AP+ compared with maintaining LDA.
Systemic inflammation in RA is associated with increased aortic stiffness, as assessed by aortic PWV, compared with healthy control subjects. This correlated with current CRP, a marker of inflammation, but not with disease duration, historical inflammation or the extent of radiological damage.29 Aortic stiffness was reduced, and concomitantly, endothelial function was normalised with anti-TNF-α and anti-IL-6,30–32 suggesting that targeting inflammation could be a potential treatment approach for atherosclerosis. Our study found a significant relationship between ca-ESR and ba-PWV progression after adjusting for gender, and a marginally significant relationship between ca-DAS28-ESR and ba-PWV progression in the multivariate analysis (data not shown). These results suggest that chronic inflammation and systemic inflammation augment the development of arterial stiffness in patients with ERA. These findings were consistent with previous studies reporting that a high level of ca-ESR was associated with higher ba-PWV and severity of carotid plaque in patients with PsA.33 34 Furthermore, the mean ca-ESR during the 5 years of our study was 34.3 mm/hour, indicating that the inflammatory burden of these patients remained high despite the use of antirheumatic medications. These findings underscore the significance of achieving sustained LDA over time in reducing the risk of AP+.
Longer exposure to bDMARDs may protect patients with RA from non-calcified plaque progression, as well as plaque maturation and remodelling, independent of systemic inflammation, statin and prednisone use.35 In PsA, bDMARDs have also been reported to reduce the progression of carotid plaque and mean cIMT.36 37 Persistent LDA had a protective effect on AP+ in our study, regardless of the use of bDMARDs, emphasising that adequate suppression of disease activity may be more important than blocking a particular inflammatory pathway in preventing AP+. In our study, from year 1 to year 5, around 50–60% of patients achieved LDA or remission, most likely due to the low prevalence of b/tsDMARDs use as a result of financial constraint. Nevertheless, there were no CVEs probably because achieving LDA is already good enough to prevent CVE as reported by previous study.38 Indeed, in a recent publication from our group which included 261 patients with ERA treated with a similar T2T protocol, and 783 age, sex and CV risk factor-matched ERA controls who were followed for 5 years, CVE occurred in 6/261 (2.3%) and 26/783 (3.3%, p=0.4; HR 0.53, 95% CI 0.15 to 1.79, p=0.3), respectively, suggesting that control of inflammation using this T2T approach may be able to close the CV risk gap between patients with RA and control.14 However, in view of the small number of patients who achieved remission, whether there is a difference in CVEs favouring remission over LDA would need to be addressed in future study with a larger sample size.
In our study, a longer duration of LEF exposure augmented the development of AP+ after adjusting for traditional CV risk factors and other medications. LEF has been associated with an increased prevalence of hypertension39 and may contribute to CVD development.40 However, the associations between LEF and atherosclerosis are not well described, and further mechanistic studies are needed to explore the effect of LEF on the risk of CVD in patients with RA.
There are several limitations to our study that need to be acknowledged. First, we were not able to include all definitions of remission according to EULAR/ACR criteria due to omission of physician global assessment score in a significant number of clinic visits after the first year. It is worth noting that in this pragmatic study, data on CDAI were not available for certain patients, as it reflects routine practice beyond the first year. Instead, DAS28 was commonly used by some rheumatologists to assess disease activity. Consequently, data on physician global assessment were not accessible for some patients. It is essential for future studies to investigate the impact of achieving sustained LDA or remission based on CDAI and its association with long-term vascular outcomes in RA. Second, not all potential causes of atherogenesis, such as physical activity or family history of CVEs, were assessed; however, the effect of these factors is likely reflected by other traditional risk factors that were measured. Third, tight control was initially implemented for the first year primarily due to feasibility and cost considerations. However, despite the absence of a stringent follow-up protocol after the first year, we ensured regular monitoring of disease activity at least once a year. We were pleased to observe that disease control remained stable for the majority of patients in the subsequent years as illustrated in figure 1. The proportion of bDMARDs use (<10% of patients) (online supplemental table 1) was low in our study compared with other studies35 as these drugs are not reimbursed by the government. The relative low b/tsDMARD usage might be related to the low LDA rate at year 5. Future studies will be needed to address whether earlier treatment of bDMARDs in combination with csDMARDs would have additional benefits for CVD prevention in patients with ERA than the use of csDMARDs alone. Furthermore, without a formal evaluation of drug compliance, the study may lack precise data on adherence rates and potential impact on outcomes. Future studies might consider incorporating additional methods to assess medication adherence. Fourth, there is a limitation in defining persistent LDA based on the ca-DAS28-ESR, as there may be periods when the DAS28 exceeds the threshold of 3.2 and other periods when it falls below it. Future prospective studies should aim to achieve true persistent LDA, where the DAS28 consistently remains below 3.2, or even remission (<2.6), to address this question. Fifth, the lack of funding prevented the implementation of annual carotid ultrasound assessments. Conducting regular ultrasound examinations throughout the study is advantageous compared with relying solely on baseline and end-of-study assessments. This approach ensures that relatively recent data on cIMT are available for participants who drop out. It is worth noting that the dropout rate for this study was 13.3%, which is considered acceptable in comparison to other studies. Last but not least, during the time of our analysis, no patients experienced CVEs. However, we will continue to observe the occurrence of CVEs in our patients in subsequent research, aiming to understand the relationship between disease activity and CVEs, as well as the association between AP+ and CVEs.
Conclusion
Our findings underscore the significance of achieving sustained LDA over time in reducing the risk of AP+. These results further support the need for effective suppression of inflammation using a T2T approach in order to prevent CVD in patients with ERA.
Data availability statement
No data are available.
Ethics statements
Patient consent for publication
Ethics approval
This study involves human participants and was approved by the Joint Chinese University of Hong Kong–New Territories East Cluster Clinical Research Ethics Committee for the Prince of Wales Hospital (Ref No CRE 2011.483-T). Participants gave informed consent to participate in the study before taking part.
References
Supplementary materials
Supplementary Data
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Footnotes
HM and ITC are joint first authors.
HM and ITC contributed equally.
Contributors All authors were involved in drafting the article or revising it for important intellectual content, and all authors approved the final version to be submitted for publication. HM completed the study conception and design, data collection, analysed and interpreted the patient data and drafted the manuscript. ITC completed the data collection, analysed and interpreted the patient data and revised the manuscript. BPYY and APL completed the data collection. HS completed the data collection and revised the manuscript. L-ST designed the study and revised the manuscript. All authors accept full responsibility for the finished work and/or the conduct of the study, had access to the data and controlled the decision to publish.
Funding This study is supported by the Hong Kong Society of Rheumatology Project Fund.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.