Hanene Lassoued Ferjani ^1,2, Yosr El Mabrouk^1*, Emna Laben^2,3, Dorra Ben Nessib^1,2, Dhia Kaffel^1,2, Kaouther Maatallah^1,2, Wafa Hamdi^1,2, Mouna ChelLy Bouaziz^2,3, Hend Riahi^2,3.

¹Rheumatology department, Kassab Orthopedics Institute, Ksar Saïd, Tunisia.

² Faculty of Medicine of Tunis, University Tunis el Manar, Tunisia.

³ Radiology department, Kassab Orthopedics Institute, Ksar Saïd, Tunisia.

*Corresponding Author:Yosr El Mabrouk, Rheumatology department, Kassab Orthopedics Institute, Ksar Saïd, Tunisia.

Citation: Hanene Lassoued Ferjani, Yosr El Mabrouk, Emna Laben, Dorra Ben Nessib, Dhia Kaffel, et al. (2024) Could DAS28-Gammagt Substitute the Intima-Media Thickness Measurements in The Cardiovascular Risk Assessment in Rheumatoid Arthritis?. Medcina Intern 6: 219.

Received: April 29, 2024; Accepted: May 18, 2024; Published: May 21, 2024.

Copyright: © 2024 Yosr El Mabrouk, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

DAS28-GGT may be a simple tool to assess cardiovascular events in rheumatoid arthritis (RA) patients. We aimed to investigate the correlation between DAS28-GGT and carotid intima-media thickness (IMT) in CVR stratification in RA.

Methods

This is a cross-sectional case study conducted in the rheumatology and radiology departments over 2 years (2020 - 2021) having collected patients with RA. Sociodemographic, clinical, biological, and immunological data were collected. Cardiovascular risk was assessed by the FRAMINGHAM score (10-year risk): People at low risk are 10% or less at age 10, with intermediate risk of 10-20% and high risk of 20% or more.  CVR was also assessed by IMT of carotid arteries: it is considered high in the event of an IMT >0.9 mm at any measurement site of the carotid arteries. The increase in GGT levels was defined as a level > 40 IU/L. The DAS28-GGT was calculated according to this formula: 0.56 *√AD + 0.28 * √AT + 2 * ln(GGT) + 0.014 * EVA. DAS28-GGT

Results

Fifty patients were included, with a sex ratio (M/F) of 0.3. The average age was 54 years [31-76]. Four patients had an elevated GGT level. The DAS-GGT was 7.5 in 33 cases. A strong correlation was found between DAS 28 CRP and DAS28-GGT (r=0.851, p<0.001).  We found a correlation between the DAS-GGT and the FRAMINGHAM score (r=0.1; p=0.024). According to IMT, thirty percent of patients had high CVR. No correlation was found between IMT and DAS28-GGT (r=-0.142, p=0.363 at the right CCa; and r=-0.129, p=0.403 at the left CCa).

Conclusion

In addition to the evaluation of disease activity, DAS28 GGT could be considered a simple and useful tool for evaluating cardiovascular risk in routine. However, routine use of DAS28-GGT would be unlikely to greatly reduce the need for CVD risk assessment in RA by carotid ultrasound.

Keywords: DAS28-GGT, cardiovascular risk, intima-media, FRAMINGHAM score

Rheumatoid arthritis (RA) is the most common chronic inflammatory rheumatism with a prevalence of 0.3 to 1% [1]. In addition to joint and systemic complications, the cardiovascular risk (CVR) is very high during this disease, increasing morbidity and mortality. Recent epidemiological studies have reported an increased risk of approximately 50% of cardiovascular morbidity and mortality in patients with RA [2,3]. This could be explained by inflammation in RA, which is thought to trigger a cascade of events leading to atherosclerosis [4,5].

Current CVR management recommendations emphasize the need for comprehensive assessment in all RA patients. This should be done at least every 5 years in low-risk patients and more frequently in high-risk patients [3,6]. CVR assessment is based on the evaluation of several CVR prediction equations such as the Framingham score and Systematic Coronary Risk Evaluation (SCORE) [7]. Nevertheless, these risk scores were shown to over- or underestimate the risk of cardiovascular events. Therefore, the carotid ultrasound was developed as a non-invasive technique allowing the visualization of the first structural changes of atherosclerosis in the arterial wall. Indeed, the evaluation of the intima-media thickness (IMT) by ultrasound of the carotid arteries detected atherosclerosis at a subclinical stage and predicted the occurrence of cardiovascular events [3].

However, this approach can be not suitable in low-income countries and requires access to radiologists, which may be not feasible in daily practice.

Therefore, the DAS28-GGT, a novel index was proposed to predict disease activity and CVR in RA patients. Gamma-glutamyl transferase (GGT) are pro-inflammatory enzymes that can be increased during systemic conditions and liver affections. GGT is expressed on the membrane surface of most cells [8-10]. Lipoproteins are thought to carry circulating GGT into atherosclerotic plaques where its extracellular effects on glutathione metabolism cause low-density lipoprotein oxidation and increase plaque vulnerability. The inclusion of this enzyme in RA disease activity indices has been proposed as an innovative means for the assessment of the disease as well as its CVR [11-13]. The use of this cost-effective tool may improve patient outcomes, guide treatment decisions, and lead to better cardiovascular risk management compared to traditional risk assessment methods.

While a strong correlation was reported between DAS28-GGT and CVR assessed by the Framingham score, any previous study was focused on its link with the IMT in RA patients. Therefore, we aimed to investigate the relationship between DAS28-GGT and carotid IMT as a way to stratify the CVR in RA and compare it to the traditional disease activity indices.

*Study Design

This is a cross-sectional study conducted in the rheumatology and radiology departments over 2 years (2020 - 2021) having collected patients with RA.

*Inclusion and Exclusion Criteria

-We included patients aged 30 years and over, with RA according to the ACR / EULAR 2010 criteria [14] and agreeing to participate in the study.

-We are not included in this study: Patients followed for other chronic inflammatory rheumatism, those with a history of cardiovascular events, known cardiovascular risk factors (dyslipidemia, diabetes, and arterial hypertension (HTA) under treatment, or those with liver diseases.   

*Data Collection

Data collection was carried out identically by a single examiner, from all patients during hospitalization and outpatient consultation. A pre-established data sheet for this purpose made it possible to identify sociodemographic, cardiovascular, and RA-specific data. For each patient, and during the week of inclusion, we carried out a biological assessment and a carotid ultrasound, at the biology and radiology laboratories. We identified in all patients:

•Sociodemographic data

•Cardiovascular risk factors: Smoking, family history of cardiovascular diseases, menopausal status, blood pressure (in mmHg), fasting glycemia, body mass index (BMI) (in Kg/m2), abdominal obesity (cm).

*Cardiovascular Risk Assessment

•Framingham score: This score corresponds to a sex-specific algorithm used to estimate the 10-year risk of developing coronary heart disease in a patient who does not already have a known cardiovascular pathology [15]. This score takes into account age, sex, smoking, diabetes, systolic blood pressure, diastolic blood pressure, total cholesterol, and HDL cholesterol. The subjects can be distributed as follows:

?People at low risk: have a risk of developing cardiovascular disease of 10% or less at 10 years.

?People at intermediate risk: have a risk of developing cardiovascular disease of 10 to 20%.

?Those at high risk: have a risk of developing cardiovascular disease of 20% or more.

•Assessment of intima-media thickness: The measurement of the IMT was performed at the common, internal, and external carotid levels.

•A plaque is defined by the presence of localized thickening, at least 50% greater, of the adjacent wall or by a focal lesion with an IMT greater than 1.5 mm, distinct from neighboring structures and protruding into the arterial lumen [16,17].

The cardiovascular risk is considered high in the event of IMT ≥0.9 mm and/or the presence of atherosclerotic plaques [18].

*Disease Activity Parameters

•The disease activity score (DAS28): was used to assess disease activity. These are two composite indices of RA activity (DAS28-CRP: C-reactive protein) and (DAS28-ESR: erythrocyte sedimentation rate), concerning 28 joints [19].

• The Clinical Disease Activity Index (CDAI): This is a recently developed and validated index, taking into account four parameters: number of swollen joints, number of painful joints on the 28 joint sites proposed by EULAR, the global assessment of the disease by the patient (visual analog scale from 0 to 10), the global assessment of the disease by the healthcare team (visual analog scale from 0 to 10) [19].

•The simple disease activity index (SDAI): this score includes the same parameters as the CDAI in addition to the C-reactive protein (CRP) [20].

* The functional impact of the disease: was assessed during recruitment by the health assessment questionnaire (HAQ) score [19].

* The disease activity score (DAS28) GGT: was calculated according to this formula:

 0.56 *√AD + 0.28 * √AT + 2 * ln(GGT) + 0.014 * EVA [11-13].

*Laboratory Tests

All patients benefited from a measurement of ESR and CRP, a metabolic assessment including fasting blood sugar (FBS), cholesterolemia: total cholesterol (TC), HDL cholesterol (HDL-C) and LDL cholesterol (LDL-C), trygliceridemia (TG), was performed after 12 hours of fasting and GGT. CRP was considered high if it exceeded 6 mg/l, and the ESR (mm) was considered high if it exceeded a value calculated from the patient's age and gender: VS > age/2 for the man or (age+10)/2 for the woman [21], high FBS if > 6,05 mmol/l, high TC>5,2 mmol/l, low HDL-C <1,3 mmol/l, high LDL-C > 4,1 mmol/l, high TG>1,7 mmol/l, the increase in GGT levels was defined as a level > 40 IU/L, according to our laboratory usual values.

*Statistical Analysis

The statistical study was carried out using the Statistical Package for the Social Sciences (SPSS) version 25.0 software. We analyzed the normality of all quantitative variables with the Kolmogorov-Smirnov test.  We calculated the median and variance of data with no Gaussian distribution and the mean with Standard deviation in quantitative variables with the normal curve. Categorical variables were compared using the chi-square test or Fisher exact test and continuous variables using the student test or Mann-Whitney test. The Spearman test was used to calculate the correlation coefficient (r) between two quantitative variables. The significance level was set at p < 0.05 for all statistical tests.

*Ethical Considerations

All patients participating in the study were informed of the type and objective of the study and gave their consent for the use of their clinical and paraclinical data for carrying out this study. The local ethical committee approved the study.

*Patients Characteristics

Overall, 50 patients with a gender ratio (M/F) of 0.31 were included. The mean age was 54 ± 11.36 years.  The mean disease duration was 7±5.3 years. Positive rheumatoid factors and anti-CCP antibodies were detected in 65% of patients. RA was erosive in 26% of patients. The mean levels of TC, HDL-C, LDL-C, and TG were 4.5±1.2 mmol/l; 1.3 ±0.5 mmol/l; 2.6±0.9 mmol/l; and 1.2±0.6 mmol/l; respectively.

 Detailed characteristics of patients and RA activity are summarized in Table 1.

Table 1: Patient’s characteristics and RA activity.

SD: standard deviation, DAS: disease activity score, HAQ: health assessment questionnaire, CDAI: Clinical disease activity index, SDAI: simple disease activity index, BMI: body mass index, TC: total cholesterol, ESR: erythrocyte sedimentation rate, CRP: C-reactive protein

*Cardiovascular Risk Assessment

The mean Framingham cardiovascular risk score was 7.9% in patients. Cardiovascular risk assessment according to the Framingham score revealed that 24% of patients had a moderate to severe cardiovascular risk.

•Intima-media thickness: the mean intima-media thickness of the right common carotid was at 0.067±0.017 cm. The measurements of the IMT in the other sites are detailed in Table 2.

 Table 2:  Intima-media thickness of the carotid arteries.

CCa: Common carotid artery, ICa: internal carotid artery, ECa: external carotid artery, IMT: intima-media thickness 

•Detection of atherosclerotic plaques: Six patients (12%) had an atheroma plaque.

The cardiovascular risk is considered high in the event of IMT ≥0.09 mm and/or the presence of atherosclerotic plaques at any measurement site of the carotid arteries. Fifteen patients (30%) had a high CVR.

* Correlation between DAS 28 GGT and disease activity

The GGT levels were high in 8% of RA patients, and the mean DAS28-GGT was 7.9±1.97.

DAS28-GGT was <5.5 in 12%, between 5.5 and 7.5 in 22%, and high than 7.5 in 66% of RA patients. The DAS28-GGT was correlated to the usual disease scores (Table 3).

Table 3: Correlation between DAS 28-GGT and disease activity parameters.

DAS: disease activity score, HAQ: health assessment questionnaire, CDAI: Clinical disease activity index, SDAI: simple disease activity index, ESR: erythrocyte sedimentation rate, CRP: C-reactive protein

* Correlation between DAS 28 GGT and cardiovascular risk

As shown in Table 4, the DAS28-GGT was correlated only to the Framingham score.

Table 4: Correlation between DAS 28-GGT and cardiovascular risk assessed by the intima-media thickness and the Framingham score.

CCa: Common carotid artery, ICa: internal carotid artery, ECa: external carotid artery, IMT: intima-media thickness 

?Six patients had a DAS-GGT score <5.5:  RA was in remission according to the DAS28-ESR and the FRAMINGHAM score was < 10%.

?Eleven patients had a DAS28-GGT between 5.5 and 7.5: Eight of them had a FRAMINGHAM score < 10% and 3 an intermediate risk.

?The rest of the patients (33) had a DAS28-GGT > 7.5:  seventeen had high disease activity, 2 had a FRAMINGHAM score ≥ 20%, and 4 had an intermediate score.

There is a first study focusing on the link between IMT thickness and DAS28-GGT. Our findings demonstrated that no correlation exists between these two parameters. However, Framingham was correlated with DAS28-GGT, as reported by Dupont and al, in their study involving 796 RA patients [11]. DAS28-GGT value of 9.4 had the best sensitivity and specificity for diagnosing the occurrence of cardiovascular events [11]. Further analysis of the relationship between DAS28-GGT and CVR factors revealed that DAS28-GGT increased in parallel with the number of CVR factors and the Framingham score. Patients with a DAS28-GGT <5.5 were associated with low CVR, while those with a DAS28-GGT >5.5 had a moderate to severe cardiovascular risk score [13]. In our study, there were six patients with a DAS28-GGT score <5.5, and they had a Framingham score of less than 10%. Eleven patients had a DAS28-GGT between 5.5 and 7.5, with eight of them having a Framingham score of less than 10% and three having an intermediate risk. The remaining patients had a DAS28-GGT >7.5, and two of them had a Framingham score of 20% or higher, while four had an intermediate score. Our results were different from those of Vergenault and al [13]. Several factors can contribute to these discrepancies, including variations in study design, sample sizes, patient populations, measurement techniques, and potential confounding variables [22-24]. Ethnicity can play a significant role in influencing disease outcomes and CVR. Different populations may have distinct genetic predispositions, lifestyle habits, and environmental exposures that can impact the relationships between biomarkers like DAS28-GGT and CVR measures like the Framingham score.

It's worth noting that epidemiological studies have also found a link between GGT concentrations and CVR. Higher serum GGT levels have been associated with an increased risk of cardiovascular mortality in large meta-analyses of prospective studies [25]. Interestingly, in patients with established coronary artery disease, coronary revascularization has been shown to abolish the prognostic value of GGT concentrations in predicting cardiac death and myocardial infarction. This finding further supports the idea that GGT may play a role in the vulnerability of arterial plaques, which are associated with cardiovascular events [26].

Moreover, GGT levels are elevated, in liver diseases, as well as in many systemic conditions [22-24]. Increased GGT levels are also a marker of systemic inflammation as reported in patients with RA in previous studies [27,28]. DAS28-GGT seems to reflect the disease activity as the traditional RA scores [13]. Our findings confirmed this conclusion by showing the correlation between DAS28-GGT and all disease activity scores: CDAI, SDAI, ESR, CRP, DAS28 ESR, and DAS28 CRP. It was also associated with the HAQ score.

Patients with a DAS28-GGT score <5.5, had RA in remission according to DAS28 ESR. Only half of the patients with a DAS28-GGT > 7.5 had high disease activity, contrary to the results of Vergenault et al [13].

According to our results and those of previous studies, we believe that DAS28-GGT could be used as a simple tool to assess both RA activity and CVR, replacing the Framingham score. However, it cannot conclude the usefulness of this score in the detection of subclinical atherosclerosis assessed by carotid ultrasound.  The idea of using DAS28-GGT as a simple tool to assess both RA activity and CVR is intriguing and has potential benefits. This could provide a more holistic approach to patient assessment, considering both RA disease activity and potential cardiovascular implications.

Replacing the Framingham score with DAS28-GGT for CVR assessment in RA patients might simplify the evaluation process, as it utilizes existing clinical data without the need for additional risk assessment tools. However, before adopting such an approach, there are several considerations and limitations to address. The use of DAS28-GGT as a substitute for the Framingham score in CVR assessment needs to be rigorously validated in larger and more diverse patient populations. Comparisons with existing risk assessment tools, like the Framingham score, should be performed to ensure its accuracy and reliability. The applicability and performance of DAS28-GGT may vary in different patient populations with varying risk profiles, ethnicities, and comorbidities. The potential impact of these factors on the score's effectiveness should be evaluated.

Secondly, the sensitivity and specificity of DAS28-GGT in identifying patients at high risk of cardiovascular events should be thoroughly assessed. It is crucial to determine if this score is as effective as other established risk scores in distinguishing low-risk from high-risk patients. Effectively, the routine use of DAS28-GGT may not be sufficient for detecting subclinical atherosclerosis assessed by carotid ultrasound. The use of carotid ultrasound and other imaging modalities for assessing atherosclerosis remains relevant in comprehensive CVR assessment, even if DAS28-GGT is used as a supplementary tool.

Long-term follow-up studies are necessary to assess the predictive value of DAS28-GGT in identifying future cardiovascular events and its ability to guide preventive measures.

While DAS28-GGT shows promise in providing a combined assessment of RA activity and CVR, it is essential to approach its adoption cautiously. Collaborative efforts among researchers, rheumatologists, and cardiologists will be crucial in determining the utility and validity of DAS28-GGT as a comprehensive CVR assessment tool for RA patients. Until then, the current guidelines for CVR management, including regular assessments with tools like the Framingham score and consideration of carotid ultrasound, should continue to be followed.

None

from local ethical comitee

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