Materials and methods

Study population

Our study included RA patients (n  =  353) participating in an ongoing prospective cohort study, ie, the CARRÉ investigation, conducted at the Jan van Breemen Institute, investigating CVD and its risk factors in RA patients.2 The patients’ ages ranged from 50 to 75 years at the time of inclusion and RA was diagnosed according to the 1987 American College of Rheumatologists criteria.12 At baseline patients’ demographic, clinical and laboratory data (erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)) were collected. Disease activity was assessed by the disease activity score in 28 joints (DAS28).13 RA patients with a previous CVD event were excluded (n  =  62), because these patients are on secondary prevention therapy interfering with (the features of) the MetS and because the Framingham risk score is based on CVD event-free patients. CVD was defined as a verified history of coronary, cerebral or peripheral arterial diseases. Coronary artery disease included a myocardial infarction, a coronary artery bypass graft procedure or percutaneous transluminal coronary angioplasty. Cerebral arterial disease was defined as a cerebral vascular accident, a transient ischaemic attack or carotid endarterectomy. Peripheral arterial disease included a peripheral arterial bypass, an ankle/brachial blood pressure index of less than 0.90 or leg amputation. As diabetes can be considered a CVD event equivalent, and consequently patients are on secondary prevention therapy, those with known diabetes (n  =  20, 10 of them already excluded for a CVD event) were excluded. Diabetes was defined as a known medical history of diabetes mellitus or the use of a glucose-lowering agent. To compare hypothyroid RA patients with euthyroid RA patients, (sub)clinical hyperthyroid RA patients (n  =  23, two patients already excluded), defined as a decreased serum thyroid-stimulating hormone (<0.4 mU/l) or a documented medical history of clinical hyperthyroidism, were excluded.7 Subjects for whom no blood samples were available (n  =  4, one of them already excluded) or patients with both hypothyroidism and known diabetes mellitus (n  =  1, already excluded for a CVD event) were also excluded, ultimately resulting in 257 RA patients eligible for this study. These patients were classified in two groups: RA (patients with RA alone) and hypothyroid RA (patients with both RA and hypothyroidism). Hypothyroidism was defined by a documented medical history of clinical hypothyroidism or by the presence of subclinical hypothyroidism. Subclinical hypothyroidism was defined by an increased serum thyroid-stimulating hormone (>4.0 mU/l) in the presence of a normal (11–25 pmol/l) serum free thyroxine (fT4) assessed from blood samples.7 This study was performed in accordance with the Declaration of Helsinki. All patients provided written informed consent and the Jan van Breemen Institute received approval by the local medical ethics committee.

Metabolic syndrome

The MetS was defined according to the original National Cholesterol Education Program (NCEP) Third Adult Treatment Panel definition.14 According to this definition patients fulfil the criteria for MetS when three or more of the following factors are present:

• Abdominal obesity: in women waist circumference greater than 88 cm, and in men waist circumference greater than 102 cm;

• Raised blood pressure: systolic blood pressure 130 mm Hg or greater or diastolic blood pressure 85 mm Hg or greater;

• Raised triglycerices: 1.7 mmol/l or greater (150 mg/dl);

• Reduced HDL-cholesterol: in women less than 1.29 mmol/l (50 mg/dl), and in men less than 1.03 mmol/l (40 mg/dl);

• Raised fasting plasma glucose: 6.1 mmol/l or greater (110 mg/dl).

The waist circumference was measured at the level midway between the lowest rib margin and the iliac crest. The mean value of two measurements was used. Double readings of the systolic and diastolic blood pressure were obtained on the right arm with the subject in a sitting position after a 5-minute rest. For each patient fasting blood samples were collected for the assessment of glucose, triglycerides and HDL-cholesterol levels. Triglyceride levels were measured by an enzymatic method using Roche clinical chemistry analysers and HDL-cholesterol was determined enzymatically with polyethyleneglycol-modified enzymes.

Framingham risk score

The Framingham risk score is an algorithm, which includes age, gender, smoking, blood pressure and cholesterol, to estimate the 10-year cardiovascular risk in patients without prevalent CVD.11

Statistical analyses

The characteristics of the two groups (RA and hypothyroid RA) were expressed as mean (SD) or median (interquartile range) and were compared using a Student’s t test, Mann–Whitney U test or χ² tests, when appropriate. With RA patients as the reference category, logistic regression analyses were performed to calculate prevalence odds ratios regarding the MetS for hypothyroid RA patients. Five separate models were used: (1) univariable analysis, using the crude, uncorrected data; (2) multivariable analysis, adjusting for age and gender; (3) adjusting for age, gender and DAS28; (4) adjusting for age, gender and current use of prednisolone; (5) adjusting for age, gender and cardiovascular risk management (defined as lipid-lowering, blood pressure-lowering or glucose-lowering agents).15 A p value below 0.05 was considered statistically significant. For all analyses SPSS 15.0 for Windows was used.

Results

Characteristics

The main characteristics of the study population are summarised in table 1. In total, 257 RA patients were included: 236 RA without hypothyroidism (91.8%) and 21 hypothyroid RA (8.2%).

Hypothyroid RA versus RA

MetS was present in 42.9% of hypothyroid RA patients and in 19.9% of RA patients (p = 0.024). Moreover, low HDL-cholesterol was more prevalent in hypothyroid RA patients when compared with RA patients (p = 0.053). These results were similar after using the 2005 revised NCEP criteria (data not shown). Hypothyroid RA patients had a higher estimated median 10-year CVD risk than non-hypothyroid patients, although this difference did not reach statistical significance. Subgroup analysis showed a significantly higher estimated 10-year CVD risk in female hypothyroid RA patients (13%) when compared with euthyroid female RA patients (9%) (p = 0.039).

Prevalence odds ratios for MetS in hypothyroid RA relative to RA

Hypothyroid RA patients had a more than threefold increased age and gender-adjusted chance of having the MetS compared with RA patients (see table 2, model 2). Adjustment for inflammatory markers, by means of DAS28 (see table 2, model 3) and separately CRP and ESR (data not shown) did not influence these results. Further adjustment for glucocorticoids and drugs for cardiovascular risk management only slightly decreased the chance of having the MetS (see table 2 models 4 and 5). Replacement of glucocorticoids by the current use of disease-modifying antirheumatic drugs did not alter the results (data not shown).

Discussion

This study demonstrated a substantially elevated prevalence of the MetS in hypothyroid RA patients (43%) compared with patients with RA alone (19%). This increased prevalence of the MetS in hypothyroid RA patients is an important finding, because the presence of the MetS increases the risk of a future CVD event. This is illustrated by the observations of a recent systematic review reporting that middle-aged individuals with the MetS have an approximately 1.5-fold increased risk of cardiovascular events.9 In agreement, a Dutch community-based study, with a similar study design to the present study, demonstrated that the MetS was associated with a twofold higher 10-year risk of incident CVD.16 It is important to realise that, although MetS predicts future CVD risk, the literature suggests that the MetS does not enhance the predictive power for CVD of established scoring algorithms such as the Framingham score. However, the advantage of the MetS is that it serves well as a simple clinical tool for identifying high-risk individuals predisposed to CVD.17 18

No prevalence data are available of MetS in hypothyroid patients without RA. However, in non-RA euthyroid populations decreasing serum levels of thyroxine are associated with an increased risk of MetS and with higher triglyceride, lower HDL-cholesterol levels and abdominal obesity, independent of the presence of insulin resistance in non-RA patients.8 19 A remaining, intriguing, question is whether the presence of a concomitant disease such as hypothyroidism in RA amplifies the risk of the MetS synergistically or independently. Unfortunately, we were unable to address this question because control groups with only hypothyroidism were lacking, making the testing for interaction impossible.

Pathophysiological mechanisms explaining the development of the MetS have not been fully understood. It has been established that inflammation influences several CVD risk factors, some of which are incorporated in the MetS.20 Indeed, an inverse correlation between inflammatory markers and HDL-cholesterol levels was observed (data not shown). This was expected, as inflammation leads to a deteriorated lipid profile with low HDL-cholesterol levels.21 22 23 However, adjusting for inflammatory activity did not alter the odds ratios for having MetS in the hypothyroid group, suggesting that additional mechanisms are involved in the higher prevalence of MetS in hypothyroid RA patients. Similar results were observed, when DAS28 was replaced by ESR or CRP in the third model (data not shown). These results, however, need to be interpreted carefully due to the cross-sectional study design. Microvascular dysfunction is another interesting possible mechanism underlying the development of MetS, as it has been proposed to play a causative role in the association between hypertension, insulin resistance and the MetS.24 Several rheumatic diseases, ie, RA and ankylosing spondylitis, have been associated with impaired microvascular function and, interestingly, microvascular dysfunction also appears to be present in hypothyroid patients.25 26 27 This may explain, at least partly, the amplified prevalence of MetS in RA with a concomitant disease such as hypothyroidism.

A key message of the present study is that in daily clinical practice, particularly in RA patients with hypothyroidism, the MetS requires more attention, because the MetS reflects an increased, but theoretically modifiable, cardiovascular risk. Clinicians should be aware of the increased need for cardiovascular risk management in specific subpopulations of RA patients, such as hypothyroid RA patients, because relatively simple lifestyle and/or pharmacological interventions may prevent future CVD in this group of patients with an already enhanced background risk of CVD.

Several limitations need to be taken into consideration. First, the predictive and scientific value of the MetS have recently been debated. This debate is based on the assumption that the MetS has no improved predictive value for CVD events than established algorithms such as Framingham and SCORE. Moreover, critics of the MetS state that the CVD risk of MetS is not greater than its individual features.28 Others reject the MetS as a clinical entity as there is no consensus on a common underlying feature. Second, although the Framingham risk score is an established tool for identifying people at risk of a future CVD event, the use of this algorithm for an estimation of the 10-year CVD risk in this study can be perceived as a limitation as the Framingham score has not been validated for comorbid populations such as ours. Finally, due to the low number of cases in the hypothyroid group, our results need to be interpreted with caution as independent associations between MetS and hypothyroidism can not be demonstrated. However, our conclusions are strengthened by the fact that the odds ratios are practically unchanged after adjusting for several possible confounders.

In conclusion, this is the first study reporting that concomitant hypothyroidism in RA patients is associated with a very high prevalence of MetS. Moreover, female hypothyroid RA patients have a higher estimated 10-year CVD risk. These results suggest the need for an intensified cardiovascular risk management in hypothyroid (female) RA patients.