This cross-sectional observational study has demonstrated that long-term exposure to GCs, particularly at medium doses, is associated with increased prevalence of two of the components of the metabolic syndrome (high TG and hypertension), but not any of the other components (low HDL, obesity, and glucose intolerance) or the presence of the metabolic syndrome itself. We have presented data having used the NECP III criteria for metabolic syndrome as they are the most up-to-date and widely used, allowing comparison of our results with those of other studies in RA and other conditions. However, for the purpose of completeness, we have also analysed the data on the basis of other metabolic syndrome classification criteria, including those of the World Health Organisation [34
], the International Diabetes Federation [35
], and the European Group for the Study of Insulin Resistance [36
], in order to ensure that the definition used would not affect the outcome of this study. The lack of any association between GC exposure and the presence of the metabolic syndrome in this RA cohort was present irrespective of the metabolic syndrome criteria used (data not shown).
Although no statistically significant association between GC exposure and the metabolic syndrome was found, the multivariate analysis did demonstrate a trend in the OR as steroid exposure increased (LE 1.13 (0.62 to 2.04) versus ME 1.64 (0.92 to 2.92)). Thus, a possible limitation of the present study may be that, despite the fact that it is by far the largest to date to assess metabolic syndrome in RA, its power may not have been sufficient to detect such an association, although the clinical significance of such a weak association would then come into question. The most important limitation of this study, however, is its cross-sectional design, which does not allow definitive interpretation of the causality and directionality of the associations found. Notwithstanding these limitations, this study has addressed an original question that has not been addressed elsewhere in the literature in a large, very well-characterised RA population, with prospective data collection, thus allowing adjustment for many potential confounders and minimising selection and recall bias or missing values, which are all common problems in retrospective studies.
The absence of a relationship between long-term GC use and the presence of the metabolic syndrome may be explained by physical and metabolic changes occurring as part of the disease process or as an indirect consequence of treatments other than steroids [37
]. It is possible that the beneficial effects produced by suppressing the impact of inflammation on the metabolic syndrome may outweigh the harmful effects of GCs. For example, in RA, many components of the lipid profile are suppressed by the ongoing inflammatory burden, including HDL [40
]. However, suppression of the inflammatory load via drug use (for example, DMARDs) produces a significant increase in lipid levels, particularly HDL [41
]. Conversely, it may be that patients with RA have significantly modified their risk factors for the metabolic syndrome as a consequence of inflammation and that the addition of GC use cannot worsen these further.
Central obesity is associated with increased cardiovascular risk and is one of the components of the metabolic syndrome. GC use has been shown to redistribute body fat and result in central obesity with relative sparing of the extremities [42
]. Long-term GC use can also be complicated by the development of a steroid-induced myopathy [37
], which may further exacerbate the imbalance between fat mass and muscle bulk. Although steroid myopathy primarily manifests with proximal muscle weakness in the absence of muscle atrophy [44
], muscle wasting may occur as a consequence of a reduction in functional capacity. The systemic inflammation associated with RA causes a hypercatabolic state, which, together with a sedentary lifestyle, results in a loss of muscle bulk and an increased tendency to gain fat in the presence of stable or even slightly decreased weight, often referred to as rheumatoid cachexia [45
]. It has been reported that almost two thirds of patients with RA have features of rheumatoid cachexia [46
], and a recent study has demonstrated the need for redefining the body mass index in RA to take into account these changes [33
]. It is therefore possible that, in RA patients, alterations in body fat/muscle may have already occurred as part of the disease process and thus any additional changes that are induced by long-term GC exposure may be insignificant. Alternatively, better control of inflammation due to steroid usage may counterbalance some of the body composition abnormalities that would have otherwise occurred. The latter possibility would be supported by our findings in RA patients treated with anti-TNF biologics [47
A relationship between RA and abnormalities in the lipid profile has been observed for several decades [48
], with the key contributing factor thought to be inflammation [49
]. The typical pattern of dyslipidaemia seen in active RA is a reduction in total cholesterol, low-density lipoprotein, and HDL [40
]. Data regarding TG levels in RA are conflicting, with some studies reporting an increase [50
] and others a decrease [51
]. The metabolic syndrome definition takes in to account only two components of the lipid profile, TG and HDL. GC use, independent of dose, has been shown to increase HDL levels [52
]. Endogenous GC hormones regulate HDL plasma concentrations by increasing synthesis and secretion by the liver [55
]. Consequently, high doses of exogenous GCs such as those being received by RA patients are likely to accelerate this pathway. Therefore, in RA, HDL levels previously suppressed by disease activity will rise, producing a less atherogenic profile. This was reflected in our study, in which an increase in HDL levels was seen in patients receiving long-term GCs (P
= 0.011). The observed rise in HDL levels may also be explained by the indirect effects of GCs. Patients requiring GCs as part of their disease management are likely to have aggressive disease, which contributes to a reduction in mobility as a result of joint stiffness and damage. Therefore, GC use in this subset of patients may result in suppression of disease activity and allow patients to lead a more active lifestyle with a further beneficial effect on HDL levels [56
Elevation of TG levels in patients receiving GCs on a long-term basis has also been demonstrated [57
]. However, many of the studies have been limited due to the lack of control for other potential lipid-influencing factors such as metabolic, nutritional, or comorbid conditions. Although the proportion of patients fulfilling the NCEP III-specified cut off levels for TGs was significantly higher in the group receiving long-term GCs in this study (P
= 0.026), this alone was not sufficient to impact significantly on the overall prevalence of the metabolic syndrome, possibly being counterbalanced by increases in HDL, producing an overall less atherogenic lipid profile.
Shortly after the discovery of GC by Hench and colleagues [59
] in 1948, it became apparent that patients were frequently developing adverse effects, including hypertension and diabetes [60
]. Despite this, there is limited evidence to support these initial observations. In the general population, studies attempting to assess the association between GC use and hypertension have been hampered by poor study design [61
], thus resulting in a distinct lack of direct evidence to support this relationship. In RA, this association has been studied in more detail, with two recent studies demonstrating an increase in blood pressure in patients treated with long-term medium-dose (≥ 7.5 mg) GC [12
]. One of these studies, a large cross-sectional study, confirmed an association independent of other risk factors for hypertension and RA disease activity or severity [12
]. Although it appears that there is a link between GC exposure and hypertension in RA, it has also been speculated that RA itself may predispose patients to an increased prevalence of hypertension [63
]. The data produced in the present study show a significant increase in the numbers of patients fulfilling the NCEP III-specified cut off levels for hypertension (= 130/85 mm Hg or taking anti-hypertensives) in those receiving long-term GC. It may be that, despite hypertension being prevalent in RA, there is still scope for further modification through the actions of GCs. Irrespective of this, it appears again that the increased frequency of patients satisfying both the hypertensive and hypertrigylceridaemic components of the metabolic syndrome in the steroid-treated group is not sufficient to also increase the frequency of those qualifying for a diagnosis of the metabolic syndrome.
GC-induced hyperglycaemia is a well-recognised complication of long-term GC use [64
]. It is known that patients with active RA have impaired glucose handling and that glucose metabolism may be affected directly or indirectly by inflammatory mediators [65
]. Several studies have demonstrated an association between GC use and decreased insulin sensitivity [10
]. However, there is smaller bank of conflicting data demonstrating that GC use in RA paradoxically restores glucose handling to normal whilst also inducing hyperinsulinism [68
]. In the present RA population, it is possible that GC use restored glucose handling to normal via anti-inflammatory mechanisms, hence explaining why this component was not significant in the univariate analysis and had no impact on the frequency of the metabolic syndrome.