In severe untreated rheumatoid arthritis (RA), reductions in high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol and total cholesterol have been noted; this is in line with findings in other pathologies/conditions associated with inflammation or infection, such as sepsis, cancer, trauma or the postoperative period. Although the precise mechanisms remain to be established, cytokine-induced activation of the reticuloendothelial system is potentially critical to such changes. Consequently, dampening of inflammation in severe RA—as occurs with several biologics—may lead to increases, not only in high-density lipoprotein-cholesterol, but also with other lipid moieties, including total and low-density lipoprotein-cholesterol and, perhaps, triglycerides. This concept is consistent with findings following antitumour necrosis factor treatment and interleukin-6 receptor inhibition in patients with RA. At the same time, it is increasingly apparent that potent dampening of inflammation, however achieved, broadly reduces the risk of cardiovascular disease in RA. Therefore, changes in lipid profiles, particularly increases in cholesterol and triglycerides that occur with treatments for severe inflammation, may not represent increased cardiovascular risk as in the usual understanding of lipid-level elevations in individuals without significant inflammation. Rather, changes in lipid levels, in part or largely, may represent a predictable response to attenuation of inflammation. These observations are increasingly important clinically and should aid in the understanding and interpretation of lipid changes under inflammatory conditions, as well as in the context of potent anti-inflammatory interventions.
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Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease that affects 0.5–1.0% of the population worldwide.1 The life expectancy of patients with RA may be reduced by 5 to 15 years compared with healthy individuals,1 and cardiovascular disease (CVD) is a leading cause of death.2 In comparison with the general population, patients with RA have greater rates of CVD morbidity and mortality, with an incidence that may be more than threefold greater.3 This excess risk is only partially explained by traditional risk factors.4
The heightened inflammatory state associated with RA almost certainly promotes atherogenesis. A stronger association has been reported between systemic inflammation and atherosclerosis in individuals with autoimmune conditions compared with the general population.5 Moreover, a causal link between inflammation and CVD is easier to establish with high-grade chronic inflammation in RA,6 than it is with low-grade inflammation. Furthermore, the progression of atherogenesis is increased in patients with prolonged RA (⩾20 years) compared with RA of shorter duration (⩽7 years). This suggests that atherogenesis accelerates following the onset of RA, and that systemic inflammation exacerbates adverse changes in both established and novel CVD risk factors.1 2 4 7
This review presents a detailed discussion of the relationship between CVD risk, inflammation and lipids levels in patients with RA. It summarises recent evidence of increased lipid levels in patients treated with biologic therapies and outlines possible underlying mechanisms. In addition, this review demonstrates that the pattern of lipid changes in the context of high-grade inflammation poses a challenge to conventional thinking.
CARDIOVASCULAR RISK AND LIPID PROFILES IN RHEUMATOID ARTHRITIS
Cardiovascular risk factors in the general population
Risk factors associated with coronary heart disease (CHD) include age, gender, abnormal plasma lipid levels, hypertension, physical inactivity, obesity, diabetes mellitus, smoking, and a low fruit and vegetable and/or high saturated fat intake.8 Recent data indicate that interleukin 6 (IL-6) levels are as strongly associated with CHD risk as some established risk factors.9 In CHD, atherosclerosis progresses through plaque initiation and plaque development to possible plaque rupture and thrombus formation, leading to major adverse cardiovascular events. Inflammation contributes to all stages of atherosclerosis.10
The link between abnormal lipid profiles (elevated total cholesterol or low-density lipoprotein (LDL)-cholesterol and low levels of high-density lipoprotein (HDL)-cholesterol) and CVD in the non-RA population is well recognised. Less established CVD risk factors include elevated lipoprotein(a) (Lp(a)) and C-reactive protein (CRP).8 10 11 Although there is much interest in CRP, its relative contribution to CVD risk in the general population remains controversial.12
Changes in cardiovascular risk factors with rheumatoid arthritis
CHD risk factors are generally more prevalent in individuals with active RA. Patients with RA have high levels of thrombogenic and inflammatory factors, greater oxidative stress, vascular dysfunction, and blood pressure may be elevated (reviewed in Sattar et al).7 Patients with active RA consistently demonstrate reduced HDL-cholesterol levels and higher Lp(a), and often a higher total cholesterol:HDL-cholesterol ratio,13 suggesting a greater and more consistent reduction in HDL-cholesterol.14 However, some studies also report lower total and LDL-cholesterol levels in RA.2 14
Effects of inflammation on lipid levels and impact of treatment
Reduced HDL-cholesterol and elevated Lp(a) correlate with elevated serum CRP levels and thus inflammatory activity in RA.15 Interestingly, inflammatory activation may also drive lower total and LDL-cholesterol levels in RA. The following lines of evidence support this supposition:
Inverse associations between inflammatory markers and lipid levels in rheumatoid arthritis
Cholesterol and triglyceride levels appear normal or even low in patients with early active RA and high-grade inflammation.16 Additionally, in RA and related conditions, higher inflammatory marker levels—or greater disease severity—correlate inversely with total cholesterol and HDL-cholesterol levels, and with related apolipoproteins (apo), B and A-I.17 18
Of course, not all studies are consistent. Potential reasons for such inconsistencies include: (1) confounding effects of differences between patients with RA and controls in age, obesity levels, smoking and gender; (2) lack of power due to low numbers; (3) too narrow ranges of disease severity; (4) confounding effects of treatments such as steroids; and (5) differing stages of RA. Interestingly, cholesterol and triglyceride levels appear elevated before RA develops, albeit modestly,19 which suggests that the progressively lower cholesterol levels observed in active RA are related to the disease process. Therefore, current evidence, on balance, supports lower total and LDL-cholesterol levels in active, established RA.
Lipid levels also correlate inversely with disease severity in other conditions
Total and HDL-cholesterol decline at the onset of acute illness.20 For example, in children with severe meningococcal sepsis, total, HDL- and LDL-cholesterol levels on admission correlate inversely with disease severity.21 Similarly, lower lipid levels are seen in patients with cancer.22 A significant inverse association has also been noted between elevations in IL-6 and reductions in cholesterol in the immediate postoperative period.23 Finally, in all the examples above, spontaneous or treatment-related reductions in disease activity are commonly associated with lipid levels that are significantly and rapidly increased (thereby excluding dietary confounding), and/or “normalised”.21–23
Lipid changes with disease-modifying antirheumatic drug treatment
Some disease-modifying antirheumatic drug (DMARD) treatment studies support an inverse change of HDL-cholesterol and total cholesterol with inflammation. For example, Lee and colleagues reported a significant correlation between DMARD-induced reduction in erythrocyte sedimentation rate and increases in both HDL-cholesterol and total cholesterol.24 Total and HDL-cholesterol also appear to increase more in DMARD responders compared with non-responders.25 Methotrexate may also induce increases in both total cholesterol and triglyceride levels, changes termed as “normalisation” in a recent study.26
Potential mechanisms underlying changes in lipid levels in rheumatoid arthritis
High-density lipoprotein-cholesterol and apolipoprotein A-I
Decreases in HDL-cholesterol during infection or inflammation are common to many species, and the most consistent lipid abnormality in RA. Although the exact mechanisms remain unclear, reverse cholesterol transport is inhibited at a number of steps, leading to a lower cholesterol efflux from cells to HDL particles.27 In addition, displacement of apo A-I in HDL particles by other acute phase proteins (eg, serum amyloid A or haptoglobin) leads to a loss of the normal anti-inflammatory and anti-oxidative activities of HDL, and a reduction in circulating apo A-I levels in inflammation/infection.27 Interestingly, synovial fluid apo A-I may be increased in patients with untreated RA,28 suggesting that joints in patients with untreated RA become infiltrated by HDL particles.
Total and low-density lipoprotein-cholesterol
Rises in markers of inflammation or infection are commonly associated with a reduction in total and LDL-cholesterol in primates and humans, accompanied often by reduced serum apo B.27 The reticuloendothelial system may be a significant player. Its suppression leads to increases in LDL-cholesterol by dampening LDL receptor independent clearance.29 Thus, its activation (as occurs in inflammation or infection) would lower LDL-cholesterol, a finding confirmed by recent studies in activated macrophages.30 Other mechanisms, such as reduced LDL particle synthesis, may also be involved. The reticuloendothelial system may also be involved in lowering triglyceride levels in chronic inflammatory conditions. Clearly, more mechanistic studies are needed.
RHEUMATOID ARTHRITIS TREATMENTS: THE NEED FOR BIOLOGICS
The suboptimal response to DMARDs (either alone or in combination) and their toxicity with long-term use has led to the development of biological agents that target particular signalling pathways in patients with RA. These drugs are called biologics. Biologics initially targeted the proinflammatory cytokine tumour necrosis factor (TNF)-α and, more recently, the IL-6 receptor. These agents are, of course, generally used in patients with moderate-to-severe disease. As mentioned above, severe inflammation lowers lipid levels and this effect is more likely to be observed in patients with RA prior to biologic treatment because such patients, by indication, generally have more severe RA. Significant dampening of inflammation by these agents would, therefore, be predicted to increase HDL-cholesterol and total cholesterol levels.
Tumour necrosis factor antagonist treatments and lipid profiles in patients with rheumatoid arthritis
Available anti-TNF agents include the monoclonal anti-TNF antibodies infliximab and adalimumab, and the TNF receptor fusion protein, etanercept.
Data concerning lipid changes with anti-TNF agents (table 1) show significant treatment-induced increases in HDL-cholesterol and total cholesterol or LDL-cholesterol in at least half of the studies, while increases in triglycerides have also been reported.
We conducted a systematic review of the effect of TNF inhibitors on lipids in RA and included seronegative inflammatory arthropathies. Searches on Medline and PubMed using the keywords “tumor necrosis factor” or “infliximab”, “etanercept” or “adalimumab” and “cholesterol” or “lipoprotein” or “lipid” up to March 2008 produced 17 articles (table 1). Fourteen of these were studies in RA, one in psoriatic arthritis, one in ankylosing spondylitis and one included all three diseases. As studies were heterogeneous with respect to design, length of follow-up and type of intervention, a meta-analysis was not possible.
Several short-term studies (<6 months) have reported that total cholesterol:HDL-cholesterol and LDL-cholesterol:HDL-cholesterol ratios tend to remain constant with anti-TNF treatment, despite tendencies for increased total cholesterol, LDL-cholesterol, HDL-cholesterol and apo A-I.31–34 Other short-term studies have produced mixed results.35 36
With longer-term anti-TNF treatment (⩾6 months), the cholesterol:HDL-cholesterol ratio is generally unchanged despite variations in lipid parameters; in part this is because HDL-cholesterol also increases.31 37 38 Notably, shortcomings include low numbers of participating patients and lack of information regarding improvement/exacerbation of RA. Furthermore, in patients who achieved a successful outcome with either infliximab or methotrexate treatment, total cholesterol levels were elevated by approximately 28% and reported to be “normalised”, while infliximab induced twofold elevations in triglycerides.26 Peters and colleagues35 reported that following an initial decrease (thus improvement) in the cholesterol:HDL-cholesterol ratio, this benefit was lost after 22 weeks. In contrast, Popa and colleagues32 reported an increase in the total cholesterol:HDL-cholesterol ratio with increases in total cholesterol following 12 months of anti-TNF treatment in combination with standard treatment. In addition, treatment with infliximab in combination with standard treatment resulted in an initial increase in HDL-cholesterol, followed by a decrease, with a significant increase in the total cholesterol:HDL-cholesterol ratio at 24 months.39 In a population of patients with various inflammatory diseases, however, an increase in HDL-cholesterol after infliximab treatment was observed.40 The most recent published study of 97 patients with RA treated with infliximab for 1 year reported increases in both total cholesterol and HDL cholesterol levels.41 In a study of patients with ankylosing spondylitis (45 patients were treated with leflunomide or placebo and 10 patients were treated with etanercept), disease activity levels were significantly and inversely correlated with total cholesterol and HDL cholesterol levels, independent of treatment.42 Finally, a recent, small study demonstrated that, compared with infliximab, etanercept treatment may have a lesser effect on lipid levels.43 However, this last finding requires confirmation.
Overall, the results suggest that anti-TNF treatment generally leads to an increase in circulating levels of all lipid fractions; with increases in total cholesterol of up to 28%, in HDL-cholesterol of up to 79% and in triglycerides of up to 125%. However, most studies have been small and only included post-hoc analyses of lipid levels. There is a need for larger, prospective studies to better document both the real scale of change in lipids following anti-TNF treatment, the time course of such changes and, importantly, the impact of these changes on CVD risk. Nevertheless, in several of the studies above, significant associations between lipid elevations and reductions of magnitude in inflammation add support for a causal link between these two processes.
Evidence that anti-tumour necrosis factor treatments lower cardiovascular disease risk
The results of anti-TNF-induced lipid elevations reviewed here should, of course, be considered in the context of mounting evidence that CVD risk is reduced, specifically, with anti-TNF treatment44 and, generally, with most RA treatments. Moreover, using data from the British Society for Rheumatology Biologics Register, Dixon and colleagues44 noted that the risk of myocardial infarction was significantly reduced in patients who had responded to anti-TNF treatment. If we consider this finding together with the observations of Saiki and colleagues discussed above26—that is, lipid levels are significantly increased only in patients who were classified as responders to anti-TNF treatment—the combined results go against the suggestion that biologic-induced elevations in lipid levels lead to enhanced CVD risk in the context of anti-TNF treatments. Rather, the potent reduction in disease activity with such treatments may explain both the pattern of lipid changes in RA (including increases in HDL-cholesterol and LDL-cholesterol) and the reduction in CVD risk. Indeed, many other risk factors, aside from the significant reduction in levels of acute-phase proteins and cytokines, clearly improve upon inflammation suppression (eg, thrombotic factors, lower oxidative stress, better vascular function, less insulin resistance).7 Finally, despite increases in total cholesterol levels, most studies appear to demonstrate that the total cholesterol:HDL-cholesterol ratio is not appreciably altered with anti-TNF treatment; even when this ratio is altered, the change is very modest (⩽25%). Lastly, it should be considered that increased LDL-cholesterol following treatment with a biological agent may not necessarily be more damaging, as its atherogenicity is dependent upon coexistent risk factors that also change upon treatment. These include a significantly suppressed systemic inflammatory status, improved vascular and metabolic function, and higher HDL-cholesterol levels.
Anti-interleukin-6 receptor antibody and lipid metabolism in rheumatoid arthritis
Inhibition of the IL-6 receptor leads to the improvement of signs and symptoms of RA, as well as systemic manifestations, and may improve several CVD risk factors. Tocilizumab is a humanised, monoclonal antibody that binds with high affinity to both the soluble and membrane-expressed forms of the IL-6 receptor,45 blocking IL-6 from binding to both membrane-expressed and circulating, soluble receptors. We performed a literature search with “tocilizumab” and “cholesterol” or “lipoprotein” or “lipid”, up to and including 2008, and collated all relevant data (see table 2 for details). In the first study by Nishimoto and colleagues,45 increases in total cholesterol, triglycerides and HDL-cholesterol were observed in the tocilizumab groups.45 In the Chugai Humanised Anti-Human Recombinant IL-6 Monoclonal Antibody (CHARISMA) study, moderate increases in total cholesterol, HDL-cholesterol and triglycerides were observed in the tocilizumab groups; however, these initial increases stabilised during the study.46 Notably, in the 8 mg/kg tocilizumab group, mean cholesterol:HDL-cholesterol ratios were reduced below baseline levels by the 20-week time point.
In the SAMURAI study, no change in the mean cholesterol:HDL-cholesterol ratio was observed during the study, although increases in total cholesterol, triglycerides and LDL-cholesterol were observed in 38%, 17% and 26% of patients, respectively.47 Cholesterol levels after treatment were reduced in 27 patients who received treatment with statins (26 patients) or fenofibrate (one patient) for abnormal lipid levels. In this study, HDL-cholesterol levels were elevated above the normal range with tocilizumab treatment in 24% of patients.
Smolen and colleagues48 have described a double-blind, randomised, placebo-controlled phase 3 trial (OPTION study) of 623 patients with moderate-to-severe active RA despite methotrexate treatment. In this study, increases in total cholesterol:HDL-cholesterol ratios occurred in 8% or 17% of patients administered 4 mg/kg or 8 mg/kg tocilizumab, respectively. Phase 3 studies with tocilizumab in populations refractory to DMARD or TNF treatments, also demonstrated similar lipid responses over 24 weeks.49 50
In these studies, tocilizumab treatment was consistently associated with increasing lipid levels in the context of decreasing levels of inflammatory markers. However, correlations between specific parameters were not reported. Importantly, no increase in cardiovascular events associated with tocilizumab was reported in any of these studies, although trials of longer duration are needed for confirmation.
Thus, critically, just as anti-TNF treatments generally increase lipid levels in patients with RA, so does IL-6-receptor inhibition. These alterations are consistent with the predicted direction of change based on the totality of evidence, described earlier, for the effects of chronic inflammation on lipid levels and the reversal of such effects upon inflammation suppression (fig 1).
Using lipid data for cardiovascular disease risk assessment in patients with rheumatoid arthritis: clinical suggestions based on totality of available data
A review of the published literature demonstrates that treatment with biologics increases lipid levels (including LDL-cholesterol, HDL-cholesterol and triglycerides in patients with RA), but that such changes are broadly predictable and coincide with reduced inflammation. Further, there is increasing evidence for CVD risk reduction with anti-TNF treatment. In contrast, data from prospective, cohort studies indicate that dyslipidaemia or hyperlipidaemia is predictive of higher cardiovascular event rates in patients with RA (although disease state is not consistently defined).51 These two observations are not necessarily inconsistent; this is because, in the general population, those destined to develop RA have a range of lipid levels and CVD risk. Correspondingly, those who have higher cholesterol levels at or before disease onset will generally also have higher cholesterol levels at any given level of disease severity; however, in general, cholesterol levels will be lower when disease is active and patients are untreated, and that is when CVD risk is consistently higher. In other words, data from cohort studies integrate baseline lipid levels with effects of disease severity and treatment factors. It is a complex picture that requires further study.
We advocate that the ratio of total cholesterol:HDL-cholesterol should be used clinically to evaluate cardiovascular risk, as this ratio is more stable than the different individual lipid parameters, such as total cholesterol, LDL-cholesterol and HDL-cholesterol. As illustrated in tables 1 and 2, this ratio often does not change dramatically with biological treatments and, even when it does, the change is modest at best as both total cholesterol and HDL-cholesterol generally shift in the same direction. Further, this ratio is a well-established predictor of CVD risk in the general population. Of course, assessment of CVD risk requires integration of information for several risk factors, including age, gender, smoking, blood pressure, lipids (total cholesterol:HDL-cholesterol ratio) and diabetes. Individuals who have existing CVD require secondary prevention and warrant CVD risk reduction with proven modalities (eg, statins). In this context, one study suggests that the addition of a statin to RA treatment regimens reduces cholesterol levels to an extent similar to that in the general population and may also dampen disease activity.52
Future research questions
Several important questions arise from our current review.
Are the effects of IL-6 receptor inhibition on lipids more pronounced than those of TNF antagonists? Direct head-to-head studies are needed, and these should address whether increases in lipid levels correlate with reductions in inflammation markers following treatment. Thus, whether potentially greater increases in LDL-cholesterol or HDL-cholesterol levels with IL-6 receptor inhibition are due simply to greater effects on inflammation suppression, needs to be examined.
The mechanisms underlying the lipid reductions with severe inflammation in RA and increases in lipid levels with treatment require further study. Kinetic studies of lipid metabolism, together with more detailed analyses of changes in lipoprotein composition and related enzymes would help.
It will also be important to clarify whether lipid reductions in RA are harmful or beneficial. On the one hand, an inflammation-induced reduction in HDL-cholesterol and apo A-I would encourage greater inflammatory activity by stimulating macrophage-T cell cross-talk.53 On the other hand, lowering cholesterol and triglyceride levels may lessen inflammation as higher levels of both have been associated with greater proinflammatory potential. Alternatively, increased macrophage uptake of lipids during inflammation may lead to a greater vascular risk via accelerated foam cell formation. At present, it is not easy to predict the net effect of a reduction in circulating lipids in active RA, nor, as we have demonstrated, is it easy to predict the net vascular effect of lipid elevations with biological treatment in patients with RA.
Non-invasive imaging studies of atherosclerosis using biological agents may complement vascular event acquisition from registries and could provide added confidence that biological agents broadly lessen vascular risk.
High-grade, chronic inflammation in RA can directly and indirectly accelerate vascular disease. In severe RA, HDL-cholesterol and total cholesterol levels are often reduced; these changes are frequently in line with inflammatory marker elevations.
Reductions in HDL-cholesterol, LDL-cholesterol and total cholesterol in active or untreated RA are similar to findings in other pathologies/conditions that are associated with inflammation or infection (eg, sepsis, cancer or the postoperative period). In humans and primates, several cytokines are known to reduce both HDL-cholesterol and LDL-cholesterol levels; activation of the reticuloendothelial system is likely associated with such changes, but other mechanisms may be involved.
Consequently, dampening of inflammation in severe RA, which occurs with several biologics, may be expected to increase lipid levels; this not only occurs in HDL-cholesterol, but also other lipid moieties, including total and LDL-cholesterol and, perhaps, triglyceride levels. This concept is consistent with emerging findings for anti-TNF treatments and IL-6 receptor inhibition in RA. Equally, some DMARDs have similar effects on lipids, albeit less marked. In any case, it is clear that potent dampening of inflammation, however achieved, broadly reduces CVD risk in RA.
Therefore, changes in lipid profiles, particularly increases in cholesterol and triglycerides that occur with treatments for severe inflammation, may not represent increased cardiovascular risk as in the usual understanding of lipid-level elevations in individuals without significant inflammation. Rather, such changes in lipid levels, in part or largely, may represent a predictable response to attenuation of inflammation.
Finally, in clinical practice, the current advice on the use of lipid profiles in any patient with RA is (1) to measure both total cholesterol and HDL-cholesterol and to use the total cholesterol:HDL-cholesterol ratio in conjunction with other established risk factors for the calculation of absolute CVD risk, and (2) to treat accordingly when the absolute CVD risk is high.
Editorial assistance with the manuscript was provided by Sarah Longnus, PhD, Phocus Services GmbH, Basel, Switzerland. Funding for editorial assistance by Phocus Services GmbH was provided by F. Hoffmann-La Roche Ltd. We would also like to thank Thasia Woodworth and Janet Lee for their helpful comments in the preparation of this article. All views in this article are those of the authors.
Competing interests: EC has provided consultancy through advisory boards and speakers bureaus for MSD, Pfizer, GSK, Abbott, Schering Plough, Wyeth, Merrimack Pharmaceutical, Chelsea Therapeutics, UCB Celltech, F. Hoffmann-La Roche, Pierre Fabre Medicament, Allergan and Jazz Pharmaceuticals. NS has received fees for lectures and consulting from F. Hoffmann-La Roche and Abbott, as well as from many companies marketing lipid-lowering therapies, both statins and non-statin agents.