BIMONTHLY UPDATE: Edited by Alan Rees
Interest in lipid changes mediated by several classes of anti-inflammatory drugs, used to treat Rheumatoid arthritis (RA), has been increasing in recent years. Most recently, Tofacitinib, a novel oral Janus kinase inhibitor, shown recently to be broadly similar to tumour necrosis factor (TNF) blockade in its clinical efficacy, was also reported to raise both LDL and HDL-cholesterol levels [1▪]. This finding follows prior evidence of a rise in cholesterol and HDL-cholesterol with the interleukin-6 receptor blocker, Tocilizumab, as reviewed , and two recent systematic reviews/meta-analyses confirming TNF blocking therapy also elevates both total and HDL-cholesterol levels [3▪,4].
At first site, these rises in total cholesterol (and in some reports of LDL-cholesterol) could be considered worrying given that RA is already associated with an elevated risk for cardiovascular disease (CVD). Thus, although these anti-inflammatory therapies lessen RA disease burden, some researchers were concerned about their potential to exacerbate CVD risk. Indeed, tocilizumab was closely scrutinized for its lipid elevations and a postmarketing CVD end-point trial [ENTRACTE (http://http://www.roche-trials.com/trialDetailsGet.action?studyNumber=WA25204&diseaseCategoryId=86&divisionName=PHA), currently recruiting], was requested by the US Food and Drug Administration.
Additional factors, however, suggest lipid rises with a broad range of anti-inflammatory therapies in RA may, at least in part, represent a reversal of an inflammatory-driven decline in circulating lipid levels (both total and HDL-cholesterol) . Indeed, total cholesterol and HDL-cholesterol levels appear to rise in parallel during anti-inflammatory therapy, and some studies also show a rise in triglyceride levels . Perhaps of greater interest to the lipoprotein field per se are the preliminary data to suggest HDL particles undergo compositional changes in RA, with a gain in acute phase and complement-related proteins [5▪], and a lessening of HDL's antioxidant and cholesterol efflux properties [6▪], more so with greater systemic inflammation. Consistent with these findings are recent data demonstrating HDL composition may be favourably affected by anti-inflammatory therapies with evidence, in particular, for a reduction in HDL-associated serum amyloid A . By contrast, circulating levels of Lp(a) (arguably a positive acute phase protein) appear to fall significantly with TNF therapy in a dose-dependent manner , notable observations given recent evidence for a causal role of Lp(a) in CVD .
But how can this mass of emerging lipid data with differential RA treatments help the average rheumatologist or primary care physician manage CVD risk in RA? It is clear that cholesterol or LDL-cholesterol levels alone may disguise the nature of the lipid-associated contribution to CVD risk in RA. Indeed, Myasoedova et al. recently demonstrated high inflammatory measures but low cholesterol (<4 mmol/l) to be associated with elevated CVD risk in RA, although admittedly the event numbers were modest (n = 62 with incident ischaemic heart disease). Nevertheless, given that cholesterol and HDL-cholesterol levels seems to change in a similar direction with contemporary RA treatments, the recent European League Against Rheumatism guidance  has proposed use of the cholesterol to HDL-cholesterol ratio in CVD risk factor charts in patients with RA. Although this message is being disseminated, there is a clear need for more prospective data from larger studies in RA patients to relate on-treatment lipids, and treatment-associated lipid changes, to robustly ascertained CVD outcomes. Whether any such studies can also link baseline HDL-compositional measures to defined end-points with adequate power would also be of interest, but this is a tall order given the complexities of assays involved. Of course, rather than the need for complex measures, such prospective studies may confirm that beyond the established risk factors only usual lipid measures and markers of inflammation improve risk prediction in RA, a testable hypothesis.
Conflicts of interest
N.S. has consulted and been on speaker's bureau for Roche and UCB pharmaceuticals.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
1▪. van Vollenhoven RF, Fleischmann R, Cohen S, et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med 2012; 367:508–519.
2. Choy E, Sattar N. Interpreting lipid levels in the context of high-grade inflammatory states with a focus on rheumatoid arthritis: a challenge to conventional cardiovascular risk actions. Ann Rheum Dis 2009; 68:460–469.
3▪. Daïen CI, Duny Y, Barnetche T, et al. Effect of TNF inhibitors on lipid profile in rheumatoid arthritis: a systematic review with meta-analysis. Ann Rheum Dis 2012; 71:862–868.
4. van Sijl AM, Peters MJ, Knol DL, et al. The effect of TNF-alpha blocking therapy on lipid levels in rheumatoid arthritis: a meta-analysis. Semin Arthritis Rheum 2011; 41:393–400.
5▪. Watanabe J, Charles-Schoeman C, Miao Y, et al. Proteomic profiling following immunoaffinity capture of high-density lipoprotein: association of acute-phase proteins and complement factors with proinflammatory high-density lipoprotein in rheumatoid arthritis. Arthritis Rheum 2012; 64:1828–1837.
6▪. Charles-Schoeman C, Lee YY, Grijalva V, et al. Cholesterol efflux by high density lipoproteins is impaired in patients with active rheumatoid arthritis. Ann Rheum Dis 2012; 71:1157–1162.
7. Raterman HG, Levels H, Voskuyl AE, et al.
HDL protein composition alters from proatherogenic into less atherogenic and proinflammatory in rheumatoid arthritis patients responding to rituximab. Ann Rheum Dis 2012. [Epub ahead of print]
8. Sattar N, Crompton P, Cherry L, et al. Effects of tumor necrosis factor blockade on cardiovascular risk factors in psoriatic arthritis: a double-blind, placebo-controlled study. Arthritis Rheum 2007; 56:831–839.
9. Clarke R, Peden JF, Hopewell JC, et al. Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N Engl J Med 2009; 361:2518–2528.
10. Myasoedova E, Crowson CS, Kremers HM, et al. Lipid paradox in rheumatoid arthritis: the impact of serum lipid measures and systemic inflammation on the risk of cardiovascular disease. Ann Rheum Dis 2011; 70:482–487.
11. Peters MJ, Symmons DP, McCarey D, et al. EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis. Ann Rheum Dis 2010; 69:325–331.
Although this study presents clinical data on a new class of anti-inflammatory therapy, given recent recognition of lipid changes with inflammation-suppressing therapies, lipid changes are also highlighted.
This study nicely collates effects on lipids from mostly retrospective studies on TNF blocking therapies.
Nice proteomic-related work to define protein changes in HDL particles in RA.
A nice study looking in detail at HDL-related functional assays in RA patients and matched controls.
FURTHER RECOMMENDED READING
▪. Curtis JR, John A, Baser O. Dyslipidemia and changes in lipid profiles associated with rheumatoid arthritis and initiation of antitumor necrosis factor therapy. Arthritis Care Res (Hoboken) 2012; 64:1282–1291.
A simple report suggesting lipids are less often checked in RA compared with patients with osteoarthritis but even so, provides evidence that the majority of patients had lipids measured.
▪. Peters MJ, van Sijl AM, Voskuyl AE, et al. The effects of tumor necrosis factor inhibitors on cardiovascular risk in rheumatoid arthritis. Curr Pharm Des 2012; 18:1502–1511. PubMed
A good summary of recent data on lipids and other CVD risk factors and their changes with TNF blockade therapy, together with a clinical context of such data.
▪. Finckh A, Courvoisier DS, Pagano S, et al. Evaluation of cardiovascular risk in patients with rheumatoid arthritis: do cardiovascular biomarkers offer added predictive ability over established clinical risk scores? Arthritis Care Res (Hoboken) 2012; 64:817–825.
A preliminary attempt to examine if novel biomarkers enhance CVD event prediction. The rationale is well explained but clearly the study's size is modest and further larger studies examining the same question would be helpful to advance the field.