Commentary

Statins in rheumatoid arthritis—two birds with one stone?

Over the past several years, numerous studies investigated the anti-inflammatory effects of statin on patients with RA. However, the findings of the individual studies were often inconsistent or conflicting.

The Pubmed, Web of Science, Embase, Cochrane Library and CNKI literature databases were searched in order to identify randomized controlled clinical trials where the association between the anti-inflammatory effect of statin and RA was investigated. Two researchers performed data extraction from eligible independently. Quality parameters and risk of bias in the included studies were assessed according to Cochrane's guidelines. The pooled Standardized Mean Difference (SMD) with a 95%CI was used to assess the anti-inflammatory effect of statin in patients with RA.

Fifteen randomized controlled clinical, classified as “high quality” and with a relatively low risk of selection bias, were included in the meta-analysis. Of these, eight reported that there was no difference in the level of serum total lipids between the atorvastatin-treated and the conventional treatment group. However, the pooled analysis showed that atorvastatin could increase the level of serum amount of high-density lipoprotein (HDL) in RA patients by approximately x ± SD95% [HDL: SMD = 0.807, 95%CI = (0.187, 1.426), p = .011]. Meanwhile atorvastatin could reduce the level of serum low-density lipoprotein (LDL), total cholesterol (TC), and triglyceride (TG) in RA patient by x ± SD95% [LDL: SMD = −4.015, 95%CI = (−5.848, −2.183), p = .000; TC: SMD = −4.497, 95%CI = (−6.457, −2.537), p = .000; TG: SMD = −1.475, 95%CI = (−2.352, −0.599), p = .001]. Nine studies reported a change in C-Reactive Protein (CRP) after atorvastatin treatment, and the pooled analysis showed that atorvastatin decreased CRP in RA patients by x ± SD95% [SMD = −3.033, 95%CI = (−4.460, −1.606), p = .000]. Seven studies investigated the change of Erythrocyte Sedimentation Rate (ESR), and the pooled analysis showed that atorvastatin decreased ESR by x ± SD95% [SMD = −2.097, 95%CI = (−3.408, −0.786), p = .002]. Nine studies reported the improvement of disease activity score in RA patients after taking atorvastatin for 12 weeks, and the pooled analysis showed atorvastatin could decrease the DAS28 score in RA patients by x ± SD95% [SMD = −2.001, 95%CI = (−3.191, −0.811), p = .001].

Statins have a significant anti-inflammatory effect in RA patients. However, atorvastatin was superior to simvastatin both in terms of its anti-inflammatory and lipid-lowering activities.

Accelerated atherosclerosis and increased cardio- (CV) and cerebrovascular morbidity and mortality have been associated with rheumatoid arthritis (RA), as well as other inflammatory rheumatic diseases. Sustained systemic inflammation may be the major driver of atherogenesis. Aspirin, statins, folic acid, angiotensin-converting enzyme inhibitors, and angiotensin II blockers have been introduced to the prevention and therapy of vascular diseases in RA. Nonsteroidal antiinflammatory drugs (NSAIDs), primarily COX-2 inhibitors may increase CV risk; therefore, we should be cautious when prescribing these compounds. There may be differences among the various NSAIDs. Corticosteroids may exert both beneficial and detrimental effects on the vasculature. The antiinflammatory action of NSAIDs and corticosteroids may override their potential atherogenic nature. Antimalarials and methotrexate have been found to be cardioprotective in most studies. Leflunomide may not increase atherosclerosis but it can cause hypertension. Biologics, primarily tumor necrosis factor alpha inhibitors, effectively suppress arthritis and they have various effects on the vascular system. Increased lipid levels observed in the case of all biologics may be explained by the “lipid paradox.” Biologics may also have beneficial effects on other metabolic markers. In most trials, anti-TNF biologics have been associated with reduced CV risk. More data are needed on rituximab, tocilizumab, and abatacept, as well as tofacitinib. In addition to atherosclerosis, heart failure, arrhythmias, and hypertension should also be considered when administering antirheumatic drugs. In the clinical practice, European League Against Rheumatism and other recommendations may guide the rheumatologist how to prevent and manage CV comorbidities in rheumatic patients.

To assess the effect of atorvastatin on lipopolysaccharide (LPS)-induced TNF-a production in RAW264.7 macrophages.

RAW264.7 macrophages were treated in different LPS concentrations or at different time points with or without atorvastatin. TNF-α level in supernatant was measured. Expressions of TNF-α mRNA and protein and heme oxygenase-1 (HO-1) were detected by ELISA, PCR, and Western blot, respectively. HO activity was assayed.

LPS significantly increased the TNF-α expression and secretion in a dose- and time-dependent manner. The HO-1 activity and HO-1 expression level were significantly higher after atorvastatin treatment than before atorvastatin treatment and attenuated by SB203580 and PD98059 but not by SP600125, suggesting that the ERK and p38 mitogen-activated protein kinase (MAPK) pathways participate in regulating the above-mentioned effects of atorvastatin. Moreover, the HO-1 activity suppressed by SnPP or the HO-1 expression inhibited by siRNA significantly attenuated the effect of atorvastatin on TNF-α expression and production in LPS-stimulated macrophages.

Atorvastatin can attenuate LPS-induced TNF-α expression and production by activating HO-1 via the ERK and p38 MAPK pathways, suggesting that atorvastatin can be used in treatment of inflammatory diseases such as sepsis, especially in those with atherosclerotic diseases.

To describe the impact of rheumatoid arthritis (RA), and its treatment, on lipoprotein levels with potential implications for atherosclerosis.

A PubMed literature search was undertaken for studies published between 1990 and May 2007, using the search terms “rheumatoid arthritis” AND “lipid” OR “lipoprotein,” and including all relevant drug treatment terms for glucocorticoids, disease-modifying antirheumatic drugs, and biologics.

Patients with RA face an increased risk of developing premature cardiovascular disease and limited ability to modify risk factors, eg, through exercise. RA is associated with an abnormal lipoprotein pattern, principally low levels of high density lipoprotein (HDL) cholesterol. Most treatments for RA tend to improve the atherogenic index (total/HDL cholesterol ratio), with more evidence for biologics in this regard. The improvement in the lipoprotein profile in RA appears to be associated with suppression of inflammation.

Lipid levels should be monitored and managed in patients with RA to minimize the long-term risk of cardiovascular disease. More research is needed to quantify the relationship between systemic inflammation and lipoprotein levels and to determine the impact of specific lipoprotein particles, eg, small dense low-density lipoprotein and subfractions of HDL on long-term risk. Control of inflammation may have an effect on modifying cardiovascular risk.

Osteoarthritis (OA) is a common joint disease; however, current pharmacologic agents for OA are only symptomatic and they can not prevent the disease progression. Matrix metalloproteinases (MMPs) produced by chondrocytes play an important role in the development of cartilage destruction in OA, and agents that can target against MMPs activity may be of therapeutical value. There were reports that statins can inhibit the secretion of MMPs in vitro and in vivo, which were believed to account for the plaque stabilizing effects of statins in the treatment of atherosclerosis. We based our hypothesis on that atherosclerosis possesses some aspects that are similar to that of osteoarthritis, such as inflammation and matrix degradation. Since statins have displayed great benefits in modifying the progression of atherosclerosis via anti-inflammatory and matrix-stabilizing mechanisms, it is conceivable that statins may also prevent the disease progression of osteoarthritis. Further work are needed to verify if statins can protect cartilage from destruction through inhibition of MMP secretion by chondrocytes, and their potential to be used as therapeutic agents in OA should be investigated.