Cardiovascular Risk Assessment and Allocation of Lipid-Lowering Therapy in Patients with Chronic Inflammatory Diseases
Epidemiology of Inflammatory Disorders and Cardiovascular Disease
Inflammation is a common underlying component of many chronic rheumatologic inflammatory joint disorders (IJD), such as rheumatoid arthritis, systemic lupus erythematosus (SLE), and psoriasis. It is also a key mediator in the progression of atherosclerosis and resultant cardiovascular disease (CVD) due to rupture of vulnerable plaques, which could account for the higher incidence of CVD and overall worse for patients with IJD.1-3 Accordingly, the increased prevalence of CVD among individuals with chronic IJD has long been recognized.
Among patients with rheumatoid arthritis, the risk of myocardial infarction is estimated to be equivalent to patients with diabetes and/or an individual who is 10 years older without rheumatoid arthritis.4-6 A meta-analysis incorporating data from 111,758 patients also demonstrated that patients with rheumatoid arthritis had a 50% higher risk for CVD death with a standardized mortality rate of 1.5 (95% CI 1.39- 1.61).7 Patients with systemic lupus erythematosus (SLE) and psoriasis also have a similarly increased risk of CVD.8,9
Rheumatoid arthritis is typically considered the most common IJD with an estimated prevalence of approximately 1,000 per 100,000, or 1.3 million US adults, with a prevalence two times greater in women than in men.10 However, data from the 2010 National Health and Nutrition Education Survey (NHANES) showed a prevalence of 3.2% or 7.2 million US adults with self-reported psoriasis.11 SLE has an estimated prevalence of approximately 54 per 100,000 among US adults, but is more prevalent among women with an estimated prevalence of 100 per 100,000.10 While there is shared pathophysiology among the IJD, the majority of data on CVD risk is derived from patients with rheumatoid arthritis and SLE, which is the focus of this review.
Evaluating CVD Risk for Patients with Inflammatory Disorders
Patients with IJD commonly have traditional CVD risk factors such as hypertension, dyslipidemia, insulin resistance, and obesity. They are also more likely to have a lower level of physical activity secondary to joint pain inherent in IJD. Dyslipidemia is estimated to affect up to two thirds of patients with rheumatoid arthritis and lipid levels are directly impacted by disease activity.12 Despite this, less than half of Medicare patients with rheumatoid arthritis are screened for lipid abnormalities and the majority of rheumatoid arthritis patients with an indication for lipid-lowering therapy are untreated.13,14
Two aspects of the relationship between dyslipidemia and CVD risk are contrary and inverse in patients with RA and referred to as the "Lipid Paradox." The first observation is that patients who are untreated and/or have high disease activity generally have decreased levels of LDL-C, HDL-C, triglycerides, and total cholesterol.15 These lower lipid levels are believed to be secondary to increased inflammation and lead to functional pro-atherogenic changes such as a decreased cholesterol efflux capacity of HDL-C.16,17 The second divergent observation is that treatment with anti-inflammatory medication, such as methotrexate or TNF-α inhibitors is associated with an increase and normalization in lipid levels, but an overall reduction in atherogenic lipid burden as demonstrated by a decrease in the total cholesterol to HDL-C ratio.18 Accordingly, CVD risk prediction with lipid levels measured when the patient has a stable and low disease activity level can be expected to produce a more accurate CVD risk estimate, while lower lipid levels measured during high disease activity may contribute to underestimation of an individual's CVD risk.12
Among the anti-inflammatory medications, biologics have the greatest effect on reducing the atherogenic lipid burden and a meta-analysis of 25 studies showed that patients taking tofacitinib 5 mg twice daily had an observed increase of 13 mg/dL for HDL- C and 11 mg/dL of LDL-C with slightly higher increases for those taking 10 mg twice daily.19 Therefore, the net change in lipid levels with anti-inflammatory treatment should be monitored, although whether the magnitude of change is associated with improved CVD outcomes is not known.20
CVD risk assessment in patients with IJD is challenging for a number of reasons including the interaction of lipids with anti-inflammatory IJD treatments, the increased risk for CVD in IJD patients, the lack of variables accounting for IJD disease severity (e.g., number of disease flare-ups) in CVD risk prediction models for the general public, and because established CVD risk prediction tools are based on a lower observed CVD in the general populations. This is especially significant for women, who are the majority of IJD patients. Established CVD risk prediction models such as the Framingham Risk Score, ACC/AHA Pooled Cohort Equation, and Systematic Coronary Risk Evaluation score (SCORE) have been shown to underestimate risk in patients with IJD.21-23
The European League Against Rheumatism (EULAR) recommends using a multiplication factor of 1.5 in order to correct for the underestimation of CVD risk in patients with rheumatoid arthritis, but not for other IJD due to a lack of evidence regarding the magnitude of the multiplicative factor in these disease states.20 However, it is estimated that less than 15% of patients are reclassified to a high or very high risk even after using the multiplication factor.24,25 Accordingly, while patients with increased disease severity are at a higher risk for CVD, the 2017 EULAR guidelines no longer mandate the use of rheumatoid arthritis-specific criteria for this multiplication factor due to evidence supporting an increased CVD risk in patients who are in the early stages of the disease.
Efforts to adapt and recalibrate traditional risk scores have not yielded a clinically significant improvement in risk prediction.21 Other efforts to improve CVD risk prediction have focused on incorporating nontraditional CVD risk factors such as disease duration, disease severity, and anti-inflammatory medication use.22 This approach resulted in a statistically significant improvement, but its comparison to commonly-used risk models was limited due to the use of categorical risk factor variables. In addition, the improvements in CVD risk prediction for both efforts were predominantly in non-event cases, downward classification of intermediate risk patients, and less so for upward classification of high-risk patients.21,22
Non-Traditional Risk Factors and Imaging for Risk Stratification
While disease duration is not strongly associated with CVD, other non-traditional risk factors can be considered as part of the clinician and patient risk discussion.22, 26 In a cohort of 44,418 rheumatoid arthritis patients, high-sensitivity C-reactive protein (hsCRP) levels >10 mg/L and erythrocyte sedimentation rate values >42 mm/h were associated with a greater than two-fold increased risk for myocardial infarction among patients with rheumatoid arthritis.27 The cumulative burden of inflammatory disease should also be considered as the number of rheumatoid arthritis flares and overall severity of functional impairment have been significantly associated with an increased risk for CVD.28 Other non-traditional IJD risk factors, including a positive anti-nuclear antibody or positive rheumatoid factor, have also been shown to have an approximately 25% increased risk for CVD.29
Moderate disease activity has also been associated with a 4.5-fold increased risk for high risk plaque morphology on cardiac CT angiography.30 Furthermore, patients in remission from rheumatoid arthritis and with a reduced inflammatory state may have a similar CVD risk as those without rheumatoid arthritis.28 Accordingly, in a meta-analysis of 66,334 individuals, treatment with low dose methotrexate was associated with a 21% lower risk for CVD.31 This observation in patients with rheumatoid arthritis formed the basis for the National Institutes of Health-sponsored Coronary Inflammation Reduction Trial (CIRT) that is targeting patients who have coronary artery disease with diabetes or metabolic syndrome and typically have higher than average levels of inflammation.
A number of studies have shown that increased carotid intima media thickness and carotid plaques are associated with a higher CVD risk factor burden and higher CVD risk score for patients with rheumatoid arthritis, but fewer studies have examined its use for improving CVD risk prediction.24,32 In a study of 105 patients followed for a mean of 12 years, CVD risk did not differ based on carotid intima media thickness, but patients with bilateral carotid artery plaques had approximately a four-fold greater CVD event rate than individuals with unilateral or no carotid plaques.33 In a separate study of 104 patients with rheumatoid arthritis who had both carotid ultrasound and coronary artery calcium (CAC) scanning, 58% of patients with CAC = 0 had carotid artery plaque, while all of the patients with CAC >100 had carotid plaques.32 This suggests that carotid ultrasonography may potentially detect atherosclerotic disease at an earlier stage, but this study did not correlate these imaging findings to CVD events.
However, CAC is a superior predictor of CVD risk compared to cIMT in the general population and significantly improves risk prediction beyond traditional risk scores; this suggests that CAC may also be of value in the setting of IJD.34 Furthermore, only 41% of rheumatoid arthritis patients with CAC ≥ 300 or ≥75th percentile CAC were correctly classified as high risk by the 2013 ACC/AHA Pooled Cohort Equation.35 Patients with IJD have higher levels of CAC compared to patients without IJD even with similar LDL-C levels and similar total cholesterol to HDL-C ratios.36,37 In an analysis from the Multi-Ethnic Study of Atherosclerosis (MESA), it was observed that the difference in CAC scores between patients with and without rheumatoid arthritis was greatest for the youngest age category of 45-54 years with rheumatoid arthritis patients having 149% higher mean CAC score (97 vs. 39).38 However, further research is needed to determine if CAC improves CVD risk prediction specifically in patients with IJD.
Given that a higher burden of atherosclerotic plaque inflammation with increased risk of vulnerable plaque rupture may be the mechanism of CV events in patients with IJD, there is emerging interest in imaging plaques and arterial inflammation with FDG-PET as a tool for risk stratification. However, though promising, this technique is not established as superior to other modalities of imaging or even superior to clinical risk scores for the purpose of risk stratification.39,40
Indications for Statin Therapy Among Patients with Inflammatory Disorders
Empiric statin therapy should be strongly considered for patients with IJD given that their risk for CVD is generally equivalent to individuals with diabetes, currently one of the four statin treatment groups recommended in the 2013 ACC/AHA guidelines, and the lack of an IJD specific risk score that has demonstrated an improvement over the systematic underestimation of risk with established risk scores. Consideration should also be given to starting statin therapy earlier rather than later for patients with IJD given that there appears to be a greater difference in subclinical atherosclerosis for younger rather than older individuals.38 This is especially relevant if they have other high-risk features such as poorly controlled IJD severity. Even in the absence of classical dyslipidemia, statins should be considered given their beneficial effects in reducing CVD events down to very low LDL-C levels and the possibility of pleiotropic effects among IJD patients such as a reduction in plaque inflammation and improvement in endothelial dysfunction.41
An analysis of 528,654 new users of statin therapy showed that high-intensity statin therapy is associated with a 23% reduction in the incidence of rheumatoid arthritis compared to low-intensity statin therapy.42 In addition to lipid lowering, statins have also been shown to reduce the severity of IJD.43 In a propensity score analysis of 2,943 individuals with rheumatoid arthritis and using at least one disease-modifying antirheumatic drug (DMARD) agent, statin therapy was associated with a 21% reduction in all-cause mortality over a mean follow-up of 4.5 years compared to individuals with rheumatoid arthritis not on statin therapy.44 Conversely, an analysis of 4,102 incident statin users who subsequently discontinued statin therapy for ≥3 months showed a 67% increase in the risk of myocardial infarction.45
The Trial of Atorvastatin for the Primary Prevention of Cardiovascular Event Patients with Rheumatoid Arthritis (TRACE RA) included patients 50 years and older or with greater than 10 years of rheumatoid arthritis duration who were without known atherosclerotic disease, diabetes, or myopathy and not on statin therapy.46 Patients were randomized to atorvastatin 40 mg/day and 2,986 patients were enrolled, but the trial was stopped early at 2.5 years due to a lower-than-expected event rate of 0.8% (expected 1.7%). Overall, the atorvastatin group had 24 CVD events and a net reduction in LDL-C of 36 mg/dL compared to 36 events in the placebo group with a hazard ratio of 0.66 (85% CI 0.40-1.11) for the primary composite CVD endpoint. While the results were not statistically significant due to early stoppage of the trial, the 34% reduction in CVD risk is in accordance with what would be expected based on the Cholesterol Treatment Trialists (CTT) Collaboration meta-analysis given that the primary composite endpoint for TRACE RA was more inclusive than that of the CTT meta-analysis.47
Clinicians may consider potential interactions of lipid lowering and anti-inflammatory therapies. In a study of 12 patients, tocilizumab seemed to reduce the mean effect ratio of simvastatin by as much as 61% after five weeks of tocilizumab infusion, suggesting that lipid levels should be reevaluated after the initiation of new anti-inflammatory treatments for IJD.48 Reduced rituximab efficacy was observed in patients with hematologic malignancies in some preclinical studies, but follow-up studies showed no significant effect.49-53 However, overall, statin therapy appears similarly efficacious in the reduction of LDL-C for patients with and without rheumatoid arthritis, with minimal side effects and/or interactions for patients actively being treated for IJD.43,54-58
Consideration of Non-Statin Lipid-Lowering Therapy
There is limited evidence for the use of non-statin therapy among patients with IJD. However, the effectiveness of simvastatin 20 mg/day and ezetimibe 10 mg/day were evaluated in a double blinded crossover trial of 20 patients with active rheumatoid arthritis and a hsCRP of >6 mg/L.59 Both simvastatin and ezetimibe showed significant reductions in LDL-C, hsCRP, and disease severity. Therefore, given efficacy for lipid-lowering it is reasonable to consider the addition of ezetimibe 10 mg/day in addition to statin therapy for IJD individuals with a high CVD risk who are similar to individuals included in the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT).60 Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors are new class of lipid-lowering medications that can reduce LDL-C levels by >50% on top of statin therapy and have recently been shown to reduce CVD events.61 PCSK9 inhibitors have not yet specifically been studied in patients with IJD, although DMARD agents were not considered an exclusion criteria in early trials, and, as such, these agents could be considered for IJD patients with a LDL-C ≥70mg/dL at high risk for recurrent CVD.
In summary, patients with IJD have an increased risk for CVD that is comparable to patients with diabetes, and this increased CVD risk is present even at the early stages of disease. However, commonly used risk prediction equations significantly underestimate the CVD risk for patients with IJD, which is in part due to the Lipid Paradox. Accordingly, noninvasive imaging with CAC (or possibly carotid ultrasound in younger patients) should be considered to improve risk prediction. Treatment of the underlying IJD and control of disease activity can significantly reduce an individual's CVD risk. In addition, empiric statin therapy should be strongly considered for patients with IJD especially if they have other high-risk features such as poorly controlled disease activity. Further IJD research to determine the best method for CVD risk reclassification and a follow-up to the TRACE RA trial to confirm the efficacy of statin therapy in patients with IJD are significant gaps in the current literature that need to be answered.
- Skeoch S, Bruce IN. Atherosclerosis in rheumatoid arthritis: is it all about inflammation? Nat Rev Rheumatol 2015;11:390-400.
- Mantel A, Holmqvist M, Jernberg T, Wallberg-Jonsson S, Askling J. Rheumatoid arthritis is associated with a more severe presentation of acute coronary syndrome and worse short-term outcome. Eur Heart J 2015;36:3413-22.
- Douglas KM, Pace AV, Treharne GJ, et al. Excess recurrent cardiac events in rheumatoid arthritis patients with acute coronary syndrome. Ann Rheum Dis 2006;65:348-53.
- van Halm VP, Peters MJ, Voskuyl AE, et al. Rheumatoid arthritis versus diabetes as a risk factor for cardiovascular disease: a cross-sectional study, the CARRE investigation. Ann Rheum Dis 2009;68:1395-400.
- Lindhardsen J, Ahlehoff O, Gislason GH, et al. The risk of myocardial infarction in rheumatoid arthritis and diabetes mellitus: a Danish nationwide cohort study. Ann Rheum Dis 2011;70:929-34.
- Hippisley-Cox J, Coupland C, Vinogradova Y, et al. Predicting cardiovascular risk in England and Wales: prospective derivation and validation of QRISK2. BMJ 2008;336:1475-82.
- Avina-Zubieta JA, Choi HK, Sadatsafavi M, Etminan M, Esdaile JM, Lacaille D. Risk of cardiovascular mortality in patients with rheumatoid arthritis: a meta-analysis of observational studies. Arthritis Rheum 2008;59:1690-7.
- Wajed J, Ahmad Y, Durrington PN, Bruce IN. Prevention of cardiovascular disease in systemic lupus erythematosus--proposed guidelines for risk factor management. Rheumatology (Oxford) 2004;43:7-12.
- Mehta NN, Azfar RS, Shin DB, Neimann AL, Troxel AB, Gelfand JM. Patients with severe psoriasis are at increased risk of cardiovascular mortality: cohort study using the general practice research database. Eur Heart J 2010;31:1000-6.
- Helmick CG, Felson DT, Lawrence RC, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I. Arthritis Rheum 2008;58:15-25.
- Rachakonda TD, Schupp CW, Armstrong AW. Psoriasis prevalence among adults in the united states. J Am Acad Dermatol 2014;70:512-6.
- Zegkos T, Kitas G, Dimitroulas T. Cardiovascular risk in rheumatoid arthritis: assessment, management and next steps. Ther Adv Musculoskelet Dis 2016;8:86-101.
- Bartels CM, Kind AJ, Everett C, Mell M, McBride P, Smith M. Low frequency of primary lipid screening among medicare patients with rheumatoid arthritis. Arthritis Rheum 2011;63:1221-30.
- Toms TE, Panoulas VF, Douglas KM, et al. Statin use in rheumatoid arthritis in relation to actual cardiovascular risk: Evidence for substantial undertreatment of lipid-associated cardiovascular risk? Ann Rheum Dis 2010;69:683-8.
- 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;70:482-7.
- 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;71:1157-62.
- Ronda N, Favari E, Borghi MO, et al. Impaired serum cholesterol efflux capacity in rheumatoid arthritis and systemic lupus erythematosus. Ann Rheum Dis 2014;73:609-15.
- Navarro-Millan I, Charles-Schoeman C, Yang S, et al. Changes in lipoproteins associated with methotrexate or combination therapy in early rheumatoid arthritis: results from the treatment of early rheumatoid arthritis trial. Arthritis Rheum 2013;65:1430-8.
- Souto A, Salgado E, Maneiro JR, Mera A, Carmona L, Gomez-Reino JJ. Lipid profile changes in patients with chronic inflammatory arthritis treated with biologic agents and tofacitinib in randomized clinical trials: A systematic review and meta-analysis. Arthritis Rheumatol 2015;67:117-27.
- Agca R, Heslinga SC, Rollefstad S, et al. EULAR recommendations for cardiovascular disease risk management in patients with rheumatoid arthritis and other forms of inflammatory joint disorders: 2015/2016 update. Ann Rheum Dis 2017;76:17-28.
- Arts EE, Popa CD, Den Broeder AA,et al. Prediction of cardiovascular risk in rheumatoid arthritis: performance of original and adapted score algorithms. Ann Rheum Dis 2016;75:674-80.
- Solomon DH, Greenberg J, Curtis JR, et al. Derivation and internal validation of an expanded cardiovascular risk prediction score for rheumatoid arthritis: A Consortium of Rheumatology Researchers of North America registry study. Arthritis Rheumatol 2015;67:1995-2003.
- Arts EE, Popa C, Den Broeder AA, et al. Performance of four current risk algorithms in predicting cardiovascular events in patients with early rheumatoid arthritis. Ann Rheum Dis 2015;74:668-74.
- Corrales A, Gonzalez-Juanatey C, Peiro ME, Blanco R, Llorca J, Gonzalez-Gay MA. Carotid ultrasound is useful for the cardiovascular risk stratification of patients with rheumatoid arthritis: Results of a population-based study. Ann Rheum Dis 2014;73:722-7.
- Karpouzas G.A. MJ, Choi T.Y., Kitas G. Differential performance of various cardiovascular risk factors in predicting surrogate coronary outcomes in rheumatoid arthritis. Ann Rheum Dis 2014;72:A413-4.
- Arts EE, Fransen J, den Broeder AA, Popa CD, van Riel PL. The effect of disease duration and disease activity on the risk of cardiovascular disease in rheumatoid arthritis patients. Ann Rheum Dis 2015;74:998-1003.
- Zhang J, Chen L, Delzell E, et al. The association between inflammatory markers, serum lipids and the risk of cardiovascular events in patients with rheumatoid arthritis. Ann Rheum Dis 2014;73:1301-8.
- Myasoedova E, Chandran A, Ilhan B, et al. The role of rheumatoid arthritis (RA) flare and cumulative burden of ra severity in the risk of cardiovascular disease. Ann Rheum Dis 2016;75:560-5.
- Liang KP, Kremers HM, Crowson CS, et al. Autoantibodies and the risk of cardiovascular events. J Rheumatol 2009;36:2462-9.
- Karpouzas GA, Malpeso J, Choi TY, Li D, Munoz S, Budoff MJ. Prevalence, extent and composition of coronary plaque in patients with rheumatoid arthritis without symptoms or prior diagnosis of coronary artery disease. Ann Rheum Dis 2014;73:1797-1804.
- Micha R, Imamura F, Wyler von Ballmoos M, et al. Systematic review and meta-analysis of methotrexate use and risk of cardiovascular disease. Am J Cardiol 2011;108:1362-70.
- Corrales A, Parra JA, Gonzalez-Juanatey C, et al. Cardiovascular risk stratification in rheumatic diseases: Carotid ultrasound is more sensitive than coronary artery calcification score to detect subclinical atherosclerosis in patients with rheumatoid arthritis. Ann Rheum Dis 2013;72:1764-70.
- Ajeganova S, de Faire U, Jogestrand T, Frostegard J, Hafstrom I. Carotid atherosclerosis, disease measures, oxidized low-density lipoproteins, and atheroprotective natural antibodies for cardiovascular disease in early rheumatoid arthritis -- an inception cohort study. J Rheumatol 2012;39:1146-54.
- Yeboah J, McClelland RL, Polonsky TS, et al. Comparison of novel risk markers for improvement in cardiovascular risk assessment in intermediate-risk individuals. JAMA 2012;308:788-95.
- Kawai VK, Chung CP, Solus JF, Oeser A, Raggi P, Stein CM. The ability of the 2013 american college of cardiology/american heart association cardiovascular risk score to identify rheumatoid arthritis patients with high coronary artery calcification scores. Arthritis Rheumatol 2015;67:381-5.
- Okazaki J, Ishikura F, Asanuma T, Otani K, Beppu S. Premature ventricular contraction during myocardial contrast echocardiography: Relationship with imaging method, acoustic power and dose of contrast agent. J Cardiol 2004;43:69-74.
- Kao AH, Wasko MC, Krishnaswami S, et al. C-reactive protein and coronary artery calcium in asymptomatic women with systemic lupus erythematosus or rheumatoid arthritis. Am J Cardiol 2008;102:755-60.
- Giles JT, Szklo M, Post W, et al. Coronary arterial calcification in rheumatoid arthritis: comparison with the multi-ethnic study of atherosclerosis. Arthritis Res Ther 2009;11:R36.
- Emami H, Tawakol A. Noninvasive imaging of arterial inflammation using FDG-PET/CT. Curr Opin Lipidol 2014;25:431-7.
- Rudd JH, Warburton EA, Fryer TD, et al. Imaging atherosclerotic plaque inflammation with [18F]-fluorodeoxyglucose positron emission tomography. Circulation 2002;105:2708-11.
- Tikiz C, Utuk O, Pirildar T, et al. Effects of angiotensin-converting enzyme inhibition and statin treatment on inflammatory markers and endothelial functions in patients with longterm rheumatoid arthritis. J Rheumatol 2005;32:2095-01.
- Tascilar K, Dell'Aniello S, Hudson M, Suissa S. Statins and risk of rheumatoid arthritis: A nested case-control study. Arthritis Rheumatol 2016;68:2603-11.
- McCarey DW, McInnes IB, Madhok R, et al. Trial of atorvastatin in rheumatoid arthritis (TARA): double-blind, randomised placebo-controlled trial. Lancet 2004;363:2015-21.
- Schoenfeld SR, Lu L, Rai SK, Seeger JD, Zhang Y, Choi HK. Statin use and mortality in rheumatoid arthritis: A general population-based cohort study. Ann Rheum Dis 2016;75:1315-20.
- De Vera MA, Choi H, Abrahamowicz M, Kopec J, Goycochea-Robles MV, Lacaille D. Statin discontinuation and risk of acute myocardial infarction in patients with rheumatoid arthritis: a population-based cohort study. Ann Rheum Dis 2011;70:1020-4.
- Kitas GD, Nightingale P, Armitage J, et al. Trial of atorvastatin for the primary prevention of cardiovascular events in patients with rheumatoid arthritis (TRACE RA). Ann Rheum Dis 2015;74:688.
- Cholesterol Treatment Trialists' (CTT) Collaborators, Mihaylova B, Emberson J, et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 2012;380:581-90.
- Schmitt C, Kuhn B, Zhang X, Kivitz AJ, Grange S. Disease-drug-drug interaction involving tocilizumab and simvastatin in patients with rheumatoid arthritis. Clin Pharmacol Ther 2011;89:735-40.
- Ennishi D, Asai H, Maeda Y, et al. Statin-independent prognosis of patients with diffuse large b-cell lymphoma receiving rituximab plus CHOP therapy. Ann Oncol 2010;21:1217-21.
- Koo YX, Tan DS, Tan IB, et al. Effect of concomitant statin, metformin, or aspirin on rituximab treatment for diffuse large B-cell lymphoma. Leuk Lymphoma 2011;52:1509-16.
- Nowakowski GS, Maurer MJ, Habermann TM, et al. Statin use and prognosis in patients with diffuse large B-cell lymphoma and follicular lymphoma in the rituximab era. J Clin Oncol 2010;28:412-7.
- Samaras P, Heider H, Haile SR, et al. Concomitant statin use does not impair the clinical outcome of patients with diffuse large b cell lymphoma treated with rituximab-CHOP. Ann Hematol 2010;89:783-7.
- Das S, Fernandez Matilla M, Dass S, et al. Statins do not influence clinical response and b cell depletion after rituximab treatment in rheumatoid arthritis. Ann Rheum Dis 2013;72:463-4.
- Semb AG, Holme I, Kvien TK, Pedersen TR. Intensive lipid lowering in patients with rheumatoid arthritis and previous myocardial infarction: An explorative analysis from the incremental decrease in endpoints through aggressive lipid lowering (IDEAL) trial. Rheumatology (Oxford) 2011;50:324-9.
- Rollefstad S, Ikdahl E, Hisdal J, et al. Systemic inflammation in patients with inflammatory joint diseases does not influence statin dose needed to obtain LDL cholesterol goal in cardiovascular prevention. Ann Rheum Dis 2015;74:1544-50.
- Sheng X, Murphy MJ, MacDonald TM, Wei L. The comparative effectiveness of statin therapy in selected chronic diseases compared with the remaining population. BMC Public Health 2012;12:712.
- Rollefstad S, Kvien TK, Holme I, Eirheim AS, Pedersen TR, Semb AG. Treatment to lipid targets in patients with inflammatory joint diseases in a preventive cardio-rheuma clinic. Ann Rheum Dis 2013;72:1968-74.
- Rollefstad S, Ikdahl E, Hisdal J, et al. Rosuvastatin-induced carotid plaque regression in patients with inflammatory joint diseases: the rosuvastatin in rheumatoid arthritis, ankylosing spondylitis and other inflammatory joint diseases study. Arthritis Rheumatol 2015;67:1718-28.
- Maki-Petaja KM, Booth AD, Hall FC, et al. Ezetimibe and simvastatin reduce inflammation, disease activity, and aortic stiffness and improve endothelial function in rheumatoid arthritis. J Am Coll Cardiol 2007;50:852-8.
- Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015;372:2387-97.
- Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713-22.
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