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High-Density Lipoprotein Cholesterol Function Improves after Successful Treatment of Psoriasis: A Step Forward in the Right Direction

2014; Elsevier BV; Volume: 134; Issue: 3 Linguagem: Inglês

10.1038/jid.2013.447

1523-1747

Nehal N. Mehta, Joel M. Gelfand,

Dermatology and Skin Diseases

There is epidemiological evidence that high-density lipoprotein (HDL) concentrations, or HDL "levels," exert protection from atherosclerosis, suggesting that HDL plays a role in vascular diseases. More accurate measures of HDL "function" are emerging, such as HDL efflux assays, which measure removal of cholesterol from peripheral tissues. Using this assay, we have demonstrated that psoriasis is associated with decreased HDL "levels" and HDL "function." The study by Holzer et al. in this issue demonstrates in an open-label, uncontrolled study that HDL function is impaired in psoriasis and improves after successful treatment of psoriasis. These findings underscore the notion that treatment of psoriasis likely extends beyond the skin and that a randomized controlled clinical trial is needed to confirm these findings. There is epidemiological evidence that high-density lipoprotein (HDL) concentrations, or HDL "levels," exert protection from atherosclerosis, suggesting that HDL plays a role in vascular diseases. More accurate measures of HDL "function" are emerging, such as HDL efflux assays, which measure removal of cholesterol from peripheral tissues. Using this assay, we have demonstrated that psoriasis is associated with decreased HDL "levels" and HDL "function." The study by Holzer et al. in this issue demonstrates in an open-label, uncontrolled study that HDL function is impaired in psoriasis and improves after successful treatment of psoriasis. These findings underscore the notion that treatment of psoriasis likely extends beyond the skin and that a randomized controlled clinical trial is needed to confirm these findings. Several lines of evidence have demonstrated that psoriasis, a chronic T-helper cells 1 and 17 inflammatory skin disease, is associated with systemic inflammation (Mehta et al., 2011Mehta N.N. Yu Y. Saboury B. et al.Systemic and vascular inflammation in patients with moderate to severe psoriasis as measured by [18F]-fluorodeoxyglucose positron emission tomography-computed tomography (FDG-PET/CT): a pilot study.Arch Dermatol. 2011; 147: 1031-1039Crossref PubMed Scopus (169) Google Scholar), metabolic diseases (Azfar et al., 2012Azfar R.S. Seminara N.M. Shin D.B. et al.Increased risk of diabetes mellitus and likelihood of receiving diabetes mellitus treatment in patients with psoriasis.Arch Dermatol. 2012; 148: 995-1000Crossref PubMed Scopus (103) Google Scholar; Langan et al., 2012Langan S.M. Seminara N.M. Shin D.B. et al.Prevalence of metabolic syndrome in patients with psoriasis: a population-based study in the United Kingdom.J Invest Dermatol. 2012; 132: 556-562Abstract Full Text Full Text PDF PubMed Scopus (324) Google Scholar; Armstrong et al., 2013Armstrong A.W. Harskamp C.T. Armstrong E.J. Psoriasis and the risk of diabetes mellitus: a systematic review and meta-analysis.JAMA Dermatol. 2013; 149: 84-91Crossref PubMed Scopus (220) Google Scholar), predisposition to cardiovascular (CV) risk factors (Neimann et al., 2006Neimann A.L. Shin D.B. Wang X. et al.Prevalence of cardiovascular risk factors in patients with psoriasis.J Am Acad Dermatol. 2006; 55: 829-835Abstract Full Text Full Text PDF PubMed Scopus (835) Google Scholar), and cardiovascular disease (Gelfand et al., 2006Gelfand J.M. Neimann A.L. Shin D.B. et al.Risk of myocardial infarction in patients with psoriasis.JAMA. 2006; 296: 1735-1741Crossref PubMed Scopus (1486) Google Scholar; Mehta et al., 2010Mehta N.N. Azfar R.S. Shin D.B. et al.Patients with severe psoriasis are at increased risk of cardiovascular mortality: cohort study using the General Practice Research Database.Eur Heart J. 2010; 31: 1000-1006Crossref PubMed Scopus (535) Google Scholar; Armstrong et al., 2012Armstrong A.W. Harskamp C.T. Ledo L. et al.Coronary artery disease in patients with psoriasis referred for coronary angiography.Am J Cardiol. 2012; 109: 976-980Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar; Yeung et al., 2013Yeung H. Takeshita J. Mehta N.N. et al.Psoriasis severity and the prevalence of major medical comorbidity: a population-based study.JAMA Dermatol. 2013; 149: 1173-1179Crossref PubMed Scopus (339) Google Scholar). Indeed, these lines of evidence span from basic cellular models (Nestle et al., 2009Nestle F.O. Kaplan D.H. Barker J. Psoriasis.N Engl J Med. 2009; 361: 496-509Crossref PubMed Scopus (2172) Google Scholar), animal models (Davidovici et al., 2010Davidovici B.B. Sattar N. Jorg P.C. et al.Psoriasis and systemic inflammatory diseases: potential mechanistic links between skin disease and co-morbid conditions.J Invest Dermatol. 2010; 130: 1785-1796Abstract Full Text Full Text PDF PubMed Scopus (528) Google Scholar), and observational human studies (Mehta et al., 2013Mehta N.N. Li K. Szapary P. et al.Modulation of cardiometabolic pathways in skin and serum from patients with psoriasis.J Transl Med. 2013; 11: 194Crossref PubMed Scopus (37) Google Scholar). The weight of the evidence, mechanistically, biologically, and epidemiologically, support the notion that systemic inflammation, either induced experimentally in humans or that what is observed in psoriasis, is associated with a heightened state of CV risk. What factors may play roles in increasing CV risk for patients with psoriasis? Indeed, conventional CV risk factors such as hypertension, tobacco use, obesity, and diabetes are more prevalent in psoriasis, but the association with CV outcomes persists even after adjusting for these factors in large, population-based studies (Gelfand et al., 2006Gelfand J.M. Neimann A.L. Shin D.B. et al.Risk of myocardial infarction in patients with psoriasis.JAMA. 2006; 296: 1735-1741Crossref PubMed Scopus (1486) Google Scholar; Ahlehoff et al., 2011Ahlehoff O. Gislason G.H. Charlot M. et al.Psoriasis is associated with clinically significant cardiovascular risk: a Danish nationwide cohort study.J Intern Med. 2011; 270: 147-157Crossref PubMed Scopus (332) Google Scholar; Langan et al., 2012Langan S.M. Seminara N.M. Shin D.B. et al.Prevalence of metabolic syndrome in patients with psoriasis: a population-based study in the United Kingdom.J Invest Dermatol. 2012; 132: 556-562Abstract Full Text Full Text PDF PubMed Scopus (324) Google Scholar; Li et al., 2012Li W.Q. Han J.L. Manson J.E. et al.Psoriasis and risk of nonfatal cardiovascular disease in U.S. women: a cohort study.Br J Dermatol. 2012; 166: 811-818Crossref PubMed Scopus (93) Google Scholar). Furthermore, dyslipidemia, defined by the conventional assessment of lipids, has been shown to be increased in psoriasis (Ma et al., 2013Ma C. Schupp C.W. Armstrong E.J. et al.Psoriasis and dyslipidemia: a population-based study analyzing the National Health and Nutrition Examination Survey (NHANES).J Eur Acad Dermatol Venereol. 2013; (e-pub ahead of print 1 August 2013)https://doi.org/10.1111/jdv.12232Crossref Scopus (22) Google Scholar) and, most recently, triglycerides were found to be increased in a dose-dependent manner with increasing body surface areas affected by psoriasis, independent of the usual risk factors, such as body mass index (Langan et al., 2012Langan S.M. Seminara N.M. Shin D.B. et al.Prevalence of metabolic syndrome in patients with psoriasis: a population-based study in the United Kingdom.J Invest Dermatol. 2012; 132: 556-562Abstract Full Text Full Text PDF PubMed Scopus (324) Google Scholar). Lipid panels usually rely on direct concentration measurements of total cholesterol, high-density lipoproteins (HDLs), and triglycerides, with calculation to estimate low-density lipoproteins (LDLs). However, these metrics have variable responses to antipsoriatic treatments, despite a large body of preclinical and human evidence demonstrating that induction of inflammation worsens HDL levels in humans (McGillicuddy et al., 2009McGillicuddy F.C. de la Llera Moya M. Hinkle C.C. et al.Inflammation impairs reverse cholesterol transport in vivo.Circulation. 2009; 119: 1135-1145Crossref PubMed Scopus (286) Google Scholar; de la Llera Moya et al., 2012de la Llera Moya M. McGillicuddy F.C. Hinkle C.C. et al.Inflammation modulates human HDL composition and function in vivo.Atherosclerosis. 2012; 222: 390-394Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar). Furthermore, it would be expected that with improvements in known CV markers and direct measurement of vascular inflammation following open-label antipsoriatic treatment (Bissonnette et al., 2013Bissonnette R. Tardif J.C. Harel F. et al.Effects of the tumor necrosis factor-alpha antagonist adalimumab on arterial inflammation assessed by positron emission tomography in patients with psoriasis: results of a randomized controlled trial.Circ Cardiovasc Imaging. 2013; 6: 83-90Crossref PubMed Scopus (72) Google Scholar) lipids, namely HDL, would improve; however, in these studies this relationship was observed inconsistently. These findings reinforce the idea that changes in HDL cholesterol levels are an inadequate surrogate for responses to therapy (Schwartz et al., 2012Schwartz G.G. Olsson A.G. Abt M. et al.Effects of dalcetrapib in patients with a recent acute coronary syndrome.N Engl J Med. 2012; 367: 2089-2099Crossref PubMed Scopus (1554) Google Scholar) and that more precise techniques to understand cholesterol composition and function are needed (Rosenson et al., 2012Rosenson R.S. Brewer Jr., H.B. Davidson W.S. et al.Cholesterol efflux and atheroprotection: advancing the concept of reverse cholesterol transport.Circulation. 2012; 125: 1905-1919Crossref PubMed Scopus (681) Google Scholar). These new measures include lipid particle size and number measured by nuclear magnetic resonance spectroscopy, which provides an assessment of the composition of the lipid content beyond concentration alone (Jeyarajah et al., 2006Jeyarajah E.J. Cromwell W.C. Otvos J.D. Lipoprotein particle analysis by nuclear magnetic resonance spectroscopy.Clin Lab Med. 2006; 26: 847-870Abstract Full Text Full Text PDF PubMed Scopus (534) Google Scholar). These metrics predicted first myocardial infarction within a prospective population-based study with equivalent performance as LDL concentration (Mora et al., 2009Mora S. Otvos J.D. Rifai N. et al.Lipoprotein particle profiles by nuclear magnetic resonance compared with standard lipids and apolipoproteins in predicting incident cardiovascular disease in women.Circulation. 2009; 119: 931-939Crossref PubMed Scopus (374) Google Scholar). In psoriasis, lipid particle size and number have also been demonstrated to be more atherogenic in a study of 100 patients (Mehta et al., 2012Mehta N.N. Li R. Krishnamoorthy P. et al.Abnormal lipoprotein particles and cholesterol efflux capacity in patients with psoriasis.Atherosclerosis. 2012; 224: 218-221Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar) and also associated with vascular inflammation (Yu et al., 2012Yu Y. Sheth N. Krishnamoorthy P. et al.Aortic vascular inflammation in psoriasis is associated with HDL particle size and concentration: a pilot study.Am J Cardiovasc Dis. 2012; 2: 285-292PubMed Google Scholar). Conventional lipid measures in these patients were "normal," including HDL levels. However, the function of HDL cholesterol, which performs a process called "reverse cholesterol transport" (RCT), was impaired in psoriasis as well (Mehta et al., 2012Mehta N.N. Li R. Krishnamoorthy P. et al.Abnormal lipoprotein particles and cholesterol efflux capacity in patients with psoriasis.Atherosclerosis. 2012; 224: 218-221Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar). This pathway involves efflux of cholesterol from macrophages (such as those within atherosclerotic plaque) to HDL acceptor particles for ultimate return to the liver and biliary excretion. HDL efflux is thought to be a central function that makes HDL the "good" cholesterol (Khera et al., 2011Khera A.V. Cuchel M. de la Llera-Moya M. et al.Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis.N Engl J Med. 2011; 364: 127-135Crossref PubMed Scopus (1533) Google Scholar). In fact, recent studies demonstrate that raising HDL pharmacologically is not protective against CV events, most likely because these approaches do not improve HDL function (Schwartz et al., 2012Schwartz G.G. Olsson A.G. Abt M. et al.Effects of dalcetrapib in patients with a recent acute coronary syndrome.N Engl J Med. 2012; 367: 2089-2099Crossref PubMed Scopus (1554) Google Scholar; Khera et al., 2013Khera A.V. Patel P.J. Reilly M.P. et al.The addition of niacin to statin therapy improves high-density lipoprotein cholesterol levels but not metrics of functionality.J Am Coll Cardiol. 2013; 62: 1909-1910Crossref PubMed Scopus (69) Google Scholar). Thus, developing new approaches to target the HDL pathway to lower CV risk is an area of intense scientific and medical interest. In this issue, Holzer et al., 2014Holzer M. Wolf P. Inzinger M. et al.Antipsoriatic therapy recovers high-density lipoprotein composition and function.J Invest Dermatol. 2014; 134: 635-642Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar followed up on a previous observation that HDL efflux is abnormal in psoriasis (Holzer et al., 2012Holzer M. Wolf P. Curcic S. et al.Psoriasis alters HDL composition and cholesterol efflux capacity.J Lipid Res. 2012; 53: 1618-1624Crossref PubMed Scopus (125) Google Scholar) by performing an open-label study of psoriasis treatment to understand the effect on HDL characteristics. HDL was isolated from 15 patients with moderate to severe psoriasis at baseline and after effective topical and/or systemic antipsoriatic therapy; they were compared with 15 age- and sex-matched controls. HDL efflux was measured using two validated techniques: (1) by depleting serum of all apolipoprotein B–containing lipids, and (2) by isolating HDL directly, using centrifugation techniques. Other known important characteristics of HDL such as HDL phospholipid content and enzymatic mediators within the RCT pathway, including HDL paraoxanase and lipoprotein-associated phospholipase A2 (Lp-PLA2), were also measured before and after therapy. The investigators confirmed earlier observations that HDL efflux was reduced in patients, consistent with the hypothesis that increased systemic inflammation impairs the RCT pathway (Holzer et al., 2012Holzer M. Wolf P. Curcic S. et al.Psoriasis alters HDL composition and cholesterol efflux capacity.J Lipid Res. 2012; 53: 1618-1624Crossref PubMed Scopus (125) Google Scholar; Mehta et al., 2012Mehta N.N. Li R. Krishnamoorthy P. et al.Abnormal lipoprotein particles and cholesterol efflux capacity in patients with psoriasis.Atherosclerosis. 2012; 224: 218-221Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar). They also observed, after 56–100 weeks of treatment, that the reduction in Psoriasis Area and Severity Index (PASI) scores was associated with improvement in HDL efflux from isolated HDL. Furthermore, supporting the notion of improvement in HDL characteristics, paraoxonase and Lp-PLA2 enzyme activity were modulated in a favorable direction. The authors also reported that there was an increase in HDL size by nuclear magnetic resonance, suggesting that phospholipid content increased within the HDL, also supporting the observation that HDL characteristics were more favorable after successful treatment of psoriasis. Finally, all of these improvements in HDL function and composition occurred, despite the lack of change in blood lipid levels and including HDL. These findings are largely consistent with earlier observations in healthy humans that experimental inflammation in vivo modulates HDL function and composition (McGillicuddy et al., 2009McGillicuddy F.C. de la Llera Moya M. Hinkle C.C. et al.Inflammation impairs reverse cholesterol transport in vivo.Circulation. 2009; 119: 1135-1145Crossref PubMed Scopus (286) Google Scholar; Mehta et al., 2009Mehta N.N. McGillicuddy F.C. Anderson P.D. et al.Experimental endotoxemia induces adipose inflammation and insulin resistance in humans.Diabetes. 2009; : 172-181PubMed Google Scholar; de la Llera Moya et al., 2012de la Llera Moya M. McGillicuddy F.C. Hinkle C.C. et al.Inflammation modulates human HDL composition and function in vivo.Atherosclerosis. 2012; 222: 390-394Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar). Our group has demonstrated that HDL efflux decreases after administration of lipopolysaccharide (LPS), a known stimulator of innate immune pathways known to be activated in psoriasis. Furthermore, in that study, LPS led to a decrease in HDL phospholipid content, and this correlated highly with HDL efflux. Holzer et al., 2014Holzer M. Wolf P. Inzinger M. et al.Antipsoriatic therapy recovers high-density lipoprotein composition and function.J Invest Dermatol. 2014; 134: 635-642Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar extend these findings by demonstrating that HDL phospholipid was reduced in psoriasis compared with healthy controls and that this content tended to improve following successful treatment. Furthermore, the increase in lecithin–cholesterol acyltransferase activity suggests that cholesterol esterfication improved following therapy, which would facilitate exit of cholesterol from the body. However, these findings must be interpreted with caution. The authors do not provide free cholesterol and cholesterol ester data before and after therapy, which are more precise measures of lecithin–cholestrol acyltransferase activity (Vaisman and Remaley, 2013Vaisman B.L. Remaley A.T. Measurement of lecithin-cholesterol acyltransferase activity with the use of a Peptide-proteoliposome substrate.Methods Mol Biol. 2013; 1027: 343-352Crossref PubMed Scopus (11) Google Scholar). Moreover, the small sample size, lack of a randomized placebo controlled design, and inability to determine which specific treatment improved HDL function all remain to be addressed. The strengths of the study are that authors used rigorous lab methods to provide the initial characterization of treatment effects on HDL properties in patients with psoriasis. The study brings to center stage the concept that the conventional methods of assessing CV risk in psoriasis may be in need of refinement (Mehta et al., 2012Mehta N.N. Krishnamoorthy P. Yu Y. et al.The impact of psoriasis on 10-year Framingham risk.J Am Acad Dermatol. 2012; 67: 796-798Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar). This concept of residual risk for CV disease, despite improvement in the usual risk factors, suggests use of newly developed functional measures. Furthermore, there are still limited data on whether treatment of psoriasis will improve outcomes for CV disease or for the risk factors alone. Another small open-label study demonstrated in humans that treatment of psoriasis utilizing anti-tumor necrosis factor (anti-TNF) therapy led to improvement in carotid intimal-medial thickness, a surrogate marker of CV disease (Jokai et al., 2013Jokai H. Szakonyi J. Kontar O. et al.Impact of effective tumor necrosis factor-alfa inhibitor treatment on arterial intima-media thickness in psoriasis: results of a pilot study.J Am Acad Dermatol. 2013; 69: 523-529Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar). However, whether improvement in such surrogate markers would hold up under a more rigorous randomized, placebo-controlled trial design and ultimately translate into improvement in CV outcome is unknown. This approach of utilizing a validated surrogate marker to understand whether there is improvement in an outcome was widely used in earlier studies of lipid treatment, using rigorous randomized controlled trials (Taylor et al., 2009Taylor A.J. Villines T.C. Stanek E.J. et al.Extended-release niacin or ezetimibe and carotid intima-media thickness.N Engl J Med. 2009; 361: 2113-2122Crossref PubMed Scopus (609) Google Scholar). Reduction in cholesterol levels as well as improvement in imaging of atherosclerosis served as proxies for lower CV outcomes. However, if psoriasis is in the causal pathway for CV diseases (i.e., an intermediate risk factor), a strategy to tease out disease treatment effects on CV outcomes will require concomitant use of surrogate end points as well as outcome studies to understand how treatment modulates short- and long-term CV risk. A strategy currently underway to advance understanding of CV risk, treatment effects, and outcomes in psoriasis includes performance of a randomized, placebo-controlled trial of psoriasis treatment (anti-TNF, UVB therapy, and placebo) with a primary outcome of vascular inflammation by fluorodeoxyglucose positron emission tomography–computed tomography (http://clinicaltrials.gov/ct2/show/NCT01553058 and http://clinicaltrials.gov/show/NCT01866592), a novel imaging biomarker that measures CV risk for both short-term (Fayad et al., 2011Fayad Z.A. Mani V. Woodward M. et al.Safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging (dal-PLAQUE): a randomised clinical trial.Lancet. 2011; 378: 1547-1559Abstract Full Text Full Text PDF PubMed Scopus (439) Google Scholar) and long-term events (Arauz et al., 2007Arauz A. Hoyos L. Zenteno M. et al.Carotid plaque inflammation detected by 18F-fluorodeoxyglucose-positron emission tomography. Pilot study.Clin Neurol Neurosurg. 2007; 109: 409-412Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar; Rominger et al., 2009Rominger A. Saam T. Wolpers S. et al.18F-FDG PET/CT identifies patients at risk for future vascular events in an otherwise asymptomatic cohort with neoplastic disease.J Nucl Med. 2009; 50: 1611-1620Crossref PubMed Scopus (277) Google Scholar). However, larger simple trials studying CV outcomes in psoriasis such as those currently underway in nonpsoriasis patients evaluating the effect of very low dose methotrexate in patients with cardiovascular disease (Ridker, 2009Ridker P.M. Testing the inflammatory hypothesis of atherothrombosis: scientific rationale for the cardiovascular inflammation reduction trial (CIRT).J Thromb Haemost. 2009; 7: 332-339Crossref PubMed Scopus (228) Google Scholar) will also need to be planned. Until then, we can certainly gain insight from this and other recent studies that suggest that successful treatment of inflammation in vivo leads to improvement in cardiometabolic diseases (Maki-Petaja et al., 2012Maki-Petaja K.M. Elkhawad M. Cheriyan J. et al.Anti-tumor necrosis factor-alpha therapy reduces aortic inflammation and stiffness in patients with rheumatoid arthritis.Circulation. 2012; 126: 2473-2480Crossref PubMed Scopus (173) Google Scholar), the most potent source of mortality in psoriasis. Preparation of this Commentary was supported by an intramural grant from the National Institutes of Health (to NNM) and grants (R01HL08974 and R01-HL111293) from the National Heart, Lung, and Blood Institute and a grant from the National Institute for Arthritis Musculoskeletal and Skin Diseases (K24-AR064310) to JMG. The funders played no role in the design, analysis, or interpretation of this work.