Flammer, Andreas J.

Ruschitzka, Frank

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EDITORIALPsoriasis and atherosclerosis: two plaques,one syndrome?Andreas J. Flammer1,2 and Frank Ruschitzka1*1Cardiovascular Center, Cardiology, University Hospital, CH-8091 Zurich, Switzerland; and 2Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic andCollege of Medicine, Rochester, MN, USAOnline publish-ahead-of-print 21 November 2011This paper was guest edited by Professor Filippo Crea, Universita Catolica del Santo Cuore, Istituto di Cardiologia, Roma, ItalyThis editorial refers to ‘Psoriasis and risk of atrial fibrilla-tion and ischaemic stroke: a Danish Nationwide CohortStudy’†, by O. Ahlehoff et al., on page 2054Psoriasis is a chronic inflammatory disease affecting up to 2% of theglobal population. While the pathogenesis of psoriasis is not fullyunderstood yet, an increasing body of evidence suggests agenetic predisposition and an environmental component. Themost common manifestations are papulosquamous plaques sym-metrically located on extensor surfaces of the joints. While mostpsoriasis patients report that their skin manifestations have a nega-tive impact on their quality of life, psoriasis is not just a skin disease.Indeed, similarly to other systemic inflammatory diseases, inflam-mation is widespread in psoriasis, and arthritis is found in up toa quarter of patients and precedes the disease in 10% of thepatients.1 Importantly, life expectancy is reduced in psoriasis byup to 4 years, which has been attributed to a higher incidence ofcardiovascular diseases.2Ahlehoff et al. now report an association of psoriasis withincreased risk of atrial fibrillation and ischaemic stroke.3 Theauthors analysed 36 765 patients with mild and 2793 patientswith severe psoriasis and compared these with . 4 million indivi-duals of a nationwide Danish registry. Indeed, several importantpieces of information can be retrieved from this study. First, thestudy is a further epidemiological milestone in delineating the asso-ciated risk of not only severe but also mild psoriasis with vasculardisease. Secondly, the study demonstrates a considerably elevatedrisk not only for cardiovascular disease per se but also for atrial fib-rillation and ischaemic stroke, in particular. While confounding andmisclassification might be a concern in any registry-based study, theauthors provide further evidence that psoriasis is not just a skindisease, but indeed a systemic disease. Notwithstanding thatpatients with psoriasis have a high prevalence of cardiovascularrisk factors, such as smoking, dyslipidaemia, hypertension,obesity, and insulin resistance, systemic inflammation beyond theskin may provide an explanation for the increased cardiovascularrisk observed in psoriasis.1Psoriasis shares striking similarities with other systemic inflam-matory diseases, such as rheumatoid arthritis and atherosclerosis.Intriguingly, the typical histological features of the psoriaticplaque with dermal inflammation and leucocyte infiltration aresimilar to those of the atherosclerotic plaque (Figure 1).4 In athero-sclerosis, psoriasis, and rheumatoid arthritis, the activation of theinnate immune system starts an inflammatory cascade, particularlyinvolving T helper 1, T helper 17, regulatory T cells, and down-stream expression of cytokines.5 Inflammation induced by psoriasisalso impacts on insulin resistance, both of which are important sur-rogates for early, subclinical atherosclerosis and prognosticmarkers for cardiovascular disease, and may alter the function ofendothelial cells, resulting in a propensity towards endothelial dys-function and early structural changes of the arterial wall. Indeed,several studies demonstrated impaired endothelial function andincreased intima-media thickness in patients with psoriasis.6Does atrial fibrillation fit into the story of psoriasis being a sys-temic inflammatory disease? Recent studies established chronicinflammation as a risk factor for atrial fibrillation7 which is of par-ticular clinical relevance as inflammation might contribute to theprothrombotic state of atrial fibrillation and its clinical sequelae.8Remarkably, Ahlehoff and colleagues also reported an increasedrate of venous thrombo-embolism in their cohort of psoriasispatients.9Since the study of Ahlehoff et al.3 adds to the increasing evi-dence of increased cardiovascular risk in patients with chronicinflammatory diseases, patients with psoriasis should be informedby their treating physician that they may have an increasedchance of cardiovascular disease. This, however, begs two*Corresponding author. Tel: +41 44 255 87 00, Fax: +41 44 255 87 01, Email: frank.ruschitzka@usz.ch† doi:10.1093/eurheartj/ehr285.The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2011. For permissions please email: journals.permissions@oup.comEuropean Heart Journal (2012) 33, 1989–1991doi:10.1093/eurheartj/ehr425important questions with regard to potential therapeutical implica-tions. First, should we be more aggressive in treating risk factors inthese patients, and secondly should we specifically target inflamma-tion? Risk factors should be assessed, and lifestyle interventionsand pharmaceuticals prescribed as appropriate.10 Since LDLlevels are elevated and correlate with the severity of psoriasis,11initiation of statins should be considered, and goals for LDL chol-esterol levels should be based on cardiovascular risk assessment.Close monitoring of liver function and creatine kinase are manda-tory, especially in patients receiving immunosuppressive drugs, toavoid liver toxicity and rhabdomyolysis. In addition to their well-documented LDL-lowering effects, statins exert additional pleio-tropic, anti-inflammatory effects, that may contribute to theimprovement of endothelial function demonstrated in patientswith atherosclerotic vascular disease as well as in patients withrheumatoid arthritis, especially in those with high levels of systemicinflammation.12 Intriguingly, cardiovascular treatment aimed at pre-venting and treating atherosclerosis may also be beneficial in redu-cing psoriasis disease severity, as statins reduced psoriaticcutaneous plaque activity.13 While many patients with psoriasispresent with low HDL levels,11 there is currently no indicationfor niacin and fibrates in patients with psoriasis, especially asboth of these drugs are associated with a worrisome higher rateof side effects in patients with systemic inflammatory diseases.ln patients with psoriasis and elevated blood pressure, lifestylechanges should be implemented, and calcium antagonists, thiazidediuretics, and angiotensin-converting enzyme inhibitors (ACEIs)may represent the drugs of first choice. ACEIs also exert anti-inflammatory and antioxidative effects, and are similarly effectiveas statins in improving endothelial dysfunction in rheumatoid arth-ritis.14 In contrast, beta-blockers should be prescribed with cautionsince they are reported to be associated with the exacerbation ofpsoriasis. While patients with systemic inflammatory disease havenot been included in previous cardiovascular outcome trials, ag-gressive management of conventional cardiovascular risk factorsseems prudent in patients with systemic inflammatory diseasewho show an increased cardiovascular risk similar to that ofdiabetics.The benefit of any specific anti-inflammatory therapy, however,still remains to be established. In fact, anti-inflammatory drugsmight be double-edged, especially non-steroidal anti-inflammatorydrugs (NSAIDs) that are commonly used in psoriatic arthritis.Their anti-inflammatory and analgesic effects notwithstanding,NSAIDs and selective cyclo-oxygenase-2 (COX-2) inhibitorsincrease blood pressure and cardiovascular risk.15 Their bloodpressure-raising effects must not be underestimated—notably aneffect is even observed with paracetamol (acetaminophen)16—ashypertension has well known effects on the incidence of atrial fib-rillation and stroke. As such, we are facing a dilemma when tryingspecifically to target systemic inflammation. While antiinflamma-tory drugs have the potential to provide benefit through targetinginflammation, they may exert potent off-target effects. This is evenmore problematic in severely symptomatic patients receivingimmunosuppressive drugs, since corticosteroids and ciclosporinnot only increase blood pressure, but also worsen dyslipidaemia,all further enhancing cardio- and cerebrovascular risk. This trueequipoise is further documented by observational studies demon-strating beneficial cardiovascular effects of low-doseFigure 1 A much simplified schema for the development of atherosclerotic (above) and psoriatic (below) plaques. &National PsoriasisFoundation.Editorial1990methotrexate.17 This sets the stage for cardiovascular outcometrials with methothrexate currently under way, and will providethe answer as to whether this anti-inflammatory and immunmodu-latory drug will improve survival in high-risk cardiovascularpatients.Novel biologics, such as tumour necrosis factor-a (TNF-a) inhi-bitors have proven to be highly effective in the treatment of psor-iasis and other inflammatory diseases. The first evidence ofwhether potent anti-inflammatory treatment would not only alle-viate symptoms but also impact on cardiovascular surrogatescame from studies demonstrating that TNF- a suppressionimproved vascular function in patients with rheumatoid arthritis18and may have a beneficial impact on carotid intima-media thicknessin psoriasis.19 Whether TNF- a blockade might beneficially impacton cardiovascular morbidity and mortality in patients at increasedrisk because of systemic inflammatory disease, however, stillremains to be determined.Novel targeted biological agents for the treatment of psoriasisare on the horizon, among them several monoclonal anti-interleukin antibodies such as briakinumab, ustekinumab, and toci-lizumab. Due to the shared immunological mechanisms betweenpsoriasis (and other inflammatory diseases) and atherosclerosis,they may hold the potential for the treatment of both diseases,4but randomized clinical trials addressing efficacy and safety areyet to be performed.Taken together, the study of Ahlehoff et al.3 adds to the increas-ing body of evidence of an association between psoriasis andcardio- and cerebrovascular diseases. Although inflammation inthese patients may not be limited to skin and joints, but indeedbe widespread throughout the vascular tree, there is an unmetneed for further research and outcome trials in this field. As a con-sequence for clinicians, psoriasis patients, particularly those withmoderate or severe forms, should not only be treated for skinlesions and arthritis but also rigorously screened for vascular riskfactors, especially as these patients are often young and couldtherefore profit most when preventive strategies are implementedearly.10 In the future, large-scale randomized clinical trials areneeded to define whether patients with systemic inflammatory dis-eases such as psoriasis will benefit from aggressive risk factorcontrol and/or anti-inflammatory treatment.This would be of particular interest for our specialty, as thebenefit of a specific anti-inflammatory treatment has yet to beestablished in the systemic inflammatory disease we care aboutthe most—atherosclerosis.FundingThe Walter and Gertrud Siegenthaler Foundation (A.J.F.); the youngacademics Support Committee of the University of Zurich (A.J.F.);the Swiss foundation for medical–biological scholarships (SSMBS;SNSF No. PASMP3_132551 to (A.J.F.); an institutional grant [SwissNational Research Foundation (32000BO-105758) to F.R.].Conflict of interest: none declared.References1. Griffiths CE, Barker JN. Pathogenesis and clinical features of psoriasis. Lancet2007;370:263–271.2. Gelfand JM, Neimann AL, Shin DB, Wang X, Margolis DJ, Troxel AB. Risk of myo-cardial infarction in patients with psoriasis. JAMA 2006;296:1735–1741.3. Ahlehoff O, Gislason GH, Jørgensen CH, Lindhardsen J, Charlot M, Olesen JB,Abildstrøm SZ, Skov L, Torp-Pedersen C, Hansen PR. Psoriasis and risk of atrialfibrillation and ischaemic stroke: a Danish Nationwide Cohort Study. Eur Heart J2012;33:2054–2064.4. Armstrong AW, Voyles SV, Armstrong EJ, Fuller EN, Rutledge JC. A tale of twoplaques: convergent mechanisms of T-cell-mediated inflammation in psoriasis andatherosclerosis. Exp Dermatol 2011;20:544–549.5. Libby P, Ridker PM, Hansson GK. Progress and challenges in translating thebiology of atherosclerosis. Nature 2011;473:317–325.6. Balci DD, Balci A, Karazincir S, Ucar E, Iyigun U, Yalcin F, Seyfeli E, Inandi T,Egilmez E. Increased carotid artery intima-media thickness and impaired endothe-lial function in psoriasis. J Eur Acad Dermatol Venereol 2009;23:1–6.7. Aviles RJ, Martin DO, Apperson-Hansen C, Houghtaling PL, Rautaharju P,Kronmal RA, Tracy RP, Van Wagoner DR, Psaty BM, Lauer MS, Chung MK.Inflammation as a risk factor for atrial fibrillation. Circulation 2003;108:3006–3010.8. Conway DS, Buggins P, Hughes E, Lip GY. Relationship of interleukin-6 andC-reactive protein to the prothrombotic state in chronic atrial fibrillation. J AmColl Cardiol 2004;43:2075–2082.9. Ahlehoff O, Gislason GH, Lindhardsen J, Charlot MG, Jorgensen CH, Olesen JB,Bretler DM, Skov L, Torp-Pedersen C, Hansen PR. Psoriasis carries an increasedrisk of venous thromboembolism: a Danish nationwide cohort study. PLoS One2011;6:e18125.10. Friedewald VE, Cather JC, Gelfand JM, Gordon KB, Gibbons GH, Grundy SM,Jarratt MT, Krueger JG, Ridker PM, Stone N, Roberts WC. AJC editor’sconsensus: psoriasis and coronary artery disease. Am J Cardiol 2008;102:1631–1643.11. Rocha-Pereira P, Santos-Silva A, Rebelo I, Figueiredo A, Quintanilha A, Teixeira F.Dislipidemia and oxidative stress in mild and in severe psoriasis as a risk for car-diovascular disease. Clin Chim Acta 2001;303:33–39.12. Hermann F, Forster A, Chenevard R, Enseleit F, Hurlimann D, Corti R, Spieker LE,Frey D, Hermann M, Riesen W, Neidhart M, Michel BA, Hellermann JP, Gay RE,Luscher TF, Gay S, Noll G, Ruschitzka F. Simvastatin improves endothelial func-tion in patients with rheumatoid arthritis. J Am Coll Cardiol 2005;45:461–464.13. Shirinsky IV, Shirinsky VS. Efficacy of simvastatin in plaque psoriasis: a pilot study.J Am Acad Dermatol 2007;57:529–531.14. Flammer AJ, Sudano I, Hermann F, Gay S, Forster A, Neidhart M, Kunzler P,Enseleit F, Periat D, Hermann M, Nussberger J, Luscher TF, Corti R, Noll G,Ruschitzka F. Angiotensin-converting enzyme inhibition improves vascular func-tion in rheumatoid arthritis. Circulation 2008;117:2262–2269.15. White WB, West CR, Borer JS, Gorelick PB, Lavange L, Pan SX, Weiner E,Verburg KM. Risk of cardiovascular events in patients receiving celecoxib: ameta-analysis of randomized clinical trials. Am J Cardiol 2007;99:91–98.16. Sudano I, Flammer AJ, Periat D, Enseleit F, Hermann M, Wolfrum M, Hirt A,Kaiser P, Hurlimann D, Neidhart M, Gay S, Holzmeister J, Nussberger J,Mocharla P, Landmesser U, Haile SR, Corti R, Vanhoutte PM, Luscher TF,Noll G, Ruschitzka F. Acetaminophen increases blood pressure in patients withcoronary artery disease. Circulation 2010;122:1789–1796.17. Prodanovich S, Ma F, Taylor JR, Pezon C, Fasihi T, Kirsner RS. Methotrexatereduces incidence of vascular diseases in veterans with psoriasis or rheumatoidarthritis. J Am Acad Dermatol 2005;52:262–267.18. Hurlimann D, Forster A, Noll G, Enseleit F, Chenevard R, Distler O, Bechir M,Spieker LE, Neidhart M, Michel BA, Gay RE, Luscher TF, Gay S, Ruschitzka F. Anti-tumor necrosis factor-alpha treatment improves endothelial function in patientswith rheumatoid arthritis. Circulation 2002;106:2184–2187.19. Di Minno MN, Iervolino S, Peluso R, Scarpa R, Di Minno G. Carotid intima-mediathickness in psoriatic arthritis: differences between tumor necrosis factor-alphablockers and traditional disease-modifying antirheumatic drugs. ArteriosclerThromb Vasc Biol 2011;31:705–712.Editorial 1991

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