INTRODUCTION

Beginning in the early 1970s accelerated atherosclerosis leading to premature cardiovascular disease (CVD) began to be recognized as a significant cause of morbidity and mortality in autoimmune diseases and in particular in Systemic Lupus Erythematosus (SLE). This was initially felt to be due to traditional risk factors for atherosclerosis and to the use of certain drugs, in particular corticosteroids. More recently however, it is has been shown that traditional risk factors alone cannot explain the extent of observed premature atherosclerosis and that the chronic inflammation seen in patients with autoimmune diseases is an important contributing factor. It has also been demonstrated that the atherosclerotic process starts in childhood and that chronic inflammation, as demonstrated by an elevated c-reactive protein, leads to early cardiovascular disease. It has become evident that the identification of subclinical atherosclerosis prior to cardiovascular or cerebrovascular events is needed to allow the clinician to design preventive therapy.1

Atherosclerosis is a chronic inflammatory disease characterized by accumulation of oxidized lipoproteins, increased cell death and hypertrophic degeneration of the arterial intima. The disease process is associated with local formation of modified self antigens that are targeted by both innate and adaptive immune responses. Although it remains to be firmly established it is likely that these autoimmune responses initially have a beneficial effect facilitating the removal of potentially harmful rest products from oxidized LDL and dying cells. However, studies performed on hypercholesterolaemic mice deficient in different components of the immune system uniformly suggest that the net effect of immune activation is pro-atherogenic and that atherosclerosis, at least to some extent, should be regarded as an autoimmune disease. These observations point to the possibility of developing new treatments for atherosclerosis based on modulation of immune responses against plaque antigens, an approach presently tested clinically for several other chronic inflammatory diseases with autoimmune components. Pilot studies in animals have provided promising results for both parental and oral vaccines based on oxidized LDL antigens. The time when this concept is ready for clinical testing is rapidly approaching but it will be important not to underestimate the difficulties that will be encountered in transferring the promising results from experimental animals into humans.2

EPIDEMIOLOGY

SLE adalah penyakit kronik, penyakit autoimun kambuhan yang dapat berimbas pada sistem organ manapun. Tahapan penyakit ini bervariasi, mulai dari ringan dengan fase tanpa gejala yang lama hingga kondisi berat dengan gejala kemerahan yang sering hingga membutuhkan terapi imunosupresan jangka panjang, sampai kerusakan organ. SLE pada umumnya didominasi wanita usia reproduktif, dan 10-20% diantaranya terjadi di usia kanak-kanak dan dewasa. Walaupun gejala klinis dan penanda laboratorium pada pasien pediatrik (pSLE) sama dengan pasien dewasa, pasien dengan pSLE cenderung memiliki gangguan organ mayor dan perjalanan klinis yang lebih agresif. 3

*SLE is a chronic, relapsing-remitting autoimmune disease that can affect any organ system. The disease course varies from a mild disease with long quiescence phases to a severe disease with frequent flares requiring long-term immunosuppressive therapy and leading to considerable organ damage. It predominantly affects women of childbearing age, with 1020% of cases presenting during childhood and adolescence. Although the clinical symptoms and findings of laboratory tests in patients with pediatric onset SLE (pSLE) are similar to those seen in adults, patients with pSLE tend to have a higher rate of major organ involvement and a more aggressive clinical course.3

Satu masalah yang timbul saat menilai prevalensi dari pSLE dan manifestasinya, dan berlaku sama pada penyakit pediatrik lainnya, adalah tidak adanya konsensus yang menjelaskan batas umur pediatrik yang tegas, dengan berbagai penelitian yang memiliki batas atas usia 14 tahun hingga 18 tahun, tergantung peraturan negara. Namun begitu, kebanyakan penelitian menggunakan batas atas 16 atau 18 tahun. Diluar ketidak jelasan batas atas usia, usia median diagnosis pSLE ditetapkan pada usia 11-12 tahun, dengan onset penyakit di usia kurang dari 8 tahun timbul pada kurang dari 20% kasus. (Gbr, 1) 3,4

*One problem when determining the prevalence of pSLE and its manifestations, which applies similarly to other pediatric diseases, is that there is no consensus regarding the appropriate cutoff age to define pediatric, with studies having an upper limit of as young as 14 years and as old as

18 years, depending on the practice of the country. However, most studies use either 16 years or 18 years as the upper cutoff age. Despite this lack of a clear cutoff age, the median age at diagnosis in pSLE is consistently around 1112 years, with disease onset under the age of 8 years occurring in fewer than 20% of cases. (Fig. 1) 3,4

Figure 1. Age at onset in 155 children with SLE.

Seperti yang tampak pada adult-onset SLE (aSLE), pSLE terjadi lebih sering dan di diagnosis di usia lebih muda pada pasien berkulit gelap daripada pasien berkulit putih. Walaupun pSLE lebih umum terjadi pada wanita, rasio angka kejadian pria dan wanita pada pSLE (4-5:1) lebih rendah dari yang tampak pada aSLE (9:1). Penelitian terbaru menunjukkan bahwa perbedaan rasio kejadian wanita dan pria ini dipengaruhi status pubertas, sementara penelitian paling akhir mengindikasikan bahwa pengaruh pubertas pada rasio wanita dan pria tampaknya tergantung dari etnis populasi yang diteliti. Alasan perbedaan etnis di usia onset dan jenis kelamin ini tidak diketahui, begitupula alasan persentase pria pada pSLE yang relatif lebih tinggi dibandingkan aSLE. 3

*As is seen in adult-onset SLE (aSLE), pSLE is more frequent and diagnosed at a younger age in non-white patients than in white patients. Although pSLE is more common in females than in males, the female and male ratio in pSLE (45:1) is lower than that seen in aSLE (9:1). Early studies suggested that the female and male ratio differed depending on puberty status, while more-recent studies indicate that the effect of puberty on the female and male ratio seems to

depend on the ethnicity of the population studied. The reason for the ethnic differences in age of onset and sex in pSLE is not known, nor is the reason for the relatively increased percentage of males with pSLE compared to aSLE.3

Figure 2. Presenting manifestations at onset of SLE in 155 children.

Dari penelitian multicenter di Perancis yang melibatkan 155 pasien dimana SLE timbul diusia sebelum 16 tahun (Gbr 2.), manifestasi awal yang paling sering adalah hematologi (72%), kulit (70%), muskuloskeletal (64%), ginjal (50%) dan demam (58%). Tiga puluh dua persen anakanak dengan gejala asimtomatik, sebagian besar melibatkan gejala abdominal pada 26 pasien, dengan hasil laparotomi negatif pada dugaan appendicitis. Pada 40% pasien, manifestasi berat pada renal, neurologi, hematologi, abdominal, kardiak, pulmoner, trombotik dan/ atau kutaneus timbul dalam bulan pertama setelah di diagnosis. Nilai tengah laju endap darah adalah 72 29 mm/jam, dan nilai tengah C-reactive protein 22 21 mg/L. Antibody antinuclear, antibody antidouble stranded DNA dan nilai C3 atau C4 rendah ditemukan masing-masing pada 97%, 93% dan 78% pasien.4

*From the French multicenter study involved 155 patients in whom SLE developed before the age of 16 years (Fig. 2), the most common initial manifestations are hematologic (72%), cutaneous (70%), musculoskeletal (64%), renal (50%), and fever (58%). Thirty-two percent of children have atypical symptoms, mainly including abdominal involvement in 26 patients, which

lead to negative laparotomy results for presumed appendicitis. Severe renal, neurologic, hematologic, abdominal, cardiac, pulmonary, thrombotic, and/or cutaneous manifestations occurred within the first month after the diagnosis in 40% of patients. The mean erythrocyte sedimentation rate was 72 29 mm/h, and the mean C-reactive protein value 22 21 mg/L. Antinuclear antibodies an, anti-double stranded DNA antibodies, and low C3 or C4 level were retrieved in 97%, 93%, and 78 % of patients, respectively.4

PATHOGENESIS OF ATHEROSCLEROSIS IN SLE

Inflamasi Hasil observasi epidemiologis telah mengaitkan inflamasi dengan kejadian kardiovaskuler. Observasi epidemiologi klinis sangat mengesankan faktor resiko konvensional klasik dan mekanisme lain (non-konvensional/ faktor spesifik-penyakit) mendorong percepatan

atherosklerosis pada penyakit seperti SLE. Resiko berlebihan yang diamati pada penyakit autoimun timbul sebagai akibat inflamasi sistemik, langsung ataupun tidak langsung dengan merusak pembuluh darah; dan demikian konsep inflamasi ini menjadi faktor resiko kardiovaskuler. SLE dan gangguan autoimun kronis lainnya bisa jadi telah memberikan pengertian yang dalam tentang interaksi rumit antara penyakit tradisional dan non-tradisional terkait (termasuk: inflamasi, dislipidemia, homosistein, stress oksidatif, variabel trombotik, insulin resisten dan autoantigen) faktor-faktor resiko. 5

Inflammation * Epidemiological observations have linked inflammation with the cardiovascular events. Clinical epidemiological observations strongly suggest that, together with classical conventional risk factors, other mechanisms (non-conventional/disease-specific factors) promote accelerated atherosclerosis in disease like SLE. The excess risk observed in autoimmune disease appears to be driven by systemic inflammation, directly or indirectly through its damaging effects on the vasculature; and thus the concept of inflammation as a cardiovascular risk factor. SLE and other autoimmune chronic inflammatory disorders may provide insight into these complex interactions between traditional and non-traditional/disease related (including: inflammation, dyslipidaemia,

homocysteine, oxidative stress, thrombotic variables, insulin resistance and autoantigens) risk factors.5

Pandangan atherosklerosis di zaman sekarang telah meluas meliputi peran aktif dan kompleks inflamasi, diatur oleh mediator-mediator sistem imun, sehingga atherosklerosis dilihat sebagai proses inflamasi aktif dan immune-mediated dimana inflamasi sistemik dan mekanisme soluble immune berperan dalam mempercepat patologi pembuluh darah. Dengan demikian walaupun banyak faktor menyebabkan atherosklerosis, inflamasi pada bagian pembuluh darah yang rusak memperantarai terjadinya atherogenesis. Hal terbaru mengenai ilmu dasar telah melahirkan peran penting inflamasi dalam memediasi semua tahapan atherosklerosis dan mempercepat jalur respon seluler dan molekuler, yang dapat ditandai dengan jelas sebagai proses inflamasi menunjukkan banyak ekuivalen terhadap penyakit autoimun seperti SLE. 5

*The contemporary view of atherosclerosis has broadened to include an active and complex role for inflammation, orchestrated in part by mediators of the immune system, that is, atherosclerosis is seen as an active inflammatory and immune-mediated process in which systemic inflammatory and soluble immune mechanisms (circulating antibodies, immune complexes, complement activation products) play a role in accelerating vessel pathology. Thus, although many factors cause atherosclerosis, inflammation at the site of vascular injury mediates atherogenesis. Recent advances in basic science have established the fundamental role for inflammation in mediating all stages of atherosclerosis and in precipitating a cascade of cellular and molecular responses that can, at best, be characterized as an inflammatory process exhibiting many equivalents to autoimmune diseases such as SLE.5

Endothelial Dysfunction Disfungsi endotelial (ED) sebagai kunci terjadinya atherogenesis muncul jauh sebelum pembentukan struktural lesi atherosklerotik. ED umum terjadi pada semua tahapan inflamasi. Peningkatan kadar meditor inflamasi yang kronis dapat mendorong inflamasi yang kemudian berkontribusi merusak endotelial. ED kronik dan inflamasi vaskuler yang di induksi oleh faktor resiko konvensional dan inflamasi sistemik adalah mekanisme penting pada atherogenesis. Inflamasi kronik dan ED menjadi peran kunci di semua tahapan proses atherosklerotik. Dibawah

pengaruh faktor resiko CVD, termasuk inflamasi, endotelium menggambarkan adhesi molekul (intercellular adhesion molecule 1[ICAM-1], vascular cell adhesion molecule 1 [VCAM-1], selectins) yang diikuti monosit. Gambaran adhesi molekul ini diinduksi oleh mediator-mediator pro-inflamatory - tumour necrosis alpha (TNF-), interleukin 1 (IL-1), C-reactive protein (CRP) dan CD40/CD40 ligand interaction. Mediator-mediator tersebut diatas banyak sekali terdapat di penyakit-penyakit autoimun seperti RA dan efek yang merusak endotelium (Gbr. 3). 5

*Endothelial dysfunction (ED) is a key event in atherogenesis appearing long before the formation of a structural atherosclerotic lesion. ED is common in most inflammatory states. Chronically raised levels of inflammatory mediators may drive the inflammation that subsequently contributes to endothelial damage. Chronic ED and vascular inflammation induced both by conventional risk factors and systemic inflammation are important mechanisms in atherogenesis. Chronic inflammation and ED play key roles in all stages of the atherosclerotic process. Under the influence of CVD risk factors, including inflammation, the endothelium expresses adhesion molecules (intercellular adhesion molecule 1[ICAM-1], vascular cell adhesion molecule 1 [VCAM-1], selectins) that promote the adherence of monocytes. The expression of adhesion molecules is induced by pro-inflammatory mediators - tumour necrosis alpha (TNF-), interleukin 1 (IL-1), C-reactive protein (CRP) and CD40/CD40 ligand interaction. The aforementioned mediators are all abundant in autoimmune diseases such as RA and exert deleterious effects on the endothelium (Fig. 3).5

Figure 3. Inflammation may promote atherogenesis in several ways. TNF- = tumour necrosis factor, IL-1 = interleukin-1, IL-6 = interleukin-6, CRP = C-reactive protein.

Pada penyakit-penyakit autoimun, seperti Rheumatoid Arthritis (RA) dan SLE, telah terbukti terjadi disfungsi endotelial. Penelitian terkini telah membuktikan fungsi endotelial terganggu pada pasien-pasien RA bahakan pada stadium awal penyakit, pada pasien usia menengah tanpa faktor resiko CVS. Hasil yang sama juga dilaporkan pada SLE, menujukkan bahwa inflamasi pada hakekatnya dapat merusak fungsi vaskuler. ED pada SLE juga dibantu oleh dposis kompleks-imun, aktivasi komplemen lokal dan antibodi anti-endotelial. Antibodi anti-endotelial dapat ditemukan pada serum penderita SLE dan tampaknya berhubungan dengan aktivitas penyakit. Observasi ini memberi kesan bahwa inflamasi kronik dapat berakibat ED, selanjutnya atherosklerosis dan kejadian CVS pada penyakit autoimun seperti RA dan SLE. 6

*In systemic autoimmune diseases, like Rheumatoid Arthritis (RA) and SLE, endothelial dysfunction has been shown to occur. Recent studies have demonstrated impaired endothelial function in RA patients even at the early stage of the disease, in youngmiddle-aged patients without CVS risk factors. Similar results were also reported in SLE, indicating that inflammation per se may impair vascular function. ED in SLE is also aided by immune-complex deposition,

local complement activation and anti-endothelial antibodies. The anti-endothelial antibodies have been shown in the sera of SLE patients and seem to be related to disease activity. These observations suggest that chronic inflammation may lead to ED, subsequent atherosclerosis and CVS events in autoimmune diseases like RA and SLE.

C-Reactive Protein (CRP) Inflamasi sistemik dapat dianggap sebagai pemercepat proses atherosklerotik. Kadar sistemik mediator inflamasi seperti CRP telah dihubungkan dengan resiko CVS pada populasi umum. Studi klinis dan epidemiologi telah juga menunjukkan hubungan yang kuat dan konsisten antara marker inflamasi dan resiko kejadian CVS di masa mendatang. Yang paling dapat dipercaya diantara semua marker inflamasi dan lipid dalam memprediksi kejadian CVS adalah highsensitivity CRP (hsCRP). Studi epudemiologis menyimpulkan bahwa kadar CRP sebagai faktor resiko independen untuk infark miokard dan strike pada pria dengan atau tanpa faktor resiko.

*Systemic inflammation may be regarded as accelerating the atherosclerotic process. Systemic levels of inflammatory mediators such as CRP have been associated with CVS risk in the general population. Epidemiological and clinical studies have shown strong and consistent relationships between markers of inflammation and risk of future CVS events, the most reliable, surpassing all inflammatory and lipid markers in predicting CVS events, currently being, high-sensitivity CRP (hsCRP). Epidemiological studies have established that CRP level is an independent risk factor for myocardial infarction and stroke in men with and without risk factors.7

CRP sebagai protein fase akut yang umum dinilai pada penyakit-penyakit inflamasi autoimun, kini dianggap sebagai peserta aktif dan langsung atherogenesis, pada inisiasi dini lesi atherosklerotik dan pada konversi plak stabil dan tak stabil. Efek biologis dari CRP pada perkembangan atherosklerotik tampaknya melingkupi jaringan kompleks interaksi dengan pemain lain pada imunitas dan inflamasi, seperti sistem komplemen begitupun efek langsung CRP terhadap sel-sel yang terlibat pada pertumbuhan dan perkembangan lesi. Baru-baru ini penelitian menunjukkan bahwa CRP menguasai properti proatherogenic yang mengaktifkan sistem komplemen, menginduksi produksi endotelial dari monocyte chemotactic protein-1(MCP1) and secretion of endothelin-1 (ET1) and interleukin 6 (IL-6), upregulates adhesion molecules

(ICAM-1, VCAM-1, selectins), memperantarai uptake macrophage LDL dan menstimulasi produksi monosit faktor jaringan. High sensitivity CRP telah dianggap makin berperan tetap dalam mendeteksi inflamasi vaskuler dan resiko CVS. Studi epidemiologi prospektif telah menunjukkan bahwa peningkatan kadar CRP, memprediksi kejadian koroner pada individu sehat dan pasien dengan stable dan atau unstable angina. Predictive value CRP yang kuat mungkin menjelaskan stabilitas yang lama selama penyimpanan, umur hidup yang panjang, ketiadaaan variasi diurnal, dan ketiadaan ketergantungan pada usia dan jenis kelamin. Dengan adanya pengertian patogenesis atherosklerosis, semua bukti yang ada dan paralel dengan patobiologi yang timbul antara penyakit autoimun dan atherosklerosis maka kita akan mendapat pengertian yang lebih baik dan terkini dalam strategi terapeutik kedua hal ini.

*CRP, an acute phase protein commonly measured in inflammatory autoimmune diseases, is now known not to be an innocent bystander, but an active and direct participant in atherogenesis, both in the early initiation of atherosclerotic lesions and in the conversion of stable to unstable plaques. The biological effect of CRP on atherosclerosis development seems to encompass a complex network of interactions with other players in immunity and inflammation, such as the complement system as well as a direct effect of CRP on the cells involved in lesion growth and development. Recently, studies have shown that CRP possesses proatherogenic properties - it activates the complement system, induces endothelial production of monocyte chemotactic protein-1(MCP-1) and secretion of endothelin-1 (ET1) and interleukin 6 (IL-6), upregulates adhesion molecules (ICAM-1, VCAM-1, selectins), mediates macrophage uptake of LDL and stimulates monocyte production of tissue factor. High sensitivity CRP, a means of detecting and quantifying variations in CRP, has assumed an increasingly prominent role in the detection of vascular inflammation and CVS risk. Prospective epidemiological studies have shown that increased levels of CRP, predicts coronary events in healthy individuals and in patients with stable and or unstable angina. This strong predictive value of CRP may be explained by its longterm stability during storage, its long-life, its lack of diurnal variation, and its lack of age and sex dependency. Hand in hand with the advances in the understanding of the pathogenesis of atherosclerosis coupled with all the evidence that has come to surface and the parallels and shared pathobiology existing between the autoimmune diseases and atherosclerosis comes the better understanding and advances in the therapeutic strategies in managing the two entities.7

DETECTION OF EARLY ATHEROSCLEROSIS

Dewasa dengan SLE, penyakit autoimun yang terutama menyerang wanita, memiliki resiko atherosklerosis dini yang lebih besar yang tidak dapat dijelaskan dengan faktor resiko kardiovaskuler Framingham saja. Peningkatan beban kardiovaskuler pada SLE telah dianggap paling tidak sebagian tanda inflamasi kronik dan faktor spesifik SLE seperti aktifitas penyakit, penggunaan kortikosteroid dan imunosuppresan juga antibodi anti-phospholipid. Kira-kira 20% pasien SLE di diagnosis diusia kanak-kanak atau dewasa muda. Pemeriksaan pada atherosklerosis dini pediatrik (pSLE) adalah area penting penelitian, karena pasien ini cenderung memiliki faktor resiko tradisional minimal untuk atherosklerosis, termasuk abnormalitas lipid, dibandingkan yang dewasa dan juga endotelium bebas atherosklerotik pada saaat penegakkan diagnosis SLE. Oleh karena itu, dengan berkembangnya atherosklerosis dini dapat diselidiki pada pasien pSLE dengan faktor pendukung yang lebih sedikit.

*Adults with Systemic Lupus Erythematosus (SLE), an autoimmune disease that primarily affects women, are at increased risk of premature atherosclerosis that cannot be explained by traditional Framingham cardiovascular risk factors for atherosclerosis alone. It has been suggested that the increased burden of cardiovascular disease in SLE can be at least partially attributed to chronic inflammation and SLE-specific factors such as disease activity, corticosteroid and immunosuppressant use and antiphospholipid antibodies.8 Approximately twenty percent of patients with SLE have their diagnosis during childhood or adolescence. Examination of early atherosclerosis in pediatric SLE (pSLE) is an important area of study, as these patients tend to have less traditional risk factors for atherosclerosis, including lipid abnormalities, than their adult counterparts and so should have a relatively atherosclerotic free endothelium at the time of diagnosis of SLE.9 Therefore, the influence of SLE specific factors, including chronic inflammation, on the development of premature atherosclerosis can be investigated in pSLE patients with fewer confounding factors.

Identifikasi atherosklerosis subklinis sebelum kejadian kardiovaskuler atau serebrovaskuler dibutuhkan agar klinisi bisa memberiakan terapi preventif. Penelitian penelitian pada pasien dengan aSLE telah menunjukkan abnormalitas flow-mediated dilatation (FMD), carotid intima media thickness (CIMT) dan pulse-wave velocity (PWV) berhubungan dengan beban atherosklerotik dan pengukuran vaskuler dapat dilakukan serial mengikuti perubahan ukur. Hingga saat ini masih belum ada studi pada pSLE secara longitudinal memeriksa dan menghubungkan ukuran vaskuler multipel dengan faktor resiko tradisional dan non-tradisional mutipel pada atherosklerosis.

The identification of subclinical atherosclerosis prior to cardiovascular or cerebrovascular events is needed to allow the clinician to institute preventive therapy. Studies in patients with adult SLE have shown that abnormalities of flow-mediated dilatation (FMD), carotid intima media thickness (CIMT) and pulse-wave velocity (PWV) correlate with atherosclerotic burden and vascular measurements can be serially followed to measure change. To date there has not been any study in pSLE longitudinally examining and correlating multiple vascular measures with multiple traditional and non-traditional risk factors for atherosclerosis.10

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5. Anna Abou-Raya, Suzan Abou-Raya. Inflammation: A pivotal link between autoimmune diseases and atherosclerosis. J. Autrev. 2005.12.006 6. Bacon PA. Endothelial cell dysfunction in systemic vasculitis: New developments and therapeutic prospects. Curr Opin Rheumatol 2005;17:4955. 7. Antoni P, Edward TH, Lawrence C. A proatherogenic role for C- reactive protein in vivo. Curr Opin Lipidol 2005;16(5):5127. 8. Gasparyan AY, Stavropoulos-Kalinoglou A, Mikhailidis DP, Toms TE, Douglas KMJ, Kitas GD. The rationale for comparative studies of accelerated atherosclerosis in rheumatic diseases. Curr Vasc Pharmacol. 2010 Jul;8(4):437-449. 9. Boros CA, Bradley TJ, Cheung MH, Bargman JM, Russell JL, McCrindle BW, et al. Assessment of the Risk Factors for Atherosclerosis in Pediatric Systemic Lupus Erythematosus. Clin Exp Rheumatol. 2010;in press. 10. Lorenz MW, Markus HS, Bots ML, Rosvall M, Sitzer M. Prediction of clinical cardiovascular events with carotid intima-media thickness: a systematic review and meta-analysis. Circulation. 2007;115(4):459-67.