Lupus (2007) XX, 1–4 http://lup.sagepub.com
PAPER
Peripheral vascular disease in systemic lupus erythematosus SP Bhatt1, R Handa1*, GS Gulati2, S Sharma2, RM Pandey3, P Aggarwal1, L Ramakrishnan4 and S Shankar1 1Department
of Medicine, 2Department of Cardiac Radiology, 3Department of Biostatistics and 4Department of Cardiac Biochemistry, All India Institute of Medical Sciences, New Delhi, India
With increasing longevity of lupus patients, peripheral vascular disease (PVD) has become an important cause of morbidity. With no systematic study of PVD in systemic lupus erythematosus (SLE), this study was undertaken to define the frequency and spectrum of PVD in SLE and factors affecting such an occurrence. All medium-sized peripheral arteries of bilateral upper and lower extremities were studied in 50 SLE patients using Doppler ultrasonography. PVD was defined clinically as one or more of intermittent claudication, absent/unequal pulses, gangrene or ischemic ulcers and sub-clinically as asymptomatic patients with Doppler abnormalities, with ⱖ50% reduction in diameter considered hemodynamically significant. Mean (SD) age of the patients was 31.6 (10.1) years. Forty-one percent were hypertensive. Dyslipidemia was found in 62%. Fifteen (30%) had Raynaud’s phenomenon. Fourteen (28%) patients had PVD, of whom three had positive markers for anti-phospholipid antibody (APLA) and six were asymptomatic. Ischemic ulcers were seen in eight (16%), gangrene in three (6%), femoral artery plaques in two (4%), stenosis in four (8%) and intermittent claudication in none. Dyslipidemia was found to independently affect occurrence of PVD (Odds Ratio ⫽ 5.37, 95% Confidence Interval 1.05–27.5, P ⫽ 0.05). The causes of PVD overlap significantly and further studies are needed to ascertain the relative contribution of each. Lupus (2007) 00, 1–4. Key words: atherosclerosis; Doppler; lupus; peripheral; vascular
Introduction A wide array of vascular manifestations has been associated with systemic lupus erythematosus (SLE), including vasculitis, vasospasm and thromboembolism.1,2 Increasing attention has been drawn to late complications of lupus like atherosclerotic vascular disease. About 6–10% of lupus patients have clinically recognized premature atherosclerosis.3 When screening studies are performed, the prevalence appears to be even greater, approaching 40%. Women with lupus have a high frequency of coronary artery disease and those in the 35–44 year age group have a 50-fold higher rate of ischemic heart disease than women without SLE.3 Adding to the atherosclerotic burden is the fact that Asian Indians as an ethnic group have a higher incidence of insulin resistance and the resulting metabolic syndrome.4 Though there is a significant amount
*Correspondence: Dr Rohini Handa, Department of Medicine, All India Institute of Medical Sciences, New Delhi, India. E-mail:
[email protected] Received 3 October 2006; accepted 9 May 2006 © 2007 SAGE Publications
of literature on coronary artery and cerebrovascular complications, data on another important component, peripheral vascular disease (PVD) in these patients, is scarce. We undertook a prospective study to find the frequency and spectrum of PVD (clinical and subclinical) in patients with SLE and to study the factors influencing such an occurrence.
Material and methods This was a cross sectional, observational study of 50 consecutive cases of SLE attending the rheumatology clinic of a tertiary care hospital catering to a large population spread across north India. Cases were defined by the 1997 American College of Rheumatology (ACR) criteria for SLE5 and formed part of an earlier study reported by us.6 Exclusion criteria included essential hypertension (blood pressure ⬎140/90 mm Hg, diabetes mellitus, lupus overlap with other connective tissue diseases such as scleroderma, rheumatoid arthritis, and polymyositis and childhood lupus (age ⬍16 years). Hypertension and diabetes with disease onset prior to diagnosis of lupus were excluded as these conditions are 10.1177/0961203307081123
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well known to be associated with PVD. Patients developing hypertension or diabetes during the course of lupus were included in the study. Informed consent was taken from study participants and the project was approved by the department ethics committee. The disease activity and disease damage were assessed at the time of study using Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)7 and Systemic Lupus International Collaborating Clinics/American College Of Rheumatology (SLICC/ACR) scores,8 respectively. Dyslipidemia was defined using the borderline high value of the National Cholesterol Education Programme-Adult Treatment Panel III Guidelines.9 Anti-cardiolipin antibodies (aCL) and lupus anticoagulant were estimated in those patients clinically suspected to have vascular disease or with positive Doppler findings. Doppler evaluation was done of all medium sized peripheral arteries in all patients using a Hewlett Packard Sonos 4500 (Andover, CA, USA) ultrasound machine with a 3–11 MHz linear array probe. This included bilateral subclavian, axillary, brachial, radial, ulnar, common and superficial femoral, popliteal, anterior and posterior tibial and the dorsalis pedis arteries. PVD was defined clinically as one or more of intermittent claudication, absent/unequal pulses, gangrene, ischemic leg ulcers and carotid bruit and subclinically as Doppler abnormalities without the above mentioned clinical features, with ⬎50% reduction in diameter being taken as hemodynamically significant. Doppler data were recorded in terms of appearance of vessel wall, intimomedial thickness (IMT) of the femoral arteries, presence of plaque, tenosis, peak systolic and diastolic velocities and spectral waveform. A stenosis of 50–99% was indicated by a monophasic waveform with loss of reverse flow component and forward flow throughout the cardiac cycle, extensive spectral broadening, peak systolic velocity increase of ⱖ100% relative to adjacent proximal segment and monophasic distal waveform with reduced systolic velocity. Total stenosis or occlusion was indicated by no flow detected within imaged arterial segment; preocclusive ‘thump’ heard just proximal to site of occlusion, monophasic distal waveforms with reduced systolic velocities.10 Lesser degrees of stenosis were defined by spectral broadening. IMT was measured as the distance from the leading edge of the lumen–intima interface to the leading edge of the media-adventitia junction. Plaque was defined as a focal protrusion of ⱖ50% of the surrounding intimo-media. Descriptive analysis was done for common variables affecting occurrence of PVD. Independent t-test was used to compare continuous variables and chisquare and Fisher’s exact test for categorical variables. Bivariate and multivariate logistic regression analyses were performed to find significant predictors of PVD Lupus
and odds ratios with 95% confidence intervals were computed. All data were analysed using SPSS (Chicago, IL) version 11.5. A P-value ⱕ0.05 was considered significant in all analyses.
Results Our cohort included 47 females and three males with lupus. Ten patients with overlap syndrome were excluded from the study. The mean (⫾SD) age was 31.6 ⫾ 10.1 years (median 30.5, range 16–55) and the mean (⫾SD) body mass index was 22.4 ⫾ 5.4. None of the patients reported history of smoking. Hypertension was observed in 22 (44%) patients while dyslipidemia was seen in 31 (62%) patients. The mean (⫾SD) low density cholesterol, high density cholesterol and triglyceride levels were 112.7 ⫾ 38.9, 42.7 ⫾ 5.6, and 153.8 ⫾ 80.1 mg/dl, respectively. None of the patients was on lipid lowering therapy. Hypothyroidism was seen in four patients while two patients developed diabetes during the course of lupus. The median disease duration was 46 months (range 6–168). Nineteen (38%) patients had a disease duration of ⱕ3 years and only 13 (26%) had a disease duration of ⬎5 years. Seventy-four percent of the patients were on oral corticosteroids at the time of study with a mean daily prednisolone dose of 6.25 mg in the month preceding the study (range 0–60 mg/day). Only one patient had never been on steroids. The median duration of steroid use in the patients was 36 months (range 0–158 months). Eight (17%) females were postmenopausal. Only one patient reported a history of oral contraceptive use while three reported pregnancy losses. The mean (⫾SD) SLICC score was 0.5 ⫾ 0.8. Musculoskeletal, mucocutaneous, haematological, neurological and cardiorespiratory involvement was seen in 100, 96, 52, 22 and 16% of patients respectively. Forty-eight percent had evidence of lupus nephritis. Four (8%) reported history of having had deep vein thrombosis, three of cerebrovascular events. The mean (⫾SD) erythrocyte sedimentation rate was 38.5 ⫾ 21.5 and the SLEDAI score 8.4 ⫾ 4.6. On the basis of clinical and Doppler criteria, 14 patients had evidence of PVD (Table 1). Fifteen patients had Raynaud’s phenomenon, and 8(16%) had ischemic ulcers, of whom three developed gangrene. Five of these patients were proven by biopsy to have vasculitis and all patients responded to immunosuppressive therapy. Four patients were found to have stenosed peripheral arteries. Two had complete occlusion of the anterior and posterior tibial arteries and two had stenosis of the subclavian artery. Provocative positioning and exercises were done to rule out thoracic outlet obstruction in the latter two patients. Spectral
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Table 1 Spectrum of peripheral vascular disease (PVD) n ⫽ (50) Intermittent claudication Absent/unequal distal pulses Ischemic ulcers Gangrene Carotid bruit Stenosis Spectral broadening Femoral plaque
0 3 (6%) 8 (16%) 3 (6%) 0 4 (8%) 27 (54%) 2 (4%)
broadening was seen in 27 cases. Lupus patients exhibited greater carotid IMT thickness than controls and carotid plaques were seen in seven (14%) cases. These have been reported by us previously.6 Two patients with ischemic ulcers and one with stenosis had significantly elevated titers of aCL. The factors affecting occurrence of PVD are summarized in Table 2. On multivariate analysis, dyslipidemia was the only factor found to significantly affect the occurrence of PVD.
Discussion Several studies have drawn attention to atherosclerotic vascular disease, notably carotid atherosclerosis, coronary artery disease and cerebrovascular events in SLE.11–21 One area of vascular morbidity that has received scant attention in the past is PVD. To our knowledge this is the first observational study of clinical and subclinical PVD in lupus. As many as 28% of our patients, despite being young and with a relatively short disease duration, exhibited features of PVD. It is pertinent to note that 62% lupus patients
were dyslipidemic using the borderline high criteria of ATP III. Of the 50 controls matched for age and gender, which formed part of an earlier study reported by us, 44% were found to be dyslipidemic.6 On multivariate analysis, dyslipidemia was the only factor independently predicting the occurrence of PVD. The contribution of disease duration and hypertension was not found to be statistically significant in our study. This might be because of the small sample size or short disease duration. McDonald et al. have demonstrated that occurrence of PVD is affected by longer disease duration and greater duration of steroid use.22 We could not assess the influence of corticosteroid therapy in our patients because of nonavailability of reliable long term treatment data from patient records. Also, all the patients in the study cohort were on hydroxychloroquine, a drug which has hypolipidemic effects. Various modalities have been employed to detect vascular disease in lupus. Theodoridou et al. reported abnormal ankle-brachial index in 37% patients which correlated with age but not with disease duration, cumulative steroid dosage, ECLAM score or any other Q1 traditional risk factors for atherosclerosis.23 Lin CC et al. using xenon133 muscle washout showed that muscle perfusion in the lower extremities of SLE patients without symptoms or signs of PVD is significantly decreased and is related to abnormal myocardial perfusion.24 Thallium-201 muscle perfusion scans have shown reduced perfusion reserve in distal muscles in asymptomatic lupus patients.25 We used Doppler ultrasonography since it can detect upper limb disease in addition to that of lower limbs and has the advantage of delineating structural lesions. Vascular disease in lupus patients can be due to vasculitis, thromboembolism, vasospasm and premature
Table 2 Predictors of peripheral vascular disease (PVD) Variable
PVD (n ⫽ 14)
No PVD (n ⫽ 36)
Unadjusted odds ratio (95% CI)
Age (years) Sex Male Female BMI (kg/m2) SLICC SLEDAI Disease duration (months) SBP (mm Hg) DBP (mmHg) Hypertension ESR (mm) Creatinine (mg/dL) Postmenopausal Nephritis Dyslipidemia*
30.7 ⫾ 8.7 1 13 21.8 ⫾ 5.9 0.7 ⫾ 0.6 9.6 ⫾ 4.6 49.4 ⫾ 24.9 131.6 ⫾ 20.2 85.4 ⫾ 13.7 7 46.1 ⫾ 24.9 1.3 ⫾ 1.1 1 7 12
31.9 ⫾ 10.6 2 34 22.7 ⫾ 5.3 0.5 ⫾ 0.9 7.9 ⫾ 4.6 53.5 ⫾ 40.7 129.7 ⫾ 14.8 83.1 ⫾ 9.4 15 35.5 ⫾ 19.6 0.9 ⫾ 0.4 7 17 19
0.99 (0.93–1.05) 0.77 (0.06–9.17) 0.97 (0.86–1.09) 1.38 (0.68–2.81) 1.09 (0.95–1.24) 0.99 (0.98–1.02) 1.00 (0.97–1.05) 1.02 (0.96–1.08) 1.4 (0.41–4.84) 1.02 (0.99–1.05) 1.85 (0.69–4.95) 0.32 (0.04–2.87) 1.12 (0.33–3.84) 5.37 (1.05-27.5)
*P ⱕ 0.05 All values expressed as Mean ⫾ SD. PVD, peripheral vascular disease; CI, confidence intervals; BMI, body mass index; SLICC, systemic lupus international collaborating clinics; SLEDAI, systemic lupus erythematosus disease activity index; SBP, systolic blood pressure; DBP, diastolic blood pressure; ESR, erythrocyte sedimentation rate. Lupus
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atherosclerosis. Although, the relative contribution of each component is difficult to assess in view of overlapping pathophysiology, the documentation of femoral plaques and increased carotid IMT supports the view that premature atherosclerosis is likely to be the major contributor to PVD in our patients. One limitation of our study is that we measured aCL titers only in those patients who had symptoms or signs of vascular disease and hence could not include this factor in our analysis. Previous studies have shown that although serial measurements of aCL antibodies can help predict the occurrence of vascular events, it is probably not a cost effective measure.26 Apart from disease-related variables, ethnicity could be playing a role as Asian Indians are known to be a metabolically disadvantaged group with high incidence of insulin resistance and the resulting metabolic syndrome, leading to higher levels of triglycerides and small dense LDL, lower levels of HDL-cholesterol, procoagulant tendency, increased proinflammatory cytokines and endothelial dysfunction.4 Studies specifically addressing the issue of insulin resistance in Indian lupus patients are not available. To conclude, PVD is a common problem in patients with systemic lupus and dyslipidemia is an important risk factor. The causes of PVD overlap significantly and further studies are needed to ascertain the relative contribution of each.
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9 Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults, Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). J Am Med Assoc 2001; 285: 2486–2497. 10 Jager KA, Rciketts HJ, Strandness DE Jr. Duplex scanning for the evaluation of lower limb arterial disease. In Bernstein EF ed. Noninvasive Diagnostic Techniques in Vascular Disease, St.Louis: Mosby, 1985: 619–631. 11 Urowitz MB, Gladman DD. Accelerated atheroma in lupus–background. Lupus. 2000; 9: 161–165. 12 Manzi S, Selzer F, Sutton-Tyrrell K et al. Prevalence and risk factors of carotid plaque in women with systemic lupus erythematosus. Arthritis Rheum 1999; 42: 51–60. 13 Rahman P, Aguero S, Gladman DD, Hallett D, Urowitz MB. Vascular events in hypertensive patients with systemic lupus erythematosus. Lupus 2000; 9: 672–675. 14 Toloza SM, Uribe AG, McGwin G Jr et al. LUMINA Study Group. Systemic lupus erythematosus in a multiethnic US cohort (LUMINA). XXIII. Baseline predictors of vascular events. Arthritis Rheum 2004; 50(12): 3947–3957. 15 Svenungsson E, Jensen-Urstad K, Heimburger M et al. Risk factors for cardiovascular disease in systemic lupus erythematosus. Circulation 2001; 104: 1887–1893. 16 Doria A, Shoenfeld Y, Wu R et al. Risk factors for subclinical atherosclerosis in a prospective cohort of patients with systemic lupus erythematosus. Ann Rheum Dis 2003; 62:1071–1077. 17 Vlachoyiannopoulos PG, Kanellopoulos PG, Ioannidis JP, Tektonidou MG, Mastorakou I, Moutsopoulos HM. Atherosclerosis in premenopausal women with antiphospholipid syndrome and systemic lupus erythematosus: a controlled study. Rheumatology (Oxford) 2003; 42: 645–651. 18 Bruce IN, Urowitz MB, Gladman DD, Ibanez D, Steiner G. Risk factors for coronary heart disease in women with systemic lupus erythematosus: the Toronto Risk Factor Study. Arthritis Rheum 2003; 48: 3159–3167. 19 Roman MJ, Beth-Ann Shanker, Davis A et al. Prevalence and correlates of accelerated atherosclerosis in systemic lupus erythematosus. NEJM 2003; 349: 2399–2406. 20 Wolak T, Todosoui E, Szendro G et al. Duplex study of the carotid and femoral arteries of patients with systemic lupus erythematosus: a controlled study. J Rheumatol 2004; 31: 909–914. 21 Bessant R, Hingorani A, Patel L, MacGregor A, Isenberg DA, Rahman A. Risk of coronary heart disease and stroke in a large British cohort of patients with systemic lupus erythematosus. Rheumatology (Oxford) 2004; 43(7): 924–929. 22 McDonald J, Stewart J, Urowitz MB, Gladman DD. Peripheral vascular disease in patients with systemic lupus erythematosus. Ann Rheum Dis 1992; 51(1): 56–60. 23 Theodoridou A, Bento L, D’Cruz DP, Khamashta MA, Hughes GR. Prevalence and associations of an abnormal ankle-brachial index in systemic lupus erythematosus: a pilot study. Ann Rheum Dis 2003; 62: 1199–1203. 24 Lin CC, Ding HJ, Chen YW, Wang JJ, Ho ST, Kao A. High prevalence of asymptomatically poor muscle perfusion of lower extremities measured in systemic lupus erythematosus patients with abnormal myocardial perfusion. Rheumatol 2004; 24(4): 227–229. 25 Hsu HB, Sun SS, Chen JJ, Tsai JJ, Kao CH, ChangLai SP. Usefulness of thallium-201 muscle scan to investigate perfusion reserve in the lower limbs of patients with systemic lupus erythematusus. Int 2004; 24(5): 291–293. 26 Wang CR, Chou CC, Hsieh KH, Chuang CY, Chen CY. Lupus patients with peripheral vascular thrombosis: the significance of measuring anticardiolipin antibody. J Emerg Med 1993; 11(5): 468–470.
Author Query Q1
Please provide the expansion for ECLAM in the text.
