International Journal of Rheumatic Diseases 2013; 16: 319–324
ORIGINAL ARTICLE
Peripheral arterial disease in patients with systemic lupus erythematosus: a prospective controlled study Ayman A. HASSAN,1 Hisham M. HABIB2 and Ashraf A. EISSA3 1 Vascular Surgery Department, Ain Shams University, Cairo, 2Rheumatology and Rehabilitation Department, Mansoura University, Mansoura, and 3Radiology Department, Bani Sweef University, Beni Sweef, Egypt
Abstract Aim: The aim of our study was to: (i) map out the presence of peripheral vascular disease in a sample of systemic lupus erythematosus (SLE) patients; and (ii) correlate our findings with disease characteristics, activity indices, traditional risk factors of atherosclerosis and thrombotic variables. Methods: The study population comprised 120 SLE patients and 100 controls. Clinical data were collected for patients and controls with stress on clinical issues of SLE patients, including British Isles Lupus Assessment Group index score, anti-double stranded DNA titer C3 and C4 levels, and treatment taken, mainly steroids. Measurements of thrombotic variables were performed. Non-invasive arterial assessment was performed, including carotid duplex scanning and measurement of carotid artery intima-media thickness (IMT) and peripheral arterial assessment and measurement of ankle–brachial pressure index (ABPI). Results: The mean age of SLE patients was 32 years and mean disease duration was 8 years. There were no statistically significant differences in the traditional vascular risk factors measured between SLE patients and controls. There were significantly higher plasma levels of thrombotic variables in SLE patients. The average IMT was statistically significantly greater in SLE patients compared to controls. Thirty SLE patients (25%) had an ABPI < 1.0 compared with six controls (6%), which was statistically significant. Conclusion: This study showed an increased prevalence of peripheral arterial disease in SLE patients as shown by the higher carotid artery IMT and lower ABPI in such patients compared with controls. Multiple risk factors are likely to be involved in such findings. Key words: peripheral arterial disease, systemic lupus erythematosus.
INTRODUCTION Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that can affect any part of the body. As occurs in other autoimmune diseases, the immune system attacks the body’s cells and tissue, resulting in inflammation and tissue damage.1 Arterial vascular disease in SLE has a number of pathogenic mechanisms, including arteritis, intravascular
coagulation frequently associated with a lupus anticoagulant, and in chronic lupus atherosclerosis.2 SLE is associated with accelerated atherosclerosis3,4 which is recognized as a major cause of death and morbidity in such patients.3,5 Coronary artery atherosclerosis in patients with SLE has been widely reported,3,6,7 although peripheral arterial disease (PAD) has been infrequently described.
AIM Correspondence: Asst Prof Hisham M. Habib, Rheumatology Department, Al Ahsa Hospital, PO Box 3230, Al Ahsa 31982, Saudia Arabia. Email: [email protected]
The aim of our study was to: (i) to map out the presence of PAD in a sample of SLE patients; and (ii) correlate our findings with disease characteristics, activity
© 2013 The Authors International Journal of Rheumatic Diseases © 2013 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
A. A. Hassan et al.
indices, traditional risk factors of atherosclerosis and thrombotic variables.
METHODS The protocol for the research project was approved by a suitably constituted ethics committee of the Al Ahsa Hospital, Saudia Arabia, and it conformed to the provisions of the World Medical Association’s Declaration of Helsinki. An informed consent has been obtained for all investigations on subjects of the study (and patient anonymity was preserved).
Study and control populations The study population comprised 120 consecutive patients (110 women, 10 men) diagnosed with SLE collected from the rheumatology clinics of four central hospitals in the Hofuf District. SLE was diagnosed by a consultant rheumatologist using the American Rheumatism Association criteria for classification of SLE.8 The control populations consisted of 100 volunteered persons (90 women, 10 men) of the same age range as patients (0–5 years range difference). They had no history of inflammatory arthritis or cardiovascular diseases.
Collection of data and measurements The following data were recorded from SLE patients only: ● disease duration (all patients had a disease duration of at least 5 years at inclusion into the study), steroid treatment (current or past) and current non-steroidal anti-inflammatory as well as immunosuppressive medications for SLE control. Overall clinical assessment and disease activity index of SLE patients was performed using the BILAG (British Isles Lupus Assessment Group) disease activity index;9 ● measurements of anti-double stranded DNA (antidsDNA) titer (IU), erythrocyte sedimentation rate (ESR) (mm/h), and complement 3 (C3) and C4 (mg/dL) levels. The following data were recorded from all subjects (SLE patients and controls): ● a questionnaire recording demographic data, medical history, family history for vascular disease, amount of exercise per week and smoking history (current, past, never smoked); ● measurements of blood pressure, weight and height to derive body mass index (BMI: weight/height2),
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and overnight fasting blood glucose and serum lipids (total cholesterol, high-density lipoprotein [HDL], low-density lipoprotein [LDL] and triglycerides [TG]); and ● measurements of thrombotic variables, including plasma fibrinogen, von-Willebrand factor antigen (vWF), tissue plasminogen activator antigen (tPA) and fibrin D-dimer.
Non-invasive arterial assessment Carotid duplex scanning and measurement of carotid artery intima-media thickness (IMT) were performed. All subjects underwent carotid duplex scanning and measurements were made by an experienced radiology consultant whose duplex results have been previously validated. High-resolution B-mode carotid ultrasonography was performed with HDI 5000 ATL machine (Phillips Medical Systems). A 7.5 MHz array transducer was used. The subject lay supine with the neck extended and the chin turned contralateral to the side being examined. Scanning involved examination of the carotid arteries in transverse and longitudinal planes. Measurement of the common carotid artery intima-media thickness (IMT) was made 1 cm proximal to the carotid bifuraction in the posterior wall. If an area of significantly increased IMT was observed the maximum thickness at that site was also recorded. Measurements were made over both right and left carotid arteries and average IMT (mean of two sides) were recorded. Carotid artery stenoses were recorded, according to the severity of stenosis; normal, minimal disease (< 20% stenosis), moderate (20–49%), severe (50– 74%) and critical stenosis ( 75%). Peripheral arterial assessment and measurement of ankle–brachial pressure index (ABPI) was also performed. All study subjects were assessed at a vascular clinic. ABPI was measured by the vascular consultant and measurements were made for both lower limbs. The subject rested for approximately 10 min. Right brachial systolic pressure was recorded using a sphygmomanometer. Ankle pressure was recorded using a Doppler ultrasound velocity detector (Imex pocket Doppler 8 MHz; Imex, Golden, CO, USA). A suitably sized sphygmomanometer cuff was placed around the ankle, 3 cm proximal to the malleolus. The cuff was inflated at a rate of 2 mmHg/s. Ankle pressures were recorded with the appearance of blood velocity signals at the anterior and posterior tibial arteries at the ankle. Finally, ABPI was
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Peripheral arterial disease in SLE
measured for both lower limbs and the average ABPI (mean of the two sides) was recorded.
Table 2 Data of SLE patients
Statistical analysis
Duration of the disease: mean (range) years Mean BILAG (SD) ESR mean (SD) mm/h Antids-DNA titer (SD) IU (positive > 1) C3 mean level (SD) mg/dL (normal 50–120 mg/dL) C4 mean level (SD) mg/dL (normal 20–50 mg/dL)
Analysis was performed according to the intention-totreat principle. Comparison of the studied groups was done using sStudents t-test. The Chi-squared test was used to compare categorical variables. A probability value (P-value) < 0.05 was considered significant. Data were collected and tabulated using Microsoft Excel version 7 (Microsoft Cooperation, New York, NY, USA) and analyzed using SPSS for windows v.11 (SPSS, Inc, Chicago, IL, USA).
RESULTS Demographic data for both groups (Table 1) were nearly similar with no statistically significant differences. Data of SLE patients is listed in Table 2. The mean age of SLE patients was 32 years and mean disease duration was 8 (5–15) years. At time of the study, 79 patients (65.8%) were currently on long-term steroid use (6 months), 22 patients (18.3%) had histories of previous long-term steroid therapy and 99 patients (82.5%) were on immunosuppressive medications, including azathioprin, hydroxycholoroquine, myclofenolate mofetil and cyclophosphamide. Traditional arterial risk factors are listed in Table 3. There were no statistically significant differences in the traditional arterial risk factors measured between SLE patients and controls. Although systolic and diastolic blood pressures were higher in SLE patients, when compared with controls (mean 134 and 84 mmHg vs. 128 and 80 mmHg, respectively), none of these results were statistically significant (P = 0.24 and 0.38, respectively). Table 1 Demographic data of SLE patients and controls
Number of subjects Sex (male/female) Mean age (range) (years) Male mean age (years) Female mean age (years) Body mass index mean (SD) (kg/m²)
Patients
Controls
P-value
120 10/110 32 (19–50)
100 10/90 30 (18–51)
NS NS
31 (20–48)
29 (20–44)
NS
33 (19–50)
34 (18–51)
NS
26.8 (3.6)
27.2 (3.8)
NS
SD, standard deviation; NS, not significant.
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Variable
Data 8 (5–15) 9 (2.38) 49 (7.2) 2.5 (0.3–3) 55 (11.2) 22 (4.7)
ESR, erythrocyte sedimentation rate; SD, standard deviation; BILAG, British Isles Lupus Assessment Group; C3, complement 3; C4, complement 4.
Ten patients (8.3%) and six controls (6%) had a past history of hypertension and were receiving anti-hypertensive drugs. Seventeen patient (14.1%) and 12 controls (12%) had a systolic blood pressure 160 mmHg at time of the study; none of these results were statistically significant (P = 0.73 and 0.8, respectively). Ten SLE patients (8.3%) and six controls (6%) had diabetes mellitus which was not statistically significant (P = 0.86). Total lipid profiles were nearly similar in SLE patients and controls. The number of SLE patients with total cholesterol > 200 mg/dL were 28 patients (23%) and 25 controls (25%) which was not significant (P = 0.86). Other variables, including positive family history of vascular diseases, exercise at least once/week, current and ex-smokers and BMI were nearly similar in patients and controls with no significant differences. Thrombotic variables are listed in Table 4. There were significantly higher plasma levels of thrombotic variables, including fibrinogen, vWF, tPA, and fibrin D-dimer in SLE patients compared with controls. Non-invasive arterial assessment results are listed in Table 5.
Carotid duplex study and measurement of IMT results The average IMT ([right + left]/2) was statistically significantly greater in the SLE group (mean 0.79 [0.27 SD] mm vs. 0.63 [0.14] mm) in the control group (P = 0.001). Within the SLE group, there were no differences in the measured IMT between sexes and there was a positive correlation between IMT and disease duration and disease activity indexes, including high BILAG score, high ESR, lowered C3 and C4 levels (all
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Table 3 Traditional arterial risk factors in SLE patients and controls Variables
Patients
Positive family history of arterial disease Exercise (at least once/week) Smokers Current smokers Ex-smokers Body mass index mean (SD) (kg/m²) Systolic blood pressure mean (SD) mmHg Diastolic blood pressure mean (SD) mmHg Prevelance of diabetes mellitus Fasting blood glucose mean (SD) mg/dL Serum total cholesterol mean (SD) mg/dL Number of subjects with serum cholesterol > 200mg/dL Serum HDL cholesterol mean (SD) (mg/dL) Serum LDL cholesterol mean (SD) (mg/dL) Serum triglycerides mean (SD) (mg/dL)
12/120 (12%) 18/120 (15%) 22/120 (18%) 10/120 (8%) 26.8 (3.6) 134 (21.1) 84 (13.5) 10/120 (8%) 104 (19.6) 191 (39.5) 28/120 (23%) 50 1(3.2) 129 (29.6) 141 (42.5)
Controls
P-value
10/100 (10%) 18/100 (18%)
0.73 (NS) 0.59 (NS)
20/100 (20%) 12/100 (12%) 27.2 (3.8) 128 (19.5) 80 (12.1) 6/100 (6%) 101 (18.3) 186 (38.1) 25/100 (25%) 52.5 (13.8) 126 (28.8) 138 (41.9)
0.8 (NS) 0.73 (NS) 0.86 (NS) 0.24 (NS) 0.38 (NS) 0.86 (NS) 0.92 (NS) 0.89 (NS) 0.86 (NS) 0.56 (NS) 0.76 (NS) 0.82 (NS)
NS, not significant; SD, standard deviation.
Table 4 Thrombotic variables in SLE patients and controls Thrombotic variables Fibrinogen mean (SD) g/L vWF mean (SD) IU/L tPA mean (SD) Fibrin D-dimer mean (SD) ng/mL
Patients
Controls
P-value
3.9 (1.1) 146 (23.5) 6.6 (2.8) 74.4 (11.5)
2.9 (0.7) 98 (19.6) 5.1 (1.9) 63.6 (9.3)
0.001 (S) 0.001 (S) 0.006 (S) 0.028 (S)
S, significant; vWF, von Willebrand factor; tPA, tissue plasminogen activator; SD standard deviation.
P < 0.05). Moreover, IMT correlated positively within the SLE group with long steroid usage (P = 0.04). In both groups, IMT correlated positively with age, total cholesterol and greater thrombotic variables (for SLE, P = 0.001, P = 0.04, P = 0.01) and for controls (P = 0.01, P = 0.04, P = 0.03), respectively. In addition IMT correlated positively with lower ABPI in the SLE group but not in the control group (P = 0.02). Carotid plaques were present in 15 patients (12.5%) and eight controls (8%), which was not statistically significant. Furthermore, moderate internal carotid artery stenosis was found in four patients (3.3%) and one control (1%). None of patients or controls had severe stenosis and neither of these results were statistically significant.
Ankle brachial pressure index (ABPI) results Thirty SLE patients (25%) had an ABPI < 1.0 compared with six controls (6%), which was statistically significant (P = 0.001). Of these subjects with lower ABPI, 18 patients (15%) and three controls (3%) had ABPI 0.9 which was also statistically significant (P = 0.007). Within SLE patients, there were a positive significant correlations between lowered ABPI and dis-
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ease duration, and high BILAG score, high ESR and lowered C3 and C4 levels (all P < 0.05). Moreover, lowered ABPI correlated positively with presence of long steroid usage and higher thrombotic variables (P = 0.04 and P = 0.02, respectively).
DISCUSSION Patients with SLE may develop premature atherosclerosis, notably coronary artery disease.7,10 With increasing longevity of SLE patients, PAD has become an important cause of morbidity.11 The aim of this study was to map out the presence of PAD in a population of SLE patients and to correlate our findings with disease characteristics, activity indices and traditional risk factors of atherosclerosis. We found that SLE patients have a higher prevalence of PAD compared with age- and sex-matched controls. This was true when comparing the significantly higher carotid artery IMT and lower ABPI in SLE patients with those of controls. An ABPI < 1 was demonstrated in 25% of our SLE patients. Bhatt et al.11 found 28% of SLE patients had PAD on Doppler, a similar result to
International Journal of Rheumatic Diseases 2013; 16: 319–324
Peripheral arterial disease in SLE
Table 5 Non-invasive arterial assessment results Variables Carotid disease assessment Average IMT (mean of two sides) (SD) mm Presence of carotid plaques Internal carotid stenosis Moderate (20–49%) Severe (50–74%) Peripheral vascular assessment ABPI < 1 ABPI 0.9
Patients
Controls
P-value
0.79 (0.27)
0.63 (0.14)
0.001 (S)
15/120 (12.5%)
8/100 (8%)
NS
4/120 (3.3%) 0/120 (0%)
1/100 (1%) 0/100 (0%)
NS NS
30/120 (25%) 18/120 (15%)
6/100 (6%) 3/100 (3%)
0.001 (S) 0.007 (S)
IMT, intima media thickness; ABPI, ankle brachial pressure index; NS, not significant; S, significant.
our findings. In addition, McDonald et al. found an increasing prevalence of PAD in SLE patients compared to controls which was not related to disease activity or traditional risk factors. Furthermore, an increased carotid artery IMT reflects not only increased prevalence of PAD but also has been proposed as an early manifestation of atherosclerosis12 and has been linked to myocardial infarction and stroke.13 From previous data, it is evident that SLE patients have an increased prevalence of PAD and atherosclerosis, a result that is similar to the results of other studies.10,11,14 The question now is ‘why do these patients have a high risk for PAD and atherosclerosis?’ Although the reason of this is not yet clear, there are some positive data from this study. Among the traditional vascular risk factors for PAD, including positive family history, degree of exercise, smoking, hypertension, diabetes mellitus, dyslipidemia and obesity, we found no significant differences between SLE patients and controls. This indicates that increased prevalence of PAD and atherosclerosis in SLE patients is due to disease-specific factors rather than these traditional risk factors, a finding similar to other studies.10,14 However, Urowitz et al.15 in their multinational inception cohort of SLE, reported that SLE patients with atherosclerotic vascular events have significant features, including Caucasian ethnicity, older age at diagnosis of SLE, hypertension, obesity, smoking and positive family history of coronary artery disease, compared to SLE patients without vascular events. Another important finding in our study is the significant increases in evidence of PAD and atherosclerosis in SLE patients who are or were on long-term steroid therapy. This suggests that steroid therapy may be a contribution to the higher rate of such vascular events in SLE patients. Other reports have
International Journal of Rheumatic Diseases 2013; 16: 319–324
suggested that prolonged treatment with steroids accelerates the development of atherosclerosis.10,16 In addition, steroids (particularly in high doses) are generally prescribed in active cases of SLE and prolonged steroid usage itself may be a marker of more active and severe forms of SLE. This is supported by our finding that increased carotid artery IMT and lower ABPI in SLE patients correlated positively with high BILAG score, high ESR and lowered C3 and C4 levels, which may be caused by immunological factors, a finding of another study.10 Burgos et al. in their study found that SDI (Systemic Lupus International Collaborating Clinics Damage Index) was statistically significant with peripheral arterial damage in SLE patients in multi-variable analyses. Azathioprine, warfarin and statins were also statistically significant, and glucocorticoid use was borderline statistically significant.17 Another interesting finding in our study is the significant elevation of thrombotic variables, including plasma fibrinogen vWF antigen, tPA antigen and fibrin D-dimer compared with controls. Elevation of these thrombotic variables correlated positively with the prevalence of PAD in our patients. So, elevation of such variables could be considered an important risk factor for PAD and atherosclerosis. Danesh et al.18 reported an association between elevated plasma fibrinogen and cardiovascular disease. Also, there is increasing evidence that increased plasma levels of vWF antigen, tPA antigen and fibrin D-dimer are associated with increased risk of coronary heart disease and stroke.19 Such studies suggest roles of these thrombotic variables in PAD and atherosclerosis in SLE patients and support the findings in our data. In addition, Lowe et al.20 reported that increase of such thrombotic variables may be secondary to vascular endothelial injury, which may be prothrombotic,
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also by increasing platelet adhesion and up-regulation of fibrinolysis as a response to fibrin formation. Furthermore, other reports21,22 suggest a link between release of such thrombotic variables and the immunological disease mechanism, such as clonally expanded CD4 + CD28 T-cells, systemic endothelial activation and circulating immune complexes, which may be involved in the development of PAD and the increased risk of atherosclerosis in SLE patients.
CONCLUSION In conclusion, this study showed an increased prevalence of PAD in SLE patients as shown by the higher carotid artery IMT and lower ABPI in such patients compared with controls. Multiple risk factors are likely to be involved in such findings. Among these risk factors, we found that long-term steroid usage, high disease activity indices and increased thrombotic variables are the most important. However, further studies are needed to evaluate other potential risk factors that may be involved, such as endothelial dysfunction and immune activation.
DISCLOSURE OF INTEREST None declared.
REFERENCES 1 James W, Berger T, Elston D (2005) Andrews” Diseases of the Skin: Clinical Dermatology, 10th edn. Saunders, Philadelphia. ISBN 0-7216-2921-0 2 McDonald J, Stewart J, Urowitz M, Gladman DD (1992) Peripheral vascular disease in patients with systemic lupus erythematosus. Ann Rheum Dis 51, 56–60. 3 de Leeuw K, Smit AJ, De Groot E, van Roon AM, Kallenberg CG, Bijl M (2009) Longitudinal study on premature atherosclerosis in patients with systemic lupus erythematosus. Atherosclerosis 206, 546–50. 4 Manzi S, Meilahn EN, Rairie JE et al. (1997) Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham Study. Am J Epidemiol 145, 408–15. 5 De Leeuw K, Graaff R, De Vries R et al. (2007) Accumulation of advanced glycation endproducts in patients with systemic lupus erythematosus. Rheumatology (Oxford) 46, 1551–6. 6 Gladman DP, Urowtz MB. (1987) Morbidity in systemic lupus erythematosus. J Rheumatol 14(Supp.15), 223–6. 7 Spiera H, Rothenberg RR (1983) Myocardial infarction in four young patients with SLE. J Rheumatol 10, 464–6.
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8 Tan EM, Cohen AS, Fries JF et al. (1982) The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 25, 1271–7. 9 Hay EM, Bacon PA, Gordon C et al. (1993) The BILAG index: a reliable and valid instrument for measuring clinical disease activity in systemic lupus erythematosus. Q J Med 86, 447–58. 10 McDonald J, Stewart J, Murray U (1992) Peripheral vascular disease in patients with systemic lupus erythematosus. Ann Rheum Dis 51, 56–60. 11 Bhatt SP, Handa R, Gulati GS et al. (2007) Peripheral vascular disease in patients with systemic lupus erythematosus. Lupus 16, 720–3. 12 Parciullo P, Lannuzzi A, Sartorio R (1994) Increased intima-media thickness of the common carotid arteries in hypercholestremic children. Arterioscler Thromb 14, 1075– 9. 13 O’Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson SK Jr (1999) Carotid artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. N Engl J Med 340, 14–22. 14 Liong MH, Mandl LA, Costenbader K, Fox E, Karlson E (2002) Atherosclerotic vascular disease in systemic lupus erythematosus. J Natl Med Assoc 94, 813–9. 15 Urowitz MB, Gladman D, Ibanez D et al. (2010) Atherosclerotic vascular events in a multinational inception cohort of systemic lupus erythematosus. Arthritis Care Res (Hoboken) 62, 881–7. 16 Alkaabi JK, Ho M, Levison R, Pullar T, Belch JJ (2003) Rheumatoid arthritis and macrovascular disease. Rheumatology 42, 292–7. 17 Burgos PI, Vila LM, Reveille JD, Alarc on GS (2009) Peripheral vascular damage in systemic lupus erythematosus: data from LUMINA, a large multi-ethnic U.S. cohort (LXIX). Lupus 18, 1303–8. 18 Danesh J, Collins R, Appleby P (1998) Association of fibrinogen, C-reactive protein, albumin and leukocyte counts with coronary heart disease. J Am Med Assoc 279, 1477–82. 19 Lowe GD, Yarnell JW, Sweetnam PM, Rumley A, Thomas HF, Elwood PC (1998) Fibrin D-dimer, tissue plasminogen activator inhibitor and the risk of major ischemic heart disease in the Carephilly study. Thromb Haemost 79, 129–33. 20 Lowe GD, Rumley A (1999) Use of fibrinogen and fibrin D-dimer in predilection of arterial thrombotic events. Thromb Haemost 82, 667–62. 21 Liuzzo G, Goronzy JJ, Yang H et al. (2000) Monoclonal T cell proliferation and plaque instability in acute coronary syndrome. Circulation 101, 2883–8. 22 Turesson C, England P, Jacobsson LT et al. (2001) Increased endothelial expression of HLA-DQ and interleukin alpha in extra-articular rheumatoid arthritis. Results from immunohistochemical studies of skeletal muscle. Rheumatology (Oxford) 40, 1346–54.
International Journal of Rheumatic Diseases 2013; 16: 319–324
ORIGINAL ARTICLE
Peripheral arterial disease in patients with systemic lupus erythematosus: a prospective controlled study Ayman A. HASSAN,1 Hisham M. HABIB2 and Ashraf A. EISSA3 1 Vascular Surgery Department, Ain Shams University, Cairo, 2Rheumatology and Rehabilitation Department, Mansoura University, Mansoura, and 3Radiology Department, Bani Sweef University, Beni Sweef, Egypt
Abstract Aim: The aim of our study was to: (i) map out the presence of peripheral vascular disease in a sample of systemic lupus erythematosus (SLE) patients; and (ii) correlate our findings with disease characteristics, activity indices, traditional risk factors of atherosclerosis and thrombotic variables. Methods: The study population comprised 120 SLE patients and 100 controls. Clinical data were collected for patients and controls with stress on clinical issues of SLE patients, including British Isles Lupus Assessment Group index score, anti-double stranded DNA titer C3 and C4 levels, and treatment taken, mainly steroids. Measurements of thrombotic variables were performed. Non-invasive arterial assessment was performed, including carotid duplex scanning and measurement of carotid artery intima-media thickness (IMT) and peripheral arterial assessment and measurement of ankle–brachial pressure index (ABPI). Results: The mean age of SLE patients was 32 years and mean disease duration was 8 years. There were no statistically significant differences in the traditional vascular risk factors measured between SLE patients and controls. There were significantly higher plasma levels of thrombotic variables in SLE patients. The average IMT was statistically significantly greater in SLE patients compared to controls. Thirty SLE patients (25%) had an ABPI < 1.0 compared with six controls (6%), which was statistically significant. Conclusion: This study showed an increased prevalence of peripheral arterial disease in SLE patients as shown by the higher carotid artery IMT and lower ABPI in such patients compared with controls. Multiple risk factors are likely to be involved in such findings. Key words: peripheral arterial disease, systemic lupus erythematosus.
INTRODUCTION Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that can affect any part of the body. As occurs in other autoimmune diseases, the immune system attacks the body’s cells and tissue, resulting in inflammation and tissue damage.1 Arterial vascular disease in SLE has a number of pathogenic mechanisms, including arteritis, intravascular
coagulation frequently associated with a lupus anticoagulant, and in chronic lupus atherosclerosis.2 SLE is associated with accelerated atherosclerosis3,4 which is recognized as a major cause of death and morbidity in such patients.3,5 Coronary artery atherosclerosis in patients with SLE has been widely reported,3,6,7 although peripheral arterial disease (PAD) has been infrequently described.
AIM Correspondence: Asst Prof Hisham M. Habib, Rheumatology Department, Al Ahsa Hospital, PO Box 3230, Al Ahsa 31982, Saudia Arabia. Email: [email protected]
The aim of our study was to: (i) to map out the presence of PAD in a sample of SLE patients; and (ii) correlate our findings with disease characteristics, activity
© 2013 The Authors International Journal of Rheumatic Diseases © 2013 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
A. A. Hassan et al.
indices, traditional risk factors of atherosclerosis and thrombotic variables.
METHODS The protocol for the research project was approved by a suitably constituted ethics committee of the Al Ahsa Hospital, Saudia Arabia, and it conformed to the provisions of the World Medical Association’s Declaration of Helsinki. An informed consent has been obtained for all investigations on subjects of the study (and patient anonymity was preserved).
Study and control populations The study population comprised 120 consecutive patients (110 women, 10 men) diagnosed with SLE collected from the rheumatology clinics of four central hospitals in the Hofuf District. SLE was diagnosed by a consultant rheumatologist using the American Rheumatism Association criteria for classification of SLE.8 The control populations consisted of 100 volunteered persons (90 women, 10 men) of the same age range as patients (0–5 years range difference). They had no history of inflammatory arthritis or cardiovascular diseases.
Collection of data and measurements The following data were recorded from SLE patients only: ● disease duration (all patients had a disease duration of at least 5 years at inclusion into the study), steroid treatment (current or past) and current non-steroidal anti-inflammatory as well as immunosuppressive medications for SLE control. Overall clinical assessment and disease activity index of SLE patients was performed using the BILAG (British Isles Lupus Assessment Group) disease activity index;9 ● measurements of anti-double stranded DNA (antidsDNA) titer (IU), erythrocyte sedimentation rate (ESR) (mm/h), and complement 3 (C3) and C4 (mg/dL) levels. The following data were recorded from all subjects (SLE patients and controls): ● a questionnaire recording demographic data, medical history, family history for vascular disease, amount of exercise per week and smoking history (current, past, never smoked); ● measurements of blood pressure, weight and height to derive body mass index (BMI: weight/height2),
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and overnight fasting blood glucose and serum lipids (total cholesterol, high-density lipoprotein [HDL], low-density lipoprotein [LDL] and triglycerides [TG]); and ● measurements of thrombotic variables, including plasma fibrinogen, von-Willebrand factor antigen (vWF), tissue plasminogen activator antigen (tPA) and fibrin D-dimer.
Non-invasive arterial assessment Carotid duplex scanning and measurement of carotid artery intima-media thickness (IMT) were performed. All subjects underwent carotid duplex scanning and measurements were made by an experienced radiology consultant whose duplex results have been previously validated. High-resolution B-mode carotid ultrasonography was performed with HDI 5000 ATL machine (Phillips Medical Systems). A 7.5 MHz array transducer was used. The subject lay supine with the neck extended and the chin turned contralateral to the side being examined. Scanning involved examination of the carotid arteries in transverse and longitudinal planes. Measurement of the common carotid artery intima-media thickness (IMT) was made 1 cm proximal to the carotid bifuraction in the posterior wall. If an area of significantly increased IMT was observed the maximum thickness at that site was also recorded. Measurements were made over both right and left carotid arteries and average IMT (mean of two sides) were recorded. Carotid artery stenoses were recorded, according to the severity of stenosis; normal, minimal disease (< 20% stenosis), moderate (20–49%), severe (50– 74%) and critical stenosis ( 75%). Peripheral arterial assessment and measurement of ankle–brachial pressure index (ABPI) was also performed. All study subjects were assessed at a vascular clinic. ABPI was measured by the vascular consultant and measurements were made for both lower limbs. The subject rested for approximately 10 min. Right brachial systolic pressure was recorded using a sphygmomanometer. Ankle pressure was recorded using a Doppler ultrasound velocity detector (Imex pocket Doppler 8 MHz; Imex, Golden, CO, USA). A suitably sized sphygmomanometer cuff was placed around the ankle, 3 cm proximal to the malleolus. The cuff was inflated at a rate of 2 mmHg/s. Ankle pressures were recorded with the appearance of blood velocity signals at the anterior and posterior tibial arteries at the ankle. Finally, ABPI was
International Journal of Rheumatic Diseases 2013; 16: 319–324
Peripheral arterial disease in SLE
measured for both lower limbs and the average ABPI (mean of the two sides) was recorded.
Table 2 Data of SLE patients
Statistical analysis
Duration of the disease: mean (range) years Mean BILAG (SD) ESR mean (SD) mm/h Antids-DNA titer (SD) IU (positive > 1) C3 mean level (SD) mg/dL (normal 50–120 mg/dL) C4 mean level (SD) mg/dL (normal 20–50 mg/dL)
Analysis was performed according to the intention-totreat principle. Comparison of the studied groups was done using sStudents t-test. The Chi-squared test was used to compare categorical variables. A probability value (P-value) < 0.05 was considered significant. Data were collected and tabulated using Microsoft Excel version 7 (Microsoft Cooperation, New York, NY, USA) and analyzed using SPSS for windows v.11 (SPSS, Inc, Chicago, IL, USA).
RESULTS Demographic data for both groups (Table 1) were nearly similar with no statistically significant differences. Data of SLE patients is listed in Table 2. The mean age of SLE patients was 32 years and mean disease duration was 8 (5–15) years. At time of the study, 79 patients (65.8%) were currently on long-term steroid use (6 months), 22 patients (18.3%) had histories of previous long-term steroid therapy and 99 patients (82.5%) were on immunosuppressive medications, including azathioprin, hydroxycholoroquine, myclofenolate mofetil and cyclophosphamide. Traditional arterial risk factors are listed in Table 3. There were no statistically significant differences in the traditional arterial risk factors measured between SLE patients and controls. Although systolic and diastolic blood pressures were higher in SLE patients, when compared with controls (mean 134 and 84 mmHg vs. 128 and 80 mmHg, respectively), none of these results were statistically significant (P = 0.24 and 0.38, respectively). Table 1 Demographic data of SLE patients and controls
Number of subjects Sex (male/female) Mean age (range) (years) Male mean age (years) Female mean age (years) Body mass index mean (SD) (kg/m²)
Patients
Controls
P-value
120 10/110 32 (19–50)
100 10/90 30 (18–51)
NS NS
31 (20–48)
29 (20–44)
NS
33 (19–50)
34 (18–51)
NS
26.8 (3.6)
27.2 (3.8)
NS
SD, standard deviation; NS, not significant.
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Variable
Data 8 (5–15) 9 (2.38) 49 (7.2) 2.5 (0.3–3) 55 (11.2) 22 (4.7)
ESR, erythrocyte sedimentation rate; SD, standard deviation; BILAG, British Isles Lupus Assessment Group; C3, complement 3; C4, complement 4.
Ten patients (8.3%) and six controls (6%) had a past history of hypertension and were receiving anti-hypertensive drugs. Seventeen patient (14.1%) and 12 controls (12%) had a systolic blood pressure 160 mmHg at time of the study; none of these results were statistically significant (P = 0.73 and 0.8, respectively). Ten SLE patients (8.3%) and six controls (6%) had diabetes mellitus which was not statistically significant (P = 0.86). Total lipid profiles were nearly similar in SLE patients and controls. The number of SLE patients with total cholesterol > 200 mg/dL were 28 patients (23%) and 25 controls (25%) which was not significant (P = 0.86). Other variables, including positive family history of vascular diseases, exercise at least once/week, current and ex-smokers and BMI were nearly similar in patients and controls with no significant differences. Thrombotic variables are listed in Table 4. There were significantly higher plasma levels of thrombotic variables, including fibrinogen, vWF, tPA, and fibrin D-dimer in SLE patients compared with controls. Non-invasive arterial assessment results are listed in Table 5.
Carotid duplex study and measurement of IMT results The average IMT ([right + left]/2) was statistically significantly greater in the SLE group (mean 0.79 [0.27 SD] mm vs. 0.63 [0.14] mm) in the control group (P = 0.001). Within the SLE group, there were no differences in the measured IMT between sexes and there was a positive correlation between IMT and disease duration and disease activity indexes, including high BILAG score, high ESR, lowered C3 and C4 levels (all
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Table 3 Traditional arterial risk factors in SLE patients and controls Variables
Patients
Positive family history of arterial disease Exercise (at least once/week) Smokers Current smokers Ex-smokers Body mass index mean (SD) (kg/m²) Systolic blood pressure mean (SD) mmHg Diastolic blood pressure mean (SD) mmHg Prevelance of diabetes mellitus Fasting blood glucose mean (SD) mg/dL Serum total cholesterol mean (SD) mg/dL Number of subjects with serum cholesterol > 200mg/dL Serum HDL cholesterol mean (SD) (mg/dL) Serum LDL cholesterol mean (SD) (mg/dL) Serum triglycerides mean (SD) (mg/dL)
12/120 (12%) 18/120 (15%) 22/120 (18%) 10/120 (8%) 26.8 (3.6) 134 (21.1) 84 (13.5) 10/120 (8%) 104 (19.6) 191 (39.5) 28/120 (23%) 50 1(3.2) 129 (29.6) 141 (42.5)
Controls
P-value
10/100 (10%) 18/100 (18%)
0.73 (NS) 0.59 (NS)
20/100 (20%) 12/100 (12%) 27.2 (3.8) 128 (19.5) 80 (12.1) 6/100 (6%) 101 (18.3) 186 (38.1) 25/100 (25%) 52.5 (13.8) 126 (28.8) 138 (41.9)
0.8 (NS) 0.73 (NS) 0.86 (NS) 0.24 (NS) 0.38 (NS) 0.86 (NS) 0.92 (NS) 0.89 (NS) 0.86 (NS) 0.56 (NS) 0.76 (NS) 0.82 (NS)
NS, not significant; SD, standard deviation.
Table 4 Thrombotic variables in SLE patients and controls Thrombotic variables Fibrinogen mean (SD) g/L vWF mean (SD) IU/L tPA mean (SD) Fibrin D-dimer mean (SD) ng/mL
Patients
Controls
P-value
3.9 (1.1) 146 (23.5) 6.6 (2.8) 74.4 (11.5)
2.9 (0.7) 98 (19.6) 5.1 (1.9) 63.6 (9.3)
0.001 (S) 0.001 (S) 0.006 (S) 0.028 (S)
S, significant; vWF, von Willebrand factor; tPA, tissue plasminogen activator; SD standard deviation.
P < 0.05). Moreover, IMT correlated positively within the SLE group with long steroid usage (P = 0.04). In both groups, IMT correlated positively with age, total cholesterol and greater thrombotic variables (for SLE, P = 0.001, P = 0.04, P = 0.01) and for controls (P = 0.01, P = 0.04, P = 0.03), respectively. In addition IMT correlated positively with lower ABPI in the SLE group but not in the control group (P = 0.02). Carotid plaques were present in 15 patients (12.5%) and eight controls (8%), which was not statistically significant. Furthermore, moderate internal carotid artery stenosis was found in four patients (3.3%) and one control (1%). None of patients or controls had severe stenosis and neither of these results were statistically significant.
Ankle brachial pressure index (ABPI) results Thirty SLE patients (25%) had an ABPI < 1.0 compared with six controls (6%), which was statistically significant (P = 0.001). Of these subjects with lower ABPI, 18 patients (15%) and three controls (3%) had ABPI 0.9 which was also statistically significant (P = 0.007). Within SLE patients, there were a positive significant correlations between lowered ABPI and dis-
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ease duration, and high BILAG score, high ESR and lowered C3 and C4 levels (all P < 0.05). Moreover, lowered ABPI correlated positively with presence of long steroid usage and higher thrombotic variables (P = 0.04 and P = 0.02, respectively).
DISCUSSION Patients with SLE may develop premature atherosclerosis, notably coronary artery disease.7,10 With increasing longevity of SLE patients, PAD has become an important cause of morbidity.11 The aim of this study was to map out the presence of PAD in a population of SLE patients and to correlate our findings with disease characteristics, activity indices and traditional risk factors of atherosclerosis. We found that SLE patients have a higher prevalence of PAD compared with age- and sex-matched controls. This was true when comparing the significantly higher carotid artery IMT and lower ABPI in SLE patients with those of controls. An ABPI < 1 was demonstrated in 25% of our SLE patients. Bhatt et al.11 found 28% of SLE patients had PAD on Doppler, a similar result to
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Peripheral arterial disease in SLE
Table 5 Non-invasive arterial assessment results Variables Carotid disease assessment Average IMT (mean of two sides) (SD) mm Presence of carotid plaques Internal carotid stenosis Moderate (20–49%) Severe (50–74%) Peripheral vascular assessment ABPI < 1 ABPI 0.9
Patients
Controls
P-value
0.79 (0.27)
0.63 (0.14)
0.001 (S)
15/120 (12.5%)
8/100 (8%)
NS
4/120 (3.3%) 0/120 (0%)
1/100 (1%) 0/100 (0%)
NS NS
30/120 (25%) 18/120 (15%)
6/100 (6%) 3/100 (3%)
0.001 (S) 0.007 (S)
IMT, intima media thickness; ABPI, ankle brachial pressure index; NS, not significant; S, significant.
our findings. In addition, McDonald et al. found an increasing prevalence of PAD in SLE patients compared to controls which was not related to disease activity or traditional risk factors. Furthermore, an increased carotid artery IMT reflects not only increased prevalence of PAD but also has been proposed as an early manifestation of atherosclerosis12 and has been linked to myocardial infarction and stroke.13 From previous data, it is evident that SLE patients have an increased prevalence of PAD and atherosclerosis, a result that is similar to the results of other studies.10,11,14 The question now is ‘why do these patients have a high risk for PAD and atherosclerosis?’ Although the reason of this is not yet clear, there are some positive data from this study. Among the traditional vascular risk factors for PAD, including positive family history, degree of exercise, smoking, hypertension, diabetes mellitus, dyslipidemia and obesity, we found no significant differences between SLE patients and controls. This indicates that increased prevalence of PAD and atherosclerosis in SLE patients is due to disease-specific factors rather than these traditional risk factors, a finding similar to other studies.10,14 However, Urowitz et al.15 in their multinational inception cohort of SLE, reported that SLE patients with atherosclerotic vascular events have significant features, including Caucasian ethnicity, older age at diagnosis of SLE, hypertension, obesity, smoking and positive family history of coronary artery disease, compared to SLE patients without vascular events. Another important finding in our study is the significant increases in evidence of PAD and atherosclerosis in SLE patients who are or were on long-term steroid therapy. This suggests that steroid therapy may be a contribution to the higher rate of such vascular events in SLE patients. Other reports have
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suggested that prolonged treatment with steroids accelerates the development of atherosclerosis.10,16 In addition, steroids (particularly in high doses) are generally prescribed in active cases of SLE and prolonged steroid usage itself may be a marker of more active and severe forms of SLE. This is supported by our finding that increased carotid artery IMT and lower ABPI in SLE patients correlated positively with high BILAG score, high ESR and lowered C3 and C4 levels, which may be caused by immunological factors, a finding of another study.10 Burgos et al. in their study found that SDI (Systemic Lupus International Collaborating Clinics Damage Index) was statistically significant with peripheral arterial damage in SLE patients in multi-variable analyses. Azathioprine, warfarin and statins were also statistically significant, and glucocorticoid use was borderline statistically significant.17 Another interesting finding in our study is the significant elevation of thrombotic variables, including plasma fibrinogen vWF antigen, tPA antigen and fibrin D-dimer compared with controls. Elevation of these thrombotic variables correlated positively with the prevalence of PAD in our patients. So, elevation of such variables could be considered an important risk factor for PAD and atherosclerosis. Danesh et al.18 reported an association between elevated plasma fibrinogen and cardiovascular disease. Also, there is increasing evidence that increased plasma levels of vWF antigen, tPA antigen and fibrin D-dimer are associated with increased risk of coronary heart disease and stroke.19 Such studies suggest roles of these thrombotic variables in PAD and atherosclerosis in SLE patients and support the findings in our data. In addition, Lowe et al.20 reported that increase of such thrombotic variables may be secondary to vascular endothelial injury, which may be prothrombotic,
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also by increasing platelet adhesion and up-regulation of fibrinolysis as a response to fibrin formation. Furthermore, other reports21,22 suggest a link between release of such thrombotic variables and the immunological disease mechanism, such as clonally expanded CD4 + CD28 T-cells, systemic endothelial activation and circulating immune complexes, which may be involved in the development of PAD and the increased risk of atherosclerosis in SLE patients.
CONCLUSION In conclusion, this study showed an increased prevalence of PAD in SLE patients as shown by the higher carotid artery IMT and lower ABPI in such patients compared with controls. Multiple risk factors are likely to be involved in such findings. Among these risk factors, we found that long-term steroid usage, high disease activity indices and increased thrombotic variables are the most important. However, further studies are needed to evaluate other potential risk factors that may be involved, such as endothelial dysfunction and immune activation.
DISCLOSURE OF INTEREST None declared.
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