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Cardiovascular involvement in systemic autoimmune diseases
Autoimmunity Reviews 8 (2009) 281–286
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Autoimmunity Reviews j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / a u t r e v
Cardiovascular involvement in systemic autoimmune diseases Simona Sitia a, Fabiola Atzeni b, Piercarlo Sarzi-Puttini b, Vitantonio Di Bello c, Livio Tomasoni a, Luigi Delfino a, Francesco Antonini-Canterin c, Giovanni Di Salvo c, Vito De Gennaro Colonna d, Salvatore La Carrubba c, Scipione Carerj c, Maurizio Turiel a,⁎ a b c d
IRCCS Orthopedic Galeazzi Institute, University of Milan, Department of Health Technologies, Cardiology Unit, Milan, Italy Rheumatology Unit, L. Sacco University Hospital, Milan, Italy On behalf of the Italian Society of Cardiovascular Echography (SIEC) Research Group, Italy Department of Pharmacology, Chemotherapy and Medical Toxicology, University of Milan, Italy
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Article history: Received 12 July 2008 Accepted 25 August 2008 Available online 24 September 2008 Keywords: Systemic autoimmune diseases Microcirculation abnormalities Coronary angiography Non-invasive diagnostic tools
a b s t r a c t Autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), primary antiphospholipid syndrome (APS), systemic sclerosis and systemic vasculitis, affect a large number of people in whom one of the leading causes of morbidity and mortality is cardiovascular disease. Cardiovascular disease is associated with the development of accelerated atherosclerosis. It seems to occur at a younger age than in the general population, is often asymptomatic and, in addition to traditional risk factors, also involves specific risk factors as chronic inflammation, the duration and activity of the autoimmune disease, and immunosuppressive therapy. The early phases of cardiovascular involvement in patients with autoimmune diseases may be clinically silent, with only a microcirculation disorder present. There are various means of detecting morphological cardiac damage: coronary angiography remains the gold standard for diagnosing coronary stenosis, but new, non invasive and more reliable methods have been introduced into clinical practice in order to detect subclinical microcirculation abnormalities. © 2008 Elsevier B.V. All rights reserved.
Contents 1. 2.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnostic methods . . . . . . . . . . . . . . . . . . . . . . . 2.1. Imaging techniques . . . . . . . . . . . . . . . . . . . . 2.1.1. Transthoracic echocardiography . . . . . . . . . . 2.1.2. Transthoracic stress echocardiography with coronary 2.1.3. Tissue Doppler imaging (TDI) . . . . . . . . . . . 2.1.4. Transesophageal echocardiography . . . . . . . . . 2.1.5. Computed tomography . . . . . . . . . . . . . . 2.1.6. Coronary magnetic resonance angiography . . . . . 2.1.7. Angiography . . . . . . . . . . . . . . . . . . . 2.1.8. Common carotid Doppler ultrasound . . . . . . . . 2.2. ADMA measurements . . . . . . . . . . . . . . . . . . .
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⁎ Corresponding author. IRCCS Orthopedic Galeazzi Institute, University of Milan, Department of Health Technologies, Cardiology Unit, Via R. Galeazzi 4, 20161 Milano, Italy. Tel.: +39 02 50319955; fax: +39 02 50319956. E-mail address: [email protected] (M. Turiel). 1568-9972/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.autrev.2008.08.004
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3. Effects of anti-rheumatic 4. Conclusions . . . . . . Take-home . messages . . . . References . . . . . . . . .
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1. Introduction Systemic autoimmune diseases make up a family of conditions that share common pathogenetic mechanisms and multi-organ involvement including the heart. Autoimmune diseases occur because the physiological tolerance to self-antigens is lost and, although circulating antibodies do not always play a pathogenetic role, they represent specific markers of ongoing tissue damage. In the case of systemic autoimmune diseases, the autoantibodies are against ubiquitous antigens (i.e. nuclear antigens in systemic lupus erythematosus or SLE), and the tissue damage is generalised. Systemic autoimmune diseases affect many patients with rheumatoid arthritis (RA), SLE, primary antiphospholipid syndrome (APS), systemic sclerosis and systemic vasculitis, in whom one of the leading causes of morbidity and mortality is cardiovascular disease, which is associated with the development of accelerated atherosclerosis [1,2]: for example, cardiovascular mortality accounts for 40–50% of all deaths in RA [3]. Furthermore, cardiovascular disease seems to occur at a younger age than in the general population, is often asymptomatic (at least in the early stages) and, in addition to traditional risk factors, also involves specific risk factors. In particular, the excess cardiovascular mortality and morbidity can be explained by chronic inflammation, the duration and activity of the autoimmune disease, and the effects of immunosuppressive therapy (glucocorticoids and methotrexate) [4]. Wolfe et al. [5] have observed that minimal disease activity and a short disease duration are associated with better outcomes in RA. All of the components of the heart can be affected by a number of pathogenetic mechanisms that may involve the valves, the coronary arteries, the conduction system, or the myocardium, endocardium or pericardium. The clinical manifestations of cardiac involvement include: pericarditis, myocarditis and myocardial fibrosis, rhythm and conduction disturbances, coronaritis with ischemic heart disease, valvular diseases, pulmonary hypertension, syncope, and diastolic or systolic heart failure [1,6]. It has recently been recognised that chronic inflammation plays an important role in the development of atherosclerotic
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plaque [7–9], and the prime mover in this process seems to be endothelial dysfunction [10], which is largely characterised by a reduction in nitric oxide (NO) production by NO synthase. Asymmetric dimethyl arginine (ADMA) is an endogenous inhibitor of NO synthase and has recently emerged as a novel marker of cardiovascular risk; it has already been demonstrated that plasma ADMA levels are high in RA patients [11]. Moreover, it has been shown that anti-rheumatic drugs reduce systemic inflammation and may improve endothelial dysfunction [12], and the same effect has been observed after statin therapy [13,14]. As autoimmune diseases are characterised by a high degree of cardiovascular risk, and cardiac involvement is associated with adverse outcomes and a poor prognosis, the early identification of patients at higher risk is essential. Knowing the mechanisms responsible for cardiovascular damage in systemic autoimmune diseases is an important step in choosing appropriate drugs that can block/slow the development of atherosclerosis. 2. Diagnostic methods 2.1. Imaging techniques The early phases of cardiovascular involvement in patients with autoimmune diseases may be clinically silent, with only the presence of a microcirculation disorder (Table 1). The diagnostic imaging techniques capable of detecting morphological cardiac damage can be divided into: 1. non invasive (transthoracic echocardiography, tissue doppler imaging) 2. semi-invasive (transthoracic stress echocardiography, transesophageal echocardiography) 3. computed tomography and coronary magnetic resonance angiography 4. invasive techniques (angiography) 2.1.1. Transthoracic echocardiography Transthoracic echocardiography is a reliable non-invasive technique that allows an accurate evaluation of valvular
Table 1 Cardiovascular involvement in patients with systemic autoimmune diseases, diagnostic imaging techniques and treatment: salient points and recommendations Early phases of cardiovascular involvement in patients with systemic autoimmune diseases may be clinically silent The diagnostic imaging techniques capable of detecting morphological cardiac damage can be divided into: – non invasive (transthoracic echocardiography, tissue doppler imaging) – semi-invasive (transthoracic stress echocardiography, transesophageal echocardiography) – computed tomography and coronary magnetic resonance angiography – invasive techniques (angiography) ⁎ADMA has been shown to be a marker of endothelial dysfunction that represents an early stage of atherosclerosis The effects may go beyond controlling inflammation and disease activity, including the endothelial effects of anti-tumour necrosis factor (TNF) α agents, and the effects of conventional therapy and biological drugs on vascular function. The efficacy of anti-rheumatic therapy in reducing or slowing the progression of atherosclerosis have drawn attention to the need for a more aggressive therapeutic approach to patients with systemic autoimmune diseases. ⁎ADMA: Asymmetric dimethyl arginine.
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abnormalities, pericardial diseases and ventricular wall motion defects. Doppler analysis is useful for studying left ventricular diastolic filling, valve function and pulmonary pressures. Rexhepaj et al. [15] used Doppler echocardiography to assess the prevalence of left and right ventricular diastolic dysfunction in RA patients without any clinical signs of cardiovascular disease. They found significant differences in early diastolic flow velocity (E), atrial flow velocity (A) and the E/A ratio between patients and controls, which suggests that asymptomatic RA patients have reduced left and right ventricular function, but no differences in left ventricular size or thickness, systolic function or the myocardial performance index. 2.1.2. Transthoracic stress echocardiography with coronary flow reserve evaluation It has recently been shown that coronary flow reserve (CFR) evaluated by means of transthoracic dipyridamole stress echocardiography is a highly sensitive (N90%) diagnostic marker of coronary artery disease (CAD) [16,17] and, when associated with the evaluation of regional wall motion, is also highly specific [18]. A CFR of b2 in the distal left anterior descending artery (LAD) accurately predicts the presence of coronary stenosis [17]. In the absence of an epicardial coronary stenosis, an abnormal CFR may reflect an impaired coronary microcirculation in patients suffering from a reperfused myocardial infarction, arterial hypertension with or without left ventricular hypertrophy, diabetes mellitus, hypercholesterolemia, syndrome X, hypertrophic cardiomyopathy and other diseases [19]. CFR has also been used to assess prognosis in various cardiac conditions, and it has been shown that a reduced CFR correlates with a negative prognosis [20]. Patients have to abstain from xanthine containing food and drinks during the 24 h preceding a dipyridamole stress echocardiography test with coronary flow reserve evaluation. With the patient in a stable 90° left lateral recumbent position, a modified two-chamber view is used to identify the distal LAD artery, in which CFR is evaluated before and during dipyridamole infusion (0.56 mg/kg over 4 min + 0.28 mg/kg over the next 2 min) using an 8 MHz transducer to assess the systolic and diastolic components of the Doppler signal. Coronary blood flow in the mid-distal portion of the LAD artery is measured under the guidance of color Doppler flow mapping synchronised with electrocardiogram. CFR is calculated as the ratio between peak diastolic velocity during hyperemia and baseline diastolic velocity (Fig. 1). At the end of the analysis, 125–250 mg of aminophylline should be administered to counteract the effect of dipyridamole. Hirata et al. [21] used stress echocardiography to evaluate CFR in premenopausal women with SLE and found that it was significantly lower than in age- and gender-matched controls. They concluded that microvascular impairment in SLE could be due to a functional alteration in the endothelium decreasing vasodilation in response to pharmacological stress. 2.1.3. Tissue Doppler imaging (TDI) It has recently been shown that this new imaging modality allow the measurement of myocardial velocities with Doppler. The pulsed wave Doppler cursor is placed at the mitral annulus using the apical window in order to measure velocities that represent longitudinal contraction (positive
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systolic wave, Sa) and relaxation (early negative diastolic wave, Ea, and late negative diastolic wave, La). Ea is a good index of left ventricular relaxation as it correlates with the time constant of isovolumic relaxation and with age: in particular, low E/A velocities with E/A b1 indicate impaired ventricular relaxation. Birdane et al. [22] compared left and right ventricular TDI parameters in RA patients and healthy subjects and observed a significantly reduced E/A ratio in the patients; moreover, the E/A ratio in the RA patients correlated with patient age and the use of steroids. 2.1.4. Transesophageal echocardiography This examination is widely recognised as being more sensitive than the transthoracic approach in detecting valvular lesions [23] and identifying intracardiac masses. We followed up 56 patients with primary APS for five years. All of the patients underwent transesophageal echocardiography, and we observed a large prevalence of cardiac involvement: 61% showed valvular thickening or vegetations and/or potential sources of embolism [24]. 2.1.5. Computed tomography Electron-beam computed tomography is a highly sensitive means of detecting even small amounts of calcium in coronary arteries, and the radiation doses received during CT study are much lower than those used for angiography [25]. Recent studies have shown the accuracy of multi slice computed tomography associated with the administration of an iodinate contrast medium to visualise the coronary artery lumen in detecting CAD [26]. Kiani et al. [11] used helical computed tomography in 200 asymptomatic SLE patients and found that they had increased coronary calcium that significantly correlated with plasma ADMA levels. Furthermore, Chung et al. [27] studied the extent of coronary artery calcification by means of electron-beam computed tomography and demonstrated the higher prevalence and greater severity of coronary calcification in patients with established RA than in those with early disease, which was partially related to smoking and an increased erythrocyte sedimentation rate (ESR). 2.1.6. Coronary magnetic resonance angiography This allows the non invasive visualisation of the major epicardial coronary arteries in the majority of subjects. It has high sensitivity, negative predictive, and overall accuracy values in detecting CAD, and is not exercise dependent. In comparison with computed tomography, coronary magnetic resonance angiography has the advantage of not requiring exposure to ionising radiation or the injection of contrast agents [28]. 2.1.7. Angiography This remains the gold standard for diagnosing coronary stenosis as it detects the presence, extent and position of atheromatous lesions. However, its use for screening purposes is limited by its invasiveness and potentially high level of risk [29]. 2.1.8. Common carotid Doppler ultrasound Non invasively measured common carotid intima-media thickness (IMT) is a clinically useful marker of early stage
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Fig. 1. Examples of CFR values obtained in control subjects (A) and ERA patients (B). ⁎ indicates the diastolic velocity in Doppler signal at baseline (upper panels) and during hyperaemia (lower panels).
atherosclerosis that closely correlates with the presence of CAD [30]. Kumeda et al. [31] found that IMT of common carotid and femoral arteries is greater in RA patients than healthy controls, and that the increase was associated with the duration and severity of the disease. In line with this, Ciftci et al. [32] found the presence of increased IMT and impaired coronary microvascular function in RA patients related to disease duration. 2.2. ADMA measurements In addition to instrumental diagnostic investigations, there is increasing evidence indicating a close association between plasma ADMA levels and cardiovascular disease in
patients with autoimmune diseases. Released by endothelial cells, ADMA has been shown to be a marker of the endothelial dysfunction that represents an early stage of atherosclerosis. Increased plasma ADMA levels have been found in various pathological conditions characterised by a high cardiovascular risk, including hypercholesterolemia [33], hypertriglyceridemia [34], peripheral arterial disease [35], hypertension [36], type 2 diabetes mellitus [37], acute coronary syndrome [38] and end-stage renal disease [39]. Kiani et al. [11] have reported higher ADMA levels in SLE patients, associated with coronary calcium and a poor prognosis; moreover, the SLE patients with abnormal ADMA levels were also more likely to have “mild” carotid plaque, although the difference was not statistically significant.
Fig. 2. DAS 28 (left panel) and CFR (right panel) values before and after long-term disease modifying anti-rheumatic drugs.
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Furthermore, Surdacki et al. [40] found an association between increased plasma ADMA levels and greater common carotid IMT in RA patients. In line with these data, we found a lower CFR and higher plasma ADMA levels in a group of 25 off therapy patients with early RA and no evidence of CAD than in a group of age- and gender-matched healthy controls, as well as a negative correlation between CFR and plasma ADMA levels.
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diseases. However, increased IMT reflects a later stage of the atherosclerotic process when anatomical changes have already occurred, whereas impaired CFR and altered plasma ADMA levels are earlier markers of functional damage. The beneficial effects of new anti-rheumatic drugs on cardiovascular damage and their efficacy in reducing or slowing the progression of atherosclerosis have drawn attention to the need for a more aggressive therapeutic approach to patients with systemic autoimmune diseases.
3. Effects of anti-rheumatic therapy Take-home messages Evidence has recently emerged indicating that the effects of anti-rheumatic therapy may go beyond controlling inflammation and disease activity, including the endothelial effects of anti-tumor necrosis factor (TNF) α agents and the effects of conventional therapy and biological drugs on vascular function. Hurlimann et al. [12] found that TNFα antagonism not only reduces RA activity but also improves endothelial function. They also observed that the reduction in local and systemic inflammation induced by disease modifying antirheumatic drugs can reverse endothelial dysfunction [14]. It is worth noting that the pleiotropic effects of statin lipidlowering therapy seem to protect the vascular endothelium, as shown Mäki-Petäjä et al. [13] who demonstrated the efficacy of ezetimibe and simvastatin in reducing systemic inflammation, disease activity and aortic stiffness in RA patients, concomitantly improving endothelial function. However, the possible effectiveness of statins and biological therapies in changing the course of CAD in RA patients remains to be investigated. To this end, we designed a follow up study of 15 RA patients without any signs of CAD aimed at assessing the effects of anti-rheumatic therapy on endothelial dysfunction. All of the patients were evaluated in terms of disease activity, Doppler-derived CFR and plasma ADMA levels at baseline off therapy, and after 24 months of DMARD or anti-TNFα treatment. The final results of the study showed that, as well as significantly reducing disease activity, the antirheumatic drugs improved CFR in the absence of any significant changes in plasma ADMA levels (Fig. 2). 4. Conclusions As patients with systemic autoimmune diseases are at higher risk of developing cardiovascular diseases than the general population, it is essential to detect endothelial dysfunction and impaired coronary microcirculation earlier in asymptomatic subjects. Coronary angiography remains the gold standard for the diagnosis of coronary stenosis, but new, non invasive and more reliable diagnostic techniques have been introduced into clinical practice to detect sub-clinical microcirculation abnormalities. In particular, echocardiography with its numerous applications (CFR evaluation, TDI, transesophageal) seems to be the most appropriate screening technique as it non-invasively, reliably, sensitively and specifically identifies preclinical cardiac involvement in systemic autoimmune diseases. Common carotid IMT measured by means of carotid ultrasound can provide additional information that is useful for stratifying cardiovascular risk in patients with systemic autoimmune
• Patients with systemic autoimmune diseases are at increased risk of developing cardiovascular diseases • The early phases of cardiovascular involvement in patients with autoimmune diseases may be clinically silent, with only a microcirculation disorder present. • Echocardiography with its numerous applications (CFR evaluation, TDI, transesophageal) seems to be the most suitable means of screening. • Common carotid IMT measured by means of carotid ultrasound may provide additional information that is useful for stratifying cardiovascular risk in patients with systemic autoimmune diseases. References [1] Knonkaert DC. Cardiac involvement in systemic inflammatory diseases. Eur Heart J 2007;28:1797–804. [2] Soltész P, Szekanecz Z, Kiss E, Shoenfeld Y. Cardiac manifestations in antiphospholipid syndrome. Autoimmun Rev 2007;6:379–86. [3] Del Rincon I, Williams K, Stern MP, Freeman GL, Escalante A. High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors. Arthritis Rheum 2001;44:2737–45. [4] Hahn BH, Grossman J, Chen W, McMahon M. The pathogenesis of atherosclerosis in autoimmune rheumatic diseases: roles of inflammation and dyslipidemia. J Autoimmun 2007;28:69–75. [5] Wolfe F, Rasker JJ, Boers M, Wells GA, Michaud K. Minimal disease activity, remission, and the long-term outcomes of rheumatoid arthritis. Arthritis Rheum 2007;57:935–42. [6] Rav-Acha M, Plot L, Peled N, Amital H. Coronary involvement in Takayasu's arteritis. Autoimmun Rev 2007;6:566–71. [7] Sattar N, McCarey DW, Capell H, McInnes IB. Explaining how “highgrade” systemic inflammation accelerates vascular risk in rheumatoid arthritis. Circulation 2003;108:2957–63. [8] Bassi N, Ghirardello A, Iaccarino L, Zampieri S, Rampudda ME, Atzeni F, et al. OxLDL/beta2GPI-anti-oxLDL/beta2GPI complex and atherosclerosis in SLE patients. Autoimmun Rev 2007;7:52–8. [9] Staub HL, Franck M, Ranzolin A, Norman GL, Iverson GM, von Mühlen CA. IgA antibodies to beta2-glycoprotein I and atherosclerosis. Autoimmun Rev 2006;6:104–6. [10] Arosio E, De Marchi S, Rigoni A, Prior M, Delva P, Lechi A. Forearm hemodynamics, arterial stiffness and microcirculatory reactivity in RA. J Hypertens 2007;25:1273–8. [11] Kiani AN, Mahoney JA, Petri M. Asymmetric dimethylarginine is a marker of poor prognosis and coronary calcium in Systemic Lupus Erythematosus. J Rheumatol 2007;34:1502–5. [12] Hurlimann D, Forster A, Noll G, Enseleit F, Chenevard R, Distler O, et al. Anti-tumor necrosis factor-alpha treatment improves endothelial function in patients with rheumatoid arthritis. Circulation 2002;106:2184–7. [13] Mäki-Petäjä KM, Booth AD, Hall FC, Wallace SM, Brown J, McEniery CM, et al. Ezetimibe and simvastatin reduce inflammation, disease activity, and aortic stiffness and improve endothelial function in rheumatoid arthritis. J Am Coll Cardiol 2007;50:852–8. [14] Belizna CC, Richard V, Thuillez C, Lévesque H, Shoenfeld Y. Insights into atherosclerosis therapy in antiphospholipid syndrome. Autoimmun Rev 2007;7:46–51. [15] Rexhepaj N, Bajraktari G, Berisha I, Beqiri A, Shatri F, Hima F, et al. Left and right ventricular diastolic functions in patients with rheumatoid arthritis without clinically evident cardiovascular disease. Int J Clin Pract 2006;60:683–8.
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Apoptosis-associated antigens recognized by autoantibodies in patients with the autoimmune liver disease primary biliary cirrhosis Primary biliary cirrhosis (PBC) is characterized by progressive destruction of small intra-hepatic bile ducts and the presence of antimitochondrial antibodies. The etiopathogenesis of this autoimmune disease remains to be elucidated. One of the attractive concepts for the induction of autoimmunity is the defective clearance of apoptotic cells. These cells undergo necrosis and release inflammatory factors and intracellular antigens which might induce autoimmunity if not cleared appropriately. In a recent study Berg CP et al (Apoptosis 2008;13:63–75) studied the role of apoptosis in PBC. Following induction of apoptosis in 3 malignant cell lines, intracellular antigens were recognized by purified IgG from patients with PBC but not by IgG from healthy donors. The PBC-IgG recognized antigen expressed on the cells surface, mitochondrial antigen and cytosolic proteins. A major role was demonstrated for Caspase-3 in generation of these proteins. PBC-IgG also recognized caspase-dependent antigens in the supernatant of apoptotic cells (the necrotic phase). Last but not least, among the caspase substrates recognized by PBC-IgG components of PDC-E2 and E1β, the main antigens of anti-mitochonrial antibodies, were identified. Thus it might be concluded that a defect in clearance of apoptotic cells might play a role in the pathogenesis of PBC disease. Antimitochondrial Antibody–Negative Primary Biliary Cirrhosis Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease of unclear cause. It is characterized by destruction of the bile ducts and the presence of anti-mitochondrial antibodies (AMA) which can be detected in most patients. There is some controversy as to whether the lack of AMA defined as AMA-negative PBC and AMA-positive PBC represent the same entities clinically and immunologically. Recently Mendes F. and Lindor KD (Gastroenterol Clin N Am 2008;37:479–484) reviewed the literature on this subsets of PBC. Both variants occur predominantly in middle aged women and present clinically and histological similarly. Moreover no significant differences were observed regarding disease progression, response to therapy and outcome of liver transplantation. The advent of more sensitive and specific techniques for detection of AMA have already shown that in some patients previously defined as AMA-negative PBC these antibodies can be detected. Thus it might be concluded that AMA-negative and AMA-positive PBC patients have a similar disease, and improved methods of AMA detection might decrease the percentage patients diagnosed with AMA-negative PBC.
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Autoimmunity Reviews j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / a u t r e v
Cardiovascular involvement in systemic autoimmune diseases Simona Sitia a, Fabiola Atzeni b, Piercarlo Sarzi-Puttini b, Vitantonio Di Bello c, Livio Tomasoni a, Luigi Delfino a, Francesco Antonini-Canterin c, Giovanni Di Salvo c, Vito De Gennaro Colonna d, Salvatore La Carrubba c, Scipione Carerj c, Maurizio Turiel a,⁎ a b c d
IRCCS Orthopedic Galeazzi Institute, University of Milan, Department of Health Technologies, Cardiology Unit, Milan, Italy Rheumatology Unit, L. Sacco University Hospital, Milan, Italy On behalf of the Italian Society of Cardiovascular Echography (SIEC) Research Group, Italy Department of Pharmacology, Chemotherapy and Medical Toxicology, University of Milan, Italy
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Article history: Received 12 July 2008 Accepted 25 August 2008 Available online 24 September 2008 Keywords: Systemic autoimmune diseases Microcirculation abnormalities Coronary angiography Non-invasive diagnostic tools
a b s t r a c t Autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), primary antiphospholipid syndrome (APS), systemic sclerosis and systemic vasculitis, affect a large number of people in whom one of the leading causes of morbidity and mortality is cardiovascular disease. Cardiovascular disease is associated with the development of accelerated atherosclerosis. It seems to occur at a younger age than in the general population, is often asymptomatic and, in addition to traditional risk factors, also involves specific risk factors as chronic inflammation, the duration and activity of the autoimmune disease, and immunosuppressive therapy. The early phases of cardiovascular involvement in patients with autoimmune diseases may be clinically silent, with only a microcirculation disorder present. There are various means of detecting morphological cardiac damage: coronary angiography remains the gold standard for diagnosing coronary stenosis, but new, non invasive and more reliable methods have been introduced into clinical practice in order to detect subclinical microcirculation abnormalities. © 2008 Elsevier B.V. All rights reserved.
Contents 1. 2.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnostic methods . . . . . . . . . . . . . . . . . . . . . . . 2.1. Imaging techniques . . . . . . . . . . . . . . . . . . . . 2.1.1. Transthoracic echocardiography . . . . . . . . . . 2.1.2. Transthoracic stress echocardiography with coronary 2.1.3. Tissue Doppler imaging (TDI) . . . . . . . . . . . 2.1.4. Transesophageal echocardiography . . . . . . . . . 2.1.5. Computed tomography . . . . . . . . . . . . . . 2.1.6. Coronary magnetic resonance angiography . . . . . 2.1.7. Angiography . . . . . . . . . . . . . . . . . . . 2.1.8. Common carotid Doppler ultrasound . . . . . . . . 2.2. ADMA measurements . . . . . . . . . . . . . . . . . . .
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⁎ Corresponding author. IRCCS Orthopedic Galeazzi Institute, University of Milan, Department of Health Technologies, Cardiology Unit, Via R. Galeazzi 4, 20161 Milano, Italy. Tel.: +39 02 50319955; fax: +39 02 50319956. E-mail address: [email protected] (M. Turiel). 1568-9972/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.autrev.2008.08.004
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3. Effects of anti-rheumatic 4. Conclusions . . . . . . Take-home . messages . . . . References . . . . . . . . .
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1. Introduction Systemic autoimmune diseases make up a family of conditions that share common pathogenetic mechanisms and multi-organ involvement including the heart. Autoimmune diseases occur because the physiological tolerance to self-antigens is lost and, although circulating antibodies do not always play a pathogenetic role, they represent specific markers of ongoing tissue damage. In the case of systemic autoimmune diseases, the autoantibodies are against ubiquitous antigens (i.e. nuclear antigens in systemic lupus erythematosus or SLE), and the tissue damage is generalised. Systemic autoimmune diseases affect many patients with rheumatoid arthritis (RA), SLE, primary antiphospholipid syndrome (APS), systemic sclerosis and systemic vasculitis, in whom one of the leading causes of morbidity and mortality is cardiovascular disease, which is associated with the development of accelerated atherosclerosis [1,2]: for example, cardiovascular mortality accounts for 40–50% of all deaths in RA [3]. Furthermore, cardiovascular disease seems to occur at a younger age than in the general population, is often asymptomatic (at least in the early stages) and, in addition to traditional risk factors, also involves specific risk factors. In particular, the excess cardiovascular mortality and morbidity can be explained by chronic inflammation, the duration and activity of the autoimmune disease, and the effects of immunosuppressive therapy (glucocorticoids and methotrexate) [4]. Wolfe et al. [5] have observed that minimal disease activity and a short disease duration are associated with better outcomes in RA. All of the components of the heart can be affected by a number of pathogenetic mechanisms that may involve the valves, the coronary arteries, the conduction system, or the myocardium, endocardium or pericardium. The clinical manifestations of cardiac involvement include: pericarditis, myocarditis and myocardial fibrosis, rhythm and conduction disturbances, coronaritis with ischemic heart disease, valvular diseases, pulmonary hypertension, syncope, and diastolic or systolic heart failure [1,6]. It has recently been recognised that chronic inflammation plays an important role in the development of atherosclerotic
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plaque [7–9], and the prime mover in this process seems to be endothelial dysfunction [10], which is largely characterised by a reduction in nitric oxide (NO) production by NO synthase. Asymmetric dimethyl arginine (ADMA) is an endogenous inhibitor of NO synthase and has recently emerged as a novel marker of cardiovascular risk; it has already been demonstrated that plasma ADMA levels are high in RA patients [11]. Moreover, it has been shown that anti-rheumatic drugs reduce systemic inflammation and may improve endothelial dysfunction [12], and the same effect has been observed after statin therapy [13,14]. As autoimmune diseases are characterised by a high degree of cardiovascular risk, and cardiac involvement is associated with adverse outcomes and a poor prognosis, the early identification of patients at higher risk is essential. Knowing the mechanisms responsible for cardiovascular damage in systemic autoimmune diseases is an important step in choosing appropriate drugs that can block/slow the development of atherosclerosis. 2. Diagnostic methods 2.1. Imaging techniques The early phases of cardiovascular involvement in patients with autoimmune diseases may be clinically silent, with only the presence of a microcirculation disorder (Table 1). The diagnostic imaging techniques capable of detecting morphological cardiac damage can be divided into: 1. non invasive (transthoracic echocardiography, tissue doppler imaging) 2. semi-invasive (transthoracic stress echocardiography, transesophageal echocardiography) 3. computed tomography and coronary magnetic resonance angiography 4. invasive techniques (angiography) 2.1.1. Transthoracic echocardiography Transthoracic echocardiography is a reliable non-invasive technique that allows an accurate evaluation of valvular
Table 1 Cardiovascular involvement in patients with systemic autoimmune diseases, diagnostic imaging techniques and treatment: salient points and recommendations Early phases of cardiovascular involvement in patients with systemic autoimmune diseases may be clinically silent The diagnostic imaging techniques capable of detecting morphological cardiac damage can be divided into: – non invasive (transthoracic echocardiography, tissue doppler imaging) – semi-invasive (transthoracic stress echocardiography, transesophageal echocardiography) – computed tomography and coronary magnetic resonance angiography – invasive techniques (angiography) ⁎ADMA has been shown to be a marker of endothelial dysfunction that represents an early stage of atherosclerosis The effects may go beyond controlling inflammation and disease activity, including the endothelial effects of anti-tumour necrosis factor (TNF) α agents, and the effects of conventional therapy and biological drugs on vascular function. The efficacy of anti-rheumatic therapy in reducing or slowing the progression of atherosclerosis have drawn attention to the need for a more aggressive therapeutic approach to patients with systemic autoimmune diseases. ⁎ADMA: Asymmetric dimethyl arginine.
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abnormalities, pericardial diseases and ventricular wall motion defects. Doppler analysis is useful for studying left ventricular diastolic filling, valve function and pulmonary pressures. Rexhepaj et al. [15] used Doppler echocardiography to assess the prevalence of left and right ventricular diastolic dysfunction in RA patients without any clinical signs of cardiovascular disease. They found significant differences in early diastolic flow velocity (E), atrial flow velocity (A) and the E/A ratio between patients and controls, which suggests that asymptomatic RA patients have reduced left and right ventricular function, but no differences in left ventricular size or thickness, systolic function or the myocardial performance index. 2.1.2. Transthoracic stress echocardiography with coronary flow reserve evaluation It has recently been shown that coronary flow reserve (CFR) evaluated by means of transthoracic dipyridamole stress echocardiography is a highly sensitive (N90%) diagnostic marker of coronary artery disease (CAD) [16,17] and, when associated with the evaluation of regional wall motion, is also highly specific [18]. A CFR of b2 in the distal left anterior descending artery (LAD) accurately predicts the presence of coronary stenosis [17]. In the absence of an epicardial coronary stenosis, an abnormal CFR may reflect an impaired coronary microcirculation in patients suffering from a reperfused myocardial infarction, arterial hypertension with or without left ventricular hypertrophy, diabetes mellitus, hypercholesterolemia, syndrome X, hypertrophic cardiomyopathy and other diseases [19]. CFR has also been used to assess prognosis in various cardiac conditions, and it has been shown that a reduced CFR correlates with a negative prognosis [20]. Patients have to abstain from xanthine containing food and drinks during the 24 h preceding a dipyridamole stress echocardiography test with coronary flow reserve evaluation. With the patient in a stable 90° left lateral recumbent position, a modified two-chamber view is used to identify the distal LAD artery, in which CFR is evaluated before and during dipyridamole infusion (0.56 mg/kg over 4 min + 0.28 mg/kg over the next 2 min) using an 8 MHz transducer to assess the systolic and diastolic components of the Doppler signal. Coronary blood flow in the mid-distal portion of the LAD artery is measured under the guidance of color Doppler flow mapping synchronised with electrocardiogram. CFR is calculated as the ratio between peak diastolic velocity during hyperemia and baseline diastolic velocity (Fig. 1). At the end of the analysis, 125–250 mg of aminophylline should be administered to counteract the effect of dipyridamole. Hirata et al. [21] used stress echocardiography to evaluate CFR in premenopausal women with SLE and found that it was significantly lower than in age- and gender-matched controls. They concluded that microvascular impairment in SLE could be due to a functional alteration in the endothelium decreasing vasodilation in response to pharmacological stress. 2.1.3. Tissue Doppler imaging (TDI) It has recently been shown that this new imaging modality allow the measurement of myocardial velocities with Doppler. The pulsed wave Doppler cursor is placed at the mitral annulus using the apical window in order to measure velocities that represent longitudinal contraction (positive
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systolic wave, Sa) and relaxation (early negative diastolic wave, Ea, and late negative diastolic wave, La). Ea is a good index of left ventricular relaxation as it correlates with the time constant of isovolumic relaxation and with age: in particular, low E/A velocities with E/A b1 indicate impaired ventricular relaxation. Birdane et al. [22] compared left and right ventricular TDI parameters in RA patients and healthy subjects and observed a significantly reduced E/A ratio in the patients; moreover, the E/A ratio in the RA patients correlated with patient age and the use of steroids. 2.1.4. Transesophageal echocardiography This examination is widely recognised as being more sensitive than the transthoracic approach in detecting valvular lesions [23] and identifying intracardiac masses. We followed up 56 patients with primary APS for five years. All of the patients underwent transesophageal echocardiography, and we observed a large prevalence of cardiac involvement: 61% showed valvular thickening or vegetations and/or potential sources of embolism [24]. 2.1.5. Computed tomography Electron-beam computed tomography is a highly sensitive means of detecting even small amounts of calcium in coronary arteries, and the radiation doses received during CT study are much lower than those used for angiography [25]. Recent studies have shown the accuracy of multi slice computed tomography associated with the administration of an iodinate contrast medium to visualise the coronary artery lumen in detecting CAD [26]. Kiani et al. [11] used helical computed tomography in 200 asymptomatic SLE patients and found that they had increased coronary calcium that significantly correlated with plasma ADMA levels. Furthermore, Chung et al. [27] studied the extent of coronary artery calcification by means of electron-beam computed tomography and demonstrated the higher prevalence and greater severity of coronary calcification in patients with established RA than in those with early disease, which was partially related to smoking and an increased erythrocyte sedimentation rate (ESR). 2.1.6. Coronary magnetic resonance angiography This allows the non invasive visualisation of the major epicardial coronary arteries in the majority of subjects. It has high sensitivity, negative predictive, and overall accuracy values in detecting CAD, and is not exercise dependent. In comparison with computed tomography, coronary magnetic resonance angiography has the advantage of not requiring exposure to ionising radiation or the injection of contrast agents [28]. 2.1.7. Angiography This remains the gold standard for diagnosing coronary stenosis as it detects the presence, extent and position of atheromatous lesions. However, its use for screening purposes is limited by its invasiveness and potentially high level of risk [29]. 2.1.8. Common carotid Doppler ultrasound Non invasively measured common carotid intima-media thickness (IMT) is a clinically useful marker of early stage
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Fig. 1. Examples of CFR values obtained in control subjects (A) and ERA patients (B). ⁎ indicates the diastolic velocity in Doppler signal at baseline (upper panels) and during hyperaemia (lower panels).
atherosclerosis that closely correlates with the presence of CAD [30]. Kumeda et al. [31] found that IMT of common carotid and femoral arteries is greater in RA patients than healthy controls, and that the increase was associated with the duration and severity of the disease. In line with this, Ciftci et al. [32] found the presence of increased IMT and impaired coronary microvascular function in RA patients related to disease duration. 2.2. ADMA measurements In addition to instrumental diagnostic investigations, there is increasing evidence indicating a close association between plasma ADMA levels and cardiovascular disease in
patients with autoimmune diseases. Released by endothelial cells, ADMA has been shown to be a marker of the endothelial dysfunction that represents an early stage of atherosclerosis. Increased plasma ADMA levels have been found in various pathological conditions characterised by a high cardiovascular risk, including hypercholesterolemia [33], hypertriglyceridemia [34], peripheral arterial disease [35], hypertension [36], type 2 diabetes mellitus [37], acute coronary syndrome [38] and end-stage renal disease [39]. Kiani et al. [11] have reported higher ADMA levels in SLE patients, associated with coronary calcium and a poor prognosis; moreover, the SLE patients with abnormal ADMA levels were also more likely to have “mild” carotid plaque, although the difference was not statistically significant.
Fig. 2. DAS 28 (left panel) and CFR (right panel) values before and after long-term disease modifying anti-rheumatic drugs.
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Furthermore, Surdacki et al. [40] found an association between increased plasma ADMA levels and greater common carotid IMT in RA patients. In line with these data, we found a lower CFR and higher plasma ADMA levels in a group of 25 off therapy patients with early RA and no evidence of CAD than in a group of age- and gender-matched healthy controls, as well as a negative correlation between CFR and plasma ADMA levels.
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diseases. However, increased IMT reflects a later stage of the atherosclerotic process when anatomical changes have already occurred, whereas impaired CFR and altered plasma ADMA levels are earlier markers of functional damage. The beneficial effects of new anti-rheumatic drugs on cardiovascular damage and their efficacy in reducing or slowing the progression of atherosclerosis have drawn attention to the need for a more aggressive therapeutic approach to patients with systemic autoimmune diseases.
3. Effects of anti-rheumatic therapy Take-home messages Evidence has recently emerged indicating that the effects of anti-rheumatic therapy may go beyond controlling inflammation and disease activity, including the endothelial effects of anti-tumor necrosis factor (TNF) α agents and the effects of conventional therapy and biological drugs on vascular function. Hurlimann et al. [12] found that TNFα antagonism not only reduces RA activity but also improves endothelial function. They also observed that the reduction in local and systemic inflammation induced by disease modifying antirheumatic drugs can reverse endothelial dysfunction [14]. It is worth noting that the pleiotropic effects of statin lipidlowering therapy seem to protect the vascular endothelium, as shown Mäki-Petäjä et al. [13] who demonstrated the efficacy of ezetimibe and simvastatin in reducing systemic inflammation, disease activity and aortic stiffness in RA patients, concomitantly improving endothelial function. However, the possible effectiveness of statins and biological therapies in changing the course of CAD in RA patients remains to be investigated. To this end, we designed a follow up study of 15 RA patients without any signs of CAD aimed at assessing the effects of anti-rheumatic therapy on endothelial dysfunction. All of the patients were evaluated in terms of disease activity, Doppler-derived CFR and plasma ADMA levels at baseline off therapy, and after 24 months of DMARD or anti-TNFα treatment. The final results of the study showed that, as well as significantly reducing disease activity, the antirheumatic drugs improved CFR in the absence of any significant changes in plasma ADMA levels (Fig. 2). 4. Conclusions As patients with systemic autoimmune diseases are at higher risk of developing cardiovascular diseases than the general population, it is essential to detect endothelial dysfunction and impaired coronary microcirculation earlier in asymptomatic subjects. Coronary angiography remains the gold standard for the diagnosis of coronary stenosis, but new, non invasive and more reliable diagnostic techniques have been introduced into clinical practice to detect sub-clinical microcirculation abnormalities. In particular, echocardiography with its numerous applications (CFR evaluation, TDI, transesophageal) seems to be the most appropriate screening technique as it non-invasively, reliably, sensitively and specifically identifies preclinical cardiac involvement in systemic autoimmune diseases. Common carotid IMT measured by means of carotid ultrasound can provide additional information that is useful for stratifying cardiovascular risk in patients with systemic autoimmune
• Patients with systemic autoimmune diseases are at increased risk of developing cardiovascular diseases • The early phases of cardiovascular involvement in patients with autoimmune diseases may be clinically silent, with only a microcirculation disorder present. • Echocardiography with its numerous applications (CFR evaluation, TDI, transesophageal) seems to be the most suitable means of screening. • Common carotid IMT measured by means of carotid ultrasound may provide additional information that is useful for stratifying cardiovascular risk in patients with systemic autoimmune diseases. References [1] Knonkaert DC. Cardiac involvement in systemic inflammatory diseases. Eur Heart J 2007;28:1797–804. [2] Soltész P, Szekanecz Z, Kiss E, Shoenfeld Y. Cardiac manifestations in antiphospholipid syndrome. Autoimmun Rev 2007;6:379–86. [3] Del Rincon I, Williams K, Stern MP, Freeman GL, Escalante A. High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors. Arthritis Rheum 2001;44:2737–45. [4] Hahn BH, Grossman J, Chen W, McMahon M. The pathogenesis of atherosclerosis in autoimmune rheumatic diseases: roles of inflammation and dyslipidemia. J Autoimmun 2007;28:69–75. [5] Wolfe F, Rasker JJ, Boers M, Wells GA, Michaud K. Minimal disease activity, remission, and the long-term outcomes of rheumatoid arthritis. Arthritis Rheum 2007;57:935–42. [6] Rav-Acha M, Plot L, Peled N, Amital H. Coronary involvement in Takayasu's arteritis. Autoimmun Rev 2007;6:566–71. [7] Sattar N, McCarey DW, Capell H, McInnes IB. Explaining how “highgrade” systemic inflammation accelerates vascular risk in rheumatoid arthritis. Circulation 2003;108:2957–63. [8] Bassi N, Ghirardello A, Iaccarino L, Zampieri S, Rampudda ME, Atzeni F, et al. OxLDL/beta2GPI-anti-oxLDL/beta2GPI complex and atherosclerosis in SLE patients. Autoimmun Rev 2007;7:52–8. [9] Staub HL, Franck M, Ranzolin A, Norman GL, Iverson GM, von Mühlen CA. IgA antibodies to beta2-glycoprotein I and atherosclerosis. Autoimmun Rev 2006;6:104–6. [10] Arosio E, De Marchi S, Rigoni A, Prior M, Delva P, Lechi A. Forearm hemodynamics, arterial stiffness and microcirculatory reactivity in RA. J Hypertens 2007;25:1273–8. [11] Kiani AN, Mahoney JA, Petri M. Asymmetric dimethylarginine is a marker of poor prognosis and coronary calcium in Systemic Lupus Erythematosus. J Rheumatol 2007;34:1502–5. [12] Hurlimann D, Forster A, Noll G, Enseleit F, Chenevard R, Distler O, et al. Anti-tumor necrosis factor-alpha treatment improves endothelial function in patients with rheumatoid arthritis. Circulation 2002;106:2184–7. [13] Mäki-Petäjä KM, Booth AD, Hall FC, Wallace SM, Brown J, McEniery CM, et al. Ezetimibe and simvastatin reduce inflammation, disease activity, and aortic stiffness and improve endothelial function in rheumatoid arthritis. J Am Coll Cardiol 2007;50:852–8. [14] Belizna CC, Richard V, Thuillez C, Lévesque H, Shoenfeld Y. Insights into atherosclerosis therapy in antiphospholipid syndrome. Autoimmun Rev 2007;7:46–51. [15] Rexhepaj N, Bajraktari G, Berisha I, Beqiri A, Shatri F, Hima F, et al. Left and right ventricular diastolic functions in patients with rheumatoid arthritis without clinically evident cardiovascular disease. Int J Clin Pract 2006;60:683–8.
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Apoptosis-associated antigens recognized by autoantibodies in patients with the autoimmune liver disease primary biliary cirrhosis Primary biliary cirrhosis (PBC) is characterized by progressive destruction of small intra-hepatic bile ducts and the presence of antimitochondrial antibodies. The etiopathogenesis of this autoimmune disease remains to be elucidated. One of the attractive concepts for the induction of autoimmunity is the defective clearance of apoptotic cells. These cells undergo necrosis and release inflammatory factors and intracellular antigens which might induce autoimmunity if not cleared appropriately. In a recent study Berg CP et al (Apoptosis 2008;13:63–75) studied the role of apoptosis in PBC. Following induction of apoptosis in 3 malignant cell lines, intracellular antigens were recognized by purified IgG from patients with PBC but not by IgG from healthy donors. The PBC-IgG recognized antigen expressed on the cells surface, mitochondrial antigen and cytosolic proteins. A major role was demonstrated for Caspase-3 in generation of these proteins. PBC-IgG also recognized caspase-dependent antigens in the supernatant of apoptotic cells (the necrotic phase). Last but not least, among the caspase substrates recognized by PBC-IgG components of PDC-E2 and E1β, the main antigens of anti-mitochonrial antibodies, were identified. Thus it might be concluded that a defect in clearance of apoptotic cells might play a role in the pathogenesis of PBC disease. Antimitochondrial Antibody–Negative Primary Biliary Cirrhosis Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease of unclear cause. It is characterized by destruction of the bile ducts and the presence of anti-mitochondrial antibodies (AMA) which can be detected in most patients. There is some controversy as to whether the lack of AMA defined as AMA-negative PBC and AMA-positive PBC represent the same entities clinically and immunologically. Recently Mendes F. and Lindor KD (Gastroenterol Clin N Am 2008;37:479–484) reviewed the literature on this subsets of PBC. Both variants occur predominantly in middle aged women and present clinically and histological similarly. Moreover no significant differences were observed regarding disease progression, response to therapy and outcome of liver transplantation. The advent of more sensitive and specific techniques for detection of AMA have already shown that in some patients previously defined as AMA-negative PBC these antibodies can be detected. Thus it might be concluded that AMA-negative and AMA-positive PBC patients have a similar disease, and improved methods of AMA detection might decrease the percentage patients diagnosed with AMA-negative PBC.