Anti-Cardiolipin Antibodies in Patients with Inflammatory Bowel Disease

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<ul><li><p>Anti-Cardiolipin Antibodies in Patients with</p><p>In ammatory Bowel Disease</p><p>BERENDT W. AICHBICHLER, MD, WOLFGANG PETRITSCH, MD, GERHARD A. REICHT, MD,</p><p>HEIMO H. WENZL, MD, ANDREAS J. EHERER, MD, THOMAS A. HINTERLEITNER, MD,</p><p>PIET AUER-GRUMBACH, MD, and GUENTER J. KREJS, MD</p><p>Elevated leve ls of anti-cardiolipin antibodie s are associated with an increased risk for venousand arterial thrombosis. In patients with in ammatory bowe l disease thrombosis is a wellknown complication. We determined the prevalence of elevated anti-cardiolipin antibodie s in136 patients with in ammatory bowel disease compared with 136 healthy controls andanalyzed thromboembolic complications in patients with increased anti-cardiolipin antibodylevels. Anti-cardiolip in antibody titers were signi cantly elevated in patients with Crohn sdisease (5.7 units/ml) and ulce rative colitis (5.3 units/ml) compared to the control group (2.5units/ml) . We found no corre lation between disease activity and anti-cardiolipin antibodylevels. Seven patients had deep venous thrombosis in the ir history, in three of them this wascomplicate d by pulmonary embolism. In only two of the seven patients with deep venousthrombosis were anti-cardiolipin antibody leve ls increased. In conclusion, anti-cardiolipinantibody titers were signi cantly increased in patients with in ammatory bowe l disease .Elevated anti-cardiolipin antibody leve ls appear to play no role in the pathoge nesis ofthromboembolic events in patients with in ammatory bowe l disease .</p><p>KEY WORDS: in ammatory bowel disease ; anti-cardiolipin antibodies; deep venous thrombosis.</p><p>The etiology of Crohn s disease (CD) and ulce rative</p><p>colitis (UC) is still unknown. Some authors sugge sted</p><p>that CD may be mediated by chronic mesenteric</p><p>vasculitis, which causes multifocal gastrointe stinal in-</p><p>farctions (1). Cutaneous, ocular, and systemic vascu-</p><p>litis has also been described in patients with this</p><p>disorder. With this theory of pathogenesis, a se-</p><p>quence of events in CD has been sugge sted that</p><p>include s vascular injury, focal arteritis, brin deposi-</p><p>tion, arterial occlusion (mainly at the level of the</p><p>muscularis propria) , and tissue infarction or neovas-</p><p>culization (2).</p><p>Anti-cardiolipin (ACL) antibodie s are targe ted</p><p>against anionic phospholipids and are mainly found in</p><p>sera of patients with autoimmune diseases. In exper-</p><p>imental studies ACL antibodie s inhibit the effect of</p><p>the prothrombin activator complex; however, they do</p><p>not induce bleeding, but rathe r lead to arterial and/or</p><p>venous thrombosis with such complications as pulmo-</p><p>nary embolism (3). Numerous studie s have shown</p><p>that there is a close association between elevated</p><p>ACL titers and increased risk for venous and arterial</p><p>thrombosis, mainly in patients with systemic lupus</p><p>erythematosus (SLE), but also for ischemic stroke,</p><p>and non-SLE disorde rs, thrombocytope nia, recurrent</p><p>abortion, and lymphoma (4 9). Ginsburg et al have</p><p>also shown an increased risk of 5% for deep venous</p><p>thrombosis or pulmonary embolism in healthy adults</p><p>with elevated ACL titers (10) .</p><p>In UC and CD thromboembolism occurs with a</p><p>prevalence of 1 7% (11) and thrombosis is a severe</p><p>Manuscript received August 28, 1998; revised manuscript re -ce ived October 27, 1998; accepte d Decembe r 7, 1998.</p><p>From the Departments of Internal Medicine and Dermatology,Karl Franzens Unive rsity, Graz, Austria.</p><p>Address for reprint requests: Dr. Berendt W. Aichbichler, Divi-sion of Gastroenterology and Hepatology, Department of InternalMedicine, Karl Franzens University, Graz, Auenbrugge rplatz 15,A-8036 Graz, Austria.</p><p>Digestive Diseases and Sciences, Vol. 44, No. 4 (April 1999), pp. 852 856</p><p>852 Digestive Diseases and Sciences, Vol. 44, No. 4 (April 1999)0163-2116/99/0400-0852$16.00/0 1999 Plenum Publishing Corporation</p></li><li><p>complication with a mortality rate of 25% (12) . In</p><p>addition, case reports sugge st an association between</p><p>recurrent thrombosis and increased ACL in patients</p><p>with IBD (13 19) .</p><p>The present study was performed to inve stigate</p><p>whether ACL leve ls are increased in patients with UC</p><p>and CD compared to healthy controls and whether or</p><p>not a corre lation exists between increased ACL levels</p><p>and thromboembolic complications in these patients.</p><p>MATERIALS AND METHODS</p><p>Patients. A total of 136 consecutive patients with IBDseen in our department either as outpatients or duringhospital admission were included into this study. CD waspresent in 73 and UC in 63 patients. Epidemiologic data ofthe patients and the control group (see below) are given inTable 1. Diagnosis was based on medical history, clinical,endoscopic, and/or radiological examination and appropri-ate histopathology. Classi cation of IBD was based uponthe criteria of Lennard-Jones (20). Patients with an inde-terminate colitis were excluded from this study. Medicalrecords were surveyed for history of deep venous thrombo-sis, pulmonary embolism, disease activity, and abdominalsurgery during the course of the disease . In addition, duringfurther follow-up visits patients were reevaluated for pastthrombotic events including speci c questions regardingany thromboembolic event in the past and a physical exam-ination. Doppler ultrasound and phlebography were notperformed routinely. Activity of IBD was assessed by usingthe Crohns disease activity index (CDAI) (21) in patientswith CD and using the Truelove-Witts criteria in patientswith UC, respectively (22). Active disease was de ned as arecent onset or exacerbation of symptoms, with a CDAIhigher 150 in patients with CD. In patients with UC a scorehigher than 6 points was de ned to be an active disease . Inaddition, the acute-phase protein C-reactive protein (CRP)was recorded in each patient using routine laboratory tech-niques.As a control group 136 age - and sex-matched healthy</p><p>adults were recruited from an internal medicine practice.Their mean age was 39 6 10 years (range 20 60); 49%were males and 51% were females. Blood samples weretaken from the controls when they were seen for a check-upas part of a preventive medicine program. Electrocardio-gram, blood pressure, and standard laboratory ndingswere normal in all healthy controls.</p><p>Analysis of Samples. Commercially available puri edcardiolipin (Elias, Freiburg, Germany) was used for thedetection of antibodies against cardiolipin in sera with astandardized synchrone enzyme-linked immunosorbent as-say as described elsewhere (3, 7 9). Values were measuredphotometrically at 492 nm and compared with a standardcurve. All measurements were performed in duplicate. Con-centrations were expressed in IgG phospholipid units permilliliter. ACL levels above 10 GPL units/ml were consid-ered to be elevated (mean 1 2 SD of the control group).Statis tical Methods. Since IgG ACL levels were not</p><p>normally distributed the median 6 rst quartile rather thanthe mean was used for presentation. To determine differ-ences in IgG ACL leve ls between the different groups, theMann-Whitney rank sum test was performed; to calculatecorrelations, the Spearman rank test was used. McNemarstest with the Yates correction was done for comparing thefrequency of elevated IgG-ACL in patients and controls.Con dence intervals of the frequency of increased IgGACL levels were determined by z test. Statistical analyseswere done using statistical software (23) . P , 0.05 wasconsidered as signi cant.</p><p>RESULTS</p><p>In patients with CD, 26 had ileocecal disease, 30</p><p>had extended disease of the small and large inte stine,</p><p>13 had Crohn s colitis, and in four patients only the</p><p>small inte stine was involve d. Patie nts with CD</p><p>showed signi cantly highe r IgG ACL leve ls in com-</p><p>parison to the control group (5.7 6 1.7 versus 2.5 60.6, P , 0.001) (Figure 1 and Table 2). The frequencyof increased IgG ACL levels was 24% higher (95%</p><p>con dence inte rval, 15 33% , P . 0.001) in CD pa-tients compared with controls.</p><p>Of the 63 patients with UC, 11 had proctitis, 28 had</p><p>left-sided colitis, and 24 had pancolitis. Similarly, in</p><p>patients with UC, IgG ACL levels were signi cantly</p><p>TABLE 1. PATIENT CHARACTERISTICS *</p><p>CD UC Controls</p><p>Total number 73 63 136</p><p>Age (mean 6 SD) 33 6 10 36 6 11 39 6 10 NSSex (male/female ) 35/38 30/33 67/69 NS</p><p>Disease active/inactive 27/46 22/41Patients with intestinal operations 46 3</p><p>* There were no signi cant differences with respect to age and sex</p><p>distribution between the patient and control groups (NS 5 notsigni cant) .</p><p>Fig 1. IgG ACL titers in 73 patients with Crohns disease (CD), 63</p><p>patients with ulcerative colitis (UC), and 136 healthy controls. Thehorizontal lines indicate median values, the dotted line repre sents</p><p>the upper limit of normal.</p><p>ANTI-CARDIOLIPIN ANTIBODIES IN IBD</p><p>853Digestive Diseases and Sciences, Vol. 44, No. 4 (April 1999)</p></li><li><p>higher than in controls (5.3 6 3.1 versus 2.5 6 0.6,P , 0.001) , but not signi cantly different from pa-tients with CD (Figure 1 and Table 2). The frequency</p><p>of increased IgG ACL leve ls was 13% increased (95%</p><p>con dence interval, 5 21% , P 5 0.003) in UC pa-tients compared with controls.</p><p>Neither in patients with CD nor in patients with</p><p>UC we could nd a correlation between disease ac-</p><p>tivity (measured by CDAI index in CD patients and</p><p>Truelove -Witts criteria in patients with UC) and IgG</p><p>ACL leve ls. Corre lation coef cients were r 5 0.12,P 5 0.52 in patients with CD and r 5 0.26, P 5 0.14in patients with UC, respective ly. In addition, we</p><p>assessed if disease activity determined by the acute -</p><p>phase protein CRP was correlated with IgG ACL</p><p>leve ls. Again the correlations were weak and not</p><p>signi cantly different in both groups (r 5 0.15, P 50.22 in patients with CD, and r 5 0.11, P 5 0.41 inpatients with UC). Analyzing both groups toge ther</p><p>did not change the results (r 5 0.11, P 5 0.19) .Forty-three patients with active disease received</p><p>corticosteroids at the time of blood sampling. The</p><p>presence of elevated IgG ACL titers was not corre-</p><p>lated with current corticoste roid therapy (P 5 0.48) .Of 136 consecutive patients with IBD, seven pa-</p><p>tients (5% ), three with UC and four with CD, had had</p><p>deep venous thrombosis, in three of them compli-</p><p>cated by pulmonary embolism. IgG ACL levels were</p><p>elevated in two (29% ) (Table 3). The time between</p><p>blood sampling and the thromboembolic event was</p><p>1 60 months (median 2 months) . Also in these seven</p><p>patients there was no corre lation between disease</p><p>activity and IgG ACL titers (r 5 0.11, P 5 0.58) . Onlyone of four patients with a thromboembolic event</p><p>within the last 2 months had an elevated ACL titer</p><p>(patient 1 in Table 3).</p><p>Four of these seven patients had active disease at</p><p>the time of blood sampling. One of those four pa-</p><p>tients with active disease had an elevated ACL titer</p><p>(patient 1 in Table 3). In addition, no elevation of IgG</p><p>ACL levels could be found in those two patients who</p><p>underwent resection of the in amed bowe l.</p><p>DISCUSSION</p><p>We report signi cantly elevated IgG ACL leve ls in</p><p>patients with Crohn s disease and ulce rative colitis</p><p>when compared to a group of healthy controls. We</p><p>also found an increased risk for deep venous throm-</p><p>bosis with a prevalence of 5% in our patients with</p><p>IBD. Since only two of seven patients with deep</p><p>venous thrombosis showed high ACL titers, elevated</p><p>ACL titers do not seem to play a role in the etiology</p><p>of thrombosis in IBD patients.</p><p>Recently numerous studies have provided evidence</p><p>that there is an association of elevated ACL, mainly</p><p>of the IgG type (7 9), and thrombosis, thrombocyto-</p><p>penia, neurologic diseases, and recurrent fetal loss (4,</p><p>5, 10). Although the pathogenesis of thrombosis in</p><p>patients with elevated IgG ACL is unknown, several</p><p>mechanisms have been proposed, including direct</p><p>endothe lial damage , antibody-m ediated plate le t acti-</p><p>vation, and inhibition of endogenous anticoagulants</p><p>such as thrombomodul in, prote in C, antithrombin III,</p><p>prekallikre in, or prostacyclin (4, 5). The target anti-</p><p>gens to which ACL antibodie s are directed have not</p><p>yet been characterized. There is evidence that in-</p><p>TABLE 2. PLASMA LEVELS OF IgG ACL IN IBD PATIENTS AND</p><p>CONTROLS</p><p>IgG ACL (units/ml)</p><p>CD UC Controls</p><p>Median 6 1st quartile 5.7 6 1.7* 5.3 6 3.1* 2.5 6 0.6Range 0.1 39.6 0.1 188.4 0.1 21.1</p><p>Number of positive (% )( . 10 units/ml) 20 (27) 10 (16) 4 (3)</p><p>* P , 0.001 vs controls (Mann-Whitney rank sum test). P , 0.001 vs controls (McNemar s test with the Yates correction).</p><p>TABLE 3. CHARACTERISTICS OF PATIENTS WITH IBD AND DEEP VENOUS THROMBOSIS</p><p>Patient</p><p>1 2 3 4 5 6 7</p><p>Age, sex 47/F 32/M 42/F 49/F 34/F 35/M 52/M</p><p>Diagnosis CD UC UC CD UC CD CDIgG ACL (units/ml) 39.7 66.1 1.0 4.3 1.3 1.3 1.0</p><p>Months since venous thrombosis 1 56 1 60 36 1 2Pulmonary embolism yes no no yes no yes no</p><p>Active disease* yes no yes no yes ye s noCRP level (mg/liter) 40 3 22 6 38 58 9</p><p>* CDAI . 150 in patients with Crohns disease and a score . 6 (Truelove-Witts criteria) in patients withUC at time of study.</p><p>AICHBICHLER ET AL</p><p>854 Digestive Diseases and Sciences, Vol. 44, No. 4 (April 1999)</p></li><li><p>creased ACL leve ls of the IgG type are more close ly</p><p>associate d with thrombosis than IgM ACL (7 9).</p><p>Thromboembolic complications occur in 1 7% of</p><p>patients with IBD (11, 12, 24) . Talbot et al (12) found</p><p>in a study in 7199 patients with IBD an incidence of</p><p>deep venous thrombosis of 1% with a mortality rate</p><p>of 25% . Thrombosis must therefore be conside red as</p><p>a severe complication in patients with this disease.</p><p>Although the mechanism leading to thrombosis in</p><p>IBD is not known, a hypercoagulable state in associ-</p><p>ation with exacerbations of IBD seems to be impor-</p><p>tant. In support of this concept, elevated leve ls of</p><p>factors V, VIII, and brinogen and decreased levels</p><p>of antithrombin III, and proteins S and C with or</p><p>without thrombocytosis were found in active UC and</p><p>CD (25 31) . Several ndings indicate that ACL is</p><p>increased in patients with IBD and may facilitate</p><p>thrombus formation. Two small studie s, one of 20 and</p><p>one of 50 patients with CD showed increased levels of</p><p>ACL in 6 and 11 patients, respective ly (32, 33) . One</p><p>recent study showed increased ACL levels in 16 of 41</p><p>patients with CD and 6 of 19 patients with UC (34) .</p><p>Vianna et al (13) reported the case of a patient with</p><p>CD who suffered from recurrent thrombosis in the</p><p>presence of increased IgG ACL leve ls. Similarly Papi</p><p>et al (14) described a patient with severe cerebral</p><p>infarction in combination with UC and elevated ACL.</p><p>During the course of their disease, seven of our</p><p>patients (5% ) deve loped deep venous thrombosis</p><p>(three patients with UC, four with CD), complicate d</p><p>by pulmonary embolism in three of them. However,</p><p>we could demonstrate elevated ACL levels in only</p><p>two of these seven patients (29% ). One patient died</p><p>of massive pulmonary embolism. In addition to</p><p>thrombocytosis and increased CRP, an elevated IgG</p><p>ACL titer (39.7 GPL units/ml) was also associate d</p><p>with thrombosis in this patient. Our data for mortality</p><p>are in agreement with those in the lite rature (11, 12) .</p><p>Our data concerning patients with thrombosis are</p><p>retrospective in this study, and they agree with the</p><p>results of...</p></li></ul>


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