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Anti-Cardiolipin Antibodies in Patients with Inflammatory Bowel Disease

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  • Anti-Cardiolipin Antibodies in Patients with

    In ammatory Bowel Disease

    BERENDT W. AICHBICHLER, MD, WOLFGANG PETRITSCH, MD, GERHARD A. REICHT, MD,

    HEIMO H. WENZL, MD, ANDREAS J. EHERER, MD, THOMAS A. HINTERLEITNER, MD,

    PIET AUER-GRUMBACH, MD, and GUENTER J. KREJS, MD

    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 .

    KEY WORDS: in ammatory bowel disease ; anti-cardiolipin antibodies; deep venous thrombosis.

    The etiology of Crohn s disease (CD) and ulce rative

    colitis (UC) is still unknown. Some authors sugge sted

    that CD may be mediated by chronic mesenteric

    vasculitis, which causes multifocal gastrointe stinal in-

    farctions (1). Cutaneous, ocular, and systemic vascu-

    litis has also been described in patients with this

    disorder. With this theory of pathogenesis, a se-

    quence of events in CD has been sugge sted that

    include s vascular injury, focal arteritis, brin deposi-

    tion, arterial occlusion (mainly at the level of the

    muscularis propria) , and tissue infarction or neovas-

    culization (2).

    Anti-cardiolipin (ACL) antibodie s are targe ted

    against anionic phospholipids and are mainly found in

    sera of patients with autoimmune diseases. In exper-

    imental studies ACL antibodie s inhibit the effect of

    the prothrombin activator complex; however, they do

    not induce bleeding, but rathe r lead to arterial and/or

    venous thrombosis with such complications as pulmo-

    nary embolism (3). Numerous studie s have shown

    that there is a close association between elevated

    ACL titers and increased risk for venous and arterial

    thrombosis, mainly in patients with systemic lupus

    erythematosus (SLE), but also for ischemic stroke,

    and non-SLE disorde rs, thrombocytope nia, recurrent

    abortion, and lymphoma (4 9). Ginsburg et al have

    also shown an increased risk of 5% for deep venous

    thrombosis or pulmonary embolism in healthy adults

    with elevated ACL titers (10) .

    In UC and CD thromboembolism occurs with a

    prevalence of 1 7% (11) and thrombosis is a severe

    Manuscript received August 28, 1998; revised manuscript re -ce ived October 27, 1998; accepte d Decembe r 7, 1998.

    From the Departments of Internal Medicine and Dermatology,Karl Franzens Unive rsity, Graz, Austria.

    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.

    Digestive Diseases and Sciences, Vol. 44, No. 4 (April 1999), pp. 852 856

    852 Digestive Diseases and Sciences, Vol. 44, No. 4 (April 1999)0163-2116/99/0400-0852$16.00/0 1999 Plenum Publishing Corporation

  • complication with a mortality rate of 25% (12) . In

    addition, case reports sugge st an association between

    recurrent thrombosis and increased ACL in patients

    with IBD (13 19) .

    The present study was performed to inve stigate

    whether ACL leve ls are increased in patients with UC

    and CD compared to healthy controls and whether or

    not a corre lation exists between increased ACL levels

    and thromboembolic complications in these patients.

    MATERIALS AND METHODS

    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

    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.

    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

    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.

    RESULTS

    In patients with CD, 26 had ileocecal disease, 30

    had extended disease of the small and large inte stine,

    13 had Crohn s colitis, and in four patients only the

    small inte stine was involve d. Patie nts with CD

    showed signi cantly highe r IgG ACL leve ls in com-

    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%

    con dence inte rval, 15 33% , P . 0.001) in CD pa-tients compared with controls.

    Of the 63 patients with UC, 11 had proctitis, 28 had

    left-sided colitis, and 24 had pancolitis. Similarly, in

    patients with UC, IgG ACL levels were signi cantly

    TABLE 1. PATIENT CHARACTERISTICS *

    CD UC Controls

    Total number 73 63 136

    Age (mean 6 SD) 33 6 10 36 6 11 39 6 10 NSSex (male/female ) 35/38 30/33 67/69 NS

    Disease active/inactive 27/46 22/41Patients with intestinal operations 46 3

    * There were no signi cant differences with respect to age and sex

    distribution between the patient and control groups (NS 5 notsigni cant) .

    Fig 1. IgG ACL titers in 73 patients with Crohns disease (CD), 63

    patients with ulcerative colitis (UC), and 136 healthy controls. Thehorizontal lines indicate median values, the dotted line repre sents

    the upper limit of normal.

    ANTI-CARDIOLIPIN ANTIBODIES IN IBD

    853Digestive Diseases and Sciences, Vol. 44, No. 4 (April 1999)

  • 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

    of increased IgG ACL leve ls was 13% increased (95%

    con dence interval, 5 21% , P 5 0.003) in UC pa-tients compared with controls.

    Neither in patients with CD nor in patients with

    UC we could nd a correlation between disease ac-

    tivity (measured by CDAI index in CD patients and

    Truelove -Witts criteria in patients with UC) and IgG

    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

    assessed if disease activity determined by the acute -

    phase prote