Clinical significance of anticardiolipin and anti B2GPI antibodies.pdf

7/29/2019 Clinical significance of anticardiolipin and anti B2GPI antibodies.pdf

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Original Paper

Int Arch Allergy Immunol 2004;135:148153

DOI: 10.1159/000080658

Clinical Significance of Anticardiolipin

and Anti-2-Glycoprotein I Antibodies

Gerlinde Obermosera Waltraud Bitterlichc Friedebert Kunzb

Norbert T. Seppa

Departments ofaDermatology and bInternal Medicine, University Hospital of Innsbruck, Innsbruck, andcDepartment of Psychiatry, Private Medical University of Salzburg, Salzburg, Austria

Received: April 15, 2004

Accepted: June 24, 2004

Published online: September 2, 2004

Correspondence to: Dr. Gerlinde ObermoserDepartment of Dermatology, University Hospital InnsbruckAnichstrasse 35AT6020 Innsbruck (Austria)Tel. +43 512 504 22971, Fax +43 512 504 22990, E-Mail [email protected]

ABCFax +41 61 306 12 34E-Mail [email protected]

2004 S. Karger AG, Basel10182438/04/13520148$21.00/0

Accessible online at:www.karger.com/iaa

Key Words

Anticardiolipin antibody W Anti-2-glycoprotein I

antibody W Antiphospholipid syndrome W Lupus

anticoagulant

Abstract

Background:Anticardiolipin (aCl) and anti-2-glycopro-

tein I (anti-2-gpI) antibodies are autoantibodies associat-

ed with the antiphospholipid syndrome (APS), which is

characterized by both arterial and venous thrombosis

and miscarriages. The scope of this study was to explore

the clinical characteristics of patients with aCl and anti-

2-gpI antibodies. Methods:ACl were tested in 3,600

consecutive sera in our laboratory between January

1999 and June 2001. The clinical diagnosis and preva-

lence of thrombosis and pregnancy morbidity were ret-

rospectively reviewed in aCl-positive patients. Further-

more, the frequency of anti-2-gpI antibodies, lupus anti-

coagulant (LA), prolonged activated partial thromboplas-

tin time (aPTT), and thrombocytopenia were investi-gated in aCl-positive patients. Results:147 aCl-positive

patients, 110 women and 37 men with a mean age of 41

years (range 7.882.5), were identified. 42 (28.6%) aCl-

positive patients fulfilled the criteria for APS which was

secondary to a connective tissue disorder in 8 patients.

The frequency of anti-2-gpI antibodies and LA, pro-

longed aPTT, and thrombocytopenia in aCl-positive pa-

tients was 23.8, 27.2, 25.7 and 9.2%, respectively. The

presence of both aCl and anti-2-gpI antibodies was

strongly associated with clinical symptoms of APS (p =

0.007) compared to p = 0.008 for LA. Conclusion:Our

data suggest that assessment of anti-2-gpI antibodies in

addition to aCl is a valuable diagnostic tool in the workup

of patients with APS.Copyright 2004 S. Karger AG, Basel

Introduction

In 1983, Hughes [1] first reported the association oflupus anticoagulant (LA) with stroke, deep venous throm-bosis, pulmonary embolism, and recurrent pregnancy lossin a group of patients suffering from systemic lupus ery-thematosus (SLE). This so-called antiphospholipid syn-drome (APS) is an acquired autoimmune coagulation dis-

order characterized by arterial and venous thrombosisand obstetrical complications. It can either be secondaryto other disorders or occur as a primary disease [24].Thus, APS patients are not only treated in rheumatologyclinics, but also in many other specialized clinics, withsymptoms ranging from thrombocytopenia to valvularheart disease and infertility.

APS is associated with autoantibodies directed againstnegatively charged phospholipids. However, mostly these

This study was presented, in part, in abstract form at the 6th Interna-

tional Lupus Conference, Barcelona, 2001 (Lupus2001;10:61).


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Antibodies and the Antiphospholipid

Syndrome

Int Arch Allergy Immunol 2004;135:148153 149

autoantibodies do not target the phospholipid itself butrecognize phospholipid binding proteins like 2-glycopro-tein I [57] or prothrombin [8, 9]. Antiphospholipid anti-bodies can be either directly detected by ELISA, e.g. anti-cardiolipin antibodies (aCl) and anti-2-glycoprotein I(anti-2-gpI) antibodies, or by their ability to interfere

with phospholipid-depending clotting assays (e.g. acti-vated partial thromboplastin time, aPTT, and LA).The aim of this study was to explore the prevalence

and clinical characteristics of patients with aCl. Further-more, in aCl-positive patients the frequency of other APS-related laboratory parameters, namely anti-2-gpI anti-bodies, LA, thrombocytopenia, and prolonged aPTT, wasinvestigated.

Patients and Methods

Patients

3,600 consecutive sera were tested for IgG and IgM aCl in ourlaboratory between January 1999 and June 2001. Tests for anti-2-gpI antibodies were performed in all aCl-positive sera or if specifical-ly requested (in total, 1,238 sera were assessed for the presence ofanti-2-gpI antibodies). Clinical and laboratory characteristics of aCland/or anti-2-gpI-antibody-positive patients were investigated bychart review. The following clinical symptoms were recorded: deepvenous thrombosis, pulmonary embolism, retinal and hepatic vesselthrombosis, stroke, miscarriage, transitory ischemic attacks, avascu-lar bone necrosis, loss of one or more pregnancies, and the cata-strophic APS. All data on vascular complications had been con-firmed by ultrasound or computed tomography, and reproductiveproblems had been assessed in a specialized obstetrical clinic.

Anticardiolipin Assay

Antibodies were measured by an ELISA kit (RelisaTM Cardioli-pin, Immuno Concepts, Sacramento, Calif., USA) for the determina-tion of aCl IgG and IgM. In brief, nonirradiated microwells coatedwith a stabilized preparation of cardiolipin from beef heart wereincubated with patient samples and phosphate-buffered sample dil-uent containing bovine 2-gpI as a cofactor. Autoantibodies weremeasured with a spectrophotometer using goat anti-human IgG orIgM labelled with horseradish peroxidase and tetramethylbenzidineas a chromogenic substrate. The average intra-assay coefficients ofvariation were 6.9 for both aCl IgG and aCl IgM. The average inter-assay coefficients of variation for aCl IgG and aCl IgM were 5.2 and6.4%, respectively. Results were expressed in GPL units for IgG aCland MPL units for IgM aCl according to an internationally recog-nized standard reference preparation from the AntiphospholipidStandardization Laboratory. Samples with 115 GPL or 115 MPLunits, respectively, were reported as positive.

Anti-2-gpI Antibody Assay

IgG anti-2-gpI antibodies were detected by a commercially avail-able enzyme immunoassay using purified human 2-gpI (Varelisa;Pharmacia & UpJohn, Freiburg, Germany). The detection limit ofthe Varelisa anti-2-gpI antibody IgG assay was 1 U/ml; the averageintra- and interassay variabilities (assessed by the coefficients of vari-

Table 1. Characteristics of the aCl-positive patients

Patients

n %

Sex, females/males 110/37 74.8/25.2Connective tissue disease

includingSLESclerodermaSharp syndromeDermatomyositisPolymyositis

30/147

26/301/301/301/301/30

20.4

Antiphospholipid syndromePrimarySecondary

42/14734/428/42

28.68119.1

Positive aCl 147/147 100Positive anti-2-gpI 35/147 23.8Positive LA 22/81 27.2Prolonged aPTT 28/109 25.7Thrombocytopenia 12/130 9.2

The mean age of the aCl-positive patients was 41 years (range7.882.5 years).

ation of OD450 values) were 5.3 and 8.2%, respectively. Results werereported positive above a cutoff value of 15 U/ml. All samples weretested in duplicate for aCl and anti-2-gpI antibodies.

Other Laboratory Tests

The following tests were performed at the Coagulation Laborato-

ry and the Central Laboratory of the University Hospital of Inns-bruck: LA, aPTT and platelet counts.

Statistical Analysis

Fishers exact test for two-tailed 2 ! 2 contingency tables wascalculated using SPSS version 8.0. Sensitivity and specificity werecalculated for aCl and anti-2-gpI antibodies, LA, aPTT, and combi-nations of these laboratory parameters.

Results

Frequency of aCl and Anti-2-gpI Antibodies,

Prolonged aPTT and ThrombocytopeniaOf the 3,600 sera tested, 147 were positive for aCl (IgG

87.8%, IgM 8.8%, IgG and IgM 3.4%). In 53 of the 1,238samples tested, anti-2-gpI antibodies were detected: 9 ofthese anti-2-gpI-antibody-positive patients were negativeand 44 were positive for aCl. LA was present in 22 of 81(27.2%), prolonged aPTT in 28 of 109 (25.7 %), andthrombocytopenia in 11 of 120 (9.2%) aCl-positive pa-tients tested (table 1).


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150 Int Arch Allergy Immunol 2004;135:148153 Obermoser/Bitterlich/Kunz/Sepp

Table 2. Association of aCl and anti-2-gpIantibodies and LA with clinical features ofAPS

Deep venousthrombosis, %

Pulmonaryembolism, %

Stroke, % Pregnancyloss, %

All events%

aCl+ 17.7p = NS

9.5p = NS

6.1p = NS

9.5p = NS

33.3p = 0.273

Anti-2-gpI+ 25.0

p = 0.158

11.4

p = 0.542

13.6

p = 0.016

13.6

p = 0.223

43.2

p = 0.086LA+ 43.5

p = 0.10321.7p = 0.076

21.7p = 0.076

21.7p = 0.203

69.2p = 0.008

aCl+anti-2-gpI+

28.6p = 0.073

14.3p = 0.31

17.1p = 0.004

17.1p = 0.086

51.4p = 0.007

aCl+LA+ 45.5p = 0.001

22.7p = 0.03

22.7p = 0.003

22.7p = 0.03

72.7p ! 0.001

aCl+anti-2-gpI+LA+

50.0p = 0.003

21.4p = 0.116

35.7p ! 0.001

28.6p = 0.024

78.6p ! 0.001

NS = Statistically nonsignificant.

Patient Characteristics

Of the 147 aCl-positive patients, 110 women and 37men with a mean age of 41 years (range 7.882.5), 26patients suffered from SLE and 1 patient each from scle-roderma, Sharp syndrome, dermatomyositis and poly-myositis. Forty-two (28.6%) aCl-positive patients fulfilledthe criteria for APS [3]; 34 of them showed no signs ofconnective tissue disease and were therefore classified asprimary APS [2]. All of the 8 patients with secondary APSsuffered from SLE (defined by the presence of at least fourcriteria of the American College of Rheumatology classifi-cation [10]).

10.2% of the serum samples were referred to the labo-ratory by four private physicians (two dermatologists, onegeneral practitioner and one reproductive endocrinologist 7.1%) and by the following departments of the Universi-ty Hospital of Innsbruck: 6.5% by the Department ofNeurology, 4.5% by Obstetrics and Gynecology, 1.9% byInternal Medicine, 2.6% by Pediatrics, 1.3% by IntensiveCare, 5.2% by Vascular Surgery, 30.3% by the Coagula-

tion Clinic, and 37.4% by the Department of Dermatolo-gy with its Autoimmune Skin Disease Clinic. ACl andanti-2-gpI antibody testing was ordered (1) as part of ageneral connective tissue disease screening panel, (2) be-cause of a past medical history of thrombotic-, embolic-and/or obstetrical complications, or (3) for the diagnosticworkup of reproductive problems.

Nine aCl-negative anti-2-gpI-antibody-positive pa-tients were identified: 3 patients had no sign or symptom

associated with APS [4]; in the remaining 6 patients thepast medical history revealed deep vein thrombosis (in 1patient), coronary heart disease (in 2 patients), and infer-tility (in 2 women); Raynauds phenomenon was presentin 2 and livedo reticularis and skin ulcers in 1 patienteach.

Correlation with Clinical and Laboratory Features

In 33.3% (p = 0.273), a positive aCl test was associatedwith APS-related clinical features [4] (table 2). When onlythe clinical symptoms satisfying the Sapporo classifica-tion of APS (arterial or venous thrombosis, miscarriagewith more than two consecutive spontaneous abortions,fetal death beyond the 10th week of gestation, or prema-ture birth because of severe preeclampsia/placental insuf-ficiency [3]) were taken into account, the association withpositive aCl antibodies was 28.6% (p = 0.446).

Anti-2-gpI antibodies were present in 43.2% (p =0.086) and LA in 69.6% (p = 0.008) of the patients withclinical symptoms. The presence of both aCl and anti-2-

gpI antibodies was strongly associated with clinical symp-toms of APS (p = 0.007, vs. p = 0.008 for LA). ProlongedaPTT values were significantly associated with anti-2-gpI antibodies (p = 0.021) and LA (p ! 0.001). Thrombo-cytopenia correlated best with the presence of anti-2-gpIantibodies (p = 0.011) or the combination of aCl and anti-2-gpI antibodies (p = 0.003; table 2).


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Syndrome


Table 3. Sensitivity and specificity of aCl and anti-2-gpI antibodies,LA, and aPTT for clinical APS features

Sensitivity%

Specificity%

aCl+ 97 7.4Anti-

2-gpI+ 36 75

LA+ 60 73Prolonged aPTT 44 84aCl+anti-2-gpI+ 35 83aCl+LA+ 31 93aCl+anti-2-gpI+LA+ 20 96aCl+prolonged aPTT 32 89aCl+anti-2-gpI+prolonged aPTT 14 96aCl+LA+prolonged aPTT 18 96aCl+anti-2-gpI+LA+prolonged aPTT 10 98

Comparison of Sensitivity and Specificity of aCl,Anti-2-gpI Antibodies, LA and aPTT for Clinical

Symptoms

ACl had the highest sensitivity (97%) but lowest speci-ficity (7.4%) for clinical symptoms of APS. Presence ofLA per se indicated a higher specificity (73%). Anti-2-gpIantibodies increased the specificity of a positive aCl testfrom 7.4 to 83%. Similarly, prolonged aPTT valuesincreased the specificity of aCl to 89% (table 3).

Discussion

In the present study, we found a prevalence of aCl of4.08% in 3,600 consecutive serum samples. 42 of the 147aCl-positive patients had a history of thrombosis or gesta-tional complications and were therefore diagnosed withAPS. APS was secondary to SLE in 8 patients, and theremaining 34 patients suffered from primary APS. Thesensitivity for clinical events of APS was highest for aCl(97%) followed by LA (60%) and anti-2-gpI antibodies(36%). Specificity of LA (73%) and anti-2-gpI antibodieswas similarly high (75%). The latter is comparable to pre-

vious studies which reported a sensitivity of anti-2-gpIantibodies for clinical features of APS ranging from 22 to43% and a specificity of 7598% [1121]. The associationwith APS-related clinical features was highest in patientspositive for LA (69.2%, p = 0.008), followed by anti-2-gpI antibodies and aCl. This is in agreement with a recentmeta-analysis by Galli et al. [22] where LA was the onlyrisk factor consistently associated with thrombosis, inde-pendent of the type and site of the event, the presence of

SLE, and the laboratory methods used. Interestingly,when our patients were positive for both aCl and anti-2-gpI antibodies, this association was comparable to LA(51.4%, p = 0.007).

The diagnostic value of anti-2-gpI antibodies is sub-ject to controversy. It is now well established that they

appear to serve as the major target antigen in APS [23].Their pathogenetic role in the generation of a prothrom-botic state, probably via endothelial cell activation [24],was demonstrated both in vitro and in vivo in mousemodels [25, 26]. Since they have LA properties in vitro[27], it was expected that the anti-2-gpI antibody ELISAcan offer an advantage over clotting assays (like LA),which give only a qualitative estimate of an in vitro phe-nomenon, and that these results should be comparable intheir correlation with clinical outcome [28]. However, arecent meta-analysis of twenty-eight studies revealed largediscrepancies on the association between anti-2-gpI anti-

bodies and thrombosis, and the authors could not draw adefinite conclusion with respect to their clinical signifi-cance [28]. To date, in contrast to tests for aCl antibodiesand LA, no international consensus statement for thedetermination of anti-2-gpI antibodies exists. The lack ofagreement between studies on anti-2-gpI antibodies mayfurther be influenced by different study populations andinclusion criteria limiting the comparability of results. Inthis study, the association of anti-2-gpI antibodies wasstrongest with stroke (p = 0.016) followed by thrombocy-topenia (p = 0.011), prolonged aPTT (p = 0.021), deepvenous thrombosis (p = 0.158) and pregnancy loss (p =0.223). Recently, Lopez et al. [29] reported that anti-2-gpI antibodies demonstrated a stronger association witharterial than with venous thrombosis. In a study of 376patients with connective tissue disorders (SLE, rheuma-toid arthritis and scleroderma), APS and syphilis, thegroup of Shoenfeld found using the same anti-2-gpIantibodies kit (Varelisa) we used in our study anti-2-gpIantibodies to be more specific than aCl [30].

Not all of the patients with antibodies to 2-gpI haveantibodies detectable in standard antiphospholipid as-says, and it was reported that these patients also have a

higher risk of clinical manifestations of APS [31]: Only 9of 1,238 sera tested in this study were positive for anti-2-gpI antibodies but negative for aCl. Six of thesepatients showed symptoms encountered in APS [4]: deepvein thrombosis (1 patient), skin ulcers (1), coronary heartdisease (2), infertility (2), livedo reticularis (1), and theRaynaud phenomenon (2). Due to the small number inour study, no definite conclusions can be drawn. In thestudy by Hsieh et al. [32], the prevalence of anti-2-gpI


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152 Int Arch Allergy Immunol 2004;135:148153 Obermoser/Bitterlich/Kunz/Sepp

antibodies was 1.7% in 418 aCl-/LA-negative patientswith a history of thrombosis; the recurrence rate of throm-bosis was not elevated in anti-2-gpI-antibody-positivepatients, and therefore the authors concluded that anti-2-gpI antibodies are no likely predictor of recurrentevents in patients without LA.

In summary, our investigations suggest that aCl ap-pears to display high sensitivity for clinical symptoms ofAPS. Assessment of anti-2-gpI antibodies in addition toaCl provides additional clinical information with highspecificity, being comparable to LA. However, our analy-

sis also confirms that these two immunological tests donot substitute functional coagulation assays used to iden-tify phospholipid-binding autoantibodies like LA.

Acknowledgments

We thank Drs. Margreiter, Rohrer, Schmlz, Unterkircher, andZech for providing clinical information on study patients. Skilfultechnical assistance by Gunda Margreiter-Stanarevic and StefanieKind is also acknowledged.

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Clinical significance of anticardiolipin and anti B2GPI antibodies.pdf