Should Anti-2GPI Antibodies be tested in patients
suspected of APS?
By Silvia Pierangeli, Ph.D. Technical Director, Louisville APL Diagnostics, Inc.
Anti-β2GPI tests have been proposed for a more specific measurement of Abs
present in APS (1-10). Current studies show that β2GPI particularly when coated
on oxidized or “high-binding” polystyrene ELISA plates is a relatively specific
antigen for autoantibodies present in APS patients (1,11).
-Anti-β2GPI Abs have been reported to be associated primarily with thrombosis in
patients with APS (8,10), but studies have shown also these antibodies in
patients with pregnancy loss and other manifestations of APS (7-9,10). Recently
some investigators have reported an unusual high prevalence of IgA anti-2GPI
antibodies in patients with SLE and in association with pregnancy losses (12,13).
-A meta-analysis by Galli et al. addressed the value of anti-β2GPI test as a risk
factor for thrombosis (14). The results suggest that IgG anti-β2GPI Abs are
associated with thrombosis. This association was particularly high in SLE
patients..
-A recent paper on the relation between anti- β2GPI Abs and venous thrombosis
in a general population showed an increased risk of a first episode of venous
thrombosis for anti-β2GPI positive patients (15). The role of anti-β2GPI Abs in
arterial thrombosis remains to be established.
1
-Studies from several laboratories suggest that the sensitivity of the anti-β2GPI
test for APS vary from 40% to 90% (1-13).
-Kaplan et al. demonstrated that positivity alone of anti-β2GPI Abs in the absence
of aCL positivity was observed only in 2 % of the samples (15). The authors
concluded that, in aCL and/or LA positive patients, anti-β2GPI test provides little
additional diagnostic value. These results suggest that perhaps anti-β2GPI
should be ordered to confirm APS (since it is more specific than aCL tests) and in
situations when all other (aCL and LA tests) is negative and there is strong
suspicion for APS.
-The value of multiple aPL Ab specificity has been addressed in few studies.
Detkova et al. observed that the simultaneous presence of circulating LA and
high titers of both aCL and β2GPI Abs identified a subset of patients with primary
APS who had a more severe clinical course of the disease. They recommend
performing anti-β2GPI Abs besides LA and aCL in order to alert the physician
about the risk of a more severe course of the illness (16). These data were then
confirmed by Lee et al. (17) who demonstrated that the rate of thrombosis
increased significantly from patient populations with single (27.6%) to patients
populations with double (38.8%) or triple (66.7%) positivity. In this study, single
positivity for anti-β2GPI accounted for 9–12% of thrombotic events and they
concluded that anti-β2GPI provides additional important information (18). The
majority of the studies published so far conclude that IgG anti-β2GPI is an
important additional tool for the diagnosis of APS. Although, based on those
2
reports, no definite conclusion can be drawn with respect to the strength of the
association of thrombosis and anti-β2GPI Abs, it seems that anti-β2GPI
measurement is an additional helpful test besides LA and aCL. Its specificity
seems better than aCL and it could allow the definition of APS in patients
negative for LA and aCL. Based on that, an international committee of experts
that gathered at the XIth International Congress on Antiphospholipid Antibodies
in Sydney, Australia (November 2004) determined that the anti-β2GPI assay
should be included in the screening panel for APS, particularly because it has
been shown that anti-β2GPI may be the sole antibody present in up to 10% of the
patients with clinical features of APS (15,19,20) (Table 1).
3
References cited
1. Roubey RAS, Eisenberg RA, Harper MF, Winfield JB. Anticardiolipin
autoantibodies recognize β2glycoprotein I in the absence of phospholipid:
importance of antigen density and bivalent binding, J Immunol 1995; 154: 954–
960
2. Balestrieri G, Tincani A, Spatola L et al. Anti-β2glycoprotein I antibodies: a
marker of antiphospholipid syndrome?, Lupus 1995; 4: 122–130
3. Arvieux J, Pouzol P, Roussel B, Jacob MC, Colomb MG.
Lupus-like
anticoagulant properties of murine monoclonal antibodies to β 2glycoprotein I, Br J
Haematol. 1992; 81: 568–573
4. Viard JP, Armoura Z, Bach JF. Association of anti-β2glycoprotein with lupus
circulating anticoagulant and thrombosis in SLE. Am J Med 1992; 93:181–186.
5. Cabiedes J, Cabral A, Alarcon-Segovia D. Clinical manifestations of the
antiphospholipid syndrome in patients with systemic lupus erythematosus
associate more strongly with anti-β2glycoprotein 1 than with antiphospholipid
antibodies, J Rheumatol 1995; 22: 1899–1906
6. Lewis S, Keil LB, Binder WL, De Bari V. Standardized measurement of major
immunoglobulin class (IgG, IgA and IgM) antibodies to β 2glycoprotein 1 in
patients with antiphospholipid syndrome, J Clin Lab Anal 1998; 12: 293–297
7. Katano K, Aoki A, Sasa H,
Ogasawara M, Matsuura E, Yagami Y.
β2glycoprotein I-dependent anticardiolipin antibodies as a predictor of adverse
pregnancy outcomes in healthy pregnant women, Hum Reprod 1996; 11: 509–
512
4
8. Martinuzzo ME, Forastiero RR, Carreras LO Anti-β2glycoprotein antibodies:
detection and association with thrombosis. Br J Haematol 1995; 89: 397–402
9.Ogasawara M, Aoki K, Matsuura E, Sasa H, Yagami Y. Anti-β2glycoprotein
antibodies and lupus anticoagulant in patients with recurrent pregnancy loss:
prevalence and clinical significance. Lupus 1996; 5: 587–592
10. Tsusumi A, Matsuura E, Ichikawa K, et al. Antibodies to β2glycoprotein I and
clinical manifestations in patients with systemic lupus erythematosus, Arthritis
Rheum 1996; 39: 1466–1474
11. Matsuura E, Igarashi Y, Yasuda T, Triplett DA, Koike T. Anticardiolipin
antibodies recognize 2glycoprotein I structure altered by interacting with an
oxygen modified solid phase surface. J Exp Med. 1994; 179: 457-462
12. Fanopoulos D, Teodorescu MR, Varga J, Teodorescu M. High frequency of
abnormal levels of IgA anti-2glycoprotein I antibodies in patients with systemic
lupus erythematosus: relationship with Antiphospholipid syndrome. J Rheumatol
1998; 25:675-680
13. Lee RM, Branch DW, Silver RM. Immunoglobulin A anti-β2glycopotein
antibodies in women who experience unexplalined recurrent spontaneous
abortion and unexplained fetal death. Am J Obstet Gynecol 2001; 185: 748-753
14. Galli M, Luciani B, Bertolini G, Barbui T. Anti-β2glycopotein I, antiprothrombin
antibodies and the risk of thrombosis in the antiphospholipid syndrome, Blood
2003; 102: 2717–2723
5
15. Kaplan V, Erkan V, Derksen W, L. et al. Real world experience with
antiphospholipid antibodies (APL): how useful is anti-β2glycoprotein (β2GPI) test?
Arthritis Rheum 2004; p. S67 [abstract].
16. .Detkov D, Gil-Aguado A, Lavilla P, Cuesta MV, Fontan G, Pascual-Salcedo
D. Do antibodies to β2glycopotein I contribute to the better characterization of
the antiphospholipid syndrome? Lupus 1999; 8: 430-438
17. Lee EY, Lee CK, Lee TH et al. Does the anti-β2glycopotein I antibody provide
additional information in patients with thrombosis, Thromb Res 2003; 111: 29–32
18. Reber G, Schousboe I, Tincani A et al. Inter-laboratory variability of antiβ2glycoprotein I measurement. A collaborative study in the frame of the
European Forum on Antiphospholipid Antibodies Standardization Group. 2002;
Thromb Haemost 2002; 88: 66–73
19.Miyakis S, Lockshin MD, Atsumi T et al. International consensus statement on
an update of the classification criteria for definite antiphospholipid syndrome
(APS). J Thromb Haemost. 2006; 4: 295-306
20. Nash MJ, Camilleri RS, Kunka S, Mackie IJ, Machin SJ, Cohen H. The
anticardiolipin assay is required for sensitive screening for antiphospholipid
antibodies, J Thromb Haemost 2004; 2: 1077–1081
6
Table 1. Current Laboratory Test included in the Sydney criteria
for definite APS (19)
LA present in plasma, on two or more occasions at least 12 weeks apart,
detected according to the guidelines of the International Society of
Haemostasis (Scientific Subcommittee on LAs/phospholipid-dependent
antibodies)
aCL antibodies of IgG and/or IgM isotype in serum or plasma, present in
medium to high titer (i.e.: >40 GPL or MPL, or >99th percentile), on two or
more occasions, at least 12 weeks apart, measured by standardized ELISA
Anti- 2GPI antibodies of IgG and/or IgM isotype in serum or plasma (in
titer>99th percentile), present on two or more occasions, at least 12 weeks
apart, measured by a standardized ELISA, according to recommended
procedures
Abbreviations:
aCL: anticardiolipin
APS: antiphospholipid syndrome
LA: lupus anticoagulant
2GPI: 2glycoprotein I.
7