Dear Sir,
We read with interest the study by Oron et al. [Citation1]. We are fully appreciative, after more than 20 years of experience [Citation2–4], not only of the difficulties of patient accrual for studies of adverse obstetric events in the context of antiphospholipid antibodies (aPL) but also of the absolute necessity of accurately defining the patients involved, both clinically and serologically, so that useful comparisons can be made within the study and with other published results of similarly defined patient populations.
In response to a comment regarding the absence of testing for anti- β2-glycoprotien I antibodies (anti- β2GPI) in our Hep/ASA trial [Citation5], we would like to reiterate that patient accrual was completed by 2004, 2 years before revised criteria for the antiphospholipid syndrome (APS) that include anti- β2GPI were published [Citation6].
Dr. Oron and colleagues based their own conclusions regarding the usefulness of anti- β2GPI in predicting adverse pregnancy outcomes on a sample of 18 patients (Group B) with APS with or without systemic lupus erythematosus (SLE), who are identified as positive for anti- β2GPI. However, it is not made clear how many of these patients were also positive for the lupus anticoagulant (LAC) or anticardiolipin antibodies (aCL). Neither is it readily apparent whether the patients in Group A were tested for anti- β2GPI and if so, what their antibody status was. As it has been recently reported by a number of authors that the LAC has the strongest correlation with both thrombosis and late pregnancy complications [Citation7,Citation8] and also that a combination of aPL tests best identifies pregnant women at risk for adverse outcome [Citation8,Citation9], it is essential that this point be clarified. If some or most of this group of 18 are also positive for the LAC, then the utility of anti- β2GPI alone, particularly as a predictive tool as proposed by this study, would be diminished if not lost entirely.
Some of the other data were also confusing. Patients in Group C (positive for aPL only once) apparently represented the “control” population for this study, and yet, counter intuitively, they had the highest prevalence of preeclampsia, intrauterine growth restriction, and deep vein thrombosis and/or pulmonary embolism (all obstetric events associated with APS) compared to the other two groups with consistently positive aPL. This anomaly may simply be the result of small sample sizes, and limits, as the authors themselves contended, any conclusions that can be drawn. Attempts to combine groups with disparate aPL status or clinical manifestations is probably not the best solution to the problem of small sample size and may have only confounded the findings.
Earlier constructs of the classification criteria for APS have included laboratory and clinical criteria, the validity of some of which (aCL and early recurrent early pregnancy loss, for example) have been recently and most appropriately questioned [Citation10–12]. Our understanding of pregnancy morbidity in women with aPL is evolving rapidly [Citation9] and subsequent classification criteria for APS will no doubt reflect this.
Yours sincerely
Christine A. Clark, PhD
Carl A. Laskin, MD, FRCP
Karen A. Spitzer, MSc
Declaration of Interest: Authors declare no conflict of interest.
References
- Oron G, Ben-Haroush A, Goldfarb R, Molad Y, Hod M, Bar J. Contribution of the addition of anti-ß2-glycoprotein to the classification of antiphospholipid syndrome in predicting adverse pregnancy outcome. J Matern Fetal Neonatal Med 2011;24:606–609.
- Laskin CA, Solonínka CA. Anticardiolipin antibodies: smoking gun or smoke screen? J Rheumatol 1988;15:7–9.
- Bruce IN, Clark-Soloninka CA, Spitzer KA, Gladman DD, Urowitz MB, Laskin CA. Prevalence of antibodies to beta2-glycoprotein I in systemic lupus erythematosus and their association with antiphospholipid antibody syndrome criteria: a single center study and literature review. J Rheumatol 2000;27:2833–2837.
- Laskin CA, Spitzer KA, Clark CA. Pregnancy and reproductive concerns in systemic lupus erythematosus. In: Lahita RG, Tsokos G, Buyon J, Koike T, editors. Systemic lupus erythematosus. 5th ed. Elsevier; 2011. pp 655–672.
- Laskin CA, Spitzer KA, Clark CA, Crowther MR, Ginsberg JS, Hawker GA, Kingdom JC, et al. Low molecular weight heparin and aspirin for recurrent pregnancy loss: results from the randomized, controlled HepASA Trial. J Rheumatol 2009;36:279–287.
- Wilson WA, Gharavi AE, Koike T, et al International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome (APS). Arthritis Rheum 199;4:295–306.
- Salmon JE, Kim M, Guerra, et al. Absence of lupus anticoagulant is a strong predictor of uncomplicated pregnancy in patients with APL antibodies. Arthritis Rheum 2008;41 Suppl:S168.
- Pengo V, Ruffatii A. Critical update of the antiphospholipid syndrome criteria. Open Autoimmun J 2010;2:18–20.
- Ruffatti A, Tonello M, Visentin MS, Bontadi A, Hoxha A, De Carolis S, Botta A, et al. Risk factors for pregnancy failure in patients with anti-phospholipid syndrome treated with conventional therapies: a multicentre, case-control study. Rheumatology (Oxford) 2011;50:1684–1689.
- Pengo V, Banzato A, Bison E, Denas G, Padayattil Jose S, Ruffatti A. Antiphospholipid syndrome: critical analysis of the diagnostic path. Lupus 2010;19:428–431.
- Galli M. Clinical utility of laboratory tests used to identify antiphospholipid antibodies and to diagnose the antiphospholipid syndrome. Semin Thromb Hemost 2008;34:329–334.
- Branch DW, Silver RM, Porter TF. Obstetric antiphospholipid syndrome: current uncertainties should guide our way. Lupus 2010;19:446–452.