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The Sydney Classification Criteria for

Definite Antiphospholipid Syndrome
 Neha Garg, MD
 Atul Deodhar, MD
Wed, 03/28/2012
Volume:
26
 Fibromyalgia, Rheumatic Diseases

ABSTRACT: Amendments to the Sapporo criteria for antiphospholipid syndrome (APS)
addressed clinical, laboratory, and experimental insights gained since they were adopted in 1999.
A committee of experts concurred that patients with APS should be stratified according to the
presence or absence of other (inherited or acquired) contributing causes of thrombosis. It was
agreed that there are inherent problems in applying the pregnancy-related morbidity criterion in
practice and research because there is no widely accepted definition for placental insufficiency or
characteristic histopathological placental abnormality in APS. Both lupus anticoagulant and
anticardiolipin antibodies were maintained as laboratory criteria. The issue of several other APS-
related conditions (cardiac, neurological, skin, or renal; thrombocytopenia) also was addressed.
The newer criteria have several advantages over the older ones but also have limitations. (J
Musculoskel Med. 2012;29:73-77)

The original antiphospholipid syndrome (APS) classification criteria (the Sapporo criteria),
published in 1999, helped galvanize research in this disorder.1 New clinical, laboratory, and
experimental insights gained since then were addressed at the Eleventh International Congress on
Antiphospholipid Antibodies in Sydney, Australia, in 2006.2 On the basis of these discussions,
amendments to the Sapporo criteria were proposed. The newer criteria have many advantages
over the older ones.

This is the fourth article in a series on new or modified classification and diagnostic criteria for
various rheumatologic conditions. The first article (“New Classification Criteria for RA,” The
Journal of Musculoskeletal Medicine, November 2011, page 422) discussed recent revisions in
rheumatoid arthritis classification criteria. The second article (“New Axial and Peripheral
Spondyloarthritis Classification Criteria,” The Journal of Musculoskeletal Medicine, December
2011, page 454) reviewed the new classification criteria for the spondyloarthropathies. In the
third article (“New and Modified Fibromyalgia Diagnostic Criteria,” The Journal of
Musculoskeletal Medicine, February 2012, page 13), we discussed the new American College of
Rheumatology diagnostic criteria for fibromyalgia syndrome and their modification as survey
criteria. In this article, we focus on revised classification criteria for APS.

The Need for New Criteria

IgG. the experts recommended strict adherence to conventional clinical definitions of eclampsia.11. The Process of Developing New Classification Criteria A panel consisting of 39 experts from around the world met and discussed various issues regarding APS classification at a workshop held during the international congress. It was agreed that there are inherent problems in applying this criterion in practice and research because there is no widely accepted definition for placental insufficiency or characteristic histopathological placental abnormality in APS and the timing of delivery usually is subject to the attending physician's judgment. There were no clear cutoffs for “medium to high titers” of IgG and IgM anticardiolipin (aCL) antibodies.12 The committee introduced a clear statement on the threshold for a positive finding (see Table 1) on the basis of best available evidence.3. severe preeclampsia. Also. Thrombotic phenomenon. IgM.9.4 The Sapporo criteria performed poorly in older populations because of the high frequency of antiphospholipid antibodies (aPL) along with frequent thromboembolic disease in hospitalized patients.3 very few studies have validated these criteria. Special attention was paid to defining some terms that were thought to be described ambiguously in the older criteria.13-17 .5 TABLE 1 Revised classification criteria for APS Pregnancy-related morbidity.10 It was thought that the thresholds to distinguish moderate to high titers of IgG and IgM aCL antibodies from low levels had no standardized definition and were difficult to define. The committee concurred that additional factors that contribute to thrombosis should be assessed. In addition.7.3.6 To avoid misclassification. this categorization was maintained in the revision. and anti-β2 glycoprotein-1 (anti- β2GP1) assays were added by a majority on the basis of the extent of clinical evidence. They agreed that patients with APS should be stratified according to (a) the presence or (b) the absence of other (inherited or acquired) contributing causes of thrombosis (Table 1). Recommendations were made on the basis of level of evidence in the usual manner. and the issue of difference in timing of laboratory testing in relation to the clinical event was not clarified adequately in the original criteria. Both lupus anticoagulant (LA) and aCL antibodies were maintained as laboratory criteria in the revision. The Sapporo classification criteria were divided into “clinical” and “laboratory” categories.8 and placental insufficiency (see Table 1).Although the Sapporo criteria were found to have high sensitivity and specificity in APS seen in conjunction with lupus and lupus-like disease. They also recommended that this criterion be considered positive in the presence of any of the above along with the decision of a qualified physician to deliver a morphologically normal fetus before 34 weeks of gestation. Laboratory criteria. various clinical entities associated with APS were a source of major confusion.

The committee provided relevant definitions of heart valve lesions in APS (see Table 2). the Sydney criteria propose that documenting the coexistence of SLE and APS is more appropriate than classifying patients as having “primary” or “secondary” APS. also was addressed.4 and include the following 5 clinical and 6 laboratory entities: TABLE 2 Definition of aPL-associated cardiac valve disease • Cardiac. TABLE 3 Definition of aPL-associated livedo reticularis . Therefore. and recognizing rare cases with biopsy-proven myocardial microthrombosis or intracardiac thrombi as meeting the thrombosis criteria for APS. Persistent positivity of the laboratory test finding is important for making a diagnosis of APS.” They are summarized in Tables 2 . unless a patient’s young age and lack of identifiable risk factors suggest another cause. Most patients with secondary APS have systemic lupus erythematosus (SLE).The evidence suggested a more severe disease course with multiple aPL positivity. However.22. a concern has been that the transient presence of aPL could be a common epiphenomenon in clinical practice that may risk misclassification. a common source of confusion. The new criteria suggest that at least 12 weeks between the symptom and the laboratory test is appropriate and state that there should not be a time lapse of more than 5 years between the clinical event and the test to classify as APS.23 The revision suggests increasing this interval to 12 weeks. against routine testing in all patients with coronary artery disease. the revised criteria subclassify patients with APS into 4 categories on the basis of number of aPL assays that have positive findings (see Table 1). which is unlikely to affect sensitivity and coupled with the previous proposal of time difference between clinical and laboratory event provides greater reassurance that the aPL detected actually is predisposing to APS.24 Other APS-Related Conditions Addressed The issue of several other APS-related conditions. The Sapporo criteria suggested an interval of 6 weeks between 2 positive test results. These conditions have been addressed separately in the Sydney document as “features associated with APS but not included in revised criteria.” The committee advised against using the term. Therefore. The entity of catastrophic APS was not addressed because a consensus statement had been issued in 2003. The experts addressed the concept of “secondary APS. and the interplay between these 2 entities when present together in a patient—whether they are part of same disease or 2 separate diseases or 1 predisposes to the other—remains unclear. The following recommendations are made: against adoption as a criterion.18-21 The issue of the timing of laboratory testing in relation to the event was not clarified adequately in the original criteria.

TABLE 4 Definition of aPL-associated nephropathy Sydney Criteria Advantages Advantages of the Sydney Criteria over the older Sapporo classification criteria include the following: • Having clear cutoffs for levels of IgG and IgM aCL antibodies for use in the criteria has obvious advantages. is not the same as idiopathic thrombocytopenia. Livedo reticularis (LR) has been associated with APS. (3) IgA aCL. They also provide a platelet count of less than 100 × 109/L-1 as the cutoff limit for definition of thrombocytopenia in APS. • Thrombocytopenia. Many other skin manifestations are not included in the new criteria. (2) aCL assay. transverse myelitis. The committee concluded that there was insufficient evidence to include cognitive dysfunction. • Skin. The committee recommended the term “aPL-associated nephropathy” (aPLN) to describe renal involvement in APS. (5) antibodies against prothrombin alone. • The following 6 laboratory tests are discussed: (1) LA. but routine renal biopsy is not recommended in all patients with APS and should be guided by conventional clinical indications. The committee proposed the term “aPL-associated thrombocytopenia” to stratify patients for clinical studies. and patients with histologically proven aPLN satisfy the revised APS thrombosis criteria. which is an acute event. into the laboratory criteria. None merited inclusion in the current revision. Isolated thrombocytopenia in patients with persistent aPL. Routine biopsy is not recommended because there are no pathognomonic findings. most lesions represent chronic nonspecific vascular damage apart from thrombotic microangiopathy.• Neurological. and epilepsy in the revised criteria but recommended that the data suggesting cognitive decline warrant further study.and non–SLE-related APS. • Renal. multiple sclerosis. The current revision also incorporates the anti-β2GP1 antibodies. and prospective studies were recommended. in the absence of other clinical manifestations of APS. General guidelines include the following: aPLN lesions are similar in SLE. they are independent of lupus nephritis and do not correlate with progression to end-stage renal disease. Several neurological manifestations may be associated with APS. and the revision provides a definition of LR-associated APS (see Table 3). patients are at increased risk for thrombosis and should be monitored closely. headache or migraine. (4) IgA anti-β2GP1. which have evidence-based clinical and prognostic significance. and (6) antibodies to phosphatidylserine- prothrombin complex. . and specific definitions were provided (see Table 4).

this is not evidence- based. The interval between 2 consecutive positive laboratory test findings has been increased and has been suggested to better correlate with APS. well-designed. • Common risk factors for cardiovascular disease and conditions that confer risk for thrombosis have been clearly defined and taken into account. Limitations of the New Classification Criteria The pregnancy-associated morbidity of APS remains fairly hard to discern in routine clinical practice. the authors saw no advantage in removing the preeclampsia/placental insufficiency criterion. In the current update. References: REFERENCES . • Several other APS-related conditions have been clearly defined and allow for classification of these separate clinical entities within the APS spectrum of disease with reasonable clarity. the time interval between clinical and laboratory event and the new time interval between 2 positive laboratory test results have not been validated prospectively.25 The inclusion of the new antibody (IgM and IgG anti-β2GP1). this feature of APS is hoped to gain specificity and applicability in routine practice. With the advent of better histopathological and laboratory features of placental insufficiency. Assessing the truly relevant definitions remains extremely difficult because of the interplay of a multitude of factors that affect the classic clinical manifestations of APS.• Subcategorization of patients with APS on the basis of coexistence of more than 1 positive laboratory test result allows for identification of high-risk patients with an increased risk of thrombosis. Similarly. The association of SLE and APS probably merits further classification because of the frequent simultaneous occurrence of these 2 conditions. • Sticking to strict guidelines regarding pregnancy-related morbidity decreases the chances of misclassification and has been strongly recommended in this update. however. The sensitivity and specificity of these cutoff values and definitions in association with APS have not been validated in prospectively designed clinical studies. and inclusion definitions of the APS- related clinical features are based mostly on “expert opinion” and have little evidence base. There still is no international consensus on laboratory testing and cutoff values for aCL antibodies. the cutoff values for certain tests (eg. aCL and anti-β2GP1 antibodies and platelet count).13-16This issue has been addressed in a 2011 update. prospective studies are needed to determine the contribution of APS to the overall problem of preterm birth from severe preeclampsia or placental insufficiency. and that makes it difficult to attribute the clinical event to APS. However. • The timing of laboratory testing with respect to the clinical thrombotic/obstetric event has been better defined.

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