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

Although the Sapporo criteria were found to have high sensitivity and specificity in APS seen in
conjunction with lupus and lupus-like disease,3 very few studies have validated these
criteria.3,4 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. There were no clear cutoffs for “medium to high titers” of IgG and IgM
anticardiolipin (aCL) antibodies, and the issue of difference in timing of laboratory testing in
relation to the clinical event was not clarified adequately in the original criteria. Also, various
clinical entities associated with APS were a source of major confusion.

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.
Recommendations were made on the basis of level of evidence in the usual manner. The Sapporo
classification criteria were divided into “clinical” and “laboratory” categories; this categorization
was maintained in the revision. Special attention was paid to defining some terms that were
thought to be described ambiguously in the older criteria.

Thrombotic phenomenon. The committee concurred that additional factors that contribute to
thrombosis should be assessed. 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).5

TABLE 1

Revised classification criteria for APS

Pregnancy-related morbidity. 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.6 To avoid misclassification, the
experts recommended strict adherence to conventional clinical definitions of eclampsia, severe
preeclampsia,7,8 and placental insufficiency (see Table 1). 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. Both lupus anticoagulant (LA) and aCL antibodies were maintained as
laboratory criteria in the revision. In addition, IgG, IgM, and anti-β2 glycoprotein-1 (anti-
β2GP1) assays were added by a majority on the basis of the extent of clinical evidence.3,9,10 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.11,12 The committee
introduced a clear statement on the threshold for a positive finding (see Table 1) on the basis of
best available evidence.13-17
The evidence suggested a more severe disease course with multiple aPL positivity. Therefore,
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).18-21

The issue of the timing of laboratory testing in relation to the event was not clarified adequately
in the original criteria. 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.

Persistent positivity of the laboratory test finding is important for making a diagnosis of APS.
The Sapporo criteria suggested an interval of 6 weeks between 2 positive test results. However, a
concern has been that the transient presence of aPL could be a common epiphenomenon in
clinical practice that may risk misclassification.22,23 The revision suggests increasing this interval
to 12 weeks, 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.

The experts addressed the concept of “secondary APS.” The committee advised against using the
term. Most patients with secondary APS have systemic lupus erythematosus (SLE), 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. Therefore,
the Sydney criteria propose that documenting the coexistence of SLE and APS is more
appropriate than classifying patients as having “primary” or “secondary” APS. The entity of
catastrophic APS was not addressed because a consensus statement had been issued in 2003.24

Other APS-Related Conditions Addressed

The issue of several other APS-related conditions, a common source of confusion, also was
addressed. These conditions have been addressed separately in the Sydney document as “features
associated with APS but not included in revised criteria.” They are summarized in Tables 2 - 4
and include the following 5 clinical and 6 laboratory entities:

TABLE 2

Definition of aPL-associated cardiac valve disease

• Cardiac. The committee provided relevant definitions of heart valve lesions in APS (see Table
2). The following recommendations are made: against adoption as a criterion; against routine
testing in all patients with coronary artery disease, unless a patient’s young age and lack of
identifiable risk factors suggest another cause; and recognizing rare cases with biopsy-proven
myocardial microthrombosis or intracardiac thrombi as meeting the thrombosis criteria for APS.

TABLE 3

Definition of aPL-associated livedo reticularis

• Neurological. Several neurological manifestations may be associated with APS. The committee
concluded that there was insufficient evidence to include cognitive dysfunction, headache or
migraine, multiple sclerosis, transverse myelitis, and epilepsy in the revised criteria but
recommended that the data suggesting cognitive decline warrant further study.

• Skin. Livedo reticularis (LR) has been associated with APS, and the revision provides a
definition of LR-associated APS (see Table 3). Routine biopsy is not recommended because
there are no pathognomonic findings. Many other skin manifestations are not included in the new
criteria.

• Renal. The committee recommended the term “aPL-associated nephropathy” (aPLN) to

describe renal involvement in APS, and specific definitions were provided (see Table 4). General
guidelines include the following: aPLN lesions are similar in SLE- and non–SLE-related APS;
they are independent of lupus nephritis and do not correlate with progression to end-stage renal
disease; most lesions represent chronic nonspecific vascular damage apart from thrombotic
microangiopathy, which is an acute event; and patients with histologically proven aPLN satisfy
the revised APS thrombosis criteria, but routine renal biopsy is not recommended in all patients
with APS and should be guided by conventional clinical indications.

• Thrombocytopenia. Isolated thrombocytopenia in patients with persistent aPL, in the absence of

other clinical manifestations of APS, is not the same as idiopathic thrombocytopenia; patients are
at increased risk for thrombosis and should be monitored closely. The committee proposed the
term “aPL-associated thrombocytopenia” to stratify patients for clinical studies. They also
provide a platelet count of less than 100 × 109/L-1 as the cutoff limit for definition of
thrombocytopenia in APS.

• The following 6 laboratory tests are discussed: (1) LA, (2) aCL assay, (3) IgA aCL, (4) IgA
anti-β2GP1, (5) antibodies against prothrombin alone, and (6) antibodies to phosphatidylserine-
prothrombin complex. None merited inclusion in the current revision, and prospective studies
were recommended.

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. The current revision also incorporates the anti-β2GP1 antibodies, which
have evidence-based clinical and prognostic significance, into the laboratory criteria.
• 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.

• The timing of laboratory testing with respect to the clinical thrombotic/obstetric event has been
better defined. The interval between 2 consecutive positive laboratory test findings has been
increased and has been suggested to better correlate with APS. However, this is not evidence-
based.

• Common risk factors for cardiovascular disease and conditions that confer risk for thrombosis
have been clearly defined and taken into account.

• Sticking to strict guidelines regarding pregnancy-related morbidity decreases the chances of

misclassification and has been strongly recommended in this update.

• 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.

Limitations of the New Classification Criteria

The pregnancy-associated morbidity of APS remains fairly hard to discern in routine clinical
practice. With the advent of better histopathological and laboratory features of placental
insufficiency, this feature of APS is hoped to gain specificity and applicability in routine
practice. In the current update, the authors saw no advantage in removing the
preeclampsia/placental insufficiency criterion; however, well-designed, prospective studies are
needed to determine the contribution of APS to the overall problem of preterm birth from severe
preeclampsia or placental insufficiency.

There still is no international consensus on laboratory testing and cutoff values for aCL
antibodies.13-16This issue has been addressed in a 2011 update.25

The inclusion of the new antibody (IgM and IgG anti-β2GP1), the cutoff values for certain tests
(eg, aCL and anti-β2GP1 antibodies and platelet count), and inclusion definitions of the APS-
related clinical features are based mostly on “expert opinion” and have little evidence base. The
sensitivity and specificity of these cutoff values and definitions in association with APS have not
been validated in prospectively designed clinical studies. Similarly, the time interval between
clinical and laboratory event and the new time interval between 2 positive laboratory test results
have not been validated prospectively.

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, and that makes it
difficult to attribute the clinical event to APS. The association of SLE and APS probably merits
further classification because of the frequent simultaneous occurrence of these 2 conditions.

References:
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