Antiphospholipid Antibody Syndrome. Rare Diseases of the Immune System

5. Classification Criteria for the Antiphospholipid Syndrome

Ronald H. W. M. Derksen  and Ruth Fritsch-Stork 

(1)

Department of Rheumatology and Clinical Immunology, University Medical Centre Utrecht, 85500, Utrecht, 3508 GA, The Netherlands

Ronald H. W. M. Derksen (Corresponding author)

Email: r.h.w.m.derksen@umcutrecht.nl

Ruth Fritsch-Stork

Email: R.Fritsch@umcutrecht.nl

Keywords

Classification criteriaAntiphospholipid syndromeObstetric APSThrombotic APS

5.1 Introduction

The history of antiphospholipid antibodies (aPL) dates back to 1952, when both the phenomenon of “biological false-positive serological tests for syphilis” (BFP-STS), which is the presence of antibodies that are reactive with extracts from bovine heart as detected with the Wassermann or the VDRL tests, with negative results with more specific syphilis tests [49], and a peculiar inhibitor of coagulation in patients with systemic lupus erythematosus (SLE) [10] were described. The latter was shown to be caused by antibodies and appeared phospholipid dependent [39]. It was termed lupus anticoagulant (LAC) in 1972 [19]. Recognition that BFP-STS associate with LAC [38] and that the phospholipid cardiolipin is the major antigen in serological screening tests for syphilis resulted in development of solid phase assays to detect anticardiolipin antibodies (aCL) [232943]. Major interest in aPL arose worldwide when clinical studies showed that both presence of LAC [6] and aCL [29] characterize a subset of SLE patients with thrombosis and/or fetal loss [1440] and associate with thrombocytopenia [62730]. The presence of LAC or aCL in combination with thrombosis, fetal loss, and/or thrombocytopenia was named antiphospholipid syndrome (APS) in 1985 [31]. Originally, APS was described in patients with SLE, but soon, similar combinations of serological and clinical findings were recognized in otherwise healthy people (primary APS) [23]. Over the years it became clear that LAC and aCL also associate with clinical features like livedo reticularis, heart valve lesions, microangiopathic nephropathy, cognitive dysfunction, and chorea [17]. Recognition that autoimmune aCL and LAC require the plasma protein β2-glycoprotein I (β2GPI) as cofactor for binding to anionic phospholipids [204647] led to development of solid phase assays to detect anti-β2GPI antibodies. Although by definition a misnomer, LAC, aCL, and anti-β2GPI collectively are indicated by the term aPL. This umbrella comprises overlapping, not necessarily identical antibodies. Clinicians are interested in APS as its recognition influences treatment [131624364461], whereas fundamental researchers unraveled many possible pathogenic pathways [11122462].

5.2 Classification Criteria

5.2.1 1987: The First Proposal

The risks of therapy that follows a diagnosis of APS, combined with difficulties in standardization of aCL assays, led to the first proposal for APS criteria (Table 5.1) [26]. As low aCL levels are clinically irrelevant, a cutoff was set in GPL and MPL units for both IgG and IgM isotypes, based on association studies and standardization efforts [2832]. IgG class aCL antibodies were found more relevant than IgM [28], and the latter were not included as a stand-alone serologic criterion [26]. Definitions of the clinical criteria were not provided. To be “more sure” about the diagnosis, it was advised to have positive serology confirmed with an interval of at least 8 weeks.

Table 5.1

Proposed criteria for antiphospholipid antibody syndromea [26]

Clinical

Serology

1. Venous thrombosis

1. IgG anticardiolipin antibody (>20 GPL units)

2. Arterial thrombosis

2. Positive test for lupus anticoagulant

3. Recurrent fetal loss

3. IgM anticardiolipin antibody (>20 GPL units) AND positive test for lupus anticoagulant

4. Thrombocytopenia

 

aPatients with APS should have at least one clinical and one serological feature at some time in their disease course. An aPL test should be positive on at least two occasions, more than 8 weeks apart

5.2.2 1999: Preliminary Classification Criteria for Definite APS

To facilitate studies of treatment and causation and to align the diverse clinical and basic science disciplines involved in APS, consensus criteria were formulated in October 1998 in Sapporo, Japan (Table 5.2) [69]. Clinical criteria included: (1) objectively verified vascular thrombosis of any vessel and (2) pregnancy morbidity defined according to strict definitions [7]. There was consensus that presence of other contributing causes of thrombosis does not preclude a diagnosis of APS. For future studies, it was recommended to stratify patients according to presence or absence of additional thrombotic risk factors besides aPL. Also by consensus it was decided not to designate other features of APS (such as thrombocytopenia, transient cerebral ischemia, cardiac valve disease, and livedo reticularis) as criteria, because their associations with aPL were judged not as strongly based on clinical and experimental data as the chosen clinical criteria. Further studies of these additional associated features of APS are encouraged.

Table 5.2

Preliminary criteria for the classification of APSa [69]

Clinical criteria

1. Vascular thrombosis

 One or more clinical episodes of arterial, venous, or small vessel thrombosis, in any tissue or organ

 Thrombosis must be confirmed by imaging or Doppler studies or histopathology, with the exception of superficial venous thrombosis

 For histopathologic confirmation, thrombosis should be present without significant evidence of inflammation in the vessel wall

2. Pregnancy morbidity

 (a) One or more unexplained deaths of a morphologically normal fetus at or beyond the 10th week of gestation, with normal fetal morphology documented by ultrasound or by direct examination of the fetus

 (b) One or more premature births of a morphologically normal neonate at or before the 34th week of gestation because of severe preeclampsia or eclampsia or severe placental insufficiency

 (c) Three or more unexplained consecutive spontaneous abortions before the 10th week of gestation, with maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal causes excluded

 In studies of populations of patients who have more than one type of pregnancy morbidity, investigators are strongly encouraged to stratify groups of subjects according to a, b, or c above

Laboratory criteria

1. Anticardiolipin antibody of IgG and/or IgM isotype in blood, present in medium or high titer, on 2 or more occasions, at least 6 weeks apart, measured by a standardized enzyme-linked immunosorbent assay for β2-glycoprotein I-dependent anticardiolipin antibodies

2. Lupus anticoagulant present in plasma, on 2 or more occasions at least 6 weeks apart, detected according to the guidelines of the International Society on Thrombosis and Haemostasis [8], in the following steps:

 (a) Prolonged phospholipid-dependent coagulation demonstrated on a screening test, e.g., activated partial thromboplastin time, kaolin clotting time, dilute Russell’s viper venom time, dilute prothrombin time, Textarin time

 (b) Failure to correct the prolonged coagulation time on the screening test by mixing with normal platelet-poor plasma

 (c) Shortening or correction of the prolonged coagulation time on the screening test by the addition of excess phospholipid

 (d) Exclusion of other coagulopathies, e.g., factor VIII inhibitor or heparin, as appropriate

aAPS is considered to be present in a given patient when at least 1 of the clinical criteria and at least 1 of the laboratory criteria are met

The laboratory criteria included aCL and LAC. For aCL it was specified that the assay should be β2GPI dependent [33] and titers medium or high. IgG and IgM isotypes were weighted equally. Guidelines for the detection of LAC were provided [8]. Extension of the laboratory criteria with anti-β2GPI antibodies was discussed but not executed because the assay was insufficiently standardized and it was felt that association studies did not convincingly show that their inclusion would have added value.

The criteria require that positive laboratory tests are confirmed with an interval of at least 6 weeks, reasoning that this will help to exclude aPL positivity that represents an epiphenomenon to clinical events. However, it was explicitly stated that no specific limits are placed on the interval between a clinical event and positive laboratory findings.

Two validation studies have been performed in patients regarded as having APS by their physicians [4268]. Because patients with low aCL levels, thrombocytopenia, or livedo reticularis in absence of classical clinical features do not classify for APS according to the criteria, reported sensitivities of 70–80 % are not surprising.

5.2.3 2006: Update of the Classification Criteria for Definite APS

In November 2004 the classification criteria for APS were revised in Sydney, Australia [48] (Table 5.3). The update resulted from a review of literature data in different fields of APS, grading of evidence, and consensus reached by open discussions. The classical clinical criteria were left unchanged, but some clarifications were added. These include (1) a list of coexisting inherited or acquired factors for thrombosis for which patients should be stratified in clinical studies, (2) strict definitions of eclampsia and severe preeclampsia [1], and (3) a list of commonly used clinical definitions for placental insufficiency. Superficial venous thrombosis was omitted as clinical criterion.

Table 5.3

Revised classification criteria for APSa [48]

Clinical criteria

1. Vascular thrombosis

 One or more clinical episodes of arterial, venous, or small vessel thrombosis, in any tissue or organ

 Thrombosis must be confirmed by objective validated criteria (i.e., unequivocal findings of appropriate imaging studies or histopathology)

 For histopathologic confirmation, thrombosis should be present without significant evidence of inflammation in the vessel wall

2. Pregnancy morbidity

 (a) One or more unexplained deaths of a morphologically normal fetus at or beyond the 10th week of gestation, with normal fetal morphology documented by ultrasound or by direct examination of the fetus

 (b) One or more premature births of a morphologically normal neonate before the 34th week of gestation because of: (i) eclampsia or severe preeclampsia defined according to standard definitions [1], or (ii) recognized features of placental insufficiency

 (c) Three or more unexplained consecutive spontaneous abortions before the 10th week of gestation, with maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal causes excluded

 In studies of populations of patients who have more than one type of pregnancy morbidity, investigators are strongly encouraged to stratify groups of subjects according to a, b, or c above

Laboratory criteria

1. Lupus anticoagulant present in plasma, on two or more occasions at least 12 weeks apart, detected according to the guidelines of the International Society on Thrombosis and Haemostasis (Scientific Subcommittee on LAs/phospholipid-dependent antibodies) [8]

2. Anticardiolipin (aCL) antibody of IgG and/or IgM isotype in serum or plasma, present in medium or high titer (i . e ., > 40 GPL or MPLor > the 99th percentile), on two or more occasions, at least 12 weeks apart, measured by a standardized ELISA

3. Anti - β2GPI antibody of IgG and / or IgM isotype in serum or plasma ( in titer > the 99th percentile )present on two or more occasions at least 12 weeks apartmeasured by a standardized ELISAaccording to recommended procedures [56]

Differences between these and the Sapporo criteria are indicated in bold-italics

aAPS is present if at least 1 of the clinical criteria and at least 1 of the laboratory criteria are met

The committee advised against subdivision between primary and secondary APS as the clinical consequences of aPL among patients in these two categories are the same (Evidence Level I) but regarded documentation of coexisting SLE (or other disease) as advantageous.

The committee considered adoption of additional clinical features like heart valve disease, livedo reticularis, thrombocytopenia, nephropathy, and neurological manifestations as independent criteria for definite APS. It was decided not to do so, as it was felt that this would decrease the diagnostic specificity, even though association of these features with APS is recognized. Separate recognition of non-criteria features of APS in studies is, however, encouraged, and definitions of these features were provided.

Significant changes were executed in the laboratory criteria. Based on expert opinion the time interval for repeated testing for aPL was extended from 6 (Sapporo criteria) to 12 weeks, to reduce the risk for misclassification by transient presence of epiphenomenal aPL. Also new was the inclusion of a maximum time interval (5 years) between a clinical manifestation and aPL testing. It was felt that a longer interval may not reflect a causative relationship. Recommendations for LAC testing became more stringent. Use of two or more LAC tests with different assay principles was advised before presence of LAC is excluded, as no single test is 100 % sensitive for LAC. The issue of testing for LAC in patients using vitamin K antagonists was addressed. With an international normalized ratio (INR) >3.5, testing for LAC should not be performed. With less prolonged INRs test samples should be diluted with normal plasma.

There was a strong debate on the difficulties with testing for aCL, which include the still marginal interlaboratory agreement, absence of a standard for the threshold used to distinguish between moderate/high and low aCL levels, and the difficult definition of the level that best corresponds to clinical manifestations. There was, however, no consensus to remove aCL tests completely from the criteria. The committee decided to define new cutoff levels that were felt to be appropriate until an international consensus is reached. These new cutoffs are >40 GPL or MPL or >99th percentile.

The most important revision in the criteria was the inclusion of IgG and IgM isotype anti-β2 GPI antibodies as a stand-alone laboratory criterion for APS, despite recognition of problems with standardization of the anti-β2 GPI assay (results being among others dependent on types of plates and purity, concentration, and source of β2 GPI) and with the definition of appropriate cutoffs (no uniformly accepted calibrators and units). Statements that anti-β2 GPI antibodies are independent risk factors for thrombosis and pregnancy complications were graded with evidence level II and I, respectively. Of note, at least two members voted against inclusion of anti-β2 GPI in the criteria as they considered existing evidence too weak. It was decided to use a threshold of >99th percentile of controls for both IgG and IgM class anti-β2 GPI to define a positive result.

The committee strongly advised to classify APS patients in studies according to their serological profile as follows: (I) more than one laboratory criteria present (any combination), (IIa) LA present alone, (IIb) aCL antibody present alone, and (IIc) anti-β2 GPI antibody present alone.

Not surprisingly, studies that applied both the Sapporo and revised criteria on patients in aPL databases found that 3–9 % more patients classify for APS with the revised criteria, simply because these had anti-β2 GPI antibodies in presence of classical clinical criteria, but negative LAC and aCL assays [1535556364]. This increase in patients classifying for APS due to introduction of anti-β2 assays is counteracted by loss of patients that do not fulfill the revised criteria, when these are applied strictly. One study found that only 58 % of patients that classified APS according to the Sapporo criteria also fulfilled the updated criteria [35]. The patients that did not classify any more had aCL levels below the newly defined cutoff and had an interval greater than 5 years between a clinical event and the first aPL test and/or an interval between test and retest between 6 and 12 weeks.

5.3 Critics on and Shortcomings of Current Classification Criteria

The revisions that the committee made in the clinical and laboratory criteria for APS evoked many comments. A major contributor to the confusion on APS is the unclear border between diagnostic and classification criteria. Although it is acknowledged that classification criteria are intended to serve research, they are uniformly applied for diagnostic purposes and to guide treatment [3763]. In APS the situation is complex because thrombosis and pregnancy morbidities are multicausal and relatively common in the general population and the tests included in the laboratory criteria are unspecific and difficult to standardize.

5.3.1 Methodological Issues

Serious shortcomings were noted in an evaluation of the developmental methodology and measurement properties of both sets of classification criteria [4]. Although the revised criteria may have incremental face and content validity over the Sapporo criteria, the complexity of both the criteria and the diagnostic and immunologic tests limits their feasibility. Before a classification criterion can confidently be used in multicenter trials, it is a prerequisite that its reliability is established [34]. However, at present the reliability of individual APS criteria is unknown.

5.3.2 Comments on Clinical Criteria

It has been questioned, whether removal of superficial thrombosis (confirmed by imaging techniques), as clinical criterion and exclusion of APS when vasculitis is simultaneously present is correct [9]. Mondor’s disease can be a manifestation of APS [545] and APS can coexist with vasculitis [5057]. Lackner et al. argued against joining of primary and secondary APS [37] because the prevalence of APS is low in otherwise healthy persons and high in SLE and test performances always depend strongly on prevalence of disease. Based upon interpretation of reported inconsistent findings on associations between aPL and consecutive spontaneous abortions before the 10th week, and increasing evidence that this clinical problem has other etiologies than late fetal loss or early delivery with placental insufficiency, some advocate withdrawal of the “recurrent spontaneous abortions” criterion from clinical APS criteria [25].

5.3.3 Comments on Laboratory Criteria

Lackner et al. strongly criticized the decision of the committee to include anti-β2 GPI as stand-alone laboratory criterion by showing that they strongly overestimated the power of studies used to justify their decision [37]. The authors stress that clinicians need solid tests with high predictive values for future APS manifestations and prefer tests with high specificity over high sensitivity. They warned that addition of inconclusive laboratory tests without firm evidence to support their use can be harmful [37].

Although specification of time intervals between serologic tests and between serology and clinical manifestations in the revised criteria improves face validity, the value of these time intervals must be tested in clinical studies before these can be useful [4]. Formulation of these time intervals was not based on scientific data. One study found that a wider time interval between serologic tests is unlikely to make a difference [63].

In the revised criteria the cutoff for positive aCL was set at >40 GPL or MPL or >the 99th percentile, suggesting these are similar. This, however, is not the case. The 99th percentile of the geometric mean of 100 normal subjects is always lower than 40 Units and corresponds with 15–26 GPL and 16–27 MPL [22585964]. Most APS patients with IgG aCL levels between the 99th percentile and 40 GPL have pregnancy morbidity and test negative for LAC and anti-β2 GPI (category IIb of the revised criteria) [58]. Others plead to use different cutoffs for obstetric and thrombotic APS, namely, the 95th and the 99th percentile, respectively [22], as many patients with obstetric APS have, in contrast to those with thrombotic APS IgG class aCL or anti-β2 GPI antibodies between 5 and 20 Units. It was argued that by applying the higher cutoff, such patients will probably be withhold proper treatment [22]. Clinically relevant aPL levels for thrombotic APS are higher than for obstetric APS, but in absence of a generally accepted international definition cutoff level, any arbitrarily chosen value will leave doubts about its validity [64]. However, good arguments to prefer a cutoff for a positive aCL test based on the 99th percentile of the healthy population instead of 40 GPL/MPL include: (1) the 99th percentile is simple, objective (for the given population and laboratory), and uniform; (2) there are no widely accepted and validated calibrators; and (3) the available standard has fluctuations from lot to lot [65].

There is general agreement that aCL and anti-β2-GPI of IgM isotype are of significantly less clinical importance than those of the IgG class [46466]. It is to be regretted that the updated criteria do not separate IgG and IgM isotypes in the laboratory subclassification (categories IIb and IIc) [64]. Subclassification of patients based on aPL test results is relevant as multiple positivity (category I of the revised criteria) associates with higher risks. Presence of LAC together with IgG aCL and/or IgG anti-β2 GPI associates with higher risk for clinical complications (notably thrombosis) than presence of LAC alone (category IIa of the revised criteria) [64]. Patients with obstetric APS have significantly more often than those with thrombotic APS an IgG aCL level <40 GPL [58]. Furthermore, there is a progressive increase in IgG aCL level when one compares groups of APS patients that are only aCL positive (category IIb), double positive, or triple positive in that order [58].

In 2008 a group of prominent APS researchers published a provocative paper to evoke a debate on the serological criteria, so that these would identify exclusively patients who suffer from APS with high probability and simultaneously reduce over diagnosis of APS [21]. The group proposed (1) implementation of strict guidelines for performance of LAC assays, (2) exclusion of aCL from the criteria, and (3) limitation of anti β2-GPI antibody measurement to IgG isotype. Several groups responded [516567]. There was not much discussion on the need for updated guidelines for LAC that should include rules for pre-analytic handling of plasma samples, expression of results of LAC assays, interpretation of the degree of reduction that extra phospholipids must induce to mark the LAC assay as positive, and for the minimal number, type and combination of assays that reach a sufficiently high sensitivity and specificity for proper diagnosis of LAC. An update along these lines, including guidelines for LAC detection in patients on antithrombotic treatment [66], was soon delivered by the subcommittee on lupus anticoagulant/phospholipid-dependent antibodies from the International Society on Thrombosis and Haemostasis (ISTH) [54].

The arguments to remove the aCL test from APS criteria as proposed by Galli et al. [21] were both clinical and technical. The association between a solitary positive aCL test (category IIb of the revised criteria) and thrombosis is poor, and the assay has many technical difficulties and also detects irrelevant antibody reactivity. Respondents of the evoked debate [516567] agreed to maintain aCL of medium/high titer as criterion, although they conceded the validity of the issues raised [21]. This also applied for 9/13 international experts in the field who participated in a 2007 survey [51]. Arguments to maintain the aCL test for APS classification included that, in patients with negative LAC assays, a positive result for the same isotype in both aCL and anti-β2-GPI assays reinforces suspicion of APS and that aCL values serve as a control both for the quality of the antibodies tested and performance of the anti-β2-GPI test [51]. Swadzba added that it has not been proven beyond doubt that aCL antibodies directed against proteins other than β2-GPI are completely devoid of prothrombotic properties [65]. Another argument to maintain the aCL test is that positivity in both LAC, aCL, and anti-β2-GPI tests (triple positivity) strongly associates with classical clinical APS events [525360]. On a different note, Wahl [67] counters the proposed modifications of the APS criteria by stating that such important decision should not be based on expert opinion, but on new data and appropriate systematic reviews.

The many data showing that IgM class antibodies are not associated with thrombosis and pregnancy morbidity [46466] support the proposal made by Galli et al. [21] to remove these as laboratory criterion for APS. Pengo, however, considers the IgM tests still useful in special cases where LAC is not associated with positive IgG aCL or IgG anti-β2-GPI [51].

5.4 Concluding Remarks

There is no doubt that some aPL(-profiles) associate with risks for thrombosis and pregnancy morbidity and that APS exists. Classification criteria aim at provision of homogeneous groups of patients in clinical and laboratory studies. In APS, clinical studies should aim at identification of aPL profiles that distinguish patients at high risk for (recurrent) manifestations from those patients with a low risk, while taking into account the presence or absence of other risk factors for thromboembolic events, cardiovascular disease, and pregnancy complications. In that way, the context can be discovered where the presence of aPL should dictate management and medical treatment of patients. We agree with Wahl that we should leave the concept of a syndrome and regard aPL as risk factors for recurrent clinical events, a policy that is also advocated for hereditary thrombophilia [67]. We strongly feel that laboratory criteria for classification and diagnosis of obstetric APS should not necessarily be the same. The associations linking aPL subtypes and obstetrical morbidities show variable specificities and sensitivities and are different from those with thrombotic APS, although LAC apparently is a strong risk factor for both [254158]. Most women presenting with pregnancy failure and aPL do not experience thromboembolic events, and the pathogenetic mechanisms of aPL-mediated thrombosis and pregnancy loss are diverging [2462].

Inevitably, classification criteria are used in daily practice for diagnosis and to guide therapy. A decision to reserve adaptations of treatment for (suggested) high-risk aPL profiles (e.g., triple positivity) simultaneously leaves many patients with other profiles (e.g., single positivity for aCL or anti-β2-GPI positivity or IgM) with standard treatment. We see in daily life that clinicians often feel uncomfortable to go for high specificity instead of high sensitivity as they fear that they wrongly withhold adaptation of (suggested) beneficial treatment. Unfortunately, one has to ascertain that decades after the first proposal of APS classification, no unequivocal data on risks for clinical events and treatment are available, because undisputable, large-scale prospective clinical studies have not been performed. This explains why all (suggestions for) adaptations of criteria were mainly based on consensus, using data from imperfect studies.

It is a great step forward that the Antiphospholipid Syndrome Alliance for Clinical Trials and International Networking (APS-ACTION) was recently founded and started international initiatives [18]. Hopefully APS-ACTION succeeds in execution of appropriate trials that are so urgently needed in this field to get answers to at least part of the many uncertainties that surround APS.

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