Consensus on methodology and cut-offs is always challenging for any lab test that is used as a test. The more sensitive , the less specific and the more specific, the less sensitive.  Many conferences and articles have been published on this issue.

As a practical matter, the performance characteristic of a test will be related to Bayes theorem and applying a pre-test "guesstimate" or likelihood based upon other factors( clinical, pathologist , imaging or labs or some combination), applying the test to then get a post-test likelihood.  The PPV and NPV of a test and concepts of FP and TP enter with any test we order on a patient.  Anti-Beta 2 Glycoprotein Abs are currently thought to be more pathogenic and need assay method different that ACL antibodies. I have seen very high IgM titers in patients who when followed for 20 years never had an arterial or venous thrombotic event. Others without detectable levels of ACL, but anti b2GP + with low titer had a devastating clinical course.

So, pragmatically, I favor clinical judgement when interpreting the results of the test.

Hope these principles help.  Also see our paper published on FcR polymorphisms in this population of clinically severe patients.

Arthritis Rheum. 1997 Nov;40(11):1998-2006.

Anticardiolipin IgG subclasses: association of IgG2 with arterial and/or venous thrombosis.

Sammaritano LR1, Ng S, Sobel R, Lo SK, Simantov R, Furie R, Kaell A, Silverstein R, Salmon JE.

Author information

Abstract

OBJECTIVE:

To determine whether the presence of anticardiolipin antibodies (aCL) of a specific IgG subclass is associated with clinical complications of the antiphospholipid antibody syndrome (APS) and whether polymorphisms of Fc receptors for IgG (FcgammaR) with differential binding preferences contribute to an increased risk of thrombotic complications.

METHODS:

In 60 patients with IgG aCL, we assessed clinical complications of the APS, measured the level of antibody activity, and determined the IgG subclass distribution of aCL by a modified enzyme-linked immunosorbent assay (ELISA) with murine anti-human IgG subclass monoclonal antibodies. Selective IgG subclass adsorption studies were performed to determine the relative contribution of specific IgG subclasses to overall aCL activity. Fcgamma receptor IIA (FcgammaRIIA) genotypes of aCL patients with thrombosis and of non-systemic lupus erythematosus controls were determined by polymerase chain reaction amplification of genomic DNA and allele-specific probes.

RESULTS:

IgG2 aCL, detected in 75% of the patients, was the major subclass of aCL. Selective adsorption studies demonstrated that IgG2, in contrast to IgG1, was the predominant subclass responsible for aCL reactivity. IgG2 aCL was the only subclass associated with clinical complications, specifically, arterial and/or venous thrombosis (P < 0.04). The presence of FcgammaRIIA-H131, a receptor expressed on platelets, monocytes, and endothelial cells and the only human FcgammaR which efficiently recognizes IgG2, was associated with thrombosis in aCL patients. Among 45 high-titer (>40 GPL [IgG phospholipid] units) aCL patients with thrombosis, 40% were homozygous for FcgammaRIIA-H131, compared with 25% of disease-free controls (P = 0.042).

CONCLUSION:

While all 4 IgG subclasses are found in autoimmune aCL, only the presence of IgG2 is significantly associated with thrombotic complications. Reactivity in aCL ELISA is largely due to the presence of IgG2 in high-titer patients. The presence of IgG2 aCL, particularly in association with FcgammaRIIA-H131, may be a useful clinical predictor of increased thrombotic risk in patients with autoimmune IgG aCL. Allelic variants of FcgammaRIIA with distinct capacities to interact with IgG subclasses provide a mechanism for genetic susceptibility to an autoantibody-induced prothrombotic state.

Comment in

IgG2 restriction of anti-beta2-glycoprotein I as the basis for the association between IgG2 anticardiolipin antibodies and thrombosis in the antiphospholipid syndrome: comment on the article by Sammaritano et al. [Arthritis Rheum. 1998]

PMID:

9365089

[PubMed - indexed for MEDLINE]

Perhaps several explanations

GLP and MLP units have been defined from standard called Harris standards. One unit corresponds to a concentration of 1 mg / ml of aCL. The preparations used as standards unfortunately varies greatly. Monoclonal calibrators have been introduced to promote the standardization of results.

The manufacturer of the reagent should provide indications on the correspondence. You may be able to better compare the results of different studies

Remember that the probability of the existence of this rare disease is even greater than the antibody concentration is high. A value> 40 GPL-U / ml corresponds to a high probability of disease

Criteria may vary depending on the manufacturer: for ThermoFisher, a value between 10-40 GPL is a low positive value. This does not rule out the disease but can be observed in other autoimmune diseases and elderly patients without disease.

The clinic is still the essential element

In my opinion, I think that we should consider clinical manifestations rather than the real rate of antiphospholipid antibodies. As long as they are positive, and clinical manifestations are pointing to an antiphospholipid syndrome we should consider the diagnosis. According to the diagnosis criteria we must have a sustained positivity of the antibodies after 12 weeks so perhaps that in the beginning the rates are not too high but in a second control they will increase

I agree and captured the aspect of my response above that in essence concurs with your thinking!

As a practical matter, the performance characteristic of a test will be related to Bayes theorem and applying a pre-test "guesstimate" or likelihood based upon other factors( clinical, pathologist , imaging or labs or some combination), applying the test to then get a post-test likelihood.  The PPV and NPV of a test and concepts of FP and TP enter with any test we order on a patient.  Anti-Beta 2 Glycoprotein Abs are currently thought to be more pathogenic and need assay method different that ACL antibodies. I have seen very high IgM titers in patients who when followed for 20 years never had an arterial or venous thrombotic event. Others without detectable levels of ACL, but anti b2GP + with low titer had a devastating clinical course.

So, pragmatically, I favor clinical judgement when interpreting the results of the test.

Anticardiolipin antibody (aCL) titre in patients with antiphospholipid syndrome (APS)? - ResearchGate. Available from: https://www.researchgate.net/post/Anticardiolipin_antibody_aCL_titre_in_patients_with_antiphospholipid_syndrome_APS#view=56ddcd10b0366d25c26a7a91 [accessed Mar 7, 2016].

According to the revised Sapporo criteria, definite APS is considered if at least one of the following clinical criteria and at least one of the following laboratory criteria are satisfied:

Clinical — The presence of either vascular thrombosis or pregnancy morbidity, defined as follows:

Vascular thrombosis is defined as one or more episodes of venous, arterial, or small vessel thrombosis, with unequivocal imaging or histologic evidence of thrombosis in any tissue or organ. Superficial venous thrombosis does not satisfy the criteria for thrombosis for APS.

Pregnancy morbidity is defined as otherwise unexplained fetal death at ≥10 weeks gestation of a morphologically normal fetus, or one or more premature births before 34 weeks of gestation because of eclampsia, preeclampsia, or placental insufficiency, or three or more embryonic (40 units GPL or MPL or >99th percentile for the testing laboratory)

Antibodies to ß 2 -glycoprotein I (anti-β 2 GPI) of IgG or IgM isotype at a titer >99th percentile for the testing laboratory when tested according to recommended procedures.

Lupus anticoagulant (LA) activity detected according to published guidelines.