What is the significance of low titre antiphospholipid (antibody) anticardiolipin antibodies?

From the Guidelines

A low titre antiphospholipid (antibody) anticardiolipin antibody result is generally not considered clinically significant on its own, and no specific treatment is typically required for low titre results. When interpreting this finding, it's essential to consider the patient's overall clinical picture, including their medical history and presence of any symptoms suggestive of antiphospholipid syndrome (APS) 1. According to the 2020 American College of Rheumatology guideline, testing for antiphospholipid antibodies (aPL) should be performed in patients with systemic lupus erythematosus (SLE) or SLE-like disease, and in patients with suggestive histories or physical findings 1.

Some key points to consider when evaluating a patient with low titre anticardiolipin antibodies include:

• The presence of aPL modifies the recommendations in many circumstances, and therefore is considered separately 1
• Patients with lower-titer aCL and/or anti-β2 GPI (or non-criteria aPL) who do not meet laboratory classification criteria may still have some degree of risk that is difficult to quantify 1
• Recommendations for these patients are not offered in the guideline; decisions regarding therapy rest on discussion between the patient and the physician, taking into account additional relevant risk factors 1
• The guideline defines "positive aPL" as laboratory criteria only, including persistent moderate-high–titer anticardiolipin antibody (aCL) (≥40 units or ≥99th percentile), moderate-high–titer anti–β-glycoprotein I (anti-β2GPI) (≥40 units or ≥99th percentile), or 2 positive lupus anticoagulant (LAC) tests 1

In clinical practice, repeating the test in 12 weeks to confirm the result is recommended, as transient elevations can occur due to infections or other temporary factors. If the patient has no symptoms or history suggestive of APS, reassurance can be provided. However, if there are concerns such as recurrent miscarriages, unexplained thrombosis, or other autoimmune symptoms, further evaluation may be warranted, including testing for other antiphospholipid antibodies like lupus anticoagulant and anti-β2 glycoprotein I. The presence of anticardiolipin antibodies, even at low levels, may be relevant in certain clinical scenarios, so it's essential to consider the patient's full medical history. Low titre results are often not associated with increased thrombosis risk, but patients should be advised to minimize other cardiovascular risk factors as a general health measure.

From the Research

Significance of Low Titre Antiphospholipid Antibodies

The significance of low titre antiphospholipid (antibody) anticardiolipin antibodies is a topic of ongoing discussion in the medical community.

• Low titre anticardiolipin antibodies have been found to have limited clinical significance in terms of predicting antiphospholipid syndrome (APS) or related disorders 2.
• Studies have shown that patients with low-positive IgG anticardiolipin antibodies are not at increased risk for developing APS-related disorders, and their risk is similar to that of patients with negative test results 2.
• However, repeat testing is still warranted in patients with low titre anticardiolipin antibodies, especially if they experience new or recurrent clinical symptoms 2.

Inter-Laboratory Variation and Test Result Consensus

There is significant inter-laboratory variation in the results of anticardiolipin antibody assays, which can lead to limited consensus among laboratories 3.

• One study found that inter-laboratory variation for both IgG and IgM anticardiolipin antibodies was higher than 50% in 48.8% of testing cases 3.
• Total consensus among laboratories occurred in less than 20% of cases for IgG anticardiolipin antibodies, and in about 50% of serum testing occasions, there was no general consensus in returned laboratory data 3.
• This high inter-laboratory variation and lack of test result consensus highlight the need for caution when interpreting the results of anticardiolipin antibody assays, and suggest that single point laboratory results should be used with caution before making a clinical diagnosis of APS or related disorders 3.

Clinical Approach to Establishing Low/Medium Antibody Threshold

A clinical approach to establishing the low/medium antibody threshold for anticardiolipin antibody assays has been proposed, which takes into account the clinical performance and comparison to traditional enzyme-linked immunosorbent assays (ELISAs) 4.

• This approach has been used to establish the low/medium threshold for QUANTA Flash aCL IgG and IgM assays, which was found to improve agreement between CIA and ELISA assay results 4.
• The use of a platform-specific low/medium antibody threshold can help to reduce inter-laboratory variation and improve the accuracy of anticardiolipin antibody assays 4, 5.