What is IgM (Immunoglobulin M) B2GP (Beta-2 Glycoprotein)?

What is IgM B2GP (Beta-2 Glycoprotein I Antibody)?

IgM anti-beta-2 glycoprotein I (IgM aβ2GPI) is an autoantibody of the immunoglobulin M class that targets beta-2 glycoprotein I protein and serves as one of the laboratory criteria for diagnosing antiphospholipid syndrome (APS). 1, 2

Definition and Clinical Context

IgM aβ2GPI represents one of three major antibody isotypes (IgG, IgM, and IgA) that can target beta-2 glycoprotein I, a phospholipid-binding protein involved in the pathophysiology of APS 1. Beta-2 glycoprotein I is recognized as a major antigenic target in APS, and antibodies against it can induce thrombosis, pregnancy morbidity, and other autoimmune manifestations 1.

Laboratory Detection

• IgM aβ2GPI should be measured using solid-phase assays (ELISA or other validated systems) 2
• Results are reported with their titer level, with positivity defined as values above the 99th percentile of normal controls 2
• Diagnosis requires two consecutive positive tests at least 12 weeks apart to rule out transient positivity 2
• Medium to high titers are defined as above 40 MPL units or above the 99th percentile measured by standardized ELISA 1

Clinical Significance and Risk Stratification

Role in Different APS Presentations

The clinical significance of IgM aβ2GPI differs substantially between thrombotic and obstetric APS 1:

• In obstetric APS: Isolated IgM aβ2GPI is more frequent and represents an independent risk factor 1. In women with suspected obstetric APS, both IgM and IgG should be tested 1

• In thrombotic APS: Isolated IgM aβ2GPI is rare 1. First-line testing for IgM is not strictly necessary but may be useful for risk stratification, as IgM positivity in addition to IgG and lupus anticoagulant increases thrombotic risk 1

• In stroke patients: Isolated IgM may be more frequent and clinically relevant 1, 3. Patients with isolated IgM APS presenting with stroke have higher relapse rates with antiplatelet agents alone compared to vitamin K antagonists 3

Hierarchy of Clinical Relevance

IgG aβ2GPI antibodies show stronger association with clinical events than IgM 1:

• IgG antibodies are often associated with IgM positivity 1
• The 2023 ACR/EULAR APS classification criteria attribute low weight to isolated IgM aβ2GPI 1
• Concordance of isotype (both aCL and aβ2GPI of the same isotype) reinforces clinical probability of APS 1

Risk Profile Classification

IgM aβ2GPI contributes to APS risk stratification 1, 2:

• High-risk profile: Presence of double positivity (any combination including IgM aβ2GPI) or triple positivity carries highest thrombotic risk 2
• Low-risk profile: Isolated IgM aβ2GPI at low-medium titers, particularly if transiently positive 1
• Triple positivity with concordance of isotype has higher odds ratios than triple positivity with mixed isotypes 1

Important Clinical Caveats

Specificity Considerations

IgM aβ2GPI has lower specificity than IgG for APS diagnosis 4:

• Elevated IgM levels can be seen in various thrombotic and non-thrombotic disorders including SLE (21%), rheumatoid factor (23%), infectious mononucleosis (43%), and HIV (27%) 4
• The median value for IgM in these conditions ranges from 2-7 arbitrary units, compared to much higher values for IgG in APS patients 4

Testing Strategy

A rational approach to IgM aβ2GPI testing depends on clinical presentation 1:

• Mandatory testing: Women with suspected obstetric APS 1
• Selective testing: Thrombotic APS for risk stratification purposes 1
• Consider testing: Patients with thrombocytopenia (significantly associated with IgM) 1 or stroke patients where isolated IgM may be more frequent 1, 3

Interpretation Pitfalls

• Laboratory results must be interpreted in clinical context with knowledge of anticoagulation status 2
• Single positive IgM is considered less clinically relevant than IgG positivity 2
• Isolated IgM positivity without other antiphospholipid antibodies requires careful clinical correlation 1
• The presence of both aCL and aβ2GPI of the same isotype (both IgM) significantly increases diagnostic confidence 1

Special Population: Isolated IgM APS

Patients with isolated IgM APS (14% of APS population) have distinct characteristics 3:

• Tend to be approximately 9.5 years older at diagnosis 3
• Strong association with stroke as presenting manifestation 3
• IgM isotype remains isolated in approximately 71% of patients over time 3
• Antiplatelet agents alone appear insufficient for stroke prevention; vitamin K antagonists are preferred 3