What is the purpose of Intravenous Immunoglobulin (IV IG) in patients with Antiphospholipid Antibody Syndrome (APAS)?

Purpose of Intravenous Immunoglobulin (IVIG) in Antiphospholipid Antibody Syndrome

IVIG serves as adjunctive therapy in three specific clinical scenarios in APS: (1) refractory obstetric APS when conventional therapy with aspirin plus heparin has failed, (2) catastrophic APS (CAPS) as part of combination therapy, and (3) recurrent thrombosis despite adequate anticoagulation with warfarin. 1

Primary Indications for IVIG in APS

Refractory Obstetric APS

• IVIG is indicated for pregnant women with recurrent pregnancy losses who have failed standard treatment with low-dose aspirin plus low-molecular-weight heparin, or when anticoagulation is contraindicated due to bleeding risk 1, 2
• The typical dosing regimen is 0.4 g/kg/day for 2 days, then 1.5 g/kg/day for 1 day, administered monthly throughout pregnancy, though protocols vary 3
• IVIG succeeded in achieving successful pregnancy outcomes in the vast majority of APS patients with recurrent abortions when used either alone or combined with aspirin/heparin 2
• Consider IVIG when concomitant autoimmune manifestations or active infections are present, as these complicate standard anticoagulation therapy 1

Catastrophic Antiphospholipid Syndrome (CAPS)

• IVIG represents an important component of combination therapy for CAPS, which is a life-threatening multi-organ thrombotic emergency 1
• IVIG should be administered alongside anticoagulation, corticosteroids, and plasma exchange in the acute management of CAPS 1

Recurrent Thrombosis Despite Adequate Anticoagulation

• IVIG may prevent recurrent thrombotic events in APS patients who experience breakthrough thrombosis despite therapeutic anticoagulation with warfarin (INR 2.0-3.0) 1, 4, 5
• In a prospective study, no venous or arterial thromboses occurred in APS patients treated with monthly IVIG (0.4 g/kg/day) for 2 years in addition to conventional anticoagulation, whereas the control group experienced 3 thrombotic events 5
• Long-term follow-up (mean 89.2 months) of 5 high-risk primary APS patients with relapsing thrombosis showed no further thromboses when IVIG was combined with hydroxychloroquine 6

Mechanisms of Action

• IVIG contains anti-idiotypic antibodies directed against pathogenic antiphospholipid antibodies, which neutralize their prothrombotic effects 2
• IVIG inhibits anticardiolipin antibodies and lupus anticoagulant activity in vitro and ameliorates experimental APS in animal models 2
• Treatment results in statistically significant decreases in anticardiolipin antibody titers (IgG and IgM) and anti-β2-glycoprotein I antibody levels 5
• IVIG modulates the systemic inflammatory response and provides antibodies that can neutralize circulating autoantibodies 3

Dosing Protocols

• Standard monthly maintenance: 0.4 g/kg/day as a single infusion every month for extended periods (12-24 months minimum) 5, 6
• Intensive induction protocol: Three consecutive daily infusions of 0.4 g/kg/day for 3 months, followed by single monthly infusions for 9 months 6
• Obstetric protocol: 1.5 g/kg administered over 2 weeks for 2 months, then monthly for 4 months during pregnancy 3

Critical Limitations and Caveats

• IVIG is not first-line therapy for APS—standard anticoagulation with warfarin (INR 2.0-3.0) remains the primary treatment for thrombotic APS 7
• IVIG should never replace conventional anticoagulation but rather serves as adjunctive therapy in refractory cases 1, 5
• The evidence base consists primarily of small case series and observational studies; large randomized controlled trials are lacking 1, 6
• IVIG use is restricted by high costs and limited availability, making it impractical for routine use 6
• Some studies show controversial results regarding efficacy, particularly in preventing initial thrombosis versus recurrent events 1
• IVIG is not indicated for asymptomatic patients with positive antiphospholipid antibodies alone, as no treatment is warranted without clinical manifestations 7

When NOT to Use IVIG

• Do not use IVIG as monotherapy for thrombotic APS—anticoagulation remains mandatory 1
• Do not use IVIG for primary prevention in asymptomatic antibody-positive patients 7
• Do not use IVIG as first-line therapy for obstetric APS—aspirin plus heparin is the established standard 1
• Avoid IVIG when standard therapy has not been adequately trialed or optimized first 1