What is the role of Intravenous Immunoglobulin (IVIG) in the treatment of Antiphospholipid Syndrome (APAS) in adult patients?

IVIG Function in Antiphospholipid Syndrome (APAS)

IVIG is not recommended as standard therapy for thrombotic antiphospholipid syndrome, but may be considered as adjunctive treatment in refractory cases where conventional anticoagulation has failed to prevent recurrent thrombosis. 1

Standard Treatment Remains Anticoagulation

The 2024 American Heart Association/American Stroke Association guidelines and 2020 American College of Rheumatology guidelines establish that anticoagulation with vitamin K antagonists (VKAs) targeting an INR of 2-3 is the mainstay of treatment for thrombotic APS. 1 IVIG is notably absent from first-line or even second-line recommendations in these authoritative guidelines.

Limited Role in Obstetric APS

For obstetric APS, the American College of Rheumatology strongly recommends against adding IVIG to standard therapy (low-dose aspirin plus prophylactic-dose heparin/LMWH) in patients who have failed conventional treatment. 1 This recommendation is based on:

• Lack of controlled studies demonstrating benefit in pregnancy loss despite standard therapy 1
• Recognition that 25% of obstetric APS pregnancies still experience pregnancy loss even with optimal treatment 1
• No data showing improved outcomes with IVIG addition 1

The guideline acknowledges this is based on absence of compelling data rather than data showing clear harm, but the recommendation stands firm. 1

Potential Use in Refractory Thrombotic Cases

While not guideline-endorsed, research evidence suggests IVIG may have a role in highly selected refractory cases:

• Small prospective studies show IVIG (0.4 g/kg/day monthly) added to conventional anticoagulation prevented recurrent thrombosis in patients who had failed standard therapy, with follow-up extending beyond 5 years in some cohorts 2, 3
• These studies demonstrated statistically significant decreases in anticardiolipin antibody titers during IVIG treatment 4, 2
• One study of 5 refractory primary APS patients showed no further thromboses over mean follow-up of 89.2 months when IVIG was combined with hydroxychloroquine 3

However, these are small, uncontrolled studies that cannot override the absence of guideline support. The evidence quality is insufficient to recommend IVIG routinely. 5, 6

Mechanism of Action

When IVIG is used in APS, the proposed mechanisms include:

• Increased pathogenic catabolism of antiphospholipid antibodies 1
• Immunomodulatory effects that reduce antibody production 5
• Reduction in anticardiolipin IgG, IgM, and anti-β2-glycoprotein I antibody levels 2, 3

Dosing When Considered

If IVIG is used in refractory cases (off-guideline), research protocols have employed:

• 0.4 g/kg/day monthly as maintenance therapy for thrombosis prevention 2, 3
• Initial loading with 3 consecutive daily infusions of 0.4 g/kg/day, followed by single monthly infusions 3
• Infusions administered over several hours (not a fixed 4-hour timeframe) 7

Critical Caveats

• IVIG carries rare but serious thrombotic complications including stroke, deep vein thrombosis, and pulmonary embolism—particularly problematic in APS patients already at high thrombotic risk 8
• Renal failure risk requires monitoring, especially in patients with reduced renal function 8
• Aseptic meningitis can occur; concomitant corticosteroids may reduce this risk 8
• Cost and limited availability restrict use 3

Clinical Algorithm for Decision-Making

1. First-line: VKA targeting INR 2-3 for thrombotic APS 1
2. Recurrent thrombosis on VKA: Verify adequate anticoagulation intensity, consider adding hydroxychloroquine, optimize cardiovascular risk factors 1, 6
3. Persistent recurrence despite optimized anticoagulation: Consider rituximab or eculizumab before IVIG 6
4. IVIG consideration only if: Multiple treatment failures, contraindications to other therapies, and after thorough discussion of limited evidence and thrombotic risks 5, 3

The bottom line: IVIG lacks guideline support in APS and should not be used routinely. Its role is restricted to exceptional refractory cases where all standard options have been exhausted, and even then, the evidence base is weak. 1, 5