What is the role of Intravenous Immunoglobulin (IVIG) with rituximab in the treatment of myasthenia gravis?

IVIG with Rituximab in Myasthenia Gravis

For severe or refractory myasthenia gravis (Grade 3-4), IVIG should be administered at 2 g/kg IV over 5 days (0.4 g/kg/day) as initial therapy, with rituximab added if the patient remains refractory to IVIG or plasmapheresis. 1

Treatment Algorithm by Disease Severity

Grade 3-4 (Severe) Myasthenia Gravis

• Permanently discontinue immune checkpoint inhibitors if applicable 1
• Admit patient with ICU-level monitoring capability for patients with severe weakness limiting mobility, respiratory compromise, dysphagia, or rapidly progressive symptoms 1
• Initiate IVIG 2 g/kg IV over 5 days (0.4 g/kg/day) as first-line rescue therapy 1
• Add rituximab if refractory to IVIG or plasmapheresis, using either:
  • 1000 mg repeated on day 15, OR
  • 375 mg/m² once weekly for 4 weeks 1
• Continue corticosteroids (prednisone 0.5 mg/kg orally daily for Grade 2; higher doses for Grade 3-4), with taper beginning 3-4 weeks after initiation 1

Grade 2 (Moderate) Myasthenia Gravis

• Hold immunotherapy temporarily and may resume only if symptoms resolve and steroid taper completed 1
• Pyridostigmine starting at 30 mg PO three times daily, gradually increasing to maximum 120 mg PO four times daily 1
• Corticosteroids (prednisone 0.5 mg/kg orally daily) 1
• Strongly consider inpatient care as patients can deteriorate quickly 1

Rituximab as Primary Therapy in Refractory Disease

Rituximab demonstrates superior efficacy when used earlier in the disease course rather than as late salvage therapy. 2

• New-onset generalized MG: Median time to remission with rituximab was 7 months versus 11 months with conventional immunosuppressants (HR 2.97,95% CI 1.43-6.18, p=0.004) 2
• Refractory versus new-onset disease: Time to remission was significantly shorter in new-onset disease (7 vs 16 months, HR 2.53,95% CI 1.26-5.07, p=0.009) 2
• Rescue therapy requirements: Patients on rituximab required fewer rescue therapy episodes in first 24 months (mean 0.38 vs 1.31 times, p<0.001) 2
• Treatment discontinuation: Lower rates due to adverse events with rituximab versus conventional therapies (3% vs 46%, p<0.001) 2

Evidence for Combined IVIG and Rituximab

All 14 patients with refractory MG responded dramatically to rituximab, measured by changes in manual muscle testing score, prednisone dose reduction, or decreased frequency of IVIG infusions or plasmapheresis. 3

• Rituximab allows reduction in IVIG frequency in patients previously requiring regular IVIG infusions 3
• Six patients with refractory MG treated with rituximab (375 mg/m² on days 1,8,15,28, then one dose every 2 months) stopped corticosteroids and tapered cholinesterase inhibitors after 2 years follow-up 4
• Rituximab probably results in large reduction in relapse requiring rescue therapy beyond 9 months (RR 0.45,95% CI 0.26-0.78, moderate-certainty evidence) 5

Pre-Treatment Workup Before Rituximab

Obtain baseline immunoglobulin levels (IgG, IgM, IgA), determine hepatitis B and C antibody levels, and screen for latent tuberculosis prior to administering rituximab. 1

Essential Laboratory Assessment

• Acetylcholine receptor antibodies and anti-striational antibodies 1
• CPK, aldolase, ESR, and CRP for possible concurrent myositis 1
• Pulmonary function assessment with negative inspiratory force (NIF) and vital capacity (VC) 1
• Troponin, ECG, and consider echocardiography to evaluate concomitant myocarditis 1
• Electrodiagnostic studies including neuromuscular junction testing with repetitive stimulation and/or jitter studies 1

Critical Safety Considerations

IVIG Administration

• Check serum IgA level before administering IVIG because IgA deficiency may lead to fever, infusion reactions, and/or severe anaphylaxis 1
• If IgA deficiency detected, patient should receive IVIG preparation with reduced IgA levels 1
• Subcutaneous immunoglobulin may be better tolerated for patients with IgA deficiency who developed anti-IgA antibodies 6

Rituximab Safety

• Progressive multifocal leukoencephalopathy has been reported in rheumatic patients treated with rituximab; caution should be used in immunosuppressed patients 1
• Severe infectious complications are a concern with rituximab therapy 1
• High index of suspicion for JC virus reactivation should be maintained for any patient presenting with CNS abnormalities 1

Medication Interactions to Avoid

Review and stop medications with known risk of worsening myasthenia: beta-blockers, IV magnesium, fluoroquinolones, aminoglycosides, and macrolide antibiotics 1

Monitoring During Treatment

• Daily neurologic review for Grade 3-4 patients 1
• Frequent pulmonary function assessment to monitor for respiratory compromise 1
• Regular assessment of clinical response using standardized measures such as muscle strength and disability scores 6
• Periodic IgG trough levels to ensure adequate replacement 6
• Laboratory monitoring including blood counts and serum chemistry at least every 6-12 months 6

Common Pitfalls to Avoid

• Do not administer plasmapheresis immediately after IVIG as it will remove immunoglobulin 1
• Do not delay rituximab in truly refractory cases - evidence suggests earlier use yields better outcomes 2
• Do not overlook concurrent myocarditis - troponin and cardiac imaging should be obtained in severe cases 1
• Do not restart immunotherapy prematurely - only resume after symptom resolution and steroid taper completion 1