What is the role of Rituximab (rituximab) in treating myasthenia gravis?

Rituximab in Myasthenia Gravis

Primary Recommendation

Rituximab is an established treatment option for myasthenia gravis, particularly effective in MuSK-antibody positive disease and refractory cases, though its role in acetylcholine receptor (AChR) antibody-positive MG remains less certain. 1, 2

Evidence-Based Indications

MuSK-Positive Myasthenia Gravis

• Rituximab demonstrates high efficacy in MuSK-antibody positive MG and should be considered as a primary treatment option in this subgroup. 1, 3
• The American Academy of Ophthalmology recognizes rituximab as an established treatment for myasthenia gravis, with particular strength in MuSK-positive disease. 1

Refractory Disease

• Rituximab is widely used off-label for patients who fail conventional immunosuppressive therapies, with approximately 15% of MG patients being refractory to standard treatments. 3
• In refractory cases, rituximab has shown clinical improvement in 11 of 14 patients (79%) in real-world practice. 4

AChR-Positive Disease

• The evidence for AChR-antibody positive MG is less robust and more uncertain. 2
• A recent Cochrane review found very uncertain effects on symptom severity (QMG score MD -1.62,95% CI -3.53 to 0.29) and functional ability (MG-ADL MD -1.16,95% CI -2.48 to 0.16) beyond nine months. 2
• However, rituximab probably results in a large reduction in relapse requiring rescue therapy (RR 0.45,95% CI 0.26 to 0.78), reducing relapses from 490 per 1000 to 220 per 1000 patients. 2

Dosing Regimens

Standard Protocol

• The most commonly studied regimen is 375 mg/m² weekly for 4 weeks, consistent with lymphoma protocols. 1
• This dosing is supported by clinical trial data and aligns with standard practice. 1

Low-Dose Alternative

• A lower dose of 1 gram total (500 mg × 2 doses, two weeks apart) appears effective and may be sufficient for many patients. 4
• This regimen achieved B-cell depletion in 13 of 14 patients and clinical improvement in 11 of 14 patients. 4
• B-cell recovery typically occurs between 9-30 months (median 12.3 months) and correlates with symptom recurrence, guiding re-treatment timing. 4

Monotherapy vs. Combination

• Rituximab alone is as effective as rituximab combined with corticosteroids in treatment-naïve generalized MG patients. 5
• Patients receiving rituximab alone had similar outcomes at 3,6,9, and 12 months compared to those receiving rituximab plus steroids (≥0.5 mg/kg). 5
• Importantly, the rituximab-alone group required significantly fewer rescue therapies (20.41% vs 47.37%, p=0.037). 5
• This suggests avoiding steroids when using rituximab may reduce side effects and decrease need for rescue therapy without compromising outcomes. 5

Steroid-Sparing Effect and Clinical Outcomes

Immunosuppression Reduction

• Rituximab allows reduction of other immunosuppressive medications in 12 of 14 patients (86%), though complete cessation is achieved in only a minority. 4
• The evidence suggests little to no difference in steroid-sparing effect beyond nine months (RR 1.00,95% CI 0.92 to 1.09). 2

Relapse Prevention

• The most compelling benefit is the substantial reduction in relapses requiring rescue therapy, with a 55% relative risk reduction. 2

Safety Profile

Serious Adverse Events

• The evidence regarding serious adverse events is very uncertain (RR 0.81,95% CI 0.47 to 1.41), preventing definitive conclusions about safety. 2
• One patient demonstrated no severe infectious complications after 10 years of rituximab treatment, indicating good long-term tolerance is possible. 1

Known Risks

• Infusion reactions occur in approximately 20% of patients. 6
• Rare but serious complications include severe mucocutaneous reactions, hepatitis B reactivation, and progressive multifocal leukoencephalopathy. 6
• Risk of hypogammaglobulinemia increases with multiple courses, requiring monitoring of serum immunoglobulin levels. 6

Monitoring Requirements

• Unlike conventional oral immunosuppressants, rituximab does not require regular hematological monitoring, which is a practical advantage. 3
• Serial monitoring of peripheral blood B-lymphocyte counts is useful for guiding re-treatment timing, as B-cell recovery consistently correlates with symptom worsening. 4
• Antibody titre reduction occurs in only a minority of patients and does not reliably predict clinical improvement. 4

Supportive Care During Treatment

• Prophylactic trimethoprim-sulfamethoxazole should be administered to prevent Pneumocystis jirovecii pneumonia. 7
• Standard monitoring during therapy should include CBC, hepatic and renal function tests. 6

Critical Caveats

Evidence Limitations

• Only two randomized controlled trials exist, using different dosing strategies (low-dose at disease onset vs. high-dose as add-on therapy). 2
• Studies predominantly assessed AChR-antibody positive MG, with limited data on other subtypes. 2
• The optimal dosing regimen and patient characteristics that predict response remain inadequately defined. 2, 3

Regulatory Status

• Despite widespread off-label use, rituximab lacks regulatory approval specifically for myasthenia gravis. 3
• Patients must understand the off-label nature and provide informed consent regarding potential risks. 8

Clinical Application

• For MuSK-positive MG: Consider rituximab as a primary treatment option given strong efficacy signals. 1, 3
• For refractory AChR-positive MG: Rituximab is reasonable after conventional immunosuppression failure, primarily for its relapse-prevention benefit. 2, 3
• For treatment-naïve generalized MG: Rituximab monotherapy (without steroids) is a viable option that may reduce rescue therapy needs. 5