Is rituximab (Truxima) a suitable second-line treatment for a patient with seronegative autoimmune encephalitis who has failed first-line therapies, including steroids, Intravenous Immunoglobulin (IVIG), and Cellcept (Mycophenolate Mofetil)?

Rituximab is Appropriate Second-Line Therapy for This Patient with Seronegative Autoimmune Encephalitis

This patient with seronegative autoimmune encephalitis who has failed first-line therapies (steroids, IVIG) and maintenance therapy (Cellcept) with documented clinical worsening clearly meets guideline-based criteria for rituximab as second-line therapy. 1, 2, 3

Guideline-Supported Indication for Second-Line Therapy

The American Academy of Neurology explicitly recommends adding second-line agents such as rituximab when there is no meaningful clinical or radiological response to optimized first-line therapy after 2-4 weeks. 1, 3 This patient has exceeded this timeframe substantially, having failed both acute first-line therapy during hospitalization and subsequent maintenance therapy with mycophenolate mofetil over a three-year period. 2

The patient meets all criteria for treatment escalation:

• Inadequate response to optimized first-line immunotherapy (steroids and IVIG) 1, 2
• Failure of maintenance immunosuppression (Cellcept) 2
• Clinical deterioration evidenced by worsening hallucinations and delusions requiring hospitalization 2
• Symptom exacerbation when Cellcept was decreased, demonstrating inadequate disease control 2

Rituximab as Standard Second-Line Therapy

Rituximab is the preferred second-line agent for autoimmune encephalitis, particularly in seronegative cases. 1, 3 The American Academy of Neurology guidelines note that rituximab is less toxic than cyclophosphamide and is preferentially considered by most clinicians, with 80% of experts choosing rituximab for cases with unknown antibodies. 1, 3

The American Society of Clinical Oncology Clinical Practice Guideline (2018) specifically states: "If positive for autoimmune encephalopathy or paraneoplastic antibody and limited or no improvement, may offer rituximab or plasmapheresis in consultation with neurology." 2, 3 While this patient is seronegative, the clinical diagnosis of autoimmune encephalitis and treatment failure clearly warrant second-line therapy. 2

Evidence Supporting Rituximab in Seronegative Cases

Rituximab demonstrates efficacy regardless of antibody status. 4 A 2016 institutional cohort study of 80 patients with autoimmune limbic encephalitis treated with rituximab as second-line therapy found that 43.8% were antibody-negative, and the effect of rituximab was the same regardless of autoantibody status. 4 Functional improvement occurred more frequently in the rituximab group compared to controls. 4

A 2020 meta-analysis demonstrated that good functional outcome (mRS ≤2) following rituximab therapy occurred in 72.2% of patients, with mean mRS score decreasing by 2.67 points. 5 Relapses following rituximab therapy occurred in only 14.2% of patients. 5

Standard of Care vs. Experimental Status

Rituximab is established as standard second-line therapy in multiple peer-reviewed clinical practice guidelines from major medical societies (American Academy of Neurology, American Society of Clinical Oncology). 2, 3 Off-label use of rituximab for autoimmune conditions is well-established and guideline-supported. 2

While rituximab is not FDA-approved specifically for autoimmune encephalitis, this does not render it experimental. 2 The distinction between off-label use supported by clinical practice guidelines and experimental therapy is critical—rituximab falls into the former category based on consensus expert recommendations from major neurological societies. 1, 2, 3

Dosing Regimens

Common rituximab dosing regimens for autoimmune encephalitis include:

• 375 mg/m² weekly for 4 weeks, OR 1
• Two doses of 1000 mg given 2 weeks apart 1

Additional monthly rituximab therapy has been associated with improved mRS scores and favorable outcomes in patients with autoimmune limbic encephalitis. 4

Safety Monitoring Requirements

Essential monitoring includes:

• Screening for hepatitis B reactivation before initiating therapy 6, 2
• Monitoring serum immunoglobulin levels before and periodically after rituximab, particularly with multiple courses, due to risk of hypogammaglobulinemia 1, 6, 2
• CBC, hepatic and renal function tests during therapy 6
• Awareness of infusion reactions occurring in approximately 20% of patients 1, 6

Rare but serious complications to counsel patients about:

• Progressive multifocal leukoencephalopathy 1, 6, 2
• Severe mucocutaneous reactions 1, 6, 2
• Hepatitis B reactivation 1, 6, 2

Neurological Consultation

Ongoing management should be guided by neurological consultation, as recommended in all autoimmune encephalitis guidelines. 2, 3 This ensures appropriate monitoring for treatment response and management of any neurological complications.

Common Pitfall to Avoid

The primary pitfall in this clinical scenario would be continuing to adjust or cycle through first-line therapies (such as increasing Cellcept dose or adding back higher-dose steroids) when the patient has already demonstrated clear treatment failure. 1, 2 Delaying second-line therapy in patients who meet criteria for escalation can result in worse outcomes, as early aggressive immunotherapy is associated with better functional recovery in autoimmune encephalitis. 1, 3