Is the use of Rituximab (Rituxan) for multiple sclerosis (MS) considered medically necessary and standard of care?

Is Rituximab Medically Necessary for Multiple Sclerosis Treatment in This Patient?

Yes, rituximab is medically necessary for this patient with relapsing-remitting multiple sclerosis (RRMS) who demonstrates ongoing disease activity with balance dysfunction and gait impairment, despite the off-label nature of this indication. The treatment meets established clinical criteria for disease-modifying therapy in MS and represents standard practice supported by substantial evidence.

Medical Necessity Analysis

Disease Activity and Treatment Indication

The patient demonstrates clear evidence of active MS requiring disease-modifying therapy. She has:

• Documented RRMS with chronic gait dysfunction and progressive balance impairment 1
• Persistent neurological deficits including inability to perform single leg stance and increased sway with eyes closed 1
• History of falls (most recent July 2024) indicating functional decline 1
• Ongoing left-sided weakness and balance issues despite home exercise program 1

Rituximab has demonstrated substantial efficacy in preventing relapses and disease progression in RRMS patients. In relapsing MS, rituximab results in a large reduction in relapses compared with interferon beta or glatiramer acetate (HR 0.14,95% CI 0.05 to 0.39), and likely reduces relapses compared with dimethyl fumarate (HR 0.29) and natalizumab (HR 0.24) 1. Real-world data shows an overall annualized relapse rate of 0.03 with rituximab treatment, with 79% of patients achieving NEDA-3 (no evidence of disease activity) status 2.

Off-Label Use is Clinically Justified

Despite lacking FDA approval for MS, rituximab represents established standard of care in clinical practice. Off-label rituximab for MS is used in most countries surveyed by the International Federation of MS, including high-income countries where on-label disease-modifying treatments are available 1. In some jurisdictions, rituximab is the most commonly used disease-modifying drug for MS subtypes 3.

The Aetna policy explicitly recognizes rituximab as medically necessary for relapsing-remitting MS treatment when prescribed by appropriate specialists (neurologist, immunologist, or rheumatologist) and when not used concomitantly with other MS drugs (excluding Ampyra) [@CPB 0314@].

Safety Profile Supports Continued Use

The safety profile of rituximab in MS is well-characterized and manageable. Common adverse events include:

• Infusion-related reactions (manageable with standard protocols) 2
• Infections (9.3% in real-world cohorts, predominantly CTCAE grade 2-3) 2
• Neutropenia (4.4%) and hypogammaglobulinemia (5.2%) requiring monitoring 2
• Serious adverse events are relatively rare, with annualized drug discontinuation rate of 0.05 2

Enhanced surveillance is appropriate for this patient given her history of recurrent UTIs and neurogenic bladder. Follow-up MRI should be conducted at least annually, with T2 FLAIR and gadolinium-enhanced T1-weighted sequences to monitor disease activity 4.

Standard of Care Assessment

Evidence Base for Rituximab in MS

Rituximab is supported by substantial clinical evidence despite the absence of phase 3 registration trials. Data from phase 2 RCTs, multiple observational studies, and large registry analyses demonstrate:

• High efficacy in preventing relapses and MRI activity 5, 1
• Effectiveness comparable to approved high-efficacy DMTs like natalizumab 6
• Low discontinuation rates related to favorable benefit-risk profile 3
• Good patient compliance 3

The treatment is not experimental or investigational—it represents established clinical practice. Multiple systematic reviews and meta-analyses support rituximab's efficacy and safety in MS 5, 1. Real-world effectiveness studies from multiple countries, including large Swedish MS registry data, provide robust evidence for clinical decision-making 1.

Dosing Regimen Considerations

The patient's dosing regimen requires clarification against established protocols. While optimal dose and frequency have not been definitively established, common regimens include:

• 1 g once every 2 weeks for 2 doses, then 1 g every 6-12 months [@Lexicomp@]
• Alternative: 500 mg to 1 g once every 6-12 months [@Lexicomp@]

The specific dosing frequency for this patient should be documented and justified based on disease activity monitoring, B-cell depletion status, and clinical response 5.

Critical Monitoring Requirements

Ongoing Surveillance Needed

This patient requires enhanced monitoring given her comorbidities:

• Annual brain MRI at minimum to assess disease activity 4
• Monitoring for infections, particularly given recurrent UTI history 2
• Assessment of immunoglobulin levels and complete blood counts for neutropenia 2
• Coordination with physical therapy to objectively measure functional outcomes 4

Physical Therapy Integration

The referral to Bryn Mawr Rehab for physical therapy is appropriate and necessary to address:

• Gait dysfunction and balance impairment 1
• Single leg stance deficits 1
• Fall prevention strategies 1
• Functional mobility optimization to maintain quality of life 1

Conclusion on Medical Necessity

Both questions are answered affirmatively:

1. The treatment plan is medically necessary because the patient has active RRMS with documented neurological deficits requiring disease-modifying therapy, and rituximab represents an effective, evidence-based option that meets payer criteria for relapsing-remitting MS [@CPB 0314@, 1].

2. The treatment is standard of care, not experimental based on extensive real-world evidence, systematic reviews, and widespread international clinical practice, despite the off-label designation 3, 5, 1, 2. The treatment is proven safe and effective with manageable adverse event profiles when appropriate monitoring is implemented 2.

The off-label status should not preclude coverage given the substantial evidence base, explicit payer policy recognition, and lack of superior alternatives for this patient's clinical situation 3, 1.