Is Ravulizumab-cwvz (Ultomiris) medically necessary for the treatment of infection-associated hemolytic-uremic syndrome (aHUS)?

Medical Necessity of Ravulizumab-cwvz for Infection-Associated Hemolytic Uremic Syndrome

Ravulizumab-cwvz (Ultomiris) is medically necessary for this patient with genetically confirmed atypical HUS (aHUS) who has demonstrated positive response to therapy, despite the initial diagnosis code of D59.31 (infection-associated HUS). The clinical documentation clearly establishes this as complement-mediated aHUS triggered by COVID-19 infection, not typical infection-associated HUS, making complement inhibition the appropriate standard of care.

Diagnostic Clarification

The diagnosis code D59.31 appears to be a coding error that does not reflect the actual clinical diagnosis:

• The patient has genetically confirmed aHUS with homozygous CFHR3-CFHR1 deletion, which is a well-established genetic abnormality causing complement-mediated thrombotic microangiopathy 1, 2
• COVID-19 served as a trigger for aHUS manifestation, not the primary cause of typical infection-associated HUS 3
• The 2025 Italian multidisciplinary consensus confirms that aHUS is characterized by dysregulated complement activity requiring complement inhibition, regardless of infectious triggers 3

Evidence Supporting Medical Necessity

Continuation Therapy Criteria Met

All three required criteria from the insurance policy are clearly satisfied:

Criterion 1 - No Evidence of Toxicity or Disease Progression:

• Documentation states "patient is doing much better and has been tolerating Ravulizumab well" [@case documentation@]
• No adverse events reported during treatment course 2, 4

Criterion 2 - Positive Response to Therapy:

• Hemoglobin normalized with no evidence of ongoing hemolysis [@case documentation@]
• Kidney function at baseline [@case documentation@]
• LDH normalized at 155 Units/L (normal range) [@case documentation@]
• Platelet count normalized at 255 × 10⁹/L [@case documentation@]
• These parameters meet the definition of complete thrombotic microangiopathy response: normalization of platelet count and lactate dehydrogenase with improved renal function 3, 5

Criterion 3 - No Combination with Other Complement Inhibitors:

• Explicitly documented: "No other complement inhibitor (e.g., Soliris) for the treatment of aHUS" [@case documentation@]

FDA-Approved Indication and Dosing

• Ravulizumab is FDA-approved for treatment of aHUS in both adults and pediatric patients 1
• The 3,600 mg maintenance dose every 8 weeks is appropriate for patients ≥40 kg per FDA labeling 1
• The FDA label confirms ravulizumab inhibits complement-mediated thrombotic microangiopathy in patients with aHUS 1

Guideline Support for Long-Term Therapy

• The 2025 Italian consensus (highest quality, most recent guideline) recommends eculizumab/ravulizumab as first-line treatment for aHUS with sustained therapy to prevent relapse 3
• Discontinuation of complement inhibition carries substantial risk of aHUS recurrence, renal failure, and life-threatening complications 3
• Ravulizumab and eculizumab have equivalent efficacy, but ravulizumab offers superior convenience with 8-week dosing intervals versus 2-week intervals 3

Clinical Evidence Base

• Phase 3 trials demonstrate 53.6% complete TMA response rate in complement inhibitor-naïve adults with aHUS treated with ravulizumab 5
• Long-term follow-up (median 76.7 weeks) shows sustained normalization of platelet count, LDH, and hemoglobin with maintained renal function improvements 4
• Real-world Japanese post-marketing surveillance confirms 97% TMA event-free status in patients switched from eculizumab to ravulizumab 6
• Pediatric data support safety and efficacy comparable to adults 2, 7

Critical Clinical Context

Prevention of Life-Threatening Complications

Without continued complement inhibition, this patient faces:

• Risk of thrombotic microangiopathy relapse with acute renal failure requiring dialysis 3, 2
• Potential for systemic complications including neurological, cardiac, and gastrointestinal manifestations 3
• High morbidity and mortality associated with untreated aHUS 5, 4

Prior Treatment History

• Patient previously required dialysis in the acute phase, demonstrating severe disease [@case documentation@]
• Successful transition from eculizumab to ravulizumab with maintained disease control [@case documentation@]
• Patient has remained dialysis-free since initiation of complement inhibitor therapy [@case documentation@]

Safety Monitoring Compliance

The clinical documentation demonstrates appropriate safety measures:

• Meningococcal vaccination required prior to complement inhibitor therapy 3, 1
• Regular laboratory monitoring of hemolysis markers and renal function [@case documentation@]
• No meningococcal infections reported in clinical trials 5, 4, 6

Common Pitfalls to Avoid

Do not confuse infection-triggered aHUS with typical STEC-HUS:

• Typical STEC-HUS is self-limited and does not require complement inhibition 3
• aHUS triggered by infection (COVID-19 in this case) requires ongoing complement inhibition due to underlying genetic complement dysregulation 3

Do not discontinue therapy based on clinical improvement:

• Normalization of laboratory parameters reflects therapeutic efficacy, not disease resolution 4
• Premature discontinuation risks catastrophic relapse with potential irreversible organ damage 3