Rituximab has been used to treat JMG for over a decade, often part of multi-drug regimens. Zilucoplan, a recently approved complement C5 inhibitor, is increasingly used in combination with other therapies. Because complement activation contributes to one pathway of Rituximab-mediated B-cell depletion, inhibition of this pathway by Zilucoplan may reduce Rituximab’s effectiveness.  

Following Rituximab initiation in February 2024, CD19+ B cells remained at 0%, with a single measurement of 0.1% at nine months post-infusion. Zilucoplan was initiated in September 2025. After a Rituximab dose on October 13, 2025, CD 19+ levels rose to 3.4% by March 2026, representing the first clear B-cell repopulation since Rituximab treatment began. By April 2026, CD19+ levels reached 6.3%, within the normal range, occurring six months after the last rituximab dose.  Before Zilucoplan was initiated, the patient was able to go 9+ months with strong B cell depletion post Rituximab infusion. When Zilucoplan was added, the patient began B cell repopulation at 5-6 months post Rituximab infusion.  

Zilucoplan may reduce the effectiveness of Rituximab-mediated B cell depletion, potentially necessitating more frequent dosing. However, the combination did allow for complete discontinuation of steroids. Alternative B-cell therapies that do not rely on complement pathways, such as inebilizumab, may offer advantages when used with complement inhibitors. Further studies are needed to find the most effective combination strategies in JMG.