Switching from Complement Inhibitors in AQP4-IgG–Positive NMOSD: Clinical Characteristics, an Operational “Cluster Phase,” and Potential Strategies to Prevent Therapeutic Gaps

Background: Neuromyelitis optica spectrum disorder (NMOSD) can cause severe neurological disability after a single relapse. Although relapse rates have markedly decreased with the emergence of targeted biologics, treatment switches are increasingly encountered due to long-term treatment considerations and adverse events. However, safe switching strategies, especially within 12 months after a relapse, which we defined operationally as the “cluster phase”, have not been established. We investigated relapse risk and potential preventive strategies when switching from complement inhibitors in AQP4-IgG–positive NMOSD. Methods: We retrospectively reviewed patients with AQP4-IgG–positive NMOSD treated at St. Marianna University School of Medicine who underwent at least one biologic switch. Clinical records were assessed for patient characteristics, treatment history, timing of switching, and relapse occurrence. Particular attention was given to switching from complement inhibitors during the cluster phase. Results: Among 14 patients who switched biologics, 5 switched from complement inhibitors, 4 switched between complement inhibitors, 2 between B-cell–depleting therapies, and 3 from IL-6 receptor inhibitors. Of the 5 who switched from complement inhibitors, 3 switched during the cluster phase and 2 in the non-cluster phase. All cluster-phase switches were to B-cell–depleting agents. One of the two patients switched without bridging therapy during the cluster phase experienced optic neuritis relapse, while no relapses occurred in the other 13 switching cases. This observation suggests a possible vulnerability during the cluster phase, although definitive conclusions cannot be drawn due to the small sample size. Conclusions: Switching from complement inhibitors during the cluster phase may be associated with an increased susceptibility to relapse. Bridging strategies, such as plasma exchange or temporary biologic overlap, may help reduce the likelihood of therapeutic gaps, but these findings remain hypothesis-generating. Clinicians should proactively discuss future switching scenarios and develop long-term treatment plans with patients.