Disease stabilization with ravulizumab in a patient with AQP4+ NMOSD following prior therapy breakthrough

History, initial presentation and treatments
In January 2007, a previously healthy 38-year-old female (base­line Expanded Disability Status Scale [EDSS] score, 0) presented with acute right upper limb weakness and numb­ness. Within days, the patient’s sen­sory and motor deficits progressed to involve her other limbs. She had no relevant medical comorbidities and no family history of demyelinating or auto­immune diseases.

Cervical spine MRI revealed longi­tudinally extensive transverse myelitis (LETM). (Figure 1) At that time, her EDSS score peaked at 9.

She was initially treated with intra­venous (IV) methylprednisolone for 3 days and had partial response. Treat­ment was then switched to oral pred­nisolone. Her EDSS score stabilized at 7 with rehabilitation. However, she experienced a relapse in April 2007 (EDSS score, 9) and developed bilat­eral optic neuritis (ON) and worsen­ing of lower limb weakness. She was formally diagnosed with neuromyelitis optica spectrum disorder (NMOSD) after identification of anti-aquaporin-4 antibodies (AQP4+).

Subsequent treatments and responses
Following confirmation of NMOSD in April 2007, the patient received sev­en plasmapheresis sessions and start­ed azathioprine (AZA). Her EDSS score improved to 6 with rehabilitation and to 3 in 2008. Over the next decade, she relapsed in 2009, 2013–2014 and 2019 with limb weakness and ON. EDSS fluctuated between 3 and 5 without returning to baseline. These relapses required repeated courses of oral corticosteroids with rehabilitation, AZA with/without plasmapheresis, AZA dose escalation, and switching of AZA to mycophenolate mofetil (MMF) in July 2014 due to treatment failure. She relapsed three times (in May, August and October) in 2019 and re­ceived corticosteroids and MMF dose intensification. (Figure 2)

In October 2019, the patient ex­perienced severe cervical and thorac­ic LETM complicated by pulmonary embolism, deep vein thrombosis, and rectal bleeding, which raised EDSS to 9 and required a prolonged hospital stay. During this time, MMF was switched to rituximab, and prolonged rehabilitation improved EDSS to 6.5 by August 2020. Her condition remained relatively stable over the next few years with a minor re­lapse in June 2021. However, her long-term rituximab therapy was complicated by recurrent infections, including cellulitis, sepsis, influenza A, three episodes of uri­nary tract infection, and two episodes of COVID-19, which led to multiple hospital admissions between 2020 and 2024.

In September 2024, the patient ex­perienced breakthrough relapse with ex­tensive cervical–thoracic myelitis (EDSS up to 9) while on rituximab. Given the in­adequate disease control, she agreed to switch treatment to ravulizumab. Ravuli­zumab initiation was scheduled at the end of the standard 6-month rituximab dosing interval, which allowed sufficient time for the mandatory meningococcal vaccina­tion and partial B-cell reconstitution. MRI in March 2025 showed interval improve­ment, with a reduction in the extent of the previously noted cervical and thoracic spinal cord swelling and increased cord signal. She was safely transitioned and received the first dose of ravulizumab in April 2025.

Since then, the patient has re­mained clinically stable (EDSS, 6.5) with no further relapses. She continues to receive ravulizumab Q8W infusions, with comprehensive clinical follow-up evaluations scheduled Q16W. She has experienced no significant recur­rent infections or ravulizumab-related adverse events. While her EDSS re­mains at 6.5, she has achieved highly meaningful functional improvements: She can now walk significantly further and for longer periods using her rol­lator, and tolerates substantially more daily activities, greatly improving her overall quality of life. (Figure 2)

Discussion
NMOSD is a rare, severely dis­abling autoimmune channelopathy of AQP4 on astrocytes.^1-3 The relation­ship between inflammatory attacks and disability is particularly important in NMOSD.⁴ While disability progres­sion in multiple sclerosis (MS) may become partly independent of inflam­matory relapse activity, a progressive disease course is rare in NMOSD. In­stead, neurodegeneration and accu­mulating disability in NMOSD appear to be largely driven by inflammatory attacks.⁴ This distinction underscores the importance of preventing relaps­es, as individual attacks in NMOSD may result in irreversible neurological injury and stepwise disability accu­mulation.^1-4 This pattern was reflect­ed in our patient, whose recurrent attacks were accompanied by sub­stantial increases in disability/EDSS scores.

However, contemporary targeted therapies can achieve durable dis­ease stabilization, as illustrated by the absence of flares and stable EDSS in our patient after initiating ravulizum­ab, following nearly two decades of escalating immunotherapy.^1-3,5

Of note, as EDSS was original­ly developed for monitoring MS pa­tients’ condition, it may not fully reflect NMOSD status.^2,3 For example, while an EDSS of 7 in MS typically implies exclusive wheelchair use, our patient could still walk with a rollator.⁶

Addressing breakthrough disease activity on rituximab
Rituximab reduces relapses in NMOSD in both real-world and clin­ical trial settings, but some AQP4+ patients still experience breakthrough disease.^1,2 Real-world data indicate a rituximab failure rate of approximately 30 percent.^1,7 Long-term rituximab use is also associated with hypogamma­globulinaemia and recurrent infections, as seen in our patient.^1,2

The clinical reality of these lim­itations is further elucidated by a real-world retrospective cohort study of 176 patients with NMOSD followed for a median of 9 years. The study retrospectively compared the efficacy and safety of approved NMOSD-spe­cific treatments, including the com­plement C5 inhibitors eculizumab and ravulizumab, with rituximab.¹

Within the AQP4+ subgroup, which corresponds to our patient’s clinical profile, the Kaplan–Meier curve for relapse-free survival demonstrated a progressive, continuous decline in relapse-free probability over time for rituximab-treated patients, with failures still occurring beyond the first 6 months (38 percent of failures occurred earlier). This was similar to our patient’s expe­rience, who relapsed 10 months after initiating rituximab therapy. Meanwhile, the complement C5 inhibitors had a relapse-free probability of 100 percent beyond 5 years.¹ (Figure 3A)

In the overall population, the com­plement C5 inhibitors also showed the lowest risk of relapse vs rituximab (hazard ratio [HR], 0.12; 95 percent confidence interval [CI], 0.07–0.24), the lowest annualized relapse rate, and fewer serious infections. Similar results were also observed in the AQP4+ sub­group, demonstrating an 88 percent reduction in relapse risk with comple­ment C5 inhibitors (adjusted HR, 0.12; 95 percent CI, 0.07–0.29).¹ (Figure 3B)

Our patient’s 20-year treatment journey provides a striking real-world validation of these comparative data. (Figure 2) Her initial treatment with azathioprine (relapses in 2009 and 2013) and subsequent treatment with MMF (severe relapse in 2014 and three relapses in 2019) reflect the low relapse-free survival rates shown in Figure 3A. Her transition to rituximab in October 2019 initially suppressed re­lapse frequency, but her clinical course was complicated by frequent infections requiring multiple hospitalizations. Ulti­mately, she suffered a major cervical– thoracic myelitis breakthrough relapse in September 2024, demonstrating the ongoing breakthrough risk over long-term rituximab follow-up. Her subse­quent transition to ravulizumab in April 2025 provided immediate, complete relapse-free disease stabilization and clinical improvement, confirming the clinical utility of terminal complement blockade.¹

In the absence of head-to-head clinical trials, clinicians often rely on indirect comparisons and network meta-analyses to evaluate the com­parative efficacy of these newer bio­therapies. However, as highlighted in a recent review, external comparisons of treatment efficacies are complicat­ed by the heterogeneity of random­ized controlled trial designs.^5,8 Spe­cifically, some pivotal trials allowed concomitant use of background wide-spectrum immunosuppressants in both treatment groups, whereas oth­ers evaluated monotherapies.⁵ Fur­thermore, as NMOSD is an ultra-rare disease, the population sizes in these clinical trials were small, which limits the statistical power of indirect com­parisons and underscores the value of  real-world comparative data, such as the previously discussed retrospective cohort study.^1,5,8

Current Neuromyelitis Opti­ca Study Group recommenda­tions position the four approved NMOSD-specific therapies (ie, ec­ulizumab, ravulizumab, inebilizum­ab and satralizumab) as substitute options when rituximab or other stan­dard immunosuppressants fail to ade­quately control disease activity.²

Ravulizumab: Stabilization in patients with high baseline disability
Ravulizumab is indicated for adult patients with AQP4+ NMOSD. As a long-acting terminal complement C5 inhibitor, it provides sustained inhibi­tion of the complement cascade.^3,9 In the end-of-study analysis of the pivotal placebo-controlled, phase III CHAMPION-NMOSD trial, a 98.9 percent reduction in risk of adjudi­cated relapses was achieved with ravulizumab vs an external place­bo group (95 percent CI, 91.8–100; p<0.0001).¹⁰ Of note, no adjudicat­ed on-trial relapse occurred in pa­tients receiving ravulizumab through­out the primary treatment period (PTP; 84.0 patient-years) and long-term extension period (LTE; 105.7 patient-years).^3,10 Furthermore, even in patients with prior rituximab expo­sure, analysis during the PTP found a 93.7 percent reduction in relapse risk.³ (Figure 4) The safety profile of ravulizumab during the LTE was con­sistent with that seen during the PTP, and no new safety concerns were identified.¹⁰

Despite a high baseline EDSS of 7 and a breakthrough relapse on prior rituximab within the preceding year, our patient has remained re­lapse-free since starting ravulizumab, with radiological improvement and a modest, sustained EDSS improve­ment to 6.5, demonstrating that rav­ulizumab can achieve meaningful dis­ease stabilization even in patients with substantial pre-existing disability and treatment-refractory disease.

As with other complement in­hibitors, meningococcal vaccination is required before initiation to miti­gate infection risk.⁹ In our patient, the switch was scheduled after me­ningococcal vaccination and par­tial B-cell reconstitution following rituximab.