Inebilizumab and the problem of overlapping autoimmunity in AQP4-positive NMOSD
Neuromyelitis optica spectrum disorder rarely travels alone. In this two-patient case series, AQP4-IgG-positive NMOSD appeared alongside other autoimmune disease, creating exactly the kind of diagnostic and therapeutic friction that can delay treatment and complicate immunotherapy choices. One patient presented with area postrema syndrome and lupus-like serology after a recent delivery; the other had clinically stable NMOSD and then developed AChR-IgG-positive generalized myasthenia gravis. Both improved after inebilizumab, with no relapse recorded to date.
The report matters because it pushes beyond the familiar NMOSD frame. B-cell–driven autoimmunity does not always stay neatly within one diagnosis, and in patients with AQP4-IgG seropositivity, the overlap with systemic autoimmune disease is common enough to affect real-world decision-making. A therapy that depletes CD19-positive B cells offers a biologically plausible way to address both the central nervous system disease and the broader autoimmune context, at least in selected patients.
Area postrema syndrome as the first warning sign
Case 1 involved a 29-year-old woman admitted on October 26, 2024, after 20 days of recurrent, progressively worsening hiccups and 3 days of dysphagia. She also reported dizziness, fever, and expectoration. The timing was clinically awkward: she had delivered a full-term infant three months earlier, and her symptoms arrived in the setting of elevated inflammatory markers and positive autoimmune serology, making a straightforward bedside interpretation difficult.
Initial testing showed a white blood cell count of 10.63×10^9/L, neutrophils 8.60×10^9/L, CRP 150 mg/L, ESR 64 mm/h, ALT 74 U/L, and D-dimer 1.85 mg/L. Antinuclear antibody testing was strongly positive at 1:1000, with anti-SS-A and anti-Ro-52 antibodies both above 8.0. Rheumatology reviewed her because of the serologic profile, but she lacked malar rash, photosensitivity, alopecia, oral ulcers, sicca symptoms, inflammatory arthritis, skin tightening, Raynaud phenomenon, or other clinical features of systemic lupus erythematosus. Hydroxychloroquine was started for the lupus-like serologic autoimmune phenotype, while antibiotics were given empirically for suspected respiratory infection.
A single symptom was doing a lot of clinical work here. Persistent hiccups and vomiting can be dismissed as gastrointestinal, yet in NMOSD they may reflect area postrema syndrome, a dorsal medullary inflammatory lesion that sits outside the blood-brain barrier’s usual comfort zone. When APS is isolated, the diagnosis is easy to miss; when fever and inflammatory markers are present, the noise becomes even louder.
Medullary inflammation, CSF abnormalities, and AQP4-IgG positivity
MRI of the head and neck showed an abnormal signal in the medulla oblongata, consistent with a demyelinating process. Lumbar puncture on hospital day 2 added more support for central nervous system autoimmunity: cerebrospinal fluid showed elevated microalbumin, immunoglobulin G, and immunoglobulin A. Serum testing for demyelinating antibodies returned positive for AQP4-IgG at a titer of 1:100.
The neurologic workup did not support myasthenia gravis in this case. Neostigmine testing, electromyography, repetitive nerve stimulation, and AChR antibody testing were negative. Even so, the broader point remains intact: autoimmune overlap can be serologically suggestive before it becomes clinically obvious, and the absence of one diagnosis at presentation does not guarantee its permanent absence.
Based on the clinical picture, MRI findings, and antibody profile, the patient was diagnosed with APS as a manifestation of NMOSD. Her Expanded Disability Status Scale score was 4, driven mainly by impaired swallowing. In a disease where disability often accumulates through repeated inflammatory attacks, dysphagia is not a minor complaint; it is a direct threat to nutrition, airway safety, and functional recovery.
Why CD19 depletion fits this phenotype
Inebilizumab binds CD19 on B-cell surfaces and depletes the populations that sustain pathogenic antibody production. In AQP4-IgG-positive NMOSD, that mechanism is attractive because the disease is tightly linked to autoantibody-mediated astrocytic injury, complement activation, and secondary demyelination. The same logic also offers a rationale in patients with concomitant autoimmune disease, where B-cell dysregulation may be contributing to more than one clinical syndrome at the same time.
The clinical precedent for inebilizumab in NMOSD is already established. The pivotal N-MOmentum trial showed a 73% reduction in attack risk versus placebo, and an even larger relative reduction among AQP4-IgG-seropositive patients. This case series does not compete with controlled trial data; it extends the conversation into the messy terrain of overlapping autoimmune disease, where randomized studies are scarce and bedside decisions depend on biologic plausibility plus observed response.
In Case 1, the patient improved substantially after inebilizumab, and no relapse has been recorded to date. Serial MRI showed progressive regression of the dorsal medullary lesion over time, matching the clinical trajectory rather than contradicting it. Imaging improvement here is more than a radiographic curiosity. It supports the idea that early targeted B-cell depletion can quiet active inflammation before it hardens into fixed brainstem disability.
The second patient and the NMOSD-MG overlap
The second patient had established, clinically stable NMOSD and then received a new diagnosis of acetylcholine receptor antibody-positive generalized myasthenia gravis. The case is notable because NMOSD and MG create a therapeutic mismatch: corticosteroids may aggravate MG, while conventional NMOSD maintenance agents do not always address the full autoimmune spectrum. After treatment with inebilizumab, this patient also showed significant clinical improvement, with no relapse reported to date.
That overlap phenotype is clinically awkward in exactly the way neurologists fear. One autoimmune disease can mask the other, and the treatment that helps one disorder may destabilize the other. A therapy that suppresses pathogenic B-cell activity across both axes is therefore appealing, even though the evidence base remains thin and largely limited to case-level experience.
What this case series can and cannot support
These two patients do not establish a new standard of care. They do, however, show that inebilizumab can be used in AQP4-IgG-positive NMOSD even when the clinical picture is complicated by systemic autoimmunity or by MG overlap. The absence of relapse so far is encouraging, but the report is still a pair of observations, not proof of long-term comparative benefit.
The remaining questions are practical ones. How durable is the response in patients with overlapping autoimmune disease? Can inebilizumab reduce steroid exposure in mixed phenotypes without creating unacceptable safety tradeoffs? And in patients whose first clue is APS rather than optic neuritis or myelitis, how early can treatment start before disability is fixed? Those answers will require prospective data, not just carefully documented cases.