NMOSD patient’s relapses, disability worsening halted with ofatumumab

The woman, 67, had a genetic variant tied to a poor rituximab response

Patricia Inacio, PhD avatar

by Patricia Inacio, PhD |

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Ofatumumab, a medication approved for multiple sclerosis (MS), effectively prevented relapses and disability progression in a 67-year old woman with neuromyelitis optica spectrum disorder (NMOSD) who failed to respond to rituximab, a Chinese case report described.

Both ofatumumab and rituximab — often used off-label in NMOSD — promote the death of antibody-producing B-cells. Ofatumumab is sold by Novartis as Kesimpta and rituximab, or RTX, is marketed as Rituxan in the U.S. and MabThera in Europe, with biosimilars available.

The researchers discovered later that the woman carried a genetic variant previously associated with poor responses to rituximab.

“Ofatumumab might be an effective alternative in RTX-unresponsive NMOSD, and seems to be safe in elderly patients,” the researchers wrote in the case report, “Successful treatment of rituximab-unresponsive elderly-onset neuromyelitis optica spectrum disorder and hypogammaglobulinemia with ofatumumab plus intravenous immunoglobulin therapy in a patient with mutant FCGR3A genotype: A case report,” which was published in Frontiers in Immunology.

NMOSD is caused by the immune system abnormally producing self-reactive antibodies, or autoantibodies, against certain proteins in cells of the nervous system. A feature of the disease is inflammation in the optic nerve, which relays information between the eye and the brain, and the spinal cord.

It occurs more often in young women and rarely at later ages, when disease relapses are more severe. Treating older patients who have NMOSD can be challenging due to the presence of other health conditions and the high risk of treatment-induced side effects.

Ofatumumab is an antibody that targets and blocks the activity of CD20, a protein on the surface of immune B-cells, leading to their depletion. B-cells are responsible for producing antibodies, including the autoantibodies that drive autoimmunity in conditions like NMOSD and MS.

Administered through under-the-skin injections, ofatumumab is approved for adults with relapsing forms of MS.

“However, the efficacy of ofatumumab against NMOSD is unclear,” the researchers wrote, noting a previous study that reported success with it in a pediatric NMOSD patient who’d failed to respond to rituximab.

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Confirming NMOSD diagnosis

A team of researchers in China described the case of a 67-year-old woman with NMOSD who also failed to respond to rituximab, but was treated successfully with ofatumumab.

The woman was admitted to the hospital after reporting needle-like pain in the upper back and lower leg weakness. Her clinical history included thyroid cancer, for which she underwent surgery four years before and was being given appropriate replacement therapy. She was also diagnosed with Sjögren’s syndrome, another autoimmune disease, “but had not received any immunosuppressive treatment prior to admission,” the researchers wrote.

At admission, she had general discomfort, muscle weakness in the lower limbs, and was unable to walk. She had hyperactive reflexes in her tendons and reduced sense of sensation just below the shoulder blades. She presented moderate to severe disability, as assessed by the Expanded Disability Status Scale.

Blood work showed she was positive for antibodies against the AQP4 protein, the most common target of NMOSD-causing autoantibodies. Imaging scans showed inflammation and lesions along the spinal cord. These findings confirmed a NMOSD diagnosis.

Additional tests for other health conditions such as autoimmune diseases, infections, or cancer detected no abnormalities.

The woman received five cycles of plasma exchange therapy and five doses of intravenous (into-the-vein) immunoglobulin (IVIG).

Plasma exchange is used to “clean” the blood by removing and replacing a person’s plasma — the liquid portion of blood that contains water, salts, and proteins such as antibodies. IVIG delivers specific antibodies purified from healthy people to neutralize self-reactive antibodies in the bloodstream and block these antibodies abnormal production.

The treatment reduced her symptoms and she was able to walk again. She was prescribed weekly infusions of rituximab for four weeks to prevent relapses.

Genetic variant associated with poor response to rituximab

Two months after treatment, however, she had another severe attack, which caused severe optic nerve inflammation — that can lead to vision loss, if left untreated — and insufficient B-cell depletion.

The woman seemed to not respond to rituximab and genetic testing confirmed she was positive for a variant in the FCGR3A gene, called FCGR3A-158F, that’s been associated with a poorer rituximab response.

As a result, physicians opted to switch to a therapeutic regimen that included anti-inflammatory oral steroids and two immunosuppressive medications — mycophenolate mofetil (sold as CellCept) and tacrolimus (sold as Prograf, among others). She experienced five relapses over 1.5 years, despite this regimen.

In the last relapse, she developed severe disability and showed low immunosuppressive therapy-induced levels of all antibodies, which may increase the risk of serious infections.

The woman’s physicians prescribed ofatumumab at its recommended dose combined with monthly IVIG. The ofatumumab recommendation includes three doses of 20 mg, one week apart, followed by monthly injections at the same dose.

The therapy was generally well tolerated and “six months later, she was able to walk independently … and experienced no further relapse,” the researchers wrote.

The B-cells were effectively depleted after the first ofatumumab dose and remained low during treatment.

The case suggests “ofatumumab might be an effective alternative in patients with incomplete B cell depletion after RTX genetic testing in NMOSD, and highlights the potential safety of ofatumumab in elderly patients,” the researchers said.