MS Patient Dies from Anti-Drug AntibodiesA reaction to anti-natalizumab (Tysabri) antibodies - facebook prikbord

MS Patient Dies from Anti-Drug AntibodiesA reaction to anti-natalizumab (Tysabri) antibodies appears to have killed a Swedish woman with multiple sclerosis who received the drug, researchers said.

Significant neurological abnormalities developed after she had received six infusions of natalizumab, and her doctors found that she had extremely high titers of antibodies against the drug, reported Anders Svenningsson, MD, PhD, of Umeå University in Sweden, and colleagues.

Seven months after starting on the drug, she was dead, the researchers wrote online in Neurology. Her physicians ruled out progressive multifocal leukoencephalopathy (PML), a known and frequently fatal side effect of natalizumab therapy.

Svenningsson and colleagues concluded that her death resulted from "rebound neuroinflammation as a result of the development of natalizumab anti-drug antibodies."

Noteworthy was that the patient had shown unusual reactions to the drug starting with the fourth infusion, including chills and fever, they suggested.

"We recommend that repeated moderate to severe infusion reactions in the beginning of natalizumab treatment should prompt the cessation of treatment and assessment for the development of natalizumab anti-drug antibodies," Svenningsson and colleagues wrote.

The patient was first diagnosed with MS in 2001 when she was 32. She was initially treated with interferon-beta-1a, but was switched to natalizumab in November 2007 when MRI scans showed growth in brain lesions. Because the scans did not show contrast enhancement, her doctors determined that her blood-brain barrier remained intact.

Natalizumab was given at the standard dose of 300 mg every 4 weeks by infusion.

The chills and fever that started with the fourth treatment became progressively more severe with subsequent infusions, the researchers indicated. After the sixth, she developed progressive gait abnormalities, ataxia, and significant mental deterioration.

MRI scans showed new hyperintense T2 lesions as well as multiple areas of contrast enhancement. Molecular tests of the patient's cerebrospinal fluid for the JC virus were negative, arguing against PML, which is caused by reactivation of latent JC virus infection.

At that point, she was transferred to a regional hospital. Her disability level progressed to 9 on the EDSS scale, compared with a level of 3 when she started on natalizumab. She was unable to get out of bed and was uncommunicative.

Another MRI scan showed additional contrast-enhancing lesion growth. Brain biopsy results were consistent with acute MS inflammation, Svenningsson and colleagues reported, "with infiltrating activated macrophages as well as signs of blood-brain barrier breakdown."

Most important, anti-natalizumab antibodies were found at a level of 335 mg/L, "among the highest recorded among anti-drug antibody positive patients identified in Sweden," the researchers indicated. The antibodies were predominantly of the IgG3 complement-fixing class.

The woman underwent plasmapheresis and her doctors wanted to perform an autologous stem cell transplant, but her condition was too poor for that, and she died in June 2008.

Autopsy findings showed no evidence of infectious pathogens in the central nervous system. The conclusion was that acute MS inflammation was the cause of her symptoms and eventual death.

Svenningsson and colleagues considered the possibility that the anti-natalizumab antibodies had triggered an anti-idiotype reaction, which could have led to an autoimmune attack on ligands of VLA-4, VCAM-1, and fibronectin. But in vitro studies using serum samples from the patient showed no signs of anti-idiotype reactivity.

Other clinicians have reported cases in which patients worsened while on natalizumab or who showed severe relapses after stopping the drug, Svenningsson and colleagues said, but their case was unusual in its fatal outcome.

The study was funded by ALF, the KI Foundation, and the Swedish Association of Persons with Neurological Disabilities.

Study authors reported relationships with Biogen Idec, Bayer-Schering, Baxter Medical, Sanofi, and Merck Serono.

Primary source: Neurology

Source reference: Svenningsson A, et al "Fatal neuroinflammation in a case of multiple sclerosis with anti-natalizumab antibodies" Neurology 2013; DOI: 10.1212/WNL.0b013e3182840be3.