Tocilizumab Effective in Refractory Autoimmune Limbic Encephalitis

Nancy A. Melville

October 24, 2016

BALTIMORE — The anti-interleukin-6 (IL-6) antibody drug tocilizumab shows efficacy in the treatment of patients with autoimmune limbic encephalitis (ALE) who do not respond to rituximab, new research suggests.

"This study revealed that the clinical benefit of tocilizumab treatment in autoimmune encephalitis refractory to the first-line immunotherapy and standard regimen rituximab was statistically significant over observation without further immunotherapies and maintenance of monthly rituximab," said coauthor Jung-Ah Lim, MD, from Seoul National University Hospital, South Korea. "Furthermore, most of the responders to tocilizumab showed clinical improvements during the early treatment phase."

He presented the findings here at the American Neurological Association (ANA) 2016 Annual Meeting.

The understanding of autoimmune encephalitis, which is becoming recognized as a leading cause of encephalitis, continues to evolve. First-line treatments include tumor removal in cases caused by tumor (if possible), corticosteroids plus intravenous immunoglobulin, or plasmapheresis.

Rituximab has been demonstrated, including in research published in the journal Neurology earlier this year by Dr Lim and colleagues, to have efficacy as a second-line immunosuppressant treatment of the condition, regardless of the patient's autoantibody status.

For cases refractory to first-line or rituximab treatment, the research team evaluated tocilizumab, which has established efficacy in the treatment of rheumatoid arthritis and the rare condition systemic juvenile idiopathic arthritis, usually combined with methotrexate.

The new study included 91 patients from the Korea Autoimmune Synaptic and Paraneoplastic Encephalitis Registry (KASPER) with ALE who showed inadequate response to first-line immunotherapy and subsequent rituximab treatment, defined as a lack of obvious improvement of the most disabling symptoms 1 month after completion of rituximab.

The patients were randomly assigned to treatment with tocilizumab (n = 30 [33%]), additional rituximab (n = 31 [34%]), or observation (n = 30 [33%]).

In terms of main outcomes, patients in the tocilizumab group showed significantly more frequent favorable modified Rankin Scale scores of 2 or lower or improvement by 2 or more points at 2 months from initiation and at the last follow-up, compared with the other groups (P < .001).

Among tocilizumab patients showing clinical improvement at 1 month, 89.5% maintained a long-term favorable clinical response.

Dr Lim noted that none of the clinical or laboratory characteristics evaluated was associated with a favorable clinical response to tocilizumab.

In terms of safety profiles, three patients (10%) had decrement of absolute neutrophil counts (<1000 cells /dL, grade 3), while there were no reports of serious infusion-related or infectious adverse events.

Four patients in the rituximab group had infusion-related adverse effects, all involving a grade 1 rash, and seven infectious events occurred, all involving grade 3 pneumonia.

Tocilizumab, which is administered monthly through intravenous infusion, has multimodal properties, including induction of B-cell differentiation and proliferation and promotion of the differentiation of IL-17-producing T-helper cells.

The study was also published this month in the journal Neurotherapeutics.

In an editorial that accompanied the paper, Russell C. Dale, MD, from the Institute for Neuroscience and Muscle Research, The Kids Research Institute at the Children's Hospital at Westmead, and University of Sydney, Australia, noted the encouraging finding of a relatively rapid response.

"For an agent to be a useful acute rescue therapy in AE [autoimmune encephalitis], the speed of immune suppression needs to be rapid; reassuringly, the data by Lee et al. appear to show clinical benefit within a month of commencing tocilizumab therapy," Dr Dale writes.

He adds that the research sheds important light on immune therapy options in the challenging treatment of autoimmune encephalitis, prompting discussion of the issue of broad-spectrum vs targeted therapies.

"Therapies that target a specific molecule will only work if that molecule is central to the disease process," Dr Dale explains.

"In complex acquired autoimmune diseases, although there are often specific initiators of disease, in established disease one might expect more complex and diverse involvement of the immune system with a mixture of 'primary' and 'secondary' immune activation.

"Therefore, targeted therapies, although appealing, may not always work. Targeting IL6 is relatively appealing in autoimmune central nervous system (CNS) disease given its established role in CNS inflammation and its pleiotropic stimulatory role."

The study brings important attention to the potential benefits of that approach, Dr Dale writes.

"The study by Lee et al. provides a good option to clinicians faced with a patient with autoimmune encephalitis or suspected AE who is not responding to conventional therapy," he says.

"Second, the study emphasizes that if a patient is not improving, it is important to consider using an agent with a different mechanism of action, rather than re-dosing a drug that appears to be ineffective."

Further commenting on the study, Stacey L. Clardy, MD, PhD, an assistant professor of neuroimmunology and neurology at University of Utah Health Care, Salt Lake City, agreed that the study offers insights on potential benefit of a treatment in an area much in need of more options.

"The study proposes a potential new agent that could be considered to treat autoimmune encephalitis, and given the limited number of commonly used second-line therapies, the possibility of having another agent available as a possible treatment for a subset of patients is always of interest," she told Medscape Medical News.

"As far as other options, we commonly treat with rituximab or Cytoxan or other immunosuppressive therapies," she noted.

"While there is a longer experience and broader literature around those agents, we still do not have any therapies to treat autoimmune encephalitis that have actually been tested rigorously, especially by way of a double-blind placebo-controlled trial."

She added, however, that much more evidence is needed to understand the best role for tocilizumab.

"The study is interesting, but quite preliminary. We do not have any controlled trials of tocilizumab in this setting, or even any good retrospective or observational data on a cohort of patients with autoimmune encephalitis treated with tocilizumab."

The authors have disclosed no relevant financial relationships. Dr Dale has received research funding from the National Health and Medical Research Council, MS Research Australia, Star Scientific Foundation, Pfizer Neuroscience, Tourette Syndrome Association, University of Sydney, and Petre Foundation, and he has received honoraria from Biogen-Idec as an invited speaker. Dr Clardy has disclosed no relevant financial relationships.

American Neurological Association (ANA) 2016 Annual Meeting. Abstract M112. Presented October 17, 2016.

Neurotherapeutics. 2016;13:824-832, 821-823. Abstract, Editorial

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