Novel therapeutics and biomarker discovery
May 12, 2021
Over the past 20 years, significant advances have improved our understanding of diagnosis, treatment, and underlying causes of AE. The number of new publications has increased dramatically in the past few years. And here, we will share some recent advances made in the area of novel therapeutics and biomarker discovery.
Sell at al., Autoimmune encephalitis: novel therapeutic targets at the preclinical level, Expert Opinion on therapeutic Targets, 2021
Summary: The current treatment of AE is based on immunotherapy. It has been established according to clinical experience, and the concept of a B cell mediated pathology induced by highly specific autoantibodies to neuronal surface antigens, like the NMDA receptor. In general, immunotherapy is applied in an escalating manner, starting with ‘first line’ therapy, which includes steroids, IVIG, and plasma exchange. These initial treatments may be followed by ‘second line’ therapy consisting of B cell depletion with rituximab or immunosuppression with cyclophosphamide. ‘Third line’ therapy consists of Il-6 receptor blockage with tocilizumab or plasma cell depletion with bortezomib, both with varying reports regarding outcome and efficacy. Unfortunately, not everyone responds well to immunotherapy; relapses are found in 12-35% of patients, as patients deal with negative consequences of AE, like memory deficits and fatigue.
Therefore, more specific and effective therapeutic approaches are needed. In principle, two different strategies are promising to establish such novel therapeutics. First, target-directed, symptomatic treatment that can be applied in addition to immunotherapy might overcome the delay of treatment response and improve disease symptoms more effectively. Second, there is a need for immunotherapy specifically interfering with the immunopathology of the disease. This review summarizes the current progress in developing and establishing specific treatment strategies in the spectrum of AE.
Yang et al., Tofacitinib treatment for refractory autoimmune encephalitis, Epilepsia, 2020
Summary: It is crucial to develop novel immunotherapies that cross the blood-brain barrier to treat patients who do not respond to conventional immunotherapies. Tofacitinib is a Janus kinase (JAK) inhibitor used to treat refractory immune‐mediated diseases that effectively penetrate the BBB. Accordingly, tofacitinib could be a new option for patients with refractory autoimmune encephalitis. JAK inhibitors block cytokine pathways and suppress the immune system in that manner.
Lee et al., Ca V α2δ Autoimmune Encephalitis: A Novel Antibody and its Characteristics, Ann Neurol, 2021
Summary: Many AE patients have no detectable antibody by current diagnostics, probably because hidden antibodies have yet to be discovered or because these patients have a non-antibody-mediated mechanism. Dr. Lee and colleagues identified a novel antibody against Ca V α2δ (voltage-gated calcium channel alpha-2/delta subunit) and revealed the mechanism of the antibody. Future studies are needed with a more significant number of patients to describe the clinical presentation of Ca V α2δ encephalitis.
Summary: The pathogenesis of anti-NMDAR encephalitis involves T cell and B cell cytokines. T cells likely assist B cells in producing antibodies. IL-2, CXCL10, CCL3, IL-10, CCL22, and IL-6 are all cytokines (messenger molecules) that may represent new biomarkers in anti-NMDAR encephalitis. Given the lack of research on IL-10, CCL3, and CCL22 in this disease, it will be informative to explore their potential role in pathogenesis in more extensive studies.
The common theme in all these papers is that translational research needs to be intensified to discover novel therapies in autoimmune encephalitis. Clinical trials have to be conducted in well-defined groups of AE patients.
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