Treatment Options in Refractory Autoimmune Encephalitis

In recent years, the advances in the diagnostic assays and the recognition of novel clinical syndromes have helped to define the new emerging field of autoimmune neurology. Autoimmune encephalitides (AEs) represent a broad spectrum of immune-mediated and potentially treatable disorders that are currently being more frequently recognized. The underlying pathogenesis of these conditions is related to the presence of pathogenic antibodies directed against neuronal cell surface antigens or to a T-cell-mediated process in paraneoplastic disorders associated with non-pathogenic antibodies directed against intracellular targets [1, 2].

Prompt immunotherapy [3, 4] is the mainstay of AEs treatment and includes first-line and second-line medications. Intravenous steroids [5, 6], intravenous immunoglobulins [7], and plasma exchange [8] represent first-line immunotherapies. These treatments may be administered sequentially or in association, in particular steroids and plasma exchange/intravenous immunoglobulins, in the case of rapidly progressive or severe symptoms at onset [9].

Second-line treatment should be subsequently administered in the case of no clinical improvement after 2–4 weeks of first-line immunotherapy [10]. Rituximab and cyclophosphamide are the most frequently administered treatments. In particular, cyclophosphamide is preferred over rituximab in paraneoplastic disorders, as it depletes T cells, crosses the blood–brain barrier (BBB), and may be part of the oncological treatment scheme [11]. Antibody specificity also influences treatment choices, as demonstrated by the different response to rituximab in patients with antibodies to N-methyl-d-aspartate receptor (anti-NMDAR) [10], Leucine-rich Glioma Inactivated 1 (LGI1) [12‐15], or Contactin-associated protein-like 2 (CASPR2) [16].

A minority of patients will not respond to second-line treatments [4] with consequent high disability and prolonged admissions to intensive care units. Despite the lack of a proper definition, these patients are labeled as “refractory” and the therapeutic approach is still debated [9]. Indeed, there are no phase III clinical trials for third-line agents and the evidence mostly relies on small studies or case series/reports.

Different molecules have been proposed as potential treatments for refractory AEs and include plasma cell-depleting agents (bortezomib, daratumumab), cytokine-based drugs (interleukin-2/basiliximab, tocilizumab, anakinra, tofacitinib), and treatments targeting intrathecal immune cells or their trafficking through the BBB (intrathecal methotrexate, natalizumab).

The aim of this narrative review is to summarize and discuss therapeutic options for refractory AEs (data are summarized in Table 1 and Fig. 1). Relevant studies were identified through a PubMed search (“refractory autoimmune encephalitis”) and by cross-referencing all significant results.

The evidence of treatment efficacy in refractory AE is still largely anecdotical and many questions remain still unsolved. Some major potential limitations and biases in the interpretation of these studies must be mentioned.

The first and most notable is that most of these studies include small series or individual case reports, and prospective or controlled studies are rare. The heterogeneity in terms of clinical syndromes, antibody specificity (i.e., most of the patients treated with tocilizumab and nearly all patients who received bortezomib were affected by anti-NMDAR encephalitis; one patient after tofacitinib treatment was affected by myelin oligodendrocyte glycoprotein-associated disorder, which differs from other AEs in terms of pathogenesis), previous treatments, follow-up duration, and treatment regimens (administration route, number of cycles) also hinders the proper evaluation of treatment efficacy and the comparison among different third-line therapies. Moreover, most of these studies used mRS as a reported main outcome, rather than other disease-severity scales, such as the Clinical Assessment Scale in Autoimmune Encephalitis score [73], which may be more sensitive to detect subtle improvements in severely affected patients.

Another limitation is that clinical improvement, in some patients, might reflect the expected natural disease course rather than treatment response, as a delayed improvement may be seen in patients with severe AE (particularly in those with anti-NMDAR antibodies) regardless of treatments [74]. However, some cases showed a dramatic response temporally related to third-line treatments [40, 43, 60].

The lack of a proper control group in most of the studies performed, which are composed mainly of uncontrolled case reports/series, represents another relevant limitation, which makes it impossible to distinguish a spontaneous improvement versus a treatment response. Moreover, when control groups were included, some relevant biases were introduced, such as being an historical cohort [51] or including patients not escalating to second-line therapies, possibly indicative of a less severe disease course [19].

Moreover, reporting biases (i.e., reporting only patients who improve with a specific third-line therapy) represents a major issue when dealing predominantly with case reports or series and, finally, most of these studies have a short follow-up duration after third-line treatments. The lack of a proper follow-up is extremely relevant (a) to properly determine a disease prognosis, (b) to identify a relapsing course, and (c) to guide long-term management. Indeed, there are currently few data regarding long-term immunotherapy and treatment de-escalation in patients with refractory AEs [53, 75].

Taking into account all these factors, tocilizumab and bortezomib seem to have the most compelling, even though limited, evidence of efficacy based on prospective and retrospectively controlled studies [9]. Of note, the administration of tocilizumab was constantly associated with a clinical improvement in different studies, whereas a negative-result study [51] and the incapability of crossing the BBB, which is relevant for these conditions often associated with intrathecal antibodies, pose some concerns regarding the efficacy of bortezomib. Moreover, treatment with bortezomib has been reported mostly in patients with anti-NMDAR encephalitis, whilst tocilizumab has been successfully applied in sporadic cases with different autoantibodies. Data regarding a direct comparison between the two treatments are not available yet, thus the choice should be tailored to each individual patient. Escalation therapy should be performed as soon as possible, within 1 month according to studies performed using tocilizumab [19, 20], although an improvement may be seen even in the case of a late escalation to third-line therapies [39]. Side effects of these two drugs are predominantly of hematological or infectious origin and should always be considered, especially in patients receiving multiple immunosuppressants with different mechanisms of action in a relatively short period of time.

The efficacy evidence of the remaining treatments herein reviewed is still extremely limited, although promising, in particular for those drugs acting on the intrathecal immune response (such as intrathecal methotrexate, tofacitinib, and possibly daratumumab), which may be implied in the refractoriness of these conditions and may be unaffected by some second-line or third-line therapies. These medications should be considered only after tocilizumab and/or bortezomib failure as (a) some patients did not improve after tocilizumab/bortezomib, but improved after daratumumab [56‐58] or tofacitinib [32], (b) the evidence of efficacy of these drugs is mostly anecdotal and, on the contrary, the effects of bortezomib and tocilizumab rely only on case reports/series lacking a control group, and (c) these drugs may be associated with relevant side effects that should not be overlooked. Among the analyzed treatments, natalizumab may represent a safe and effective treatment for refractory T-cell-mediated encephalitides, such as those associated with cancer immunotherapy or intracellular antibodies [67‐69].

Refractory AE poses relevant clinical challenges and the current evidence of therapeutic options is overall unsatisfactory, as it is mostly based on case reports/series or a few controlled studies with relevant biases. To date, tocilizumab seems to be the most effective option in refractory cases, whereas bortezomib could be useful, but more evidence is mandatory. The evidence for other treatments mostly relies on a small uncontrolled number of cases and no definite recommendations may be drawn.

Several methodological issues should be taken into account in further studies, in particular (a) the lack of an unique definition of refractoriness; (b) the necessity of a control group with a consistent follow-up to determine treatment efficacy and rule out spontaneous improvement; (c) the use of dedicated clinical scales, more sensible to evaluate subtle improvements, rather than mRS; (d) the inclusion of specific clinical phenotypes and antibody specificities in clinical trials; (e) a consistent evaluation of antibody titers, in both serum and CSF, to evaluate systemic and intrathecal treatment responses; and (f) the evaluation of potential biomarkers, such as neurofilament light chain, which may help in treatment decisions [76].