Tocilizumab in Autoimmune Encephalitis Refractory to Rituximab: An Institutional Cohort Study

Abstract

A considerable portion of autoimmune encephalitis (AE) does not respond to conventional immunotherapies and subsequently has poor outcomes. We aimed to determine the efficacy of tocilizumab, an anti-interleukin-6 antibody, in rituximab-refractory AE compared with other treatment options. From an institutional cohort of AE, 91 patients with inadequate clinical response to first-line immunotherapy and following rituximab were retrospectively reviewed. Patients were grouped according to their further immunotherapy strategies. Thirty (33.0 %) patients were included in the tocilizumab group, 31 (34.0 %) in the additional rituximab group, and 30 (33.0 %) in the observation group. Outcomes were defined as the favorable modified Rankin Scale scores (≤2) at 1 and 2 months from the initiation of each treatment strategy and at the last follow-up. Favorable clinical response (improvement of the modified Rankin Scale scores by ≥ 2 points or achievement of the mRS scores ≤ 2) at the last follow-up was also analyzed. The tocilizumab group showed more frequent favorable mRS scores at 2 months from treatment initiation and at the last follow-up compared with those at the relevant time points of the remaining groups. The majority (89.5 %) of the patients with clinical improvement at 1 month from tocilizumab treatment maintained a long-term favorable clinical response. No serious adverse effects of rituximab or tocilizumab were reported. Therefore, we suggest that tocilizumab might be a good treatment strategy for treating AE refractory to conventional immunotherapies and rituximab. The tocilizumab-mediated clinical improvement manifests as early at 1 month after treatment initiation.

Keywords: Autoimmune disorders; encephalitis; immunotherapy; prognosis; tocilizumab.

Fig. 1

Study outline *The occurrence of clinical response to the rituximab therapy was evaluated 1 month after the last weekly rituximab therapy AE = autoimmune encephalitis; mRS = modified Rankin Scale

Fig. 2

Modified Rankin Scale (mRS) score profiles during the courses of immunotherapy. mRS scores are compared across (A) all patients and (B–D) subgroups. The groups are as follows: (A) all patients (n = 91), (B) the group with tocilizumab therapy (n = 30), (C) the group with additional monthly rituximab maintenance (n = 31), and (D) the group with follow-up without further immunotherapy (n = 30). The solid lines represent the change in the frequencies of mRS scores 0 to 2 at each time point during the immunotherapy *Baseline: at the time of tocilizumab initiation in the tocilizumab group, at the time of monthly rituximab therapy initiation in the additional rituximab group, and at 1 month after the last cycle of weekly rituximab therapy in the observation group First-line = at initiation of first-line immunotherapies; RTX = at initiation of standard-regimen weekly rituximab; RTX 1 mo = at 1 month from the initiation of weekly rituximab therapy; 1 mo = at 1 month from the baseline time points; 2 mo = at 2 months from the baseline time points; last FU = at the last clinical follow-up point

Fig. 3

Intergroup comparisons of the proportion of patients with favorable modified Rankin Scale scores (mRS) during the courses of immunotherapy. Each time point during the courses of immunotherapy were denoted as follows: first-line = at initiation of first-line immunotherapies; RTX = at initiation of standard-regimen weekly rituximab; RTX 1 mo = at 1 month from the initiation of weekly rituximab therapy; 1 mo = at 1 month from the baseline time points; 2 mo = at 2 months from the baseline time points; last FU = at the last clinical follow-up point. **p < 0.05 for the tocilizumab group vs the observation group; ^† p < 0.05 for the tocilizumab group vs the additional rituximab group; ^‡ p < 0.05 for the additional rituximab group vs the observation group *Baseline: at the time of tocilizumab initiation in the tocilizumab group, at the time of monthly rituximab therapy initiation in the additional rituximab group, and at 1 month after the last cycle of weekly rituximab therapy in the observation group