Interleukin-6 Receptor Blockade in Treatment-Refractory MOG-IgG-Associated Disease and Neuromyelitis Optica Spectrum Disorders

Abstract

Background and objectives: To evaluate the long-term safety and efficacy of tocilizumab (TCZ), a humanized anti-interleukin-6 receptor antibody in myelin oligodendrocyte glycoprotein-IgG-associated disease (MOGAD) and neuromyelitis optica spectrum disorders (NMOSD).

Methods: Annualized relapse rate (ARR), Expanded Disability Status Scale score, MRI, autoantibody titers, pain, and adverse events were retrospectively evaluated in 57 patients with MOGAD (n = 14), aquaporin-4 (AQP4)-IgG seropositive (n = 36), and seronegative NMOSD (n = 7; 12%), switched to TCZ from previous immunotherapies, particularly rituximab.

Results: Patients received TCZ for 23.8 months (median; interquartile range 13.0-51.1 months), with an IV dose of 8.0 mg/kg (median; range 6-12 mg/kg) every 31.6 days (mean; range 26-44 days). For MOGAD, the median ARR decreased from 1.75 (range 0.5-5) to 0 (range 0-0.9; p = 0.0011) under TCZ. A similar effect was seen for AQP4-IgG+ (ARR reduction from 1.5 [range 0-5] to 0 [range 0-4.2]; p < 0.001) and for seronegative NMOSD (from 3.0 [range 1.0-3.0] to 0.2 [range 0-2.0]; p = 0.031). During TCZ, 60% of all patients were relapse free (79% for MOGAD, 56% for AQP4-IgG+, and 43% for seronegative NMOSD). Disability follow-up indicated stabilization. MRI inflammatory activity decreased in MOGAD (p = 0.04; for the brain) and in AQP4-IgG+ NMOSD (p < 0.001; for the spinal cord). Chronic pain was unchanged. Regarding only patients treated with TCZ for at least 12 months (n = 44), ARR reductions were confirmed, including the subgroups of MOGAD (n = 11) and AQP4-IgG+ patients (n = 28). Similarly, in the group of patients treated with TCZ for at least 12 months, 59% of them were relapse free, with 73% for MOGAD, 57% for AQP4-IgG+, and 40% for patients with seronegative NMOSD. No severe or unexpected safety signals were observed. Add-on therapy showed no advantage compared with TCZ monotherapy.

Discussion: This study provides Class III evidence that long-term TCZ therapy is safe and reduces relapse probability in MOGAD and AQP4-IgG+ NMOSD.

Figure 1. Disease Courses and Individual Maintenance Immune Therapies of Patients With MOGAD

First attacks are indicated as red diamonds and further attacks as blue diamonds. IVIG = IV immunoglobulin; IVMP = IV methylprednisolone; MOG = myelin oligodendrocyte glycoprotein; MOGAD = MOG-IgG–associated disease.

Figure 2. Disease Courses and Individual Maintenance Immune Therapies of Patients With AQP4-IgG–Seropositive NMOSD

First attacks are indicated as red diamonds and further attacks as blue diamonds. AQP4 = aquaporin-4; IVIG = IV immunoglobulin; NMOSD = neuromyelitis optica spectrum disorder; IVMP = IV methylprednisolone; PE = plasma exchange; SLE = systemic lupus erythematosus. (a) Twelve years before tocilizumab (TCZ) initiation. (b) Twenty-four years before TCZ initiation. (c) Therapy of chronic polyarthritis 2 and a half years before TCZ initiation. (d) Fifteen years before TCZ initiation. (e and f) Sixteen years before TCZ initiation. (g) Ten and a half years before TCZ initiation. (h) Twenty-two years before TCZ initiation. (i) Eleven and a half years before TCZ initiation. (j) Psoriasis therapy; psoriasis flare-up finally remitted completely under rituximab; ^#loss to follow-up.

Figure 3. ARR Before and During TCZ Treatment

Box-and-whisker plots showing the median, IQR, and range of the annualized relapse rate 2 years before and during TCZ treatment for the MOGAD (A), the AQP4-IgG+ NMOSD (B) and the double seronegative (C) subgroups of patients, as well as for the total cohort (D). Each dot indicates 1 single patient. Hatched bars represent those patients who had been treated with TCZ for at least 12 months. AQP4 = aquaporin-4; ARR = annualized relapse rate; IQR = interquartile range; MOGAD = MOG-IgG–associated disease; NMOSD = neuromyelitis optica spectrum disorder; TCZ = tocilizumab.

Figure 4. Level of Disability Measured as EDSS Score Before and During TCZ Treatment

Box-and-whisker plots showing the median, IQR, and range of the EDSS score 2 years before and during TCZ treatment for the MOGAD (A), the AQP4-IgG+ NMOSD (B) and the double seronegative (C) subgroups of patients, as well as for the total cohort (D). Each dot indicates 1 single patient. Hatched bars represent those patients who had been treated with TCZ for at least 12 months. AQP4 = aquaporin-4; EDSS = Expanded Disability Status Scale; IQR = interquartile range; MOGAD = MOG-IgG–associated disease; NMOSD = neuromyelitis optica spectrum disorder; TCZ = tocilizumab.

Figure 5. Longitudinal Aquaporin-4-IgG Titers Before and During TCZ Treatment

Individual longitudinal courses of AQP4-IgG titers (assessed by cell-based assays) for patients with AQP4-IgG–seropositive NMOSD (n = 16) are shown. Most patients (12/16) showed decreased or stable titers on initiation of TCZ; in 4/16 patients, the AQP4-IgG titer increased. AQP4 = aquaporin-4; NMOSD = neuromyelitis optica spectrum disorder; TCZ = tocilizumab.