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Table 1 Efficacy and safety of anti–IL-6 therapies on neuropathic pain in patients with NMOSD

From: Interleukin-6: evolving role in the management of neuropathic pain in neuroimmunological disorders

Anti–IL-6 therapy
Author, year (study design) Clinical characteristics of patients Prior/concomitant medications Dose, frequency of administration, and duration of treatment Efficacy (NRS/VAS) Safety
NRS/VAS at baseline NRS/VAS at the end of treatment/last follow-up
Araki et al., 2013 (CR) [20] A 36-year-old female patient with NMO Combination of PSL and AZA 8 mg/kg i.v. every month for 6 months NRS: 4 NRS: 0 Decline in SBP, lymphocytopenia, viral enteritis, and upper respiratory infection of unknown origin
Araki et al., 2014 (pilot study) [21] Seven (six female and one male) patients with refractory AQP4-Ab-seropositive NMO or NMOSD PSL or AZA alone or PSL in combination with AZA, CyA, or tacrolimus 8 mg/kg every month for 1 year NRS, mean ± SEM: 3.0 ± 1.5 NRS at 6 months, mean ± SEM: 1.3 ± 1.3
NRS at 12 months, mean ± SEM: 0.9 ± 1.2
Upper respiratory infection (n = 2), acute enterocolitis (n = 2), acute pyelonephritis (n = 1), leukocytopenia, and/or lymphocytopenia (n = 3), anemia (n = 2), and a slight decline in SBP (n = 1)
Ringelstein et al., 2015
(ROS) [22]
Eight female patients with highly active AQP4-Ab-seropositive NMO (n = 6) or NMOSD (n = 2) Immunomodulatory or immunosuppressant therapy (e.g., rituximab, interferon beta-1β, AZA) 6–8 mg/kg at a 4- to 6-week interval followed up to 10–51 months NRS, median ((IQR): 6.5 (5.0–7.0) NRS, median (IQR): 2.5 (0.3–4.5) (p = 0.02)
7/8 patients had less pain at the last follow-up, with two of them completely pain free
Mild post infusion nausea
(n = 1), transient gastritis (n = 1), transient diarrhea (n = 1), headache (n = 1), fatigue (n = 2), recurrent urinary tract infections (n = 3), deep venous thrombosis (n = 1), transient mild liver enzyme increase (n = 3), recurrent CRP elevation (n = 1), leukopenia or neutropenia (n = 2) and elevation of cholesterol levels (n = 6)
Araki, 2019 (CS) [23] 19 patients with refractory NMOSD Corticosteroids and/or immunosuppressants Dose not specified; monthly infusion up to 6 years and 8 months NRS, mean ± SD: 3.2 ± 2.2 NRS at 1 year after treatment: 1.7 ± 2.6 (p < 0.001)
In one patient with comorbid SLE, severe neuropathic pain disappeared
Not reported
Yamamura et al., 2019 (CT) [24] 83 patients with AQP4-Ab- seropositive or AQP4-Ab- seronegative NMOSD: satralizumab, 41; placebo, 42 Oral glucocorticoids, AZA, MMF, AZA + glucocorticoids, and MMF+oral glucocorticoids 120 mg s.c. at weeks 0, 2, and 4 and every 4 weeks during the double-blind perioda VAS (mean ± SD
Satralizumab group: 27.6 ± 28.2
Placebo group: 34.6 ± 26.1
The between-group difference in the change in the mean VAS pain score was 4.08 (95% CI, − 8.44 to 16.61, p = 0.52) Satralizumab vs placebo (%): Infection (68% vs 62%), IRR (12% vs 5%), neoplasmb (7% vs 7%), and serious infection (5% vs 7%)
Traboulsee et al, 2020 (CT) [25] 95 patients with AQP4-Ab- seropositive or AQP4-Ab-seronegative NMOSD: satralizumab,63; placebo, 32 Previous: B-cell depleting therapy and immunosuppressants. Analgesics were permitted during satralizumab therapy 120 mg s.c. at weeks 0, 2, and 4 and every 4 weeks thereafter in the double-blind period (maximal duration of 1.5 years after the random assignment of the last patient enrolled) VAS (mean ± SD)
Satralizumab group: 31.7 ± 28.9
Placebo group: 27.6 ± 30.8
The adjusted mean of the VAS pain score change from baseline did not differ significantly between the two groups (between-group difference in mean score change 3.21 (95% CI, − 5.09 to 11.52; p = 0.44). Satralizumab vs placebo (%): Infections (54% vs 44%), IRR (13% vs 16%), and serious infections (10% vs 9%)
  1. aThe duration of the double-blind period ended when the total number of relapses reached 26. The median duration of treatment was 107.4 weeks (range, 2 to 224) in the satralizumab group and 32.5 weeks (range, 0 to 180) in the placebo group. Patients who experienced a relapse in the double-blind period or those who completed the double-blind period without any relapse could enter the open-label extension period wherein they could receive satralizumab s.c. at weeks 0, 2, and 4 and monthly thereafter for 1 year (depending on the condition) in combination with a baseline treatment or as a monotherapy. The median duration of treatment among patients who received satralizumab in the double-blind and open-label extension periods was 143.1 weeks (range, 15 to 224)
  2. bBenign neoplasm of the thyroid gland, colon adenoma, and uterine leiomyoma occurred in one patient each in the anti–IL-6 therapy group
  3. AQP4-Ab aquaporin-4 antibody, AZA azathioprine, CI confidence interval, CR case report, CRP C-reactive protein, CS case series, CT phase 3, double-blind, randomized, placebo-controlled trial, CyA cyclosporine, IQR interquartile range, IRR injection-related reaction, i.v. intravenous, MMF mycophenolate mofetil, NMO neuromyelitis optica, NMOSD neuromyelitis optica spectrum disorder, NRS numerical rating scale, PSL prednisolone, ROS retrospective observational study, SBP systolic blood pressure, s.c. subcutaneous, SD standard deviation, SEM standard error of the mean, SLE systemic lupus erythematosus, VAS visual analog scale