RESUMEN
Objective: To assess whether canakinumab, a monoclonal antibody against IL-1ß approved for autoinflammatory diseases, is effective as target-specific therapy in patients with sporadic inclusion body myositis (sIBM). Methods: Because in sIBM IL-1ß colocalizes with amyloid precursor protein and upregulates amyloid aggregates enhancing degeneration, targeting IL-1ß with canakinumab may arrest disease progression. On this basis, 5 ambulatory patients with sIBM participated in an institutional review board--approved open-labeled study with 150 mg canakinumab [4 bimonthly, then monthly subcutaneous injections] for a mean period of 15.8 months. Patients were assessed bimonthly with a manual dynamometer in 12 proximal and distal muscles and with grip force (GF) in both hands. Total muscle strength (TMS) was expressed in kilograms. Efficacy was defined as >15% increased strength after 12 months. Results: Patient 1 stopped at month 5 because of 23% loss in TMS and 32.35% in GF; patient 2 showed 37.1% increase in TMS and 13% in GF by month 9; patient 3 exhibited 26.7% reduction in TMS and 10% in GF at month 33; patient 4 showed 6.5% reduction in TMS and 1.6% in GF after 15 months, denoting relative stability; and patient 5 showed 30.4% loss in TMS and 20.8% in GF after 18 months. In patients 2 and 4, in whom 3-year longitudinal data were available, no effect on disease progression was noted. Conclusions: In this long-term, open-label study, canakinumab showed small, but not clinically appreciable, stabilizing benefits in 2 of 5 patients with sIBM over 1 year, was ineffective in 2 others, and might have worsened one. No patient improved. Classification of evidence: This study provides Class IV evidence that canakinumab was ineffective for patients with sIBM.
Asunto(s)
Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/farmacología , Interleucina-1beta/antagonistas & inhibidores , Miositis por Cuerpos de Inclusión/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Progresión de la Enfermedad , Femenino , Fuerza de la Mano , Humanos , Inyecciones Subcutáneas , Masculino , Persona de Mediana Edad , Fuerza Muscular/efectos de los fármacos , Resultado del TratamientoRESUMEN
OBJECTIVE: In stiff person syndrome (SPS), an antibody-mediated impaired γ-aminobutyric acidergic (GABAergic) neurotransmission is believed to cause muscle stiffness and spasms. Most patients improve with GABA-enhancing drugs and intravenous immunoglobulin, but some respond poorly and remain disabled. The need for more effective therapy prompted a trial with the anti-CD20 monoclonal antibody rituximab. METHODS: This was a placebo-controlled randomized trial of rituximab (2 biweekly infusions of 1g each). The primary outcome was a change in stiffness scores at 6 months. Secondary outcomes were changes in heightened-sensitivity and quality of life scores. Enrolling 24 patients was calculated to detect 50% change in stiffness scores. RESULTS: Randomization was balanced for age, sex, disease duration, and glutamic acid decarboxylase autoantibody titers. No significant changes were noted at 6 months after treatment in all outcomes. Specifically, no differences were noted in the stiffness index, the primary outcome, or sensitivity scores, the secondary outcome, at 3 or 6 months. Quality of life scores improved significantly (p < 0.01) at 3 months in both groups, but not at 6 months, denoting an early placebo effect. Blinded self-assessment rating of the overall stiffness for individual patients revealed improvement in 4 patients in each group. At 6 months, improvement persisted in 1 patient in the placebo group versus 3 of 4 in the rituximab group, where these meaningful improvements were also captured by video recordings. INTERPRETATION: This is the largest controlled trial conducted in SPS patients and demonstrates no statistically significant difference in the efficacy measures between rituximab and placebo. Rituximab's lack of efficacy could be due to a considerable placebo effect; insensitivity of scales to quantify stiffness, especially in the less severely affected patients; or drug effectiveness in only a small patient subset. Ann Neurol 2017;82:271-277.