Trial of canakinumab, an IL-1β receptor antagonist, in patients with inclusion body myositis

Abstract

ObjectiveTo assess whether canakinumab, a monoclonal antibody against IL-1β approved for autoinflammatory diseases, is effective as target-specific therapy in patients with sporadic inclusion body myositis (sIBM).MethodsBecause in sIBM IL-1β colocalizes with amyloid precursor protein and upregulates amyloid aggregates enhancing degeneration, targeting IL-1β 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.ResultsPatient 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.ConclusionsIn 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 evidenceThis study provides Class IV evidence that canakinumab was ineffective for patients with sIBM.

NLRP3 inflammasome up-regulates major histocompatibility complex class I expression and promotes inflammatory infiltration in polymyositis

“…The active involvement of IL-1 in the inflammatory process leads to the development of targeted therapies using IL-1 blockade. Yet the clinical results of IL-1β blockade were mixed [ 38 – 40 ]. Zong et al [ 38 ] reported a satisfactory outcome of anakinra treatment in patients with refractory inflammatory myopathies.…”

“…In their study, 3 out of 6 PM patients, 3 out of 4 dermatomyositis (DM), and 1 out of 5 inclusion body myositis (IBM), showed clinical response to anakinra treatment. However, other reports using IL-1β blockade (canakinumab or anakinra) to treat IBM showed less satisfactory results [ 39 , 40 ]. Further understanding of the molecular mechanisms of IL-1β in the pathogenesis of myositis is required.…”

NLRP3 Inflammasome Up-Regulates Major Histocompatibility Complex Class I Expression and Promotes Inflammatory Infiltration in Polymyositis

“…The active involvement of IL-1 in the in ammatory process leads to the development of targeted therapies using IL-1 blockade. Yet the clinical results of IL-1β blockade were mixed [38][39][40]. Zong et al [38] reported a satisfactory outcome of anakinra treatment in patients with refractory in ammatory myopathies.…”

Autoimmune Neurogenic Dysphagia

“…Glucocorticoids, methotrexate, cyclosporine, azathioprine, or mycophenolate is ineffective, and although some patients initially experience mild improvements, there is no long-term benefit. Treatment with alemtuzumab, a B and T cell-depleting anti-CD52 monoclonal antibody, has shown some promising results in an uncontrolled trial [ 25 ], while treatment with canakinumab, an anti-IL-1β monoclonal antibody, yielded mixed results in a small trial of 5 patients [ 26 ]. Anakinra, an IL-1 receptor blocker, had also shown mild short-term improvements in a subset of patients in the first series [ 27 ] and in a later study of 15 patients [ 28 ].…”