Therapeutic efficacy of humanized recombinant anti–interleukin‐6 receptor antibody in children with systemic‐onset juvenile idiopathic arthritis

Abstract

Objective. To investigate the safety and efficacy of a recombinant human anti-interleukin-6 (anti-IL-6) receptor monoclonal antibody (MRA) that indirectly inhibits the effects of IL-6 in children with systemiconset juvenile idiopathic arthritis (JIA) refractory to high-dose, long-term corticosteroids.Methods. An individual escalating-dose trial was conducted in 11 children with active systemic-onset JIA who met the inclusion criteria. All were first administered an intravenous dose of 2 mg/kg MRA. Each child without active inflammation was given a second identical dose 2 weeks later and a third identical dose 2 weeks after the second dose. Children with disease flares according to laboratory marker values received a 4-mg/kg dose. Those without disease flares at this dose received a second 4-mg/kg dose 2 weeks later and a third 4-mg/kg dose 2 weeks after the second dose, while those with active inflammation received an additional 3 doses of 8 mg/kg MRA. Efficacy was evaluated every 2 weeks according to responses on the JIA core set of improvement criteria and the results of laboratory tests.Results. MRA abruptly reduced disease activity in 10 of the 11 children, as assessed by the occurrence of febrile episodes, active arthritis, scores on the Childhood Health Assessment Questionnaire, and levels of acute-phase reactants. However, levels of inflammatory reactants fluctuated until the proper MRA dose for each child was reached. Two weeks after the third fixed dose of MRA, 90.9% of all patients had a 30% improvement response, 90.9% had a 50% improvement response, and 63.6% had a 70% improvement response.Conclusion. MRA treatment of children with active systemic disease results in clinical improvement and in normalized levels of acute-phase reactants. MRA was safe and well tolerated and provided greater clinical benefit than conventional corticosteroids, considering the ill effects of IL-6 and adverse events.

Anti‐interleukin‐6 receptor antibody, tocilizumab, for the treatment of autoimmune diseases

“…RA (in more than 90 countries worldwide) [36][37][38][39][40][41][42] Castleman's disease (in Japan) [52,53] Systemic and polyarticular JIA (in Japan) [57][58][59] Candidate diseases for tocilizumab therapy: Systemic autoimmune diseases SLE [130] Systemic sclerosis [115] Giant cell arteritis and Takayasu arteritis [90,91] Polymyositis Organ specific autoimmune diseases Crohn's disease [73] Relapsing polychondritis [108] Multiple sclerosis, neuromyelitis optica Acquired hemophilia A [149] Chronic inflammatory diseases Adult-onset Still's disease [61][62][63][64][65][66][67][68] Reactive AA amyloidosis [48][49][50][51] Polymyalgia rheumatica [80,91] RS3PE [85] Spondyloarthritides [100,[102][103][104][105] Behcet's disease Uveitis GVHD [150] Autoinflammatory diseases (TRAPS) [152] Tocilizumab has been approved as a biological drug for the treatment of RA, Castleman's disease and juvenile idiopathic arthritis, and is expected to be applicable to various other autoimmune and inflammatory diseases. Abbreviations: RA, rheumatoid arthritis; JIA, juvenile idiopathic arthritis; SLE, systemic lupus erythematosus; RS3PE, remitting seronegative, symmetrical synovitis with pitti...…”

Targeting the interleukin‐6 receptor: A new treatment for systemic juvenile idiopathic arthritis?

“…In their study, Yokota et al used a humanized mAb to IL-6R (20). This antibody was obtained by grafting the complementarity-determining regions of a murine antihuman IL-6R into a human IgG1 (68).…”

“…In their study, Yokota et al used escalating doses of MRA (2-8 mg/kg every 2 weeks) to treat 11 patients with steroid-dependent systemic JIA (20). The study was limited to a small number of patients, and information on short-term treatment (from ϳ40 days to ϳ80 days) is provided.…”

“…In 1998, summarizing the evidence available at that time, it was suggested that IL-6 inhibition could be a suitable therapy for patients with systemic JIA (19). In this issue of Arthritis & Rheumatism, Yokota and coworkers report promising results on the therapeutic efficacy of IL-6 inhibition in children with systemic JIA (20).…”

Biological therapy with TNF-inhibitors in pediatric rheumatology. Review of the litterature and personal experience

“…Infatti, la maggior parte dei nostri pazienti presentavano una malattia di lunga durata ed erano in fase di attività poliartritica, ma senza sintomi sistemici (79). La scarsa efficacia dell'inibizione del TNF sull'attività sistemica dell'AIG, era ipotizzabile sulla base delle osservazioni che indicavano l'IL-6 come principale responsabile delle manifestazioni sistemiche della malattia (80-82), confermate, nelle prime esperienze cliniche, dalla drammatica efficacia del Tocilizumab (inibitore di IL-6) sulle manifestazioni cliniche sistemiche dell'AIG e sulla soppressione dei reattanti della fase acuta (83,84). Alcuni studi suggeriscono, invece, che l'Etanercept possa essere un utile agente terapeutico nella sindrome da Sindrome da Attivazione Macrofagica (MAS), che viene considerata una linfo-istiocitosi emofagocitica secondaria ed è una complicazione tipica e potenzialmente fatale dell'AIG sistemica (85)(86)(87).…”