Etanercept Treatment in Children With New-Onset Type 1 Diabetes

Abstract

OBJECTIVETo gather preliminary data on the feasibility and efficacy of etanercept therapy to prolong endogenous insulin production in pediatric patients with newly diagnosed type 1 diabetes.RESEARCH DESIGN AND METHODSThis was a 24-week double-blind, randomized, placebo-controlled study conducted at the Diabetes Center, Women and Children's Hospital of Buffalo. Eighteen subjects (11 male and 7 female, aged 7.8–18.2 years) were randomly assigned to receive either placebo or etanercept. Inclusion criteria included age 3–18 years, GAD-65 and/or islet cell antibody positivity, A1C >6%, three insulin injections per day, white blood cell count 3,000–10,000, platelets >100,000, and normal liver and renal function. Intention-to-treat analysis was used.RESULTSA1C at week 24 was lower in the etanercept group (5.91 ± 0.5%) compared with that in the placebo group (6.98 ± 1.2%; P < 0.05) with a higher percent decrease from baseline than in the placebo group (etanercept 0.41 ± 0.1 vs. placebo 0.18 ± 0.21; P < 0.01). The percent change in C-peptide area under the curve from baseline to week 24 showed a 39% increase in the etanercept group and a 20% decrease in the placebo group (P < 0.05). From baseline to week 24 insulin dose decreased 18% in the etanercept group compared with a 23% increase in the placebo group (P < 0.05). Seventeen patients completed the study, and none withdrew because of adverse events.CONCLUSIONSIn this small pilot study, treatment of pediatric patients newly diagnosed with type 1 diabetes with etanercept resulted in lower A1C and increased endogenous insulin production, suggesting preservation of β-cell function. A larger study is needed to further explore safety and efficacy.

TNF-α Antibody Therapy in Combination With the T-Cell–Specific Antibody Anti-TCR Reverses the Diabetic Metabolic State in the LEW.1AR1-iddmRat

“…At the same time, immune cell infiltration in the islets was completely abolished. Monotherapy with anti-TNF-a was not successful in the diabetic animals, confirming earlier studies (18,46). Anti-TCR monotherapy did also not yield a sustained success under the same therapy regimen, as we reported in detail in a previous study in this rat model (25).…”

“…However, although a monotherapy with anti-TNF-a is an established successful therapy in a number of autoimmune diseases (15)(16)(17), anti-TNF-a is not effective in T1D treatment (18)(19)(20)(21)(22)(23). Anti-TNF-a neutralizes TNF-a, produced by the immune cells infiltrating the target organ during the inflammatory process (11,14,15,45), and the combination of anti-TNF-a with anti-TCR also prevents the release of IL-1b, the other critical proinflammatory cytokine for the disease process (3), from the activated T cells (25).…”

What is the role of autoimmunity in type 1 diabetes? A clinical perspective

“…Indeed, this observation has given rise to the hypothesis that the generation of autoantibodies in type 1 diabetes may be a secondary event triggered by a primary islet-destructive process. Follow-up studies using other immune modulatory treatments, including cytotoxic T-lymphocyte antigen 4 (CTLA4)-immunoglobulin fusion protein [12], anti-CD20 antibody [13], anti-CD3 antibody [14][15][16], DiaPep277 [17], TNF-α receptor fusion protein [18] and anti-IL-1β antibody or IL-1 receptor antagonist [19], showed mild initial benefit, or no benefit at all. Of note, in cases where clinical benefits were observed, the typical pattern was an initial improvement in insulin production, followed by a decline which paralleled that observed in untreated patients.…”

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“…People have type one diabetes, lack of endogenous insulin production (Mastrandrea, 2009). It affects approximately 5% to 10% of people with disease (Devendra, 2004).…”