Anti-TNFα therapy—killing two birds with one stone?

Arif, Sefina; Cox, Patricia; Afzali, Behdad; Lombardi, Giovanna; Lechler, Robert I.; Peakman, Mark; Mirenda, Vincenzo

doi:10.1016/s0140-6736(10)60394-7

Cited by 12 publications

(7 citation statements)

References 4 publications

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“…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).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2015

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Anti–tumor necrosis factor-α (TNF-α) therapy (5 mg/kg body weight), alone or combined with the T-cell–specific antibody anti–T-cell receptor (TCR) (0.5 mg/kg body weight), was performed over 5 days immediately after disease manifestation to reverse the diabetic metabolic state in the LEW.1AR1-iddm rat, an animal model of human type 1 diabetes. Only combination therapy starting at blood glucose concentrations below 15 mmol/L restored normoglycemia and normalized C-peptide. Increased β-cell proliferation and reduced apoptosis led to a restoration of β-cell mass along with an immune cell infiltration–free pancreas 60 days after the end of therapy. This combination of two antibodies, anti-TCR/CD3, as a cornerstone compound in anti–T-cell therapy, and anti–TNF-α, as the most prominent and effective therapeutic antibody in suppressing TNF-α action in many autoimmune diseases, was able to reverse the diabetic metabolic state. With increasing blood glucose concentrations during the disease progression, however, the proapoptotic pressure on the residual β-cell mass increased, ultimately reaching a point where the reservoir of the surviving β-cells was insufficient to allow a restoration of normal β-cell mass through regeneration. The present results may open a therapeutic window for reversal of diabetic hyperglycemia in patients, worthwhile of being tested in clinical trials.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2015

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“…In animal models, TNF-␣ propels or lessens the diabetogenic response early or late in the T1D process, respectively (94,207,241,480). Adding to the confusion are some clinical case reports documenting the development of T1D in arthritis (JIA or RA) patients following etanercept treatment (49, 60, 418), but also the resolution of T1D in patients requiring anti-TNF-␣ therapy for RA (18). These opposing outcomes need to be clarified soon.…”

Section: B Non-antigen-specific Intervention Trials In T1dmentioning

confidence: 99%

Type 1 Diabetes: Etiology, Immunology, and Therapeutic Strategies

Belle

Coppieters

Herrath

2011

Physiological Reviews

858

695

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Type 1 diabetes (T1D) is a chronic autoimmune disease in which destruction or damaging of the beta-cells in the islets of Langerhans results in insulin deficiency and hyperglycemia. We only know for sure that autoimmunity is the predominant effector mechanism of T1D, but may not be its primary cause. T1D precipitates in genetically susceptible individuals, very likely as a result of an environmental trigger. Current genetic data point towards the following genes as susceptibility genes: HLA, insulin, PTPN22, IL2Ra, and CTLA4. Epidemiological and other studies suggest a triggering role for enteroviruses, while other microorganisms might provide protection. Efficacious prevention of T1D will require detection of the earliest events in the process. So far, autoantibodies are most widely used as serum biomarker, but T-cell readouts and metabolome studies might strengthen and bring forward diagnosis. Current preventive clinical trials mostly focus on environmental triggers. Therapeutic trials test the efficacy of antigen-specific and antigen-nonspecific immune interventions, but also include restoration of the affected beta-cell mass by islet transplantation, neogenesis and regeneration, and combinations thereof. In this comprehensive review, we explain the genetic, environmental, and immunological data underlying the prevention and intervention strategies to constrain T1D.

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“…Although there are no other trials of TNF inhibitors for diabetes treatment, there are case reports of patients with autoimmune diabetes who experienced improved glycemic control and/or hypoglycemia after initiating treatment with etanercept [80, 81], adalimumab [82–84], and infliximab [85], suggesting that the effects of etanercept on type 1 diabetes are generalizable to TNF inhibitors as a group. Of note, there are two reported cases of type 1 diabetes developing shortly after TNF inhibitors were started, raising the concern that TNF inhibitors were the cause [86, 87].…”

Section: Diabetes-specific Effects Of Rheumatologic Immune Modulatorsmentioning

confidence: 99%

Immune-Modulating Therapy for Rheumatologic Disease: Implications for Patients with Diabetes

et al. 2016

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Immune modulators used to treat rheumatologic disease have diverse endocrine effects in patients with diabetes. Providers should be aware of these effects given that diabetes and rheumatologic disease overlap in prevalence and cardiovascular morbidity. In patients with type 1 diabetes, clinical trials have demonstrated that immune modulators used early in the disease can improve pancreatic function, though their efficacy in adults with longstanding autoimmune diabetes is unknown. In patients with type 2 diabetes, hydroxychloroquine is an effective antihyperglycemic and may be preferred for rheumatologic use in patients with difficult glycemic control. In patients without diabetes, hydroxychloroquine and tumor necrosis factor (TNF) inhibitors have been found to decrease diabetes incidence in observational studies. Additionally, dapsone and sulfasalazine alter erythrocyte survival resulting in inaccurate HbA1c values. These multifaceted effects of immune modulators create a need for coordinated care between providers treating patients with diabetes to individualize medication selection and prevent hypoglycemic events. More research is needed to determine the long-term outcomes of immune modulators in patients with diabetes.

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Anti-TNFα therapy—killing two birds with one stone?

Cited by 12 publications

References 4 publications

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

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

Type 1 Diabetes: Etiology, Immunology, and Therapeutic Strategies

Immune-Modulating Therapy for Rheumatologic Disease: Implications for Patients with Diabetes

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