The Effect of TNF-α Blockage on Diabetic Neuropathy


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  • DMARD= Disease Modifying Antirheumatic Drugs: it ’s a type of drug to treat inflammatory disease. The reason is called DMARD is bc we originally used them to treat rheumatoid arthritis. Monoclonal means producing one type of antibody TNF-alpha: it ’s a pleiotropic (multiple effects) inflammatory cytokine Purpose of my study: it ’s a large scale study to see if blocking TNF-alpha improves the symptoms of diabetic neuropathy.
  • Endogenous:means something that your own body makes, and it doesn ’t come from outside the body Pyrogen: Is something capable of creating fever or inflammation. Apoptotic: cell death Sepsis: is like a response to inflammation Gene Cachexia: means wasting This slide briefly covers the action of tumor necrosis factor alpha. As previously mentioned TNF alpha is an inflammatory mediator (it helps facilitate inflamation) which has a variety of effects in the body. Such as apoptosis, inflammation and inhibiting viral replication. Dysregulation of TNF production has been implicated in a variety of human diseases, including Alzheimer's disease, cancer, major depression, and inflammatory bowel disease (IBD).
  • Mechanism of action Infliximab blocks TNF-alpha. It ’s an antibody blocking TNF-alpha from binding to its receptors site.
  • Signaling cascade shows the effects of TNF-alpha Just say there are multiple inflammatory effects from TNF-alpha. This is the pathway involve with TNF alpha as you can see it interacts with multiple intracellular messengers to carry out inflammatory and other associated effect.
  • This is the pathogenins of diabetic neuraathy. The part that we ’ve been concentrating on is inflammation but as you can see, it is a multifactorial disease.
  • We had some studies in mice that took 2sets of mice in one, they had TNF-alpha and the other they did not have TNF-alpha because it was genetically inactivated. What we found was that the mice without TNF-alpha tended to have better outcomes. In these mice, the researchers saw an amelioration(to make it better) of diabetic neuropathy symptoms for a period of weeks. However, this was in a mouse model and the results do not necessarily translate to humans. Hence, there is a need for a controlled study to see if anti TNF-alpha agents would have the same effect in humans.
  • Ppl with diabetes even if they control their sugar level and their cardiac risk factors (cholestrol, blood pressure) then we still saw TNF-alpha system is increased.(higher level of TNF-alpha)
  • Diabetic polyneuropathy is a bad complication of diabetes because it lessen the sensation in the feet leading to injury, ulceration, infection and in some cases amputation.
  • Its classified into clinical syndromes. Each having a characteristic set of symptoms and signs. The bulleted list shows these clinical syndromes all of which can occur in diabetes. The distal symmetric polyneuropathy is the most common and is the one observed in most diabetics.
  • Is the benefit that people might get from using infliximab as a treatment for diabetic neuropathy sufficient to offset the risk of taking infliximab. And lastly, To see 1) if the drug work and also 2) does it have the lasting effect?
  • The study will use 2 group – one is a control (they are getting the placebo meaning they are getting sugar pills but not infliximab) and one will get infliximab Neither the patients nor the researchers will know which is getting placebo and which is getting infliximab This controls for bias in the result (double blind trial), i.e. you don ’t know which group is which so you can’t say, oh they’re getting better b/c they’re on infliximab
  • Study milestones are safety measures Side-effects or events could be significant so these can stop the study should the need arise
  • Chart showing what was discussed previously
  • Exclude those with inflammatory conditions as these could confound (interfere) studying neuropathy Neuropathy is part inflammatory so we can not look at people who already have a huge amount of inflammation Exclude those who can ’t take the drug for whatever reason Control blood sugar in all – this is the right thing to do, and it lets us study inflammation without worry about the effects of high sugar on neuropathy
  • These are the conditions we will exclude. These are the FDA indications for infliximab: Picture (left to right): Ankylosing spondylitis, Crohn ’s disease, rheumatoid arthritis
  • How the study can be analyzed T-test shows a difference in means ANOVA is t-testing with more than 2 groups Tukey-Kramer tells is there are intergroup differences Hierarchical models looks at nested data, i.e. groups within groups and compare them Time series is individual or aggregate and looks at changes over time
  • We expect patients will show improvement; otherwise, we wouldn ’t do the study The improvement, if there is one, may be lasting or it may not Some people may get better and better where as others may not People in the placebo group may get better due to the placebo effect, i.e. just by taking a sugar pill, they may think they ’re taking medication and show improvement
  • The Effect of TNF-α Blockage on Diabetic Neuropathy

    1. 1. The Effect of TNF-α blockage on amelioration of symptoms of diabetic neuropathy Brian Wells, MPH, MSM
    2. 2. Introduction• Tumor necrosis factor (TNF)-α is a potent proinflammatory cytokine involved in the pathogenesis of diabetic neuropathy.• The TNF-α inhibitor, infliximab (Remicade), a monoclonal antibody anti-TNF-α, is a DMARD TNF-α inhibitor type drug. This drug, metabolized by CYP450 in the liver with a half-life of 8 to 9.5 days, is capable of binding and inhibiting TNF-α, reducing inflammation and altering immune response. • Currently used in treating a variety of autoimmune disorders in humans, including ankylosing spondylitis, Crohn’s disease and ulcerative colitis• This opens the possibility of studying the effect of TNF-α on people with diabetic neuropathy.
    3. 3. Action of TNF-αThe primary role of TNF is inthe regulation of immunecells. TNF, being anendogenous pyrogen, is ableto induce fever,to induce apoptotic cell death,to induce sepsis (through IL1& IL6 production), toinduce cachexia,induce inflammation, and toinhibit tumorigenesis and viralreplication. Dysregulation ofTNF production has beenimplicated in a variety ofhuman diseases,including Alzheimersdisease, cancer, majordepression, and inflammatorybowel disease (IBD).
    4. 4. Mechanism of Action
    5. 5. Pathway
    6. 6. Pathogenesis
    7. 7. Introduction• Previous genetic inactivation studies in mice have shown a relationship between this proinflammatory cytokine and the symptoms of diabetic neuropathy.• Found that suppressing the TNF-α is associated with amelioration of the electrophysiological and biochemical deficits for a period of weeks. However, since this is a mouse model, the results are not necessarily directly translatable to humans• Hence, the need for a controlled study to demonstrate the efficacy of TNF-α inhibitors in the amelioration of diabetic neuropathy symptoms.
    8. 8. Introduction• Studies in humans have shown that the TNF-α system is increased in subjects with type 1 diabetes mellitus and diabetic neuropathy, regardless of their glycemic control and cardiovascular risk factors associated with insulin resistance.• This data is highly suggestive that TNF-α may play a pathogenic role in the development of diabetic neuropathy.
    9. 9. Why is this important?• Diabetes is one of the most common chronic diseases in children and adolescents; about 151,000 people below the age of 20 years have diabetes.• In the last 2 decades, type 2 diabetes has been reported among U.S. children and adolescents with increasing frequency.• Over 170 million people worldwide have type 2 diabetes, an astonishing 2.8% of the world’s population.
    10. 10. Why is this important?• Diabetic polyneuropathy is the most common neuropathy in the Western world.• Particularly debilitating complication of diabetes and accounts for significant morbidity by predisposing the foot to ulceration and lower extremity amputation.• Prevalence estimates are that approximately 50% of patients with diabetes will eventually develop neuropathy.• The total costs of diagnosed diabetes have surged to $174 billion in 2007, up from $44 billion in 1997.
    11. 11. Diabetic neuropathy• Diabetic neuropathy is classified into distinct clinical syndromes. A characteristic set of symptoms and signs exist for each syndrome, depending on the component of the peripheral nervous system that is affected. The most frequently encountered neuropathies: • Distal symmetric polyneuropathy (most common) • Individual cranial and peripheral nerve involvement causing focal mononeuropathies, especially affecting the oculomotor nerve and the median nerve • Autonomic neuropathy • Thoracic and lumbar nerve root disease, causing polyradiculopathies • Asymmetric involvement of multiple peripheral nerves, resulting in a mononeuropathy multiplex
    12. 12. Objectives• This study is designed to measure the effectiveness of infliximab in the treatment of diabetic neuropathy.• Building upon previous studies related to blockage of TNF- α, this study will assess the treatment’s generalized application to the human population.• Objectives • To evaluate the role that TNF-α plays in diabetic neuropathy symptomatology • To assess whether TNF-α blockage can be used to ameliorate symptoms, as in the mouse model • To measure the risk:benefit ratio involved in using infliximab as a treatment for diabetic neuropathy • To assess short-term outcomes of using infliximab as a treatment for diabetic neuropathy (i.e. does the treatment work?)
    13. 13. Study Design• This study is designed to be a parallel-group, randomized controlled trial.• The study population will be split into two groups – those with diabetic neuropathy taking infliximab and those with diabetic neuropathy not taking infliximab.• Making the study double-blind should control for bias on the part of the patient and the researcher and randomization should help control for normal confounders, such as age, gender and various cormorbidities.• Those in the non-infliximab group will be given placebo treatment so as to minimize confounding observational effects.
    14. 14. Study Design• Five study milestones will be established at 0 months, 3 months, 6 months, 9 months and one year.• The purpose of these waypoints will be for study assessment to determine numbers in each group, current outcomes, projected outcomes, and whether the study should continue to go forward based on data available at that time, such as frequency of side-effects or other unintended consequences.• Significant and/or life-threatening events will qualify the patient to be classed as discontinued follow-up (N14 or N24 groups).
    15. 15. Study Design
    16. 16. Study Design• Before patients are included in the study, those with inflammatory comorbidities will be excluded, as these conditions would potentially confound the effect of TNF-α blockage on diabetic neuropathy.• Additionally, those with absolute contraindications to infliximab therapy and those who have previously taken infliximab will also be excluded for reasons of patient safety and avoiding confounding, respectively.• Finally, for all patients enrolled, strict glycemic control will be maintained in compliance with best practice clinical guidelines and will be monitored by glucose level and HbA1c. This will serve to not only provide good medical care, but also to minimize any confounding effect of diabetes on the progression of neuropathy.
    17. 17. Study Design• Comorbid Exclusion Criteria • Ankylosing spondylitis • Crohn’s disease • Psoriasis/Psoriatic arthritis • Rheumatoid arthritis • Ulcerative colitis • Contraindications to infliximab therapy • Previous use of anti-TNF-α therapy
    18. 18. Study Results Analysis• Analysis of results will be by three methodologies.• First will be a comparison of the infliximab and control groups using a Student t-test. This will be followed up by an ANOVA analysis and Tukey-Kramer pairwise comparison to see if there are significant differences between the groups.• Second will be a hierarchical linear model. The study’s design is such that nested groups can be well evaluated by this method to assess differences between groups and outcomes.• Finally, a time series analysis will be conducted.• Where applicable, statistical testing will use α = 0.05 with two-tailed testing.
    19. 19. Expected Results• Based on previous studies in mice and observed human pathophysiology, patients in the infliximab ground are expected to show improvement by the second milestone.• Whether this improvement will persist or will be transient in nature has yet to be explored.• It is also possible that some subjects may continue to show improvement throughout the study.• An additional possibility is that some patients in the placebo group will show improvement via the placebo effect. This effect will be accounted for in the statistical analysis.