1. The Effect of TNF- blockage on ameliorationof symptoms of diabetic neuropathy Brian Wells, MPH, MSM

2. Introduction Tumor necrosis factor (TNF)- is a potent proinflammatorycytokine involved in the pathogenesis of diabeticneuropathy. The TNF- inhibitor, infliximab (Remicade), a monoclonalantibody anti-TNF-, is a DMARD TNF- inhibitor typedrug. This drug, metabolized by CYP450 in the liver with ahalf-life of 8 to 9.5 days, is capable of binding andinhibiting TNF-, reducing inflammation and alteringimmune response. Currently used in treating a variety of autoimmune disorders in humans, including ankylosing spondylitis, Crohns disease and ulcerative colitis This opens the possibility of studying the effect of TNF-on people with diabetic neuropathy. 3. Action of TNF-The primary role of TNF is inthe regulation ofimmunecells. TNF, being anendogenous pyrogen, is ableto induce fever,to induceapoptoticcell death,to induce sepsis (through IL1& IL6 production), toinducecachexia,induceinflammation, and toinhibittumorigenesisandviralreplication. Dysregulation ofTNF production has beenimplicated in a variety ofhumandiseases,includingAlzheimersdisease,cancer,majordepression,andinflammatorybowel disease(IBD). 4. Mechanism of Action 5. Pathway 6. Pathogenesis 7. Introduction Previous genetic inactivation studies in mice have shown arelationship between this proinflammatory cytokine and thesymptoms of diabetic neuropathy. Found that suppressing the TNF- is associated withamelioration of the electrophysiological and biochemical deficitsfor 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 theefficacy of TNF- inhibitors in the amelioration of diabeticneuropathy symptoms. 8. Introduction Studies in humans have shown that the TNF- system isincreased in subjects with type 1 diabetes mellitus anddiabetic neuropathy, regardless of their glycemic controland cardiovascular risk factors associated with insulinresistance. This data is highly suggestivethat TNF- may play apathogenic role in thedevelopment ofdiabetic neuropathy. 9. Why is this important? Diabetes is one of the most common chronic diseases inchildren and adolescents; about 151,000 people below theage of 20 years have diabetes. In the last 2 decades, type 2 diabetes has been reportedamong U.S. children and adolescents with increasingfrequency. Over 170 million people worldwide have type 2 diabetes,an astonishing 2.8% of the worlds population. 10. Why is this important? Diabetic polyneuropathy is the most common neuropathyin the Western world. Particularly debilitating complication of diabetes andaccounts for significant morbidity by predisposing the footto ulceration and lower extremity amputation. Prevalence estimates are that approximately 50% ofpatients with diabetes will eventually develop neuropathy. The total costs of diagnosed diabeteshave surged to $174 billion in 2007,up from $44 billion in 1997. 11. Diabetic neuropathy Diabetic neuropathy is classified into distinct clinicalsyndromes. A characteristic set of symptoms and signsexist for each syndrome, depending on the component ofthe peripheral nervous system that is affected. The mostfrequently 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. Objectives This study is designed to measure the effectiveness ofinfliximab in the treatment of diabetic neuropathy. Building upon previous studies related to blockage of TNF-, this study will assess the treatments generalizedapplication to the human population. Objectives To evaluate the role that TNF- plays in diabetic neuropathy symptomatology To assess whether TNF- 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. Study Design This study is designed to be a parallel-group, randomizedcontrolled trial. The study population will be split into two groups thosewith diabetic neuropathy taking infliximab and those withdiabetic neuropathy not taking infliximab. Making the study double-blind should control for bias onthe part of the patient and the researcher andrandomization should help control for normal confounders,such as age, gender and various cormorbidities. Those in the non-infliximab group will be given placebotreatment so as to minimize confounding observationaleffects. 14. Study Design Five study milestones will be established at 0 months, 3months, 6 months, 9 months and one year. The purpose of these waypoints will be for studyassessment to determine numbers in each group, currentoutcomes, projected outcomes, and whether the studyshould continue to go forward based on data available atthat time, such as frequency of side-effects or otherunintended consequences. Significant and/or life-threatening events will qualify thepatient to be classed as discontinued follow-up (N14 or N24groups). 15. Study Design 16. Study Design Before patients are included in the study, those withinflammatory comorbidities will be excluded, as these conditionswould potentially confound the effect of TNF- blockage ondiabetic neuropathy. Additionally, those with absolute contraindications to infliximabtherapy and those who have previously taken infliximab will alsobe excluded for reasons of patient safety and avoidingconfounding, respectively. Finally, for all patients enrolled, strict glycemic control will bemaintained in compliance with best practice clinical guidelinesand will be monitored by glucose level and HbA1c. This willserve to not only provide good medical care, but also tominimize any confounding effect of diabetes on the progressionof neuropathy. 17. Study Design Comorbid Exclusion Criteria Ankylosing spondylitis Crohns disease Psoriasis/Psoriatic arthritis Rheumatoid arthritis Ulcerative colitis Contraindications to infliximab therapy Previous use of anti-TNF- therapy 18. Study Results Analysis Analysis of results will be by three methodologies. First will be a comparison of the infliximab and controlgroups using a Student t-test. This will be followed up byan ANOVA analysis and Tukey-Kramer pairwisecomparison to see if there are significant differencesbetween the groups. Second will be a hierarchical linear model. The studysdesign is such that nested groups can be well evaluatedby this method to assess differences between groups andoutcomes. Finally, a time series analysis will be conducted. Where applicable, statistical testing will use = 0.05 withtwo-tailed testing. 19. Expected Results Based on previous studies in mice and observed humanpathophysiology, patients in the infliximab ground areexpected to show improvement by the second milestone. Whether this improvement will persist or will be transient innature has yet to be explored. It is also possible that some subjects may continue toshow improvement throughout the study. An additional possibility is that some patients in theplacebo group will show improvement via the placeboeffect. This effect will be accounted for in the statisticalanalysis.