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

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. Action of TNF-α
The primary role of TNF is in
the regulation of immune
cells. TNF, being an
endogenous pyrogen, is able
to induce fever,
to induce apoptotic cell death,
to induce sepsis (through IL1
& IL6 production), to
induce cachexia,
induce inflammation, and to
inhibit tumorigenesis and 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).

4. Mechanism of Action

5. Pathway

6. Pathogenesis

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. 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. 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.

11. 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.

12. 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

13. 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?)

14. 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.

15. 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).

16. Study Design

17. 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.

18. 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

19. 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.

20. 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.