Pleased to announce that the lead story on 60 Minutes Australia on their November 5, 2011 broadcast is their in-depth report about our revolutionary anti-TNF treatment for Alzheimer’s.
The transcript and full-story can be viewed here:
Many thanks to all our patients, friends, and staff that have helped to make this happen and bring this forward.
A newly published randomized study from Chiba University in Japan provides robust scientific support for our pioneering work utilizing novel methods of delivery and indications for etanercept. The new study, published ahead-of-print in the leading journal Spine demonstrated the superiority of epidural administration of etanercept over an epidural steroid injection for treatment of sciatica associated with spinal stenosis. This method of treatment was invented at the INR (U.S. patent 6419944, issued to Edward Tobinick M.D.) a decade ago. When the INR first published our work with etanercept for sciatica in 2003 and 2004 there were many who were [incorrectly] skeptical. This new study joins a favorable randomized, placebo-controlled study conducted by the U.S. Army in conjunction with Johns Hopkins researchers published in 2009 after their [uncredited] consultation with us several years before. Pleased that the truth has again been confirmed.
In the News: November 7, 2010
Anti-TNF Therapies for Rheumatoid Arthritis Could Reduce Alzheimer’s Risk
Source: American College of Rheumatology (ACR)
Newswise — Anti-TNF therapies commonly used to treat rheumatoid arthritis have been found to potentially reduce the risk of developing Alzheimer’s dementia among people with rheumatoid arthritis, according to research presented this week at the American College of Rheumatology Annual Scientific Meeting in Atlanta.
Rheumatoid arthritis is a chronic disease that causes pain, stiffness, swelling, and destruction of the joints. People with RA often experience limitation in the motion and function of multiple joints. Though joints are the principal body parts affected by RA, inflammation can develop in other organs as well. An estimated 1.3 million Americans have RA, and the disease typically affects women twice as often as men.
A complication of chronic inflammation in RA is amyloidosis, caused by excess deposits of amyloid proteins in different organs, which can cause harmful effects to the normal function of many organs. While people with Alzheimer’s disease are found to have local deposits of a type of amyloid protein—beta-amyloid peptide—in the brain, the actual cause of Alzheimer’s remains unclear.
Researchers recently set out to evaluate if there is a relationship between different treatments for RA and the incidence of Alzheimer’s dementia. They reviewed medical and pharmacy claims data of over eight million subjects in the U.S. from a commercial database (Verisk Health). A total of 42,193 people with RA were identified. Each RA subject with newly diagnosed Alzheimer’s dementia was compared to 10 people with RA who did not have Alzheimer’s dementia (called “controls”). As researchers made these comparisons, they ensured they were comparing people of the same age, gender, and with the same use of methotrexate, a medication commonly used for RA. Researchers examined the exposure of these individuals to several drugs used to treat RA including sulfasalazine, prednisone, three anti-TNFs (infliximab, etanercept, and adalimumab) and rituximab.
A total of 165 RA subjects with Alzheimer’s dementia were compared to 1,383 RA controls without Alzheimer’s dementia. Researchers found that those who received anti-TNF treatment had a 55 percent reduction in risk of developing Alzheimer’s dementia. This effect was not seen with other drugs used for treatment of RA, including sulfasalazine, prednisone and rituximab
The researchers concluded that anti-TNF agents used to treat people with RA may be useful in reducing the development of Alzheimer’s dementia, although the mechanisms need further investigation.
“In this study, the incidence of Alzheimer’s disease was found to be lower in patients with rheumatoid arthritis who had been treated with anti-TNF agents,” says Dr. Richard Chou, MD, PhD; assistant professor at Dartmouth Medical School and lead investigator in the study. “Although the cause of Alzheimer’s disease is not known, the results suggest that TNF may play a role in its development.”
TNF-antagonists (also called biologics or anti-TNF therapy) are a class of drugs that have been used since 1998. Overall, they have been given to more than 600,000 people worldwide. These drugs are given to lessen inflammation by interfering with a biologic substance called TNF that cause or worsen inflammation.
Patients should talk to their rheumatologists to determine their best course of treatment.
The American College of Rheumatology is an international professional medical society that represents more than 8,000 rheumatologists and rheumatology health professionals around the world. Its mission is to advance rheumatology. The ACR/ARHP Annual Scientific Meeting is the premier meeting in rheumatology. For more information about the meeting, visit www.rheumatology.org/education or join the conversation on Twitter by using the official hashtag: #ACR2010.
Editor’s Notes: Richard C. Chou, MD, PhD will present this research during the ACR Annual Scientific Meeting at the Georgia World Congress Center at 2:30 PM on Monday, November 8 in Room A411. Dr. Chou will be available for media questions and briefing at 1:30 PM on Tuesday, November 9 in the on-site press conference room, B 212.
Presentation Number: 640
Tumor Necrosis Factor Inhibition Reduces the Incidence of Alzheimer’s Disease in Rheumatoid Arthritis Patients
Richard C Chou, MD, PhD (Section of Rheumatology, Dartmouth-Hitchcock Medical Center and Dartmouth Medical School, Lebanon, NH)
Michael A Kane, MD (Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital and Massachusetts Institute of Technology, Boston, MA)
Sanjay Ghimire, MD (Verisk Health, Waltham, MA)
Shiva Gautam, PhD (Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA)
Body: Objective: To investigate the relationship between different rheumatoid arthritis treatments and Alzheimer’s dementia
Background: A complication of chronic inflammation in rheumatoid arthritis (RA) is the deposition of amyloid proteins, resulting in secondary amyloidosis. Alzheimer’s dementia (AD) is associated with the local deposition of beta-amyloid peptide in the brain, although the pathogenetic mechanisms of AD are unclear. The relationship between RA and AD has not been established.
Design/Methods: We reviewed medical and pharmacy claims data from January 2000 to November 2007 for a commercially insured cohort of 8.5 million adults throughout the US. We derived a subcohort of 42,193 patients with a pre-existing diagnosis of RA. In this subcohort, we conducted a nested case-control study of the incidence of AD. We excluded individuals with psoriatic arthritis, inflammatory bowel disease, previous stroke or previous AD. For each individual with newly diagnosed AD (cases) we matched up to 10 controls who did not have a prior diagnosis of AD and were free of AD during the exposure assessment period. Matching criteria included age, gender, duration of exposure assessment period and methotrexate treatment. We examined exposure to sulfasalazine, prednisone, three anti-tumor necrosis factor (TNF) agents (infliximab, etanercept, adalimumab) and rituximab.
Results: In this nested case-control study, a total of 165 patients with AD (cases) were matched to 1,383 controls without AD. Treatment with anti-TNF agents in RA was associated with lower risk for incident AD [adjusted odds ratio (OR) 0.440; 95% confidence interval (CI) 0.223-0.868; p=0. 0178). The risk of AD was not affected by exposure to sulfasalazine, prednisone or rituximab. The results were similar [adjusted OR 0.448; 95% CI 0.225-0.892; p = 0.0222) after adjustment for covariates, including hypertension, hyperlipidemia, diabetes mellitus, peripheral vascular disease, and coronary artery disease.
Conclusion: In this population of adults with RA, we observed that the risk of AD was reduced by TNF inhibitor therapy, but not by other disease modifying agents used for treatment of RA. Tumor necrosis factor may be an important component in the pathogenesis of AD.
Disclosure: Richard Chou, nothing to disclose; Michael Kane, Verisk Health: Consulting fees; Shiva Gautama, nothing to disclose, Sanjay Ghirmire, Verisk Health: Employment (full or part-time).
Welcome to the INR Blog!
This Blog is still in development. The aim of this blog is to add further scientific information to the content of the INR website as soon as it becomes available. If possible in the future postings and comments from website visitors will be enabled. Thank you for your interest.
Edward Tobinick MD
Recent published research results:
Anti-TNF-alpha reduces amyloid plaques and tau phosphorylation and induces CD11c-positive dendritic-like cell in the APP/PS1 transgenic mouse brains. Shi JQ, Shen W, Chen J, Wang BR, Zhong LL, Zhu YW, Zhu HQ, Zhang QQ, Zhang YD, Xu J. Brain Res. 2010 Oct 21.
Inflammation plays an important role in the pathogenesis of Alzheimer’s disease (AD). Overexpression of tumor necrosis factor-alpha (TNF-alpha) occurs in the AD brain. Recent clinical studies have shown that the anti-TNF-alpha therapy improves cognition function of AD patients rapidly. However, the underlying mechanism remains elusive. The present study investigates the effects of intracerebroventricular injection of the monoclonal TNF-alpha antibody, Infliximab, on the pathological features of AD in the APP/PS1 double transgenic mice. We found that Infliximab administration reduced the levels of TNF-alpha, amyloid plaques and tau phosphorylation as early as three days after daily injection of 150micrograms of Infliximab for three days. The number of CD11c-positive dendritic-like cells and the expression of CD11c were found to be increased concurrently after Infliximab injection. These data suggested that the CD11c-positive dendritic-like cells might contribute to the Infliximab-induced reduction of AD-like pathology. Further, our results support the use of anti-TNF-alpha for the treatment of AD.
Copyright © 2010. Published by Elsevier B.V.
Therapeutic evaluation of etanercept in a model of traumatic brain injury. Chio CC, Lin JW, Chang MW, Wang CC, Kuo JR, Yang CZ, Chang CP. J Neurochem. 2010 Nov;115(4):921-9. doi: 10.1111/j.1471-4159.2010.06969.x. Epub 2010 Sep 28.
J. Neurochem. (2010) 115, 921-929. ABSTRACT: Antagonism of tumor necrosis factor-alpha with etanercept has proved to be effective in the treatment of spinal cord injury and centrally endotoxin-induced brain injury. However, etanercept may offer promise as therapy for traumatic brain injury (TBI). In this study, anesthetized rats, immediately after the onset of TBI, were divided into two major groups and given the vehicle solution (1mL/kg of body weight) or etanercept (5mg/kg of body weight) intraperitoneally once per 12h for consecutive 3?days. Etanercept caused attenuation of TBI-induced cerebral ischemia (e.g., increased cellular levels of glutamate and lactate-to-pyruvate ratio), damage (e.g., increased cellular levels of glycerol) and contusion and motor and cognitive function deficits. TBI-induced neuronal apoptosis (e.g., increased numbers of terminal deoxynucleotidyl transferase ?UTP nick-end labeling and neuronal-specific nuclear protein double-positive cells), glial apoptosis (e.g., increased numbers of terminal deoxynucleotidyl transferase UTP nick-end labeling and glial fibrillary acidic protein double-positive cells), astrocytic (e.g., increased numbers of glial fibrillary acidic protein positive cells) and microglial (e.g., increased numbers of ionized calcium-binding adapter molecule 1-positive cells) activation and activated inflammation (e.g., increased levels of tumor necrosis factor-alpha, interleukin-1? and interleukin-6) were all significantly reduced by etanercept treatment. These findings suggest that etanercept may improve outcomes of TBI by penetrating into the cerebrospinal fluid in rats. © 2010 The Authors. Journal of Neurochemistry © 2010 International Society for Neurochemistry.
An association study of 21 potential Alzheimer’s disease risk genes in a Finnish population. Sarajärvi T, Helisalmi S, Antikainen L, Mäkinen P, Koivisto AM, Herukka SK, Haapasalo A, Soininen H, Hiltunen M. J Alzheimers Dis. 2010;21(3):763-7.
Alzheimer’s disease (AD) is a genetically complex disorder encompassing several individual susceptibility genes with low risk effects. To assess the risk gene effects in a cohort consisting of 1300 Finnish AD patients and controls, 21 candidate gene polymorphisms were selected for genotyping on the basis of the meta-analyses retrieved from the AlzGene database. A significant genotype and allele association with AD was observed with rs1800629 in the tumor necrosis factor-alpha (TNF). Risk analysis revealed a protective effect for the minor allele carriers of rs1800629. This suggests that genetic alteration in TNF gene may play a role in AD.
Higher Serum sTNFR1 Level Predicts Conversion from Mild Cognitive Impairment to Alzheimer’s Disease. Diniz BS, Teixeira AL, Ojopi EB, Talib LL, Mendonça VA, Gattaz WF, Forlenza OV. J Alzheimers Dis. 2010 Oct 7.
The activation of inflammatory cascades has been consistently demonstrated in the pathophysiology of Alzheimer’s disease (AD). Among several putative neuroinflammatory mechanisms, the tumor necrosis factor alpha (TNF-alpha) signaling system has a central role in this process. Recent evidence indicates that the abnormal production of inflammatory factors may accompany the progression from mild cognitive impairment (MCI) to dementia. We aimed to examine serum levels of TNFalpha and its soluble receptors (sTNFR1 and sTNFR2) in patients with MCI and AD as compared to cognitively unimpaired elderly subjects. We further aimed to investigate whether abnormal levels of these cytokines predict the progression from MCI to AD upon follow-up. We utilized cross-sectional determination of serum levels of TNF-alpha, sTNFR1, and sTNFR2 (ELISA method) in a test group comprising 167 older adults (31 AD, 72 MCI, and 64 healthy controls), and longitudinal reassessment of clinical status after 18.9 ± 10.0 months. At baseline, there were no statistically significant differences in serum TNF-alpha, sTNFR1, and sTNFR2 between patients with MCI and AD as compared to controls. Nevertheless, patients with MCI who progressed to AD had significantly higher serum sTNFR1 levels as opposed to patients who retained the diagnosis of MCI upon follow-up (p=0.03). Cox regression analysis showed that high serum sTNFR1 levels predicted the conversion from MCI to AD (p=0.003), whereas no significant differences were found with respect to serum levels of TNF-alpha and sTNFR2. Abnormal activation of TNF-alpha signaling system, represented by increased expression of sTNFR1, is associated with a higher risk of progression from MCI to AD.