New study identifies two proteins that may contribute to stroke recurrence

EXACTLY WHOM is going to do the followup research? Since there is NO leadership in stroke; NOTHING WILL BE DONE!

New study identifies two proteins that may contribute to stroke recurrence 

The study discovered genetic markers in inflammation that may be related to a second stroke or other major cardiovascular event following a stroke. These findings could help identify drug targets to mitigate stroke-related disability and mortality.

Peer-Reviewed Publication

Boston University School of Public Health

EMBARGOED UNTIL 2 p.m. Monday, July 22, 2024

Contact:

Jillian McKoy ,jpmckoy@bu.edu

Michael Saunders, msaunder@bu.edu

Jarka Meleszkiewicz, jarka.meleszkiewicz@bristol.ac.uk

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New Study Identifies Two Proteins That May Contribute to Stroke Recurrence

The study discovered genetic markers in inflammation that may be related to a second stroke or other major cardiovascular event following a stroke. These findings could help identify drug targets to mitigate stroke-related disability and mortality.

People who experience an arterial ischemic stroke (AIS) or transient ischemic stroke (TIA) are at an increased risk of suffering a second stroke or other major adverse cardiovascular event (MACE), making it critically important to identify risk factors and treatments to prevent these subsequent occurrences. 

A new study led by Boston University School of Public Health (BUSPH), the National Institute for Health and Care Research (NIHR) Bristol Biomedical Research Centre (Bristol BRC), and Veteran’s Affairs Boston Healthcare System (VA Boston), has identified new genetic and molecular risk factors that may reveal new pathways for treating patients after they experience their first stroke.

Published in Stroke, a journal of the American Heart Association, the study identified CCL27 and TNFRSF14, two proteins that are associated with subsequent MACE, but not initial strokes. These proteins are known to activate inflammation, which plays a key role in the development of strokes and many chronic conditions and diseases. The findings suggest that inflammation is a contributing factor to MACE outcomes among people after they have their first stroke.

“While previous studies have found associations between inflammation and incident AIS/MACE, our study found that these causal proteins may also have a role in subsequent MACE, which could lead to potential novel drug targets,” says study co-lead author Nimish Adhikari, a PhD student in biostatistics at BUSPH and VA Boston. The study was also co-led by Andrew Elmore, senior research associate in health data science at NIHR Bristol BRC. 

Utilizing genetic information and medical history data from two large biobanks, the VA’s Million Veteran Program and UK Biobank, the research team conducted ancestry-specific genome-wide association studies (GWAS) to find associations between DNA and incident and subsequent AIS and MACE. 

GWAS are typically performed to determine whether individuals have had a medical event for the first time, but applying this method to subsequent MACE events could shed novel insights about stroke progression, information that would be valuable for therapeutic drug identification, the researchers say. 

In total, the researchers examined 93,422 individuals who had an incident stroke, among which 51,929 had subsequent MACE and 45,120 had subsequent AIS. 

In population specific analyses, they observed two significant genetic variants: rs76472767, near gene RNF220 on chromosome 1 in the African ancestry GWAS for subsequent MACE, and rs13294166, near gene LINC01492 on chromosome 9 in the same ancestry GWAS for subsequent AIS.

“We used that data to find if there were certain molecules that were associated with either incident or subsequent states,” says Elmore. “From that, we were able to identify a link between certain molecules that play a part in inflammation and these stroke and MACE outcomes.” 

While the prevalence of stroke has declined worldwide over the last three decades, it is still the second-leading cause of death and third-leading cause of disability across the globe, and it remains a significant public health issue. Stroke also continues to disproportionately affect populations among racial, ethnic, socioeconomic, and geographical lines, furthering health inequities in both high- and low-income countries. Identifying novel drug targets for new therapeutic interventions that thwart stroke progression could save millions of people from experiencing stroke-related disability and mortality.

It’s unknown if targeting other modifiable risk factors for stroke could also offer pathways for effective treatment after someone experiences their first stroke.

“We are looking forward to extending this research to other cardiometabolic outcomes beyond stroke,” says co-senior and corresponding author Gina Peloso, associate professor of biostatistics at BUSPH.

Lavinia Paternoster, associate professor in genetic epidemiology at NIHR Bristol BRC and Bristol Medical School, and Kelly Cho, director of data science and analytics at the division of population health and data science, VA Boston Healthcare System and associate professor of medicine at Mass General Brigham, Harvard Medical School, are also co-senior authors.

Randomized controlled trial validating the use of perispinal etanercept to reduce post-stroke disability has wide-ranging implications

Prior to this research I was extremely antagonistic towards Dr. Edward Tobinicks' use of this method. All he did was provide videos with no factual context and it seemed like a scam to pick money out of survivors pockets.  So we finally have some RCTs that look promising.

Randomized controlled trial validating the use of perispinal etanercept to reduce post-stroke disability has wide-ranging implications

Ian A Clark

Pages 203-205 | Received 13 Jan 2020, Accepted 05 Feb 2020, Accepted author version posted online: 06 Feb 2020, Published online: 13 Feb 2020

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• https://doi.org/10.1080/14737175.2020.1727742
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In this article

• ABSTRACT
• 1. Relevance of TNF
• 2. The novel perispinal route of administration
• 3. Unusual delay in an RTC testing perispinal etanercept
• 4. Validation of perispinal etanercept technique in a randomized controlled trial
• 5. Wider ramifications of this RCT
• 6. Five-year view
• Additional information
• References

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ABSTRACT

Developing effective drug treatments for neurodegenerative disorders has always been hamstrung by the accepted inability of large molecules (roughly those with a molecular weight greater than 600 Daltons) to cross the blood-brain barrier (BBB) in therapeutic quantities when administered systemically. The dogma has been that a simple, noninvasive way to accomplish this goal is not possible with many agents, including biologicals, because they are too large. Various novel technologies to breach the BBB have been attempted, but with little success. A randomized double-blind, placebo-controlled clinical trial (RCT) administering a widely used anti-tumor necrosis factor (TNF) biological, etanercept, given via perispinal injection, which bypasses the BBB, turns this dogma on its head. This new trial holds much promise for stroke survivors, as well as having implications for developing treatments based on other large molecules for this and other brain disorders.

KEYWORDS:

• Blood-brain barrier
• etanercept
• double-blind controlled trial
• perispinal route of administration
• post-stroke therapy
• TNF

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1. Relevance of TNF

The polypeptide tumor necrosis factor (TNF), first described in the mid 1970s, has proved to be an extremely pleiotropic cytokine that has a central role in physiology, pathology, and the innate immune system in organisms ranging from corals to humans. At physiological levels, it is an important and widespread signaling molecule. Once TNF had been appreciated to be generated and act in the brain as well as elsewhere, it proved to be a multifunction gliotransmitter that caused trouble if generated excessively.

2. The novel perispinal route of administration

The Key Paper discussed here [1] employs perispinal delivery of etanercept, a biological agent widely used to treat chronic systemic inflammatory disease, to address post-stroke syndromes. The outcome is discussed below. Etanercept acts through potently and specifically neutralizing TNF. Edward Tobinick, whose extensive collection of published observational studies over a decade this trial formally tests, published an extended review on perispinal etanercept delivery to the brain in Expert Review of Neurotherapeutics in 2010 [2] and an update elsewhere six years later [3]. Parenthetically, it should be noted that the term perispinal had sometimes been used in the 1970s as a regional anatomical term [4], which is quite different to its precise usage here [3]. With much attention being drawn to this cytokine’s roles in chronic degenerative disease in the central nervous system, as well as its central involvement in disease pathogenesis generally (see [5,6] and [7] for reviews), any excess generation of it is an obvious therapeutic target. The challenge is how to get enough of these large TNF-neutralizing molecules through or past the BBB into the brain, where studies employing intracerebroventricular injections in mice over the years had demonstrated activity. Over 15 years ago Tobinick farsightedly addressed this challenge. Equipped with intimate knowledge of the anatomy and physiology of a long-forgotten venous system, he reasoned that it plausibly constituted a direct vascular route for drug delivery to the brain [8]. In this publication he used the term ‘cerebrospinal venous system’ (CSVS) to describe these vessels. In the same year (2006) Tobinick and colleagues reported the effects of perispinally injected etanercept followed by Trendelenburg positioning in a six-month open trial in Alzheimer’s disease [9]. The results were very promising, but by 2008 both of the Big Pharmas who had earlier acquired the etanercept patent inexplicably refused to discuss furthering the perispinal approach or funding the trials needed to achieve regulatory approval.

Years earlier, during aviation medicine research into the effects of negative gravity in rabbits, Wen and coworkers had demonstrated that head-down positioning for a short period made the blood-cerebrospinal fluid (CSF) barrier permeable to plasma albumin [10]. Mindful of this, in 2009 Tobinick and colleagues from Stanford demonstrated, in a rat model, that perispinal injection of radiolabelled etanercept, followed by head-down (Trendelenburg positioning), enabled it to rapidly reach the choroid plexus and the CSF within the cerebral ventricles [11]. This was consistent with Wen’s report with albumin, despite etanercept being a larger molecule (150,000 vs. 66,000 Daltons). Delivery of a labeled anti-TNF molecule via perispinal injection to the choroid plexus plus head-down positioning has recently been confirmed in an additional rat model [12].

In addition, collections of observational studies using this perispinal method of delivering etanercept to the brain, beginning in 2010, have reported impressive outcomes in treating post-stroke neurological dysfunction in many patients [13–17]. To summarize a recent text [12] that illustrates and quotes additional anatomical detail, perispinal injection followed by a short period of head-down positioning [10] may therefore be expected to enable etanercept to be delivered to the brain through the choroid plexus, the cerebral venous system, and the cerebrospinal fluid, thus bypassing the BBB. Such a route is consistent with the reported presence of labeled etanercept within the brain in experimental studies [11,12].

3. Unusual delay in an RTC testing perispinal etanercept

Unfortunately, a clinical trial of these promising observational studies continued to be delayed for over a decade. In the course of much favorable off-label treatment of post-stroke patients, many independent observers, from 2011 to the present, including non-neurological medical practitioners, nurses, speech pathologists, and neuroscientists, have witnessed this negligibly invasive treatment technique and its outcome in post-stroke patients. When faced with a striking mix of rapid onset, effectiveness, and persistence of outcome in an important circumstance where the usefulness of present treatments is very low, a common conclusion by these observers has been that this novel approach warrants an independent RCT. Nevertheless, the American Academy of Neurology (AAN), despite no member of its governing board having witnessed the treatment, or having addressed the science behind it, continues to display an on-line Clinical Advisory that explicitly discourages its members, and indeed any neurologist who reads it, from any association with this approach. In effect, the AAN fell in line behind the Big Pharma patent owners. Their position continues unchanged, despite the validity of the AAN’s actions being questioned in an editorial some years ago in Expert Review of Neurotherapeutics [18] and the publication of additional supportive evidence [19,20]. Thus almost all neurologists, following the AAN’s advice, have ignored invitations to observe or engage in this work, thereby establishing, for years, a quite unjustified barrier to clinical translation of the perispinal method, with its potential for wide application in disease and research.

4. Validation of perispinal etanercept technique in a randomized controlled trial

This bottleneck has now been overcome by a clinical trial outside the US funded by the community-based Stroke Recovery Trial Fund (https://strokerecoverytrialfund.org), a national health promotion charity formed by Dr Coralie Graham in 2015 in Queensland, Australia, and funded by individual donations from the public, to compensate for AAN and Pharma intransigence. The first publication arising from the funding of this organization is a modestly-sized university-conducted randomized, placebo-controlled, double-blind trial of perispinal etanercept for chronic intractable central post-stroke pain [1]. This condition is notoriously difficult to treat and its unmet medical need is substantial. The trial subjects were selected for having had, among their symptoms, unrelenting central post-stroke pain for an average of more than 4 years. Approval of the study was obtained from the Griffith University Human Research Ethics committee (MSC/10/14/HREC).

Results were consistent with the previously published observational studies, in that shoulder flexion and pain attenuation demonstrated statistically significant improvements in study participants receiving perispinal etanercept compared to the placebo control. Indeed, in an appreciable percentage of those receiving perispinal etanercept, despite their history of years of daily intractable pain, there was rapid (within 30 minutes) and often nearly complete pain abatement, whereas no change occurred in the saline control group with the same pain. This outcome is remarkable, and quite unmatched by any present therapeutic approach for post-stroke pain. From the limited trial duration it was possible to fund, this relief lasted for at least 30 days. In addition, 90% of the etanercept group, but none of the placebo group, showed highly significant rapid enhancements in both active and passive shoulder flexion range of movement, indicating less spasticity of arm muscles. The effect was clear cut (p = 0.003) after the first treatment and more so (p = 0.001) after the second, 14 days later. A dose response such as this, Bradford-Hill’s ‘biological gradient’, is one of the standard causation indicators.

Clearly, the larger trials necessary for regulatory approval are a pressing need. The rapidity and unprecedented nature of outcomes in patients achieved by perispinal delivery of etanercept in this initial trial is especially notable. This indicates a direct effect of etanercept on the brain following its perispinal injection, and is consistent with the location of labeled etanercept within the brain in animal models after perispinal delivery [11,12].

5. Wider ramifications of this RCT

Moreover, since this trial was the first RCT testing of perispinal administration of any agent, other therapeutics aspiring to access the brain might well benefit from its further validation. An example is the novel experimental anti-TNF therapeutic, XPro1595, an engineered dominant negative inhibitor of TNF [21]. Unfortunately, as with etanercept, its size greatly retards brain entry, with about one-thousandth of the concentration attained in the plasma after peripheral injection being detected in the cerebrospinal fluid [22]. Given the outcome of the present RCT, XPro1595 may be most effective in human brain disease if also administered perispinally to bypass the BBB. Once proven safe and effective in humans, its unique characteristics [23] may give XPro1595 an advantage over etanercept, when frequent administration is required, of allowing the TNF-dependent innate immune system to keep latent Mycobacterium tuberculosis suppressed. Even so, regular testing for evidence of this organism has allowed regular subcutaneous etanercept to thrive as a treatment of rheumatoid arthritis, where the dose is much higher that was used in the RCT under discussion here. Much off-label experience indicates that only one or two doses of perispinal etanercept, and therefore predictably its biosimilars, are required to treat a number of acquired brain injury states, including stroke.

6. Five-year view

The tantalizing prospect now emerges of perispinal delivery revolutionizing the treatment of a range of brain disorders, including the neurodegenerative states, by enabling effective brain delivery of not only etanercept, but also other large molecules. This includes other biologicals, but the principle is open ended. Regulatory approval of perispinal etanercept will, through widely utilizing the perispinal route in science, broaden the research base of chronic neurodegenerative states, and other cerebral conditions, such as brain cancer.

Article highlights

• The blood-brain barrier has effectively excluded the brain from much of the biotech revolution. Much research has attempted to clear this roadblock, but without success to date.

• Perispinally injected etanercept, which involves injecting this anti-TNF biological into the cerebrospinal venous system before a short period of head-down tilt, has been commonly used by the originator of the technique since 2011 to treat post-stroke syndromes. Without witnessing the treatment, the Big Pharma owners of the patent for etanercept and the American Academy of Neurology have actively discouraged a trial.

• Funding from the Australia public has made possible the first formal controlled trial of perispinal etanercept on post-stroke patients. Within the goals set, the outcome was statistically significant, often markedly so.

• If confirmed in larger trials, this technique will likely have widespread usefulness in getting larger pharmaceuticals, particularly biologicals, into the brain in many different brain disease states, including cancer.

Is Alzheimer's Risk Lower With TNF Inhibitors?

 You'll want your doctor following this.

Is Alzheimer's Risk Lower With TNF Inhibitors?

For arthritis patients with cardiovascular disease, the answer may be yes

by Judy George, Senior Staff Writer, MedPage Today April 8, 2022

Tumor necrosis factor (TNF) inhibitors for rheumatoid arthritis were linked with a lower risk of Alzheimer's disease and related dementia, but only in people with cardiovascular disease, data from the DREAM (Drug Repurposing for Effective Alzheimer's Medicines) study showed.

Among more than 22,000 older adults, targeted disease-modifying antirheumatic drugs overall were not associated with a reduced risk of Alzheimer's disease and dementia, reported Rishi Desai, PhD, of Brigham and Women's Hospital and Harvard Medical School in Boston, and co-authors.

However, a subgroup of people with cardiovascular disease whose arthritis was treated with TNF inhibitors showed a potentially lower risk of Alzheimer's and dementia, the researchers reported in JAMA Network Open.

Other research has suggested that anti-TNF drugs may reduce Alzheimer's risk. "TNF-alpha is a key mediator of inflammation," co-author Madhav Thambisetty, MD, PhD, of the NIH National Institute on Aging, told MedPage Today. "The links between higher levels of inflammation and both cardiovascular disease and Alzheimer's disease are well known."

"Our findings from the DREAM study suggest that in some rheumatoid arthritis patients with co-existing heart disease, TNF-alpha inhibitors may lower the risk of incident Alzheimer's disease," Thambisetty said. "These results are especially significant given a recent large genome-wide association study suggesting that genetic variants related to TNF-alpha signaling may be causally linked to Alzheimer's."

"The molecular mechanisms underlying these findings remain to be identified, although accumulating evidence suggests that targeting systemic or peripheral inflammation in subgroups of patients who might benefit the most may be a promising approach to disease modification," he added.

In the DREAM study, cytokine signaling, including TNF and interleukin (IL)-6 through the Janus kinase (JAK)-signal transducer and activator of transcription pathway, was hypothesized to modify the risk of Alzheimer's disease and related dementia.

Desai and co-authors evaluated 22,569 propensity score-matched pairs among Medicare fee-for-service rheumatoid arthritis patients ages 65 and older from 2007 to 2017. The researchers grouped patients into three cohorts based on initiation of the JAK inhibitor tofacitinib (Xeljanz), the IL-6 inhibitor tocilizumab (Actemra), or TNF inhibitors, assessing them against a common comparator, the T-cell activation inhibitor abatacept (Orencia).

The main outcome was onset of Alzheimer's and related dementia based on diagnosis codes. The researchers evaluated 4,224 tofacitinib pairs (mean age 72, 82% women), 6,369 tocilizumab pairs (mean age 72, 79% women), and 11,976 TNF inhibitor pairs (mean age 73, 82% women). Diabetes and hypertension were common in all three cohorts.

There were no statistically significant associations overall between incident Alzheimer's and dementia with tofacitinib, tocilizumab, or TNF inhibitors, compared with abatacept.

Subgroup analyses by age, sex, and baseline cardiovascular disease showed results consistent with the main analyses, except for patients with cardiovascular disease on TNF inhibitors. For these patients, point estimates indicated a lower incidence of Alzheimer's and dementia in two analyses: one incorporating a 6-month induction period (HR 0.74, 95% CI 0.56-0.99) and one that combined symptomatic prescriptions and diagnosis codes to identify Alzheimer's and dementia (HR 0.45, 95% CI 0.21-0.98).

"One key hypothesis that merits testing in future studies is that these patients may have significantly perturbed TNF-alpha signaling at baseline, and that correcting these abnormalities by TNF-alpha inhibitors mediates the protective effect on Alzheimer's disease," Thambisetty observed.

The study had several limitations, the researchers noted. Outcomes were small for tofacitinib and tocilizumab, partly owing to short mean follow-up duration. In addition, the pathogenesis of Alzheimer's and dementia may begin many years before a clinical diagnosis, and longer treatment or observation periods may be needed to draw firmer conclusions.

The findings about TNF inhibitors highlight why precision medicine may be important, Thambisetty pointed out. "A one-size-fits-all approach to treating and preventing Alzheimer's is unlikely to be as effective as identifying particular risk profiles of patients who may benefit from specific drugs to lower their risk of Alzheimer's disease," he said.

"In an ongoing study called PREVENT-AD, we are studying candidate Alzheimer's treatments such as TNF-alpha inhibitors to better understand their mechanisms of action relevant to Alzheimer's disease," he added. "These studies involve experimental validation in cell culture-based phenotypic screens, as well as experimental studies in relevant transgenic animal models of Alzheimer's."

• Judy George covers neurology and neuroscience news for MedPage Today, writing about brain aging, Alzheimer’s, dementia, MS, rare diseases, epilepsy, autism, headache, stroke, Parkinson’s, ALS, concussion, CTE, sleep, pain, and more. Follow

Disclosures

The Drug Repurposing for Effective Alzheimer Medicines (DREAM) study is funded by the NIH's National Institute on Aging.

Desai reported receiving grants from Bayer, Novartis, and Vertex. Co-authors reported relationships with Bristol Myers Squibb, Merck, Pfizer, Lilly, IntraCellular Therapies, Eisai, Alkermes, NIH, Patient-Centered Outcomes Research Institute, Altarum Institute, Arnold Foundation, FDA, American College of Physicians, Sanofi, Childhood Arthritis and Rheumatology Research Alliance, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Center for Advancing Translational Sciences, American College of Rheumatology, AbbVie, Roche, Boehringer Ingelheim, and Aetion.

Primary Source

JAMA Network Open

Source Reference: Desai RJ, et al "Comparative risk of Alzheimer disease and related dementia among Medicare beneficiaries with rheumatoid arthritis treated with targeted disease-modifying antirheumatic agents" JAMA Netw Open 2022; DOI: 10.1001/jamanetworkopen.2022.6567.

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Anti-TNF and CNS Events: The Link Strengthens

If you are thinking of doing the (INR - Institute of Neurological Recovery)Dr. Tobinick etanercept(Enbrel) injection you need to know of this risk.  But I  know nothing since I'm not medically trained, don't listen to me, make your own decision based on all factors.

Etanercept is a tumor necrosis factor (TNF) blocker that is used in adults to prevent joint damage caused by rheumatoid arthritis, psoriatic arthritis, or ankylosing spondylitis.

Anti-TNF and CNS Events: The Link Strengthens

— Three-fold higher risk of inflammatory CNS adverse events in autoimmune diseases treated with TNF inhibitors

by Nancy Walsh, Contributing Writer, MedPage Today May 18, 2020

Patients with autoimmune diseases who were treated with tumor necrosis factor (TNF) inhibitors had an increased risk of developing inflammatory central nervous system (CNS) adverse events, a nested case-control study found.
Among patients with diseases such as rheumatoid arthritis (RA), psoriasis, and ulcerative colitis who were exposed to TNF inhibitors, there was a three-fold increased risk of any inflammatory CNS event in the study's primary analysis, with an adjusted odds ratio of 3.01 (95% CI 1.55-5.82, P=0.001), according to Andrew McKeon, MD, of the Mayo Clinic in Rochester, Minnesota, and colleagues.
And the risk was almost five-fold higher among the subgroup of patients with RA specifically, with an adjusted OR of 4.82 (95% CI 1.62-14.36, P=0.005), the researchers reported in JAMA Neurology.
A link between TNF inhibitors and demyelinating CNS events(not good, this is the multiple sclerosis problem) has been suspected since shortly after those agents became available more than 20 years ago. These events included multiple sclerosis (MS), optic neuritis, transverse myelitis, and neuromyelitis optica spectrum disorder. In a Spanish registry, there have been 740 reports of demyelinating events, 254 of which were MS, and 358 cases of optic neuritis.
There also have been reports of inflammatory nondemyelinating CNS events such as neurosarcoidosis and CNS vasculitis, although less is known about these events.
To explore these potential associations in a large population, McKeon and colleagues examined the electronic health record system of the Mayo Clinic's three locations (Rochester; Scottsdale, Arizona; and Jacksonville, Florida) for the years 2003 to 2019.
The study population included more than 32,000 patients who had been diagnosed with RA, psoriasis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, or ulcerative colitis, and who had been treated with any disease-modifying therapy. They identified 106 patients who developed CNS events, matching them with 106 controls who had the same autoimmune diseases but without CNS events.
Two-thirds of the patients were women. Median age was 36 at the onset of the autoimmune disease for patients and 35 for controls, and median disease duration was 12 years for patients and 13 years for controls. The most common diagnosis was RA in 45%.
Inflammatory demyelinating events developed in 56 patients, with most being MS, and inflammatory nondemyelinating events such as aseptic meningitis, CNS vasculitis, and idiopathic leptomeningitis were reported in 50.
Among the 106 patients who developed CNS events, 60% had been exposed to any of the available TNF inhibitors, which were etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), golimumab (Simponi), and certolizumab pegol (Cimzia). Among the control group, 40% had received anti-TNF treatment.
Among the patients who had demyelinating events, 70% had anti-TNF exposure compared with 50% of controls, while of those who had nondemyelinating events, 50% of patients were exposed compared with 28% of controls.
When the analysis was stratified according to the type of CNS event, similar results were seen as in the primary analysis:

• Inflammatory demyelinating CNS events: adjusted OR 3.09 (95% CI 1.19-8.04, P=0.02)
• Inflammatory nondemyelinating CNS events: adjusted OR 2.97 (95% CI 1.15-7.65, P=0.02)

Unlike the RA subgroup, a pooled analysis of patients with ankylosing spondylitis, psoriasis, psoriatic arthritis, Crohn's disease, and ulcerative colitis found no significant risk of inflammatory CNS events (OR 2.13, 95% CI 0.90-5.05, P=0.09).
In 90% of patients who developed the neurologic symptoms, anti-TNF exposure took place within 1 year of the symptom onset, suggesting a temporal association, the researchers noted.
"We hypothesized that TNF inhibitors may further dysregulate already aberrant immune responses, triggering inflammatory CNS events in patients with certain autoimmune diseases," they wrote.
The TNF cytokine has multiple functions ranging from immune regulation to inhibition of tumor cells and defense against pathogens. "Proposed mechanisms for the paradoxical development of inflammatory CNS events in association with TNF inhibitor exposure include immune dysregulation from the inhibition of apoptosis of autoreactive T cells, which may then enter the CNS and cause demyelination," they explained.
They also emphasized that the TNF inhibitors are highly effective therapies for these diseases, and the CNS events are uncommon, and also acknowledged that their study does not imply causality.
"Further research is needed to explore whether this association indicates de novo inflammation or exacerbation of already aberrant inflammatory pathways," they concluded.
In an accompanying editorial, Jeffrey M. Gelfand, MD, and Jinoos Yazdany, MD, of the University of California San Francisco cautioned that "the effect size reported in the study should be interpreted with some caution," because the analysis did not adjust for severity of underlying disease. "It is plausible that individuals with more severe autoimmune diseases were both more likely to receive biological agents such as TNF inhibitors and more prone to develop neuroinflammatory events," the editorialists wrote.
"The next steps should include population-based observational studies that control for disease severity," they wrote.

Last Updated May 18, 2020

Disclosures

The study was funded by the National Center for Advancing Translational Sciences.
The authors disclosed relevant relationships with Biogen, Pfizer, Genentech, AbbVie, Sanofi-Genzyme, Alexion, Viela Bio, Union Chimique Belge, Astellas, Griffols, Autoimmune Encephalitis Alliance, Chugai/Roche, Mitsubishi Tanabe, Novartis, Caladrius, Brainstorm Therapeutics, Roivant, Euroimmun, and Medimmune.

Primary Source

JAMA Neurology

Source Reference: Kunchok A, et al "Association between tumor necrosis factor inhibitor exposure and inflammatory central nervous system events" JAMA Neurol 2020; DOI: 10.1001/jamaneurol.2020.1162.

Secondary Source

JAMA Neurology

Source Reference: Gelfant J, Yazdany J "Risk of neuroinflammatory adverse events with tumor necrosis factor inhibitor treatment" JAMA Neurol 2020; DOI: 10.1001/jamaneurol.2020.1160.

Nanotherapeutics for Gene Modulation that Prevents Apoptosis in the Brain and Fatal Neuroinflammation

Stopping apoptosis and neuroinflammation sounds wonderful for stroke survivors. Now if we only had a stroke leader we could ask to follow this up with translational protocols.
http://www.sciencedirect.com/science/article/pii/S1525001617305075

• Sang-Soo Kim^{1, 3},
• Antonina Rait¹,
• Emilio R. Garrido-Sanabria²,
• Kathleen F. Pirollo¹,
• Joe B. Harford³,
• Esther H. Chang^{1, ,}

 Show more

https://doi.org/10.1016/j.ymthe.2017.10.003

Get rights and content

---

Abstract

The failure of therapeutic agents to cross the blood-brain barrier (BBB) has been a major impediment in the treatment of neurological disorders and brain tumors. We have addressed this issue using an immunoliposome nanocomplex (designated scL) that delivers therapeutic nucleic acids across the BBB into the deep brain via transcytosis mediated by transferrin receptors. We validated brain delivery of payloads after systemic administration by monitoring uptake of fluorescently labeled payloads and by confirming up- or down-modulation of specific target gene expression in the brain, mainly in neuronal cells. As proof of concept for the therapeutic potential of our delivery system, we employed scL delivering an siRNA targeting tumor necrosis factor alpha to suppress neuroinflammation and neuronal apoptosis and to protect mice in lethal endotoxemia triggered by bacterial lipopolysaccharide. Brain delivery of therapeutic payloads via scL has major implications for the development of treatments for neurological disorders and brain tumors.

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Corresponding author Esther H Chang, Department of Oncology, Georgetown University Medical Center, Lombardi Comprehensive Cancer Center, 3970 Reservoir Rd NW, TRB/E420, Washington, DC 20057-1468, USA. Phone: 202-687-8418, Fax: 202-687-8434.

New function of MK2 in protecting cells from the cytotoxic effect of TNF

But is this other blocking of TNF better?

Developing drugs to reduce brain impairment after stroke -CAL-101 to block TNF December 2015.

  The latest here:

New function of MK2 in protecting cells from the cytotoxic effect of TNF

29 September 2017 Ghent University

Identification of a novel cell death checkpoint in the TNF signalling pathway
The group of Prof. Mathieu Bertrand (VIB/UGent) reveals a new function of MK2 in protecting cells from the cytotoxic effect of TNF.
Tumor necrosis factor (TNF) is a proinflammatory cytokine that plays a very important role in orchestrating the immune response. Nevertheless, inappropriate signalling by TNF can also be detrimental and implicated in a variety of human inflammatory diseases, such as rheumatoid arthritis, inflammatory bowel disease and psoriasis. The pathogenic role of TNF in inflammatory conditions has long been thought to result from the ability of TNF to induce expression of a wide panel of proinflammatory mediators, but more recent studies have demonstrated that binding of TNF to its cognate receptor also promotes inflammation by inducing cell death, in the form of apoptosis and necrosis. Interfering with cell death induction therefore emerges as a promising therapeutic approach for the treatment of inflammatory conditions.
The research team of Prof. Bertrand (VIB/UGent), in the unit headed by Prof. Vandenabeele, is investigating the molecular mechanisms that protect the cells from death, and which are dysregulated in pathologic conditions. In the current issue of Nature Cell Biology, the group of Prof. Bertrand reveals the existence of a new cell death checkpoint in the TNF pathway. Dondelinger, Delanghe and colleagues show that MK2 protects the cells from death by inactivating the kinase RIPK1 through phosphorylation. Importantly, they show that this protective mechanism is affected in some inflammatory conditions and consequently results in cell death. This cell death can however be completely prevented by pharmacological inhibition of RIPK1.  Together with other studies, this work highlights the promising therapeutic potential of RIPK1 kinase inhibitor for the treatment of inflammatory diseases.
https://www.nature.com/ncb/journal/vaop/ncurrent/full/ncb3608.html

• Full bibliographic information“MK2 phosphorylation of RIPK1 regulates TNF-mediated cell death”
  Dondelinger, Delanghe et al. Nature Cell Biology 2017.

Biomarkers May Help Predict Ischemic Stroke Risk

Anything in here that tests for stiff arteries?  What about for hemorrhagic strokes? 

Biomarkers May Help Predict Ischemic Stroke Risk

Patients with high levels of four blood biomarkers may be more likely to have an ischemic stroke than those with low rates of the markers, researchers reported.
In an observational study, natural logarithmic statistical transformation of markers of inflammatory, endothelial, and oxidative stress – C-reactive protein (CRP), tumor necrosis factor 2 (TNF2), total homocysteine (tHcy), and vascular endothelial growth factor (VEGF) – were each tied to a greater risk of incident ischemic stroke, Ashkan Shoamanesh, MD, of McMaster University, and colleagues reported online in Neurology.
"Identification of persons at high risk of stroke allows for development of targeted interventions to reduce the burden of stroke at the individual and population levels," study co-author Jose Romero, MD, of Boston University, told MedPage Today.
Using the biomarkers also helped better predict the risk of a stroke over the more traditionally used Framingham Stroke Risk Study, Romero said.
However, given that the study was observational, the results don't mean that elevation of these markers causes strokes, "nor do we provide thresholds for clinicians to consider increased risk," Romero noted.
Additionally, while the study doesn't suggest that these markers should be measured routinely in clinical practice, it does shed light on additional markers to identify those at a greater risk of a stroke, he said.
For their study, the researchers measured the levels of 15 biomarkers associated with inflammation in the blood of those from the Framingham Heart Study Offspring Cohort who'd never had a stroke. The 3,224 participants averaged 61 years of age at the study's onset and were observed for an average of nine years. During that period, 98 had a stroke.
In a model adjusted for age and sex, four of the 15 biomarkers were linked to an increased stroke risk, they found:

• CRP: HR 1.28, 95% CI 1.04 to 1.56
• TNFR2: HR 1.33, 95% CI 1.09 to 1.63
• tHcy: HR 1.32, 95% CI 1.11 to 1.58
• VEGF: HR 1.25, 95% CI 1.07 to 1.46

Three of the biomarkers remained significantly associated with stroke risk in a model adjusted for systolic blood pressure, hypertension treatment, current smoking, diabetes, cardiovascular disease, and atrial fibrillation. Only CRP was no longer significant, the researchers said.
Adding the four biomarkers to the Framingham Stroke Risk Profile improved the ability to predict which patients would be at greatest risk for ischemic stroke, they reported.
They also found in exploratory analyses a significant relationship between CRP and a subtype of ischemic stroke: atherosclerotic brain infarction (HR 1.31, 95% CI 1.06 to 1.33). They also saw a relationship between cerebral embolism and both interleukin 6 (HR 1.11, 95% CI 1.06 to 1.33) and fibrinogen (HR 1.40, 95% CI 1.06 to 1.86).
The study was limited by the fact that conditions that may affect vascular and systemic inflammation, such as chronic inflammatory diseases and infections, and long-term use of medications that have anti-inflammatory properties, were unaccounted for. Also, the biomarkers were measured at single time points and not repeated over time, the researchers said.
Deepak Gulati, MD, of the Ohio State University who wasn't involved in the study, called it "preliminary" in terms of establishing any solid evidence of an association between the biomarkers and ischemic stroke, but said it "brings about this important concept that needs to be explored further."
Gulati said that biomarkers must be accurately and reproducibly measurable, clinically feasible, cost effective, and prospectively validated in randomized clinical trials.
"Biomarkers are interesting, but nothing has yet been validated in terms of an ischemic stroke," he said.
Romero said future research could abet the development of "clinically meaningful thresholds" that may be used in practice and the testing of treatments and drugs in clinical trials that incorporate these markers to assess their benefit in treatment decisions for stroke risk reduction.
In an accompanying editorial, Stephen Williams, PhD, of the University of Virginia, and Svetlana Lorenzano, MD, PhD, of Sapienza University in Rome, agreed that the study "helped refine a well-established stroke risk clinical model ... and helped enhance individual stroke risk prediction," but similarly cautioned that it "should be further assessed in prospective investigations."
As of now, added Romero, stroke prevention should continue to focus on the assessment and treatment of modifiable risk factors as suggested by current stroke prevention guidelines.

Neither the researchers nor the editorialists reported any financial relationships with industry.

• Reviewed by Henry A. Solomon, MD, FACP, FACC Clinical Associate Professor, Weill Cornell Medical College

• Primary Source

  Neurology

  Source Reference: Shoamanesh A, et al "Circulating biomarkers and incident ischemic stroke in the Framingham Offspring Study" Neurology 2016; 87: 1-6.

• Secondary Source

  Neurology

  Source Reference: Williams SR, Lorenzano S "Seeking the 'holy grail' of biomarkers to improve stroke risk prediction of clinical scores" Neurology 2016; 87: 1-2.

Frequent Nut Consumption Associated with Less Inflammation

Will your doctor inform you of this and add it to your diet stroke protocol?

Frequent Nut Consumption Associated with Less Inflammation

In a study of more than 5,000 people, investigators from Brigham and Women’s Hospital have found that greater intake of nuts was associated with lower levels of biomarkers of inflammation, a finding that may help explain the health benefits of nuts. The results of the study appear July 27 in the American Journal of Clinical Nutrition.
“Population studies have consistently supported a protective role of nuts against cardiometabolic disorders such as cardiovascular disease and type 2 diabetes, and we know that inflammation is a key process in the development of these diseases,” said corresponding author Ying Bao, MD, ScD, an epidemiologist in BWH’s Channing Division of Network Medicine. “Our new work suggests that nuts may exert their beneficial effects in part by reducing systemic inflammation.”
Previously Bao and her colleagues observed an association between increased nut consumption and reduced risk of major chronic diseases and even death, but few prospective cohort studies had examined the link between nut intake and inflammation. In the current study, the research team performed a cross-sectional analysis of data from the Nurses’ Health Study, which includes more than 120,000 female registered nurses, and from the Health Professionals Follow-Up Study, which includes more than 50,000 male health professionals. The team assessed diet using questionnaires and looked at the levels of certain telltale proteins known as biomarkers in blood samples collected from the study participants. They measured three well-established biomarkers of inflammation: C-reactive protein (CRP), interleukin 6 (IL6) and tumor necrosis factor receptor 2 (TNFR2).
After adjusting for age, medical history, lifestyle and other variables, they found that participants who had consumed five or more servings of nuts per week had lower levels of CRP and IL6 than those who never or almost never ate nuts. In addition, people who substituted three servings per week of nuts in place of red meat, processed meat, eggs or refined grains had significantly lower levels of CRP and IL6.
Peanuts and tree nuts contain a number of healthful components including magnesium, fiber, L-arginine, antioxidants and unsaturated fatty acids such as α-linolenic acid. Researchers have not yet determined which of these components, or if the combination of all of them, may offer protection against inflammation, but Bao and her colleagues are interested in exploring this further through clinical trials that would regulate and monitor diet.
“Much remains unknown about how our diet influences inflammation and, in turn, our risk of disease,” said Bao. “But our study supports an overall healthful role for nuts in the diet and suggests reducing inflammation as a potential mechanism that may help explain the benefits of nuts on cardiometabolic diseases.”
This study was supported by the grants UM1 CA186107, UM1 CA167552, R01 CA49449, U54CA155626, and P30DK046200 from the National Institutes of Health and by a grant from the International Tree Nut Council Nutrition Research & Education Foundation. This work was also conducted with the support of a KL2/Catalyst Medical Research Investigator Training award (an appointed KL2 award) from Harvard Catalyst | The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Award KL2 TR001100).

Brain injury victim's family pushes for AMA to pass controversial new stroke treatment - etanercept

Another anecdotal story on this.  This would be so easy to prove if it works or not. TNF is supposed to be reduced as a result of this treatment. Test TNF levels before and after in a double blinded clinical trial. In my opinion, this is still just pure quackery. Nothing works in just minutes. The placebo response was strong in this one.
http://www.abc.net.au/news/2016-05-23/hopes-ama-will-pass-new-stroke-treatment/7436406
By Elly Bradfield

An Australian family is pushing for a controversial new stroke treatment to be made available in Australia, saying the results have been life-changing for their son.

Key points:

• Off-label use means using a drug outside of its original purpose
• Use of perispinal etanercept for injuries such as Joel's is not approved by the AMA
• Ms Graham is leading a push for the treatment to be available to Australians

After suffering a brain injury as a child, Joel Shepherd was unable to communicate or walk and had constant seizures.
But since receiving the new treatment for strokes in America, a drug called perispinal etanercept, his condition improved dramatically.
Mr Shepherd's mother, Coralie Graham, said up until the treatment her son spent most of his life relying on other people.
"He could walk only if somebody held him up; his speech was very, very poor. His swallowing was poor," she said.
"He had frequent chest infections. His continence was very poor. His concentration was poor. His memory was poor."
Ms Graham said there were not many options for Mr Shepherd.
"We were kind of told 'this is your lot in life, here's your human, go home and deal with it'," she said.
"For 23 years we had basically no hope."
But two years ago Ms Graham saw a TV program on perispinal etanercept.
Entanercept is a drug commonly used to treat arthritis, but American doctor Edward Tobinick developed a new use for the drug.
The perispinal method involves injecting the drug into the spine to enter the vascular system.
"This is a completely different application. We're using it for neurological inflammation, something it was not originally designed for," Dr Tobinick said.

Audio: Listen to Elly Bradfield's report (AM)

The use of the drug for something other than its original purpose is called off-label use.
"All off-label uses begin as something that would be controversial," Dr Tobinick said.
The Australian Medical Association (AMA) has warned there are clinical, safety, ethical, legal and financial risks related to using off-label drugs.
But Ms Graham said as a nurse she was confident in the treatment, and 93 days after hearing about it had mortgaged her house to pay for the trip to America.

Nearly two years since the treatment began, Ms Graham said she would not have it any other way.
"[Joel is] now able to walk unassisted for a fair distance; he chases me sometimes in the park, which he enjoys," she said.
"His cough reflex is back and he's able to swallow. His concentration has improved markedly, his memory has improved."

I remember crying in the room because I was so moved by his treatment response.

Dr Edward Tobinick

Dr Tobinick said Mr Shepherd's story was one he could never forget.
"I remember my initial emotional reaction when I saw Joel improve within minutes — able to tie his shoelaces for the first and then start to walk unassisted," he said.
"It was extremely moving and I remember crying in the room because I was so moved by his treatment response."
Mr Shepherd said it was the simple things that made the most difference to his life.
"Walk, run, talk better, to go to the toilet," he said.
Now Ms Graham is leading a push for the treatment to be made available to Australians.
The delivery method remains untested in Australia.
Griffith University has a clinical trial approved, but it is unfunded.
The group has raised nearly $90,000 of the $250,000 needed and is confident the trial will go ahead.
Ms Graham said with her son's help, she would keep fighting until other families had the same access.

Anti-TNFs(etanercept) in RA: No Link With Stroke

If Dr. Tobinick was really interested in how etanercept worked he would be all over this research and publishing his own articles on etanercept. But I bet he will do nothing on this. You can draw your own conclusion from his lack of clinical trials on his use of etanercept.
http://www.medpagetoday.com/Rheumatology/Arthritis/55798?
Treatment with tumor necrosis factor (TNF) inhibitors was not associated with an increased risk of ischemic stroke in patients with rheumatoid arthritis (RA), a British study found.
Compared with RA patients receiving conventional disease-modifying anti-rheumatic drugs (DMARDs), there was no significant association between the risk of a first ischemic stroke and ever-exposure to anti-TNF therapy (HR 0.99, 95% CI 0.54-1.81), according to Kimme Hyrich, MD, PhD, of the University of Manchester, and colleagues.
And although the numbers were small, there was a trend toward a reduced mortality among patients receiving a TNF inhibitor at the time of their ischemic stroke compared with those who had never received a biologic, the researchers reported online in Arthritis & Rheumatology.
TNF alpha is a key driver of inflammation, which is believed to be involved in the atherosclerotic process leading to ischemic stroke. Previous studies showed that inhibition of TNF alpha does not influence the occurrence of ischemic stroke compared to DMARD therapy, but only in the short term.

More at link.

Developing drugs to reduce brain impairment after stroke -CAL-101 to block TNF

An easier to understand writeup on TNF blocking. Don't expect anything from this to reach your hospital for at least 50 years.

Developing drugs to reduce brain impairment after stroke

Stroke claims five million lives worldwide each year and is the second biggest killer after ischaemic heart disease. Of those who survive, a significant number (around five million) live with neurological deficits that profoundly affect their quality of life.
Current treatment for ischaemic stroke, which results from a blood clot, aren’t very effective (Only 12%). But research published by my colleagues and I today in the journal Nature Communications shows an emerging drug treatment is effective in mice and could one day reduce the neurological impact in people who’ve suffered an ischaemic stroke.
By 2020, the World Health Organization predicts that worldwide, the number of years lost to disability resulting from stroke will reach 61 million. The economic burden is similarly massive, costing Australia $49.3 billion a year. So finding better treatments is crucial.

Brain inflammation after stroke

Quick treatment is one way to enhance the prospect of recovering from a stroke.
If patients are treated within around three hours of the stroke, the stroke-inducing clots can be broken down relatively efficiently(Only 12% is not very effective) using a substance called tissue plasminogen activator (tPA). This allows the blood to start flowing again, supplying the brain with the oxygen required to keep the tissue alive.

But after the clot is removed and blood starts flowing, the body produces an unwanted neuroimmune response. This occurs because the damaged brain tissue contains elevated levels of molecules known as proinflammatory cytokines, which regulate the body’s response to infection, inflammation and trauma.
These cytokines are able to recruit many other immune cells to the area, leading to further cell death.
Limiting the initial release of these cytokines should therefore help to decrease the excessive local inflammatory response, leading to a decrease in tissue damage and better patient outcomes.

Targeting a critical molecule

A key cytokine involved in this process is tumour necrosis factor-α (TNF-α). In previous work, we showed that the secretion of TNF-α is dependent on a molecule named phosphoinositide 3-kinase delta (PI3Kδ). For our latest study, we hypothesised that PI3Kδ could be similarly involved in stroke.
In collaboration with Garrie Arumugam from the University of Queensland, researchers at Monash University and international colleagues in London and Hamburg, we induced strokes in mice to demonstrate that – as expected – PI3Kδ controlled the release of TNF-α from immune cells of the central nervous system.
This suggested to us that by inhibiting PI3Kδ activity, we would be able to prevent the rise in TNF-α secretion and therefore limit inflammation of the brain and cell death.
Two separate lines of evidence indicated this was the case: mice genetically modified to have inhibited PI3Kδ activity had only limited TNF-α release, and mice that were given the PI3Kδ-inhibiting drug CAL-101 showed similar effects.
Further, blocking PI3Kδ activity (through genetic manipulation or medication) decreased blood clot-induced brain damage and resulted in improved performance on neurological tests.

These results indicate that we successfully identified a pathway critical to post-treatment inflammation of the brain, and that we could limit the damage by blocking PI3Kδ, a key molecule within that pathway.
While the genetic manipulation played a role in identifying the signalling pathway involved, it is the efficacy of CAL-101 that is particularly exciting and relevant to stroke therapy. Not only was the drug effective in improving post-stroke recovery, but its effects could be seen when given up to three hours after the clot was removed and blood started flowing.
Since initial stroke treatment is typically initiated by medically trained staff, CAL-101 (or a related molecule) could potentially be injected alongside tPA to reduce inflammation of the brain and improve patient outcomes.

Taking it to the clinic

The next obvious question is whether CAL-101 or a similar derivative may ultimately be used to improve stroke treatment in humans.
Our study was conducted in mice, and translating findings in animal models to the development of clinical therapies can be very difficult – clinical trials of drugs fail frequently due to safety or efficacy concerns.
In positive news, however, CAL-101 (also known as GS-1101 or idelalisib) has recently undergone phase three clinical trials in the United States for the treatment of certain forms of lymphoma and the results look promising.
CAL-101 is therefore a very promising molecule. Not only does it treat lymphomas, it has the potential to alleviate the complications that arise following initial stroke treatment. We’re now also looking into other medical conditions that could be improved by reducing inflammation of the brain with CAL-101 or a similar compound.