Inflammation

Posted on Pain Management, Rheumatoid arthritis

Why some people with rheumatoid arthritis have pain without inflammation

Synovial tissue

In this image, abnormal synovial tissue is shot through with excessive tissue growth, including blood vessels (in magenta). Synovium should be thin and smooth. CREDIT Bai et al.

Treatment for rheumatoid arthritis (RA) has come a long way in recent years. In many cases, a battery of medications can now successfully stymy the inflammatory cells that cause swelling and pain when they infiltrate tissues around the joints.

Yet for some reason, about 20% of patients with painful, visibly swollen joints consistently get no relief from multiple rounds of even the strongest of these anti-inflammatory drugs.

Surgical interventions intended to remove inflamed tissue have revealed why: “In some cases, their joints aren’t actually inflamed,” says co-senior author Dana Orange, an associate professor of clinical investigation in Rockefeller’s Laboratory of Molecular Neuro-oncology. “With these patients, if you press on the joint, it feels mushy and thick to the touch, but it’s not caused by the infiltrating immune cells. They have excessive tissue growth, but without inflammation. So why are they experiencing pain?”

She and her colleagues suggest an explanation in a new paper in Science Translational Medicine. These patients have a suite of 815 genes that activate abnormal growth of sensory neurons in tissues that cushion the affected joints.

“These 815 genes are rewiring the sensory nerves, which explains why anti-inflammatory drugs don’t work to alleviate pain for these patients,” says Orange. The findings may lead to new treatments for these outliers.

A puzzling disconnection

Rheumatoid arthritis is a tricky chronic disease. Its symptoms—stiffness, tenderness, swelling, limited motion, and pain—slowly emerge in the hands, wrists, feet, and other joints. It occurs symmetrically (not just in one hand but in both, for instance) and sporadically, with irregular flare-ups. Extreme fatigue and depression are also common.

Most cases of RA are caused by products of immune cells such as cytokines, bradykinins, or prostanoids invading the synovium—a soft tissue lining the joints—where they bind to damage-sensing pain receptors. Drugs that target immune mediators have made RA a far more tolerable condition for most, but those suffering from the disconnection between inflammation and ache haven’t benefitted.

Doctors often prescribe these patients drug after anti-inflammatory drug in an ultimately fruitless attempt to give relief. As a result, “we are subjecting some patients to a lot of medications that cause immunosuppression and yet have little chance of making their symptoms better,” Orange says.

She and her colleagues sought answers in the genes expressed in the joint tissue samples of these patients.

Genetic culprits

The researchers looked at tissue samples and self-reported pain reports from 39 patients with RA who had pain but little inflammation. They also developed a machine-learning analysis that they coined graph-based gene expression module identification (GbGMI).

GbGMI tests every possible combination of genes in a dataset to determine the optimal set of genes that together associate with a targeted clinical feature—in this case, pain.

Using RNA sequencing, the researchers found that of the 15,000 genes expressed in the tissue samples, about 2,200 had increased expression in the 39 patients. Using GbGMI, they identified 815 genes that together associated with patient reports of pain.

“This is a challenging problem, because we have a large number of genes but a limited number of patients,” says co-senior author Fei Wang, professor of population health sciences and founding director of the Institute of Artificial Intelligence for Digital Health at Weill Cornell Medicine. “The graph-based approach we used effectively explored the collective associations between a gene set and patient-reported pain.”

Single cell sequencing analysis found that of the four types of fibroblasts in synovial tissue, CD55+ fibroblasts exhibited the highest expression of pain-associated genes. Located in the outer synovial lining, CD55+ cells secrete synovial fluid, allowing for frictionless joint movement. They also expressed the NTN4 gene, which codes for a protein called Netrin-4. Proteins in the netrin family guide axon growth paths and promote new vascular growth.

Surprising pain pathways

These genes, it turned out, were enriched in pathways that are important for neuron axon growth, the researchers discovered. The keys to sensation, sensory neurons receive and transmit information to the central nervous system. Axons are the tendrils that branch out from them into tissues.

“That led us to hypothesize that perhaps the fibroblasts are producing things that alter the growth of sensory nerves,” Orange says.

But what role was the protein playing in the sensation of pain?

To find out, they grew neurons in vitro and then doused them with Netrin-4, which sparked the sprouting and branching of CGRP+ (gene-related peptide) pain receptors. It’s the first time that Netrin-4 has been shown to alter the growth of pain-sensitive neurons, she notes.

Imaging of RA synovial tissue also revealed an overabundance of blood vessels, which feed and nurture new cells. These vessels were encased by CGRP+ sensory nerve fibers and were growing towards the lining fibroblasts in areas of excessive tissue growth, or hyperplasia. This process likely leads to the squishy swelling that many rheumatologists and surgeons have mistaken for inflammation.

Better drugs

In the future, the researchers aim to home in on other products that fibroblasts may be producing that can affect the growth of pain-sensitive neurons. They’ll also delve into the other types of sensory nerves that might be affected.

“We studied one type, but there are about a dozen. We don’t know if all nerves are affected equally. And we don’t want to block all sensation. Sensory nerves are important for knowing that you should avoid certain movements and the position of your joint in space, for instance,” Orange says.

“We want to drill down on those details so that hopefully we can come up with other treatments for patients who don’t have a lot of inflammation. Right now, they’re taking medications that can cost $70,000 a year but have no chance of working. We must do a better job of getting the right drug to the right patient.”

Posted on Diet

Research shows swapping out pulses for common proteins and grains improves our diet

Benefits of Swapping Grains for Pulses

Substituting ½ cup of pulses daily in place of one ounce of refined grains while keeping calories constant increases fibre, magnesium, copper, and potassium, a nutrient of concern, by more than 10% Coalition to Advance Pulses

  A recently published study[i] in Nutrients, an open-access peer-reviewed scientific journal, demonstrates that exchanging pulses for small amounts of typical protein sources and refined grains significantly improves the nutritional profile of the American diet.  This new research adds to the extensive established body of evidence showcasing the multiple benefits of including pulses in a healthy diet. 

Researchers modelled the nutritional impact of substituting servings of protein foods and/or refined grains with servings of pulses (e.g., dry peas, lentils, chickpeas, dry beans) while keeping calories consistent in the Healthy U.S.-Style Dietary Pattern identified in the 2020-2025 Dietary Guidelines for Americans.  Results showed an improved nutritional profile of the diet.  Specifically, the addition of about ¼ cup of pulses per day in place of one ounce per day of common protein foods increases fibre, a nutrient of concern, and decreases cholesterol, each by more than 10%.  Additionally, they found that substituting ½ cup of pulses daily instead of one ounce of refined grains while keeping calories constant increases fibre, magnesium, copper, and potassium, a nutrient of concern, by more than 10%. 

“Our results suggest that encouraging increased pulse consumption may be an effective strategy for improving nutrient intake and achieving a healthier dietary pattern,” author Victor Fulgoni III, PhD, of Nutrition Impact, LLC.  “Pulses (dry peas, lentils, chickpeas, beans) are excellent sources of fibre, folate and potassium and good plant protein sources.”  The study was funded by the Coalition for the Advancement of Pulses.

The findings are consistent with the body of existing peer-reviewed studies that show the inclusion of pulses as part of a plant-forward dietary strategy imparts cardiovascular, metabolic, and gut protective effects; improves weight outcomes, and low-grade inflammation, and may play a role in immune-related disease risk management.[ii]  The American Heart Association and other public health organizations recommend adding more plant-based and less animal protein to reduce the risk of heart disease, high blood pressure and high cholesterol.[iii]

“This research underscores the fact that pulses are a nutritional powerhouse,” said Tim McGreevy, CEO, USA Dry Pea and Lentil Council and American Pulses Association.  “They are high in fiber, plant protein and several important macronutrients.  We know this and are working with our partners to increase awareness about the nutritional benefits of regular pulse consumption.”

Pulses are so nutritious that dietary guidelines globally include them in both the vegetable and/or protein food groups or as a separate food group all together. i, [iv],[v],[vi] The Dietary Guidelines for Americans 2020 – 2025 and the USDA’s Choose My Plate indicate that beans, peas, and lentils can be considered as part of the vegetable or protein groups.

Posted on Diet

Is red meat intake linked to inflammation?

Inflammation is a risk factor for many chronic diseases, including cardiovascular disease (CVD), and the impact of diet on inflammation is an area of growing scientific interest. In particular, recommendations to limit red meat consumption are often based, in part, on old studies suggesting that red meat negatively affects inflammation – yet more recent studies have not supported this.

“The role of diet, including red meat, on inflammation and disease risk has not been adequately studied, which can lead to public health recommendations that are not based on strong evidence,” said Dr. Alexis Wood, associate professor of pediatrics – nutrition at the USDA/ARS Children’s Nutrition Research Center at Baylor College of Medicine and Texas Children’s Hospital. “Our team sought to take a closer look by using metabolite data in the blood, which can provide a more direct link between diet and health.”

Wood and her team analyzed cross-sectional data captured from approximately 4,000 older adults participating in the Multi-Ethnic Study of Atherosclerosis (MESA), and recently published their findings in The American Journal of Clinical Nutrition. Cross-sectional data is a useful source of evidence on how diet affects health; it uses data that is observed with free-living people, without attempting to influence their usual lifestyle. In this way, it may be easier to take results from such studies and apply them to non-research settings. In addition to assessing participants’ self-reported food intake and several biomarkers, researchers also measured an array of dietary intake metabolites in blood. Plasma metabolites can help capture the effects of dietary intake as food is processed, digested and absorbed. 

Researchers found that when adjusted for body mass index (BMI), intake of unprocessed and processed red meat (beef, pork or lamb) was not directly associated with any markers of inflammation, suggesting that body weight, not red meat, may be the driver of increased systemic inflammation. Of particular interest was the lack of a link between red meat intake and C-reactive protein (CRP), the major inflammatory risk marker of chronic disease.

“Our analysis adds to the growing body of evidence that indicates the importance of measuring plasma markers, such as metabolites, to track diet and disease risk associations, versus relying on self-reported dietary intake alone,” Wood said. “Our analysis does not support previous observational research associations linking red meat intake and inflammation.”

Because observational studies cannot indicate cause and effect, randomized controlled trials (RCTs) where individuals are randomly assigned to consume a dietary factor of interest or not consume it, are needed as an additional line of evidence to adequately understand if red meat does not alter inflammation. Several RCTs have demonstrated that lean unprocessed beef can be enjoyed in heart-healthy dietary patterns.

“We have reached a stage where more studies are needed before we can make recommendations to limit red meat consumption for reducing inflammation if we want to base dietary recommendations on the most up-to-date evidence,” Wood said. “Red meat is popular, accessible and palatable – and its place in our diet has deep cultural roots. Given this, recommendations about reducing consumption should be supported by strong scientific evidence, which doesn’t yet exist.”

Posted on A to Z of Medical Conditions, Infectious Diseases

Vagus nerve stimulation – an electric pill for inflammation?

aVNS


Individualised auricular vagus nerve stimulation at the right time and with the right strength. CREDIT TU Wien

A system out of balance

When a virus – such as SARS-CoV-2 – triggers an inflammatory response in the body, this information is transmitted to the brain via the sensory nervous system. The Vagus nerve, which extends from the brain to most organs in the human body, responds in a regulatory way with an anti-inflammatory reflex. However, if the anti-inflammatory response is too weak, an excessive inflammation may negatively affect the body’s own regeneration. To restore the balance between the initially protective inflammatory response and the regenerative processes, aVNS systems can be used.

To test their hypothesis that aVNS also supports the healing process in severe Covid-19 cases, TU researchers worked closely with the Hospital Favoriten, the Medical University of Vienna, the Health Service Centre of the Vienna Private Clinic, the Sigmund Freud Private University Vienna and the Immunological Day Clinic Vienna.

aVNS in severe Corona courses

In its most recent study, the research team was able to show that the positive effect that Vagus nerve stimulation has on the course of severe Corona diseases, which was already predicted in 2020 – at the beginning of the pandemic – actually exists. For this purpose, the team investigated the use of aVNS on patients who were acutely ill with Corona and were about to receive artificial respiration.

When the virus attacks the body, the inflammatory response and healing process can become unbalanced. The inflammatory response of the body then causes more damage than the virus itself. This balance must be restored – for example, by using an aVNS system. “The electrostimulation of the auricular vagus nerve was not only able to stop the inflammatory reaction in Covid-19 patients, it was even able to counteract it,” Eugenijus Kaniusas, professor at the Institute for Biomedical Electronics at TU Wien, emphasises the result.

Stimulating at the exact right time

The therapeutic success of aVNS also increases by adapting the system. If an aVNS system constantly sends electrical impulses, this can lead to side effects such as pain. The power consumption is also significantly higher compared to when the system reacts individually to the patient and sends targeted stimuli. To realise this, the researchers around PhD student Babak Dabiri have integrated a closed-loop control. Eugenijus Kaniusas explains: “This allows us to stimulate the Vagus nerve exactly when the brain is listening. This is the case when the heart is contracting and blood is flowing into the vessels or when the person is exhaling.” In this way, over- and under-stimulation can be prevented, which often results from persistent aVNS.

While simple measurements refer exclusively to the past, Kaniusas and his team worked with predictions: “In the study, we were able to show that predictive stimulation works and leads to the desired result. This was possible due to a feedback function of the system, via which the aVNS system can constructively interfere with the parasympathetic system,” the electrical engineer Kaniusas says. “The aVNS system listens to the measured biosignals and sends its stimulus at exactly the right time, like an intelligent electric pill,” he finally draws a comparison. This is an important step in the direction of personalisation, through which the research team also expects better therapeutic success and more acceptance by users.

Posted on Vitamins

Down on Vitamin D? It could be the cause of chronic inflammation

Sunset


There’s a direct link between low levels of vitamin D and high levels of inflammation. CREDIT Rebecca Wood

Inflammation is an essential part of the body’s healing process. But when it persists, it can contribute to a wide range of complex diseases including type 2 diabetes, heart disease, and autoimmune diseases.

Now, world-first genetic research from the University of South Australia shows a direct link between low levels of vitamin D and high levels of inflammation, providing an important biomarker to identify people at higher risk of or severity of chronic illnesses with an inflammatory component.

The study examined the genetic data of 294 ,970 participants in the UK Biobank, using Mendelian randomization to show the association between vitamin D and C-reactive protein levels, an indicator of inflammation.

Lead researcher, UniSA’s Dr Ang Zhou, says the findings suggest that boosting vitamin D in people with a deficiency may reduce chronic inflammation.

“Inflammation is your body’s way of protecting your tissues if you’ve been injured or have an infection,” Dr Zhou says.

“High levels of C-reactive protein are generated by the liver in response to inflammation, so when your body is experiencing chronic inflammation, it also shows higher levels of C-reactive protein.

“This study examined vitamin D and C-reactive proteins and found a one-way relationship between low levels of vitamin D and high levels of C-reactive protein, expressed as inflammation.

“Boosting vitamin D in people with deficiencies may reduce chronic inflammation, helping them avoid a number of related diseases.”

Supported by the National Health and Medical Research Council and published in the International Journal of Epidemiology the study also raises the possibility that having adequate vitamin D concentrations may mitigate complications arising from obesity and reduce the risk or severity of chronic illnesses with an inflammatory component, such as CVDs, diabetes, and autoimmune diseases.

Senior investigator and Director of UniSA’s Australian Centre for Precision Health, Professor Elina Hyppönen, says these results are important and provide an explanation for some of the controversies in reported associations with vitamin D.

“We have repeatedly seen evidence for health benefits for increasing vitamin D concentrations in individuals with very low levels, while for others, there appears to be little to no benefit.” Prof Hyppönen says. 

“These findings highlight the importance of avoiding clinical vitamin D deficiency, and provide further evidence for the wide-ranging effects of hormonal vitamin D.”