Rheumatoid arthritis

Posted on Rheumatoid arthritis

Women with rheumatoid arthritis are more likely to achieve remission if they take sex hormones.

A large study of women with rheumatoid arthritis found that those taking oral contraceptives or hormone replacement therapy (HRT) had a greater chance of remission.

Led by the University of South Australia, researchers linked remission, reproductive status, and sex hormone use, after assessing data from 4474 female rheumatoid arthritis (RA) patients treated with the anti-inflammatory drug Tocilizumab and other immuno-suppressive medications.

The study revealed the following:

The findings suggest that female sex hormones could play a major role in improving the outcome of women taking drugs prescribed for rheumatoid arthritis.

Remission rates were higher in some groups of women who were taking HRT or oral contraceptives at the same time they were taking medicines for RA, and in fact, RA remission was twice as high in peri-menopausal women.

Lead researcher UniSA Associate Professor Michael Wiese says it’s premature to say that HRT and oral contraceptives protect against rheumatoid arthritis. Still, the study has revealed a potential connection.

“We looked at whether women who used oral contraceptives or HRT had different outcomes when treated with drugs for rheumatoid arthritis. We found that women entering menopause who were not taking HRT or contraceptives were less likely to achieve remission compared with RA women still experiencing a regular menstrual cycle,” Assoc Prof Wiese says.

“The decision to use HRT is a complex one,” Assoc Prof Wiese says. “It does improve menopause symptoms, but it can modify the risk of some cancers and cardiovascular disease. This study suggests it could also be beneficial for women with rheumatoid arthritis, but the decision to use it requires an in-depth discussion with a general practitioner because each woman has different risk factors.”

Rheumatoid arthritis is an autoimmune inflammatory condition that is four times more prevalent in women aged under 50 years than men in the same age bracket and is twice as common in women over 60 years.

Compared with males, rheumatoid arthritis is more aggressive in women and the prognosis is worse.

“The peak age of onset of rheumatoid arthritis among females is 45-55 years, corresponding with a drop in oestrogen when women typically enter a peri-menopausal period, where their periods become irregular.

“Furthermore, at the onset of menopause there is an increase in pro-inflammatory proteins.”

Early menopause, or menopause that occurs in women under 45 years, increases the risk of developing rheumatoid arthritis and the incidence also sharply spikes in post-menopausal women.

Conversely, younger women with rheumatoid arthritis who fall pregnant experience a 50 per cent decline in inflammatory activity.

Early post-menopausal women (post-menopausal women aged <45 years) made up five per cent of the participants, 25 per cent were pre-menopausal (still experiencing a regular menstrual cycle), nine per cent were peri-menopausal, experiencing intermittent and irregular periods, and 63 per cent post-menopausal.

Rheumatoid arthritis affects up to two per cent of the population worldwide and is primarily genetic. It mainly causes joint disease but can also affect the whole body, including organs.

Posted on Pain Management, Rheumatoid arthritis

NB Folks with RA – Taking care of your teeth could help prevent chronic joint pain

research illustration


Proposed model for the role of periodontal inflammation in rheumatoid arthritis (RA). Periodontal inflammation is associated with a chemical change in supragingival bacteria caused by an enzyme released as part of an immune response mechanism known as NETosis. This chemical change ‘decorates’ bacterial antigens with a molecular tag. Periodontitis and inflammation can cause breaches of the mucous membrane lining inside the mouth, releasing the tagged bacterial antigens into the blood. As a result, antibodies that target these molecular tags are activated, and they bind or trap the tagged antigens, forming molecules known as immune complexes. Immune complexes and plasmablasts deposit in joint tissue, also known as synovium, and contribute to its inflammation. Repeated episodes of oral bacteremia cause a heightened autoimmune response, affecting join tissue. CREDIT Image courtesy of Dana Orange and Bill Robinson

 Regular visits to the dentist might help keep joint pain at bay, too.

When Rice University computational biologist Vicky Yao found traces of bacteria associated with periodontal disease in samples collected from rheumatoid arthritis patients, she was not sure what to make of it.

Her finding helped spark a series of experiments that confirmed a connection between arthritis flare-ups and periodontitis. The study is published in Science Translational Medicine.

Tracing this connection between the two conditions could help develop therapies for rheumatoid arthritis, an autoimmune inflammatory disease that attacks the lining of the joints and can cause heart-, lung- and eye-problems. The approach that led to the study could prove fruitful in other disease contexts, such as cancer.

“Data gathered in experiments from living organisms or cells or tissue grown in petri dishes is really important to confirm hypotheses, but, at the same time, this data perhaps holds more information than we are immediately able to derive from it,” Yao said.

Yao’s hunch was confirmed when she took a deeper look into data collected from rheumatoid arthritis patients by Dana Orange, an associate professor of clinical investigation and a rheumatologist, and Bob Darnell, a professor and attending physician at Rockefeller University and the Howard Hughes Medical Institute.

Yao was collaborating with Orange and others on a different project that tracked changes in gene expression during rheumatoid arthritis flare-ups.

“Orange, working with Darnell, collected data from arthritis patients at regular intervals while, at the same time, monitoring when the flares happened,” Yao said. “The idea was that perhaps looking at this data retroactively, some pattern would become visible giving clues as to what might cause the arthritis to flare up.

“While I was working on that project, I went to this talk that I thought was really cool because it pointed out that in the data that gets ignored or thrown out, you can actually find traces of microbes. You’re looking at a human sample but you get a snapshot of the microbes floating around. I was intrigued by this.”

When she looked into it, Yao found that the germs in the samples that changed consistently across patients prior to flares were largely ones associated with gum disease.

“I was curious about this tool that allowed you to detect microbes in human samples. It was sort of like, for free, you’re getting an extra perspective on the data,” Yao said. “At the time, I hadn’t worked much on microbial data at all. Since then, Dana leveraged all this expertise and got together with people studying these bacteria.

“One of the things that came up when we were discussing this was, how cool would it be if you could prescribe some kind of mouthwash to help prevent rheumatoid arthritis flares.”

Yao’s focus since joining Rice in 2019 has shifted to cancer research. The discovery of meaningful information in data that would usually be ignored or discarded inspired Yao to take a similar approach in looking at data from cancer patients.

“I got really interested in what else we can find mining for microbial signatures in human samples,” Yao said. “Now, we’re doing something similar in looking at cancer.

“The hope here is that if we find some interesting microbial or viral signatures that are associated with cancer, we can then identify productive experimental directions to pursue. For instance, if having a tumor creates this hotbed of specific microbes that we recognize, then we can maybe use that knowledge as a means to diagnose the cancer sooner or in a less invasive or costly way. Or, if you have microbes that have a very strong association with survival rates, that can help with prognosis. And if experiments confirm a causal link between a specific virus or bacteria and a type of cancer, then, of course, that could be useful for therapeutics.”

One of the better known examples of a pathogen associated with cancer is the human papillomavirus (HPV). Yao used this well-documented connection to verify her approach.

“When we did the same exercise looking at cervical cancer tumor samples, we consistently detected the virus,” she said. “It’s a nice proof-of-principle finding that shows that the presence of specific pathogens can be meaningful for certain types of cancer.

“I’m really interested in using computational approaches to bridge the gap between available experimental data and ways to interpret it. Computational analysis is a way to help interpret data and prioritize hypotheses for clinicians or experimental scientists to test.”

Posted on autoimmune conditions, Multiple Sclerosis, Rheumatoid arthritis

Potential treatment of autoimmune diseases revealed in the new study like multiple sclerosis and rheumatoid arthritis.

Diagram showing the results of mice that were treated with PEP


Mice that have neuroinflammation caused by autoimmunity were treated with PEP. The results found that PEP-treated mice showed improved signs of recovery compared to mice not treated with PEP. CREDI Tsung-Yen Huang (OIST)

Scientists in Japan have revealed a chemical compound that could be used for the treatment of various autoimmune diseases like multiple sclerosis and rheumatoid arthritis. These diseases occur when the body’s immune response goes wiry. The immune system, which normally attacks pathogens and infections, instead attacks healthy cells and tissues. For the millions of people who suffer from autoimmune diseases worldwide, the result can be debilitating—rheumatoid arthritis causes excessive joint pain, while multiple sclerosis can disable one’s brain and spinal cord function.

“The key to the development of autoimmune diseases, and thus the way to inhibit this development, lies in our cells, but the underlying mechanism has always been unclear,” stated Prof. Hiroki Ishikawa, who leads the Immune Signal Unit at the Okinawa Institute of Science and Technology (OIST). “Now, our recent research has shed light on a compound that could suppress the development of these diseases.”

Prof. Ishikawa went on to explain that this research, published in Cell Reports, could lead to the development of treatments for autoimmune diseases.

The research focused on T helper 17 cells, or Th17 cells. Th17 cells are a type of T cell—a group of cells, which form major parts of the immune system. These cells, which exist in high numbers in our guts, evolved to help us fight invasive pathogens but, sometimes, they’re overactivated and mistake normal, healthy tissue as pathogens, resulting in autoimmunity. The generation of Th17 cells requires glycolysis, a metabolic process in which glucose is broken down and converted to energy to support the metabolic needs of cells. Glycolysis is essential for the growth of not only Th17 cells but also a variety of cells in our body.

“What’s interesting in that excessive glycolysis seems to suppress Th17 cell activity,” stated first author, Mr. Tsung-Yen Huang, a PhD candidate in the Immune Signal Unit. “So, we hypothesized that molecules produced during glycolysis may inhibit the cells.”

Enter phosphoenolpyruvate, or PEP for short. This chemical compound is a metabolite produced when glucose is converted to energy. Since it is part of such an important process, PEP is generated every day in our bodies. The researchers found that treatment with PEP can inhibit the maturation of TH17 cells, leading to resolution of inflammatory response.

Mr. Huang explained how this was, at first, a confusing result, as it went against all other research on the topic, but he decided to persevere and take a closer look at what could be occurring.

The research led them to a protein called JunB, which is essential for the maturation of Th17 cells. JunB promotes Th17 maturation by binding to a set of specific genes. The researchers found that PEP treatment inhibits the generation of Th17 cells by blocking JunB activity.

Armed with this knowledge, the researchers went on to treat mice that had neuroinflammation caused by autoimmunity with PEP. This disease is very similar to multiple sclerosis and these mice showed positive signs of recovery. The scientists have now filed a patent to continue with this research.

“Our results show the clinical potential of PEP,” explained Mr. Huang. “But first we need to increase its efficiency.”

In the past, researchers who were interested in developing a treatment for autoimmune diseases, often looked at inhibiting glycolysis and thus Th17 cells. But glycolysis is essential to various types of cells in the body and inhibiting it could have significant side-effects. PEP has the potential to be used as a treatment without resulting in such side-effects.

Posted on Rheumatoid arthritis

Digital twin opens the way to effective treatment of Rheumatoid Arthritis

Illustration of digital twins


A vision of how digital twins can be used to tailor drugs: (A) Patients with different immune diseases. (B) Computers construct (C) digital twins of each patient’s disease mechanisms. These interact in molecular programmes, controlled by (D) switch proteins, which are measured in blood or tissue to (E) find the dominant protein(s) at which to target therapy. Illustration: The research group. CREDIT Karolinska Institutet

Inflammatory diseases like rheumatoid arthritis have complex disease mechanisms that can differ from patient to patient with the same diagnosis. This means that currently available drugs have little effect on many patients. Using so-called digital twins, researchers at Karolinska Institutet have now obtained a deeper understanding of the “off and on” proteins that control these diseases. The study, which is published in Cell Reports Medicine, can lead to more personalised drug therapies.

Many patients with inflammatory diseases such as rheumatoid arthritis, Crohn’s disease and ulcerative colitis, never feel fully healthy despite being on medication. It is a problem that causes significant suffering and expense. 

In an inflammatory disease, thousands of genes alter the way they interact in different organs and cell types. Moreover, the pathological process varies from one patient to another with the same diagnosis, and even within the same patient at different times.

It is exceedingly difficult to diagnose and treat such complex and varied changes. In a project that has been underway for five years, researchers from a constellation of institutions including Karolinska Institutet in Sweden have been trying to solve this problem and tailor drugs to individual patients by constructing and data-processing their digital twins, i.e. digital models of each patient’s unique disease mechanisms.

Now, the research group has found a possible solution: the changes can be organised in molecular programmes. These molecular programmes are regulated by a limited number of “off and on” switch proteins, of which some are known targets for drugs such as TNF inhibitors. But it is not a therapeutic option that helps everyone.

“Our analyses of patients who responded or didn’t respond to TNF therapy revealed different switch proteins in different individuals,” says the study’s corresponding author Mikael Benson, researcher at the Department of Clinical Science, Intervention and Technology, Karolinska Institutet. “Another important discovery was that the proteins did not switch off the diseases but were more like dimmer switches that raised or lowered the disease programmes.”

Every physiological process can be described with mathematical equations. This advanced digital modelling technique can be adjusted to a patient’s unique circumstances by analysing the activity of each and every gene in thousands of individual cells from blood and tissue. Such a digital twin can be used to calculate the physiological outcome if a condition changes, such as the dosage of a drugs.

Digital twins have revealed to the researchers new opportunities for the effective treatment of serious diseases.

“The methods can be developed to tailor the right combination of drugs for “on” proteins for individual patients,” Dr Benson continues. “The programmes we describe will be made available to the research community so that more clinical studies can be done of patients with different immune diseases.”

In the current study, the researchers combined analyses of a mouse model of rheumatoid arthritis and digital twins of human patients with various inflammatory diseases.

“Even though only the joints were inflamed in mice, we found that thousands of genes changed their activity in different cell types in ten organs, including the skin, spleen, liver and lungs,” says Dr Benson. “As far as I’m aware, this is the first time science has obtained such a broad picture of how many organs are affected in rheumatoid arthritis. This is partly due to the difficulty of physically sampling so many different organs.”