MAO-B and GABA were found to be present in the joint fibroblast-like synoviocytes cells (FLSs), and the expression of MAO-B and GABA was associated with the degree of inflammation. CREDIT Institute for Basic Science

Rheumatoid arthritis (RA) is an autoimmune disease that causes extensive inflammation of the joints, causing severe pain and discomfort in patients. But did you know that the disease is also commonly accompanied by neuropsychiatric complications, such as cognitive impairment and depression? Previous studies show that up to 70% of RA patients can have such cognitive disorders. These neurological symptoms are thought to be caused by neuroinflammation, which originates from systemic inflammation. However, the precise mechanisms of such cognitive impairment in RA remain unclear.

Previously, a team led by Director C. Justin LEE at the Center for Cognition and Sociality within the Institute for Basic Science (IBS) in Daejeon, South Korea, explored the hippocampus of dementia patients to better understand the overall mechanism of memory impairment. The group found that reactive astrocytes release an increased level of monoamine oxidase-B (MAO-B)-dependent gamma-aminobutyric acid (GABA), which in turn leads to neurological disorder.

MAOs, including MAO-A and MAO-B, are enzymes that catalyze the oxidation of monoamines and are bound to the outer mitochondrial membrane in cells of several organs, such as the brain and the immune system. More than 30 years ago, previous research suggested that MAO inhibitors can relieve pain and stiffness in RA patients. However, there have been no follow-up studies of these results, and further studies related to the role of MAO in RA have been generally lacking even until today.

Recently, Director Lee’s team revealed that interleukin-1β (IL-1β), one of these inflammatory substances that are responsible for RA, causes aberrant expression of MAO-B infibroblast-like synoviocytes cells (FLSs) isolated from joint tissues of RA patients. It was been revealed that both MAO-B and GABA are aberrantly expressed in these cells.

The team’s findings indicate that the expression of MAO-B and MAO-B products, such as GABA and H₂O₂, can exacerbate joint inflammation by upregulating the expression of proinflammatory factors. It was also observed that MAO-B and GABA levels were significantly increased in the RA tissue compared to the osteoarthritis (OA) tissue, which generally has a lower level of inflammation.

Notably, the researcher also observed that the RA animal model showed increased cognitive impairment. In routine behavioral experiments, normal healthy mice had no difficulty remembering a new object or location. On the other hand, it was shown that RA model mice were unable to distinguish new things and objects, which is a hallmark of a cognitive impairment disorder.

Similarly to the joint tissues, the secretion of astrocytic MAO-B-dependent GABA was aberrantly increased in the hippocampus, which is thought to be the main cause of this cognitive dysfunction. It has been known that hippocampal astrocytic MAO-B-mediated GABA inhibits neurons, causing memory and cognitive impairment. Based on the fact that astrocytes respond sensitively to inflammation, it was hypothesized that astrocytes would also be affected during the course of RA disease progression, which would lead to cognitive impairment.

The first author, Dr. WON Woojin states, “Until now, research on RA has focused only on the mechanism of inflammation, so the cause and treatment of cognitive impairment have not been clear. With a new approach of astrocytes and MAO-B, we were able to determine the cause of cognitive impairment.”

Subsequently, the IBS researchers decided to administer an MAO-B inhibitor called “KSD2010” in the RA animal model. KDS2010 is a newly developed selective and reversible MAO-B inhibitor, which is currently being tested in phase 1 clinical trials, Once administered in mice, it was discovered that both the joint inflammation decreased and cognitive function recovered at the same time.

Taken together, this study revealed both joint inflammation and cognitive impairment have a common underlying mechanism in RA patients, namely aberrant MAO-B expression. This opens the possibility of treating both of these symptoms with one drug.

“The mechanism by which cognitive impairment in RA is induced by reactive astrocytes caused by chronic inflammation was first presented. It is hoped that the newly developed and improved MAO-B inhibitor KDS2010 will become an effective next-generation treatment for RA,” explains Director C. Justin LEE, who supervised this work.

For the first time, researchers have shown that a class of anti-fibrotic drugs slows the progression of interstitial lung disease (ILD) in patients with rheumatoid arthritis (RA). Research conducted, in part, at National Jewish Health showed that pirfenidone was safe and effective in these patients. The study published earlier this month in the journal The Lancet Respiratory Medicine is the first prospective treatment trial of patients with RA-ILD.

“ILD is a relatively common complication in people with RA and can progress and lead to premature death in up to 10% of these patients,” said Joshua Solomon, MD, director of the Interstitial Lung Disease Program at National Jewish Health and first author of the study. “This research is a big step forward for patients suffering from RA-ILD.”

Rheumatoid arthritis (RA) is one of the most common autoimmune diseases in the world. The treatment for Rheumatoid Arthritis and Interstitial Lung Disease 1 (TRIAL1) was a randomized, double blind, placebo-controlled phase 2 trial done in 34 academic centers specializing in ILD across four countries.  Patients with RA-ILD were treated for 52 weeks with either pirfenidone, an anti-scarring medication, or a placebo. The COVID-19 pandemic prevented trial participant enrollment goals from being reached, but the results showed that pirfenidone was safe, well tolerated and slowed down the rate of progression of lung fibrosis over a year. 
This was the first and only prospective multi-centered international interventional treatment trial focused on RA-ILD. While the trial was foreshortened because of recruitment challenges during the pandemic, the intervention appeared safe and in context, slowed the rate of forced vital capacity (FVC) decline; as FVC decline is associated with early mortality, slowing the decline may be associated with longer life.

“With this study, we are demonstrating that anti-fibrotics as a class of medications have a reproducible effect in reducing the rate of disease progression when measured by force vital capacity,” said Dr. Ivan Rosas, corresponding author of the paper, and professor of medicine and section chief of pulmonary, critical care and sleep medicine at Baylor College of Medicine. “This could have an impact on the overall survival of these patients.”

An article in Arthritis & Rheumatology describes how the Supreme Court’s June 24th decision to overturn Roe v. Wade portends grave consequences for the practice of rheumatology.

Abortion bans that have been drafted by more than half of US states can now be implemented, and many more are in development. For patients with rheumatic diseases, family planning choices will be limited, thereby restricting their options for medical treatment. Providers will be forced to weigh delivering evidence-based clinical recommendations against the personal, professional, and legal risks of violating constraints on reproductive rights.

The authors stress that pregnancy can be dangerous for some individuals with rheumatic diseases, and many of the medications that benefit patients with conditions such as rheumatoid arthritis and lupus have been linked to birth defects. 

“Many patients with rheumatic diseases are reproductive aged women whose complicated diseases are exacerbated by pregnancy, especially when unplanned. This burden of illness is more pronounced in racial and ethnic minority women, who face both greater morbidity and mortality due to their illness and often live in states with the most restrictive abortion legislation,” said lead author Bonnie L. Bermas, MD, of UTSouthwestern Medical Center. “Thus, the recent Supreme Court Dobbs v. Jackson Women’s health organization decision not only negatively impacts our ability to provide the best healthcare for all of our patients, but also furthers the existing structural racism that impedes the delivery of appropriate reproductive and rheumatic disease care for our minoritized patients.”

Scientists have identified a protein known as sulfatase-2 that plays a critical role in the damage caused by rheumatoid arthritis. A chronic disease in which the immune system attacks the body’s own joint tissues, rheumatoid arthritis affects an estimated 1.5 million Americans.

Published in the journal Cellular & Molecular Immunology, the discovery sheds new light on the molecular processes that drive inflammation seen in rheumatoid arthritis. It could also someday lead to improved treatment of the disease, which currently has no cure.

“Tumor necrosis factor-alpha—or TNF-alpha for short—is one of the main inflammatory proteins that drive rheumatoid arthritis and is targeted by many currently available therapies,” said senior author Salah-Uddin Ahmed, a professor in Washington State University’s College of Pharmacy and Pharmaceutical Sciences. “However, over time patients can develop a resistance to these drugs, meaning they no longer work for them. That is why we were looking for previously undiscovered drug targets in TNF-alpha signaling, so basically proteins that it interacts with that may play a role.”

Though sulfatases such as sulfatase-2 have been extensively studied for their roles in different types of cancer, Ahmed said no one had looked at how they might be involved in inflammatory or autoimmune diseases such as rheumatoid arthritis.

The research team first explored this idea using cells called synovial fibroblasts, which line the joints and keep them lubricated to ensure fluid movement.

“In rheumatoid arthritis, these normally quiescent cells get activated by TNF-alpha and other inflammatory molecules, and they take on this aggressive character,” said first author Ruby J. Siegel, a PhD graduate in the WSU College of Pharmacy and Pharmaceutical Sciences. “They are not dying when they should, and they proliferate in a way that is almost tumor-like, forming this massive synovial tissue that should not be anywhere near that size and at the same time activating proteins that destroy cartilage and bone.”

Using the joint-lining cells of rheumatoid arthritis patients, they removed sulfatase-2 from one group of cells before stimulating all cells with the inflammatory TNF-alpha. What they found was that cells lacking sulfatase-2 did not show the same exaggerated inflammatory response to TNF-alpha as cells that were left intact.

“Looking at sulfatases for their potential role in inflammation was an educated guess, but once we did we saw a very consistent pattern of increased sulfatase-2 expression throughout different tissues and samples we studied,” Ahmed said. “This tells us that TNF-alpha relies on sulfatase-2 to drive inflammation, because as soon as we removed sulfatase-2 the inflammatory effects of TNF-alpha were markedly reduced.”

Resulting from a series of experiments spanning four years, the researchers’ findings open the door to future animal studies to test the effectiveness of inhibiting sulfatase-2 to ease rheumatoid arthritis symptoms. This could someday lead to the development of new combination therapies that along with other inflammatory proteins would also target sulfatase-2 to prevent bone loss, cartilage damage and deformed joints. Such therapies could help address the shortcomings of currently available rheumatoid arthritis drugs, many of which come with significant side effects.

“These drugs shut off TNF-alpha in your whole body, but it does have important immune functions,” Siegel said, adding that patients who take these types of drugs are more susceptible to infection and have an increased risk of developing cancer with long-term use. She also noted that TNF-alpha inhibitors are not effective in all people and are not recommended for patients with certain other health conditions.

Fish oil and Omega-3 fatty acids are among the most popular supplements on the market. Most likely, you heard about the benefits of fish oil in decreasing triglycerides, cholesterol and cardiovascular risk…But have you heard about using fish oil or omega-3 fatty acids for rheumatoid arthritis? Let’s learn about the scientific evidence of using fish oil for rheumatoid arthritis