US Pharm. 2022;47(11):42-46.

 Single Strategy to Treat RA Joint Pain and Cognitive Impairment?

Rheumatoid arthritis (RA) is an autoimmune disease that causes extensive inflammation of the joints, causing severe pain and discomfort in patients. 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 neurologic 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 leads to the neurologic 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 until now, further studies related to the role of MAO in RA have been generally lacking.

Recently, Director Lee’s team revealed that Interlaken-1B (IL-1B), one of the inflammatory substances responsible for RA, causes aberrant expression of MAO-B in fibroblast-like synoviocytes cells isolated from joint tissues of RA patients. It has 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 with the osteoarthritis tissue, which generally has a lower level of inflammation.

Notably, the researchers 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.

First author 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 I 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 Dr. Lee.

Multiple Sclerosis Quality of Life May Depend on Several Factors

Quality of life is a measure of a person’s level of comfort, health, and happiness. For people with multiple sclerosis (MS), a new study in Neurology has found there are specific factors that may affect a person’s physical and mental quality of life.

MS is a disease of the central nervous system, which is made up of the brain, spinal cord, and optic nerves. It is chronic and can be unpredictable and disabling. Symptoms may include fatigue, numbness and tingling, loss of balance, weakness, and problems with vision. While there is currently no cure for MS, there are medications to modify the course of the disease and delay its progress as well as treat the symptoms.

“People with multiple sclerosis report a lower quality of life when compared to people without the disease, and even those with other chronic conditions,” said study author Julia O’Mahony, PhD, of the Health Sciences Centre Winnipeg in Winnipeg, Canada. “There are several factors that may play a role. Our research sought to identify such factors so they can be addressed early in the course of the disease.”

The study involved 4,888 people participating in the North American Research Committee on Multiple Sclerosis (NARCOMS) Registry; 81% were women, who had an average age of 42 years when diagnosed with MS. All had been diagnosed within 3 years of the start of the study.

Each person was assessed at least three times for health-related quality of life and filled out an average of 12 quality-of-life questionnaires over up to 27 years.

For physical quality of life, researchers divided participants into five groups. The first group, 26% of participants, had consistently low and stable quality of life. The second group, 29%, had moderately low and stable quality of life. The third group, 13%, had moderate-to-low quality of life within the first years after diagnosis followed by normal quality of life thereafter. The fourth group, 17%, had early decline and then an increase to moderate-to-normal quality of life. The fifth group, 14%, had normal quality of life for 20 years and then a decline.

Researchers found people who were older when diagnosed with MS and those with worse physical impairments or worse fatigue had an increased risk of being in the group with the worst physical quality of life. The people in the lowest group had an average age of 46 years at diagnosis, compared with an average age of 38 years for the group with the highest quality of life. The people in the worst group had moderate disability, such as problems with their gait and mobility or were starting to use a cane for walking, while those in the best group had normal functioning or mild disability.

For mental quality of life, researchers divided participants into four groups. The first group, 19% of participants, had chronically low quality of life. The second group, 33%, had moderately low and stable quality of life. The third group, 22%, reported moderately low quality of life with the first 10 years after diagnosis followed by normal mental health. The fourth group, 26%, reported chronically normal quality of life.

Researchers found people who had an annual income of $50,000 or less or no postsecondary education had an increased risk of being in the group with the worst mental quality of life. A total of 62% of the people in the lowest group had incomes of $50,000 or less, compared with 44% of those in the highest group. And 38% of those in the lowest group had no postsecondary education, compared with 22% of those in the highest group.


Increasing Heart Attack Risk Among Hiv and Hepatitis C Patients

As people with HIV age, their risk of heart attack increases far more if they also have untreated hepatitis C virus, even if their HIV is treated, according to new research in the Journal of the American Heart Association.

Since the introduction of antiretroviral therapies to treat HIV in the late 1990s, the life span of people with HIV has increased dramatically. However, even with treatment, studies have found the heart disease risk among people with HIV is at least 50% higher than people without HIV. This new study evaluated if people with HIV who also have hepatitis C, a viral liver infection, have a higher risk of heart attack.

“HIV and hepatitis C coinfection occurs because they share a transmission route—both viruses may be transmitted through blood-to-blood contact,” said Keri N. Althoff, PhD, MPH, senior author of the study and an associate professor in the Department of Epidemiology at the Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland. “Due in part to the inflammation from the chronic immune activation of two viral infections, we hypothesized that people with HIV and hepatitis C would have a higher risk of heart attack as they aged compared to those with HIV alone.”

Researchers analyzed health information for 23,361 people with HIV (17% female, 49% non-Hispanic white) in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) between 2000 and 2017 and who had initiated antiretroviral treatment for HIV. All were aged between 40 and 79 years when they enrolled in the NA-ACCORD study (median age of 45 years). One in five study participants (4,677) were also positive for hepatitis C. During a median follow-up of about 4 years, the researchers compared the occurrence of a heart attack between the HIV-only and the HIV-hepatitis C–coinfected groups as a whole, and by each decade of age.

The analysis found the following:

• With each decade of increasing age, heart attacks increased 30% in people with HIV alone and 85% in those who were also positive for hepatitis C.

• The risk of heart attack increased in participants who also had traditional heart disease risk factors, such as high blood pressure (more than 3 times), smoking (90%), and type 2 diabetes (46%).

 • The risk of heart attack was also higher (40%) in participants with certain HIV-related factors, such as low levels of CD4 immune cells (200 cells/mm3, signaling greater immune dysfunction), and 45% in those who took protease inhibitors (one type of antiretroviral therapy linked to metabolic conditions).

“People who are living with HIV or hepatitis C should ask their doctor about treatment options for the viruses and other ways to reduce their cardiovascular disease risk,” said lead study author Raynell Lang, MD, MSc, an assistant professor in the Department of Medicine and Community Health Sciences at the University of Calgary in Alberta, Canada.

“Several mechanisms may be involved in the increased heart attack risk among coinfected patients. One contributing factor may be the inflammation associated with having two chronic viral infections,” Dr. Lang said. “There also may be differences in risk factors for cardiovascular disease and non-medical factors that influence health among people with HIV and hepatitis C that play a role in the increased risk.”

According to a June 2019 American Heart Association scientific statement, Characteristics, Prevention, and Management of Cardiovascular Disease in People Living With HIV, approximately 75% of those with HIV are aged older than 45 years. “Even with effective HIV viral suppression, inflammation and immune dysregulation appear to increase the risk for heart attack, stroke, and heart failure.” The statement called for more research on cardiovascular disease prevention, causes, and treatment in people with HIV.

“Our findings suggest that HIV and hepatitis C coinfections need more research, which may inform future treatment guidelines and standards of care,” Dr. Althoff said.

The study is limited by lacking information on additional factors associated with heart attack risk, such as diet, exercise, or family history of chronic health conditions. Results from this study of people with HIV receiving care in North America may not be generalizable to people with HIV elsewhere. In addition, the study period included time prior to the availability of more advanced hepatitis C treatments.

“Because effective and well-tolerated hepatitis C therapy was not available during several years of our study period, we were unable to evaluate the association of treated hepatitis C infection on cardiovascular risk among people with HIV. This will be an important question to answer in future studies,” Dr. Lang said.

Key Protein Driving Rheumatoid Arthritis Damage Identified

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

The findings in Cellular & Molecular Immunology shed new light on the molecular processes that drive inflammation seen in RA. It could also someday lead to improved treatment of the disease, which currently has no cure.

“Tumor necrosis factor alpha [TNF-alpha] 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 (WSU) 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, Dr. Ahmed said no one had looked at how they might be involved in inflammatory or autoimmune diseases such as RA.

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 RA patients, they removed sulfatase-2 from one group of cells before stimulating all cells with the inflammatory TNF-alpha. They found 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,” Dr. 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 4 years, the researchers’ findings open the door to future animal studies to test the effectiveness of inhibiting sulfatase-2 to ease RA  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 RA 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,” Dr. 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.


Psoriasis Study Proposes Potential New Treatment Strategy

Around 250,000 people in Austria suffer from psoriasis. One-third of them develop inflammation in their joints (psoriatic arthritis) as a result of the chronic skin condition. As part of a study, a MedUni Vienna research team has discovered a key starting point for inhibiting inflammation in both psoriasis and psoriatic arthritis. The researchers’ findings may form the basis for developing new treatment, diagnostic, and prevention strategies.

The study conducted by the research group led by Erwin Wagner of the Department of Dermatology and Department of Laboratory Medicine, MedUni Vienna, focused on the S100A9 gene, which has long been at the center of its internationally acclaimed scientific research into psoriasis. The team has discovered that the severity of psoriasis (Ps) and psoriatic arthritis (PsA) can be reduced by inhibiting S100A9 systemically throughout the whole body rather than locally on the skin.

With this finding, the MedUni Vienna researchers are laying the foundation for a paradigm shift in the treatment of Ps and PsA: “Our study is an important step towards the development of targeted therapeutic options in the form of drugs that act systemically rather than locally on the skin,” said Dr. Wagner. New diagnostic and prevention strategies can also build on the study.

Psoriasis is one of the most common chronic inflammatory skin conditions that can also spread to the joints. Triggers for the disease, which usually first appears in adulthood, include stress and UV radiation. However, individuals can also be genetically predisposed to developing Ps. S100A9 activation in skin and immune cells has been identified as a risk factor for the development of Ps and/or PsA.

As shown by previous basic research by Dr. Wagner’s team at MedUni Vienna, the symptoms of Ps disappear when the S100A9 gene is deactivated in all cells of the body. The recent preclinical experiments were able to shed light on the particular influence that the skin and immune cells in which S100A9 is produced have on disease severity. “We now know that the inflammatory responses in psoriasis and psoriatic arthritis are enhanced when S100A9 is only inhibited in skin cells,” Dr. Wagner explains. Therefore, drugs inhibiting S100A9 have to be administered systemically in the form of tablets or drips.


Norovirus Link to Crohn’s Might Lead to New Therapies

A new study may have solved a mystery surrounding Crohn’s disease, an inflammatory bowel illness where immune defenses meant to attack invading microbes instead mistakenly target the body’s own digestive tract. Norovirus, a common infection that causes vomiting and diarrhea, is one of several viruses and bacteria thought to trigger disease onset in Crohn’s patients, but it is not known why.

One clue emerged when past studies found that a certain genetic mutation is present in most patients with the condition. This mutation makes gut-lining cells more vulnerable to damage. The mystery deepened again, however, when it was learned that half of all Americans have this same risk-conferring genetic mutation, but fewer than a half-million individuals develop Crohn’s.

Published online in Nature, the new work in mice and in human tissue revealed that in healthy individuals, immune defender T cells secrete a protein called apoptosis inhibitor five (API5), which signals the immune system to halt the attack on gut-lining cells. This protein adds an extra layer of protection against immune damage, so even those with the mutation can have a healthy gut. However, the researchers also found that norovirus infection blocks T-cell secretion of API5 in mice bred to have a rodent form of Crohn’s disease, killing gut-lining cells in the process.

Led by researchers at the New York University (NYU) Grossman School of Medicine, the work supports the theory that API5 protects most people with the mutation against the disease until a second trigger, such as norovirus infection, pushes some across the disease threshold.

In experiments centered on mice genetically modified to have the mutation linked to Crohn’s disease in humans, mice that received an injection of API5 survived, while half of the untreated group died. This confirmed the idea that the protein protects gut cells, say the study authors. In human tissue, the investigators found that those with Crohn’s disease had between fivefold and tenfold fewer API5-producing T cells in their gut tissue as those without the illness.

“Our findings offer new insight into the key role that apoptosis inhibitor five plays in Crohn’s disease,” says study lead author and gastroenterologist Yu Matsuzawa-Ishimoto, MD, PhD. “This molecule may provide a new target for treating this chronic autoimmune illness, which has proven difficult to manage over the long term.”

Dr. Matsuzawa-Ishimoto, a postdoctoral research fellow at NYU Langone Health, notes that current therapies, which work by suppressing the immune system, put patients at high risk for infection and often become less effective after a few years of use. A treatment method targeting API5, he adds, might avert those issues.

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