Osteoarthritis: New trial drug has powerful anti-inflammatory effect

A new drug that researchers are currently trialing to treat osteoarthritis can dampen the harmful effects of an overactive immune system while protecting its beneficial functions. The drug could, therefore, potentially treat rheumatoid arthritis, as well as other conditions resulting from inflammation.

The network of cells and signaling molecules that make up the body’s immune system are critical to our survival. In the time of COVID-19, this has perhaps never been clearer.

Yet the human immune system must maintain a delicate balance. If this balance tips over into overactivity, the immune system can be extremely harmful to the body.

Indeed, an overambitious immune system causes a raft of diseases. These include inflammatory bowel disease, multiple sclerosis, and some forms of arthritis, which the medical community groups as autoimmune disorders. Scientists usually consider osteoarthritis, in contrast, to be a disease of “wear and tear,” and they have only recently begun to understand the role of inflammation in its progression.

In a study that the journal Inflammopharmacology recently published, researchers from the University of Liverpool in the United Kingdom found that a new trial drug for osteoarthritis could help keep the immune system in check while ensuring that its protective functions remain intact.

The project is a collaboration with pharmaceutical company AKL Research & Development, and the finding could lead to the use of the drug for more targeted treatments for rheumatoid arthritis and other diseases that occur due to inflammatory processes.

Neutrophils and the cytokine storm

The study focused on the role of neutrophils, which are the most common type of white blood cell and act as the first line of defense in the immune system.

When the body encounters a pathogen, it rapidly dispatches neutrophils to the site of infection where they capture and destroy the pathogen. They also produce signaling molecules called cytokines, which recruit other immune cells to help fight the infection.

Usually, this is a helpful response, but sometimes, neutrophils become hyperactive, or there is an impairment of the mechanisms that regulate their activity. Either situation results in the release of too many cytokines, sometimes even in the absence of an infection. Excessive cytokines trigger an inflammatory reaction that is detrimental to the body’s tissues. In extreme cases, the level of cytokine release is so high that it is called a “cytokine storm.”

These so-called storms of pro-inflammatory cytokines cause extreme inflammation that can damage the circulatory system, leading to leakage of serum from the blood into the tissues and collapse of the vascular system. The consequences, which include organ failure, can be severe and may even be fatal.

The new drug: APPA

In this context, the goal of drug development is to suppress the harmful activity of the immune system without impairing its ability to fight infection.

“Therapeutically targeting the harmful effects of neutrophils in inflammation, without interfering with their ability to fight off infections, has been a long-term goal of many scientists worldwide,” explains Prof. Steve Edwards, a neutrophil expert at the University of Liverpool.

In collaboration with AKL Research & Development, Prof. Edwards and his team have tested the action of a new combination drug called APPA on the functioning of neutrophils. The new drug consists of the plant-derived molecules apocynin and paeonol. AKL initially developed the drug to treat osteoarthritis, a degenerative disease of the joints that affects more than 32.5 million adults in the United States.

To look at the impact of APPA on neutrophils in detail, the team isolated these cells from the blood of healthy volunteers and treated them with APPA in a range of concentrations before looking at the effect on various important functions of the cells.

These included beneficial processes, such as phagocytosis (how neutrophils “eat” bacteria and other pathogens) and bacterial killing and movement. The researchers also considered potentially harmful processes, such as the production of reactive oxygen species (ROS, another set of signaling molecules that can cause inflammation) and cytokine release.

A targeted approach

They found that APPA successfully decreased levels of ROS and cytokine expression but had no effect on the ability of neutrophils to defend against infection by physically attacking the bacteria.

“We have shown that APPA has the potential to dampen down that bad inflammation that causes rheumatic diseases but not impact on the crucial antimicrobial function of neutrophils. We have been waiting for too many years for such a selective drug.”

– Robert Moots, professor of rheumatology at the University of Liverpool

Interestingly, some of the cytokines that APPA regulates also play a role in the cytokine storms that researchers have observed in COVID-19 patients, lending weight to the idea that APPA could have much broader applications.

“Our results suggest a prime role for APPA in helping safely modify aggressive immune response, not only in the arthritis that I treat every day but even, potentially, in COVID-19,” says Prof. Moots.

Preventing such cytokine storms in COVID-19 could become an important part of the treatment regimen. The selective approach of a drug such as APPA, which blocks the harmful effects of an overactive immune system without stopping its ability to fight infection, could be a fruitful area of research once clinical trials on this new drug are complete.

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