New therapeutic targets provide hope for targeted treatments for rheumatoid diseases.
New research about rheumatoid arthritis (RA) keeps uncovering additional mechanisms behind RA and other similar diseases, including new findings about its metabolic processes.
Inflammation is a more damaging process than previously known, recent research has found. Macrophages and dendritic cells are the first-line of defense against pathogen, but pro-inflammatory stimuli can cause these cells to move from oxidative phosphorylation toward glycolysis.
This changed metabolic pathway can increase cytokine production to damage joints and potentially affect other tissues, according to a session presented at the American College of Rheumatology and Association of Rheumatology Health Professionals annual meeting.
“Metabolites are being implicated in inflammatory events in the joints,” said Luke O’Neill, PhD, Professor and Chair of Biochemistry at Trinity College Dublin, Ireland. “In a nutshell, we are uncovering metabolic processes that can drive events like rheumatoid and osteoarthritis.”
The metabolite succinate was an early finding that lead to a better understanding of how inflammation can alter metabolic processes to promote different autoimmune diseases. Succinate is crucial for the inflammatory response in macrophages, since it shifts its metabolism toward glycolysis, which drives production of inflammatory cytokines such as interleukin-1, Dr O’Neill said.
Succinate is also able to change the behavior of mitochondria, and makes the cells create reactive oxygen species that increase the creation of interleukin-1B and other inflammatory cytokines. This causes the Krebs cycle to become coupled into producing inflammatory cytokines.
“The overarching principle of immuno-metabolism is to integrate metabolism with the production of cytokines that can result in disease,” Dr. O’Neill said. “It is an entirely new way to look at cytokine dysregulation as a result of inflammatory changes. We have long known that inflammation can disrupt cytokine regulation and production. Now we are starting to understand how and where it happens and find some really promising targets. There is already significant development in interrupting the activity of key metabolic pathways in inflammation. It is the kind of very directed basic research that could well give rise to new therapies down the line. I wouldn’t put a timeline on it, but there are some very promising new directions that I will be talking about.”
Newer research investigates other targets rather than just succinate, including the enzymes that are both active in glycolysis and antigens seen in rheumatoid diseases. One of these targets is enolase, which is an autoantigen involved with RA, and is involved with glycolysis.
Specifically, immunometabolic changes that promote glycolysis are an area of great interest, according to the session. The study of immuno-metabolism shows promise in creating new drugs, as well as new drug delivery techniques and small molecule oral drugs.
The creation of more effective small molecule oral drugs could potentially replace large molecule injectable biologic drugs that are common for rheumatoid disease treatments. Biologics have been a great improvement over older disease-modifying antirheumatic drugs, but can be costly and have serious side effects.
These biologic drugs can also have complex administration that may prevent certain patients from receiving proper treatments.
A new, targeted treatment that is more patient-friendly has been attracting interest from both pharmaceutical companies and academic researchers, according to the study.
“The whole area of immuno-metabolism is burgeoning,” Dr. O’Neill said. “The metabolic changes seen in inflamed joints have been known about for decades. It has been known for years that some of the glycolytic enzymes we see in inflamed joints are also autoantigens. We are finally starting to fit these pieces together and understand very precisely how these changes relate to disease pathogenesis.”