Push to ‘repair the mitochondria’ may revolutionize rheumatoid arthritis treatment

Last year, a presentation at the American College of Rheumatology Convergence provided a glimpse into a potential mechanism of inflammation in rheumatoid arthritis that may fundamentally alter treatment approaches.

Cornelia M. Weyand, MD, PhD, a professor of medicine and immunology at the Mayo Clinic College of Medicine and Science, and professor emerita of medicine at the Stanford University School of Medicine, presented the data at the meeting’s Klemperer Memorial Lecture, “Rheumatoid Arthritis as a Mitochondrial Disease.”

In the talk, she described the immune system of patients with RA as being “in a state of bioenergetic stress.”

According to Weyand, the root of this stress lies in the mitochondria and goes back more than a billion years into human evolution. The endoplasmic reticulum is implicated. Dead T cells are implicated. A deeper understanding of the over-production of TNF alpha has been gained.

Immunosuppressive medications to mitigate this production of TNF have been the mainstay of RA treatment for decades. However, the findings by Weyand and colleagues may upend that approach and provide clues to stopping RA before it starts.

Healio sat down with Weyand to take a deep dive into cellular biology, the concerns with TNF inhibition in RA, and how her findings may point the way toward treatment of the disease in the future.

Healio: Why is it so important to find the mechanism driving inflammation in RA?

Weyand: Seventy years of research has firmly established that RA is an autoimmune disease, yet we have not found a way of curing it. We have not been able to reset the immune system so that it will not make the mistake that leads to RA. We have developed means to suppress inflammation, but those methods are not going to the root of the disease. They are working at the very distant end of the disease process.

Today, we know that RA is a decades-long disease process. It starts long before we ever see the patient. By the time we see them, we have objective evidence that the patient has broken immune tolerance. We see that by measuring antibodies reactive against self-antigens. The immune system of the patient has lost the ability to recognize the difference between self and non-self. The end result is chronic, relentless inflammation in the joints.

Healio: How does your research fit into this narrative?

Weyand: Well, it would be much better if we understood how the patients arrived at this point where they mobilize their immune system to attack the tissues of the joint. The joints are what we see most, but the loss of self-tolerance also leads to inflammation in the cardiovascular system, the lungs, the gut, the skin, etc.

As a field we have realized that we need to think much earlier in the disease process. Pre-disease is already late. By the time we categorize an individual to be in pre-disease, the immunological problem has already occurred because that is how we find it. By the time we define pre-disease, the immune system has already escaped from tolerance and from being functional. So, we need to go much earlier into the life of our patients to understand the mechanisms and roots of disease. That gives us a chance to think in a curative way.

Healio: Why did you choose to target the mitochondria to gain this understanding? What evidence or prior research pushed you in that direction?

Weyand: The immune system of everyone ages as we go through life. It begins at about age 20, and it accelerates when we turn 50. By the time we get into our 70s, the immune system has a strong signature of immune aging.

About 20 years ago, we made the observation that the immune system of patients with RA is about 25 years older than the chronological age of that individual. Over the last 2 decades, we have investigated that observation. That led us to the mitochondria because the way the immune system ages is closely intertwined with how the mitochondria ages. Immune ageing is a consequence of mitochondrial frailty.

Healio: This takes us to the mitochondria. How do the immune cells of patients with RA have difficulty producing energy?

Weyand: Mitochondria are the power plants of the cell. They produce the energy. They produce it in a currency that is called adenosine triphosphate (ATP). ATP functions like a little battery. It briefly stores energy so that the cell can support the bioenergetic needs for survival and function.

If you go into the adaptive immune system of a patient with RA, you will see that T cells make about half as much ATP as in age-matched healthy controls. That led us to investigate how the mitochondria works precisely. We have dedicated the last 8 years to understanding how mitochondria get older, how that process of mitochondrial aging results in lower energy production and how that makes the cell an inflammatory cell.

Healio: What have you discovered in those 8 years of research?

Weyand: The first thing to understand is that mitochondria arrived in the cell as bacteria about 1.5 billion years ago. These bacteria made a deal with the cell. They agreed to pay their rent in the form of ATP, becoming the cell’s main energy producer. In return, the cell agreed to let them stay in the cytoplasm and not kill them.

However, what we have learned is that in patients with RA, the mitochondria leaks mitochondrial DNA. This leakage of bacterial DNA into the host cell is problematic for that cell. The cell is forced to deal with this bacterial DNA. We have shown that one of the outcomes is that the cell actually dies because there is too little ATP and too much mitochondrial DNA. There is nothing as inflammatory as when a cell dies in the joint.

Healio: How does cellular metabolism factor into these processes?

Weyand: In addition to the mitochondria, the cell has other organelles in its cytoplasm, including the endoplasmic reticulum. This is where proteins and lipids are produced, the place where proteins are packaged and sent on their way. Protein synthesis and protein packaging is a highly energy dependent process. The endoplasmic reticulum and the mitochondria are dependent on each other. The processing and packaging machinery can only happen if there is sufficient ATP.

So, the cells of patients with RA are under enormous stress. An interesting consequence of that stress is that the cell starts to make more TNF. This begins with the mitochondria not working properly. They only pay half of the rent. This imposes high stress on the endoplasmic reticulum, and so the cell turns into a TNF super producer. In the inflamed joint, most of the TNF comes from T cells, which is why TNF has become an important target in RA therapy.

Healio: Why is suppressing the immune system with TNF inhibitors so problematic in RA?

Weyand: About 25 years ago, we learned that suppressing TNF is a valuable and important therapeutic intervention in RA. Today, it is hard to imagine treatment of the disease without that tool. This was the beginning of the biologic era. It was a revolution in rheumatology. However, blocking TNF does not cure the disease. It is a very elegant way of treating inflammation, but it does not eradicate the root of the inflammation. That is one concern.

The other concern lies in holding patients on anti-TNF therapy longitudinally. In order to control their inflammation and their disease, patients have to stay on these cytokine blockers on and on and on. One of our hurdles is that patients begin to develop an immune response against the anti-TNF therapeutic. Their immune system cuts off the branch that we are sitting on, so to speak. So, it is not easy for us to give TNF blockers over a long period and have persistent efficacy.

Healio: Are these the only concerns with TNF inhibition in RA?

Weyand: The other limitation that those therapies have is that although they block inflammation in the joint, they also block healthy inflammation. TNF was not invented by nature to cause RA. It was invented by nature to give our immune system tools to fight cancer and infection. When we give immunosuppressants, we pay a price for that. The price we pay is that the patient is less capable of rendering healthy immune responses.

We have not yet succeeded in being able to treat the dysfunctional immune response while simultaneously letting the healthy immune response go on intact.

Healio: It would seem that if your findings are correct and can be validated, it could fundamentally alter approaches to treating RA. What are the next steps in terms of research?

Weyand: The immune system has made a mistake that results in chronic tissue inflammation. We need to get in front of the process, not the end of the process, because, right now, we are fighting the end-stage battle. If we want to turn RA into a curable disease, we need to repair the immune system before the patient ever gets sick. That is where our research comes in. Can we repair the mitochondria? Can we improve their function before cells fail? That is our push right now.

Healio: Are there genetic markers that we could target in that push?

Weyand: That is definitely part of it. We observed that the premature aging phenotype is actually associated with the genetic risk factor that has been implicated in RA, the HLA-DR B1-04 haplotype. The genetic region that controls function of the adaptive immune system predisposes patients to RA, and it also predisposes people to the premature aging of the immune system. We are deep into this.

Healio: What are your thoughts on approaches boosting and strengthening the immune system, rather than suppressing it? Should pharmacotherapeutic options be developed? Or is it a matter of exercise, mindfulness and other non-pharma approaches? Or some combination thereof?

Weyand: Efforts and approaches to make the immune system stronger in an RA patient go hand-in-hand with approaches the field is developing to manage immune aging overall. The field of managing the aging process on the human body is rapidly expanding. There is great interest in it.

Exercise and nutrition, of course, are components of it. Nutrition dovetails nicely with our studies of the mitochondria, but we are beginning to be very interested in the impact of stress on the immune system. A multifaceted approach is required to improve immunocompetence.

We also have to be careful of putting patients on immunosuppressants that further inhibit the immune system. This is why we are doing the work that we are doing, to get closer to curative therapies in RA.