The connection between fatigue and spondyloarthritis, as well as other inflammatory arthritic conditions, is well known and documented, but not always well understood. Dr. Mechiel Korte has extensive expertise in this, both as an esteemed researcher dedicated to studying fatigue, as well as someone living with spondyloarthritis for 44 years. He recently published an in-depth article on fatigue in inflammatory rheumatic conditions in the peer reviewed journal, Rheumatology, and we were thrilled to have the opportunity to discuss the topic with him. As timing would work out, the COVID-19 pandemic was underway, and we were able to touch on this pressing topic in our interview. Our deep gratitude to Dr. Korte for discussing both fatigue, and his thoughts on COVID-19 with us.
You often call people with spondyloarthritis “warriors.” Can you discuss why?
Many people with spondyloarthritis (SpA) have a gene called HLA-B27. In some people, this gene – in combination with an infection or some musculoskeletal strain or injury (also called mechanical stress) – can trigger SpA. The exact mechanism, however, is still unknown. Why do many of us have this gene when it negatively affects the body? The answer is simple: It does not only produce negative effects. The owners of this gene have a very strong immune defense system, protecting them (fully or partly) from many viruses, such as HIV (AIDS), hepatitis C, influenza, Epstein–Barr virus, herpes simplex virus, and hantavirus infection, and probably even smallpox in the past. That’s why I call people with the HLA-B27 gene – and everyone living with SpA – “warriors.” They are very strong, and genetically speaking, sometimes too strong. The immune response of people with the HLA-B27 gene can be very aggressive, combating viruses, but at the same time this aggressive immune response can have very harmful effects, as we all know too well.
How did you become interested in investigating SpA and fatigue?
When I was a teenager and visited the rheumatologist, in the waiting room I would sometimes see people in wheelchairs, people with bent spines (like my own uncle), or those walking with mobility devices. Since the introduction of biologic drugs, much has improved. Nowadays, SpA often presents like an iceberg. Above water, you don’t see much. But underwater, there are disabling symptoms, including severe fatigue. It is difficult to explain to healthy people how this fatigue feels. Unfortunately, I know exactly how it feels. When I realized I was not the only one, I decided to focus my research on this specific topic and to do my utmost to improve the quality of life of people with SpA who suffer from fatigue.
How does fatigue differ from the common state of feeling tired?
The feeling of being tired improves after sleep. This is not the case for fatigue in people with SpA. In a way, fatigue has many similarities with how you feel after a flu or food poisoning, with one big difference – it doesn’t go away after some weeks of rest.
How common is fatigue in those with spondyloarthritis, and how does it affect quality of life?
Recently, I gave a presentation for over 1,000 patients with inflammatory rheumatic disorders (including SpA) in the Netherlands. When I asked them who suffered from fatigue, about 60-80% of the audience raised their hands. Recently, the Dutch Arthritis Society asked 6,000 patients what their biggest problems were. Remarkably, they answered that fatigue was by far the biggest problem, followed by pain, and lack of understanding from family and friends, employers, and society. This is understandable, because from the outside you do not see fatigue.
How and why does fatigue occur in spondyloarthritis? What are the processes, chemical changes, and functions that produce the severe fatigue seen in spondyloarthritis?
First, the causes of fatigue: Spondyloarthritis is characterized by inflammation. During the inflammatory process many immune cells are activated, and these cells release inflammatory substances (also called cytokines, such as IL-1, IL-6 and TNF-alpha). These substances affect brain functioning via different routes. As a result, the balance of signaling substances (neurotransmitters) in the brain changes. For instance, decreased concentrations of dopamine and serotonin can be observed in specific brain areas that are involved in the regulation of motivation, reward, cognition, and more.
Second, the processes that produce fatigue: Although more research is needed, we can speculate that lower dopamine and serotonin levels in the brain increase fatigue.
Dopamine produces a motivational signal in the brain. It invigorates and energizes you toward a distinct goal. Thus, when there is more inflammation in SpA and consequently lower dopamine levels in the brain, one is not energized to do things that normally produce pleasure, like going to a movie or restaurant.
Serotonin in the brain is involved in the regulation of many behaviors, because it plays a crucial role in reward-cost valuation. As inflammation lowers serotonin levels in the brain, a signal is sent that behavioral actions have higher energy costs than they normally do, therefore causing the person to abstain from activities to conserve energy. Recently, it became clear that serotonin can directly influence neuronal powerplants (mitochondria) that produce energy in cells, including brain cells. Again, lower serotonin levels give a signal that there is less energy available, which might suppress normal social behavior.
Third, why is fatigue so prevalent: Without a doubt, this is the most difficult question. Normally, illness, including fever and fatigue brought on by infection with a virus or bacteria, can be functional (that is to say, they have an evolutionary or biological benefit). The lower serotonin and dopamine levels produce a feeling of fatigue, and because less energy is available, one is no longer energized or motivated to do things. Consequently, you withdraw socially so that A) you do not infect other group members, and B) you save your energy to fight the infection and to recover. This is functional and subsides when you recover from an infection. But inflammation in SpA is often a chronic process, so consequently, we often suffer from chronic fatigue. Remarkably, people with SpA who suffer from fatigue seem to have a biological advantage right now because they do not have the energy to be socially active and so they tend to be less exposed as a result. (On a side note, one of the problems in this pandemic is that COVID-19 does not always produce these typical sickness symptoms, such as fever or fatigue, in everyone, so infected people are sometimes still energized and motivated to do things and be socially active, meanwhile spreading the disease.)
Speaking of COVID-19, with the pandemic encircling the globe everything seems to be different. Are you concerned for your safety? What would you like to share about this health crisis with our readers?
There is always a question in the back of my mind of, “What if?” I am not a medical doctor but a neuroscientist who investigates immune-brain interactions, including the role of stress. Uncertainty and unpredictability are known to produce stress. Long-term stress is bad for the immune system. So, it is important to control stress levels. The best way to prevent stress is to focus on what you can do. What can we do? Honestly, together we can do so many things.
First, trust the medical experts, follow their advice, and ask questions when you need answers.
Second, the virus does not have legs or wings; it is just dead material. This means that the virus can only spread with the help of people. Thus, stop helping the virus by taking these steps:
Third, giving support to others is one the of best ways to suppress your own, and others’ stress levels. Even when we cannot physically visit relatives and friends (especially if we, or our loved ones, are at higher risk), we can maintain our connections virtually, and offer support through phone calls, emails, and online platforms.
If you are able and if it is safe for you to do so, offering to pick up medications and groceries (or helping order them online) can go a long way for those most at risk. If you are at higher risk, asking loved ones to help with these needs may provide them with a welcome opportunity to support you, and lower their stress levels by being supportive in this way. Please keep in mind that you should still maintain the 6-foot distance when delivering or receiving supplies.
What worries you most?
At this moment, it is clear that the virus produces asymptomatic behavior in some. What does this mean to us all? In Iceland, they tested a very large group of the population and the findings indicated that COVID-19 can produce a wide spectrum of symptoms, from people who have no symptoms at all (including many children), to people with cold-like symptoms (runny nose, congestion, sore throat, no smell, no taste), to people with high fevers, muscle aches, shortness of breath, cough, and fatigue.
Normally, with a viral infection, you experience the typical symptoms mentioned above, including fatigue. With COVID-19, however, some people get infected with the novel coronavirus without knowing it, and they may spread the disease unwittingly. This is probably one of the reasons why COVID-19 is so effectively spreading around the world. Therefore, all people, including those feeling good and healthy, should respect the 6 feet of distance rule in my opinion. This is crucial!
Thank you very much for that! Getting back to our original topic: Is fatigue caused or made worse by something a person does or doesn’t do?
First of all, let me make something clear: The severe fatigue associated with spondyloarthritis is a consequence of the inflammatory disease; it is not a character flaw. A strong character can probably make it even worse. For many years, I just ignored the feelings of fatigue and finally I ended up with serious burn-out. One must listen to their body’s signals. Often, I was frustrated – which in itself uses a lot of energy – when I was not able to join family or friends going to a restaurant or to the movies. After consulting a psychotherapist, I learned to accept the situation. Now, when I really want to go somewhere, I try not to do too much in the days before, to conserve energy. But honestly, deep inside my brain is an ambitious voice telling me never to accept SpA and fatigue. The dream that there will come a time when we can treat fatigue in everyone with SpA keeps me going. I cannot do it by myself; we need each other. That’s why I would like to collaborate much more with people with SpA, because there is so much shared knowledge among patients.
Are there different kinds of fatigue? Do they originate in different parts of the brain?
Yes, there are. This is what I learned from both patients and animal studies. Fortunately, the eminent professor in rheumatology, Dr. Joel Taurog from the University of Texas Southwestern Medical Center, Dallas, was so kind as to provide us with an animal model with the human HLA-B27 gene. Surprisingly, there are at least three different forms of fatigue that can exist in SpA: 1) Motivational fatigue (I do not want to do anything); 2) Physical fatigue (I have difficulties performing physical tasks); and finally, 3) Cognitive fatigue (I have difficulties concentrating). Indeed, evidence is accumulating that different brain areas are involved in these different types of fatigue.
Let’s discuss treatments – medications and other options that may be helpful in battling fatigue. To start, does combatting inflammation with medication always alleviate fatigue?
Fortunately, both NSAIDs and biologics can effectively reduce inflammation, but surprisingly these drugs have a much greater effect on pain than on fatigue. The hypothesis that I would like to investigate is that long-standing inflammation has changed the function and probably even the shape of brain cells. This would imply that once inflammation is lowered, brain function and the shape of brain cells do not automatically return to their original healthy state. At this moment, there is no proven effective therapy. This is one of the reasons why we desperately need to do more research!
Is there anything you personally find helpful in reducing fatigue? What does the research support?
It is too early to present solutions. At this moment, I am writing a grant to obtain funding to research food supplements that may be used to restore the neurotransmitter balance, the shape of brain cells, and brain functioning after inflammation. There is some evidence from other areas of brain research that walking every day for at least 30-60 minutes improves cognition, and may also reduce cognitive fatigue. Although this is not always easy with arthritis, remember that you can start small, because every step counts.
What is the future of fatigue research, and what do you hope to see on the horizon?
I am aiming for a cure. It is likely that a multidisciplinary approach is needed with biologics/NSAIDs as early as possible during disease development; specific amino acids and specific vitamins to restore neurotransmitter balance; psychotherapy to reduce stress and frustration; and daily exercise.
As someone living with spondyloarthritis and who understands the severe fatigue often associated with it, what do you wish others – your peers, friends, medical professionals, the general public – understood about the fatigue that you and so many others battle?
People do not choose to have a hyperactive immune system; they do not choose to have SpA or fatigue. It is fate. Fatigue is not a character flaw! It is a serious symptom of the disease, brought on by systemic inflammation throughout the body (including joints, gut, skin, and organs). It is this inflammation that prompts the brain to produce fatigue. People with SpA are not crazy or lazy, and they can perform much better when they receive support. Do not judge somebody with SpA or hold them to the same schedule that healthy people follow. In the mornings especially, motivational and physical fatigue can be responsible for a slow start. Yet research has shown that people with a chronic disease are often highly motivated to work and successfully carry on their careers. They just need support, understanding ,and some flexibility in work hours
Dr. S. M. (Mechiel) Korte is Associate Professor of Neuroimmunopharmacology, at Utrecht University, in The Netherlands. He is also a Guest Professor at the Institute of Cognitive Neuroscience at Ruhr-University Bochum, in Germany.
He is lead author of the article, “Fatigue in Inflammatory Rheumatic Disorders: Pathophysiological Mechanisms,” published in the peer reviewed journal, Rheumatology. This work was supported by the Dutch Arthritis Society. He also has a website dedicated to educating the public about fatigue, at www.whyfatigue.com.
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