Projects Funded

Understanding Fibromyalgia Flares

 Principal Investigator: Nick Fallon, Ph.D.; Andreas Goebel, M.D., Ph.D. (Co-PI)
University of Liverpool, United Kingdom

When a fibromyalgia flare hits, it’s common to ask: What did I do to cause this? Flares typically last more than three days and often occur once a month.¹ During this time, all you can do is brace yourself because treatment approaches tend to be ineffective. Until your symptoms level out, you may be down for the count (i.e., resting in bed).

Flares are debilitating and life-disrupting, but no one has figured out what sets them off. Do the pain control mechanisms in your spinal cord just give out or do the processes in your brain become more scrambled than they already are? Or perhaps the key player is a hyperactive immune system that spews out chemicals to make you feel sick.

Identifying what happens during flares will bring researchers closer to understanding what drives your fibromyalgia symptoms through the roof. And that’s the focus of this AFSA study.

Neuroimaging expert Nick Fallon, Ph.D., in collaboration with Andreas Goebel, M.D., Ph.D. (pain immunologists), form a unique team to sort out what happens during flares. “We hypothesize that fibromyalgia flares are associated with alterations in brain function and with an activation of the adaptive immune system,” says the two investigators.

Your adaptive immune processes release chemicals (such as cytokines) and antibodies to attack and destroy foreign invaders. Once the threat is neutralized, your adaptive immune system retains a memory of the invader in case it tries to strike again. Of course, a glitch in this series of events can lead to autoimmune diseases. A prior study by Goebel shows that fibromyalgia patients produce antibodies that attack the satellite glial cells or SGCs.² The SGCs surround the neurons at the entrance to spinal cord.

While autoimmune diseases usually cause visible destruction of tissue (such as the joints), antibodies around the SGCs will ramp up the pain signals entering the cord. Tissue destruction would not be visible, but the pain and other symptoms caused by the attack would be very real.

Expectations

Multiple abnormalities in the way the brain, spinal cord, and immune system function in fibromyalgia are well documented. But in every published report there is a lot of variability. That’s because these studies only take a snapshot of what happens at one point in time. Some patients may be in a flare up, while others may be having a relatively good day.

This study is more like looking at a video than a snapshot. Fallon will evaluate fibromyalgia patients while experiencing everyday baseline symptoms and then again during a serious pain and fatigue exacerbation.

Fibromyalgia involves a dynamic series of processes that produce the wide-ranging symptoms. Think of it as a team sport, except in this case, victory is the flare that cranks up your symptoms. By examining the difference between baseline and flare episodes, Fallon hopes to identify the most valuable player (MVP) on the team. This player (or process) is most responsible for your symptoms while the rest of the team just does as they are told.

The functioning of the brain, spinal cord, and adaptive immune system will be assessed before and during fibromyalgia flare episodes. In addition, all subjects will undergo a variety of pain measures at both time points to objectively confirm the significant increase in pain sensitivity. “We anticipate that flare-specific patterns of brain activity and immune activation will be observed,” says Fallon.

Brain
Do the brain networks communicate differently during flare episodes (typically a 30 percent increase in fibromyalgia symptoms)? What about regional changes in gray matter volumes? And how effectively does the brain respond to a painful stimulus during a fibro flare? These questions will be addressed by using functional MRI (fMRI) of patients at baseline and during the peak of their symptom flare.

Other brain imaging studies in fibromyalgia patients show unhealthy communications between certain brain centers. “Differences in the brain are now known to be associated with pain intensity reported on the day of testing,” says Fallon. So, during flare episodes, Fallon suspects this communication “chatter” among some brain networks will be worse.³ Commenting on this, “No research studies have ever evaluated brain function in fibromyalgia during a flare and compared it to baseline function.”

Spinal Cord
Not only is your brain not working properly, the pain inhibitory processes in your spinal cord don’t function well either. The cord is supposed to pour out opioids when the body is subjected to pain. However, when fibromyalgia patients are given a painful stimulus, about half of them feel increased discomfort.⁴

If you look at the spinal cord as one of the players on a team, it appears to be unreliable half of the time. Fallon expects to show that the spinal cord fails to score any points for relieving pain during a symptom flare. In fact, it may just rack up penalties!

Immune System
The immune system’s role in fibromyalgia consists of many players. Looking at any one player won’t give you the score on what is happening in this disease. So, Goebel is assessing the following suspects to determine which one is likely to be the team’s MVP:

Cytokines – These substances are increased when the immune system is activated and many are elevated in fibromyalgia.⁵ Fallon is measuring several cytokines and expects their concentrations to increase during flares.

GFAP – This is a chemical released by satellite glial cells (SGCs) in response to injury or inflammation. It has also been proposed as a marker of inflammation in the brain. Prior studies (including one funded by AFSA) show neuroinflammation throughout the brain in fibromyalgia patients. GFAP is included in the serum analysis to determine if it tracks with symptom severity. Perhaps when patients are in a flare, this player scores more points. In addition, Goebel says, “It could be a potential biomarker for fibromyalgia.”

Anti-SGC Antibodies – When the antibody-portion of the serum from fibromyalgia patients is injected into mice, antibodies are found attacking the SGCs. “Increased concentration of these antibodies are expected during flare episodes in fibromyalgia patients,” says Goebel.

B Cells – These cells are important players in the body’s adaptive immune response. They produce antibodies that kill infectious agents. B cells can also become overly sensitized. In fibromyalgia, this means changing the function of the cells they attack rather than destroying them. It’s like a team player that gets carried away, doesn’t follow the rules, and knocks other teammates down. Goebel suspects B cells will be more active and possibly more sensitized during flare episodes in fibromyalgia patients.

General Hypothesis
When the video reels of the fibromyalgia team players at baseline and during flares are compared, what do Fallon and Goebel expect to see?  They suspect the MVP will be enhanced B cell activity. Increased antibody concentrations (anti-SGC antibodies) and cytokines will assist the MVP to score points. These immune system players will signal the spinal cord and brain to get more involved in the game of making fibromyalgia patients feel awful.

Study Design

Twenty fibromyalgia patients will be followed over an 18-month period. They will use a cell phone app to chart their daily symptoms of pain and fatigue to detect when they are in a flare episode. A flare episode is defined as an increase in symptom scores (on a scale from 0 to 10) of at least two points for more than three days. This is roughly a 30 percent increase in symptoms.

Prior to the flare, patients will undergo a battery of testing and they will be repeated when patients are in a flare episode. Brain imaging data, spinal cord processes, and immunological functions will be compared for each patient at baseline and during the flare.   

Potential Benefits

“Investigating symptom flares may provide unique insight into the cause of a person’s fibromyalgia symptoms,” says Fallon. This study will certainly help highlight which players (or processes) make the symptoms worse, and which players are just along for the ride.

“For the first time, brain scans and immunological investigations will be carried out during a flare in fibromyalgia patients,” says Fallon. “This allows for a correlation between the neurological and immune systems. It may also address the dynamics of the disease.”

“This study may also uncover potential biomarkers that could aid in the early recognition and diagnosis of this disease,” says Goebel. Although he adds that if promising markers are found, additional larger-scale studies would be needed for validating them.

How might a biomarker fit into the team sports analogy? Consider it to be the equivalent of a “set play” or strategy that scores points at least 95 percent of the time.

Want to see more studies like this? Help AFSA fund more research. Donate Today!

1. Gomez-Arguelles JM, et al. Reumatologia 60(4):242-246, 2022.
2. Goebel A, et al. J Clin Invest 131(13):e144201, 2021.
3. Fallon N, et al. PLOS ONE 11(7):e0159198, 2016.
4. Potvin S, Marchand S. PAIN 157(8):1704-1710, 2016.
5. O’Mahony LF, et al. Rheumatology 60:2602-2614, 2021.