New Insight into the Immune System’s Role in Cluster Headache

A prospective case-control study reveals changes in cytokine levels in chronic CH, episodic CH in bout, and episodic CH in remission, compared to healthy controls.

The pathophysiological processes driving cluster headache (CH), a rare type of headache disorder characterized by intense unilateral pain in, around, or behind the eye, remain a bit of a mystery in the world of headache science. But one clue is that CH responds well to corticosteroids, like prednisone, which are drugs that quell the immune response. That’s led to the hypothesis that the condition is somehow related to a problem with the immune system.

Now, researchers from the Danish Headache Center, Rigshospitalet – Glostrup, Denmark, report new evidence for a role of the immune system in CH. The group measured levels of 45 cytokines – small cell-signaling molecules released by immune cells – in more than 300 people with chronic CH, episodic CH in bout, or episodic CH in remission, and compared them to 100 age- and sex-matched healthy controls.

Differences in plasma levels of certain cytokines emerged in all three headache groups, compared to controls. Of note, each of the three headache groups showed increased levels of Oncostatin M, a member of the interleukin (IL)-6 cytokine family and one that has been linked to inflammation and pain regulation. The study also found a difference between chronic and episodic CH, with an association of IL-1β with chronic CH, but not episodic CH in bout.

Caroline Ran, a researcher at Karolinska Institutet’s Centre for Cluster Headache, Stockholm, Sweden, who published a 2024 study in The Journal of Headache and Pain that also looked at cytokine levels in CH patients, told MSC that the results were “super interesting.”

“This study is well powered and, in combination with our work, offers some concrete evidence that inflammation is important in CH,” she said. “This opens up a lot of potentially very exciting studies for the future to understand the mechanisms behind these different cytokine patterns,” according to Ran, who was not involved with the new work.

The study appeared online ahead of print on February 21, 2025, in Annals of Neurology.

A faulty immune response
First author Nunu Laura Timotheussen Lund, a headache clinician and researcher at the Danish Headache Centre, said that CH presents differently than typical migraine or tension-type headache disorders. Not only are the attacks extremely severe, but they have a “striking rhythmicity,” according to Lund.

“Patients tell us they get these headaches at very specific time points during the day. Many wake up with attacks during the night,” she said. “But although they have these clear attack periods, something can happen, and they will often go into full remission and not have any attacks for months or even years. The big question for us has been, What is the switch?”

Lund said the immune system seemed like a good place to look for answers, especially since prednisone, which modulates cytokines, is a quite effective drug for CH, even though it does not work particularly well for migraine or other headache types.

“This led to the hypothesis that the immune system must be involved with CH, that maybe there is neuroinflammation and that explains the pain,” she said. “Imaging studies have not been able to show that, so a new approach has been to look at systemic measurements [of cytokines] in the immune system. But the studies that have taken that approach thus far have been small and inconclusive.”

In her earlier study, Ran and colleagues looked at cytokine levels in serum and cerebrospinal fluid from 34 people with CH in remission, in active bout, or during an attack. Levels of nearly a dozen cytokines differed between the headache and healthy control groups, with IL-13 differentially expressed during CH attacks; IL-13 levels were higher during an attack compared to controls and compared to patients in remission or in active bout. But, Ran said, the study’s small sample size made it difficult to detect potential differences between groups.

“There are not that many people who suffer from CH. It’s difficult to get a big enough research sample,” she said. “The IL-13 result comes from information from only three participants. While we saw a trend in the data, that’s not enough to do formal statistical testing.”

A different pattern of cytokine release
For the new research, Lund’s team made use of biological sample data from the Danish Cluster Headache Biobank, a repository of information related to potential CH biomarkers. They recruited more than 300 study participants: 99 with chronic CH, 108 with episodic CH in bout (defined as having at least one attack in the past week), and 105 with episodic CH who were in remission (being free of attacks for at least 3 weeks). They then measured levels of 45 different cytokines in the CH patients, and in 100 age- and sex-matched healthy controls.

The investigators saw alterations in 13 cytokines in the episodic CH in bout group, 3 in the episodic CH remission group, and 10 in the chronic CH group, compared to controls. One cytokine in particular, Oncostatin M, was significantly elevated in all three CH groups.

Cytokines also differed between chronic CH and episodic CH in bout, suggestive of different pathophysiological mechanisms in those CH states. Notably, higher IL-1β, the cytokine that has received the most attention in CH research, was associated with having chronic CH rather than episodic CH in bout. In terms of potential mechanisms, the authors noted in their paper that calcitonin gene-related peptide (CGRP) can stimulate the secretion of IL-1β from trigeminal neurons and other cells, while the cytokine can cause secretion of CGRP in trigeminal ganglia neurons.

Lund said the results confirm the team’s suspicion that the immune system is involved with CH.

“For some groups of cytokines, you see that the levels are elevated. For others, the levels are reduced,” she said. “This was what we expected and hoped for. But the Oncostatin M was a bit of a surprise. It was not only altered in chronic patients, but also episodic patients in bout and those who were in remission.”

Regarding Oncostatin M, previous research has shown that this cytokine can regulate pain, and it’s also been linked to migraine in some studies. And, given that receptors for Oncostatin M are expressed in the human trigeminal ganglion, Lund said it’s plausible that it could play an important part in CH.

“It is possible that this cytokine may have a role in the severe pain associated with CH, although it is a hypothesis that still needs to be confirmed,” she said.

Next steps
In terms of future work, Lund said she and her colleagues hope that they, or another group, can replicate the findings in a new group of CH patients. That could provide further information about the feasibility of targeting Oncostatin M to treat CH.

For her part, Ran said it is exciting to see the results from the new paper. While she added that few of the cytokine markers replicated across her and the Danish group’s studies, she also said it’s obvious that many of the alterations observed in the two data sets are “going in the same direction.” She also hopes future studies will delve into the mechanisms responsible for the changing levels of different inflammatory markers in CH.

“We need to understand the biological relevance because inflammatory markers often have overlapping effects. If one is higher or lower, what does it really mean? Do some markers have a joint effect in CH? How do they relate to CH? These are things we need to look at,” she said. “But these data definitely implicate that inflammatory factors could be a target for future pharmaceutical therapies. This could open up discovery of new anti-inflammatory drugs that work in CH.”

Kayt Sukel is a freelance writer based outside of Houston, Texas.

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Reference
Distinct alterations of inflammatory biomarkers in cluster headache: A case control study.
Lund et al.
Ann Neurol. 2025 Feb 21. Online ahead of print.