A pair of recently published longitudinal studies has shown a unique bidirectional association between migraine and rheumatoid arthritis (RA), suggesting the 2 disorders may be varied manifestations of similar or even shared pathophysiology.1

Studies during the past decade have examined overlaps in the occurrence of RA and migraine, although no strong correlation was established. A 2008 investigation of responses to NHANES surveys found that respondents with migraine were more likely to report at least 2 comorbid pain conditions, defined as low back pain and osteoporosis, as well as RA.2 Likewise, results of a prospective survey analysis published as the Migraine in America Symptoms and Treatments (MAST) Study in 2020 looked at the impact of comorbid conditions on the intensity of migraine-reported increases associated with the presence of other pain conditions such as osteoarthritis and RA.3 Yet another longitudinal study by Wang and colleagues found a significant increased risk for RA in patients with migraine.4 The results of all of these studies were unidirectional, and until recently, no study had evaluated the potential implications of a bidirectional correlation.

Prevalence

An estimated 40 million people in the US are affected by migraines, which are reported to occur in women more frequently than men.5,6 The prevalence in the US of about 12%, and 15% worldwide, makes migraine the second most disabling disorder affecting adults.5 Rheumatoid arthritis is the most common form of systemic arthritis, with a 1% global prevalence.6


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Korean Paired Cohorts

The paired studies evaluated 2 large, separate cohorts of patients with migraine and RA from Korea matched in a 1:4 ratio against control patients. All patients with active disease were diagnosed at least twice with either migraine or RA. Results from the first study demonstrated a higher incidence of RA among 31,589 patients previously diagnosed with migraine compared with 126,356 control patients (2% and 1.4%, respectively). The second cohort revealed a higher incidence of migraine among 9287 previously diagnosed  patients with RA compared with 37,148 control patients (6.4% and 4.6%, respectively).1

The overall prevalence of migraine in the Korean cohorts was 7.5%. About 7.6% of these patients experienced migraine with aura, which was a lower frequency than generally recognized from outside studies. The subgroup analyses supported the cross-correlation between migraine and RA, with the exception of men older than age 60 years in the RA cohort, who did not appear to have an increased risk for migraine. The study authors suggested that this trend might be related to the higher natural prevalence of migraine in  women, with a peak occurrence between the ages of 25 and 55 years, after which the incidence decreases.1

Potential Shared Mechanisms

The Korean investigations were based on hypotheses that observed mechanisms of inflammation, endothelial cell activation. and the immune system might create a bidirectional channel between migraine and RA. Currently, the underlying etiologies of migraine and RA are not well understood, although multiple mechanisms have been implicated in both. Understanding of migraine has only recently expanded beyond the original vascular mechanisms to include a broad range of potential contributing factors such as neuroinflammation, activation of CGRP, pituitary adenylate cyclase-activating peptides and proinflammatory substances, as well as hormonal changes. Endothelial and systemic inflammatory mechanisms have also been implicated in both migraine and RA, as well as metabolic dysfunction.1

That RA would be associated with migraine is not surprising, as there are a number of other diseases with inflammatory mechanisms that have been linked to migraine, including allergic rhinitis, asthma, lupus, post COVID headaches, and others, according to Vincent Martin, MD, Director of the Headache & Facial Pain Center, Gartner Neuroscience Institute at the University of Cincinnati College of Medicine, and President of the National Headache Foundation.

The literature has suggested that both inflammatory and immunologic mechanisms may be shared, contributing to a direct relationship between RA and migraine.1,3  “I suspect that inflammation is the most important mechanism,” Dr Martin said. “Inflammation tends to aggravate the sensitive trigeminal nerve that might make the development of migraine more likely. Another factor that could play a role is the fact that some of the medications used to treat RA might generate headaches.”

Shared Comorbidities

Comorbid conditions common to both RA and migraine include obesity, sleep disturbances, and particularly depression.1 These comorbidities are reported nearly twice as often in patients with chronic migraine (not episodic migraine), about 50% of whom also report pain-related comorbidities including osteoarthritis and RA. A 2019 review by Burch, et al5 also suggested that lingering comorbidities contribute to the risk for converting from episodic to chronic migraine patterns. Dawn Buse, PhD, a clinical psychologist at Montefiore Medical Center in New York City and co-author on the MAST and CAMEO studies of migraine comorbidities, found the new Korean data intriguing, having noted the comorbid connection of RA to migraine in those studies. “But those are all cross sectional and cannot determine directionality,” she said, adding that the bidirectional aspect represents a novel pattern that could be useful.

Implications

The idea that migraine and RA could exert bidirectional effects on each other suggests multiple implications, particularly to treatment. A combined approach to treatment might offer benefits to both conditions. “The implications mostly apply to the role of inflammation in the development of migraine,” said Dr Martin, noting this suggests that treatment of inflammatory diseases could reduce the likelihood of migraine. Another possible implication of these findings might be that the diagnosis of 1 of these diseases could suggest a predisposition for the other. Further research would be needed to prove these theories.

References

  1. Kim YH, Lee JW, Kim Y, et al. Bidirectional association between migraine and rheumatoid arthritis: two longitudinal follow-up studies with a national sample cohort. BMJ Open. 2021;11(6):e046283. doi:10.1136/bmjopen-2020-046283
  2. Kalaydjian A, Merikangas K. Physical and mental comorbidity of headache in a nationally representative sample of US adults. Psychosom Med. 2008;70(7):773-80. doi:10.1097/PSY.0b013e31817f9e80
  3. Buse DC, Reed ML, Fanning KM, et al. Comorbid and co-occurring conditions in migraine and associated risk of increasing headache pain intensity and headache frequency: results of the migraine in America symptoms and treatment (MAST) study. J Headache Pain. 2020;21(1):23. doi:10.1186/s10194-020-1084-y
  4. Wang YC, Huang YP, Wang MT, Wang HI, Pan SL. Increased risk of rheumatoid arthritis in patients with migraine: a population-based, propensity score-matched cohort study. Rheumatol Int. 2017;37(2):273-279. doi:10.1007/s00296-016-3604-2 Abstract
  5. Burch RC, Buse DC, Lipton RB. Migraine: Epidemiology, Burden, and Comorbidity. Neurol Clin. 2019 Nov;37(4):631-649. doi:10.1016/j.ncl.2019.06.001
  6. Wasserman A. Rheumatoid Arthritis: Common Questions About Diagnosis and Management. Am Fam Physician. 2018;97(7):455-462. PMID: 29671563.

This article originally appeared on Rheumatology Advisor