The comorbidity between RA and migraine is complex and not completely understood, but many clinical researches, epidemiological and laboratory evidences support this relationship .
The comorbidity between migraine and RA has been attributed to share of serotonergic system disorder , significant decrease in platelet serotonin levels in RA patients and inversely related to prominent clinical rheumatoid activity . The inflammatory cytokines production like TNF-α was inhibited by using serotonin reuptake inhibitor medication [22, 23].
In the current study, migraine prevalence was 28.2% in Egyptian random sample of 220 RA patients. Migraine was more common in females with RA, although statistically non-significant. This agrees with Mathieu and colleagues, who found that migraine was present in 27.4% of their study with female predominance . Namas and colleagues reported different results in their retrospective cohort study where the prevalence of migraine in their study was as low as 5.6%. This discrepancy may be due to the difference in study design, psychogenic, socioeconomic and lifestyle elements that may affect the development of migraine in RA .
This study revealed that there is no statistically significant difference regarding age, rheumatoid disease duration, current smoking, positive rheumatoid factor, positive anti-CCP, corticosteroid, methotrexate, sulfasalazine and anti-TNF-α uses between non-migraine and migraine groups with RA.
With regard to rheumatoid disease activity, our study revealed that patients in remission (DAS28 < 2.6) and low rheumatoid disease activity (DAS28 ≥ 2.6 to ≤ 3.2) were higher in non-migraine group of RA patients while moderate (DAS28 > 3.2 to ≤ 5.1) was higher among migraine group with RA with highly statistically significantly different in migraine group with RA (P < 0.001). This was in agreement with Mathieu and colleagues who found that there was statistically significant difference between migraine and non-migraine group with RA with regard to DAS-28 . As in patients with higher grades of disease activity (migraine group), there are higher levels of synovial and serum TNF-alpha as TNF-alpha positively correlates with rheumatoid arthritis disease activity . TNF-alpha could produce central inflammation with subsequent central nervous system (CNS) demyelination mediated by TNF type-1 receptor (TNFR1) (a soluble form which mainly acts on the TNF type-1 receptor). TNFR1 binding leads to chronic inflammatory process with apoptosis, which is suggested to have a role in development of migraine in RA patients .
In our study, functional losses (MHAQ) was higher (moderate + severe = 66.12%) in the migraine group when compared with the non-migraine group (moderate + severe = 37.34%) with higher statistically significant difference in the migraine group (P < 0.001). This can be explained by the higher disease activity and the burden of migraine on quality of life and daily activities.
We found that fibromyalgia was statistically significantly higher in migraine group versus non-migraine group (P < 0.001). This was in agreement with Akdag Uzun and colleagues  and may be explained by the dopaminergic disorder but it was not in agreement with Mathieu and colleagues, who found that no significant association was present between migraine and fibromyalgia .
In our study, secondary Sjogren’s syndrome was statistically significantly higher in migraine patients (P < 0.001). It was in agreement with many studies that found migraine was highly statistically significant in Sjogren's syndrome than in the control subjects and was the most common neurological complaint among these patients. This association could be a part of a common inflammatory process that occur in both conditions [27,28,29]. However, other researches denied this association .
In this research, we found that ESR, CRP, DAS-28 and MHAQ were statistically significant higher in migraine group when compared with non-migraine group (p < 0.001). However, the only predictors of the likelihood of occurrence of migraine in RA was DAS-28 (p < 0.001).
Many studies concluded that white matter hyper-intensities (WMHs) are common imaging findings in MRI brain of migraine patients . The prevalence of WMH in migraine patients were varied in different studies ranging from high prevalence as in Le Pira and colleagues and Zhang and colleagues, 43.2 and 32%, respectively [31, 32] to low prevalence as in Zeytin and colleagues which was 11.5% . This discrepancy in prevalence was attributed to the differences in the sample size and patient selection.
White matter hyper-intensities as MR imaging feature in migraine patients commonly resemble the white matter lesions observed in inflammatory disorders, such as multiple sclerosis and representing a challenge for diagnosis. However, presence of central vein sign and more than three periventricular lesions is specific for multiple sclerosis [34, 35].
In the current study, the prevalence of brain MRI white matter hyper-intensities in RA patient with migraine was 54.8%. This prevalence was higher than that in Le Pira and colleagues and Zhang and colleague. These differences may be explained by the added inflammatory effect of both migraine and rheumatoid disorders on brain micro-vasculature and ischemic brain injuries [31, 32].
In this study, brain MRI was performed for migraine group and exhibited that white matter hyper-intensities (WMHs) were significantly higher in migraine patients with aura (41.2%) than migraine patients without aura (17.9%) with statistically significant P value (p < 0.047). This was concordant with Rossato and colleagues who found that there was higher prevalence of WMHs in migraine patient with aura due to ischemic brain injury resulted from alteration of cerebral blood flow with subsequent high or low cerebral perfusion which is modulated by cortical spreading depression occurring in aura patients .
In the current study, abnormal brain MRI in the form of WMHs were significantly higher in older patients with mean age of about 45 years and in patients with longer migraine duration and with longer rheumatoid duration with statistically significant P value (p < 0.034, P < 0.004 and P < 0.015, respectively). These were in agreement with Negm and colleagues and Toghae and colleagues who found that WMHs in migraine patients were directly proportional to patient’s age and disease duration [37, 38]. On the other hand, the current study results did not match with the studies of Trauninger and colleagues and Gomez-Beldarrain and colleagues, as they concluded that there was no significant relation regarding patient’s age and duration of the disease and they concluded that there was a remission of migraine episodes with aging of the patient [39, 40].
In this study, abnormal brain MRI in the form of WMHs was significantly higher in patients with elevated ESR with statistically significant P value (P < 0.22), otherwise in this study there was no statistically significant difference regarding CRP, DAS-28 or MHAQ in development of WMHs.
Limitations of the study were small patients sample size, absence of psychiatric assessment and absence of control group study.