Headache in systemic lupus erythematosus and primary Sjogren's syndrome
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Background Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease which can affect multiple organs. The central nervous system (CNS) is frequently affected, and headache, especially migraine, is among the most frequent manifestations. The existence of a strong and specific "lupus headache" has been debated for decades, and it is still controversial whether this type of headache is a reality or a myth, and whether headache in SLE is caused by the disease's brain involvement, something that may have implications for the treatment of SLE in the individual patient. Moreover, even less is known about headaches in other autoimmune diseases, such as primary Sjogren's syndrome (pSS), and there is therefore a need to obtain more knowledge on these issues. Main objectives Investigate prevalence and characteristics of headaches in the autoimmune disease SLE. Investigate whether headaches occur with the same pattern in another autoimmune disease, namely pSS. Investigate whether headache related disability is different in these diseases compared with the general population. Investigate whether clinical , biochemical , immunological or structural brain abnormalities influence the prevalence of headache in patients with SLE. Subjects and methods Nearly all patients with autoimmune diseases in Rogaland County, Norway, are allocated to Stavanger University Hospital (SUS), which served about 310 000 people at the time of the study. We aimed at identifying all known cases with SLE and pSS in this area, and the studies in this thesis are therefore near population based. Cross- sectional- and case-control designs were used. Sixty-seven SLE patients and 71 pSS patients, as well as their age- and gender matched healthy control subjects, gave written informed consent to participate. All participants were examined by an experienced internist and neurologist. Biochemical- and immunological analyses, and cerebral magnetic resonance imaging (MRI) were performed, in the patients also analyses of the cerebrospinal fluid (CSF). International criteria for SLE and pSS, for neuropsychiatric syndromes in SLE, and for headache classification were used. Reliable and validated instruments were used for assessing depression, fatigue, and headache-related disability. Biochemical- and immunological analyses were performed at the hospital's routine laboratories and in the research laboratory at SUS. Antibodies against ribosomal P-protein (anti-P) were analyzed in professor Hirohata's research laboratory in Tokyo, Japan. MRI analyses were performed with the SPM8 software. Results Twenty-four out of 67 SLE patients and 13 out of 67 matched healthy subjects had migraine (36 % vs 19 %, P = 0.03). Out of these, nine SLE patients and 4 healthy subjects had migraine with aura (13 % vs 6 %, P = 0.14). Prevalence of tension type headache (TTH) was equal in SLE patients (60 %) and healthy subjects (58 %). SLE patients had more depression and fatigue than the healthy subjects, and depression was associated with migraine in the patients. Headaches were, with the exception of SLE photosensitivity, not associated with any SLE disease specific factors such as disease activity, accumulated organ damage, biochemical- or immunological markers in blood, impairment of the blood-brain barrier, intrathecal immunoglobulin production or white matter hyperintensities (WMHs) on cerebral MRI. Eight pSS patients (11 %) had chronic TTH, while only one of the healthy subjects had chronic TTH last year, P = 0.05. This subtype of TTH was not associated with pSS- related antibodies, depression, fatigue, abnormalities on MRI, or any other clinical or laboratory variables. Migraines and migraines with aura were equally prevalent in patients (26.8 % and 11.3 %, respectively) and control subjects (28.2 % and 15.5 %, respectively, P = 0.61). On cerebral MRI, increasing gray matter (GM) volumes in the SLE patients reduced the odds for migraine (OR 0.95, P = 0.004). No localized loss of GM was observed. Increasing global white matter volumes in the patients increased the odds for migraine (OR 1.04, P = 0.007). These findings could not be replicated in the healthy subjects. No associations with headaches in SLE patients were revealed regarding anti-NR2-, anti-P antibodies, nor protein S1008. Conclusions SLE patients have more migraine than healthy subjects. It is associated with mental depression, but not with disease activity, abnormalities detected on cerebral MRI, abnormalities in CSF, or any SLE characteristics except from SLE photosensitivity. The distribution of headache types in pSS patients differ from that observed in the SLE patients, and migraine is not more prevalent than in the healthy control subjects. However, pSS patients have more chronic TTH than the healthy subjects. Headache-related disability is considerably higher in patients with SLE and pSS than in otherwise healthy headache-sufferers. Depressive mood significantly influenced headache severity in the patients. The high headache-related disability in patients with SLE and pSS may reflect the burden of chronic disease. SLE patients with migraine have a global diffuse reduction in GM compared to patients without migraine. This GM volume reduction was not observed in the healthy subjects with migraine. Analyses of the selected biomarkers did not indicate specific pathophysiological processes in the brain. These findings indicate that unknown pathogenic and pathophysiological processes are responsible for - or influence - the increased frequency of migraine in SLE patients.
Består avPaper I: Tjensvoll AB, Harboe E, G0ransson LG, Beyer MK, Greve OJ, Herigstad A, Kval0y JT, Omdal R. Migraine is frequent in patients with systemic lupus erythematosus: a case- control study. Cephalalgia 2011; 31: 401-8. Full-text not available in BORA. https://doi.org/10.1177/0333102410372428
Paper II: Tjensvoll AB, Harboe E, G0ransson LG, Beyer MK, Greve OJ, Kval0y JT, Omdal R. Headache in primary Sj0gren's syndrome: a population-based retrospective cohort study. Eur J Neurol 2013; 20: 558-63. https://doi.org/10.1111/ene.12033
Paper III: Tjensvoll AB, Harboe E, G0ransson LG, Kval0y JT, Omdal R. High headache-related disability in patients with systemic lupus erythematosus and primary Sj0gren's syndrome. Eur J Neurol 2014; 21: 1124-30. https://doi.org/10.1111/ene.12447
Paper IV: Tjensvoll AB, Lauvsnes MB, Hirohata S, Beyer MK, Greve OJ, Kvivik I, Kval0y JT, Harboe E, G0ransson LG, Omdal R. Migraine in patients with systemic lupus erythematosus is associated with reduced cerebral gray matter volume but not with measures of glial activation or anti-NR2 or anti-P antibodies. Eur J Neurol 2016; 23: 780-6. https://doi.org/10.1111/ene.12946