The blood-brain barrier, TWEAK, and neuropsychiatric involvement in human systemic lupus erythematosus and primary Sjögren's syndrome.

OBJECTIVE: A prevailing hypothesis for neuropsychiatric involvement in systemic lupus erythematosus (SLE) and primary Sjögren's syndrome is that brain reactive autoantibodies enter the brain through a disrupted blood-brain barrier. Our aim was to investigate whether TNF-like weak inducer of apoptosis (TWEAK) plays a role in cerebral involvement in human SLE and primary Sjögren's syndrome, and whether an impaired blood-brain barrier is a prerequisite for neuropsychiatric manifestations. METHODS: TWEAK was measured in the cerebrospinal fluid and serum and compared with markers of blood-brain barrier permeability (Q-albumin and MRI contrast-enhanced lesions) and S100B, an astrocyte activation marker in 50 SLE and 52 primary Sjögren's syndrome patients. Furthermore, we estimated the general intrathecal B-cell activation (IgG index), measured anti-NR2 antibodies in cerebrospinal fluid, and explored whether these variables were associated with neuropsychiatric manifestations. RESULTS: No associations were found between TWEAK in the cerebrospinal fluid or serum and neuropsychiatric manifestations in SLE nor in primary Sjögren's syndrome patients. Furthermore, no associations were found between neuropsychiatric manifestations and indicators of blood-brain barrier integrity or astroglial activity. Anti-NR2 antibodies were associated with impaired visuospatial processing (odds ratio 4.9, P = 0.03) and motor functioning (odds ratio 6.0, P = 0.006). CONCLUSION: No clinical neuropsychiatric manifestations could be attributed to impaired integrity of the blood-brain barrier, or to TWEAK levels in cerebrospinal fluid or serum in either patient group. The TWEAK concentration was considerably higher in the cerebrospinal fluid than in blood, which indicates intrathecal production. We hypothesize that increased TWEAK and S100B result from immunological stress caused by brain-reactive antibodies produced by brain residing immune cells.

Migraine in patients with systemic lupus erythematosus is associated with reduced cerebral grey matter volume but not with measures of glial activation or anti-NR2 or anti-P antibodies.

BACKGROUND AND PURPOSE: Migraine is frequent in patients with systemic lupus erythematosus (SLE), but the pathogenesis and pathophysiology are poorly understood. Migraine is assumed to be a consequence of abnormal neuronal excitability. Based on the hypothesis that the threshold for migraine is lower in SLE patients due to cerebral disturbances, whether structural abnormalities of the brain or relevant biomarkers are associated with headaches in SLE was investigated. METHODS: Sixty-seven SLE patients and age- and gender-matched healthy subjects participated. Volumes of grey matter (GM) and white matter (WM) were estimated from cerebral magnetic resonance images with SPM8 software. Anti-NR2 and anti-P antibodies and protein S100B were measured in cerebrospinal fluid. RESULTS: In regression analyses, larger GM volumes in SLE patients reduced the odds for headache in general [odds ratio (OR) 0.98, P = 0.048] and for migraine in particular (OR 0.95, P = 0.004). No localized loss of GM was observed. Larger WM volumes in patients increased the odds for migraine (OR 1.04, P = 0.007). These findings could not be confirmed in healthy subjects. Neither anti-NR2 and anti-P antibodies nor S100B were associated with headaches in SLE patients. CONCLUSIONS: Systemic lupus erythematosus patients with migraine have a diffuse reduction in GM compared to patients without migraine. This finding was not observed in healthy subjects with migraine, and selected biomarkers did not indicate specific pathophysiological processes in the brain. These findings indicate that unknown pathogenic processes are responsible for the increased frequency of migraine in SLE patients.

Loss of cerebral white matter in primary Sjögren's syndrome: a controlled volumetric magnetic resonance imaging study.

BACKGROUND AND PURPOSE: Although brain involvement is common in primary Sjögren's syndrome (pSS), results from cerebral imaging studies are inconsistent. This study aimed to perform both voxel-wise and global brain volume analyses in a nearly population-based pSS cohort to explore whether the patients displayed any focal or diffuse volume differences compared with healthy subjects. METHODS: Global grey matter (GM) and white matter (WM) volumes were measured and compared in 60 patients with pSS and 60 age- and gender-matched healthy subjects. Regression models were constructed with potential explanatory variables for GM and WM volumes. In the same groups, voxel-wise morphometric analyses were performed. RESULTS: In analyses of global GM and WM, the patients had lower WM volumes than healthy subjects (540 ± 63 cm(3) vs. 564 ± 56 cm(3), P = 0.02), but no differences in GM. Voxel-wise analyses displayed no localized areas of GM or WM volume differences between pSS patients and healthy subjects. CONCLUSION: Individuals with pSS have a diffuse reduction of cerebral WM but no localized loss of WM or GM. This indicates a general deleterious effect on WM due to pSS itself.

Headache in primary Sjøgren's syndrome: a population-based retrospective cohort study.

BACKGROUND: We investigated whether the prevalence of primary headaches was higher in patients with primary Sjøgren's syndrome (PSS) than in healthy individuals. METHODS: This retrospective cohort study included 71 patients with PSS (patients) based on the American European Consensus Classification criteria, and 71 age- and gender-matched healthy subjects (controls). Headaches were classified according to the International Classification of Headache Disorders. We measured depression with the Beck Depression Inventory, and fatigue with the Fatigue Severity Scale. RESULTS: Fifty-one patients and 42 controls had headaches in the previous 12 months (71.8% vs. 59.2%, P = 0.10). Thirty-eight patients and 28 controls had tension type headaches (TTHs) (53.5% vs. 39.4%, P = 0.12). Eight patients (11.3%) and one control had chronic TTHs (P = 0.05). Migraines and migraines with aura were equally prevalent in patients (26.8% and 11.3%, respectively) and controls (28.2% and 15.5%, respectively; P = 0.61). CONCLUSIONS: In general, patients did not have more migraines or headaches than controls. However, patients had more chronic TTHs than controls. Chronic TTHs were not associated with PSS-related autoantibodies, fatigue, depression, abnormalities on magnetic resonance imaging or abnormalities in the cerebrospinal fluid. Patients with PSS did, however, have higher depression and fatigue scores than controls.

Cerebral white matter hyperintensities are not increased in patients with primary Sjögren's syndrome.

BACKGROUND AND PURPOSE: It is frequently thought that cerebral white matter hyperintensities (WMHs) on T-2 weighted MRI scans are increased in patients with autoimmune diseases. An increased frequency of WHMs has been described in primary Sjögren's syndrome (PSS), but no controlled studies exist. The aim of this study was therefore to compare WMHs in PSS patients and healthy subjects applying the new European-American criteria for PSS. METHODS: Cross-sectional controlled study of 68 unselected PSS patients and 68 healthy subjects was carried out. WMHs were rated using Scheltens method. RESULTS: There were no differences in total or any regional WMH scores between PSS patients and healthy subjects. CONCLUSIONS: Patients with PSS do not have increased WMH load or distribution when compared with healthy subjects.

Neuropsychiatric syndromes in patients with systemic lupus erythematosus and primary Sjögren syndrome: a comparative population-based study.

OBJECTIVES: To compare the prevalence and pattern of neuropsychiatric (NP) syndromes observed in systemic lupus erythematosus (SLE) to patients with Primary Sjögren syndrome (PSS) using the American College of Rheumatology (ACR) criteria for the 19 NP syndromes seen in SLE. METHODS: A population-based study was conducted including 68 patients with SLE (mean (SD) age 43.8 (13.6) years) and 72 with PSS (age 57.8 (13.0) years). Specialists in internal medicine, neurology and neuropsychology performed standardised examinations. Cerebral MRI scans and neurophysiological studies were performed in all patients. RESULTS: Similar prevalences in SLE and PSS were observed for headaches (87% vs 78%, p = 0.165), cognitive dysfunction (46% vs 50%, p = 0.273), mood disorders (26% vs 33%, p = 0.376), anxiety disorders (12% vs 4%, p = 0.095), cranial neuropathy (1% vs 4%, p = 0.339) and seizure disorders (7% vs 3%, p = 0.208). Cerebrovascular disease was more common in SLE than PSS (12% vs 3%, p = 0.049); but mononeuropathy (0% vs 8%, p = 0.015) and polyneuropathy (18% vs 56%, p<0.001) were less common in SLE than PSS. Other syndromes were rare or absent in both patient groups. CONCLUSIONS: Headache, cognitive dysfunction and mood disorders are common in both diseases, but otherwise there are distinct differences in NP involvement, with cerebrovascular diseases more prevalent in SLE and neuropathies more common in PSS. This indicates that some NP disease mechanisms are shared while others differ between the two diseases.

Fatigue is associated with cerebral white matter hyperintensities in patients with systemic lupus erythematosus.

BACKGROUND: Fatigue is a disabling phenomenon in many patients who have systemic lupus erythematosus (SLE). The pathophysiological processes are unknown, and no known biological disease factors influence the phenomenon. Because depressive mood is consistently associated with fatigue, and drug treatment for SLE does not ameliorate fatigue, a psychological explanation could be an alternative. In search of a somatic basis for fatigue, we looked for alternative markers of biologic activity associated with fatigue. Cerebral white matter hyperintensities (WMHs) represent biochemical changes of brain tissue and are frequently encountered in patients with SLE, and are associated with cognitive impairment in patients with multiple sclerosis. Presence of such an association between fatigue and WMHs in SLE would favour a biological axis to fatigue. METHODS: A cross-sectional, case-control study with 62 unselected patients with SLE and 62 age- and gender-matched healthy subjects. Fatigue was evaluated using the Fatigue Severity Scale (FSS) and a fatigue visual analogue scale (VAS). WMHs were rated using Scheltens' method. RESULTS: Greater fatigue and more WMHs appeared in patients with SLE versus healthy subjects. In the full group of patients (n = 62), fatigue VAS was associated with total WMH score (p = 0.009). In subgroup analysis of patients without clinical depression (n = 40), the association with total WMH remained (p = 0.035), whereas this was not the case in the depressed group (n = 18) (p = 0.211). CONCLUSION: Increased cerebral WMH load is associated with increased fatigue, indicating a biological origin for some portion of fatigue in patients with SLE.