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.

High headache-related disability in patients with systemic lupus erythematosus and primary Sjögren's syndrome.

BACKGROUND AND PURPOSE: It is often argued that patients with systemic lupus erythematosus (SLE) have more headaches than healthy subjects, but this association remains controversial. Thus the magnitude and severity of headaches in SLE were evaluated in comparison with another autoimmune disease, namely primary Sjögren's syndrome (pSS). METHODS: Sixty-seven patients with SLE, 71 pSS patients and 108 healthy subjects were included. The International Classification of Headache Disorders, Headache Impact Test-6 (HIT-6), and the Migraine Disability Assessment (MIDAS) questionnaire were used to classify and assess headache-related disability. RESULTS: Primary headaches were more prevalent in SLE patients than in healthy subjects (82% vs. 69%, P = 0.01). Amongst the headache sufferers, SLE patients (N = 55) and pSS patients (N = 51) had higher HIT-6 scores (median 51, range 36-67, and median 54, range 36-72, respectively) than healthy subjects (N = 69) (median 46, range 36-72; P = 0.02 and P = 0.0009, respectively). Also, MIDAS scores were higher in SLE (median 0, range 0-110) and pSS patients (median 1, range 0-40) than in healthy subjects (median 0, range 0-10; P = 0.04 and P = 0.003, respectively). CONCLUSION: Patients with SLE and pSS have a higher burden from headaches and more severe headaches than headache sufferers without these diseases. However, evidence of a specific bothersome SLE headache was not possible to identify as the headaches had the same characteristics and similar impact and severity in pSS patients. Depressive mood significantly influenced headache severity.

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.

The point prevalence of clinically relevant primary Sjögren's syndrome in two Norwegian counties.

OBJECTIVE: Primary Sjögren's syndrome (PSS) is a chronic autoimmune inflammatory disease characterized by exocrine gland inflammation producing clinical symptoms such as dryness of the mouth and eyes. The reported prevalence of PSS is variable, probably because of different classification criteria used and selection bias. The aim of this study was to determine the prevalence of PSS in a well-defined Norwegian Caucasian population using the revised American-European Consensus Group (AECG) criteria. METHODS: Three hospitals and three private rheumatology practices provide all of the rheumatology services to the local population in Hordaland and Rogaland counties, which included 852 342 Caucasian inhabitants as of 1 January 2009. Patients on file fulfilling the new revised AECG criteria for PSS were included, and patients with incomplete data were invited to a screening visit. RESULTS: A total of 424 PSS patients were identified. Their mean age was 61.6 ± 13.2 years; 28 (7%) were men and 396 (93%) were women. The point estimate for the proportion of PSS was 0.050% [95% confidence interval (CI) 0.048-0.052]. CONCLUSION: The prevalence of PSS in this Norwegian population of Caucasians is lower than previously reported when less stringent criteria for identifying PSS were used, but is in line with more recent studies using the same criteria and methods as in this study.

Association of EBF1, FAM167A(C8orf13)-BLK and TNFSF4 gene variants with primary Sjögren's syndrome.

We performed a candidate gene association study in 540 patients with primary Sjögren's Syndrome (SS) from Sweden (n=344) and Norway (n=196) and 532 controls (n=319 Swedish, n=213 Norwegian). A total of 1139 single-nucleotide polymorphisms (SNPs) in 84 genes were analyzed. In the meta-analysis of the Swedish and Norwegian cohorts, we found high signals for association between primary SS and SNPs in three gene loci, not previously associated with primary SS. These are the early B-cell factor 1 (EBF1) gene, P=9.9 × 10(-5), OR 1.68, the family with sequence similarity 167 member A-B-lymphoid tyrosine kinase (FAM167A-BLK) locus, P=4.7 × 10(-4), OR 1.37 and the tumor necrosis factor superfamily (TNFSF4=Ox40L) gene, P=7.4 × 10(-4), OR 1.34. We also confirmed the association between primary SS and the IRF5/TNPO3 locus and the STAT4 gene. We found no association between the SNPs in these five genes and the presence of anti-SSA/anti-SSB antibodies. EBF1, BLK and TNFSF4 are all involved in B-cell differentiation and activation, and we conclude that polymorphisms in several susceptibility genes in the immune system contribute to the pathogenesis of primary SS.

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.

Intravenous cyclophosphamide in patients with chronic systemic inflammatory diseases: morbidity and mortality.

BACKGROUND: Few data exist concerning the development of malignancies and haemorrhagic cystitis in patients with systemic autoimmune diseases previously treated with intravenous (iv) cyclophosphamide (CYC). The use of mesna prophylaxis is also controversial. METHODS: The medical records of all patients with chronic systemic inflammatory diseases treated with iv or oral CYC at Stavanger University Hospital from 1985 to 1999 were reviewed. Eighty-five patients were identified, of whom 75 patients had been treated with iv CYC only and were thus included in this study. Of these 75 patients, 20 (27%) had died and 55 (73%) were alive. Forty-two (76%) out of the 55 patients consented to undergo a comprehensive clinical examination, including a cystoscopy in 33 of them. The medical history of the patients not clinically examined was based solely on medical records. Data from the Cancer Registry of Norway and Statistics Norway were used for comparison with normative data in the general population. RESULTS: Six patients (8%) developed malignant disease compared with an expected number of 4.5, giving a standard incidence ratio of 1.5 [95% confidence interval (CI) 0.7-3.2]. The observed number of deaths was 23 compared to an expected number of 6.3, giving a standard mortality ratio of 3.7 (95% CI 2.4-5.5). CONCLUSIONS: The standard incidence ratio of cancer following iv CYC was increased, although not statistically significantly. No urinary bladder cancer or haemorrhagic cystitis developed even though mesna prophylaxis was not given.

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.

The effect of age and gender on epidermal nerve fiber density.

OBJECTIVE: Sensory neuropathies often involve small-diameter myelinated and unmyelinated nerve fibers, and neurologic and electrophysiologic findings may be normal unless larger nerve fibers are involved. The small (intra)epidermal nerve fibers (ENFs) now can be visualized with immunohistochemical techniques using the panaxonal marker anti-protein gene product 9.5 (PGP 9.5). Using this technique, the authors have established a reference range for ENF in a healthy white population and evaluated the reliability of the method. METHODS: Two punch biopsies, 3 mm in diameter, were taken from the distal part of the leg in 106 healthy volunteers (mean age, 49.0 +/- 19.6 years). Fifty-micrometer frozen thick sections were incubated with rabbit polyclonal antibodies to human PGP 9.5. The number of ENF/mm then was reported as the mean of counts in six sections (three sections from each of the two biopsies). RESULTS: The mean number of ENFs was 12.4 +/- 4.6 mm. In a multiple regression model, the density of ENF depended on age and gender (Y = 13.92 + 2.25 (gender) - 0.06 x age). The mean difference in ENF by intraobserver analysis was 0.2 +/- 1.2 ENF/mm, and by interobserver analysis, it was 0.4 +/- 1.5 fibers/mm. CONCLUSION: Normal means and ranges for the density of epidermal nerve fibers in a reference population have been established. The density of epidermal nerve fibers decreases with age and is lower in men compared with women. Intraobserver and interobserver analysis proves the reliability of the method.

Consequences of late referral of patients with end-stage renal disease.

OBJECTIVES: The aim of the present retrospective single centre study of patients entering renal replacement therapy (RRT), was to evaluate the effects of different referral patterns on morbidity, choice of therapy, and duration of hospitalization in patients with chronic renal failure. SUBJECTS: A total of 242 patients with chronic renal failure starting their first RRT between 1984 and 1998, were divided into three groups. Group 1 (n=80): RRT started 1984-88, group 2 (n=73): RRT started 1989-93 and group 3 (n=89): RRT started 1994-98. Patients were classified as early referrals (ER) or late referrals (LR) depending on whether they started first RRT more than or less than 3 months after first referral to a nephrologist. RESULTS: The proportion of LR was 27.3% (21 patients) in group 1, 27.4% (20 patients) in group 2 and 28.1% (25 patients) in group 3. In the ER, 35 patients (14.5%) received a predialytic kidney transplant, none in the LR. Comparing clinical details, the LR's in group 3 were significantly older than ER [median age 72 (53-81) vs. 56 (15-81) years, P < 0.0001], had a lower serum-albumin [median 33.0 (19.0-42.0) vs. 39 (19.0-48.0) g L-1, P < 0.0001], and serum-calcium [median 2.0 (1.4-2.6) vs. 2.3 (1.8-2.7) mmol L-1, P < 0.0001]. The ER had a significantly higher use of antihypertensive drugs, calcitriol, phosphate binders, and bicarbonate. Of the patients starting RRT on haemodialysis, all LR started on a temporary vascular access. About 43% of the ER started on a functioning arteriovenous fistula (P < 0.0001). The duration of hospital stay in connection with start of dialysis was 31 days (7-73) in the LR as compared with 7 (1-59) days in the ER (P < 0.0001). CONCLUSIONS: We conclude that in our centre, early referral to nephrologist is associated with lower age, a higher likelihood of predialytic transplantation, better metabolic status at start of RRT, a higher proportion starting haemodialysis on a functioning arteriovenous fistula, and a shorter duration of the initial hospital stay. Further research on health care delivery is warranted.

[Hypokalemic pareses secondary to renal tubular acidosis]. / Hypokalemisk induserte pareser sekundaert til renal tubulaer acidose.

A 24 year old woman presented with flaccid paralysis, severe hypokalaemia and hyperchloremia, metabolic acidosis. Immunological tests and labial glandular biopsy indicated primary Sjögren's syndrome as the underlying cause of her distal renal tubular acidosis. The patient recovered after alkali and potassium substitution and was put on oral treatment with potassium citrate.

[Adult-onset Still's disease. Diagnosis, differential diagnosis and treatment]. / Stills sykdom med debut i voksen alder. Diagnose, differensialdiagnoser og behandling.

The article describes two cases of adult Still's disease and reviews the relevant literature. Adult onset Still's disease is characterized by high peaks of fever, arthritis, arthralgia, rash, increased erythrocyte sedimentation rate, leucocytosis, liver dysfunction and negative tests for antinuclear antibodies and rheumatoid factors. Still's disease should be regarded as a possible differential diagnosis in adult patients who present such features.

Regeneration studies on a crayfish neuromuscular system. II. Effect of changing the nerve entry point into the muscle field on the gradient of innervation.

The superficial flexor muscle of the crayfish is a neuromuscular system in which the neurons form position-dependent connectivity patterns with the muscle fibers. This system could be formed with the help of a single medial-to-lateral gradient during development that embodies positional information. To test this gradient hypothesis we changed the nerve's normal medial entry point into the muscle by transplanting it to the middle of the muscle sheet. When all the muscle fibers were present in the target area, most of the neurons studied passed through a stage during regeneration in which they showed preference for either medial or lateral synapse formation. Those neurons that in normal animals innervated preferentially the medial fibers showed a medial preference for new contacts; the neuron that normally innervated the lateral fibers showed a lateral preference for new contacts; the neuron that normally innervated everywhere regenerated equally well into both medial and lateral fibers. Therefore, these neurons are able to detect information regarding their position within the muscle mass and respond to it by preferential synapse formation. The effect of a positional gradient could not be detected when half of the target field was removed prior to regeneration. In this instance, the neuron that innervated the missing target area now regenerated to almost all the available fibers. It is suggested that the interplay of positional cues with other factors at different points in time could determine the final connectivity patterns formed by these cells.