Malondialdehyde and advanced oxidation protein products are not increased in psoriasis: a controlled study.

This study investigated oxidative stress in patients with psoriasis of low and medium disease activity. We measured advanced oxidation protein products (AOPP) and malondialdehyde (MDA) in plasma using UV-spectrophotometry and high performance liquid chromatography connected to a fluorescence detector in 84 patients and 84 matched healthy subjects. AOPP is a marker of protein oxidation due to inflammation, whereas MDA is a hydroxyl radical initiated lipid peroxidation product. Clinico-demographic variables including age, gender, disease severity, and fatigue were assessed in relation to AOPP and MDA. Disease severity was evaluated with the Psoriasis Area and Severity Index and the Dermatology Life Quality Index. Median (interquartile range, IQR) AOPP concentrations were 66 µmol/l (IQR 54-102) in patients and 69 µmol/l (IQR 55-87) in healthy subjects (P = 0.75). Median plasma MDA concentrations were significantly lower in patients than in healthy subjects (0.68 µM, IQR 0.54-0.85 vs. 0.76 µM, IQR 0.60-0.97; P = 0.03). Plasma levels of AOPP and MDA did not indicate oxidative stress in patients with mild psoriasis. Higher AOPP concentrations were associated with male gender, high body mass index, and high hemoglobin values. Elevated MDA concentrations were associated with advanced age and male gender. No associations with disease severity were detected. Although, the two selected biomarkers do not provide a complete measure of oxidative damage, our study demonstrates that a number of physiological and methodological factors influence the levels of MDA and AOPP. Such methodological issues are important to consider when interpreting results using these biomarkers in patients with psoriasis.

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.

Fatigue in psoriasis: a controlled study.

BACKGROUND: Fatigue is associated with various chronic inflammatory diseases, but few studies have focused on its occurrence in psoriasis. OBJECTIVES: To describe fatigue prevalence and degree among patients with chronic plaque psoriasis vs. age- and sex-matched healthy subjects, and to examine how fatigue is influenced by essential clinical and demographic factors. METHODS: In 84 patients and 84 healthy subjects, fatigue severity was assessed using three different generic fatigue instruments: the fatigue Visual Analogue Scale (fVAS), the Fatigue Severity Scale (FSS) and the Short Form 36 (SF-36) Vitality scale. Cut-off scores for clinically important fatigue were defined as ≥ 4 for FSS, ≥ 50 for fVAS and ≤ 35 for the SF-36 Vitality scale. Disease activity was evaluated using the Psoriasis Area and Severity Index (PASI), and the impact on quality of life with the Dermatology Life Quality Index (DLQI). RESULTS: Patients and healthy control subjects, respectively, showed median fVAS scores of 51 [interquartile range (IQR) 21-67] and 11 (IQR 3-20); FSS scores of 4 (IQR 2·5-5·3) and 1·6 (IQR 1·1-2·2); and SF-36 Vitality scores of 43 (IQR 25-85) and 73 (IQR 65-85). The rates of clinically important fatigue among patients vs. healthy controls, respectively, were 51% vs. 4% (fVAS); 52% vs. 4% (FSS); and 42% vs. 2% (SF-36 Vitality) (P < 0·001 for all differences). Fatigue was associated with DLQI scores, but not PASI scores, in univariate analysis but not in multivariate analysis. CONCLUSIONS: Nearly 50% of patients with psoriasis suffered from substantial fatigue. Fatigue severity was associated with smoking, pain and depression, but not with psoriasis severity.

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.

Low Protein A20 in Minor Salivary Glands is Associated with Lymphoma in Primary Sjögren's Syndrome.

Patients with primary Sjögren's syndrome (pSS) have an increased risk of developing lymphomas, particularly the subtype mucosa-associated lymphoid tissue (MALT) lymphoma. Chronic antigen stimulation and increased activation of nuclear factor-κB (NF-κB) are important factors for the pathogenesis of MALT lymphomas. Protein A20 is an inhibitor of NF-κB. A recent study of pSS-associated MALT lymphomas identified potential functional abnormalities in the TNFAIP3 gene, which encodes protein A20. The present study aimed to assess protein A20 by immunohistochemistry (IHC) in minor salivary glands (MSGs) and lymphoma tissue sections of patients with pSS and investigate a potential association with lymphoma development. Protein A20 staining in lymphocytes was scored in four categories (0 = negative, 1 = weak, 2 = moderate and 3 = strong). For statistical purposes, these scores were simplified into negative (scores 0-1) and positive (scores 2-3). We investigated associations between protein A20-staining, focus scores, germinal centre (GC)-like structures and monoclonal B-cell infiltration in MSGs. MSG protein A20 staining was weaker in pSS patients with lymphomas than in those without lymphomas (P = 0.01). Weak protein A20 staining was also highly associated with a lack of GC formation (P < 0.01). Finally, weaker A20 staining was observed in the majority of pSS-associated MALT lymphoma tissues. In conclusion, we found absent or weak protein A20 immunoreactivity in MSGs of patients with pSS with lymphomas. This finding indicates that protein A20 downregulation in lymphocytes might be a mechanism underlying lymphoma genesis in patients with pSS.

Fatigue in psoriasis: a phenomenon to be explored.

Fatigue is a prevalent and substantial phenomenon in many patients with chronic inflammatory diseases, often rated by patients as the most troublesome symptom and aspect of their disease. It frequently interferes with physical and social functions and may lead to social withdrawal, long-standing sick leave and disability. Although psychological and somatic factors such as depression, sleep disorders, pain and anaemia influence fatigue, the underlying pathophysiological mechanisms by which fatigue is generated and regulated are largely unknown. Increasing evidence points towards a genetic and molecular basis for fatigue as part of the innate immune system and cellular stress responses. Few studies have focused on fatigue in dermatological diseases. Most of these studies describe fatigue as a phenomenon related to psoriatic arthritis and describe the beneficial effects of biological agents on fatigue observed in clinical studies. It is therefore possible that this problem has been underestimated and deserves more attention in the dermatological community. In this review, we provide a definition and explanation for chronic fatigue, describe some commonly used instruments for measuring fatigue, and present hypothetical biological mechanisms with an emphasis on activation of the innate immune system and oxidative stress. An overview of relevant clinical studies covering the theme 'psoriasis and fatigue' is given.

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.

No association of primary Sjögren's syndrome with Fcγ receptor gene variants.

The genetic background of primary Sjögren's syndrome (pSS) is partly shared with systemic lupus erythematosus (SLE). Immunoglobulin G Fc receptors are important for clearance of immune complexes. Fcγ receptor variants and gene deletion have been found to confer SLE risk. In this study, four Fcγ receptor single-nucleotide polymorphisms (SNPs) and one copy number variation (CNV) were studied. Swedish and Norwegian pSS patients (N=527) and controls (N=528) were genotyped for the Fcγ receptor gene variant FCGR2A H131R (rs1801274) by the Illumina GoldenGate assay. FCGR3A F158V (rs396991) was analysed in 488 patients and 485 controls, FCGR3B rs447536 was analysed in 471 patients and 467 controls, and FCGR3B rs448740 was analysed in 478 cases and 455 controls, using TaqMan SNP genotyping assays. FCGR3B CNV was analysed in 124 patients and 139 controls using a TaqMan copy number assay. None of the SNPs showed any association with pSS. Also, no FCGR3B CNV association was detected. The lack of association of pSS with Fcγ receptor gene variants indicates that defective immune complex clearance may not be as important in pSS pathogenesis as in SLE, and may point to important differences between SLE and pSS.

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.

Thrombotic microangiopathy and the antiphospholipid syndrome.

The antiphospholipid syndrome (APS) comprises the association between vascular thrombosis, including microthrombosis, pregnancy morbidity and the coexistence of anti-phospholipid antibodies. Thrombotic microangiopathy (TMA) can be one of the manifestations of the APS and may involve any organ. This feature of the APS is probably less recognized by clinical doctors than venous thrombosis and recurrent abortions. This case report presents a patient who developed a widespread TMA with renal failure, gastric mucosa ulceration, urinary bladder ulcerations and a finger necrosis as part of the APS.

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.

Anti-CD20 treatment in primary Sjögren's syndrome.

We performed a search for publications on rituximab (Rtx) in the treatment of primary Sjögren's syndrome (pSS), and assessed the reports for the efficacy of the drug on complaints like sicca symptoms, systemic manifestations and pSS associated lymphoma. We also reviewed the effects on laboratory parameters and potential adverse effects. From the published literature there is little evidence supporting Rtx to have an effect on sicca symptoms, and there is particularly lack of objective improvements in measures of oral and ocular dryness. Systemic manifestations such as fatigue, synovitis, arthralgia, cryoglobulinaemia-related vasculitis, neurological, renal and pulmonary involvement all seem to react favourably to Rtx treatment. The effect on pSS associated non-Hodgkin's lymphoma is also beneficial. Rheumatoid factor concentration is decreasing during Rtx treatment. The levels of anti-SSA and -SSB antibodies are, however, unaltered according to the majority of the studies. The most common complications to Rtx treatment are mild and transient infusion related reactions. Delayed moderate-to-severe reactions are less common, and occur mostly in patients who develop human anti-chimeric antibodies. In conclusion, Rtx is a promising treatment option for severe pSS with systemic complications, but more data from randomized controlled trials are warranted before conclusions on the drug's role can be made with more accuracy.