Constitutive knockout of interleukin-6 ameliorates memory deficits and entorhinal astrocytosis in the MRL/lpr mouse model of neuropsychiatric lupus.

BACKGROUND: Neuropsychiatric lupus (NPSLE) describes the cognitive, memory, and affective emotional burdens faced by many lupus patients. While NPSLE's pathogenesis has not been fully elucidated, clinical imaging studies and cerebrospinal fluid (CSF) findings, namely elevated interleukin-6 (IL-6) levels, point to ongoing neuroinflammation in affected patients. Not only linked to systemic autoimmunity, IL-6 can also activate neurotoxic glial cells the brain. A prior pre-clinical study demonstrated that IL-6 can acutely induce a loss of sucrose preference; the present study sought to assess the necessity of chronic IL-6 exposure in the NPSLE-like disease of MRL/lpr lupus mice. METHODS: We quantified 1308 proteins in individual serum or pooled CSF samples from MRL/lpr and control MRL/mpj mice using protein microarrays. Serum IL-6 levels were plotted against characteristic NPSLE neurobehavioral deficits. Next, IL-6 knockout MRL/lpr (IL-6 KO; n = 15) and IL-6 wildtype MRL/lpr mice (IL-6 WT; n = 15) underwent behavioral testing, focusing on murine correlates of learning and memory deficits, depression, and anxiety. Using qPCR, we quantified the expression of inflammatory genes in the cortex and hippocampus of MRL/lpr IL-6 KO and WT mice. Immunofluorescent staining was performed to quantify numbers of microglia (Iba1 +) and astrocytes (GFAP +) in multiple cortical regions, the hippocampus, and the amygdala. RESULTS: MRL/lpr CSF analyses revealed increases in IL-17, MCP-1, TNF-α, and IL-6 (a priori p-value < 0.1). Serum levels of IL-6 correlated with learning and memory performance (R2 = 0.58; p = 0.03), but not motivated behavior, in MRL/lpr mice. Compared to MRL/lpr IL-6 WT, IL-6 KO mice exhibited improved novelty preference on object placement (45.4% vs 60.2%, p < 0.0001) and object recognition (48.9% vs 67.9%, p = 0.002) but equivalent performance in tests for anxiety-like disease and depression-like behavior. IL-6 KO mice displayed decreased cortical expression of aif1 (microglia; p = 0.049) and gfap (astrocytes; p = 0.044). Correspondingly, IL-6 KO mice exhibited decreased density of GFAP + cells compared to IL-6 WT in the entorhinal cortex (89 vs 148 cells/mm2, p = 0.037), an area vital to memory. CONCLUSIONS: The inflammatory composition of MRL/lpr CSF resembles that of human NPSLE patients. Increased in the CNS, IL-6 is necessary to the development of learning and memory deficits in the MRL/lpr model of NPSLE. Furthermore, the stimulation of entorhinal astrocytosis appears to be a key mechanism by which IL-6 promotes these behavioral deficits.

Rheuma-VOR study: optimising healthcare of rheumatic diseases by multiprofessional coordinating centres.

OBJECTIVES: Early diagnosis of inflammatory arthritis is critical to prevent joint damage and functional incapacities. However, the discrepancy between recommendations of early diagnosis and reality is remarkable. The Rheuma-VOR study aimed to improve the time to diagnosis of patients with early arthritis by coordinating cooperation between primary care physicians, specialists and patients in Germany. METHODS: This prospective non-randomised multicentre study involved 2340 primary care physicians, 72 rheumatologists, 4 university hospitals and 4 rheumatology centres in 4 German Federal States. The two coprimary endpoints (time to diagnosis and screening performance of primary care physicians) were evaluated for early versus late implementation phase. Additionally, time to diagnosis and secondary endpoints (decrease of disease activity, increase in quality of life and overall well-being, improvement of fatigue, depression, functional ability, and work ability, reduction in drug and medical costs and hospitalisation) were compared with a reference cohort of the German Rheumatism Research Centre (DRFZ) reflecting standard care. RESULTS: A total of 7049 patients were enrolled in the coordination centres and 1537 patients were diagnosed with a rheumatic disease and consented to further participation. A follow-up consultation after 1 year was realised in 592 patients. The time to diagnosis endpoint and the secondary endpoints were met. In addition, the calculation of cost-effectiveness shows that Rheuma-VOR has a dominant cost-benefit ratio compared with standard care. DISCUSSION: Rheuma-VOR has shown an improvement in rheumatological care, patient-reported outcome parameters and cost savings by coordinating the cooperation of primary care physicians, rheumatologists and patients, in a nationwide approach.

A Call for Gene Expression Analysis in Whole Blood of Patients With Rheumatoid Arthritis (RA) as a Biomarker for RA-Associated Interstitial Lung Disease.

OBJECTIVE: Rheumatoid arthritis (RA)-associated interstitial lung disease (ILD) is one of the most common and prognostic organ manifestations of RA. Therefore, to allow effective treatment, it is of crucial importance to diagnose RA-ILD at the earliest possible stage. So far, the gold standard of early detection has been high-resolution computed tomography (HRCT) of the lungs. This procedure involves considerable radiation exposure for the patient and is therefore unsuitable as a routine screening measure for ethical reasons. Here, we propose the analysis of characteristic gene expression patterns as a biomarker to aid in the early detection and initiation of appropriate, possibly antifibrotic, therapy. METHODS: To investigate unique molecular patterns of RA-ILD, whole blood samples were taken from 12 female patients with RA-ILD (n = 7) or RA (n = 5). The RNA was extracted, sequenced by RNA-Seq, and analyzed for characteristic differences in the gene expression patterns between patients with RA-ILD and those with RA without ILD. RESULTS: The differential gene expression analysis revealed 9 significantly upregulated genes in RA-ILD compared to RA without ILD: arginase 1 (ARG1), thymidylate synthetase (TYMS), sortilin 1 (SORT1), marker of proliferation Ki-67 (MKI67), olfactomedin 4 (OLFM4), baculoviral inhibitor of apoptosis repeat containing 5 (BIRC5), membrane spanning 4-domains A4A (MS4A4A), C-type lectin domain family 12 member A (CLEC12A), and the long intergenic nonprotein coding RNA (LINC02967). CONCLUSION: All gene products of these genes (except for LINC02967) are known from the literature to be involved in the pathogenesis of fibrosis. Further, for some, a contribution to the development of pulmonary fibrosis has even been demonstrated in experimental studies. Therefore, the results presented here provide an encouraging perspective for using specific gene expression patterns as biomarkers for the early detection and differential diagnosis of RA-ILD as a routine screening test.

Performance of a novel high-resolution infrared thermography marker in detecting and assessing joint inflammation: a comparison with joint ultrasound.

OBJECTIVES: To examine the value of a novel high-resolution thermographic marker in the detection of joint inflammation compared to joint ultrasound (US) and to suggest thermographic cut-off values of joint inflammatory activity. METHODS: Infrared thermographies were performed in patients with inflammatory arthritides and healthy controls. Patients were moreover examined clinically and by joint-US [Power-Doppler-(PDUS), Greyscale-US (GSUS)]. Regions of interest (ROIs) were defined for every joint and absolute temperature values within the ROIs were documented. The hottest areas ("hotspots") were identified by a clustering algorithm and the Hotspot/ROI-Ratio (HRR)-values were calculated. Subsequently, the HRR of patient-joints with different grades of hypervascularity (PDUS I°-III°) were compared among each other and with PDUS 0° control-joints. Diagnostic HRR-performance was tested by receiver-operating-characteristics. RESULTS: 360 joints of 75 arthritis-patients and 1,808 joints of 70 controls were thermographically examined. HRR-values were statistically different between PDUS I-III vs. PDUS 0 and vs. healthy subjects for all four joint groups as well as in the majority of cases between patient-joints with different grades of hypervascularity (PDUS I°-III°; p<0.05). Taking joint-US as a reference, the best performance of HRR was found at the level of the wrist-joints by an area under the curve (AUC) of 0.91 (95%CI 0.84-0.98) with a sensitivity of 0.83 and specificity of 0.88. CONCLUSIONS: HRR showed an excellent performance in the differentiation of joints with US inflammatory activity from non-inflamed joints. Moreover, HRR was able to differentiate between joints with different grades of hypervascularity, making HRR a promising tool to assist disease activity monitoring.

Autoantibodies against the chemokine receptor 3 predict cardiovascular risk.

BACKGROUND AND AIMS: Chronic inflammation and autoimmunity contribute to cardiovascular (CV) disease. Recently, autoantibodies (aAbs) against the CXC-motif-chemokine receptor 3 (CXCR3), a G protein-coupled receptor with a key role in atherosclerosis, have been identified. The role of anti-CXCR3 aAbs for CV risk and disease is unclear. METHODS: Anti-CXCR3 aAbs were quantified by a commercially available enzyme-linked immunosorbent assay in 5000 participants (availability: 97.1%) of the population-based Gutenberg Health Study with extensive clinical phenotyping. Regression analyses were carried out to identify determinants of anti-CXCR3 aAbs and relevance for clinical outcome (i.e. all-cause mortality, cardiac death, heart failure, and major adverse cardiac events comprising incident coronary artery disease, myocardial infarction, and cardiac death). Last, immunization with CXCR3 and passive transfer of aAbs were performed in ApoE(-/-) mice for preclinical validation. RESULTS: The analysis sample included 4195 individuals (48% female, mean age 55.5 ± 11 years) after exclusion of individuals with autoimmune disease, immunomodulatory medication, acute infection, and history of cancer. Independent of age, sex, renal function, and traditional CV risk factors, increasing concentrations of anti-CXCR3 aAbs translated into higher intima-media thickness, left ventricular mass, and N-terminal pro-B-type natriuretic peptide. Adjusted for age and sex, anti-CXCR3 aAbs above the 75th percentile predicted all-cause death [hazard ratio (HR) (95% confidence interval) 1.25 (1.02, 1.52), P = .029], driven by excess cardiac mortality [HR 2.51 (1.21, 5.22), P = .014]. A trend towards a higher risk for major adverse cardiac events [HR 1.42 (1.0, 2.0), P = .05] along with increased risk of incident heart failure [HR per standard deviation increase of anti-CXCR3 aAbs: 1.26 (1.02, 1.56), P = .03] may contribute to this observation. Targeted proteomics revealed a molecular signature of anti-CXCR3 aAbs reflecting immune cell activation and cytokine-cytokine receptor interactions associated with an ongoing T helper cell 1 response. Finally, ApoE(-/-) mice immunized against CXCR3 displayed increased anti-CXCR3 aAbs and exhibited a higher burden of atherosclerosis compared to non-immunized controls, correlating with concentrations of anti-CXCR3 aAbs in the passive transfer model. CONCLUSIONS: In individuals free of autoimmune disease, anti-CXCR3 aAbs were abundant, related to CV end-organ damage, and predicted all-cause death as well as cardiac morbidity and mortality in conjunction with the acceleration of experimental atherosclerosis.

Transcriptome Analysis of BAFF/BAFF-R System in Murine Nephrotoxic Serum Nephritis.

Chronic kidney disease (CKD) is an emerging cause for morbidity and mortality worldwide. Acute kidney injury (AKI) can transition to CKD and finally to end-stage renal disease (ESRD). Targeted treatment is still unavailable. NF-κB signaling is associated with CKD and activated by B cell activating factor (BAFF) via BAFF-R binding. In turn, renal tubular epithelial cells (TECs) are critical for the progression of fibrosis and producing BAFF. Therefore, the direct involvement of the BAFF/BAFF-R system to the pathogenesis of CKD is conceivable. We performed non-accelerated nephrotoxic serum nephritis (NTN) as the CKD model in BAFF KO (B6.129S2-Tnfsf13btm1Msc/J), BAFF-R KO (B6(Cg)-Tnfrsf13ctm1Mass/J) and wildtype (C57BL/6J) mice to analyze the BAFF/BAFF-R system in anti-glomerular basement membrane (GBM) disease using high throughput RNA sequencing. We found that BAFF signaling is directly involved in the upregulation of collagen III as BAFF ko mice showed a reduced expression. However, these effects were not mediated via BAFF-R. We identified several upregulated genes that could explain the effects of BAFF in chronic kidney injury such as Txnip, Gpx3, Igfbp7, Ccn2, Kap, Umod and Ren1. Thus, we conclude that targeted treatment with anti-BAFF drugs such as belimumab may reduce chronic kidney damage. Furthermore, upregulated genes may be useful prognostic CKD biomarkers.

[Current patient care of systematic lupus erythematosus in Rhineland-Palatinate and Saarland]. / Versorgungssituation des Systemischen Lupus Erythematodes in Rheinland-Pfalz und dem Saarland.

BACKGROUND: Systemic lupus erythematosus (SLE) is a clinically heterogeneous autoimmune disease that is associated with great suffering for those affected, as well as high socioeconomic costs. Early diagnosis and adequate medical care are essential for a mild course of the disease. However, there is a lack of current figures and data on the care situation of patients in the area. METHODOLOGY: A total of 1546 general practitioners, rheumatologists, neurologists, nephrologists and dermatologists in Rhineland-Palatinate and Saarland were interviewed by fax or mail using a questionnaire regarding epidemiology, symptoms, therapy and therapy success. In addition, there was the possibility of making suggestions for improvement. RESULTS: Five out of six of the 635 reported SLE patients were female. The most common main symptoms were arthralgia, fatigue, myalgia, and skin changes. Of the patients, 68% received antimalarials (AMs), whereas 46% were treated with glucocorticoids (GCs) and 50% with an immunosuppressant (IS), mainly methotrexate. In terms of comorbidities, patients suffered mainly from cardiovascular disease, fibromyalgia syndrome and depression. Rheumatologists also frequently described anaemia, diabetes mellitus and osteoporosis. DISCUSSION: Compared with guideline recommendations, the low rate of AMs in therapy was particularly striking in patients not treated by rheumatologists (35% on average compared with 81% for rheumatologists). Additionally, (sustained) high doses of GCs are not in line with literature recommendations. In the free text field, the main requests were for more rheumatologists in private practice and faster appointment scheduling, as well as better communication and networking. In addition, the desire for more training and education was frequently expressed..

[Effects of a multimodal inpatient treatment for patients with fibromyalgia syndrome at the Rhineland-Palatinate Acute Rheumatology Center]. / Effekte einer multimodalen stationären Behandlung bei PatientInnen mit Fibromyalgiesyndrom im Akut-Rheumazentrum Rheinland-Pfalz.

INTRODUCTION: Fibromyalgia syndrome (FMS) is a complex condition that is often refractory to therapy and is associated with impaired quality of life. In some studies, multimodal rheumatological treatment has been shown to be an effective therapy option for patients with systemic-inflammatory and degenerative rheumatic diseases. However, the effects of this therapeutic approach have not been sufficiently investigated in patients with FMS. Therefore, the aim of this study was to examine the effect of a concise 9­ to 10-day inpatient multimodal fibromyalgia treatment (MFT) using patient-reported outcomes in a German cohort. METHODS: The effects of MFT were assessed using visual analog scales (VAS) for pain (P) and subjective disease activity (DA), questionnaires measuring everyday functional capacity (Health Assessment Questionnaire [HAQ], Funktions-Fragebogen-Hannover [FFbH, Hannover Functional Ability Questionnaire]), and pharmacotherapy at three time points (Visit 1: beginning of multimodal therapy, Visit 2: end of MFT, and Visit 3: 3 months after Visit 2). RESULTS: Sixty-one patients were enrolled in the study at the Rhineland-Palatinate Acute Rheumatology Center. Under MFT, a significant improvement in VAS (P) and VAS (DA) was observed between the start and end of treatment (Visit 2 versus Visit 1: median decrease from 7 to 5, p < 0.001, for both VAS [P] and VAS [DA]). Additionally, comparison of the other two assessment points showed a change in VAS (P) (Visit 3 versus Visit 1: median decrease from 7 to 6, p = 0.041, and Visit 3 versus Visit 2: median increase from 5 to 6, p = 0.004). However, there were no significant differences in FFbH and HAQ parameters among the three visits. Examination of the subgroup of patients whose medication therapy was not intensified during hospitalization also showed significant improvements in VAS (P) and VAS (DA) between the start and end of MFB (Visit 2 versus Visit 1: median decrease from 7 to 4, p < 0.001, for VAS [P] and median decrease from 6.25 to 4, p = 0.002, for VAS [DA]). CONCLUSION: These findings indicate a demonstrable benefit to patients of MFT regarding both pain and subjective disease activity. Furthermore, pain relief was even observed 3 months after the end of therapy. This shows the high value of this therapeutic approach to treating patients with FMS.

NMDA Receptors in Health and Diseases: New Roles and Signaling Pathways-Anti-N-Methyl-D-Aspartate Receptor (NMDAR) Autoantibodies as Potential Biomarkers of Fatigue in Patients with Rheumatic Diseases.

Fatigue is a widespread and complex symptom with motor and cognitive components; it is diagnosed predominantly by questionnaire. We recently published a correlation between anti-N-methyl-D-aspartate receptor (NMDAR) antibodies and fatigue in patients with SLE (systemic lupus erythematosus). In the present study, we examined whether this association also applies to patients with other rheumatic diseases. Serum samples of 88 patients with different rheumatic diseases were analyzed for the presence of anti-NR2 antibodies and Neurofilament light chain (NfL) protein. The severity of fatigue was determined according to the FSMC questionnaire (Fatigue Scale for Motor and Cognitive Functions) and correlated with the circulating antibody titer and NfL level accordingly. Positive titers of anti-NR2 antibodies were detected in patients with both autoimmune and non-autoimmune rheumatic diseases. These patients suffer predominantly from severe fatigue. The circulating NfL level did not correlate with the anti-NR2 titer and the fatigue severity in all patient groups. The association of severe fatigue with circulating anti-NR2 antibodies in patients with rheumatic diseases, independently from the main disease, suggests an individual role of these autoantibodies in fatigue pathophysiology. Thus, the detection of these autoantibodies might be a helpful diagnostic tool in rheumatic patients with fatigue.

[Delegation of medical duties to qualified rheumatology assistants : Effect on depression and anxiety in patients with rheumatoid arthritis]. / Delegation ärztlicher Leistungen an rheumatologische Fachassistenten : Effekte auf Depression und Angst bei Patienten mit rheumatoider Arthritis.

BACKGROUND: At least 1 comorbidity occurs in 80% of patients with rheumatoid arthritis (RA). In addition to cardiovascular comorbidities psychological comorbid conditions are common. The prevalence of depression and anxiety is higher in patients than in the general population. Screening for comorbidities is crucial. A shortage of outpatient specialist care barely allows resources for this. The implementation of team-based care holds the potential to improve the standard of care while simultaneously working against the shortage of care. OBJECTIVE: The aim of the study was to examine the effects of care on the course of depression and anxiety in patients with seropositive RA and active disease. MATERIAL AND METHODS: A multicenter pragmatic randomized controlled trial was conducted over the course of 1 year with 224 patients. After baseline, five more visits followed. In the intervention group (IG), three were initially carried out by qualified rheumatological assistants. Depression, anxiety and patient satisfaction with outpatient care were looked at in detail. RESULTS: In the IG the anxiety symptoms significantly improved over 12 months (p = 0.036). The proportions of patients with anxiety also significantly changed in the IG (p < 0.001), while there was no change in the control group between baseline and month 12. The values of the depression scale did not differ significantly (p = 0.866). In terms of the information dimension of the satisfaction questionnaire, patients in the IG felt significantly better informed after 6 months (p = 0.013) and 12 months (p = 0.003). CONCLUSION: A positive effect of team-based care on the course of depression and anxiety in patients with seropositive RA and active disease could be shown.

Safety of belimumab in adult patients with systemic lupus erythematosus: Results of a large integrated analysis of controlled clinical trial data.

OBJECTIVES: Systemic lupus erythematosus (SLE) is a chronic, autoimmune disease that affects multiple organ systems. Belimumab, a targeted human monoclonal antibody, binds to and inhibits soluble B-lymphocyte stimulator. The safety and efficacy of belimumab has consistently been demonstrated in multiple clinical trials for the treatment of patients with active SLE. Integration of these data provides an additional opportunity to explore the safety of belimumab in a larger and more diverse population. This post hoc pooled analysis of clinical studies evaluated the safety profile of belimumab versus placebo in adults with SLE. METHODS: This was a pooled post hoc analysis of 52-week safety data from one Phase 2 and five Phase 3 belimumab trials in adult patients with SLE. Patients received ≥1 dose of placebo or belimumab (1, 4, or 10 mg/kg intravenous or 200 mg subcutaneous), plus standard therapy. Outcomes included the incidence of adverse events (AEs), serious AEs (SAEs), severe AEs, AEs of special interest (AESI), and mortality. RESULTS: Across 4170 patients (placebo: N = 1355; belimumab: N = 2815), baseline demographics, disease characteristics, and treatment exposure were similar for placebo and belimumab. Most patients (placebo: 76.6%; belimumab: 81.0%) completed the protocol Week 52 visit. Overall, incidence of AEs, SAEs, severe AEs, AESI, and mortality were similar between groups. In both groups, the most commonly reported SAEs by system organ class were infections and infestations (placebo: 5.9%; belimumab: 5.4%) and renal and urinary disorders (placebo: 2.2%; belimumab: 1.7%). Additionally, a greater proportion of patients experienced AESI with belimumab versus placebo for post-infusion/injection systemic reactions (placebo: 8.1%; belimumab: 10.2%). Mortality rates were similar between groups (placebo: 0.4%; belimumab: 0.6%). CONCLUSIONS: These results are consistent with those of the individual studies, BASE, BLISS-LN, and long-term extension studies, making belimumab one of the most studied SLE treatments for safety. Collectively, this evidence continues to support a positive benefit-risk profile of belimumab in the treatment of adult patients with SLE.

Clinical spectrum time course in non-Asian patients positive for anti-MDA5 antibodies.

OBJECTIVES: To define the clinical spectrum time-course and prognosis of non-Asian patients positive for anti-MDA5 antibodies. METHODS: We conducted a multicentre, international, retrospective cohort study. RESULTS: 149 anti-MDA5 positive patients (median onset age 53 years, median disease duration 18 months), mainly females (100, 67%), were included. Dermatomyositis (64, 43%) and amyopathic dermatomyositis (47, 31%), were the main diagnosis; 15 patients (10%) were classified as interstitial pneumonia with autoimmune features (IPAF) and 7 (5%) as rheumatoid arthritis. The main clinical findings observed were myositis (84, 56%), interstitial lung disease (ILD) (108, 78%), skin lesions (111, 74%), and arthritis (76, 51%). The onset of these manifestations was not concomitant in 74 cases (50%). Of note, 32 (21.5%) patients were admitted to the intensive care unit for rapidly progressive-ILD, which occurred in median 2 months from lung involvement detection, in the majority of cases (28, 19%) despite previous immunosuppressive treatment. One-third of patients (47, 32% each) was ANA and anti-ENA antibodies negative and a similar percentage was anti-Ro52 kDa antibodies positive. Non-specific interstitial pneumonia (65, 60%), organising pneumonia (23, 21%), and usual interstitial pneumonia-like pattern (14, 13%) were the main ILD patterns observed. Twenty-six patients died (17%), 19 (13%) had a rapidly progressive-ILD. CONCLUSIONS: The clinical spectrum of the anti-MDA5 antibodies-related disease is heterogeneous. Rapidly-progressive ILD deeply impacts the prognosis also in non-Asian patients, occurring early during the disease course. Anti-MDA5 antibody positivity should be considered even when baseline autoimmune screening is negative, anti-Ro52 kDa antibodies are positive, and radiology findings show a NSIP pattern.

Possible misclassification of cardiovascular risk by SCORE in antisynthetase syndrome: results of the pilot multicenter study RI.CAR.D.A.

OBJECTIVES: To test the ability of an established traditional cardiovascular (CV) risk prediction score [Systematic COronary Risk Evaluation (SCORE)] and its EULAR modified version (mSCORE) to identify antisynthetase syndrome (ASyS) patients at high CV risk and to examine for the first time associations of CV and cerebrovascular surrogate markers with clinical and immunological ASyS parameters. METHODS: SCORE/mSCORE and the gold standard marker of aortic stiffness [carotid-femoral pulse wave velocity (cfPWV)] were examined in ASyS patients and healthy controls. Moreover, sonography of the common- (CCA) and internal- (ICA) carotid arteries was performed in subsets of both groups, evaluating carotid intima-media thickness (cIMT), plaques and Doppler sonographic cerebrovascular surrogates [resistance (RI) and pulsatility (PI) indices]. RESULTS: We recruited 66 ASyS patients and 88 controls. According to mSCORE, 10% of the patients had high CV risk. However, cfPWV and carotid sonography revealed an increased CV risk in 21.2% and subclinical carotid atherosclerosis (SCA) in 85.7% of the patients, respectively. cfPWV and cIMT were higher in patients compared with controls (Padj=0.021 and Padj=0.003, respectively). In the ASyS group, cfPWV and cIMT correlated significantly with age (r = 0.679; P<0.001 and r = 0.664; P<0.001, respectively). Moreover, cfPWV correlated with BMI (Padj=0.001) and diabetes (Padj=0.043). CCA-RI and CCA-PI showed significant associations with creatine phosphokinase (r = 0.629; P=0.012 and r = 0.574; P=0.032, respectively) and ICA-RI and ICA-PI were higher in patients with lung involvement (both; P=0.039). CONCLUSION: ASyS patients had higher aortic stiffness and SCA compared with controls, even after adjustment for confounders. SCORE/mSCORE performed poorly in identifying high-risk patients compared with cfPWV and carotid sonography. Thus, cfPWV and carotid sonography may improve CV and cerebrovascular screening in ASyS.

Patterns of fatigue and association with disease activity and clinical manifestations in systemic lupus erythematosus.

OBJECTIVE: The prevalence of fatigue is high in patients with systemic lupus erythematosus (SLE). In this study, we used latent class analysis to reveal patterns of fatigue, anxiety, depression and organ involvement in a large international cohort of SLE patients. METHODS: We used the Lupus BioBank of the upper Rhein to analyse patterns of fatigue using latent class analysis (LCA). After determining the optimal number of latent classes, patients were assigned according to model generated probabilities, and characteristics of classes were compared. RESULTS: A total of 502 patients were included. Significant fatigue, anxiety and depression were reported by 341 (67.9%), 159 (31.7%) and 52 (10.4%) patients, respectively. LCA revealed a first cluster (67.5% of patients) with low disease activity [median (25th-75th percentile interquartile range) Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA)-SLEDAI: 2 (0-4)], significant fatigue (55.5%, P < 0.0001), low anxiety (11.8%, P < 0.0001) and depression (0.9%, P < 0.0001). Cluster 2 (25.3%) also comprised patients with low disease activity [SELENA-SLEDAI: 2 (0-6)], but those patients had a very high prevalence of fatigue (100%, P < 0.0001), anxiety (89%, P < 0.0001) and depression (38.6%, P < 0.0001). Cluster 3 (7.2%) comprised patients with high disease activity [SELENA-SLEDAI: 12 (8-17), P < 0.0001] and high fatigue (72.2%, P < 0.0001) with low levels of anxiety (16.7%, P < 0.0001) and no depression (0%, P < 0.0001). CONCLUSION: LCA revealed three patterns of fatigue with important practical implications. Based on these, it is crucial to distinguish patients with active disease (in whom remission will be achieved) from those with no or mild activity but high levels of fatigue, depression and anxiety, for whom psychological counselling should be prioritized.

Vascular Inflammation and Dysfunction in Lupus-Prone Mice-IL-6 as Mediator of Disease Initiation.

BACKGROUND: Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease and patients are under an increased risk for cardiovascular (CV) events and mortality. The increased CV risk for patients with SLE seems to be caused by a premature and accelerated atherosclerosis, attributable to lupus-specific risk factors (i.e., increased systemic inflammation, altered immune status), apart from traditional CV risk factors. To date, there is no established experimental model to explore the pathogenesis of this increased CV risk in SLE patients. METHODS: Here we investigated whether MRL-Faslpr mice, which develop an SLE-like phenotype, may serve as a model to study lupus-mediated vascular disease. Therefore, MRL-Faslpr, MRL-++, and previously generated Il6-/- MRL-Faslpr mice were used to evaluate vascular changes and possible mechanisms of vascular dysfunction and damage. RESULTS: Contrary to MRL-++ control mice, lupus-prone MRL-Faslpr mice exhibited a pronounced vascular and perivascular leukocytic infiltration in various organs; expression of pro-inflammatory cytokines in the aorta and kidney was augmented; and intima-media thickness of the aorta was increased. IL-6 deficiency reversed these changes and restored aortic relaxation. CONCLUSION: Our findings demonstrate that the MRL-Faslpr mouse model is an excellent tool to investigate vascular damage in SLE mice. Moreover, IL-6 promotes vascular inflammation and damage and could potentially be a therapeutic target for the treatment of accelerated arteriosclerosis in SLE.

Vascular stiffness: influencing factors on carotid-femoral pulse wave velocity in systemic lupus erythematosus.

OBJECTIVES: Patients with systemic lupus erythematosus (SLE) are under increased risk for cardiovascular events (CVE) and mortality. Aortic stiffness, as measured by carotid-femoral pulse wave velocity (cfPWV), has been shown to predict CVE and mortality in the general population. The aim of the present study was to examine the factors associated with cfPWV in patients with SLE and to determine differences of SLE patients in comparison to healthy controls. METHODS: 125 patients with SLE and 104 controls were included. Demographic, medication and cardiovascular risk factor data were collected from all participants. Furthermore, clinical and laboratory SLE associated parameters were documented in the patients' group. All subjects underwent measurements of blood pressure and cfPWV. RESULTS: Interestingly, only age (ß=0.55; p<0.001), mean arterial pressure (MAP) (ß=0.29; p<0.001) and estimated glomerular filtration rate (eGFR) (ß=-0.20; p=0.033) were associated independently with cfPWV in patients with SLE. Moreover, there was no difference of cfPWV between patients with SLE and controls before (p=0.301) and after adjustment for disparities between the groups (p=0.671). CONCLUSIONS: Vascular stiffness in patients with SLE seems to be independent from SLE-related factors and from most traditional CVRF and is mainly associated with age, MAP and renal function defined as eGFR. There is an independent correlation between eGFR and cfPWV in a SLE population with a widely normally ranged eGFR. There is no difference of cfPWV between patients with SLE and controls.

Fatigue in SLE: diagnostic and pathogenic impact of anti-N-methyl-D-aspartate receptor (NMDAR) autoantibodies.

OBJECTIVES: We explored the impact of circulating anti-N-methyl-D-aspartate receptor (NMDAR) antibodies on the severity of fatigue in patients with systemic lupus erythematosus (SLE). METHODS: Serum samples of 426 patients with SLE were analysed for the presence of antibodies to the NR2 subunit of the NMDAR. In parallel, the severity of fatigue was determined according to the Fatigue Scale for Motor and Cognitive functions questionnaire. In a subgroup of patients with SLE, the hippocampal volume was correlated with the levels of anti-NR2 antibodies. Isolated immunoglobulin G from patients with anti-NR2 antibodies were used for murine immunohistochemical experiments and functional assays on neuronal cell lines. Treatment effects were studied in 86 patients with lupus under belimumab therapy. RESULTS: We found a close correlation between the titre of anti-NR2 antibodies, the severity of fatigue, the clinical disease activity index (Systemic Lupus Erythematosus Disease Activity Index 2000) and anti-double stranded DNA antibodies-independently of the presence of neuropsychiatric lupus manifestations. Pathogenic effects could be demonstrated by (1) detection of anti-NR2 antibodies in the cerebrospinal fluid, (2) in situ binding of anti-NR2 antibodies to NMDAR of the hippocampus area and (3) distinct functional effects in vitro: downregulating the energy metabolism of neuronal cells without enhanced cytotoxicity. Treatment with belimumab for at least 6 months affected both the severity of fatigue and the levels of anti-NR2 antibodies. CONCLUSION: The presence of anti-NR2 antibodies in patients with SLE with fatigue is a helpful diagnostic tool and may offer a major approach in the therapeutic management of this important disabling symptom in patients with SLE.

Predictors of fatigue and severe fatigue in a large international cohort of patients with systemic lupus erythematosus and a systematic review of the literature.

OBJECTIVE: Fatigue is reported in up to 90% of patients with SLE. This study was conducted to identify the determinants associated with fatigue in a large cohort of patients with SLE, as well as to provide a systematic review of the literature. METHODS: Patients from the Lupus BioBank of the upper Rhein, a large German-French cohort of SLE patients, were included in the FATILUP study if they fulfilled the 1997 ACR criteria for SLE and had Fatigue Scale for Motor and Cognitive Functions scores collected. Multivariate logistic regression analyses were performed to assess the determinants of fatigue and severe fatigue. RESULTS: A total of 570 patients were included (89.1% female). The median age was 42 years (interquartile range 25-75: 34-52). The median value of the SAfety of Estrogens in Lupus Erythematosus National Assessment (SELENA)-SLEDAI was 2 (0-4). Fatigue was reported by 386 patients (67.7%) and severe fatigue by 209 (36.7%). In multivariate analyses, fatigue was associated with depression [odds ratio (OR): 4.72 (95% CI: 1.39-16.05), P = 0.01], anxiety [OR: 4.49 (95% CI: 2.60-7.77), P < 0.0001], glucocorticoid treatment [OR: 1.59 (95% CI 1.05-2.41), P = 0.04], SELENA-SLEDAI scores [OR: 1.05 (95% CI: 1.00-1.12) per 1 point increase, P = 0.043] and age at sampling [OR: 1.01 (95% CI: 1.00-1.03) per 1 year increase, P = 0.03]. Severe fatigue was independently associated with anxiety (P < 0.0001), depression (P < 0.0001), glucocorticoid treatment (P = 0.047) and age at sampling (P = 0.03). CONCLUSION: Both fatigue and severe fatigue are common symptoms in SLE, and are strongly associated with depression and anxiety. Disease activity and the use of glucocorticoids were also independently associated with fatigue, although more weakly.

High cardiovascular risk in mixed connective tissue disease: evaluation of macrovascular involvement and its predictors by aortic pulse wave velocity.

OBJECTIVES: Macrovascular involvement and cardiovascular (CV) risk has not been sufficiently studied in mixed connective tissue disease (MCTD). In particular, the gold standard assessment method of aortic stiffness carotid-femoral pulse wave velocity (cfPWV) has never been evaluated in patients with this disease. The aims of the present study were therefore to examine cfPWV in MCTD and to evaluate its associations with MCTD-associated markers and traditional CV risk factors. METHODS: Measurements of cfPWV were performed in 43 MCTD patients and 107 healthy controls. The difference between cfPWV in the two groups was statistically examined and subsequently controlled for the effect of possible confounding factors. The association of cfPWV with MCTD-associated organ involvement, routine laboratory parameters and immunoserological markers was also evaluated. Finally, the relationship of cfPWV with medications and traditional CV risk factors was examined. RESULTS: Adjusted statistical analyses for confounding factors showed significantly higher cfPWV values in MCTD patients in comparison to controls (padj<0.001). cfPWV correlated in both the patients and the control group significantly with age (rho=0.69, p<0.001 and rho=0.67, p<0.001 respectively) and diastolic arterial pressure (padj=0.024 and padj=0.032 respectively). Moreover, cfPWV correlated in the control group with systolic and mean arterial pressure (padj<0.001 and p=0.002 respectively). Finally, higher cfPWV values could be documented in the subset of MCTD patients without lung involvement (padj=0.007). CONCLUSIONS: Patients with MCTD have significantly higher aortic stiffness and thus CV risk in comparison to controls. Except for the disease itself, age and blood pressure were the main predictors of cfPWV.

Implementation of a Web-Based Work-Related Psychological Aftercare Program Into Clinical Routine: Results of a Longitudinal Observational Study.

BACKGROUND: As inpatient medical rehabilitation serves to promote work ability, vocational reintegration is a crucial outcome. However, previous Web-based trials on coping with work-related stress have been limited to Web-based recruitment of study participants. OBJECTIVE: The aim of our study was to evaluate the implementation of an empirically supported transdiagnostic psychodynamic Web-based aftercare program GSA (Gesund und Stressfrei am Arbeitsplatz [Healthy and stress-less at the workplace])-Online plus into the clinical routine of inpatient medical rehabilitation, to identify characteristics of patients who have received the recommendation for GSA-Online plus, and to determine helpfulness of the intervention and satisfaction of the participants as well as improvement in quality of life and mental health status of the regular users of GSA-Online plus. METHODS: GSA-Online plus was prescribed by physicians at termination of orthopedic psychosomatic inpatient rehabilitation. Participants' use of the program, work-related attitudes, distress, and quality of life were assessed on the Web. RESULTS: In 2 rehabilitation centers, 4.4% (112/2562) of rehabilitants got a recommendation for GSA-Online plus during inpatient rehabilitation. Compared with usual person aftercare, the Web-based aftercare program was rarely recommended by physicians. Recommendations were made more frequently in psychosomatic (69/1172, 5.9%) than orthopedic (43/1389, 3.1%) rehabilitation (χ21=11.845, P=.001, Cramér V=-0.068) and to younger patients (P=.004, d=0.28) with longer inpatient treatment duration (P<.001, r=-0.12) and extended sick leaves before inpatient medical rehabilitation (P=.004; Cramér V=0.072). Following recommendation, 77% (86/112) of rehabilitants participated in Web-based aftercare. Completers (50/86, 58%) reported statistically significant improvements between discharge of inpatient treatment and the end of the aftercare program for subjective work ability (P=.02, d=0.41), perceived stress (P=.01, d=-0.38), functioning (P=.002, d=-0.60), and life satisfaction (P=.008, d=0.42). CONCLUSIONS: Physicians' recommendations of Web-based aftercare are well accepted by patients who derive considerable benefits from participation. However, a low rate of prescription compared with other usual aftercare options points to barriers among physicians to prescribing Web-based aftercare.