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.

[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..

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.

The Impact of Systemic Lupus Erythematosus Flares on Clinical and Economic Outcomes: The CHAMOMILE Claims Database Study in Germany.

INTRODUCTION: CHAMOMILE (CHaracteristics and impact of flares on clinicAl and econoMic OutcoMes In patients with systemic Lupus Erythematosus [SLE]) examined how flares in the year of SLE diagnosis impact future disease activity and damage, productivity, healthcare resource utilization (HCRU), and costs in patients with SLE in Germany. METHODS: CHAMOMILE was a retrospective cohort study of adults with an SLE diagnosis in the German Sickness Fund Database from 1 July 2010 to 31 December 2013. Patients were classified according to their greatest flare severity during the baseline year (none, mild, or moderate/severe). The number and severity of flares were assessed annually over 5-8.5 follow-up years, along with SLE organ/system damage, treatments, work disability, and HCRU metrics. RESULTS: Of 2088 patients (84.6% female; mean age [standard deviation] 51.4 [16.1] years; mean follow-up 6.8 [2.1] years), 34.3% (n = 716) were flare-free, 29.8% (n = 622) had mild flares, and 35.9% (n = 750) had moderate/severe flares at baseline. Baseline flare severity was related to future flares: rates during follow-up were higher in patients with moderate/severe baseline flares compared with those with mild or no baseline flares (89.6 vs 78.5 and 44.2 flares/100 patient years, respectively). Overall, 80.2% (n = 1675) of patients received glucocorticoids at least once during baseline and follow-up. Patients' HCRU was generally greatest in their baseline year. Costs were highest in patients with moderate/severe baseline flares. CONCLUSION: Baseline flare severity provided insight into a patient's disease course and the clinical and economic burden of SLE over time, highlighting the ramifications of uncontrolled disease for patients with SLE.

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.

Arterial Stiffness as a Surrogate Marker of Cardiovascular Disease and Atherosclerosis in Patients with Vasculitides: A Literature Review.

Vasculitis, a group of systemic inflammatory diseases that affect the cardiovascular (CV) system, presents with a variety of clinical manifestations that depend on the size of the affected blood vessels. While some types of vasculitis reveal distinct symptoms, others are characterized by more diffuse and nonspecific presentations that can result in delayed diagnosis and treatment initiation. Interestingly, patients with vasculitides share a significant comorbidity: an elevated CV risk, contributing to increased rates of CV events and mortality. This heightened risk is caused by cumulative inflammatory burden, traditional CV risk factors, medication effects, and reduced physical fitness. Traditional risk assessment tools, commonly used in the general population, frequently underestimate the CV risk in patients with inflammatory rheumatic conditions. Consequently, novel approaches are necessary to stratify the precise CV risk in vasculitis patients. A number of surrogate parameters for CV risk have been investigated, with arterial stiffness emerging as a promising marker. Pulse wave velocity (PWV) is a well-established method for assessing arterial stiffness and predicting CV risk across different populations. Among numerous PWV variants, carotid-femoral PWV (cfPWV) stands out as the most extensively studied and accepted reference standard. It has demonstrated its utility as a surrogate CV parameter both in the general population and in patients with systemic inflammatory rheumatic diseases. In recent years, research has expanded to assess arterial stiffness in systemic rheumatic diseases, such as arthritis, connective tissue diseases, rheumatologic overlap syndromes, and chronic pain disorders, using measurements of PWV and other markers of arterial compliance and elasticity. Despite burgeoning research in rheumatologic diseases, data on CV risk markers in vasculitides remain limited and fragmented. This narrative review aims to provide a comprehensive overview of arterial stiffness as a potential screening marker for CV diseases, atheromatosis, and ultimately CV risk among patients with vasculitides.

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.

Diagnostic Value of Labial Minor Salivary Gland Biopsy: Histological Findings of a Large Sicca Cohort and Clinical Associations.

(1) Background: The aim of this study was to analyze labial minor salivary gland biopsy (MSGB) findings of a large sicca cohort and to examine their associations with Sjogren's syndrome (SS)-associated laboratory markers, phenotypic characteristics and systemic manifestations. Moreover, we sought to explore the ability of MSGB to identify SS patients among subjects with pre-diagnosed fibromyalgia (FM). (2) Methods: Included were all patients of three rheumatology departments having undergone a diagnostic MSGB within 9 years. Next to the examination of histological and immunohistochemical findings, we focused on activity and chronicity parameters of the underlying disease, autoantibodies, presence of systemic and hematologic involvement, as well as chronic pain and SS comorbidities. (3) Results: Among the 678 included patients, 306 (45.1%) had a positive focus score (FS). The remaining patients (n = 372) served as control subjects. There were significant correlations between FS and hypergammaglobulinemia (p < 0.001), ANA and rheumatoid factor positivity (both; p < 0.001), a weak significant correlation with erythrocyte sedimentation rate (rho = 0.235; p < 0.001) and a negative correlation with nicotine use (p = 0.002). Within the primary SS subgroup, FS was associated significantly with glandular enlargement (p = 0.007) and systemic hematologic manifestations (p = 0.002). Next to FS, CD20 cell staining showed an excellent diagnostic performance in the diagnosis of SS by an area under the curve of 0.822 (95%CI 0.780-0.864; p < 0.001). Interestingly, 42.1% of all patients with fibromyalgia (FM) having received an MSGB could be diagnosed with SS. (4) Conclusion: By examining one of the largest cohorts in the literature, we could show that MSGB histological and immunohistochemical findings not only play a key role in the classification and diagnosis of SS but could also provide important information regarding SS phenotype and systemic manifestations. Furthermore, MSGB may help differentiate patients with FM from patients with subclinical SS who suffer primarily from chronic pain.

Transcriptome analysis of renal ischemia/reperfusion (I/R) injury in BAFF and BAFF-R deficient mice.

Acute kidney injury (AKI) accompanies with high morbidity and mortality. Incomplete renal recovery can lead to chronic and finally end-stage kidney disease, which results in the requirement of lifelong dialysis or kidney transplantation. Consequently, finding predictive biomarker and therefore developing preventive therapeutic approaches is an urgent need. For this purpose, a better understanding of the mechanism underlying AKI is necessary. The cytokine BAFF (B cell activating factor) is related to AKI by supporting B cells, which in turn play an important role in inflammatory processes and the production of antibodies. In our study, we investigated the role of BAFF and its receptor BAFF-R in the early phase of AKI. Therefore, we performed the well-established ischemia/reperfusion (I/R) model in BAFF (B6.129S2-Tnfsf13btm1Msc/J) and BAFF-R (B6(Cg)-Tnfrsf13ctm1Mass/J) deficient mice. Transcriptome of ischemic and contralateral control kidneys was analyzed and compared to wildtype littermates. We detected the upregulation of Lcn2, Lyz2, Cd44, Fn1 and Il1rn in ischemic kidneys as well as the downregulation of Kl. Furthermore, we revealed different expression patterns in BAFF and BAFF-R knockout mice. Compared to wildtype littermates, up- and downregulation of each investigated gene were higher in BAFF-R knockout and lower in BAFF knockout. Our findings indicate a positive impact of BAFF knockout in early phase of AKI, while BAFF-R knockout seems to worsen I/R injury. In addition, our study shows for the first time a remarkable renal upregulation of Lyz2 in a murine I/R model. Therefore, we consider Lyz2 as conceivable predictive or early biomarker in case of I/R and AKI.

[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.

Arterial Stiffness as a Surrogate Marker of Cardiovascular Disease and Atherosclerosis in Patients with Arthritides and Connective Tissue Diseases: A Literature Review.

The increased cardiovascular (CV) risk among patients with autoimmune rheumatic diseases, such as arthritides and connective tissue diseases, has been extensively documented. From a pathophysiological standpoint, systemic inflammation in the context of the disease can lead to endothelial dysfunction, accelerated atherosclerosis, and structural changes in vessel walls, which, in turn, are associated with exaggerated CV morbidity and mortality. In addition to these abnormalities, the increased prevalence of traditional CV risk factors, such as obesity, dyslipidemia, arterial hypertension, and impaired glucose metabolism, can further worsen the status of and overall prognosis for CV in rheumatic patients. However, data on appropriate CV screening methods for patients with systemic autoimmune diseases are scarce, and traditional algorithms may lead to an underestimation of the true CV risk. The reason for this is that these calculations were developed for the general population and thus do not take into account the effect of the inflammatory burden, as well as other chronic-disease-associated CV risk factors. In recent years, different research groups, including ours, have examined the value of different CV surrogate markers, including carotid sonography, carotid-femoral pulse wave velocity, and flow-mediated arterial dilation, in the assessment of CV risk in healthy and rheumatic populations. In particular, arterial stiffness has been thoroughly examined in a number of studies, showing high diagnostic and predictive value for the occurrence of CV events. To this end, the present narrative review showcases a series of studies examining aortic and peripheral arterial stiffness as surrogates of all-cause CV disease and atherosclerosis in patients with rheumatoid and psoriatic arthritis, as well as in systemic lupus erythematosus and systemic sclerosis. Moreover, we discuss the associations of arterial stiffness with clinical, laboratory, and disease-specific parameters.

Optical spectral transmission to assess glucocorticoid therapy response in patients with arthritis: a longitudinal follow-up comparison with joint ultrasound.

BACKGROUND: Optical spectral transmission (OST) is a modern diagnostic modality, able to assess the blood-specific absorption of light transmitted through a tissue, promising quantification of inflammation in the finger and wrist joints of patients with arthritis. To date, there are no adequate data regarding the diagnostic value of OST in the evaluation of inflammatory activity changes, during arthritis follow-up. Objectives of this study were therefore to examine the performance of OST in assessing response to anti-inflammatory therapy in patients with active arthritis and to explore OST associations with clinical, laboratory, and ultrasonographic (US) activity markers. METHODS: 1173 joints of 54 patients with arthritides of the wrist and finger joints were examined by OST before and after oral administration of glucocorticoids (GC), during a disease flare. For the same time-points patients underwent clinical, laboratory, and joint US [grayscale (GSUS), power-Doppler (PDUS)] examinations. The distribution of ΔOST-values between the two time-points was compared with the respective distributions of ΔPDUS and ΔGSUS by Bayesian statistical analyses. Moreover, the diagnostic performance of OST compared to a control group (2508 joints of 114 subjects) was examined by receiver operating characteristics and associations of OST values with clinical, laboratory, and arthrosonographic parameters were evaluated by correlation analyses. RESULTS: OST and US performed similarly in the assessment of inflammatory changes caused by GC (same value-change tendency in 83.2% of the cases). Bayesian statistics revealed no significant differences between ΔOST and ΔPDUS for all 3 examined joint categories (accuracy: metacarpophalangeal (MCP): 68.1%; proximal interphalangeal (PIP): 60.4%; wrists: 50.4%) and between ΔOST and ΔGSUS for MCP and PIP joints (accuracy: 51.1% and 78.7%, respectively). OST diagnostic performance (patients vs. controls) was excellent in both time-points [area under the curve (AUC) before GC=0.883(95%CI=0.83-0.94) and after GC=0.811(95%CI=0.74-0.881); p<0.001]. Furthermore, OST correlated significantly with all examined sonographic activity scores (all; p<0.001) and with swollen joint counts (p<0.01). CONCLUSIONS: OST was able to assess response to therapy in a similar way to joint US and correlated significantly with arthritis activity markers. Therefore, OST has proved to be a valuable tool to assist disease activity monitoring in the examined cohort. TRIAL REGISTRATION: German Registry of Clinical Trials, DRKS00016752.

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.

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.

[Multidisciplinarity as the key to success : Cooperation between dermatology and rheumatology to optimize patient care]. / Multidisziplinarität als Schlüssel zum Erfolg : Zusammenarbeit zwischen Dermatologie und Rheumatologie zur Optimierung der Patientenversorgung.

BACKGROUND: Treatment of patients with systemic autoimmune and/or autoinflammatory diseases (AI/AInf) often requires multidisciplinary collaboration of various medical specialties. OBJECTIVES: We evaluated whether the establishment of a multidisciplinary board, which we termed rheuma board (RB), can contribute to optimization of care for patients with psoriatic arthritis (PsA) or other AI/AInf. MATERIALS AND METHODS: A total of 272 patients were included in the study. Patients were divided into three groups-group 1: 41 patients with or with suspected PsA, initially assessed in the dermatology department and afterwards presented for consultation in the rheumatology department; group 2: 166 patients with or with suspected PsA presenting in the dermatology department and afterwards discussed by RB; group 3: 65 patients with other AI/AInf presenting in the dermatology department and afterwards discussed by RB. We evaluated the average duration from initial presentation to therapy initiation after completing evaluation and diagnostics by both specialties. In addition, diagnosis confirmation/verification and therapy continuation/optimization were analyzed for all three groups. RESULTS: The average duration from initial presentation until therapy initiation was 85 ± 42.24 (5-173) days in group 1, 15 ± 13.09 (0-78) days in group 2, and 20 ± 16.71 (1-75) days in group 3. In addition, in groups 2 and 3 confirmation of diagnosis was faster and waiting time for diagnosis and therapy initiation was significantly reduced. CONCLUSIONS: Establishment of a RB results in a significant reduction in the time duration between first presentation and initiation of therapy, and an improvement of care for patients with AI/AInf including confirmation of diagnosis and therapy optimization.

Fatigue is independently associated with disease activity assessed using the Physician Global Assessment but not the SLEDAI in patients with systemic lupus erythematosus.

OBJECTIVES: To analyse whether reported fatigue, one of the most challenging manifestations of systemic lupus erythematosus (SLE), may bias the assessment of disease activity in SLE according to the Physician Global Assessment (PGA). METHODS: Patients from the Lupus BioBank of the upper Rhein database, a cross-sectional multicentre collection of detailed clinical and biological data from patients with SLE, were included. Patients had to fulfil the 1997 American College of Rheumatology criteria for SLE and the PGA (0-3 scale) at the time of inclusion had to be available. Fatigue was assessed according to the Fatigue Scale for Motor and Cognitive Functions. Univariate and multivariate regression models were built to determine which variables were associated with the PGA. RESULTS: A total of 350 patients (89% female; median age: 42 years, IQR: 34-52) were included. The median Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) score was 4 (IQR: 2-6). Of these 350 patients, 257 (73%) reported significant fatigue. The PGA (p=0.004) but not the SELENA-SLEDAI (p=0.43) was significantly associated with fatigue. Both fatigue and SELENA-SLEDAI were independently associated with the PGA in two different multivariate models. CONCLUSION: Fatigue is independently associated with disease activity assessed using the PGA but not the SLEDAI. These findings highlight the fact that the PGA should capture only objectively active disease manifestations in order to improve its reliability.

[Lack of therapeutic response: Is it really a rheumatoid Arthritis?] / Fehlendes Therapieansprechen: Ist es wirklich eine rheumatoide Arthritis?

ANAMNESIS: A 78-year-old female patient was referred to our hospital with treatment-resistant seronegative anti-citrullinated protein antibodies (ACPA)-negative rheumatoid arthritis. The course was characterized by high inflammatory activity and rapid progression of the erosive changes. Under the required high-dose prednisolone therapy, osteoporosis and a deep venous thrombosis (DVT) with pulmonary embolism developed. PHYSICAL EXAMINATION: A physical examination revealed symmetrical, painful, synovial swelling of the metacarpophalangeal, proximal-interphalangeal and distal-interphalangeal (MCP, PIP, and DIP) joints, finger joint-related violaceous erythema, contractures of the long fingers, and advanced deformities bilaterally. Pain and weakness in the muscles of her proximal extremities led to difficulties in raising her arms and climbing stairs. DIAGNOSIS: The results of laboratory tests showed negative RF (rheumatoid factor) and ACPAs, positive ANA (anti-nuclear antibodies) with titer 1:5120, a nuclear fluorescence pattern and a positive anti-Mi-2 Antibodies in the myositis blot. Conventional x-ray showed erosive and advanced mutilating joint changes in both hands. A magnetic resonance imaging (MRI) of the proximal extremities showed a pronounced muscle atrophy without sights of active myositis.This clinical constellation leads to the diagnosis of an amyopathic dermatomyositis. THERAPY AND PROGRESS: The patient was started on intravenous prednisone 100 mg daily, 4 days, followed by rapid dose tapering in the setting of accompanying risk factors such as Osteoporosis, arterial Hypertension and blurred vision. This treatment leads to improvement of symptoms. The basic therapy was switched to Rituximab. An extended tumor search was recommended on an outpatient basis. CONCLUSIONS: A seronegative, ACPA negative, therapy-resistant RA with a rapidly progressive erosive course requires a diagnostic re-evaluation. An erosive, rapidly progressing polyarthritis is commonly seen as manifestation of the subtype inflammatory myopathies associated with anti-Jo 1 antibodies, known as anti-synthetase syndrome. However, associations with the presence of other myositis specific antibodies (MSA) have been also described. The anti-Mi-2 Antibodies are highly specific for dermatomyositis (DM).Amyopathic DM is not common, but the disease course and prognosis do not differ significantly from myopathic DM.As a sudden presentation of DM may be of paraneoplastic origin a further examination in order to exclude malignancy are indicated.

Novel Surrogate Markers of Cardiovascular Risk in the Setting of Autoimmune Rheumatic Diseases: Current Data and Implications for the Future.

Patients suffering from rheumatologic diseases are known to have an increased risk for cardiovascular disease (CVD). Although the pathological mechanisms behind this excess risk have been increasingly better understood, there still seems to be a general lack of consensus in early detection and treatment of endothelial dysfunction and CVD risk in patients suffering from rheumatologic diseases and in particular in those who haven't yet shown symptoms of CVD. Traditional CVD prediction scores, such as Systematic Coronary Risk Evaluation (SCORE), Framingham, or PROCAM Score have been proposed as valid assessment tools of CVD risk in the general population. However, these risk calculators developed for the general population do not factor in the effect of the inflammatory burden, as well as other factors that can increase CVD risk in patients with rheumatic diseases, such as glucocorticoid therapy, abnormal lipoprotein function, endothelial dysfunction or accelerated atherosclerosis. Thus, their sole use could lead to underestimation of CVD risk in patients with rheumatic diseases. Therefore, there is a need for new biomarkers which will allow a valid and early assessment of CVD risk. In recent years, different research groups, including ours, have examined the value of different CVD risk factors such as carotid sonography, carotid-femoral pulse wave velocity, flow-mediated arterial dilation and others in the assessment of CVD risk. Moreover, various novel CVD laboratory markers have been examined in the setting of autoimmune diseases, such as Paraoxonase activity, Endocan and Osteoprotegerin. Dyslipidemia in rheumatoid arthritis (RA) is for instance better quantified by lipoproteins and apolipoproteins than by cholesterol levels; screening as well as pre-emptive carotid sonography hold promise to identify patients earlier, when prophylaxis is more likely to be effective. The early detection of subtle changes indicating CVD in asymptomatic patients has been facilitated through improved imaging methods; the inclusion of artificial intelligence (AI) shows promising results in more recent studies. Even though the pathophysiology of coronary artery disease in patients with autoimmune rheumatic diseases has been examined in multiple studies, as we continuously gain an increased understanding of this comorbidity, particularly in subclinical cases we still seem to fail in the stratification of who really is at risk-and who is not. A the time being, a multipronged and personalized approach of screening patients for traditional CVD risk factors, integrating modern imaging and further CV diagnostic tools and optimizing treatment seems to be a solid approach. There is promising research on novel biomarkers, likewise, methods using artificial intelligence in imaging provide encouraging data indicating possibilities of risk stratification that might become gold standard in the near future. The present review concentrates on showcasing the newest findings concerning CVD risk in patients with rheumatologic diseases and aims to evaluate screening methods in order to optimize CVD risk evaluation and thus avoiding underdiagnosis and undertreatment, as well as highlighting which patient groups are most at risk.

Conceptual framework for defining disease modification in systemic lupus erythematosus: a call for formal criteria.

Disease modification has become a well-established concept in several therapeutic areas; however, no widely accepted definition of disease modification exists for SLE.We reviewed established definitions of disease modification in other conditions and identified a meaningful effect on 'disease manifestations' (ie, signs, symptoms and patient-reported outcomes) and on 'disease outcomes' (eg, long-term remission or progression of damage) as the key principles of disease modification, indicating a positive effect on the natural course of the disease. Based on these findings and the treatment goals and outcome measures for SLE, including lupus nephritis, we suggest a definition of disease modification based on disease activity indices and organ damage outcomes, with the latter as a key anchor. A set of evaluation criteria is also suggested.Establishing a definition of disease modification in SLE will clarify which treatments can be considered disease modifying, provide an opportunity to harmonise future clinical trial outcomes and enable comparison between therapies, all of which could ultimately help to improve patient outcomes. This publication seeks to catalyse further discussion and provide a framework to develop an accepted definition of disease modification in SLE.