Showing papers by "Ulf Müller-Ladner published in 2016"

Incidences and Risk Factors of Organ Manifestations in the Early Course of Systemic Sclerosis: A Longitudinal EUSTAR Study

Abstract: Objective Systemic sclerosis (SSc) is a rare and clinically heterogeneous autoimmune disorder characterised by fibrosis and microvascular obliteration of the skin and internal organs. Organ involvement mostly manifests after a variable period of the onset of Raynaud's phenomenon (RP). We aimed to map the incidence and predictors of pulmonary, cardiac, gastrointestinal (GI) and renal involvement in the early course of SSc. Methods In the EUSTAR cohort, patients with early SSc were identified as those who had a visit within the first year after RP onset. Incident SSc organ manifestations and their risk factors were assessed using Kaplan-Meier methods and Cox regression analysis. Results Of the 695 SSc patients who had a baseline visit within 1 year after RP onset, the incident non-RP manifestations (in order of frequency) were: skin sclerosis (75%) GI symptoms (71%), impaired diffusing capacity for monoxide 40mmHg (14%), and renal crisis (3%). In the heart, incidence rates were highest for diastolic dysfunction, followed by conduction blocks and pericardial effusion. While the main baseline risk factor for a short timespan to develop FVC impairment was diffuse skin involvement, for PAPsys>40mmHg it was higher patient age. The main risk factors for incident cardiac manifestations were anti-topoisomerase autoantibody positivity and older age. Male sex, anti-RNA-polymerase-III positivity, and older age were risk factors associated with incident renal crisis. Conclusion In SSc patients presenting early after RP onset, approximately half of all incident organ manifestations occur within 2 years and have a simultaneous rather than a sequential onset. These findings have implications for the design of new diagnostic and therapeutic strategies aimed to 'widen' the still very narrow 'window of opportunity'. They may also enable physicians to counsel and manage patients presenting early in the course of SSc more accurately.

An EULAR study group pilot study on reliability of simple capillaroscopic definitions to describe capillary morphology in rheumatic diseases

Abstract: OBJECTIVE: To propose simple capillaroscopic definitions for interpretation of capillaroscopic morphologies and to assess inter-rater reliability. METHODS: The simple definitions proposed were: normal-hairpin, tortuous or crossing; abnormal-not hairpin, not tortuous and not crossing; not evaluable-whenever rater undecided between normal and abnormal. Based upon an aimed kappa of 0.80 and default prevalences of normal (0.4), abnormal (0.4) and not evaluable (0.2) capillaries, 90 single capillaries were presented to three groups of raters: experienced independent raters, n = 5; attendees of the sixth EULAR capillaroscopy course, n = 34; novices after a 1-h course, n = 11. Inter-rater agreement was assessed by calculation of proportion of agreement and by kappa coefficients. RESULTS: Mean kappa based on 90 capillaries was 0.47 (95% CI: 0.39, 0.54) for expert raters, 0.40 (95% CI: 0.36, 0.44) for attendees and 0.46 (95% CI: 0.41, 0.52) for novices, with overall agreements of 67% (95% CI: 63, 71), 63% (95% CI: 60, 65) and 67% (95% CI: 63, 70), respectively. Comparing only normalvsthe combined groups of abnormal and not evaluable capillaries did increase the kappa: 0.51 (95% CI: 0.37 ,: 0.65), 0.53 (95% CI: 0.49, 0.58) and 0.55 (95% CI: 0.49, 0.62). On the condition that the capillaries were classifiable, the mean kappa was 0.62 (95% CI: 0.50, 0.74) for expert raters (n = 65), 0.76 (95% CI: 0.69, 0.83) for attendees (n = 20) and 0.81 (95% CI: 0.74, 0.89) for novices (n = 44). CONCLUSION: This multicentre, international study showed moderate reliability of simple capillaroscopic definitions for describing morphology of capillaries by rheumatologists with varying levels of expertise. Novices were capable of distinguishing normal from abnormal capillaries by means of a 1-h training session. In future studies, the class not evaluable may be obsolete.

Adipokines in bone disease.

Abstract: Adipose tissue secretes highly bioactive factors, the adipokines. Systemic levels of adipokines are often altered in the presence of inflammation. In turn, adipokines affect different tissues and cells systemically as well as locally, contributing to immunomodulatory and bone remodelling mechanisms. The role of adipokines has been evaluated in chronic inflammatory diseases, such as rheumatoid arthritis, as well as in primarily degenerative joint diseases, such as osteoarthritis, particularly with regard to their levels of expression and their effects on joint tissues including synovial membrane, cartilage and bone. Distinct adipokines have been found to modulate matrix remodelling as well as inflammatory responses. In this Review, we summarize current knowledge relating to adipokines in rheumatic diseases, with a particular focus on the effects of adipokines on bone remodelling.

A gender gap in primary and secondary heart dysfunctions in systemic sclerosis: a EUSTAR prospective study

Abstract: Objectives In agreement with other autoimmune diseases, systemic sclerosis (SSc) is associated with a strong sex bias. However, unlike lupus, the effects of sex on disease phenotype and prognosis are poorly known. Therefore, we aimed to determine sex effects on outcomes. Method We performed a prospective observational study using the latest 2013 data extract from the EULAR scleroderma trials and research (EUSTAR) cohort. We looked at (i) sex influence on disease characteristics at baseline and (ii) then focused on patients with at least 2 years of follow-up to estimate the effects of sex on disease progression and survival. Results 9182 patients with SSc were available (1321 men) for the baseline analyses. In multivariate analysis, male sex was independently associated with a higher risk of diffuse cutaneous subtype (OR: 1.68, (1.45 to 1.94); p<0.001), a higher frequency of digital ulcers (OR: 1.28 (1.11 to 1.47); p<0.001) and pulmonary hypertension (OR: 3.01 (1.47 to 6.20); p<0.003). In the longitudinal analysis (n=4499), after a mean follow-up of 4.9 (±2.7) years, male sex was predictive of new onset of pulmonary hypertension (HR: 2.66 (1.32 to 5.36); p=0.006) and heart failure (HR: 2.22 (1.06 to 4.63); p=0.035). 908 deaths were recorded, male sex predicted deaths of all origins (HR: 1.48 (1.19 to 1.84); p<0.001), but did not significantly account for SSc-related deaths. Conclusions Although more common in women, SSc appears as strikingly more severe in men. Our results obtained through the largest worldwide database demonstrate a higher risk of severe cardiovascular involvement in men. These results raise the point of including sex in the management and the decisionmaking process.

Rheumatoid synovial fibroblasts differentiate into distinct subsets in the presence of cytokines and cartilage

Abstract: Background We investigated two distinct synovial fibroblast populations that were located preferentially in the lining or sub-lining layers and defined by their expression of either podoplanin (PDPN) or CD248, and explored their ability to undergo self-assembly and transmigration in vivo.

Current concepts in chronic inflammatory diseases: Interactions between microbes, cellular metabolism, and inflammation

Abstract: Recent research indicates that chronic inflammatory diseases, including allergies and autoimmune and neuropsychiatric diseases, share common pathways of cellular and molecular dysregulation. It was the aim of the International von-Behring-Rontgen Symposium (October 16-18, 2014, in Marburg, Germany) to discuss recent developments in this field. These include a concept of biodiversity; the contribution of urbanization, lifestyle factors, and nutrition (eg, vitamin D); and new mechanisms of metabolic and immune dysregulation, such as extracellular and intracellular RNAs and cellular and mitochondrial stress. Epigenetic mechanisms contribute further to altered gene expression and therefore to the development of chronic inflammation. These novel findings provide the foundation for further development of preventive and therapeutic strategies.

The impact of serial radon and hyperthermia exposure in a therapeutic adit on pivotal cytokines of bone metabolism in rheumatoid arthritis and osteoarthritis

Abstract: Secondary osteoporosis is a frequent complication of rheumatoid arthritis (RA) and the result of an imbalance of catabolic and anabolic mechanisms of bone metabolism. The effects of serial low-dose radon and hyperthermia (LDRnHT) exposure in a therapeutic adit (12 applications in 3 weeks) on the serum levels of the cytokines osteoprotegerin (OPG), receptor activator of NF kappa-B ligand (RANKL), tumor necrosis factor-α (TNF-α), and also on the RANKL/OPG ratio were investigated in 25 RA patients and an age-matched control of 24 patients with osteoarthritis (OA). Cytokine measurements were performed at baseline and after completion of LDRnHT. Anti-CCP antibodies (ACPA) were measured in RA patients in parallel. Medication in both groups was limited to non-steroidal anti-inflammatory drugs, and low-dose prednisolone (16 of 24 RA patients) as needed. RA and OA patients showed a significant decrease of TNF-α levels (p < 0.001). Both groups showed significantly decreased levels of RANKL (RA: p < 0.001, OA: p < 0.01). Only the RA patients presented a significant increase of OPG (p < 0.01) and decrease of the RANKL/OPG ratio (p < 0.01), and the ACPA levels (p < 0.001). LDRnHT results in a reduction of osteocatabolic and an increase of osteoanabolic cytokines, which represents the molecular basis for inhibiting osteoclastic activity in secondary osteoporosis and explains in part the effect of LDRnHT this physical therapy modality in a key inflammatory disease. Although reduced ACPA levels were observed under the therapy and although this could potentially contribute to an osteoprotective effect, in this case, it is rather uncertain as the reduction was only minor in magnitude.

Influence of Extracellular RNAs, Released by Rheumatoid Arthritis Synovial Fibroblasts, on Their Adhesive and Invasive Properties

Abstract: Extracellular RNA (exRNA) has been characterized as a molecular alarm signal upon cellular stress or tissue injury and to exert biological functions as a proinflammatory, prothrombotic, and vessel permeability-regulating factor. In this study, we investigated the contribution of exRNA and its antagonist RNase1 in a chronic inflammatory joint disease, rheumatoid arthritis (RA). Upon immunohistochemical inspection of RA, osteoarthritis (OA), and psoriatic arthritis synovium, exRNA was detectable only in the RA synovial lining layer, whereas extracellular DNA was detectable in various areas of synovial tissue. In vitro, exRNA (150-5000 nt) was released by RA synovial fibroblasts (RASF) under hypoxic conditions but not under normoxia or TNF-α treatment. RNase activity was increased in synovial fluid from RA and OA patients compared with psoriatic arthritis patients, whereas RNase activity of RASF and OASF cultures was not altered by hypoxia. Reduction of exRNA by RNase1 treatment decreased adhesion of RASF to cartilage, but it had no influence on their cell proliferation or adhesion to endothelial cells. In vivo, treatment with RNase1 reduced RASF invasion into coimplanted cartilage in the SCID mouse model of RA. We also analyzed the expression of neuropilins in synovial tissue and SF, as they may interact with vascular endothelial growth factor signaling and exRNA. The data support the concepts that the exRNA/RNase1 system participates in RA pathophysiology and that RASF are influenced by exRNA in a prodestructive manner.

Rheumatologie – Integration in die studentische Ausbildung (RISA)

Abstract: The German Society of Rheumatology and the Committee for Student Training investigated what effects the structures in university medicine have on student teaching. In February 2014 a questionnaire was sent to the teaching staff and Deans of each of the 37 medical faculties. Of the locations seven were classified as being independent rheumatological university hospitals and nine universities had a W2/W3/C3 grade professor as head of a department of clinical rheumatology but answerable to superiors. In the 37 faculties in Germany the proportion of lecture hours, the proportion of obligatory lecture hours, the number of hours for practical exercises and the number of hours for bedside teaching were distributed very differently and as a rule higher in universities with academic freedom. Not all medical faculties have obligatory teaching in the field of clinical rheumatology. On average medical students see five patients with rheumatological symptoms during their studies. In summary, over the past years it has not been possible to successfully utilize the great importance of rheumatology for society and the innovation potential of this discipline in order to improve the integration of clinical rheumatology into universities.

EULAR-Empfehlungen für die Schulung von Patienten mit entzündlich-rheumatischen Gelenkerkrankungen

Abstract: Die EULAR hat 2015 im Rahmen von Empfehlungen fur die Schulung von Patienten mit entzundlich-rheumatischen Gelenkerkrankungen zwei ubergeordnete Prinzipien und acht Empfehlungen auf Basis einer systematischen Literatursuche und eines Expertenkonsenses veroffentlicht. In der vorliegenden Publikation wurden die Ergebnisse der Evaluation ins Deutsche ubertragen und kommentiert. Funfzehn deutschsprachige Experten haben die Ubersetzung abgestimmt und hinsichtlich des Grads der Empfehlung auf einer Skala zwischen 0 (keine Ubereinstimmung) und 10 (volle Ubereinstimmung) bewertet und kommentiert. Die Ubereinstimmung der Experten mit den Empfehlungen lag insgesamt bei 8,8 ± 0,49.

Europäische Versorgungsstandards für Menschen mit rheumatoider Arthritis

Abstract: In einer gemeinsamen Initiative des Vorstands der Deutschen Gesellschaft fur Rheumatologie (DGRh) und des Verbands rheumatologischer Akutkliniken (VRA) wurden die kurzlich vom European Musculoskeletal Conditions Surveillance and Information Network (eumusc.net) vorgeschlagenen und von der European League Against Rheumatism (EULAR) unterstutzten europaischen „standards of care“ fur rheumatoide Arthritis (RA) ubersetzt und kommentiert. Die Empfehlungen umfassen Aspekte des Managements der Erkrankung, der unmittelbaren medizinischen Versorgung sowie des Zugangs zu Informationen – einschlieslich aller Arten von Unterstutzung, die Menschen mit RA benotigen – und nicht zuletzt der Vermittlung des erforderlichen Wissens. Daruber hinaus geht es auch um Versorgungsstrukturen, z. B. um die Verfugbarkeit von medizinischem Personal mit entsprechender Expertise.

Low bone mineral density and vitamin d deficiency correlated with genetics and other bone markers in female Turkish immigrants in Germany

Abstract: Patients with osteoporosis have a low bone mass resulting in an increased risk for bone fractures, morbidity and mortality. One hundred thirty-one female pre-menopausal participants (98 Turkish immigrants living in Germany in comparison with 33 age-matched healthy Germans) were recruited for this study which explored vitamin D deficiency and specific genetic modifications of bone metabolism. The subjects were investigated for their femoral and lumbar bone mineral density (BMD) by dual-energy X-ray absorptiometry (DEXA) of the right total femur and the lumbar spine. Serum levels of osteologic parameters were determined: parathormone (PTH), calcium (Ca), osteocalcin (OC), phosphate (P), alkaline phosphatase (AP), beta-crossLaps (CL), tartrate-resistant acid phosphatase isoform 5b (TRAP5b), and 25-vitamin D3 (25-OH D3). The Bsml- and Fokl-polymorphisms of the vitamin D receptor (VDR) gene and the collagen type I alpha 1 (COLIA1)-gene polymorphism were also genotyped. An extremely high prevalence of vitamin D deficiency could be found in the immigrant cohort (87.8 %). Osteoporosis but not osteopenia was more prevalent in this group. Among immigrants with osteoporosis, TRAP5b was elevated in 42.9 % and beta-CL in 28.6 %. Only the Fokl FF-genotype of the VDR polymorphism was significantly more prevalent among the Turkish women, Ff-genotyped immigrants showed significantly decreased BMD. A significant correlation between the COLIA1-gene polymorphism and BMD could not be identified in the two groups. Vitamin D deficiency and osteoporosis appear to be dominant and unrecognized problem among female Turkish immigrants in Germany. Therefore, in this population, osteologic parameters and BMD should be routinely analyzed and deficiencies be treated immediately.

[Standards of care for people with rheumatoid arthritis in Europe : Translation and comments of the eumusc.net recommendations supported by EULAR performed by a national task force of the professional organisations DGRh and VRA supported by "Deutsche Rheumaliga"].

Abstract: In a joint initiative by the boards of the German Society for Rheumatology (DGRh) and the Association of Rheumatology Clinics (VRA) the European "standards of care" for rheumatoid arthritis, recently suggested by the European Musculoskeletal Conditions Surveillance and Information Network (eumusc.net) and supported by the European League Against Rheumatism (EULAR), were translated and annotated. The recommendations include aspects of the management of the disease, actual medical care, and access to information - this includes all types of support people with RA need, and, last but not least communication of the necessary knowledge. Furthermore, health care structures such as the availability of medical staff with relevant expertise are also important.

Effects of Osteoporosis Specific Standardized Physical Therapy on Functional Capacity, Bone Mineral Density and Bone Metabolism – a 2-Year Prospective and Randomized Study

Abstract: Purpose: Patients with osteoporosis inherit a high risk for pathologic fractures as consequence from falling due to deficits in coordination, balance, muscle strength and endurance. It is believed that a specific training can avoid these complications. Therefore the effects of osteoporosis specific physiotherapy (OSP) on functional capacity, bone mineral density (BMD) and bone metabolism were evaluated in a real-life long-term setting. Methods: 42 patients with manifest osteoporosis receiving adequate calcium and vitamin D supplementation and bisphosphonate therapy were included. 25 patients underwent OSP once a week (exercise group – EG) and were compared to 17 patients without OSP (control group – CG). Outcome parameters at baseline and after 1 and 2 years included assessments of functional capacity and pain as well as BMD and specific markers of bone metabolism (serum osteocalcin and crosslaps). Results: Functional capacities improved significantly only in the EG, a significant pain reduction occurred only in the EG as well. Furthermore the EG demonstrated a significant increase in BMD of the right femur after 2 years (0.84±0.10 g/cm²) as compared to baseline (0.81±0.12 g/cm²) (p Conclusions: This is the first study to show that standardized osteoporosis-specific physiotherapy once weekly results in significant protective effects on functional capacity, bone mineral density and bone metabolism, which is accompanied by a reduced risk of falling in patients with osteoporosis under adequate osteoprotective medical treatment. It needs to be emphasized that even a once-weekly exercise is sufficient to sustain these positive effects.

EULAR recommendations for patient education of people with inflammatory arthritis. Translation and evaluation in Germany

Abstract: In 2015 EULAR published recommendations for patient education of people with inflammatory arthritis. The recommendations included two superior principles and eight recommendations based on the level of evidence and expert knowledge. The German translation of the recommendations was evaluated by 15 German experts. Experts graded the strength of the recommendations (SOR) on an 11 point numerical rating scale (from 0 = no agreement to 10 = total agreement). The mean score was 8,8 ± 0,49.

FRI0199 Rituximab in Combination with Leflunomide: Results from A Multicenter Randomized Placebo Controlled Investigator Initiated Clinical Trial in Active Rheumatoid Arthritis (Amara-Study)

Abstract: Background Use of biologicals such as Rituximab (RTX) in Rheumatoid Arthritis (RA) is effective and often only licensed in combination with Methotrexate (MTX). In cases of contraindications to or intolerances, other cDMARDs are frequently used in routine care without data from RCTs. Objectives To demonstrate safety and efficacy of RTX in combination with Leflunomide (LEF) in a multicenter randomized placebo (PLA) controlled clinical trial in Germany. Methods A total of 189 patients with active RA (DAS28 >3.2 and at least 3 SJC and 3 TJC) despite stable LEF treatment were screened for a 52-weeks double-blind placebo controlled multicenter RCT. Patients were randomized to receive either two times 1000mg RTX i.v. or PLA, followed by a second course of RTX of either two times 500 or 1000 mg at week 24. The primary endpoint of the study was superiority of RTX in ACR20 and 50 responses vs. PLA during 24-weeks treatment period. Adult patients who had inadequate response to more than one antiTNF or failed more than three cDMARDs were excluded. Disease activity as well as patient reported outcomes were measured at each visit. For safety evaluation, frequency and severity of adverse events were documented. Results Of 189 screened patients 148 were randomized. The mean age was 56 years; the mean body weight 76 kg and 74% were female. The disease activity (DAS28) at baseline was 5.57 for RTX and 5.54 in the PLA group. All baseline-characteristics were well balanced between the treatment arms. RTX demonstrated significant superiority compared to PLA at week 16 in both, ACR 20 and ACR 50 response. ACR 20 response was significant superior for RTX treatment at weeks 12, 16 and 24 in both analyses, per protocol and modified intention to treat (see table). DAS28 levels in the RTX treatment-group decreased to 3.69 at week 24 (PLA 4.51) and to 3.01 at week 52. A total of 372 adverse events (AE) were observed during the one-year study period, only 14 were classified as severe (10 in RTX and 4 in PLA). 43 serious adverse events were reported, 28 of them in the RTX treatment group during the placebo controlled period. Conclusions Here we report for the first time data of a RCT of combination of RTX with LEF. The treatment with RTX in combination with LEF demonstrated significant efficacy compared to the PLA for ACR20 response and for ACR50 response as well as reduction in DAS28. The highest level of response was seen at week 16. The combination of RTX and LEF demonstrated a reasonable safety profile. Disclosure of Interest F. Behrens Grant/research support from: Roche, T. Rossmanith: None declared, M. Kohm: None declared, R. Alten Grant/research support from: Roche, M. Aringer Grant/research support from: Roche, M. Backhaus Grant/research support from: Roche, C. Baerwald Grant/research support from: Roche, G. Burmester Grant/research support from: Roche, E. Feist Grant/research support from: Roche, H. Kellner Grant/research support from: Roche, K. Kruger Grant/research support from: Roche, U. Muller-Ladner Grant/research support from: Roche, A. Rubbert-Roth Grant/research support from: Roche, H.-P. Tony Grant/research support from: Roche, S. Wassenberg Grant/research support from: Roche, H. Burkhardt Grant/research support from: Roche

OP0149 Dopamine Pathway and Bone Metabolism in Rheumatoid Arthritis

Abstract: Background A body of studies demonstrates the influence of the nervous system on the immune response. We recently described that dopamine, a neurotransmitter of the sympathetic nervous system, is locally produced by synovial fibroblasts of rheumatoid arthritis (RA) patients and influences in vitro cytokine release and inflammation (1). In addition, in vivo evidence confirmed the involvement of dopamine receptors (DR) in arthritis (2), and a subtype of DR was described to be expressed by in vitro differentiated human osteoclasts (3). These studies, together with the clinical evidence of an increased risk of osteoporosis in patients affected by Parkinson9s disease, suggest an involvement of dopamine in joint destruction during RA. The aim of this study is therefore not only to investigate the role of the dopamine pathway on bone remodeling in RA patients, but also to unravel new pathways involved in joint destruction. Objectives The aim of this study is therefore not only to investigate the role of the dopamine pathway on bone remodeling in RA patients, but also to unravel new pathways involved in joint destruction. Methods Bone tissue was obtained from osteoarthritis (OA, n=6) and RA (n=4) patients during knee joint replacement surgery. Osteoblasts were isolated from the bone spongiosa. Immunohistochemistry of paraffin-embedded bone samples and immunocytochemistry of isolated osteoblasts were performed using antibodies against the five subtypes of DR (D1 to D5). Isolated osteoblasts were treated with specific DR agonists for 24 h or 7 d. IL-6 and IL-8 were quantified after 24 h stimulation by ELISA. Expression of tyrosine hydroxylase (TH), the rate limiting enzyme for dopamine production, was quantified in untreated isolated osteoblasts by real-time PCR. Mann Whitney test was used for statistical data analysis. Results Dopamine receptors D1, D3 and D4 could be detected by immunohistochemistry in the bone remodeling zone of RA patients while OA samples did not express these receptors in the bone remodeling zone. Dopamine receptor subtypes D1, D2, D3 and D5 were present on isolated osteoblasts, with stronger expression in RA compared to OA. Stimulation of D1-like DR induced a significant dose-dependent increase of IL-6 release in RA compared to the untreated control (+79 ±43%, P Conclusions Dopamine receptors are upregulated in the bone remodeling zone of RA patients and their activation seems to have proinflammatory effects and to inhibit osteoblast activation. Expression of TH in osteoblasts suggests autocrine/paracrine effects of dopamine locally synthesized in the bone. These data underline the key involvement of the dopamine pathway in bone remodeling and joint erosion in RA. References Arthritis Rheumatol. 2014;66:2685–93 Mod. Rheumatol. 2011;21:260–6 Bone 2013;56:1–8 Disclosure of Interest None declared

A4.09 Adipokines affect differentiation of osteoarthritis and osteoporosis spongiosa-derivedmesenchymal stromal cells

Abstract: Introduction Age-related bone loss and articular cartilage destruction are accompanied by increased bone marrow fat infiltration. Bone marrow adipocytes have high secretory activity including secretion of proinflammatory (eg, adipokines) and matrix-degrading (eg, matrix metalloproteinases, MMPs) proteins and may be involved in progressive bone loss observed in osteoarthritis and osteoporosis. These adipocyte-derived factors most likely influence differentiation of bone marrow-derived mesenchymal stem cells (MSCs) into osteoblasts and adipocytes. Therefore, we analysed the effects of resistin, leptin and visfatin on MSC differentiation and their distribution in bone. Methods Spongiosa containing bone marrow from femoral heads of patients undergoing hip replacement after osteoporotic femoral neck fracture or osteoarthritis were collected. Primary spongiosa-derived mesenchymal stromal cells (hMSCs) as well as commercially obtained MSCs were cultured in adipogenic and osteogenic media 3 weeks with/without adipokines. mRNA expression of adipokines, bone marker genes, TIMPs and MMPs of stimulated hMSCs/MSCs and of bone samples were evaluated by real time PCR. Results Exression of visfatin was significantly increased in osteoporotic bone (n = 10) compared to non-osteoporotic bone (n = 11). Higher expression of leptin was also visible in osteoporotic bone. MSC stimulation with visfatin significantly increased MMP13 expression (eg, d21:72-fold) during adipogenic differentiation but not leptin and resistin. During osteogenic differentiation MMP2 was reduced. In contrast to adipogenic differentiation, viafatin led to reduced MMP13 expression (eg, d21:55-fold) in osteogenic differentiated cells (n = 2). Mainly visfatin decreased TIMP1 (eg, d21: 2.86-fold), TIMP2 (eg, d21: 3.17-fold), and RunX2 (eg, d21:5.85-fold) production, whereas leptin and resistin showed no effect. Conclusion Visfatin and leptin levels were increased in osteoporotic bone tissue. Visfatin induced MMP13 expression in adipogenic cells while the production of MMP2 and MMP13 was reduced during osteogenic differentiation. The altered MMP production mediated by visfatin might influence bone remodelling at the adipose tissue/bone interface. Moreover, high levels of leptin in the osteoporotic bone might promote bone degradation. Although leptin had no local effect on MSCs differentiation in vitro , it may promote bone degradation by affecting other cell types.

Europäische Versorgungsstandards für Menschen mit rheumatoider Arthritis. Übersetzung und Kommentierung der von der EULAR unterstützten Vorschläge des eumusc.net durch eine Task Force von DGRh und VRA mit Unterstützung der Deutschen Rheuma-Liga

Abstract: In a joint initiative by the boards of the German Society for Rheumatology (DGRh) and the Association of Rheumatology Clinics (VRA) the European aEurostandards of care" for rheumatoid arthritis, recently suggested by the European Musculoskeletal Conditions Surveillance and Information Network (eumuscnet) and supported by the European League Against Rheumatism (EULAR), were translated and annotated The recommendations include aspects of the management of the disease, actual medical care, and access to information - this includes all types of support people with RA need, and, last but not least communication of the necessary knowledge Furthermore, health care structures such as the availability of medical staff with relevant expertise are also important

FRI0268 Safety and Efficacy of Subcutaneous Tocilizumab in Early Systemic Sclerosis: Results from The Open-Label Period of The Fasscinate Trial

Abstract: Background Systemic sclerosis (SSc) is a debilitating disease with few treatment options. Interleukin-6 (IL-6) appears to play a role in SSc pathogenesis. 1,2 Data from the 48-week, double-blind (DB), placebo (PBO)-controlled period of the faSScinate trial were previously presented, 3 and open-label (OL) data are presented herein. Objectives To assess safety and efficacy of tocilizumab (TCZ) in SSc patients during 48 weeks of OL TCZ treatment. Methods Patients ≥18 y with active SSc (≤5-year duration, modified Rodnan skin score [mRSS] 15–40, and elevated acute-phase reactants) received OL TCZ 162 mg SC weekly from week 48 to week 96. Change from baseline in mRSS, patient-reported outcomes (PROs), and FVC at week 96 were exploratory measures. Observed means used all available data. Results In total, 27/43 (63%) TCZ and 24/44 (55%) PBO patients completed week 96. Baseline (BL) characteristics were similar at BL and at entry into the OL period. Patients who switched from PBO→OL TCZ showed improvement in observed mean change from BL in mRSS at week 96 (–9.4) relative to the end of the 48-week DB period (–3.1). In patients initially randomized to TCZ (TCZ→OL TCZ), mean change in mRSS was –5.6 at week 48 and –9.1 at week 96. In the OL period, improvements in PROs were noted at week 96 vs week 48 in the PBO→OL TCZ group (mean [SD] change from BL at week 96 vs week 48 in HAQ-DI: –0.3 [0.4] vs 0.2 [0.4]; Patient Global VAS: –23.8 [36.0] vs –4.0 [24.0]; FACIT-Fatigue:11.3 [12.8] vs 1.4 [7.6]). In patients who completed the study, none experienced a >10% decline in % predicted FVC during the OL period on TCZ therapy. Rates (95% CI) of serious adverse events/100 patient-years (PY) in the DB period were 76.1 (50.6, 110.0) in PBO patients and 66.7 (42.3, 100.1) in TCZ patients and were 36.0 (18.0, 64.4) in PBO→OL TCZ patients and 16.5 (5.4, 38.5) in TCZ→OL TCZ patients in the OL period. Rates (95% CI)/100PY of serious infections in the DB period were 10.9 (3.0, 27.9) in PBO patients and 34.8 (18.0, 60.8) in TCZ patients. In the OL period they were 19.6 (7.2, 42.7) in PBO→OL TCZ patients and 0.0 (0.0, 12.2) in TCZ→OL TCZ patients. No deaths occurred in the OL period (deaths in DB period: 3 TCZ, 1 PBO). Conclusions Although OL data have to be interpreted with caution, efficacy and safety in PBO-treated patients who switched to OL TCZ were generally similar to those observed in patients randomized to TCZ in the DB period. Results over 96 weeks of TCZ treatment suggest maintenance of the clinical response for mRSS in SSc patients. Serious infection rates increased in PBO patients after they switched to OL TCZ. Long-term safety was consistent with the natural history of SSc and the safety profile of TCZ. References J Rheumatol 1998;25:308. Pathobiology 1993;61:239. Ann Rheum Dis 2015;74(suppl 2):87. Disclosure of Interest D. Khanna Grant/research support from: NIH/NIAMS, NIH/ NIAID, Bayer, BMS, Consultant for: Bayer, BMS, Genetech/Roche, GSK, Genkyotex, Sanofi-Aventis, Actelion, Gilead, C. Denton Grant/research support from: GSK, Actelion, CSL Behring, Consultant for: GSK, Bayer, Actelion, Roche, Merck-Serono, MedImmune, A. Jahreis Shareholder of: Roche, Employee of: Genentech, J. van Laar Grant/research support from: MSD, Consultant for: MSD, Roche, Pfizer, BMS, Eli Lilly, L. Burke Employee of: Roche Products Ltd., H. Spotswood Shareholder of: Roche, Employee of: Roche Products Ltd., C. Lin Shareholder of: Amgen, Roche/Genentech, Employee of: Genentech, J. Pope Grant/research support from: Roche, Bayer, BMS, Consultant for: Roche, Actelion, Bayer, BMS, Y. Allanore Grant/research support from: Bristol-Myers Squibb, Roche/Genentech, Inventiva, Pfizer, Sanofi, and Servier, Consultant for: Actelion, Bayer, Roche/Genentech, Inventiva, Medac, Pfizer, Sanofi, Servier, and UCB, U. Muller-Ladner Consultant for: Roche, Chugai Pharma, Speakers bureau: Roche, Chugai Pharma, J. Siegel Shareholder of: Roche, Employee of: Genentech, D. Furst Grant/research support from: AbbVie, Actelion, Amgen, BMS, Gilead, GSK, NIH, Novartis, Pfizer, Roche/Genentech, UCB, Consultant for: AbbVie, Actelion, Amgen, BMS, Cytori, Janssen, Gilead, GSK, NIH, Novartis, Pfizer, Roche/Genentech, UCB

Gut and Liver in Vasculitic Disorders.

Abstract: Background: Although the gastrointestinal (GI) tract including its related organs is not generally regarded as one of the primary organ systems of primary and secondary vasculitic disorders, there are numerous mechanisms of these diseases operative in or around the different structures and compartments of the GI tract. Key Messages: A majority of the respective clinical symptoms and problems are linked to an alteration of (peri)vascular homeostasis. Alteration of perivascular matrix metabolism can also affect the functional integrity and motility of the GI tract. Apart from the specific GI phenomena of the individual diseases as outlined in detail in this review, the epidemiology of GI involvement follows in general the characteristics of the respective underlying systemic disease. In addition, gender and age do neither influence the occurrence nor the severity of the GI manifestations significantly. With respect to clinical symptoms, vasculitides may result in abdominal pain, bleeding, ileus, intestinal necrosis and hematochezia because of reduced blood flow and hyper-acute occlusion in the antiphospholipid syndrome. Small-bowel involvement in vasculitic entities can cause pseudoobstruction, obstruction, malabsorption and bacterial overgrowth. Laboratory parameters can point to specific diseases but are frequently nonspecific. Thus, if biopsy fails or in unclear endoscopic situations, a variety of imaging techniques including Doppler ultrasound, abdominal CT, MRI and angiography are used and required for identification and localization of the underlying disease. Therapeutic strategies in vasculitides usually include corticosteroids and immunosuppressants, for example, cyclophosphamide in granulomatosis with polyangiitis and in panarteriitis nodosa but also biologics such as rituximab in ANCA-associated vasculitides. Virostatic drugs including interferon-α and ribavirin can be used in hepatitis B- and C-triggered vasculitides such as panarteriitis nodosa and hepatitis C-associated cryoglobulinemia. Conclusions: Immediate diagnostic and therapeutic steps of action need to be performed if vasculitis of the GI tract is suspected in order to avoid irreversible damage to organs and to improve the well-being and life of the affected patient.