Showing papers by "Frank Buttgereit published in 2018"

Long-term glucocorticoid treatment in patients with polymyalgia rheumatica, giant cell arteritis, or both diseases: results from a national rheumatology database

Abstract: The objective of this study was to evaluate glucocorticoid (GC) use in patients with polymyalgia rheumatica (PMR), giant cell arteritis (GCA) or both diseases (PMR + GCA) under rheumatological care. Data from patients with PMR (n = 1420), GCA (n = 177) or PMR + GCA (n = 261) from the National Database of the German Collaborative Arthritis Centers were analyzed regarding GCs and related comorbidities (osteoporosis, diabetes and cardiovascular disease), stratified by disease duration (DD). Longitudinal data were analyzed for all patients with a DD ≤ 2 years at database entry (n = 1397). Three-year data were available for 256 patients. Predictors of GC use ≥ 3 years were examined by logistic regression analyses. A total of 76% received GCs, and 19% (PMR) to 40% (GCA) received methotrexate. Median GC doses were 12.5 mg (PMR), 11.3 mg (GCA), and 20.0 mg/day (PMR + GCA) in a 0–6-month DD. Median GC doses ≤ 5 mg/day were reached at a 13–18-month DD in PMR patients and at a 19–24-month DD in GCA or PMR + GCA patients. In the multivariate analysis, baseline methotrexate (OR 2.03, [95% CI 1.27–3.24]), GCs > 10 mg/day (OR 1.65, [1.07–2.55]), higher disease activity (OR 1.12, [1.02–1.23]) (median 0.6 years DD), and female sex (OR 1.63 [1.09–2.43]) were predictive for GC therapy at ≥ 3 years. Of the examined comorbidities, only osteoporosis prevalence increased within 3 years. GC use for ≥ 3 years was reported in one-fourth of all the patients. A difficult-to-control disease activity within the first year was a good predictor of long-term GC need.

Harm, benefit and costs associated with low-dose glucocorticoids added to the treatment strategies for rheumatoid arthritis in elderly patients (GLORIA trial) : study protocol for a randomised controlled trial

Abstract: Rheumatoid arthritis (RA) is a chronic inflammatory disease of the joints affecting 1% of the world population. It has major impact on patients through disability and associated comorbidities. Current treatment strategies have considerably improved the prognosis, but recent innovations (especially biologic drugs and the new class of so-called “JAK/STAT inhibitors”) have important safety issues and are very costly. Glucocorticoids (GCs) are highly effective in RA, and could reduce the need for expensive treatment with biologic agents. However, despite more than 65 years of clinical experience, there is a lack of studies large enough to adequately document the benefit/harm balance. The result is inappropriate treatment strategies, i.e. both under-use and over-use of GCs, and consequently suboptimal treatment of RA. The GLORIA study is a pragmatic multicentre, 2-year, randomised, double-blind, clinical trial to assess the safety and effectiveness of a daily dose of 5 mg prednisolone or matching placebo added to standard of care in elderly patients with RA. Eligible participants are diagnosed with RA, have inadequate disease control (disease activity score, DAS28 ≥ 2.6), and are ≥ 65 years. The primary outcome measures are the time-averaged mean value of the DAS28 and the occurrence of serious adverse events or adverse events of special interest. During the trial, change in antirheumatic therapy is permitted as clinically indicated, except for GCs. Cost-effectiveness and cost-utility are secondary outcomes. The main challenge is the interpretation of the trial result with two primary endpoints and the pragmatic trial design that allows co-interventions. Another challenge is the definition of safety and the relative lack of power to detect differences between treatment groups. We have chosen to define safety as the number of patients experiencing at least one serious adverse event. We also specify a decision tree to guide our conclusion on the balance of benefit and harm, and our methodology to combat potential confounding caused by co-interventions. Pragmatic trials minimise impact on daily practice and maximise clinical relevance of the results, but analysis and interpretation of the results is challenging. We expect that the results of this trial are of importance for all rheumatologists who treat elderly patients with RA. ClinicalTrials.gov, NCT02585258 . Registered on 20 October 2015.

Prevention of glucocorticoid morbidity in giant cell arteritis

Abstract: Glucocorticoids are the mainstay of treatment for GCA. Patients often require long-term treatment that may be associated with numerous adverse effects, depending on the dose and the duration of treatment. Trends in recent decades for glucocorticoid use in GCA suggest increasing cumulative doses and longer exposures. Common adverse events (AEs) reported in glucocorticoid-treated GCA patients include osteoporosis, hypercholesterolaemia, hypertension, posterior subcapsular cataract, infections, diabetes mellitus, Cushingoid appearance, adrenal insufficiency and aseptic necrosis of bone. AEs considered most worrisome by patients and rheumatologists include weight gain, psychological effects, osteoporosis, cardiometabolic complications and infections. The challenge is to maximize the benefit-risk ratio by giving the maximum glucocorticoid treatment necessary to control GCA initially and then to prevent relapse but to give the minimum treatment possible to avoid glucocorticoid-related AEs. We discuss the safety issues associated with long-term glucocorticoid use in patients with GCA and strategies for preventing glucocorticoid-related morbidity.

S3-Leitlinie zur Behandlung der Polymyalgia rheumatica

Abstract: Die Polymyalgia rheumatica (PMR) tritt fast ausschlieslich bei Menschen uber 50 Jahren auf und ist nach der rheumatoiden Arthritis die zweithaufigste entzundlich rheumatische Erkrankung im hoheren Lebensalter. Da spezifische Tests fur die Erkrankung fehlen, wird die Diagnose oft erst nach Ausschluss klinisch ahnlicher Differenzialdiagnosen gestellt. Diese Leitlinie zur Behandlung der PMR setzt voraus, dass die Diagnose einer PMR bereits gestellt worden ist. Unmittelbar nach Diagnosestellung soll eine Therapie mit Glukokortikoiden eingeleitet werden und eine angemessene Patientenschulung in Bezug auf die Auswirkungen der PMR und deren Behandlung erfolgen. Methotrexat kann bei Patienten mit hohem Risiko fur Rezidive und/oder Glukokortikoidnebenwirkungen eingesetzt werden. Diese Leitlinie wurde erarbeitet, weil trotz der relativ grosen Anzahl an Patienten mit PMR das Vorgehen zur Behandlung dieser Erkrankung im deutschsprachigen Sprachraum (aber auch europa- und weltweit) sehr heterogen ist. Als Quellleitlinie dienten die 2015 publizierten EULAR-ACR-Empfehlungen zum Management der Polymyalgia rheumatica, die durch die Leitlinienkommission aktualisiert und auf den deutschen Sprachraum angepasst wurden.

CTLA-4 Mediates Inhibitory Function of Mesenchymal Stem/Stromal Cells

Abstract: Mesenchymal stem/stromal cells (MSCs) are stem cells of the connective tissue, possess a plastic phenotype, and are able to differentiate into various tissues. Besides their role in tissue regeneration, MSCs perform additional functions as a modulator or inhibitor of immune responses. Due to their pleiotropic function, MSCs have also gained therapeutic importance for the treatment of autoimmune diseases and for improving fracture healing and cartilage regeneration. However, the therapeutic/immunomodulatory mode of action of MSCs is largely unknown. Here, we describe that MSCs express the inhibitory receptor CTLA-4 (cytotoxic T lymphocyte antigen 4). We show that depending on the environmental conditions, MSCs express different isoforms of CTLA-4 with the secreted isoform (sCTLA-4) being the most abundant under hypoxic conditions. Furthermore, we demonstrate that the immunosuppressive function of MSCs is mediated mainly by the secretion of CTLA-4. These findings open new ways for treatment when tissue regeneration/fracture healing is difficult.

EULAR 'points to consider' for the conduction of workforce requirement studies in rheumatology.

Abstract: Objective Current methods used for forecasting workforce requirements in rheumatology are disparate, as are the parameters incorporated into workforce projection studies. The objective of these European League Against Rheumatism (EULAR points to consider (PTC) is to guide future workforce studies in adult rheumatology in order to produce valid and reliable manpower estimates. Methods The EULAR Standardised Operating Procedures were followed. A multidisciplinary task force with experts including patients with rheumatic diseases from 11 EULAR countries and the USA was assembled. A systematic literature review (SLR) was conducted to retrieve workforce models in rheumatology and other medical fields. PTC were based on expert opinion informed by the SLR, followed by group discussions with consensus obtained through informal voting. The level of agreement with the PTC was voted anonymously. Results A total of 10 PTC were formulated. The task force recommends models integrating supply (=workforce available in rheumatology), demand (=health services requested by the population) and need (=health services that are considered appropriate to serve the population). In general, projections of workforce requirements should consider all factors relevant for current and future workload in rheumatology inside and outside of direct patient care. Forecasts of workforce supply should consider demography and attrition of rheumatologists, as well as the effects of new developments in healthcare. Predictions of future need/demand should take demographic, sociocultural and epidemiological development of the population into account. Conclusion These EULAR-endorsed PTC will provide guidance on the methodology and the parameters to be applied in future national and international workforce requirement studies in rheumatology.

[S3 guidelines on treatment of polymyalgia rheumatica : Evidence-based guidelines of the German Society of Rheumatology (DGRh), the Austrian Society of Rheumatology and Rehabilitation (ÖGR) and the Swiss Society of Rheumatology (SGT) and participating medical scientific specialist societies and other organizations].

Abstract: Polymyalgia rheumatica (PMR) occurs almost exclusively in persons aged 50 years or older and it is the second most common inflammatory rheumatic disease in older people after rheumatoid arthritis. Since there are no specific tests for PMR, the exclusion of clinically similar differential diagnoses is essential to ascertain the diagnosis. These recommendations for the management of PMR assume an already established diagnosis of PMR. It is recommended to initiate treatment with glucocorticoids immediately after diagnosis and to provide appropriate patient information and education about the impact of the disease and its treatment. Methotrexate should be considered in patients at high risk for relapse and/or glucocorticoid-related adverse events. These guidelines have been elaborated because there is significant heterogeneity in the management of PMR in clinical practice in Germany (but also Europe and worldwide), despite the large number of patients with this disease. These guidelines are primarily based on the 2015 EULAR-ACR recommendations for the management of PMR, which were updated by the guideline committee and adapted to the German speaking countries.

Workforce requirements in rheumatology: a systematic literature review informing the development of a workforce prediction risk of bias tool and the EULAR points to consider.

Abstract: Objective To summarise the available information on physician workforce modelling, to develop a rheumatology workforce prediction risk of bias tool and to apply it to existing studies in rheumatology. Methods A systematic literature review (SLR) was performed in key electronic databases (1946–2017) comprising an update of an SLR in rheumatology and a hierarchical SLR in other medical fields. Data on the type of workforce prediction models and the factors considered in the models were extracted. Key general as well as specific need/demand and supply factors for workforce calculation in rheumatology were identified. The workforce prediction risk of bias tool was developed and applied to existing workforce studies in rheumatology. Results In total, 14 studies in rheumatology and 10 studies in other medical fields were included. Studies used a variety of prediction models based on a heterogeneous set of need/demand and/or supply factors. Only two studies attempted empirical validation of the prediction quality of the model. Based on evidence and consensus, the newly developed risk of bias tool includes 21 factors (general, need/demand and supply). The majority of studies revealed high or moderate risk of bias for most of the factors. Conclusions The existing evidence on workforce prediction in rheumatology is scarce, heterogeneous and at moderate or high risk of bias. The new risk of bias tool should enable future evaluation of workforce prediction studies. This review informs the European League Against Rheumatism points to consider for the conduction of workforce requirement studies in rheumatology.

In silico methods - Computational alternatives to animal testing.

Abstract: A seminar and interactive workshop on “In silico Methods – Computational Alternatives to Animal Testing” was held in Berlin, Germany, organized by Annemarie Lang, Frank Butt- gereit and Andrea Volkamer at the Charite-Universitatsmedizin Berlin, on August 17-18, 2017. During the half-day seminar, the variety and applications of in silico methods as alternatives to animal testing were presented with room for scientific discus- sions with experts from academia, industry and the German fed- eral ministry (Fig. 1). Talks on computational systems biology were followed by detailed information on predictive toxicology in order to display the diversity of in silico methods and the potential to embrace them in current approaches (Hartung and Hoffmann, 2009; Luechtefeld and Hartung, 2017). The follow- ing interactive one-day Design Thinking Workshop was aimed at experts, interested researchers and PhD-students interested in the use of in silico as alternative methods to promote the 3Rs (Fig. 2). Forty participants took part in the seminar while the workshop was restricted to sixteen participants.

Role of 11β-HSD type 1 in abnormal HPA axis activity during immune-mediated arthritis

Abstract: Patients with chronic immune-mediated arthritis exhibit abnormal hypothalamo-pituitary-adrenal (HPA) axis activity. The basis for this abnormality is not known. Immune-mediated arthritis is associated with increased extra-adrenal synthesis of active glucocorticoids by the 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme. 11β-HSD1 is expressed in the central nervous system, including regions involved in HPA axis regulation. We examined whether altered 11β-HSD1 expression within these regions contributes to HPA axis dysregulation during arthritis. The expression of 11β-HSD1, and other components of glucocorticoid signaling, were examined in various brain regions and the pituitary gland of mice with experimentally induced arthritis. Two arthritis protocols were employed: The K/BxN spontaneous arthritis model for chronic arthritis and the K/BxN serum transfer arthritis model for acute arthritis. 11β-HSD1 mRNA (Hsd11b1) was expressed in the hippocampus, hypothalamus, cortex, cerebellum and pituitary gland. Hypothalamic Hsd11b1 expression did not change in response to arthritis in either model. Pituitary Hsd11b1 expression was however significantly increased in both chronic and acute arthritis models. Hippocampal Hsd11b1 was decreased in acute but not chronic arthritis. Chronic, but not acute, arthritis was associated with a reduction in hypothalamic corticotropin-releasing hormone and arginine vasopressin expression. In both models, serum adrenocorticotropic hormone and corticosterone levels were no different from non-inflammatory controls. These findings demonstrate inflammation-dependent regulation of Hsd11b1 expression in the pituitary gland and hippocampus. The upregulation of 11β-HSD1 expression in the pituitary during both chronic and acute arthritis, and thus, an increase in glucocorticoid negative feedback, could contribute to the abnormalities in HPA axis activity seen in immune-mediated arthritis.

SAT0535 Eular 2018 core set of data to be collected in giant cell arteritis registries and databases viewpoints from a eular task force

Abstract: Background Giant cell arteritis (GCA) represents the most common form of primary vasculitis and can be associated with severe and potentially life-threatening complications. Due to its low prevalence, systematically collected data on course and outcome of this disease are scarce. Objectives The aim of this EULAR Task Force was to identify a core set of data items which can easily be collected from clinicians and facilitates examination of disease course and outcome. Methods A multidisciplinary EULAR task force group of 20 experts including rheumatologists, epidemiologists and patient representatives was assembled and breakout groups formed for a meeting at which items from a previously compiled collection of core parameters for a GCA registry were evaluated. Results were presented to the other group members following a structured process for discussion and consensus finding. The meeting was followed by several rounds of discussions to achieve consensus. Results A total of 95 items were identified, subdivided into the following categories: General, Demographics, GCA-related signs and symptoms, Other medical conditions, and Treatment. Suitable instruments and assessment intervals were determined for documentation of each item. To facilitate implementation of the recommendations in both primary care and scientifically oriented registers, a minimum core set of parameters was distilled, with supplemental items that can be added optionally depending on the designated purpose of individual registers. Conclusions This core set intends to ensure that data from different GCA registries and databases can be compared for the dual purposes of clinical research and improving clinical care, thereby facilitating collaborative analyses. Disclosure of Interest L. Ehlers: None declared, J. Askling Grant/research support from: Abbvie, BMS, MSD, Pfizer, Roche, Astra-Zeneca, Eli Lilly, Samsung Bioepis, UCB, J. Bijlsma Consultant for: Roche, SUN, M. Cid Consultant for: Roche, M. Cutolo Consultant for: Mundipharma, Horizon, B. Dasgupta Grant/research support from: Napp, Roche, Consultant for: Roche, Servier, GSK, Mundipharma, Pfizer, Merck, Sobi, Speakers bureau: UCB, Merck, C. Dejaco Grant/research support from: Pfizer, MSD, Consultant for: MSD, Pfizer, UCB, AbbVie, Roche, Novartis, Lilly, Celgene, Merck, Sandoz, GSK, W. Dixon Consultant for: Bayer, N. Feltelius Employee of: Swedish Medical Products Agency, A. Finckh Consultant for: AbbVie, AB2BIO, BMS, Eli-Lilly, MSD, Pfizer, Roche, K. Gilbert Consultant for: PMRGCAuk, S. Mackie Grant/research support from: Roche, GSK, Consultant for: Roche, Sanofi, Chugai, PMRGCAuk, A. Mahr Consultant for: Roche-Chugai, E. Matteson Grant/research support from: Novartis, Bristol Meyer Squibb, Hoffman-La Roche, Genentech, Consultant for: Glaxo-Smith-Kline, Endocyte, L. Neill Consultant for: PMR-GCA Scotland, C. Salvarani Consultant for: Roche, W. Schmidt Consultant for: Roche, GlaxoSmithKline, Sanofi, A. Strangfeld Speakers bureau: AbbVie, BMS, Lilly, MSD, Pfizer, Roche, Sanofi-Aventis, UCB, R. van Vollenhoven Grant/research support from: AbbVie, BMS, GSK, Pfizer, and UCB, Consultant for: AbbVie, AstraZeneca, Biotest, BMS, Celgene, Crescendo, GSK, Janssen, Lilly, Merck, Novartis, Pfizer, Roche, and UCB, F. Buttgereit Grant/research support from: Horizon Pharma, Consultant for: Horizon Pharma, Mundipharma, Roche, Galapagos

AB0915 Bone mineral density and fracture frequencies in patients with psoriasis or psoriasis arthritis

Abstract: Background Reports on the prevalence of osteoporosis, osteoporotic fractures and risk factors for osteoporosis in patients with Psoriasis or Psoriasisarthritis are scarce, and the published results on this are, at least in part, contradictory. Additionally, there is no firm understanding of the impact of potential risk factors such as smoking and low Vitamin D (Vit D) levels have on the occurrence of osteoporotic fractures in this patient group. Objectives Rh-GIOP is an ongoing prospective study monitoring glucocorticoid (GC)-induced osteoporosis of rheumatic patients, established in 2015 at the Charite University Hospital. To date, the database comprises clinical data and bone mineral density data measured by dual x-ray absorptiometry (DXA) of 592 patients with inflammatory rheumatic diseases. (ClinicalTrials.gov Identifier NCT02719314) The objective of this cross-sectional analysis was to evaluate the prevalence of osteoporosis and frequency of fractures in patients with Psoriasis (PSO) or Psoriasisarthritis (PSOA). Additionally, smoking and Vit D status were investigated as possible risk factors for low BMD. Methods We evaluated the initial visit of 55 patients with PSO (80% female) or PSOA (60% female). Descriptive analyses were performed, and values are displayed as means and standard deviations. For subgroup analyses non-parametric tests were used. Results Overall mean age was 60 years (±12 years), and 69% of the patients were female. The mean disease duration was 16±13 years and patients generally showed a good functional status as quantified by the Health Assessment Questionnaire (HAQ mean: 1.0±0.8). While osteoporosis and osteopenia were present in 16% and 38%, respectively, osteoporotic fractures were found in 33% of all patients. However, the family history for osteoporosis was positive in 20% of the patients. The prevalence of osteopenia and osteoporosis was higher in PSO compared to PSOA patients (70% vs. 45%) without reaching statistical significance. 27% of all patients were treated with glucocorticoids: mean daily dose 3±8 mg, mean cumulative dose (GCCD) 10.9 g±20.3 g. No significant difference was seen comparing medians of BMD in patients with a GCCD >10 g versus a GCCD Conclusions In our patient cohort, the GCCD does not have a measurable impact on the BMD. Additionally, according to current literature the prevalence of osteoporosis seems to be in the same range as in the normal population.1 Keeping in mind the (still) small number of patients, neither smoking nor Vit D deficiency could be identified as possible risk factors for low BMD, but further investigations are necessary to corroborate these observations. Reference [1] Hadji, P., et al., The epidemiology of osteoporosis–Bone Evaluation Study (BEST): an analysis of routine health insurance data. Dtsch Arztebl Int, 2013. 110(4): p. 52–7. Disclosure of Interest D. Freier Grant/research support from:. Amgen, BMS, Celgene, Generic Assays GSK, Horizon, medac, Mundipharma, Pfizer and Roche, K. Zeiner Grant/research support from: Amgen, BMS, Celgene, Generic Assays GSK, Horizon, medac, Mundipharma, Pfizer and Roche, R. Biesen Grant/research support from: Amgen, BMS, Celgene, Generic Assays GSK, Horizon, medac, Mundipharma, Pfizer and Roche, E. Wiebe Grant/research support from: Amgen, BMS, Celgene, Generic Assays GSK, Horizon, medac, Mundipharma, Pfizer and Roche, T. Buttgereit Grant/research support from: Amgen, BMS, Celgene, Generic Assays GSK, Horizon, medac, Mundipharma, Pfizer and Roche, S. Hermann Grant/research support from: Amgen, BMS, Celgene, Generic Assays GSK, Horizon, medac, Mundipharma, Pfizer and Roche, F. Buttgereit Grant/research support from: Amgen, BMS, Celgene, Generic Assays GSK, Horizon, medac, Mundipharma, Pfizer and Roche

FRI0602 Eular ‘points to consider’ for the conduction of workforce requirement studies in rheumatology

Abstract: Background EULAR has developed several recommendations and strategies for early referral, diagnosis and treatment of rheumatic diseases. These strategies, however, can only be implemented if sufficient manpower is available. An estimation of how many rheumatologists are needed to meet current and future population needs must be provided in order to counsel health care planners and decision makers. Current methods used for forecasting manpower are disparate, as are the variables incorporated into workforce projection models. Consequently, projections for the need of rheumatologists may vary by a factor of five between studies.(1 Objectives The aim of this project was to develop EULAR points to consider on the methodology of future workforce calculation models for rheumatologists in order to produce reliable, standardised and realistic estimates. Methods The EULAR Standardised Operating Procedures were followed. A systematic literature review (SLR) was conducted to retrieve workforce models in rheumatology and other specialities. The task force consisted of 20 experts (rheumatologists, health professionals and representatives from PARE) from 11 EULAR countries and the USA. Points to consider were based on expert opinion informed by the SLR, followed by group discussions with consensus obtained through informal voting. The level of agreement with the recommendations was voted anonymously. Results A total of 10 points to consider were formulated (table 1). The task force recommends models integrating supply (=workforce available to rheumatology), demand (=health services requested by the population) and needs (=health services that are considered appropriate to serve the population). Projections of workforce requirements should consider all factors relevant for current and future workload in and outside rheumatology patient care. Forecasts of workforce supply should consider demography and attrition of rheumatologists, as well as the effects of new developments in health care. Conclusions These are the first EULAR points to consider providing guidance on the methodology and the parameters to be applied in future national and international workforce requirement studies in rheumatology. Reference [1] Dejaco C, et al. Arthritis Care Res2016. Disclosure of Interest None declared

OP0181 Patient perspectives of people with primary sjÖgren’s syndrome: a multicentre qualitative european study

Abstract: Background Primary Sjogren’s syndrome (pSS) is one of the most common systemic autoimmune disorders and leads to an impaired health related quality of life. However, treatment mainly focuses on the management of physical manifestations. Little is known about the lived experiences of people with pSS, including the impact on people’s life, functioning and their social relationships. Objectives To explore the perspectives of people with pSS from different European countries with various cultural backgrounds in order to achieve a broad understanding of concepts that are important and meaningful to people with pSS. This study is a part of a project which aims to evaluate the coverage of the patient perspectives by patient reported outcome measures in pSS, which is funded by the Austrian Association of Rheumatology. Methods A multicentre focus group study was performed in five European countries, namely Austria, Germany, Italy, Romania and Sweden. Patients were recruited from the outpatient clinics of the local centres. Focus groups were chaired by a trained moderator and followed an interview guide which included questions about impairments and limitations in body structures, body functions, activities and participation as well as contextual factors and resources, such as coping strategies. Focus groups were audiotaped and transcribed. We conducted a content-analysis of each focus group and subsequently combined the extracted concepts from each country, using the International Classification of Functioning, Disability and Health as a frame of reference. Results A total of 12 focus groups was conducted in seven participating centres in five countries. Fifty people (48 women; 96%) with pSS participated in the focus groups (ranging from two to four groups per country). All focus groups had a total duration of 1030 min and resulted in 252 pages of transcript. From qualitative analysis we derived concepts meaningful to people with pSS from all countries, especially those concepts that were linked to a physical dimension. However, we identified differences in the description of these experiences in daily life, for example for pain-concerning sensations or for the impact on social relationships. Furthermore, the attitudes towards the treatment and towards the disease differed between the participants. People with pSS had various coping strategies, such as gaining more knowledge about the disease or utilising non-pharmacological treatment. Conclusions This is the first multicentre qualitative European study which investigated the patient perspectives in pSS with a cross-cultural understanding. Clinicans, health professionals and researchers need to know about the perspectives, experiences and needs of people with pSS in order to ensure a comprehensive treatment. Disclosure of Interest None declared

Osteoimmunologie – IMMUNOBONE: Regulation des Knochens durch Entzündung

Abstract: Z Rheumatol 2018 · 77 (Suppl 1):S12–S15 https://doi.org/10.1007/s00393-018-0455-0 Online publiziert: 24. April 2018 © Springer Medizin Verlag GmbH, ein Teil von Springer Nature 2018 M. Rauner · F. Buttgereit · J. Distler · A. I. Garbe · M. Herrmann · L. Hofbauer · M. Hoffmann · R. Jessberger · U. Kornak · G. Krönke · S. Mundlos · C. Spies · J. Tuckermann · J. Zwerina Medizinische Klinik und Poliklinik, UniversitätsklinikumCarl Gustav Carus, Dresden, Deutschland Medizinische Klinik mit Schwerpunkt Rheumatologie und Klinische Immunologie, Campus Charité Mitte, Charité – Universitätsmedizin Berlin, Berlin, Deutschland

THU0469 Quantifying the treatment with glucocorticoids as a risk factor for the occurrence of osteoporosis and fractures in patients with ra

Abstract: Background Rheumatoid arthritis (RA) is associated with increased systemic bone loss, leading to a high risk for fragility fractures. The etiology of increased fracture risk in RA is multifactorial and comprises next to general risk factors also RA-specific risks, most prominently chronic inflammation, seropositivity and glucocorticoid (GC) use1. Yet, there is evidence that GCs may, by adequately suppressing systemic inflammation, also have a positive effect on BMD and fracture risk in RA2. Objectives The purpose of this study was to investigate the prevalence of osteoporosis and fragility fractures in RA patients and to characterise, among other risk factors, the role of GC dose, cumulative dose (GCCD) and duration as well DMARD treatment on bone health. Methods Rh-GIOP is an ongoing prospective observational study collecting and analysing disease- and bone-related data from patients with chronic rheumatic diseases treated with GCs. In this cross-sectional analysis, we evaluated the initial visit of 238 patients with RA. Descriptive analyses were performed, with values displayed as mean/standard deviation and median/range for continuous variables. For subgroup analyses, non-parametric tests were used. Results Of 238 patients with RA (79.4% women, mean age: 63.6±12.5 years), 155 were seropositive and 83 seronegative. Seronegative patients were numerically older (66.8±12.1 vs 61.8±12.1 years) and more often in menopause (78.3% vs 61.8%, ns) than seropositive, while the latter had longer disease duration (median: 4.0 vs 11.0 years, p=0.03). Overall, osteoporotic BMD was more frequent at femoral sites, with 21% of patients having T-Scores All patients received GCs (mean dose: 5.0±6.8 mg, mean GCCD 15.1±19.3 g, mean duration 7.7±8.2 years) with seropositive patients having numerically higher GCCD, longer duration of GC therapy and more often current GC doses above >10 g/day. Biological DMARDs were more frequently used in seropositive patients (n=20;24.1% vs n=67;43.2%, p=0.02). Anti-osteoporotic therapies between both groups did not differ. Neither current GC doses nor GCCD nor DMARD therapy had a statistically significant and independent effect on BMD or fragility fractures in either RA group. Conclusions Osteoporosis and fragility fractures remain a challenge in the management of RA, being determined by multiple interacting factors. Our data confirm that GCs may not per se increase fracture risk and decrease BMD in RA but rather, that optimal management of disease activity with or without GCs may be beneficial to bone health. Interestingly however, despite higher cumulative GC doses and duration, seropositive RA patients did not have lower BMD or higher prevalence of fragility fractures compared to seronegative patients. Further prospective data is warranted to better characterise the role of GCs and DMARDs in regard to osteoporosis and fracture risk in RA patients. References [1] Briot K, et al. ”Inflammatory Diseases and Bone Fragility.”Osteoporosis International2017December 1;28(12):3301–14. [2] Guler-Yuksel, et al. ”Glucocorticoids, Inflammation and Bone.”Calcified Tissue International2018January 8. Disclosure of Interest E. Wiebe Grant/research support from: Rh-GIOP is supported by a joint funding of Amgen, BMS, Celgene, Generic Assays, GSK, Horizon, medac, Mundipharma, Pfizer and Roche., R. Biesen Grant/research support from: Rh-GIOP is supported by a joint funding of Amgen, BMS, Celgene, Generic Assays, GSK, Horizon, medac, Mundipharma, Pfizer and Roche., K. Zeiner Grant/research support from: Rh-GIOP is supported by a joint funding of Amgen, BMS, Celgene, Generic Assays, GSK, Horizon, medac, Mundipharma, Pfizer and Roche., D. Freier Grant/research support from: Rh-GIOP is supported by a joint funding of Amgen, BMS, Celgene, Generic Assays, GSK, Horizon, medac, Mundipharma, Pfizer and Roche., S. Hermann: None declared, G.-R. Burmester: None declared, F. Buttgereit Grant/research support from: Rh-GIOP is supported by a joint funding of Amgen, BMS, Celgene, Generic Assays, GSK, Horizon, medac, Mundipharma, Pfizer and Roche.

SAT0055 Simulating the pathogenesis of arthritis in vitro by developing a human-based multicomponent 3d joint model

Abstract: Background Our ultimate goal is to develop a valid human in vitro 3D joint model to simulate the pathogenesis of arthritis. The in vitro 3D joint model consists of different components including an1 osteogenic and2 chondrogenic part,3 the synovial fluid and4 the synovial membrane and contains all involved cell types and thus, to allow interactions between cells by cell contacts and signalling molecules. As an alternative experimental setup for animal models, our in vitro 3D joint model will enable us to study the influence and efficacy of drug treatment. Currently, there is no valid 3D model which is able to mimic an arthritic joint. Objectives Here, we aim to mimic the1 osteogenic and2 chondrogenic part,3 the joint space with synovial fluid and4 the synovial membrane. Methods For the osteogenic component of the 3D joint model, we populated β-tricalcium phosphate (TCP) – mimicking the mineral bony part – with osteogenic pre-differentiated human bone marrow-derived mesenchymal stromal cells (hMSC) and coated the particles with an hMSC monolayer cell-sheet to get a compact bony component. Survival, adhesion and structural integrity of the cells were evaluated by Scanning Electron Microscopy (SEM), LIVE/DEAD staining and cellular release of LDH. Osteogenic differentiation was analysed by µCT for mineralization and on gene expression level using qRT-PCR. To mimic the chondrogenic part, a scaffold-free 3D cartilage construct was generated by chondrogenic differentiation of hMSC under hypoxia with intermittent mechanical stimulation. Constructs were analysed by histology and qRT-PCR. Simulating the synovial fluid, hyaluronic acid was applied to the osteochondral model. To model the synovial membrane, a confluent monolayer of hMSC was formed on a polycarbonate membrane and visualised by hemacolor staining. Results We developed an in vitro 3D bone model by successfully seeding pre-differentiated hMSC on a β-TCP scaffold. Cells consistently adhere onto the scaffold for up to 3 weeks as observed by SEM. The analysis of cell viability via LDH detection and LIVE/DEAD staining showed no toxic effects on the cells even after 3 weeks of incubation as compared to the corresponding control. mRNA expression of bone-related genes such as RUNX2, SPP1 and COL1A1 as well as µCT analysis confirmed the osteogenic phenotypic of hMSC grown in 3D. Mimicking the articular cartilage component, we verified its chondrogenic phenotype by HE and Alcian Blue staining as well as by the reduced mRNA expression of COL1A1 and an abundant expression of COL2A1. Interestingly, co-cultivation of the osteogenic and chondrogenic part for up to 3 weeks demonstrated successful colonisation, connectivity and initial calcification implying a functional transitional bridging area. Modelling the synovial membrane, we successfully and reproducibly created a confluent monolayer of hMSC, which is easily transferable to the model. Conclusions First steps towards the in vitro simulation of an arthritic joint based on a multi-component model confirm good cell vitality and phenotypic stability which indicates successful progression. To finalise the development of healthy joint model, we will combine the established parts to provide a suitable 3D multi-component joint model which enables us to study the efficacy of drug treatment in vitro. Disclosure of Interest None declared

AB0364 Remarkable international variability in reasons for non-participation in the gloria trial

Abstract: Background GLORIA is an ongoing large pragmatic trial that examines harm, benefit and costs of low-dose glucocorticoids added to the standard treatment of RA patients of 65 years or older. The eligibility criteria are non-restrictive: RA, age ≥65 years, disease activity score (DAS28) of ≥2.6, and no current glucocorticoid treatment. Patients with comorbidity are expressly included, and the impact of trial procedures on normal care is minimal. Nevertheless, inclusion proves to be challenging. We have prospectively sampled all the reasons for ineligibility across a number of centres in different countries participating in the GLORIA trial. Methods Rheumatologists from 8 centres in Germany, Hungary, The Netherlands, Portugal and Romania screened the patient list of at least two full clinic days. For each patient, the eligibility and all possible reasons of exclusion were recorded. Results In total, 385 patients were screened. Of these patients, 15 (4%) were eligible to participate in the GLORIA trial. In Germany, Romania and Portugal (Lisbon) none of the screened patients proved eligible. The most common reasons for ineligibility were inactive disease and age (both 58%) (table 1). Current glucocorticoid use was reported in 28%, 5% had a temporary reason (i.e. recent switch of therapy or glucocorticoid use), and 51% had more than one reason for ineligibility. We found remarkable differences between the sites in the distribution of the main reasons for ineligibility (table 1). Of the eligible patients, 1 was already participating, 3 were included after this screening, and 2 were currently considering participation; 9 declined participation (most common reasons: fear of glucocorticoids, not interested to participate, preference for GC injections or declining additional therapy). Conclusions In this prospective study, we found remarkable differences between countries in reasons for non-participation in our ongoing GLORIA trial. The willingness of eligible patients to participate was low in this elderly population, despite the pragmatic design. Earlier studies also showed that it is challenging to include elderly patients in a clinical trial.1 2 Pre-screening of patients in potential sites can provide important information on the potential to recruit patients in a trial, but the actual willingness of patients to participate remains hard to predict. References [1] Calamia M, et al. I’d Do Anything for Research, But I Won’t Do That: Interest in Pharmacological Interventions in Older Adults Enrolled in a Longitudinal Aging Study. PLoS One2016;11:e0159664. [2] Denson AC, et al. Participation of the elderly population in clinical trials: barriers and solutions. Cancer Control2014;21:209–14. Acknowledgements This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 6 34 886. Disclosure of Interest None declared

AB0135 Circadian rhythms of immune cells in healthy individuals and patients with rheumatoid arthritis

Abstract: Background Clinical symptoms of rheumatoid arthritis (RA), such as join stiffness, swelling and pain, manifest in circadian pattern with the highest intensity occurs at early dawn. This is known to correlate with the circadian expression of IL-6, which peaks before the onset of the symptom. Despite this finding, the circadian behaviour of immune system in cellular and molecular level in RA patients has not yet been extensively investigated. Objectives Our previous study suggested that immunological circadian rhythms in patients with RA were altered when compared to the healthy individuals. Currently, we are performing 24 hours study involving RA patients and healthy individuals to further monitor the dynamic occurrence of diverse immune cells in the periphery. Methods Up to this time five eligible RA patients aged 45–75 years and twelve eligible healthy controls were recruited to join the study. On the study day, the blood was drawn in two hours interval throughout 24 hours. The participants were provided with regular meal, allowed to eat snacks ad libitum and carry passive activities. The absolute number of circulating immune cells was determined using TruCount. RNA were isolated from CD14+ monocytes and analysed by real-time PCR. Results The major populations of immune cells in the periphery of healthy controls, including CD4 T cells, CD8 T cells, regulatory T cells, B cells and monocytes, displayed circadian rhythm that peaks during the rest phase. The rhythms are in general shifted a few hours later in the RA patients. Noteworthy, CD14 monocyte, which is one of the major sources of IL-6 in RA, showed a more pronounced rhythm with higher amplitude in RA patients compared to healthy individuals. Furthermore, the following clock genes are rhythmically expressed in CD14 monocytes of both groups: Rorα, Per1, Per2, Per3 and DBP. The peak of Rorα, Per1, Per3 DBP and CRY1 is shifted a few hours later in RA patients. Interestingly, circadian variation is not observed in the expression of RevErbα in healthy individuals, while in the RA patients a rhythm is established. Conclusions In general, circadian rhythm of immune system in cellular and molecular level in RA patients appears to undergo phase shift and peaks a few hours later in comparison to healthy individuals. New established rhythms were also observed in cellular and molecular level. Another round of study involving seven RA patients is planned this spring to complete the project. Considering our data, we will continue to investigate circadian rhythms in expanded immune cell population using mass cytometry, immunoassay and microarray. Identification of immunological circadian rhythms in patients with RA and healthy individuals will help us to expand our knowledge in autoimmunity and provide an outlook on potential future implications. Acknowledgements We thank our clinical study team: Dr. Robert Biesen, Dr. Edgar Wiebe, Dr. Kim-Nikola Zeiner, Dr. Desire Freier, Manuela Jakstadt, Lisa Ehlers, Annemarie Lang, Moritz Pfeiffenberger, Alexandra Damerau, Pierre-Louis Kraus, Gabriela May and Marius Ibach for their help and contribution on the study days. Disclosure of Interest None declared