Showing papers by "Ulf Müller-Ladner published in 2015"

Update of EULAR recommendations for the treatment of systemic sclerosis

Abstract: The aim was to update the 2009 European League against Rheumatism (EULAR) recommendations for the treatment of systemic sclerosis (SSc), with attention to new therapeutic questions. Update of the previous treatment recommendations was performed according to EULAR standard operating procedures. The task force consisted of 32 SSc clinical experts from Europe and the USA, 2 patients nominated by the pan-European patient association for SSc (Federation of European Scleroderma Associations (FESCA)), a clinical epidemiologist and 2 research fellows. All centres from the EULAR Scleroderma Trials and Research group were invited to submit and select clinical questions concerning SSc treatment using a Delphi approach. Accordingly, 46 clinical questions addressing 26 different interventions were selected for systematic literature review. The new recommendations were based on the available evidence and developed in a consensus meeting with clinical experts and patients. The procedure resulted in 16 recommendations being developed (instead of 14 in 2009) that address treatment of several SSc-related organ complications: Raynaud's phenomenon (RP), digital ulcers (DUs), pulmonary arterial hypertension (PAH), skin and lung disease, scleroderma renal crisis and gastrointestinal involvement. Compared with the 2009 recommendations, the 2016 recommendations include phosphodiesterase type 5 (PDE-5) inhibitors for the treatment of SSc-related RP and DUs, riociguat, new aspects for endothelin receptor antagonists, prostacyclin analogues and PDE-5 inhibitors for SSc-related PAH. New recommendations regarding the use of fluoxetine for SSc-related RP and haematopoietic stem cell transplantation for selected patients with rapidly progressive SSc were also added. In addition, several comments regarding other treatments addressed in clinical questions and suggestions for the SSc research agenda were formulated. These updated data-derived and consensus-derived recommendations will help rheumatologists to manage patients with SSc in an evidence-based way. These recommendations also give directions for future clinical research in SSc.

Effects and safety of rituximab in systemic sclerosis: an analysis from the European Scleroderma Trial and Research (EUSTAR) group

Abstract: OBJECTIVES To assess the effects of Rituximab (RTX) on skin and lung fibrosis in patients with systemic sclerosis (SSc) belonging to the European Scleroderma Trial and Research (EUSTAR) cohort and using a nested case-control design. METHODS Inclusion criteria were fulfilment of American College of Rheumatology classification criteria for SSc, treatment with RTX and availability of follow-up data. RTX-treated patients were matched with control patients from the EUSTAR database not treated with RTX. Matching parameters for skin/lung fibrosis were the modified Rodnan Skin Score (mRSS), forced vital capacity (FVC), follow-up duration, scleroderma subtype, disease duration and immunosuppressive co-treatment. The primary analysis was mRSS change from baseline to follow-up in the RTX group compared with the control group. Secondary analyses included change of FVC and safety measures. RESULTS 63 patients treated with RTX were included in the analysis. The case-control analysis in patients with severe diffuse SSc showed that mRSS changes were larger in the RTX group versus matched controls (N=25; -24.0±5.2% vs -7.7±4.3%; p=0.03). Moreover, in RTX-treated patients, the mean mRSS was significantly reduced at follow-up compared with baseline (26.6±1.4 vs 20.3±1.8; p=0.0001). In addition, in patients with interstitial lung disease, RTX prevented significantly the further decline of FVC compared with matched controls (N=9; 0.4±4.4% vs -7.7±3.6%; p=0.02). Safety measures showed a good profile consistent with previous studies in autoimmune rheumatic diseases. CONCLUSIONS The comparison of RTX treated versus untreated matched-control SSc patients from the EUSTAR cohort demonstrated improvement of skin fibrosis and prevention of worsening lung fibrosis, supporting the therapeutic concept of B cell inhibition in SSc.

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 normal vs the 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.

Prediction of worsening of skin fibrosis in patients with diffuse cutaneous systemic sclerosis using the EUSTAR database

Abstract: Objectives To identify predictive parameters for the progression of skin fibrosis within 1 year in patients with diffuse cutaneous SSc (dcSSc). Methods An observational study using the EUSTAR database was performed. Inclusion criteria were dcSSc, American College of Rheumatology (ACR) criteria fulfilled, modified Rodnan skin score (MRSS) ≥7 at baseline visit, valid data for MRSS at 2nd visit, and available follow-up of 12±2 months. Worsening of skin fibrosis was defined as increase in MRSS >5 points and ≥25% from baseline to 2nd visit. In the univariate analysis, patients with progressive fibrosis were compared with non-progressors, and predictive markers with p Results A total of 637 dcSSc patients were eligible. Univariate analyses identified joint synovitis, short disease duration (≤15 months), short disease duration in females/patients without creatine kinase (CK) elevation, low baseline MRSS (≤22/51), and absence of oesophageal symptoms as potential predictors for progressive skin fibrosis. In the multivariate analysis, by employing combinations of the predictors, 17 models with varying prediction success were generated, allowing cohort enrichment from 9.7% progressive patients in the whole cohort to 44.4% in the optimised enrichment cohort. Using a second validation cohort of 188 dcSSc patients, short disease duration, low baseline MRSS and joint synovitis were confirmed as independent predictors of progressive skin fibrosis within 1 year resulting in a 4.5-fold increased prediction success rate. Conclusions Our study provides novel, evidence-based criteria for the enrichment of dcSSc cohorts with patients who experience worsening of skin fibrosis which allows improved clinical trial design.

Free fatty acids: potential proinflammatory mediators in rheumatic diseases

Abstract: Objectives Due to their role in inflammatory metabolic diseases, we hypothesised that free fatty acids (FFA) are also involved in inflammatory joint diseases. To test this hypothesis, we analysed the effect of FFA on synovial fibroblasts (SF), human chondrocytes and endothelial cells. We also investigated whether the toll-like receptor 4 (TLR4), which can contribute to driving arthritis, is involved in FFA signalling. Methods Rheumatoid arthritis SF, osteoarthritis SF, psoriatic arthritis SF, human chondrocytes and endothelial cells were stimulated in vitro with different FFA. Immunoassays were used to quantify FFA-induced protein secretion. TLR4 signalling was inhibited extracellularly and intracellularly. Fatty acid translocase (CD36), responsible for transporting long-chain FFA into the cell, was also inhibited. Results In rheumatoid arthritis synovial fibroblasts (RASF), FFA dose-dependently enhanced the secretion of the proinflammatory cytokine IL-6, the chemokines IL-8 and MCP-1, as well as the matrix-degrading enzymes pro-MMP1 and MMP3. The intensity of the response was mainly dependent on the patient rather than on the type of disease. Both saturated and unsaturated FFA showed similar effects on RASF, while responses to the different FFA varied for human chondrocytes and endothelial cells. Extracellular and intracellular TLR4 inhibition as well as fatty acid transport inhibition blocked the palmitic acid-induced IL-6 secretion of RASF. Conclusions The data show that FFA are not only metabolic substrates but may also directly contribute to articular inflammation and degradation in inflammatory joint diseases. Moreover, the data suggest that, in RASF, FFA exert their effects via TLR4 and require extracellular and intracellular access to the TLR4 receptor complex.

Serum Adipokine Levels in Patients With Ankylosing Spondylitis and Their Relationship to Clinical Parameters and Radiographic Spinal Progression

Abstract: Objective Adipokines have metabolic and inflammatory functions but can also affect bone metabolism. The purpose of this study was to determine the relationship between serum levels of adiponectin, resistin, and visfatin and markers of inflammation, disease activity, and radiographic spinal progression in patients with ankylosing spondylitis (AS). Methods Levels of adiponectin, resistin, and visfatin in the serum of 86 AS patients and 25 healthy controls were measured by enzyme-linked immunosorbent assay at baseline. Radiographic spinal progression was determined by the scoring of radiographs of the spine obtained at baseline and after 2 years. Results Mean (±SD) baseline levels of resistin and visfatin were significantly higher in AS patients than in healthy controls (11.6 ± 10.6 ng/ml versus 6.6 ± 3.2 ng/ml [P = 0.01] for resistin, and 20.9 ± 48.3 ng/ml versus 3.4 ± 2.6 ng/ml [P = 0.001] for visfatin). Adipokine serum levels did not correlate with disease activity or functional indices. Only resistin serum levels correlated with markers of inflammation. Baseline levels of visfatin, but not resistin or adiponectin, were significantly higher in patients with worsening of the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) by ≥2 units after 2 years (n = 19) as compared to patients without mSASSS worsening (37.7 ± 57.8 ng/ml versus 16.1 ± 44.6 ng/ml; P = 0.029) and in patients with syndesmophyte formation/progression (n = 22) as compared to patients without such progression (37.1 ± 55.3 ng/ml versus 15.3 ± 44.8 ng/ml; P = 0.023). Visfatin levels of >8 ng/ml at baseline were predictive of subsequent radiographic spinal progression (adjusted odds ratio 3.6 for mSASSS progression and 5.4 for syndesmophyte formation/progression). Conclusion Serum levels of resistin and visfatin are elevated in AS patients. Elevated visfatin levels at baseline are predictive of subsequent progression of radiographic damage in AS patients.

Incidence and predictors of cutaneous manifestations during the early course of systemic sclerosis: a 10-year longitudinal study from the EUSTAR database

Abstract: Objectives To longitudinally map the onset and identify risk factors for skin sclerosis and digital ulcers (DUs) in patients with systemic sclerosis (SSc) from an early time point after the onset of Raynaud9s phenomenon (RP) in the European Scleroderma Trials and Research (EUSTAR) cohort Methods 695 patients with SSc with a baseline visit within 1 year after RP onset were followed in the prospective multinational EUSTAR database During the 10-year observation period, cumulative probabilities of cutaneous lesions were assessed with the Kaplan–Meier method Cox proportional hazards regression analysis was used to evaluate risk factors Results The median modified Rodnan skin score (mRSS) peaked 1 year after RP onset, and was 15 points The 1-year probability to develop an mRSS ≥2 in at least one area of the arms and legs was 69% and 25%, respectively Twenty-five per cent of patients developed diffuse cutaneous involvement in the first year after RP onset This probability increased to 36% during the subsequent 2 years Only 6% of patients developed diffuse cutaneous SSc thereafter The probability to develop DUs increased to a maximum of 70% at the end of the 10-year observation The main factors associated with diffuse cutaneous SSc were the presence of anti-RNA polymerase III autoantibodies, followed by antitopoisomerase autoantibodies and male sex The main factor associated with incident DUs was the presence of antitopoisomerase autoantibodies Conclusion Early after RP onset, cutaneous manifestations exhibit rapid kinetics in SSc This should be accounted for in clinical trials aiming to prevent skin worsening

An observational cohort study of patients with newly diagnosed digital ulcer disease secondary to systemic sclerosis registered in the EUSTAR database.

Abstract: Objectives This study describes clinical characteristics, prognostic factors, and quality of life in patients with newly diagnosed (incident) digital ulcers (DU). Methods Observational cohort study of 189 consecutive SSc patients with incident DU diagnosis identified from the EUSTAR database (22 centres in 10 countries). Data were collected from medical charts and during one prospective visit between 01/2004 and 09/2010. Results Median age at DU diagnosis was 51 years, majority of patients were female (88%), and limited cutaneous SSc was the most common subtype (61%). At incident DU diagnosis, 41% of patients had one DU and 59% had ≥2 DU; at the prospective visit 52% had DU. Pulmonary arterial hypertension (PAH) and multiple DU at diagnosis were associated with presence of any DU at the prospective visit (odds ratios: 4.34 and 1.32). During the observation period (median follow-up was 2 years) 127 patients had ≥1 hospitalisation. The event rate of new DU per person-year was 0.66, of DU-associated complications was 0.10, and of surgical or diagnostic procedures was 0.12. At the prospective visit, patients with ≥1 DU reported impairment in daily activities by 57%, those with 0 DU by 37%. The mean difference between patients with or without DU in the SF-36 physical component was 2.2, and in the mental component 1.4. DU patients were not routinely prescribed endothelin receptor antagonists or prostanoids. Conclusions This real world cohort demonstrates that DU require hospital admission, and impair daily activity. PAH and multiple DU at diagnosis were associated with future occurrence of DU.

Twenty-two points to consider for clinical trials in systemic sclerosis, based on EULAR standards

Abstract: Objective. SSc is clinically and aetiopathogenically heterogeneous. Consensus standards for more uniform trial design and selection of outcome measures are needed. The objective of this study was to develop evidence-based points to consider (PTCs) for future clinical trials in SSc. Methods. Thirteen international SSc experts experienced in SSc clinical trial design were invited to participate. One researcher with experience in systematic literature review and three trainees were also included. A systematic review using PubMed and the Cochrane Central Register of Controlled Trials was conducted and PTCs when designing clinical trials in SSc were developed. As part of that development we conducted an Internet-based Delphi exercise regarding the main points to be made in the consensus statement. Consensus was defined as achieving a median score of ≥7 of 9. Results. By consensus, the experts decided to develop PTCs for each individual organ system. The current document provides a unifying outline on PTCs regarding general trial design, inclusion/exclusion criteria and analysis. Consensus was achieved regarding all the main points of the PTCs. Conclusion. Using European League Against Rheumatism suggestions for PTCs, a general outline for PTCs for controlled clinical trials in SSc was developed. Specific outlines for individual organ systems are to be published separately. This general outline should lead to more uniform and higher-quality trials and clearly delineate areas where further research is needed.

Serum Vaspin Levels Are Associated with the Development of Clinically Manifest Arthritis in Autoantibody-Positive Individuals.

Abstract: Objectives We have previously shown that overweight may increase the risk of developing rheumatoid arthritis (RA) in autoantibody positive individuals. Adipose tissue could contribute to the development of RA by production of various bioactive peptides. Therefore, we examined levels of adipokines in serum and synovial tissue of subjects at risk of RA. Methods Fifty-one individuals positive for immunoglobulin M rheumatoid factor (IgM-RF) and/or anti-citrullinated protein antibodies (ACPA), without arthritis, were included in this prospective study. Levels of adiponectin, vaspin, resistin, leptin, chemerin and omentin were determined in baseline fasting serum samples (n = 27). Synovial tissue was obtained by arthroscopy at baseline and we examined the expression of adiponectin, resistin and visfatin by immunohistochemistry. Results The development of clinically manifest arthritis after follow-up was associated with baseline serum vaspin levels (HR1.5 (95% CI 1.1 to 2.2); p = 0.020), also after adjustment for overweight (HR1.7 (95% CI 1.1 to 2.5); p = 0.016). This association was not seen for other adipokines. Various serum adipokine levels correlated with BMI (adiponectin r = -0.538, leptin r = 0.664; chemerin r = 0.529) and systemic markers of inflammation such as CRP levels at baseline (adiponectin r = -0.449, omentin r = -0.557, leptin r = 0.635, chemerin r = 0.619, resistin r = 0.520) and ESR (leptin r = 0.512, chemerin r = 0.708), p-value<0.05. Synovial expression of adiponectin, resistin and visfatin was not associated with development of clinically manifest arthritis. Conclusions In this exploratory study, serum adipokines were associated with an increased inflammatory state in autoantibody-positive individuals at risk of developing RA. Furthermore, serum vaspin levels may assist in predicting the development of arthritis in these individuals.

Value of systolic pulmonary arterial pressure as a prognostic factor of death in the systemic sclerosis EUSTAR population

Abstract: Objective. The aim of this study was to assess the prognostic value of systolic pulmonary artery pressure (sPAP) estimated by echocardiography in the multinational European League Against Rheumatism Scleroderma Trial and Research (EUSTAR) cohort. Methods. Data for patients with echocardiography documented between 1 January 2005 and 31 December 2011 were extracted from the EUSTAR database. Stepwise forward multivariable statistical Cox pulmonary hypertension analysis was used to examine the independent effect on survival of selected variables. Results. Based on our selection criteria, 1476 patients were included in the analysis; 87% of patients were female, with a mean age of 56.3 years (S.D. 13.5) and 31% had diffuse SSc. The mean duration of follow-up was 2.0 years (S.D. 1.2, median 1.9). Taking index sPAP of 50 mmHg. In a multivariable Cox model, sPAP and the diffusing capacity for carbon monoxide (DLCO) were independently associated with the risk of death [HR 1.833 (95% CI 1.035, 3.247) and HR 0.973 (95% CI 0.955, 0.991), respectively]. sPAP was an independent risk factor for death with a HR of 3.02 (95% CI 1.91, 4.78) for sPAP 536 mmHg. 1

Achenbach's Syndrome (Paroxysmal Finger Hematoma) With Capillaroscopic Evidence of Microhemorrhages

Abstract: tracing and genetic ablation of ADAM12 perivascular cells identify a major source of profibrotic cells during acute tissue injury. Nat Med 2012;18:1262–70. 42. Bochet L, Lehuede C, Dauvillier S, Wang YY, Dirat B, Laurent V, et al. Adipocyte-derived fibroblasts promote tumor progression and contribute to the desmoplastic reaction in breast cancer. Cancer Res 2013;73:5657–68. 43. Desai VD, Hsia HC, Schwarzbauer JE. Reversible modulation of myofibroblast differentiation in adipose-derived mesenchymal stem cells. PloS One 2014;9:e86865. 44. Duffield JS, Lupher M, Thannickal VJ, Wynn TA. Host responses in tissue repair and fibrosis. Ann Rev Pathol 2013;8: 241–76. 45. Rock JR, Barkauskas CE, Cronce MJ, Xue Y, Harris JR, Liang J, et al. Multiple stromal populations contribute to pulmonary fibrosis without evidence for epithelial to mesenchymal transition. Proc Natl Acad Sci U S A 2011;108:E1475–83. 46. Goritz C, Dias DO, Tomilin N, Barbacid M, Shupliakov O, Frisen J. A pericyte origin of spinal cord scar tissue. Science 2011;333: 238–42. 47. LeBleu VS, Taduri G, O’Connell J, Teng Y, Cooke VG, Woda C, et al. Origin and function of myofibroblasts in kidney fibrosis. Nat Med 2013;19:1047–53.

OP0054 Safety and Efficacy of Subcutaneous Tocilizumab in Adults with Systemic Sclerosis: Week 48 Data from the Fasscinate Trial

Abstract: Background Systemic sclerosis (SSc) is a debilitating disease with limited treatment options. Data indicate a key role for interleukin-6 (IL-6) in the pathogenesis of SSc. 1,2 In murine models of SSc, IL-6 receptor (IL-6R) inhibition prevented and reversed skin fibrosis. 3,4 Objectives To assess safety and efficacy of the IL-6R inhibitor tocilizumab (TCZ) in pts with SSc. Methods In this first double-blind, placebo-controlled, phase 2, proof-of-concept study, the effect of inhibiting IL-6 in SSc was explored. Pts ≥18 y with active SSc (1980 ACR criteria, 5 ≤5 y disease duration, modified Rodnan skin score (mRSS) 15-40, and elevated acute-phase reactants) were randomized 1:1 to TCZ 162 mg or placebo (PBO) subcutaneously (SC) wkly for 48 wks. Primary end point was mean change in mRSS from baseline at wk 24. Mean change in mRSS at wk 48, pt-reported outcomes (PROs), and pulmonary function at wk 48 were secondary/exploratory measures. Results 87 pts (43 TCZ, 44 PBO) were enrolled. Baseline characteristics were similar between arms including mean [SD] mRSS (TCZ 26 [7.2]; PBO 26 [5.9]). At wk 24, a favorable but not statistically significant effect of TCZ over PBO on mRSS was noted (–3.9 vs –1.2; adjusted mean difference, –2.7 [95% CI: –5.85, 0.45], p =0.09; Table). At wk 48, a numerically larger change was noted in the TCZ vs PBO arm (–6.3 vs –2.8; adjusted mean difference, –3.6 [95% CI: –7.23, 0.12], p =0.06). Though not statistically significant, higher proportions of TCZ vs PBO pts had mRSS improvement from baseline of ≥20% (40% vs 27%), ≥40% (21% vs 7%), or ≥60% (12% vs 0). There were numerically greater improvements in the TCZ arm than in the PBO arm for PROs (HAQ-DI, pt global assessment VAS, and FACIT-fatigue) at wk 48 (Table). The proportion of pts with HAQ-DI improvement ≥0.22 was 28% (12/43) in the TCZ arm and 7% (3/44) in the PBO arm at wk 48 ( p =0.01). Fewer TCZ vs PBO pts showed a decline in % predicted forced vital capacity (%FVC 10% absolute decrease in %FVC (10% vs 23%; Table) at wk 48. Adverse events (AEs)/serious AEs occurred in 98%/33% of TCZ and 91%/34% of PBO pts by wk 48. One death occurred in the PBO arm and 3 deaths in TCZ pts by wk 48; all were unrelated to study drug except for a fatal lung infection in 1 TCZ pt. Conclusions Treatment with TCZ resulted in consistent, but not statistically significant, improvements in skin sclerosis (mRSS) at wks 24 and 48 and in PROs (HAQ-DI, pt global assessment VAS, and FACIT-fatigue) at wk 48. A trend toward less FVC decline with TCZ than with PBO noted at wk 24 persisted at wk 48. Observed AEs were consistent with SSc complications and the safety profile of TCZ. Overall, the effect of TCZ on skin sclerosis, PROs, and pulmonary function and the observed safety profile suggest a positive risk/benefit profile for TCZ in SSc and support further evaluation of TCZ in pts with SSc. References J Rheumatol 1998;25:308. Pathobiology 1993;61:239. Am J Pathol 2012;180:165. Arthritis Rheum 2014:66:S1312. Arthritis Rheum 1980;23:581. Disclosure of Interest D. Khanna Grant/research support from: Actelion, Bayer, BMS, EMD Seerono, Gilead, InterMune, NIH/NIAMS, NIH/NIAID, Scleroderma Foundation, Pulmonary Hypertension Association, Consultant for: Actelion, Bayer, BMS, EMD Serono, InterMune, Biogen Idec, Genentech/Roche, Cytori, Lycera, Sanofi-Aventis/Genzyme, GSK, C. Denton Grant/research support from: Roche, Novartis, Consultant for: Roche, Actelion, GlaxoSmithKline, A. Jahreis Shareholder of: Roche, Employee of: Genentech, J. van Laar Consultant for: Pfizer, Tigenix, Novartis, Roche, Eli Lilly, S. Cheng Employee of: Genentech, H. Spotswood Shareholder of: Roche, Employee of: Roche, J. Pope: None declared, Y. Allanore Grant/research support from: Actelion, BMS, Genentech/ Roche, Inventiva, Pfizer, Servier, Consultant for: Actelion, Bayer, Biogen Idec, BMS, Genentech/ Roche, Inventiva, Medac, Pfizer, Sanofi/Genzyme, UCB, U. Muller-Ladner Consultant for: Roche, Chugai, Speakers bureau: Roche, Chugai, J. Siegel Employee of: Roche, D. Furst Grant/research support from: Genentech, Consultant for: Genentech

Scientific rationale behind the development and approval of biosimilar infliximab (CT-P13) in Europe

Abstract: Biosimilars are drugs developed to be highly similar to their originator biologic (or 'reference medicinal product') with no clinically meaningful differences in purity, efficacy or safety. Production of biologics and biosimilars is highly complex and sensitive, with any change in manufacturing process having a potential impact on efficacy and safety. This review provides an overview of the manufacturing process for these drugs and considers the implications of any process changes. The scientific rationale underlying the regulatory comparability exercise for process-changed reference medicinal products and biosimilars is also discussed, as is the issue of 'switchability' from a reference medicinal product to its biosimilar. CT-P13 (Remsima(®), Inflectra(®)), a biosimilar of infliximab, is used as a case study to discuss these issues.

Gemeinsame deutschsprachige Nomenklatur für die systemische Sklerose

Abstract: Grose Datenbanken und darauf aufbauende Projekte haben im letzten Jahrzehnt ein sehr viel besseres Verstandnis des Krankheitsbildes systemische Sklerose (SSc) gebracht. Die Serologie hat sich weiterentwickelt, sodass mehr SSc-spezifische Autoantikorper auch fur die Routinetestung zur Verfugung stehen. Die Kapillarmikroskopie wurde Standard. Auch therapeutisch gibt es relevante Fortschritte. Viele Bezeichnungen, die sich in arztlichen Dokumenten finden, bilden diesen Fortschritt nicht ausreichend ab. Die Nomenklatur ist insgesamt uneinheitlich und damit unubersichtlich geworden. Auch die ICD-Nomenklatur ist aus unserer Sicht verbesserungswurdig. Diese Publikation soll dazu beitragen, fur die systemische Sklerose wieder einen gemeinsamen deutschsprachigen Standard zu etablieren, der die neuen Erkenntnisse widerspiegelt und in der klinischen Routine sinnvoll umsetzbar ist.

Fibroblasten als pathogene Zellen in der rheumatischen Entzündung

Abstract: Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovitis, synovial hyperplasia and progressive degeneration of affected joints. These processes are mediated by cells of the immune system as well as by synovial fibroblasts (RASF) originating from the lining layer of the synovium. In this scenario RASFs display an activated phenotype: they show an altered expression of adhesion molecules which allows attachment to articular cartilage and by synthesis of proteases they mediate progressive cartilage and bone destruction. Furthermore, they produce various cytokines and chemokines, which are essential for promoting the inflammatory response. In recent years it has become evident that RASFs not only passively respond to the proinflammatory milieu in the joints of RA patients but also actively contribute by the overproduction of several cytokines and chemokines. These proinflammatory cytokines trigger the transformation of RASFs into an aggressive and invasive phenotype. Additionally, the primarily altered genuine RASFs are actively involved in the recruitment and activation of immune cells. Taken together, they are key players in the development of the well-known chronic, destructive inflammatory response in joints affected by RA.

Molekulare Wirkungen physikalischer Therapiemaßnahmen

Abstract: Mittels Methoden der molekularen Medizin ist es inzwischen bei entzundlich rheumatischen Erkrankungen moglich, den Einfluss von unterschiedlichen Physiotherapeutika auf zentrale Botenstoffe des Entzundungsprozesses sowie Interaktionen zwischen Zellen des Immunsystems und des Knochens zu analysieren. Anhand aktueller Studien wird der Eingriff in diese Regulationssysteme durch diverse Physiotherapeutika vorgestellt.

THU0460 Tenascin-C in Joint Regeneration After Induced Osteoarthritis in the Newt Notophthalmus Viridescens

Abstract: Background In mammals tissue destruction often results in fibrotic scar tissue formation, which significantly impairs organ function. In contrast, many urodele amphibians have a remarkable regenerative capacity: Damaged tissues or even lost extremities are almost perfectly regenerated, both in function and size. We established the red-spotted newt Notophthalmus viridescens as a model organism to study endogenous knee joint regeneration in adult vertebrates. In this model, osteoarthritis (OA)-like symptoms can be induced by intra-articular injection of collagenase or surgical removal of articular cartilage. Treated animals primarily display joint instability and luxation, but joint functionality is completely restored after approximately 3 months. Objectives To identify key players involved in the underlying mechanisms driving knee joint regeneration using a high resolution gene analysis approach. Methods A cDNA array was performed after surgically and collagenase-induced knee damage in newts, and dysregulated candidate genes were selected. Microarray results were verified on the mRNA level by real-time PCR. Protein expression levels of the dysregulated candidates were analysed by immunohistochemistry (IHC). Additionally, in vitro experiments in newt-derived cell lines and primary newt cells (chondrocytes/fibroblasts) with tenascin-C (TN-C) knockdown were performed. Results Several matricellular proteins including TN-C were found to be upregulated during the regenerative process (at day 10 TN-C vs. control 22.4-fold in collagenase-induced OA model, 15.6-fold in surgically induced OA model). IHC revealed high TN-C expression in the periosteum in untreated newt legs. During the early phase of regeneration (at day 10) additional expression at the injury site (surgically induced OA) was observed. At later stages (20 and 40 days after injury) TN-C expression was detectable in regenerating tissues including articular cartilage. In adhesion experiments using the newt-derived cell line B1H1 TN-C coating had anti-adhesive properties (TN-C vs. control: 42% reduction). However, TN-C knock-down in newt cell lines and primary newt cells did not alter cellular adhesive behaviour. Conclusions TN-C plays an important role during knee joint regeneration. Further detailed studies will facilitate to identify additional molecular pathways guiding these regenerative processes unique for the newt and might allow the transfer to the development of new treatment options for human OA. Disclosure of Interest None declared

SAT0467 The Five Prospective Observational Trials of the International Systemic Sclerosis FP7-Health Research Project Desscipher: A Interim Report

Abstract: Background Due to lack of adequate clinical research data, drug treatment of the rare disease systemic sclerosis (SSc) is commonly off-label. The international EC-funded research project DeSScipher (acronym for “to decipher the optimal management of systemic sclerosis”) was designed to increase the evidence-based treatment strategies for SSc patients and subsequently to improve their long-term quality-of-life. Objectives The primary objective is to compare the outcomes of different treatments with respect to efficacy and safety of currently used off-label drugs from the early to the advanced phases of the main SSc-associated organ dysfunctions in a routine rheumatology in- and outpatient setting. Methods Five prospective observational trials (OTs), carried out within the EULAR Scleroderma Trials and Research (EUSTAR) group, have been designed to analyze current treatment approaches of early functionally relevant manifestations such as digital ulcers (OT1) and hand arthritis (OT2) to the morbidity and mortality-driving manifestations such as interstitial lung disease (OT3), pulmonary hypertension (OT4) and severe heart disease (OT5). The study protocols are accessible at clinicaltrials.gov Identifiers NCT01836263, NCT01834157, NCT01858259, NCT01840748, NCT01829126. Results Between April 2013 and January 2015, 1781 SSc patients have been screened at 27 contributing EUSTAR centers. 1577 (89%) patients have been enrolled into at least one of the five OTs. In particular, 1179, 127, 981, 237 and 716 patients have been enrolled into OT1-5, respectively (3240 in total; a given patient could be enrolled into multiple OTs), which represents a baseline patient recruitment rate of 79% of the target number of 4098 patients (accordingly 226%, 79%, 59%, 25% and 91% of the required number of 522, 160, 1670, 960, 786 patients for OT1-5, respectively). The completion of 1-year (OT3, OT5) and 2-year follow-up visits (OT1, OT2, OT4) are pending. Conclusions DeSScipher is currently the largest prospective observational research project ever for SSc. While patient recruitment is still ongoing, preliminary results of the five OTs are expected in late 2015 and the final results depending on the completion of follow-up visits are expected between 2017 and 2018. Acknowledgements The DeSScipher project was funded by the European Community9s Framework Programme 7 (FP7-HEALTH-2012.2.4.4-2 - Observational trials in rare diseases) under grant agreement N° 305495. We acknowledge the contribution of the following EUSTAR centers: Wuppertal (member N°192), Lille (93), Bad Bramstedt (187), Moscow (78), Assiut (168), Moscow (190), Bucharest (100), Monserrato (142), Iasi (162), Cluj-Napoca (16), Frankfurt (124), Salford/Manchester (80), Tubingen (56), Ancona (34), Zagreb (51) and Roma (94). Disclosure of Interest None declared

AB0727 There is a Need for New Systemic Sclerosis Subset Criteria. A Content Analytic Approach

Abstract: Background Systemic sclerosis (SSc) is a family of diseases unified by the presence of immune activation, vasculopathy and fibrosis. The concept of SSc subsets cannot be easily defined but is clinically indisputable. Objectives To evaluate the purpose, strengths and limitations of the limited/diffuse subset criteria, and identify areas requiring improvement. Methods We conducted a cross-sectional study with 30 SSc experts using a semi-structured interview. The interview transcripts underwent an iterative process with text deconstructed to single thought units until a saturated conceptual framework with coding was achieved and respondent occurrence tabulated. This was followed by serial cross-referential analyses establishing a set of pervasive complex thought clusters. Results Of the 30 experts, 26 (87%) were male, 19 (63%) were from Europe and 11 (37%) were from North America. The experts had seen SSc patients for a mean 23 (SD 10.7) years, and saw a mean of 122 (SD 185) new SSc patients annually. Three thematic clusters were noted regarding the utility of subsetting: to facilitate research and communication, to inform management, and to inform prognosis (prediction of internal organ involvement, survival). The strength of the limited/diffuse system was its ease of use, however 10% stated this system has “little or no value”. Limitations of the diffuse/limited classification were the risk of misclassification, predictions/generalizations did not always hold true, and that the elbow or knee threshold is arbitrary. 87% use more than 2 subsets including: SSc sine scleroderma, overlap conditions, antibody determined subsets, subsetting based on speed of progression, and age of onset (juvenile, elderly). Considerations for the next phase of criteria development include incorporation of rate of change and hierarchal clustering (limited/diffuse, then by antibodies). Conclusions We interviewed international SSc experts and synthesized their views on subset criteria. These results can inform future efforts to develop revised criteria to guide research, prognostication and management. Acknowledgements This work was supported by the World Scleroderma Foundation. Disclosure of Interest S. Johnson Grant/research support from: Canadian Institutes of Health Research, J. Fransen: None declared, D. Khanna Grant/research support from: NIH/NIAMS K24, F. van den Hoogen: None declared, M. Baron: None declared, M. Matucci-Cerinic: None declared, C. Denton: None declared, T. Medsger: None declared, P. Carreira: None declared, G. Riemekasten: None declared, J. Distler: None declared, A. Gabrielli: None declared, V. Steen: None declared, L. Chung: None declared, R. Silver: None declared, J. Varga: None declared, U. Muller-Ladner Grant/research support from: EULAR/EUSTAR and FP7 Desscipher, M. Vonk: None declared, U. Walker: None declared, F. Wollheim: None declared, A. Herrick: None declared, D. Furst: None declared, L. Czirjak: None declared, O. Kowal-Bielecka: None declared, F. DelGaldo: None declared, M. Cutolo: None declared, N. Hunzelmann: None declared, C. Murray: None declared, I. Foeldvari: None declared, L. Mouthon: None declared, N. Damjanov: None declared, B. Kahaleh: None declared, T. Frech: None declared, S. Assassi: None declared, L. A. Saketkoo: None declared, J. Pope: None declared

AB1086 An Eular Study Group Pilot Study on Reliability of “Simple” Capillaroscopic Definitions to Describe Capillary Morphology in Rheumatic Diseases

Abstract: Background The established EULAR study group on Microcirculation in Rheumatic Diseases (RD) aims to build an international network of centres of excellence to facilitate collaboration and exchange knowledge within Europe. One of its aims is to study natural evolution of microvascular morphology in RD. To this end standardisation of morphological interpretation/nomenclature across diseases is paramount. Objectives To propose simple capillaroscopic definitions for interpretation of single capillaroscopic morphologies and assess their interobserver reliability. Methods The simple definitions proposed to assess morphology were: 1) “normal”: hairpin, tortuous or crossing 1 ; 2) “abnormal”: not hairpin, tortuous or crossing 1 ; 3) “not evaluable”: whenever rater doubted in classifying between normal and abnormal. Based upon an aimed kappa of 0.80 and equal default prevalences of normal (0.4) and abnormal (0.4) capillary morphology and a smaller proportion of not evaluable (0.2) capillaries, 87 capillaries evaluated by two independent raters were necessary to obtain a half width of the 95% confidence interval (CI) of no larger than 0.2. Consequently, 90 randomly selected single capillaries were presented in 2 batches of 45 single capillaries to 3 groups of raters: experienced independent raters (AH, FI, VR, AS, VS [gold standard]) n=5; attendees to the 6th EULAR course on capillaroscopy, n=34; novices after a 1 hour institutional course at the Ghent University hospital, n=11. Inter-rater agreement was assessed by calculation of proportion of agreement and by kappa coefficients. Results Mean kappa was 0.49 (95% CI: 0.44-0.54) for expert raters, 0.40 (0.36-0.44) for attendees and 0.46 (0.41-0.52) for novices, with overall agreements of 67% (63-71), 63% (60-65) and 67% (63-70) respectively. Comparing only “normal” vs. “abnormal and not evaluable” capillaries did increase the kappa: 0.51 (0.37-0.65), 0.53 (0.49-0.58), and 0.55 (0.49-0.62). Conclusions This study shows moderate reliability of “simple” capillaroscopic definitions to describe morphology of individual capillaries by rheumatologists with different expertise on the topic. Further optimization of morphologic interpretation is ongoing. References Kabasakal Y, et al. Ann Rheum Dis. 1996;55(8):507-12. Cutolo M, Smith V. Nailfold Capillaroscopy. In: Wigley FM et al. editors. Raynaud9s phenomenon: A guide to pathogenesis and treatment. New York: Springer Science+Business Media; 2015. Disclosure of Interest None declared

[Modern disease-modifying antirheumatic drugs].

Abstract: Der Begriff „moderne Antirheumatika“ umfasst nicht nur die standig wachsende Zahl an neuen Medikamenten zur Behandlung entzundlich-rheumatischer Erkrankungen. Auch etablierte krankheitsmodifizierende Medikamente, die in den Therapiealgorithmen der verschiedenen Krankheitsentitaten neu positioniert werden, fallen darunter. Vorreiter ist in der Regel die rheumatoide Arthritis, zu der die Deutsche Gesellschaft fur Rheumatologie kurzlich eine komplett neue S1-Leitlinie erstellt hat. Erweiterungen bestehender Zulassungen gab es auch fur Kollagenosen und Vaskulitiden, insbesondere fur den Anti-CD20-Antikorper bei ANCA-assoziierten Vaskulitiden und Belimumab fur den systemischen Lupus erythematodes. Daneben sind neue antikorperbasierte Wirkstoffe aus der Gruppe der Biologika entweder bereits zugelassen, z. B. Ustekinumab fur die Psoriasisarthritis, oder sie befinden sich im Zulassungsprozess, so etwa Granulozytenwachstumshemmer und Janus-Kinase-Hemmer fur die rheumatoide Arthritis oder Atacicept fur den systemischen Lupus erythematodes. Der Ablauf der ersten Patente fur Biologika und die jetzt erfolgende Zulassung von „biosimilars“ bedeuten ein weiteres Momentum – in Bezug auf die Wirk- und Nebenwirkungsaquivalenz sowie den Einfluss auf die zukunftige Preis- und Verordnungsgestaltung ist beides Neuland.

The Elicitation of Rheumatic Symptoms at Vascular Sites

Abstract: The use of pharmacological agents is a key issue of therapeutic medicine. For more than a decade, TNF-α inhibitors have been prescribed for a growing number of conditions in different disciplines covering gastroenterology, as well as for several rheumatic disorders. The risks and side effects of TNF-α inhibitors comprise serious infections caused by latent disease reactivation or de novo disease acquisition, potential malignancies, neurological conditions and skin and other single- or even varying multi-organ involvement with partially severe courses. At least for multi-organ involvement, vascular inflammation at different sites of the organism may represent a common link. This can cause a versatile complexity of symptoms, and the ‘rheumatic' kind of symptoms seem to be the most diverse. However, drug-induced vasculitides turn out to be controllable as long as they are recognized in time and are treated adequately. However, there are still two questions to be answered regarding autoimmune reactions. First, do ‘induced' vasculitides and underlying disease pertain to the identical, i.e. simultaneous, pathogenic mechanism? Second, could key players with pivotal immunological roles prove to be false targets since several therapeutics used for the treatment of cytokine-associated disorders could act in an opposing manner?