Band 71 · Supplement 1 · Januar 2012

Zeitschrift für

Rheumatologie Research Symposium Rheumatology and Dermatology Berlin, September 16–17, 2011

Membrane-bound TNF Soluble TNF

TNF-R1

TRADD

TNF-R2 FADD TRAF2

TRAF2

Caspase 8

cIAP

NIK

Cascade of Caspases

NF-κB

JNK p38

IκB

NF-κB

ProCaspase 3 SMase

IκB p65

p50

Ceramide p65

p50

cJun, AP-1

DNA

Apoptosis NF-κB

Expression of Survival Genes

Nucleus

www.ZeitschriftfuerRheumatologie.de

Inflammation

Survival

Inflammation

Research Symposium Rheumatology and Dermatology Berlin, September 16–17, 2011 Abstracts

Guest Editors Supplement:

Prof. Dr. Frank Buttgereit, Berlin Prof. Dr. Ulf-Müller-Ladner, Bad-Nauheim Prof. Dr. Thomas Schwarz, Kiel

Content

z Content index z Answers for clinical questions 4

z From nano to macro  8

z Clinical trials 10

z From gene to prognosis 11

z Abstracts without presentation 13

Titelbild: © Springer-Verlag 2012

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Foreword Z Rheumatol 2012 [Suppl 1] · 71:3–16 DOI 10.1007/s00393-011-0943-y © Springer-Verlag 2012

Research Symposium Rheumatology and Dermatology Berlin, September 16–17, 2011

Guest Editors Supplement:

Prof. Dr. Frank Buttgereit, Berlin Prof. Dr. Ulf-Müller-Ladner, Bad-Nauheim Prof. Dr. Thomas Schwarz, Kiel

This supplement is kindly supported by Pfizer Pharma GmbH, Berlin

Foreword In the “Meistersaal” in Berlin where David Bowie and U2 have recorded songs in the eighties, a total of nearly 100 scientists who work in the TNF research area attended the 3rd Tight Junctions symposium. 25 groups of researchers, who were funded by different Pfizer grant programs, presented their findings to pre-clinical and clinical issues, new imaging techniques and study projects. They were invited by Prof. Buttgereit, Prof. Schwarz and Prof. Müller-Ladner, independently of the stage of the research project: some are already published, some are ongoing, and others are just planned. Most of the attendees found the interdisciplinary and intense discussion of the projects very helpful and inspiring for their own projects. In addition to the scientific program, this year‘s research grants were awarded to five winners; two for proposals in the indications rheumatology and dermatology each and one in the field of juvenile arthritis. Because of the outstanding interest into a deep scientific exchange between research groups, the symposium will also be hosted in 2012. The planning of the next Tight Junctions symposium has already started. Prof. Prinz will join the Steering committee and will be glad to welcome you in Munich on the 2nd and 3rd of November 2012.

Zeitschrift für Rheumatologie Suppl 1 · 2012 

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Abstracts 1 Answers for clinical questions

1.1 Health care provision of psoriasis in Germany M. A. Radtke, M. Augustin German Centre for Health Services Research in Dermatology, Institute for Health Services Research in Dermatology and Nursing, University of Hamburg, Hamburg Background. Psoriasis is a common disease that is present in approximately 2.5% of German adults and in about 2.0 million people in Germany annually. It affects 1–3% of the population worldwide. Recent data on the care of this disease show that psoriasis is of considerable socioeconomic, social and medical importance. Psoriasis is also associated with a significant psychological burden affecting all facets of a patient’s life – relationships, social activities, work, leisure and emotional wellbeing. The cumulative effect of this disability may be self-perpetuating social disconnection and failure to achieve a full life potential in some patients. Psoriasis is furthermore considered as a chronic inflammatory and recently classified as a systemic disease significantly associated with comorbidities such as the metabolic syndrome (which is defined as a combination of central obesity, diabetes mellitus type 2, hypertension and dyslipidaemia), cardiovascular disease, cancer, osteoporosis, obesity and depression, among other diseases and conditions. Therapeutic possibilities are based on the S3-guideline, which provides evidence-based treatment recommendations. In Germany, health services research is an interdisciplinary field of research, which provides information on disease and health care to uncover suboptimal and incorrect services. This information can be used to improve the quality of treatment and to increase efficiency. In order to obtain information on the health care for skin and allergic diseases the German Center for Health Services in Dermatology (CVderm) was founded in 2005. It is actively involved in the coordination and conduction of studies on health care. In the world’s largest research program for psoriasis care, health care provision has been described by the implementation of more than 25 different studies, conducted nationwide and addressing all aspects of psoriasis care. Perspectives. Based on these results, a program to improve psoriasis care in Germany has been launched under the auspices of the DDG and BVDD. Our action plan called for the establishment of decentralised regional psoriasis networks in order to improve quality of care (PsoNet) and the definition of treatment goals and national objectives in improving health care provision within the next 5 years. The activities are accompanied on a scientific level by the conduction of studies addressing the quality of psoriasis care throughout Germany.

1.2 Induction of regulatory T cells by tolerogenic antigen delivery for the treatment of murine lupus J. Humrich, R. Undeutsch, O. Weigert, J. Reiser, L. Seriot, G. Riemekasten Department of Rheumatology and Clinical Immunology, University Hospital Charité, Berlin Background. Regulatory T cells (Treg) are a promising tool for the suppression of pathogenic immune responses against self-antigens, which are detrimental in autoimmune diseases such as systemic lupus erythe-

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Zeitschrift für Rheumatologie Suppl 1 · 2012

matosus (SLE). Dendritic cells (DC) in the steady state are important for the maintenance of peripheral self-tolerance by inducing or expanding T cell subsets with regulatory properties upon tolerogenic antigen-presentation. In our previous work we found that high dose administration of the C-terminal peptide sequence of the SmD1 protein (SmD1 83-119) could delay progression of murine SLE which was associated with an increase in IL-10 producing Treg. Methods. Two different approaches for the induction of antigen-specific and Treg-mediated tolerance were evaluated in the (NZBxNZW) F1 mouse model for SLE. Firstly, repetitive peptide sequences derived from the SmD1 83-119 peptide (Oligomers) were tested for their capacity to induce Treg and to prevent disease progression. Secondly we targeted tolerogenic DC directly in vivo by using anti-DEC205 and anti-33D1 anti­bodies coupled to the SmD1 83-119 peptide and evaluated Treg expansion in vivo and the efficacy in the prevention and treatment of murine lupus. Results. Treatment of lupus prone mice with the peptide oligomers did not result in a detectable induction of auto-antigen-specific IL-10+ Treg. In addition, monthly administration of the peptide oligomers could not delay disease progression, while in the case of peptide 4-mers we even observed a significant acceleration of disease. In contrast, single injections of antigen-coupled anti-DEC205 and anti-33D1 antibodies induced an increase of CD4+Foxp3+ Treg in the lymphoid organs of lupus prone mice. The increase in Treg, however, was accompanied by an increase in conventional CD4+ T cells (Tcon) with a CD44hi effector/memory phenotype. Corresponding to this, monthly injections of both antibody conjugates in a preventive setting resulted in an earlier induction of antibodies to the SmD1 83-119 antigen and accelerated disease. In addition, treatment with neither conjugate was capable to influence already established disease. Conclusion. Although promising results had been obtained in several ­autoimmune models in the past, both approaches failed to be successful in murine lupus. This may be in part explained by the abundance of proinflammatory signals present in lupus prone mice that induce the rapid activation and maturation of DC leading to an immunogenic presentation of auto-antigens instead of a tolerogenic one.

1.3 Topoproteome analysis of psoriasis under etanercept treatment R. Böckelmann1, 2, A. Fellas1, M. Bellutti1, H. Gollnick1, B. Bonnekoh1 Klinik und Poliklinik für Dermatologie und Venerologie, Otto-von-GuerickeUniversität Magdeburg, 2Revotar Biotech GmbH, ZENIT II, Magdeburg 1

Patients and Methods. Six patients with severe chronic plaque psoriasis were treated with Etanercept (Enbrel®) in a dosage of 2×50 mg s.c. per week over 12 weeks within an investigator-initiated trial (EudraCT-No. 2008-00622731, IDEA study). For the purpose of topoproteome (TPX) analysis skin punch biopsies of 6 mm in diameter were taken from i) involved and ii) uninvolved skin immediately before start of treatment, and from originally involved skin at iii) week 2, iv) week 6, and v) week 12. Treatment was well tolerated. At baseline psoriasis area and severity index (PASI) showed an average of 21.6 (range from 15.9 to 31.4). Initially dermatology life quality index (DLQI), as measured by the 30-pointsscale of Finlay & Kahn, was 14.7 (1 to 26), and itch on a 10-points-VAS was 5.2 (0 to 10). Results. After 12 weeks of treatment with Etanercept a substantial efficacy resulted with an average decrease of PASI down to 5.8 (2.7 to 9.6). This corresponded to an overall PASI-71.2%-response, and was in coincidence with a beneficial effect upon DLQI and itch, reduced down to 4.2 (1 to 17)

and 1.7 (0 to 5), respectively. Skin biopsies are currently under TPX analysis. A broad antibody/binder-library was inauguratively established, detecting the following epitopes: actin, BCL2, c-myc, CCR6, CD11a, CD11b, CD120a, CD120b, CD138, CD15, CD1a, CD2, CD207, CD24, CD28, CD29, CD3, CD31, CD4, CD44, CD45, CD45RA, CD45RO, CD52, CD54, CD56, CD58, CD62E, CD62P, CD68, CD7, CD8, CLA, collagen IV, cytokeratin 14, factor XIII A, HLA-DR, IL-22R, IL-23R, Ki67, podoplanin, pro­ pidiumiodide-binding site, SNA1, STAT3, TIA1 and vimentin. TPXresults are presented, especially relating to the involvement of Th17 cells and lymph capillaries in the pathogenesis of psoriasis and its Etanerceptinduced remission.

inflammation as assessed by MRI was similar in patients with axSpA – irrespective of BASDAI levels.

1.4 What is the burden of disease in patients with axial spondylo­ arthritis who report low levels of disease activity? A prospective cohort study in patients with axial spondyloarthritis

Psoriatic arthritis (PsA) is an inflammatory joint disease that is distinct from other chronic arthritides and which is frequently accompanied by psoriasis vulgaris (PsV) and seronegativity for rheumatoid factor. We conducted a genome-wide association study in 609  German individuals with PsA (cases) and 990 controls with replication in 6  European cohorts including a total of 5488 individuals. We replicated PsA associations at HLA-C and IL12B and identified a new association at TRAF3IP2 (rs13190932, p=8.56×10¹). TRAF3IP2 was also associated with PsV in a German cohort including 2040 individuals (rs13190932, p=1.95×10³). Sequencing of the exons of TRAF3IP2 identified a coding variant (p.Asp10Asn, rs33980500) as the most significantly associated SNP (p=1.13×10², odds ratio =1.95). Functional assays showed reduced binding of this TRAF3IP2 variant to TRAF6, suggesting altered modulation of immunoregulatory signals through altered TRAF interactions as a new and shared pathway for PsA and PsV.

U. Kiltz, Dr. X. Baraliakos, P. Karakostas, J. Braun Rheumazentrum Ruhrgebiet, St. Josefs-Krankenhaus, Herne Background. Patients with axial spondyloarthritis (axSpA) may already have established radiographic changes in the sacroiliac joints, classified as ankylosing spondylitis (AS) or non-radiographic axial SpA (nraxSpA). International recommendations have set the cut off for minimal clinical disease activity required to fulfil criteria for anti-TNF therapy at a Bath ankylosing spondylitis disease activity index (­BASDAI) level of 4 – based on a convention arbitrarily proposed. However, the level of inflammatory activity as demonstrated by magnetic resonance imaging (MRI) or elevated C-reactive protein (CRP) levels in patients who report moderate disease activity is unknown and the nature and the relationship of these subentities are incompletely understood. The objective was to systematically compare the clinical, laboratory and imaging data of patients with axSpA, stratified by the level of disease activity: BASDAI ≥4. Methods. 100 consecutive patients with axSpA who had never been treated with TNF-blockers were included. Data on demographics were collected, and standardized assessment tools applied, laboratory parameters measured, and spinal MRI and x-rays performed and quantified with established scoring systems. Data were stratified according to the correspondent BASDAI level ≥4. Results. AS was diagnosed in 56 and nraxSpA in 44 patients, median age 40.2±10.4 years; 57% male, mean disease duration 6.4±8.4y, 88% HLA-B27+. Almost all patients took NSAIDs (94%), 54% continuously. A majority (60%) of all patients had active spinal inflammation as assessed by MRI. Significant differences between AS and nraxSpA were seen in gender, CRP, ASDAS, amount of inflammatory lesions on MRI and mSASSS (modified Stoke ankylosing spondylitis spinal score), all p<0.01, whereas there were no differences in clinical parameters analyzed. The stratification based on BASDAI levels showed statistically significant differences in most clinical parameters – with the exception of inflammatory activity. These results were confirmed by multivariate analyses adjusted for gender, CRP and mSASSS at baseline. Conclusions. These data largely confirm that the disease burden in nraxSpA and AS is similar but the groups differ regarding inflammatory activity. Expectedly, male patients were more prone to develop structural changes. However, a large group of patients with axSpA has not developed structural changes after almost 10 years of symptom duration. Thus, nraxSpA should not be regarded as pre-AS but rather as a subgroup of axial SpA that is less prone to develop structural changes in the axial skeleton. Furthermore, these data clearly challenge the concept of the arbitrarily set clinical cut off BASDAI ≥4 since the degree of

1.5 Common variants at TRAF3IP2 are associated with susceptibility to psoriatic arthritis and psoriasis F. Behrens Division of Rheumatology, University Hospital Frankfurt/Main, Johann Wolfgang Goethe-University Hospital, Frankfurt/Main

1.6 The new adipocytokine omentin/intelectin in the pathophysiology of rheumatoid arthritis E. Neumann, K. Frommer, S. Gay, U. Müller-Ladner Justus-Liebig University Giessen, Giessen and Kerckhoff-Klinik, Bad Nauheim Background. Activated synovial fibroblasts from patients with rheumatoid arthritis (RA) contribute actively to cartilage degradation. Adipocytes of the articular adipose tissue produce and secrete hormones, cytokines and enzymes. Therefore, adipocytes are able to modulate inflammation within the joints. Factors produced by adipose tissue are called adipokines or adipocytokines. The concentration of many adipokines in the synovial fluid is increased. The adipokine omentin, also called intelectin, is also present in the synovial fluid. Therefore, omentin could have inflammation and destruction modulating properties comparable to adiponectin and visfatin/PBEF (pre-B cell colony-enhancing factor). Results. Our results show that omentin is expressed locally within the RA synovium, especially in the lining layer and vessel walls. Stimulation of rheumatoid arthritis synovial fibroblasts (RASF) with omentin and subsequent Affymetrix analysis revealed that only a very limited number of genes were slightly differentially expressed. The differential expression suggested in the Affymetrix analysis results could not be confirmed on mRNA (realtime PCR) or on protein level (immunoassays). The quantitative analyses were performed for cytokines and chemokines such as MCP-1, GCP-2, MIG, IGF-1, IL-6 und IL-8. Due to the fact that RASF potentially are not the responder cells to omentin in the synovial tissue, additional cell types were analyzed for their reactivity Zeitschrift für Rheumatologie Suppl 1 · 2012 

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Abstracts to omentin stimulation. Primary chondrocytes, endo­thelial cells and lymphocytes were isolated and stimulated with different omentin concentrations in the presence or absence of added IL-1. Only non-activated lymphocytes showed a response to omentin regarding the IL-8 secretion. Interestingly, all other cell specific and pathophysiologically relevant parameters were not changed by omentin. In contrast to the strong effects observed by adipokines such as adiponectin, visfatin/PBEF or resistin, omentin has no or only limited effects in central effector cells of RA pathophysiology. Currently, additional analyses of the omentin effects on additional parameters and synovial cell types are in progress.

1.7 Influence of TNF-α blockade on the expression profiles of AMP in psoriatic patients K. Kay1, S. Böttcher2, J.O. Schröder1, R.A. Zeuner1 Section of Rheumatology, I. Medical Clinic, University Hospital SchleswigHolstein, Campus Kiel, 2II. Mecial Clinic, University Hospital SchleswigHolstein, Campus Kiel 1

Background. Dentritic cells (DC) play a pivotal role in the initiation of innate and adaptive immune responses in host reaction to microbial infection as well as in autoimmune pathology. Several inflammatory diseases have been reported to have altered DC subsets distribution such as Sjögren’s, Lupus erythematosus, Hepatitis and HIV Infection. Little data exist about the impact of TNF-blocking agents on peripheral blood DC subsets. Therefore we evaluated the distribution of blood dendritic cell (DC) subsets (myeloid DC 1, plasmocytoid DC, and myeloid DC2) prior to and during initiation of TNF-blocking therapy with Etanercept. Methods. 39 patients with active rheumatic disease [16 rheumatoid arthritis (RA), 15 ankylosing spondylitis (AS), 8 psoriatic arthritis (PSA)] requiring TNF-blocking therapy due to insufficient disease control were prospectively followed for 12 weeks after initiation of Etanercept treatment (timepoints: 0, week 2, 6 and 12). Peripheral blood DC subsets were evaluated by flow cytometry using the different expression of BDCA antigens (Milthenyi KIT). Prednisolone dose was <10  mg and the individual Prednisolone dose was not altered during the observation period. 29 healthy individuals served as controls. Results. Prior to therapy numbers of peripheral blood MDC1 were significantly lower in patients than in controls, regardless of the underlying disease. PDC were significantly reduced in patients with rheumatoid arthritis but not in patients with ankylosing spondylitis (p=0.052) or psoriatic arthritis (p=0.1). MDC2 were reduced in RA patients and SPA patients but not in patients with PSA. During etanercept therapy numbers of MDC1 significantly increased within 2 weeks and further increased by week 12 (from 6456±724/ml to 14566±2785/ml). While PDC numbers showed the same pattern (from 5583±492/ml to 9348±1310/ ml), the numbers of MDC2 were not significantly changed (992±121/ml to 1241±269/ml). Parallel to the changes in MDC and PDC counts Eta­nercept therapy induced a rapid decline in CRP (13.9mg/ l±2.3 to 6.4mg/ l+1.1), in DAS28 (from 3.69±0.48 to 2.55±0.42) and in the ­BASDAI (5.24±0.66 to 2.32±0.33) at week 2 (all data mean ± SEM). By week 12 DAS28 and BASDAI had further declined (1.75±0.35 an 1.1±0.32 respectively).

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Zeitschrift für Rheumatologie Suppl 1 · 2012

1.8 Investigating the effect of Etanercept on the peripheral B cell compartment in children with juvenile idiopathic arthritis T. Quach, S. Gläsener, F. Dressler, A. Thon, A. Meyer-Bahlburg Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover Background. Both B cells and TNF have been shown to play an important role in the pathogenesis of rheumatoid arthritis and JIA. However, it remains unclear whether these two important players and the therapies that target them are mechanistically linked. In particular, the impact of TNF inhibition on the B cell compartment in children with juvenile idiopathic arthritis has not been investigated so far. In adult patients with rheumatoid arthritis, two recent studies demonstrate a decrease in memory B cells as a result of anti-TNF treatment using Eta­ nercept or Infliximab, respectively, in patients with rheumatoid arthritis. However, so far no studies have been performed in patients with JIA in this respect. Changes within the composition of the B cell subpopulations could be a direct effect of Etanercept. Alternatively, it might be caused indirectly through alterations in T cells or B cell-activating factor (BAFF) signaling. Methods. Blood samples were collected from pediatric patients with juvenile idiopathic arthritis and PBMC isolated. In addition, serum was stored in −80°C. B and T cell subpopulations were determined by fluorescence activated cell sorting (FACS), and BAFF and APRIL (a proliferation-inducing ligand) levels in serum. Results. To date, more than 140 patients have been included into the study. Patients are grouped based on current treatment with Etanercept, Methotrexate or NSAID. First preliminary data will be presented.

1.9 Etanercept increases step activity in patients with active ­rheumatoid arthritis and shorter disease duration P. Willeke1, C. Winter2, H. Schotte1, H. Becker1, H. Pavenstädt1, J. Marx1, A. M. Jacobi, M. Gaubitz3, D. Rosenbaum2 Münster University Hospital, Münster, Germany, 2Motion Lab, University Hospital Münster, Germany, 3Westfalian-Wilhelms-Univ, Münster 1

Background. There is strong evidence, that TNF-α inhibitors improve disability and activities of daily living in patients with active rheumatoid arthritis (RA). However, the supporting data have been generated mainly by the health-assessment-questionnaire (HAQ) that is based on subjective variables. It is desirable to add objective parameters reflecting patients’ activities to the outcome parameters in RA. The StepWatch™ activity monitor (SAM) is an ankle worn step counter and an accurate instrument to measure real world activities of daily living. Our purpose was to investigate whether step counts measured with the SAM increase under a therapy with Etanercept (ETN) in patients with active RA and to correlate the data with the HAQ and the DAS28. Methods. We included 26 patients with active RA who started a therapy with ETN 50 mg subcutaneously/week. Before therapy, after 4 weeks, and after 12 weeks step activity was measured for a period of 7 days with the SAM. The results were correlated to the HAQ and the DAS28. Results. 23 patients completed the study. A significant increase of the steps per hour was measured after 12 weeks in patients with shorter disease duration of RA (<5 years, n=10; 407 steps/h ±161 vs. 512 steps/h ±134, p≤0,02). The HAQ and the DAS28 decreased significantly in this group (p<0.01).

Tab. 1  Results Essential (Core) ­Domains

Pain

Function

SJC

TJC

Participation

Stiffness

Pt Global

Self ­management

Fatigue

German (%) N=27 Other (%) N=98 Z-value P-value All patients N=125 HCPs (%) N=108 All participants (%) N=232

100

96.3

85.2

96.3

92.6

77.8

77.8

88.9

63

90.7

88.8

74.5

81.4

88.8

81.4

67.4

85.6

79.4

3.15 0.0016 92.7

1.55 0.1206 90.4

1.32 0.1881 76.6

2.78 0.0055 84.6

0.64 0.5238 89.5

−0.40 0.6865 80.5

1.13 0.2587 70.2

0.47 0.6382 86.2

−1.61 0.1064 75.6

92.6

86.9

91.4

77.6

70.8

76.4

84.3

60.4

60.2

92.6

88.7

83.3

81.3

80.9

78.6

76.3

74.7

68.1

In patients with longer disease duration (n=13) no significant increase of step activity was noted although also in this group a significant decrease of the HAQ or the DAS28 was noted (p<0.01). Conclusions. Measuring the step activity by SAM reveals an objective real life parameter of functional capacity of RA patients. If ETN is initiated in patients with shorter disease duration an increase of step activity could be achieved beside the developments in the DAS28 or the HAQ. However, the increase of step activity could not be achieved in patients with long standing disease duration. This emphasizes the need for an early effective therapy before RA activity leads to potentially irreversible destructions of the joints.

1.10 Analysis of the effect of different anti-TNF treatment strategies on the expression of functional gene clusters in psoriatic skin lesions J. Ehrchen, N.-A. Münck, C. Sunderkötter Institute of Immunology, University of Münster, Münster Background. Different subsets of T-helper (Th) cells are crucially involved in the pathogenesis of Psoriasis and other inflammatory skin disorders. There is accumulating evidence that cytokines secreted in the affected skin regulate early Th-cell differentiation. Using an animal model of Th-differentiation (experimental leishmaniasis) we identified cytokines produced by keratinocytes which control Th-differentiation. Surprisingly we identified IL-4, known as a major Th-2 cytokine, as an important early inductor of Th-1 immunity. IL-4 was produced by keratinocytes and induced production of Th-1 promoting IL-12 by dendritic cells (DC) in local draining lymph nodes (Ehrchen et al., PloS Pathogens, 2010). In humans the early phase of disease can not be analyzed, but the effect of effective treatment strategies on functional gene clusters could reveal important molecular pathways in the affected skin. We therefore analyzed gene expression patterns in psoriatic skin lesions early after Etanercept treatment. Methods. Skin biopsies were taken before and 1 week after treatment initiation from lesional and non-lesional skin from 9 patients treated with Etanercept. Skin RNA from responders (7/9) was isolated using standard procedures and subsequently processed for RNA microarray analysis (affymetrix gene arrays). Bioinformatic analysis was performed as published previously (Ehrchen et al., Blood, 2007). Results were confirmed using Real-Time PCR.

Results. We identified 4 gene clusters affected early during Etanercept treatment in psoriatic skin lesions: 1) Genes induced in psoriatic skin compared to non-lesional skin and down-regulated by Etanercept, 2) genes down-regulated in psoriatic skin lesions and further down-regulated by Etanercept, 3) genes not regulated in psoriatic skin lesions and downregulated by Etanercept and 4) genes not regulated in psoriatic skin lesions and up-regulated by Etanercept. Functional clustering revealed a striking overrepresentation of Interferon alpha (IFN-α) responsive genes in cluster 1) and a significant overrepresentation of genes involved in keratinocyte differentiation in cluster 2). Interestingly only CCL18 was induced in psoriatic skin (3-fold) and further up-regulated by Etanercept resulting in 10-fold induced expression levels compared to non-lesional skin. Conclusions. Functional clustering indicates an effect of Etanercept on keratinocytes. Moreover, CCL18 was recently described to induce tolerogenic DC while overrepresentation of IFN-α regulated genes among genes down-regulated by Etanercept could indicate an effect on plasmacytoid DC. It is tempting to speculate, that Etanercept treatment rapidly acts on the local status of proinflammatory and tolerogenic DC activity in psoriatic skin lesions which could subsequently influence Th-cell differentiation.

­ .11 1 Domain development for rheumatoid arthritis (RA) flare definition in Germany and other countries R. Alten, C. Pohl Department of Internal Medicine II, Rheumatology, Clinical Immunology, Osteology, Physical Therapy and Sports Medicine, Schlosspark-Klinik, Teaching Hospital of the Charité, University Medicine Berlin Background. It was recognized during OMERACT 8 (2006) that “RA flare” and “RA worsening” are not well defined. The OMERACT RA flare group initiated a Conceptual Framework process including international patient focus groups and an integrative Delphi process involving both patients and health care professionals. Methods. In 2009 14 RA patient focus groups with 67 participants were conducted in Australia, Canada, Germany, United Kingdom and the United States to describe flare in RA from a patient’s perspective. All documents were translated and back translated for the German patients. In parallel, a literature review and data mining for both clinical trials Zeitschrift für Rheumatologie Suppl 1 · 2012 

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Abstracts and long observational studies were performed. Data were analyzed by qualitative research to extract preliminary domains and to prepare relevant questions for a first Delphi round (performed online in 2010 in parallel for health care professionals and patients). After two additional Delphi rounds a final Delphi 3 survey (with 125 patients and 108 health care professionals) was performed to rank the domains as essential versus not essential in defining flare in RA. The participants in this final Delphi came from Australia (24), Austria (2), Brazil (1), Bulgaria (1), Canada (27), Denmark (4), France (13), Germany (43), Iceland (2), Italy (1), Japan (2), Lithuania (1), Netherlands (11), New Zealand (3), Norway (4), Poland (1), Portugal (1), Republic of Korea (1), Spain (2), Sweden (1), Switzerland (3), United Kingdom (33) and the United States (52). The number of participating German patients was 27 for Delphi 3. Results. see Table 1 Conclusions. First patient and professional international combined consensus on flare in RA. Re-analysis of German and international patient data demonstrated that results by country were similar, despite cultural and linguistic differences.

2 From nano to macro

2.1 Multifocal inflammatory lesions in AS patients depicted by whole body MRI (WB-MRI) improve by a one year therapy with Etanercept M. Karpitschka1, D. Theisen1, A. Horng1, C. Glaser1, M. Reiser1, S. Weckbach1, H. Kellner2 Walter-Brendel Institute for Surgical Research, Ludwig-Maximilian’s University, Munich; 2Medical practise for Rheumatology and Gastroenterology, Munich 1

Background. In ankylosing spondylitis (AS) multifocal inflammatory manifestations of the musculoskeletal system are common. Whole-body magnetic resonance imaging (WBMRI) is known to detect widespread inflammatory lesions. Anti-tumor necrosis factor (TNF) therapy is ­highly effective in AS, however, expensive. Therefore, accurate assessment of therapy response is of clinical relevance. The purpose of this study was to evaluate WBMRI compared to clinical exam alone in patients during Etanercept therapy.

Methods. Six patients with AS underwent a 12 months therapy with Eta­ nercept (Enbrel® 50 mg/week). Patients were examined by an established WBMRI protocol (1.5 T scanner, STIR and T1-w unenhanced and contrastenhanced sequences) at 3 different points of time (0, 12 and 52 weeks) after application of the first dose of Etanercept. WBMRI was evaluated in consensus by 2 experienced radiologists (blinded to clinical exam) for inflammatory lesions (e.  g. spondylitis, sacroileitis, bursitis, enthesitis and synovitis). The lesions were counted and graded on a grading system (severe, moderate, mild, minimal). Simultaneously, clinical examination was performed by an experienced rheumatologist, including collecting data from BASDAI, BASFI and CRP. WBMRI and clinical scores were correlated. Results. During Etanercept therapy, symptomatic therapy with NSAID could significantly be reduced, (3.0±0.4 down to 1.5±0.2 (50%, p<0.05). The clinical examination scores showed significant improvement under therapy, e. g. the BASDAI-index decreased from 5.6±0.7 (week 0) to 1.6±0.5 (weeks 12, p<0.05) and to 1.4±0.6 (week 52, p<0.05). The patients’ estimation of AS activity at week 0 averaged 6.8±1.1, physician assessment was 7.0+0.3 respectively. At week 12, the AS-activity averaged 1.2±0.5 by patients (p<0.05) and 2.0±0.3 (p<0.05) by the physician. The amount of pain diminished during therapy from 7.2±0.7 (BASDAI, week 0) to 1.3±1.0 (BASDAI, week 52).The morning stiffness significantly decreased from 72.0±18.0 (week 0) to 12.0±8.7 (week 52). In addition, clinical values improved under therapy, e.  g. CRP averaged 15.9±4.7 at week 0 and declined to 2.1±21 at week 52 (p=0.055). In WBMRI, the sum of all lesions showed a significant decrease from week 0 (30.6±12.4) to week 12 (14.2±7.5), equivalent to a 59.2±13.8% reduction of lesions. Especially for spondylitis anterior and sacroileitis, there was a significant decline of inflammatory lesion, e. g. 9.5±2.6 in week 0 to 1.0±1.0 in week 52 for spondylitis anterior (reduction about 92.7±7.3, p<0.05) or 5.5±1.0 in week 0 to 0.0±0.0 in week 52 for sacroileitis (reduction of 100%, p<0.05). WBMRI detected significantly more areas of synovialitis and enthesitis than clinical examination (p<0.05). Conclusions. Under Etanercept therapy the activity of AS significantly decreased which was proven by clinical examination, CRP and quality of life questionnaires (BASDAI) as well as by WBMRI. WB-MRI detected significantly more inflammatory lesions than clinical exam alone. The results suggest that WB-MRI improves the detection of inflammatory changes and the assessment of their course under therapy.

2.2 Synovial inflammation determined by 3 Tesla magnetic ­resonance imaging in patients with rheumatoid arthritis treated with ­Etanercept F. Sadeghlar, M. Oleszowsky, W. Willinek, M.F. Seidel

delta Ratingen score (points)

10

Medizinische Klinik und Poliklinik I, Rheumatology Unit, Bonn

5 0 -5 -10 0

10

20

30

40

50

60

70

80

cumulative percentage group

DMARD

BIOLOGICS

Fig. 1 8 Changes in Ratingen Score given as a probability plot

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90

100

Background. Conventional disease-modifying anti-rheumatic drug (cDMARD) treatment is insufficient in some patients with rheumatoid arthritis (RA) thus requiring antagonists for tumor necrosis factor alpha. Treatment with these agents demonstrates excellent remission rates that have been documented with conventional radiographs and some magnetic resonance imaging (MRI) studies. The latter method has the advantage of showing early inflammatory changes or flares as compared to conventional radiographs, and the 3 Tesla technique allows higher spatial resolution as compared to 1.5 Tesla analysis. Especially early and thus prognostically relevant subchondral bone lesions might be detected more precisely. Methods. Ongoing epidemiologic clinical pilot MRI study with 10 ACR/ EULARpositive RA patients with inadequate response to two cDMARDs

and thus an indication for Etanercept using the rheumatoid arthritis magnetic resonance imaging system (RAMRIS). These patients are compared to 10 patients adequately responding to cDMARDs. 3 Tesla MRI (PDSPAIR; T1 with and without contrast agent) using a multi-channel hand coil are performed at baseline, after four months, and after 12 months. MRI analyses include RAMRIS scoring with examination for synovitis, effusion, subchondral erosion, and also bone marrow edema. Data are compared to and correlated with CRP and clinical parameters (DAS 28, HAQ, VAS). Results. One patient adequately responding to cDMARDs had a ­R AMRIS of 17.0 at baseline. 8 patients of the Etanercept arm were included thus far. Three patients were RF+/CCP+, two patients were RF+/ CCP− and three patients were RF−/CCP−. RAMRIS at baseline was 23.3±6.9 (mean ± SD). Despite of disease regression, RAMRIS did not change after four months of treatment in five patients analysed up to date (baseline: 21,0±7.2; 4 months: 21.4±7.5). Prednisone doses were deescalated and CRP levels dropped in two patients while three patients had normal CRP at baseline and after four months. HAQ decreased in four of these patients. Conclusions. The results indicate partial biological remission after four months of treatment despite of persistent MRI inflammation. Data after 12 months are required to document solid biological remission. Outlook: In addition to MRI analysis and clinical data, further serological markers will be examined. They include soluble isoforms of the vascular cell adhesion molecule-1 (sVCAM-1), the intercellular adhesion molecule-1 (sI-CAM-1) and the endothelial-leukocyte adhesion molecule-1 (sELAM-1). They indicate cellular activation with consecutive transendothelial cellular migration as an estimate for endothelial activation and may correlate to inflammatory in-filtrates determined by MRI.

2.3 Retrospective radiographic course under medication with DMARDs and biologics – The RERUM Study S. Wassenberg Evangelisches Fachkrankenhaus Ratingen, Ratingen Background. Randomized controlled trials have shown an almost complete halt of radiographic progression in patients with rheumatoid Arthritis (RA) treated with TNF-blocking agents compared to patients treated with conventional disease-modifying anti-rheumatic drugs (DMARD). The difference in radiographic progression was observed even in patients who didn’t respond clinically and who had still active disease. The aim of our study was to find out, if this gap between clinical response and radiographic progression despite similar clinical response could also be confirmed in everyday patients on either conventional DMARD therapy or on TNF-blocking agents in a usual practice setting. A pilot study should proof, if the collection of radiographs in a multicenter study involving private rheumatology practices in Germany and a centralized evaluation after converting the radiographs into digital files was feasible. Methods. Consecutive patients with RA in whom a regular follow up of hand and feet radiographs was due according to the treating physician were eligible for the study, if hand and feet radiographs of the same patient were available that were taken at least 12 but no more than 48 months before. Patients had to give informed consensus to provide their data and were then assigned to group A if they had been on conventional DMARD treatment at the time when the first radiograph was taken or to group B, if they were treated with any of the three TNF-blocking agents (etanercept, infliximab or adalimumab) that were available at that time with or

Tab. 2  Correlation of FOIAS with assessments of disease activity in 45 patients with arthritis

TJC SJC DAS28 RAMRIS Synovitis RAMRIS total 1 ESR CRP

FOIAS PVM

FOIAS P1

FOIAS P2

FOIAS P3

0.2 0.6 0.3/0.4 0.5/0.7

0 0.1 0.2/0.4 0.3/0.4

0.2 0.4 0.2 0.6/0.9

0.4 0.6 0.3–0.4 0.5/0.9

0.6/0.8

0.5

0.7/0.9

0.6/0.9

0 0

0.4 0

0 0

0 0

0: no relevant correlation.

without DMARD combination. 16 centers, private practices and outpatient clinics should each include 10 patients in group A and 10 patients in group B. At the time of inclusion and – if available – at the time, when the first radiograph was taken, the DAS 28, ESR, CRP-values and the presence or absence of rheumatoid factor and cyclic citrullinated peptide (CCP) antibodies was recorded. Radiographs were collected and read by two experienced readers according to the Ratingen Score. Results. 156 patients were recruited, 92 in group A, 64 in group B. At the time when the first radiograph was taken (baseline) there were no significant differences in gender, age, rheumatoid factor positivity, DAS28, ESR and rate and dose of concomitant prednisolone therapy between group A and B, whereas disease duration, number of previous DMARD therapies, CRP, proportion of patients with anti-CCP antibodies and Ratingen Sore at baseline were significantly longer, higher or greater in group B. The mean change in Ratingen Score was 0.0 in group A and 0.3 in group B (Fig. 1). Conclusion. Due to the strong selection of patients with longer disease duration, higher baseline Ratingen Scores, more failed DMARD therapies and higher frequency of CCP-antibody positivity in group B the two groups cannot be compared. But the pilot study confirmed that collecting actual and retrospective data and radiographs in private practices and outpatient clinics with central evaluation of the radiographs is feasible. This encourages us to design a study that will collect radiographs at the start of anti-TNF treatment with follow up data that will be compared to the previous progression in the time before initiating the new therapy.

2.4 ICG-enhanced fluorescence optical imaging in comparison with clinical examination and MRI S. Werner1, P. Schott2, C. Schwenke3, B. Kurtz2, H.-E. Langer1 RHIO (Rheumatology, Immunology, Osteology) Center Duesseldorf and RHIO Research Institute, Duesseldorf, Germany; 2Department of Radiology, Evangelisches Krankenhaus Duesseldorf, Duesseldorf, Germany; 3mivenion GmbH, Berlin 1

Background. Indocyanine green (ICG) enhanced fluorescence optical imaging (FOI) with the commercially available Xiralite system (mivenion GmbH) is a novel imaging technology to assess inflammatory activity in rheumatic conditions. We compared FOI with clinical examination (CE) and magnetic resonance imaging (MRI) in patients with established arthritis and early untreated arthritis. Zeitschrift für Rheumatologie Suppl 1 · 2012 

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Abstracts Methods. Two cohorts were examined. Cohort 1: 25 patients with active arthritis (DAS28 >3.2). Cohort 2: 20 patients with early untreated arthritis (disease duration ≤24 months). Six healthy individuals and 6 subjects with arthralgia without any sign of an inflammatory rheumatic disease served as control group. All patients received clinical examination and lab testing. A contrast enhanced MRI of the clinically leading hand was performed. MRI was evaluated according to the OMERACT-criteria, and RAMRIS total and RAMRIS synovitis were calculated. All patients were examined by FOI using ICG as fluorophor (ICG-Pulsion® 0.1 mg/ kg/BW bolus i.v., 6 min). Image interpretation was done on three defined phases of increased signal intensities (ISI) in the finger tips: early (P1, until strong ISI in the finger tips), intermediate (P2, during ISI in the finger tips), and late phase (P3, after decreasing of ISI in the finger tips) and for an automatically generated composite image (PrimaVista Mode, PVM) on a semiquantitative scale (0–3). A fluorescence optical imaging score (FOIAS) was calculated separately for the PVM, P1, P2 and P3. Spearman’s rank-correlations were calculated. Correlations were valued as follows: 0r≤0.4 weak to moderate correlation, 0.4
3 Clinical trials

3.1 Etanercept may increase sensitivity to UVB but not to UVA in ­fair-skinned individuals without prior UV therapy C. Pfeiffer, D. Konnerth University Hospital for Dermatology, Technical University Dresden, ­Dresden Background. Phototherapy is an efficient treatment option in many patients with psoriatic skin lesions, and may be employed in synergistic combinations with other anti-psoriatic treatments such as methotrexate or retinoids, which are also known to increase sensitivity to UV. It is not known, whether Etanercept increases sensitivity to UVB or UVA. Methods. 10 patients, photo skin type 2 to 3, undergoing UV testing before induction of UV therapy where exposed to graded doses of UVA and UVB according to current national guidelines before and 48 h after a single application of 50  mg Etanercept. Photosensitivity was evalu-

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ated as the minimal erythema dose (UVB) or the minimal tanning dose (UVA). Results. 4/10 patients demonstrated an increase in sensitivity to UVB following administration of a single dose of Etanercept 50 mg. This increase averaged 36% (33–41%), necessitating a decrease in UVB starting dose to 1/3. Photosensitivity to broad spectrum UVA was unchanged in all patients. Patients who did not display increased sensitivity to UVB (6/10) had all been subjected to at least one episode of UV treatment in the year prior to testing. Conclusions. Etanercept may increase sensitivity to UVB thereby decreasing the starting dose employed for concurrent UVB therapy. This may be more important in phototherapy-naive patients. Sensitivity to UVA is not influenced.

3.2 Evaluation of the efficacy of Etanercept vs. sulfasalazine on active and chronic inflammatory lesions on magnetic resonance imaging (MRI) in active axial spondyloarthritis I.-H. Song1, K. G. KG2, H. Haibel1, C. Althoff2, D. Poddubnyy1, J. Listing3, A. Weiß3, B. Freundlich4, M. Rudwaleit1, J. Sieper1 Rheumatology, Charité Medical University, Campus Benjamin Franklin, Berlin, Department of Radiology Charité Medical University, ­Campus Charité Mitte, Berlin, 3German Rheumatism Research Center, Berlin, 4Division of Rheuma­ tology, University of Pennsylvania, ­Philadelphia, USA 1 2

Background. To evaluate the influence of Etanercept (ETA) versus sulfasalazine (SSZ) on active and chronic inflammatory lesions on magnetic resonance imaging (MRI) in active axial spondyloarthritis (SpA) of short symptom duration. Methods. A total of 76 patients with axial SpA (symptom duration of less than 5 years), were randomized to ETA (25 mg given twice weekly subcutaneously; n=40) or SSZ (2–3 g per day orally; n=36) treatment over 48 weeks. Patients who were in study remission at week 48 were assessed for sustained drug-free remission. All patients showed active inflammatory lesions on whole-body MRI (wb-MRI) in either the sacroiliac joints (SIJ) or the spine at baseline and underwent investigation by wb-MRI at weeks 0, 24, 48 and 108. MRIs were scored for active and chronic inflammatory lesions by two blinded radiologists. Results. Active inflammatory lesions detected by wb-MRI improved significantly greater in ETA-treated versus SSZ-treated patients after 48 weeks: inflammation was reduced by 60% in the SIJ, 55% in the spine and 48% on MRI-enthesitis in the ETA group vs. 35%, 14% and 0% in the SSZ group, respectively. Significantly more ETA compared to SSZ patients reached ASAS remission at week 48 (50% vs. 19%, p=0.006). Regarding chronic changes we found the following: if there was no previous inflammation in the bone no new fatty lesions occurred in SIJ quadrants and only a few (0.6%) in spine vertebral units (VUs). There was a significant relationship between disappearance of inflammation and the appearance of fatty lesions: if baseline inflammation resolved fatty lesions occurred in 10.5% of SIJ quadrants and 17.9% of VUs. If inflammation did not resolve over 1 year, fatty lesions occurred less frequently: 2.4% (SIJ quadrants) and 7.2% (VUs). After 1 year of treatment more ETA vs. SSZ patients reached study remission (ASAS remission and being free of active inflammation in the SI-joints and spine) at week 48 (33% vs. 11%, p=0.03). Drug-free remission until the end of year 2 was reached in 8% of ETA vs. 3% of SSZ. Conclusion. In patients with early axial spondyloarthritis active inflammatory lesions detected by whole-body MRI improved significantly more in ETA- vs. SSZ-treated patients. Our data indicate that there is a close interaction between inflammation, tumour necrosis factor blockade and

the development of fatty lesions in subchondral bone marrow of patients with axial SpA. Drug-free remission can be reached in about 10% of patients.

3.3 A prospective evaluation of the diagnostic, prognostic and monitoring value of MRI, ultrasound and conventional radiography in comparison to clinical examination for the assessment of heel enthesitis in patients with spondyloarthritis and controls X. Baraliakos, U. Kiltz, J. Braun Rheumazentrum Ruhrgebiet, St. Josefs-Krankenhaus, Herne Background. While the axial manifestations in SpA are already rather well characterized, this is clearly less so for the peripheral manifestations. Furthermore, while imaging is an essential part of the new classification criteria for axial SpA, this is not the same for the peripheral classification criteria. This is due to limited knowledge about the role of imaging to detect peripheral arthritis and enthesitis in SpA. Nevertheless, the majority of enthesial involvement can not be assessed by physical examination, because it is clinically silent but it still shows definite pathology on imaging techniques. The main objective of this study is to prospectively evaluate the diagnostic and prognostic value of MRI, ultrasound and conventional radiography in patients with spondyloarthritis and heel, ankle and knee pain. Methods. 100 patients with established SpA and knee, ankle or heel pain and 50 controls with no SpA will be consecutively included, when presenting to the clinic. All patients with knee, ankle or heel pain will be examined clinically and will be asked to rate their heel, ankle or knee pain on a NRS and fill out questionnaires for BASDAI, BASFI and BASMI. Thereafter, they will then undergo an x-ray examination, a power-doppler ultrasound examination and an MRI examination of the affected region. Therapy of each patient will either be started (in case of a new diagnosis), continued or changed (in case of already existing diagnosis and treatment) according to the clinical decision of the investigators and according to the currents clinical guidelines (physiotherapy, NSAIDs, DMARDs, biologics). Decision to treatment will be independent of the participation to this study. Evaluation of the patients will be performed after 3 months and after one year. Results and Conclusions. The study has now, after a long delay due to bureaucratic issue at the ethic committee, been approved without revisions. The first patients will be enrolled in the study soon. In case of first results, these will be presented at the Tight Junction Meeting in Berlin in September 2011. Furthermore, the rationale of the study and the implications of the results will be discussed in more extension.

40%. Recently, a new screening questionnaire in German language has been validated by Haerle et al. This GEPARD (German Psoriasis Arthritis Diagnostic questionnaire) has a sensitivity and specificity of 89% and 69.1% for ≥4 questions answered “yes”. Methods. Two dermatologic hospitals and 9 private dermatologic practices were involved. All consecutive patients with psoriasis were asked to fill out the questionnaire without the help of the physician and send them to the study centre. All patients with ≥4 positive questions were invited for a rheumatological examination. Patients with known PsA (question 7 answered “yes”) received a second questionnaire with regard to the history and treatment of PsA. 30% of patients with known arthritis were interviewed by a telephone call and if diagnosis was uncertain were invited for a rheumatological evaluation. Those patients with a positive questionnaire who denied coming were considered as having no arthritis. The rheumatologic assessment consisted of physical examination and laboratory tests including inflammatory markers, rheumatoid factor, ­anti-CCP antibodies and HLA B27. All patients with peripheral arthralgia received ultrasound of the joints including Doppler and X-ray of hands, feet and affected joints. In those patients with marginal changes or spinal complaints magnetic resonance imaging (MRI) was added. The CASPAR criteria were used for the diagnosis of PsA. Results. 404 questionnaires were evaluated. 204 patients (50.5%) had answered ≥4 questions with “yes”, of whom 38.2% (n=78) had a known PsA. 126 patients were invited for a clinical examination and 23% (n=29) refused to come. 98 patients with suspected PsA had a clinical evaluation at the study centre. In 49% (n=48) the CASPAR criteria were not fulfilled and in 44.9% (n=44) a new PsA was diagnosed. In two patients anti-CCP antibodies and a symmetrical arthritis made the diagnosis rheumatoid arthritis more plausible. 6.1% already had the diagnosis of PsA. In addition to the clinical evaluation the diagnosis was confirmed by radiological assessment using X-ray in 69.4% (n=68), power-doppler ultrasound in 83.7% and MRI in 39.8%. All together, of the 404 patients 44 (10.9%) were newly diagnosed having a PsA and 78 (19.3%) had a known PsA whereas 282 (69.8%) were found to have no signs of PsA. Thus the prevalence PsA among patients with psoriasis in this study was 30.2%. There were no significant differences in the patients with or without definite arthritis regarding CRP or ESR, HLAB27, gender or severity of psoriasis. Only dactylitis was significantly associated with definite PsA. Conclusions. This study uses a validated questionnaire in the forefront of a clinical evaluation in patients with suspected PsA. By using this approach the prevalence of PsA was higher than that in recent studies in Germany, UK and the United States and supports findings from Scandinavia. With nearly 50% positive questionnaires for patients without PsA the specificity should be improved.

4 From gene to prognosis

3.4 Prevalence of psoriatic arthritis in dermatological patients with psoriasis – The POPAP Trial

4.1 The relevance of TNF-α for the vitality, proliferation and stability of epidermal stem cells

J. C. Henes, M. Eisfelder, A. Adamczyk, B. Knaudt, F. Jacob, J. Lux, R. Denfeld, A. Philipp, P. Ziegler, M. Kleinhans, C. Steigleder, N. Oster, G. Fierlbeck, D. Spira, M. Horger, E. M. Ziupa, L. Kanz, I. Koetter

J. Wohlrab, C. Bruhne, M. von Laffert

Department of Internal Medicine II, University Hospital Tuebingen Background. The existing data on prevalence of psoriatic arthritis (PsA) among patients with psoriasis in the literature vary between 5.8% and

University Hospital and Outpatient Clinic, Department of Dermatology and Venereology, Martin Luther University Halle-Wittenberg The relevance of TNF-α in the pathogenesis, especially of thermal injuries of the skin, has been proven with absolute certainty, even though/ although the exact connections/interrelations are still largely unknown. Zeitschrift für Rheumatologie Suppl 1 · 2012 

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Abstracts It is known that TNF-α can serve as a key molecule in the posttraumatic cytokine cascade. The TNF-α, together with interleukin-2 (IL-2), interleukin-3 (IL-3) and interleukin-6 (IL-6), mediates significantly the inflammatory response in the burn wound. TNF-α is produced mainly by macrophages and monocytes, but also by neutrophils and keratinocytes. This IL-2 mediates a major stimulus of TNF-α expression. Ultimately, the stimulation of clonal proliferation of activated T cells is the main function of IL-2. For burns, however, it is known, that CD25 (alpha chain of IL-2R) is more clearly expressed on peripheral blood cells and the concentration of IL-2 in the serum is elevated. With respect to the epithelisation of the wound healing, an inhibitory effect, of which the metabolic and cell-biological interactions are so far poorly understood, is attributed to TNF-α. In particular, the interaction of TNF-α with epidermal stem cells is in the focus of attention. In this project the interaction of TNF-α with epidermal stem cells was investigated. The results show that TNFαhas neither an effect on proliferation, nor on the differentiation of epidermal stem cells. The stability of epidermal stem cells appears to be changed by the high concentrations of TNF-α, so that a pro-differentiating effect can be determined. In contrast, a two-dimensional epithelisation model can find no evidence for a direct influence on the epithelisation of wound healing. These data suggest that TNF-α can indirectly exert influence on the wound healing process through proinflammatory effect cascade.

4.2 Biomarkers as prognostic factors for the immune response to B cell therapies H. Mei Deutsches Rheumaforschungszentrum, Berlin Abstract not submitted at time of publication

4.3 Human epidermal Langerhans cells replenish skin xenografts and are depleted by alloreactive T cells in vivo J. Hemmerling, J. Wegner-Kops, E. von Stebut, D. Wolff, E. M. Wagner, U. F. Hartwig, M. C. André, M. Theobald, R. E. Schopf, W. Herr, R. G. Meyer Department of Hematology, Oncology, and Pneumology, University Medical Center, Johannes Gutenberg University Mainz, Mainz Background. Epidermal Langerhans cells (LC) are potent APCs surveying the skin. They are crucial regulators of T cell activation in the context of inflammatory skin disease and graft-versus-host disease (GVHD). In contrast to other dendritic cell subtypes, murine LC are able to reconstitute after local depletion without the need of peripheral blood-derived precursors. In this study, we introduce an experimental model of human skin grafted to NOD-SCID IL2Rγ(null) mice. Methods. In this model, we demonstrate that xenografting leads to the transient loss of LC from the human skin grafts. Despite the lack of a human hematopoietic system, human LC repopulated the xenografts 6 to 9 wk after transplantation. By staining of LC with the proliferation marker Ki67, we show that one third of the replenishing LC exhibit proliferative activity in vivo. We further used the skin xenograft as an in vivo model for human GVHD. HLA-disparate third-party T cells stimulated with skin donor-derived dendritic cells were injected intravenously into

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Zeitschrift für Rheumatologie Suppl 1 · 2012

­ OD-SCID IL2Rγ(null) mice that had been transplanted with human N skin. The application of alloreactive T cells led to erythema and was associated with histological signs of GVHD limited to the transplanted human skin. The inflammation also led to the depletion of LC from the epidermis. Conclusion. In summary, we provide evidence that human LC are able to repopulate the skin independent of blood-derived precursor cells and that this at least partly relates to their proliferative capacity. Our data also propose xeno-transplantation of human skin as a model system for studying the role of skin dendritic cells in the efferent arm of GVHD.

4.4 MicroRNAs as prognostic and diagnostic factors in rheumatic diseases H.-M. Jäck, J. Wittmann Department of Internal Medicine III, Nikolaus-Fiebiger-Center, University of Erlangen-Nürnberg, Erlangen Background. Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory disease affecting about 0.8% of adults worldwide. It is usually a very painful condition and leads to substantial disability and premature death if left untreated. The primary targets in RA are synovial tissues. When the joints are attacked, an inflammatory reaction is produced that often progresses to destruction of the articular cartilage and bones and may eventually result in ankylosis of the joints. Although the cause of RA is unknown, autoimmunity plays a pivotal role in its chronicity and progression. While various treatments are available to suppress the symptoms, disease-modifying anti-rheumatic drugs (DMARD) are required to inhibit or halt the underlying immune process and delay or even prevent long-term damage. In recent years, microRNAs (miRNAs) have emerged as a new class of small endogenous, non-coding RNAs which regulate gene expression at the post-transcriptional level. These ~22-nt long double-stranded RNAs mostly bind to target mRNAs based on partial sequence complementarity, leading to translational repression or to decapping, deadenylation and mRNA degradation. As cumulative data indicate that proper miRNA regulation is critical for the prevention of auto-immunity and normal immune functions, the major goal of our current project is to gain insights into the molecular circuits that control the development of rheumatoid- and autoimmune diseases. Methods and Results. If miRNAs play a role in the development and/or maintenance of rheumatic diseases, we would expect that miRNA pattern differ in synovial fibroblasts from healthy donors and patients with Osteoarthritis (OA) compared to cells from patients with RA and systemic lupus erythematosus (SLE). To test this prediction, we will determine the miRNA profiles of synovial fibroblasts from healthy controls and patients with RA, OA and SLE by a genome-wide deep sequencing approach. miRNAs in serum are more and more recognized as potential biomarkers for diagnosis and for monitoring of disease activity before and after treatment in a variety of diseases. If serum miRNAs are involved in the response to RA treatment, we might identify a miRNA pattern that could allow to estimate e.  g. the likelihood of a successful DMARD treatment. To test this prediction, we will determine the serum miRNA profile in the blood of RA patients before and after first line DMARD treatment by deep sequencing analysis. Conclusion. Our short-term aim using these experimental approaches is to identify prognostic, diagnostic and potentially therapeutic biomarkers and to better understand the role miRNAs play in the development of rheumatoid diseases.

4.5 TNF-targeted therapy with infliximab, etanercept and ­adalimumab in human TNF knock-in mice infected with ­Mycobacterium tuberculosis S. Ehlers, K. Walter, A. Kruglov, S. Nedospasov Forschungszentrum Borstel, Deutsches Rheumaforschungszentrum Background. Tumor necrosis factor (TNF) is a critical component of the antimycobacterial response and is essential for granuloma integrity. In chronically Mycobacterium tuberculosis-infected mice, antibodies against mouse TNF lead to rapid reactivation of mycobacterial replication, while a soluble mouse TNFR2 construct has a less pronounced and delayed effect. To date, it has been impossible to analyze, in the murine model of experimental tuberculosis, the TNF-targeted drugs actually used in human patients since they largely act in a species-specific manner. Methods. Human TNF knock-in mice were engineered on a C57BL/6 background to specifically answer this question. These mice are deficient in murine TNF but carry the human TNF gene under a constitutive promoter. TNF-targeted reagents for human use such as infliximab, etanercept and adalimumab can effectively neutralize human TNF in these mice, e. g. in a model of septic shock or in collagen-induced arthritis. We optimized dosing and timing of drug administration during experimental aerogenic tuberculosis in human TNF knock-in mice. We will report on the suitability of this model for testing reagents targeting human TNF in terms of the risk of exacerbating tuberculosis.

Results. Etanercept therapy resulted in no sustainable effects on serum TNF-R1 and TWEAK levels during the observation period. A correlation between TNF-R2 concentrations was found with age and TNF-R1 prior to treatment with Etanercept, indicating a physiological relationship between the serum levels of TNF receptors  1 and 2. Circulating TNF-α and TNF-R2 as measured using ELISA increased significantly during treatment with Etanercept. We could show that our anti-TNFR2 assay was able to detect circulating Etanercept in serum. Conclusions. We found no correlations between disease activity as measured using DAS28 and the levels of serum TNF-R1, TNF-α and TWEAK at any of the time points during the course of treatment with Etanercept, suggesting that the levels of these factors had little measureable influence on the response to the treatment in this group of patients. The increase of serum TNF-α during the course of treatment is related to the presence of high levels of TNF-R2 as measured using ELISA, since elevated TNF-α is found in all patients except in two where no increased TNF-R2 was detected. The fact that patients with elevated levels of TNF-α respond favorably to Etanercept suggests that this TNF-α is biologically inactive, and is probably complexed with Etanercept in the serum. Interestingly, the two RA patients in which no increase in TNF-α or TNF-R2 (Etanercept) could be measured during the course of treatment showed no reduction in the DAS28 after 12 weeks of therapy, suggesting that the measurement of TNF-α/TNF-R2 might be useful in monitoring for compliance or for individual clearance times for serum Etanercept.

5 Abstracts without presentation

4.6 Relationship of serum TNF-α, soluble TNF-α receptors R1/R2 and TWEAK to clinical parameters and therapeutic response in rheumatoid arthritis patients undergoing Etanercept treatment

5.1 Modulation of Interleukin-17 producing T cells in patients with rheumatoid arthritis undergoing anticytokine-directed therapy

G. Neeck

A. Rubbert-Roth

BIOMEDRO Biomedical Research and Development, Rostock

University of Cologne, Cologne

Objectives. Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) has been shown to be a potent arthritogenic cytokine in the mouse model of collagen-induced arthritis. Serum levels of TWEAK increase in this model during the course of disease development, and treatment with an anti-TWEAK neutralizing monoclonal antibody reduces overall disease severity. It has been shown that TWEAK induces the expression of TNF-α and that TWEAK-stimulated cell death is an indirect effect that is mediated by TNF-α/TNF-α receptor interactions. Our objective was to determine what relationships exist between the serum levels of TNF-α, the TNF-α receptors TNF-R1/-R2 and TWEAK with clinical response and disease biomarkers in a cohort of RA patients during the course of treatment with Etanercept. Patients and Methods. Twenty patients with active rheumatoid arthritis according to the classification criteria of the American College of Rheumatology (ACR) that started Etanercept therapy due to an inadequate response to the treatment with conventional DMARDs were enrolled in the study. Patients received Etanercept 50 mg subcutaneously weekly during the course of the study. Clinical and laboratory assessments were conducted prior to injection at baseline and at 4 and 12 weeks into therapy with Etanercept. Quantification of sTNF-R1, sTNF-R2, sTWEAK, IL-6 and sTNF-α in serum samples was performed using ELISA kits (R&D Systems, Wiesbaden, Germany) following the manufacturer’s protocol.

Background. Th17 cells [Interleukin-17 (IL-17) secreting T helper cells] represent a distinct lineage of CD4+ T cells that have been implicated in the pathogenesis of rheumatoid arthritis and other autoimmune diseases. There is growing evidence that the differentiation of Th17 cells is under control of other proinflammatory cytokines. TNF-α drives inflammation in rheumatoid arthritis and other inflammatory disorders. The therapeutic inhibition of TNF-α has resulted in downregulation of other proinflammatory cytokines such as IL-1β and IL-6, suggesting that TNF-α represents a dominant cytokine in induction and maintenance of inflammation. There is conflicting data, whether TNF-α is also crucial for the differentiation and activation of IL-17 T cells. Differentiation of human Th17 cells upon cytokine stimulation induced by TLR stimulation was not affected in the presence of neutralizing anti-TNF antibodies. Given the clinical effectiveness of anti-TNF directed therapies, it is temptative to speculate whether TNF-α-induced inflammatory pathways in rheumatoid arthritis involve the differentiation and activation of Th17 cells. Methods. In this study, PBMC were obtained from patients with RA after obtaining informed consent. Patients undergoing treatment with Etanercept or other cytokine inhibitors are compared to patients using conventional DMARDs only. For analysis of cytokine production by T cells, PBMCs are cultured for 3 h in the presence of phorbol myristate acetate (PMA) and ionomycin in the presence of brefeldin A before intracellular Zeitschrift für Rheumatologie Suppl 1 · 2012 

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Abstracts cytokine staining and flow cytometry as described elsewhere. Multicolour flow cytometry is applied combining fluorochrome-labeled antibodies to differentiate cell surface markers CD3, CD4, CCR6, and IL23R and antibodies to detect intracellular cytokines (IL-10, IFN-γ, IL-17 and IL-22) after fixation of cells in paraformaldehyde and permeabilization with saponin. Results. The current study is ongoing. Preliminary results show that patients on Etanercept seem to have a higher percentage of IL-22 producing CD4+ T cells vs. patients on DMARDs. The production pattern of IL-17 seemed to be comparable between patients on DMARDs versus patients on Etanercept. In selected patients, the expression of both IL-17 and IFN-γ as well as the production of both cytokines can be detected preferentially in CD4+CCR6+ T cells. These studies will be extended to a larger number of patients and, if possible, include lymphocytes derived from synovial tissue or fluid. Conclusions. In summary, preliminary results from our study suggest that the beneficial effect of TNF blockade does not correlate with the inhibition of Th17 differentiation.

liferation was found with resting ND-B25- or SLE-B25- cells. So far, no significant difference in cell viability, cytokine production or expression of costimulatory or inhibitory surface markers was found between both B cell populations. Conclusions. B25+ from SLE patients exhibit reduced regulatory capacity towards CD4+T-cells compared to B25+ from healthy donors. Future experiments deal with the mechanisms, potential correlations with treatment or disease stage, and relevance for pathogenesis of autoimmunity.

5.2 Analysis of the immunoregulatory potential of human B cells in systemic lupus erythematosus

Background. Fibroblasts possess immune regulatory capacities. They are able to suppress the proliferation of T lymphocytes and to inhibit the differentiation of dendritic cells (DC). Being ubiquitously present at the sites of lymphocyte priming and restimulation, fibroblasts may have a fundamental role in preventing inappropriate T cell responses or in the termination of immune reactions. A malfunction of fibroblasts could result in an imbalance between immune responses and self tolerance. Such a dysregulation can be observed in rheumatoid arthritis (RA) where pathogenic alterations in the function of synovial fibroblasts result in chronic inflammation and joint destruction. In this study, we directly compared the influence of normal dermal and synovial fibroblasts to that of RA synovial fibroblasts (RASF) on T lymphocyte activation and proliferation and on the differentiation, maturation and T cell stimulatory capacity of dendritic cells (DC) in vitro. Methods. Dermal fibroblasts were isolated from skin of healthy donors, synovial fibroblasts from synovectomy tissue of patients with osteoarthritis (OA) or RA. CD4+ T cells were stimulated in the presence or absence of fibroblasts, their proliferation was measured by 3H-Thymidine incorporation, the cytokine secretion was quantified by ELISA. Differentiation of monocytes into DCs was induced in presence or absence of fibroblasts, their phenotype was analysed cytometrically. The T cell stimulatory capacity of DCs was determined in mixed lymphocyte reactions. Results. All fibroblasts prevented the differentiation of monocytes into classical DCs, moreover fibroblast-modulated DCs showed a lower T cell stimulatory capacity. In addition, normal fibroblasts were highly effective in suppressing the proliferation of activated T lymphocytes and in reducing the secretion of T cell effector cytokines such as interferon gamma (IFN-γ) or tumor necrosis factor alpha (TNF-α). Interestingly, RASF had a completely different effect on stimulated T cells. They seem to have lost the capability to inhibit the proliferation and cytokine secretion of activated T cells. Remarkably, in contrast to control fibroblasts, RASF even stimulated T cells to secrete proinflammatory cytokines like IFN-γ and Interleukin-17A. Conclusions. Fibroblasts negatively regulate T cell responses, but these tolerogenic properties are partially lost in RASF. This defect may play a central role in the pathogenesis of RA. So far, treatments with biologics, including anti-TNF-γ, are often unable to achieve permanent remission. This might be due to the fact that such therapies aim to treat the inflammatory processes by suppressing overreacting immune responses, rather than by resolving the problem of a lack of tolerogenic capacities of the RASF.

T. Tretter, H.-M. Lorenz Division of Rheumatology, University Hospital Heidelberg Background. Maintenance of immune tolerance depends on regulatory mechanisms, among which regulatory T cells (Treg) are considered to be crucially important. Recent observations in mouse models for autoimmune diseases indicate that B cells are able to exert regulatory functions as well (Breg). However, there has been little evidence for human Breg and their potential role in controlling autoimmunity. Our group has recently generated human B cells with immunoregulatory properties in vitro from peripheral blood (PB) of healthy donors. Upon prestimulation via their B cell receptor (BCR) large, activated CD25+B cells (B25+), but not resting CD25-B cells (B25-), induced temporary CD4+T cell anergy and apoptosis. The inhibitory effects required direct T cell contact and sufficient amounts of IL-2. These results led us to rethink the so far pathogenic role of B cells in autoimmune disease, via their production of auto-antibodies and stimulation of self-reactive T cells. Our aim was to test the immunoregulatory capabilities of B cells from patients with systemic lupus erythematosus (SLE), as an autoimmune disease with characteristic B cell involvement. Since Treg defects are reported, at least in advanced stages of disease, it could be suspected that Breg might be affected, as well. Methods. Highly purified CD19+B cells and CD4+Th-cells were separated from PBMC of healthy donors (ND) and SLE patients by MACSsorting. B-cells were prestimulated with SAC (staphylococcus aureus cowan I antigen) for 3d and sorted into highly activated FSChiCD25+ (B25+) and small resting FSCloCD25-(B25-)B-cells by FACSorting. Upon 4d coculture with Th-cells and γCD3+IL-2, T-cell proliferation was determined by 3H-TdR incorporation. Results. CD4+T cell proliferation was significantly less inhibited in cocultures with SLE-B25+ in contrast to cocultures with ND-B25+ (58% vs 35% of T cells cultured alone, p<0.01). This effect was independent from T cell origin: in cross-over experiments ND-T cell proliferation decreased below 50% of controls in 18 of 20 cases (90%) in coculture with NDB25+, but only in 10 of 20 cases in coculture with SLE-B25+. A similar pattern was found when SLE-T cells instead of ND-T cells were cocultured with ND-B25+ vs SLE-B25+. No effect on T cell pro-

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5.3 Fibroblasts as negative regulators of inflammation: implications for the pathogenesis of rheumatoid arthritis? L.-O. Tykocinski, A. Bohnen, S. Krienke, H.-M. Lorenz Department of Medicine V, Rheumatology Section, University of Heidelberg, Heidelberg

Authors A Adamczyk, A. Alborz, P. Althoff, C. André M.C. Augustin, M.

H 3.4 1.11 3.2 4.3 1.1

B Baraliakos, X. Becker, H. Behrens, F. Bellutti, M. Böckelmann, R. Bohnen, A. Bonnekoh, B. Böttcher, S. Braun, J. Bruhne, C.

1.4; 3.3 1.9 1.5 1.3 1.3 5.3 1.3 1.7 1.4; 3.3 4.1

D Denfeld, R. Dressler, F.

3.4 1.8

E Ehlers, S. Ehrchen, J. Eisfelder, M.

4.5 1.10 3.4

F Fellas, A. Fierlbeck, G. Frommer, K. Freundlich, B.

Haibel, H. Hartwig, U.F. Hemmerling, J. Henes, JC. Hermann, KG. Herr, W. Horger, M. Horng, A. Humrich, J.

3.2 4.3 4.3 3.4 3.2 4.3 3.4 2.1 1.2

J

4.5 4.6 1.6

Theisen, D. Theobald, M. Thon, A. Tretter, T. Tycocinski, L.-O.

2.2 3.4

U

O Oleszowsky, M. Oster, N.

P

Jäck, H.-M. Jacob, F. Jacobi, A.

4.4 3.4 1.9

K Kanz, L. Karakostas, P. Karpitschka, M. Kay, K. Kellner, H. Kiltz, U. Kleinhans, M. Knaudt, B. Koetter, I. Konnerth, D. Krienke, S. Kruglov, A. Kurtz, B.

3.4 1.4 2.1 1.7 2.1 1.4; 3.3 3.4 3.4 3.4 3.1 5.3 4.5 2.4

Langer, H.-E. Listing, J. Lorenz, H.-M. Lux, J.

Pavenstädt, H. Pfeiffer, C. Philipp, A. Poddubnyy, D. Pohl, C.

Q Quach, T.

1.8

R Radtke, M. Reiser, J. Riemekasten, G. Rosenbaum, D. Rubbert-Roth, A. Rudwaleit, M.

2.4 3.2 5.2; 5.3 3.4

Marx, J. Mei, H. Meyer, RG. Meyer-Bahlburg, A. Müller-Ladner, U. Münck, N.-A.

1.9 4.2 4.3 1.8 1.6 1.10

Sadeghlar, F. Schopf, RE. Schott, P. Schotte, H. Schröder, J.O. Schwenke, C. Seidel, MF. Seriot, L. Sieper, J. Song, IH. Spira, D. Steigleder, C. Sunderkötter, S.

2.1 4.3 1.8 5.2 5.3

1.2

V 1.9 3.1 3.4 3.2 1.11

1.1 1.2 1.2 1.9 5.1 3.2

S

M 1.9 1.6 1.8 2.1 1.3

Nedospasov, S. Neeck, G. Neumann, E.

T

Undeutsch, R.

L 1.3 3.4 1.6 3.2

G Gaubitz, M. Gay, S. Gläsener, S. Glaser, C. Gollnick, H.

N

von Laffert, M. von Stebut, E.

4.1 4.3

W Wagner, E.M. Walter, K. Wassenberg, S. Weckbach, S. Wegner-Kops, J. Weigert, O. Weiß, A. Werner, S. Willeke, P. Willinek, W. Winter, C. Wittmann, J. Wohlrab, J. Wolff, D.

4.3 4.5 2.3 2.1 4.3 1.2 3.2 2.4 1.9 2.2 1.9 4.4 4.1 4.3

Z 2.2 4.3 2.4 1.9 1.7 2.4 2.2 1.2 3.2 3.2 3.4 3.4 1.10

Zeuner, R.A. Ziegler, P. Ziupa, E.M.

1.7 3.4 3.4

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Product information Enbrel® 25 mg Pulver u. Lösungsmittel zur Herstellung einer Injektionslösung Enbrel® 25 mg/50 mg Injektionslösung in Fertigspritze Enbrel® 50 mg Injektionslösung im Fertigpen (MYCLIC) Enbrel® 25 mg / ml Pulver u. Lösungsmittel zur Herstellung einer Injektionslösung zur Anw. bei Kindern u. Jugendl. Zusammensetzung: Enbrel 25 mg Durchstechflasche: 1 Durchstechfl. m. Pulver enth. 25 mg Etanercept. Sonst. Bestandteile Pulver: Mannitol, Sucrose, Trometamol. 1 Fertigspritze m. Lösungsmittel enth. Wasser f. Injektionszwecke. - Enbrel 25 mg/50 mg Fertigspritze: 1 Fertigspritze enth. 25 mg bzw. 50 mg Etanercept. Sonst. Bestandteile: Sucrose, Natriumchlorid, Argininhydrochlorid, Natriumdihydrogenphosphat-Dihydrat, Natriummonohydrogenphosphat-Dihydrat, Wasser f. Injektionszwecke. – Enbrel 50 mg Fertigpen (MYCLIC): 1 Fertigpen enth. 50 mg Etanercept. Sonst. Bestandteile: Sucrose, Natriumchlorid, Argininhydrochlorid, Natriumdihydrogenphosphat-Dihydrat, Natriummonohydrogenphosphat-Dihydrat, Wasser f. Injektionszwecke. – Enbrel 25 mg/ml f. Kdr. u. Jugendl.: 1 Durchstechfl. m. Pulver enth. 25 mg Etanercept. Gebrauchsfertige Lösung enth. 25 mg Etanercept pro ml f. max. zwei Dosen. Sonst. Bestandteile Pulver: Mannitol, Sucrose, Trometamol. 1 Fertigspritze m. Lösungsmittel enth. Wasser f. Injektionszwecke u. Benzylalkohol. Anwendungsgebiete: Enbrel 25 mg u. 50 mg: Rheumatoide Arthritis: Enbrel ist in Komb. m. Methotrexat (MTX) zur Behandl. d. mittelschweren bis schweren aktiven rheumatoiden Arthritis (RA) bei Erw. indiziert, wenn Ansprechen auf Basistherapeutika (einschl. MTX - sofern nicht kontraind.) unzureichend ist. Enbrel kann im Falle einer Unverträglichk. gegenüber MTX od. wenn eine Forts. d. Behandl. m. MTX nicht mögl. ist, als Monother. angewendet werden. Behandl. der schweren, aktiven u. progressiven rheumatoiden Arthritis bei Erw., die zuvor nicht m. MTX behandelt worden sind. Enbrel reduziert als Monother. od. in Komb. m. MTX d. Fortschreiten d. radiolog. nachweisbaren strukturellen Gelenkschädig. u. verbessert d. körperl. Funktionsfähigk. Psoriasis-Arthritis (Arthritis psoriatica): Behandl. d. aktiven u. progressiven Psoriasis-Arthritis bei Erw., wenn Ansprechen auf vorhergehende Basisther. unzureichend ist. Enbrel verbessert d. körperl. Funktionsfähigk. bei Pat. m. Psoriasis-Arthritis u. reduziert d. Fortschreiten d. radiolog. nachweisbaren strukturellen Schädig. peripherer Gelenke b. Pat. m. polyartikulären symmetrischen Subtypen d. Erkrank. Morbus Bechterew (Spondylitis ankylosans): Behandl. d. schweren aktiven Morbus Bechterew bei Erw., die unzureichend auf konventionelle Behandl. angesprochen haben. Plaque-Psoriasis: Behandl. Erwachsener m. mittelschwerer bis schwerer Plaque-Psoriasis, die auf eine andere syst. Ther. wie Ciclosporin, MTX od. Psoralen u. UVA-Licht (PUVA) nicht angesprochen haben od. bei denen eine Kontraind. od. Unverträglichk. einer solchen Ther. vorliegt. Enbrel 25 mg/ml u. zusätzl. f. Enbrel 25 mg u. 50 mg: Plaque-Psoriasis bei Kindern u. Jugendl.: Behandl. d. chron. schweren Plaque-Psoriasis bei Kindern u. Jugendl. ab 6 J., die unzureichend auf eine and. system. Ther. od. Lichtther. angesprochen haben od. sie nicht vertragen. Zusätzl. f. Enbrel 25 mg u. Enbrel 25 mg/ml: Polyartikuläre juvenile idiopathische Arthritis (pJIA): Behandl. d. aktiven pJIA bei Kindern u. Jugendl. ab 2 J., die unzureichend auf MTX-Behandl. angesprochen haben od. MTX-Behandl. nicht vertragen. Gegenanzeigen: Überempfindlichk. gegen den Wirkstoff od. einen d. sonst. Bestandteile. Nicht anw. bei Sepsis od. Risiko einer Sepsis (cave: mögl. Erhöhung d. Mortalität bei bestehender Sepsis). Ther.-Beginn nicht bei aktiven Infekt., einschl. chron. od. lokalisierter Infekt. od. bei Pat. m. aktiver Tuberkulose. Pat. m. inaktiver Tuberkulose nur nach entspr. Anti-Tuberkulose-Ther. u. sehr sorgf. Nutzen/Risiko-Abwägung. HBV-Überträger u. Pat. m. bes. HBV-Infekt.-Risiko überprüfen, ggf. Enbrel-Anw. erst nach Anti-HBV-Ther.; Zusätzl. f. Enbrel 25 mg/ml: Keine Anw. bei Frühod. Neugeborenen, weil das Lsg.-mittel Benzylalkohol enthält. Warnhinweise und Vorsichtsmaßnahmen: Pat. vor, währ. u. nach Enbrel-Behandl. auf Infekt. hin untersuchen. Vorsicht walten lassen bei Pat. m. wiederkehrenden od. chron. Infekt. i. d. Vorgeschichte od. m. Begleiterkrank., die Infekt. begünstigen können (z. B. fortgeschrittener oder schlecht eingestellter Diabetes), sowie bei neuentwickelten Infekt. Unter Anw. v. Enbrel wurden schwerw. Infekt., Sepsis, Tuberkulose (Tb) u. opportunistische Infekt., einschl. invasiver Pilzinfekt beobachtet (in einigen Fällen m. Todesfolge durch Nichterkennung u. verzögerte Behandl.). Pat.-Risiko für relevante opportunist. Infekt. berücksichtigen. Ther.-abbruch bei Entwickl. v. schwerer Infekt., sowie bei Auftreten schwerw. allerg. od. anaphylakt. Reakt. Vor Behandlungsbeginn alle Pat. auf aktive u. inaktive (latente) Tb hin untersuchen. Pat. anweisen, bei Tb-Sympt. ärztl. Rat einzuholen. Reaktivierung d. Hepatitis-B-Virus (HBV) wurde v. Pat. berichtet, die chron. Träger dieses Virus sind u. TNFAntagonisten, einschl. Enbrel, erhalten haben. Besondere Vors. bei Pat. m. Blutdyskrasie in d. Anamnese, bei Auftreten v. Sympt. eindringl. Abklärung; bei nachweisl. Blutdyskrasie Enbrel absetzen. Bei starker Exposition gegenüber Varizella-Viren Behandl. vorübergehend abbrechen, ggf. Prophylaxe m. Varizella-zoster-Immunglobulinen. Regelm. Hautuntersuch. empf., da unter Behandl. m. TNF-Antagonisten, einschl. Enbrel, über Melanome und nicht-melanozytären Hautkrebs (NMSC) berichtet wurde. Besondere Vors. bei Pat. m. Herzinsuffizienz; Pat. m. Hepatitis C i.d. Anamnese wg. mögl. Verschlecht.; Enbrel nicht zur Behandl. v. Alkohol-Hepatitis anw.; Vorsicht b. Pat., die auch an mittelschw. bis schwerer Alkohol-Hepatitis leiden. Komb. Anw. v. Enbrel m. Anakinra oder Abatacept sowie Anw. v. Enbrel bei Wegener´schen Granu-

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Zeitschrift für Rheumatologie Suppl 1 · 2012

lomatose wird nicht empf..; bei gleichz. medikamentöser Diabetes-Behandl. Fälle v. Hypoglykämie (ggf. Dosisred. v. Antidiabetika notw.); Vorsicht b. älteren Pat., insb. auf mögl. Infekt. achten. Keine gesicherten Erkenntnisse über Langzeitsicherheit v. Enbrel bei gleichzeitiger Gabe m. anderen antirheumatischen Basistherapeutika (DMARD). Anw. in Schwangerschaft u. Stillzeit nicht empf. Mögl. Risiko f. die Entwickl. v. Lymphomen, Leukämie od. and. hämatopoetischen malignen Erkrank. od. soliden Tumoren kann derzeit bei Ther. m. TNF-Antagonisten nicht ausgeschlossen werden; deshalb Behandl. abwägen bei Pat. m. maligner Erkrankung i.d. Anamnese od. Entwickl. v. maligner Erkrank.; Sicherheit u. Wirksamk. v. Enbrel bei Pat. m. Immunsuppression od. chron. Infekt. wurden bisher nicht untersucht. Lebendimpfstoffe sollten nicht gleichzeitig verabreicht werden. Sorgf. NutzenRisiko-Analyse, einschl. neurolog. Untersuchung, bei bestehender od. jüngst neu aufgetretener Entmarkungskrankheit od. evtl. erhöhtem Risiko f. Entwickl. einer Entmarkungskrankheit. Anw. v. Enbrel in Komb. m. anderen syst. Ther. od. Lichtther. zur Behandl. v. Psoriasis wurde nicht untersucht. Nur für Enbrel 25 mg / 50 mg Fertigspritze u. Enbrel 50 mg Fertigpen: Kanülenkappe d. Fertigspritze bzw. d. Fertigpens enth. Latex (Trockenkautschuk), das Überempfindlichkeitsreakt. verursachen kann. Nur für Enbrel 25 mg/ml: Enbrel enth. als sonst. Bestandteil Benzylalkohol, der bei Säugl. u. Kindern bis zum 3. Lebensj. tox. u. anaphylakt. Reakt. hervorrufen kann. Enbrel nicht bei Früh- od. Neugeborenen anw. Nebenwirkungen: Basierend auf Beobachtungen aus klin. Studien bei Erw. u. Berichten n. Markteinf.: Sehr häufig: Reakt. an d. Inj.-stelle, ggf. passagere „Recall“-Reakt. an d. Inj.-stelle, Infekt. (einschl. Infekt. d. oberen Atemwege, Bronchitis, Zystitis, Hautinfekt.). Häufig: Allerg. Reakt., Fieber, Bildung v. Autoantikörpern, Pruritus. Gelegentl.: Schwere Infekt. (einschl. Pneumonie, Erysipel, sept. Arthritis, Sepsis), nicht-melanozytärer Hautkrebs, Thrombozytopenie, systemische Vaskulitis, Uveitis, interstitielle Lungenerkrankung (einschl. pulmonale Fibrose u. Pneumonitis, z.T. letal), Angioödem, Urtikaria, Hautausschlag, psoriasisartiger Hautausschlag, Psoriasis (einschl. Erstmanifestationen od. Verschlecht. u. pustulöse Formen, primär Handflächen u. Fußsohlen). Selten: Tuberkulose (inkl. Miliartuberkulose u. extrapulmonärer Tuberkulose), opportunist. Infekt. (einschl. invasive Pilz-, Protozoen-, Bakterien-, u. atypische Mycobakterien-Infekt.), Lymphom, Melanom, Anämie, Leukozytopenie, Neutropenie, Panzytopenie, schwere allerg./anaphylakt. Reakt. (einschl. Angioödem, Bronchospasmus), Sarkoidose, Anfälle, ZNS-entmyelinisierende Ereign. m. Verdacht auf multiple Sklerose od. lokalisierte entmyelinisierende Zustände wie Neuritis nervi optici u. Querschnittsmyelitis; Verschlecht. v. Herzinsuff., erhöhte Leberenzyme, autoimmune Hepatitis, kutane Vaskulitis (einschl. leukozytoklastische Vaskulitis), Stevens-Johnson-Syndrom, Erythema multiforme, subakuter, kutaner od. diskoider Lupus erythematodes, Lupus-ähnl. Syndrom, entmyelinisierende Erkrank. d. ZNS. Sehr selten: Aplastische Anämie, toxische epidermale Nekrolyse, periphere demyelinisierende Ereignisse (einschl. Guillain-Barré-Syndr., chron.-entzündl. demyelinisierende Polyneuropathie, demyelinisierende Polyneuropathie u. multifokale motorische Neuropathie). Häufigkeit nicht bekannt: Leukämie, Merkelzell-Karzinom, Makrophagen-Aktivierungs-Syndrom. In Studien zur RA m. (Dauer bis zu 48 Mon.) wurden schwerw. Infekt. beobachtet einschl.: Abszess, Bakteriämie, Bronchitis, Bursitis, Erysipel, Cholezystitis, Diarrhoe, Divertikulitis, Endokarditis (vermutet), Gastroenteritis, Hepatitis B (Reaktivierung b. chron. HBV-Trägern), Herpes zoster, Unterschenkelgeschwür, Mundinfekt., Osteomyelitis, Otitis, Peritonitis, Pneumonie, Pyelonephritis, Sepsis, septische Arthritis, Sinusitis, Hautinfekt., Hautgeschwür, Harnwegsinfekt., Vaskulitis, Wundinfekt.; Nach Markteinf. wurde über versch. Malignome (einschl. Brust- u. Lungenkarzinom sowie Lymphom) berichtet. Bei Komb. v. Enbrel m. MTX (Studie): Raten d. schwerw. Infekt. waren gegenüber d. Monother. ähnl., jedoch ist ein Anstieg d. Infektionsrate bei Kombi-Therapie mögl. In Studien zur Plaque-Psoriasis: Schwere Infekt. wie Erysipel, Gastroenteritis, Pneumonie, Cholezystitis, Osteomyelitis, Gastritis, Appendizitis, Streptokokken-Fasziitis, Myositis, sept. Schock, Divertikulitis u. Abszess. Bei gleichz. Anw. v. Enbrel u. Anakinra wurde bei erw. Pat. ein erhöhtes Risiko f. schwerw. Infekt. u. Neutropenie beobachtet. Nebenwirk. bei Kdrn. u. Jugendl.: Diese waren i. A. denen d. Erw. ähnl. Nebenwirk. bei Kdrn. u. Jugendl. m. pJIA: Häufiger als bei Erw. waren: Kopfschmerzen, Übelkeit, Erbrechen u. Unterleibsschmerzen. Es gab Berichte über chron.entzündl. Darmerkrank.; Schwerw. NW umfassten: Varizellen-Infektion m. Zeichen u. Sympt. v. aseptischer Meningitis (ohne Folgeschäden), Blinddarmentz., Gastroenteritis, Depression/Persönlichkeitsstör., Hautgeschwür, Ösophagitis, Gastritis, sept. Schock, Typ I Diabetes mellitus, Weichteilinfekt. u. postoperative Wundinfekt. Weitere Informationen siehe Fach- u. Gebrauchsinformation. Abgabestatus: Verschreibungspflichtig. Inhaber der Zulassung: Pfizer Limited, Ramsgate Road, Sandwich, Kent CT13 9 NJ, Vereinigtes Königreich. Repräsentant in Deutschland: PFIZER PHARMA GmbH, 10785 Berlin. Stand: August 2011

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