Search

Weichteilschwellungen im Bereich der Extremitaten bedurfen einer sicheren Differenzierung zwischen benignen und malignen Entitaten. Die Bandbreite potenzieller Ursachen reicht von benignen Weichgewebetumoren uber Weichteilsarkome bis hin zu Pseudotumoren. Aufgrund der niedrigen Inzidenz maligner Veranderungen und dem deutlichen Uberwiegen benigner Raumforderungen sowie der ausgesprochenen Heterogenitat aller Tumoren der Extremitaten bedarf es eines reproduzierbaren diagnostischen und therapeutischen Konzeptes bei der Behandlung. Im vorliegenden Case Report wird der Fall eines 59-jahrigen Patienten mit rheumatoider Arthritis vorgestellt. In der orthopadisch-rheumatologischen Sprechstunde demonstrierte dieser eine massive Schwellung ventral des rechten Kniegelenkes. Die Vorgeschichte ergab eine bereits 5‑jahrige langsame Grosenprogredienz der auffalligen Veranderung. In der Stufendiagnostik (Anamnese, klinische Untersuchung, Labordiagnostik, Sonografie, Rontgen, MRT mit KM) ergab sich kein Hinweis auf eine Malignitat, sodass eine vollstandige chirurgische Exstirpation unter Einhaltung der tumorchirurgischen Handlungsempfehlungen erfolgte. Histopathologisch wurde die Diagnose einer ausgedehnten Bursitis praepatellaris gesichert. Die extreme, solide Schwellung prapatellar legte zunachst den Verdacht auf ein malignes Geschehen nahe, das bereits praoperativ jedoch weitgehend ausgeschlossen werden konnte. Wir stellen die Ratio und das orthopadisch-rheumatologische Vorgehen fur die Adressierung unklarer Raumforderungen am muskuloskeletalen System beim „Rheumatiker“ vor. Bei den entzundlichen Systemerkrankungen konnen periartikulare Schwellungen differenzialdiagnostisch zuletzt auch benigne Ursachen, wie z. B. eine organisierte Bursitis, aufweisen.

Die rheumatoide Arthritis ist mit knapp 3,5 %iger Manifestationsrate in Deutschland eine recht haufige Erkrankung. Aufgrund des Befalls der unterschiedlichen Lokalisationen am Skelett und bei oft mannigfaltigen Komorbiditaten stellt die Versorgung dieser Patienten bei einem akuten Trauma potenziell ein erhebliches Risiko dar. Die antientzundliche medikamentose Therapie birgt im perioperativen Management der Betroffenen Gefahren, wie verzogerte Wundheilung und Infektionen. Im Notfall ist eine Modifikation der Basismedikation kaum moglich, sodass die postoperative Phase nach unfallchirurgischer Versorgung eine besondere Bedeutung erhalt. Gegebenenfalls sind orthopadische oder internistische Rheumatologen konsiliarisch zur Mitbetreuung hinzuzuziehen. Absolute und dringliche operative Interventionen stellen im Hinblick auf die antirheumatische Medikation keine Kontraindikation dar. Diese sollte aber bei der Beurteilung des perioperativen Risikoprofils Beachtung finden. Eine enge Kooperation mit der Anasthesie, die minutiose Kontrolle der intraoperativen Lagerung und das postoperative Management sind von besonderer Wichtigkeit.

Fusdeformitaten und Probleme mit der Schuhversorgung treten bei „Rheumatikern“ im zeitlichen Verlauf fast regelhaft auf. Dabei unterliegen die destruktiven Prozesse meist recht typischen Charakteristika. Als Vollbild resultiert zuletzt im Ruck- und Mittelfus ein Pes planovalgus, im Vorfus ein Hallux valgus, Spreizfus und Krallenzehen. Trotz der enormen Verbesserungen der medikamentosen Therapie in den letzten Jahren kann die Entwicklung einer rheumatischen Fusdeformitat durch konservative Masnahmen meist nicht verhindert bzw. bereits bestehende Deformitaten nicht dauerhaft korrigiert werden, sodass bei vielen Betroffenen im Verlauf eine oder sogar mehrere Operationen notwendig werden. Die Wahl eines Operationsverfahrens erfolgt stadienabhangig je nach Auspragung der Fehlstellung und Destruktion der Gelenkflachen resp. der Situation der benachbarten Artikulationen. Am Ruckfus sind haufig stabilisierende Arthrodesen notwendig. Am Vorfus konnen heute – auch dank der optimierten medikamentosen Therapiemoglichkeiten – vielfach gelenkerhaltende Osteotomien angeboten werden. In fortgeschrittenen Stadien kommen am 1. Strahl Arthrodesen oder eine endoprothetische Versorgung (Groszehengrundgelenk) zum Einsatz, an den Metatarsalia 2–5 haben nach wie vor Resektionsarthroplastiken ihren Stellenwert. Eine besondere Herausforderung bei Operationen am entzundlich destruierten Fus stellt das perioperative Management dar. Durch die polyartikulare Erkrankung, zahlreiche Komorbiditaten und die immunsuppressive Therapie bestehen Besonderheiten, die der spezialisierte orthopadisch-rheumatologische Fuschirurg zu beachten weis.

In soft tissue tumors of the extremities it is of utmost importance to differentiate between benign and malignant entities. The majority of the swellings vary from benign tissue changes through soft tissue sarcomas up to pseudotumors. Because of the low incidence of malignancy and the predominantly benign alterations together with a high heterogeneity, there is a need for a reproducible diagnostic and therapeutic concept for the treatment of all tumors of the extremities. This article reports the case of a 59-year-old patient with longstanding rheumatoid arthritis who presented to the orthopedic rheumatologic consultation with a massive swelling directly ventral to the knee joint. At that point the tumor had already grown very slowly for 5 years. The staged diagnostic process (patient history, clinical, laboratory tests, sonographic examinations, X‑ray, MRI with contrast medium) revealed no trace of malignancy whatsoever. The treatment then consisted of the complete surgical excision in accordance with the recommendations for tumor surgery. Histopathological findings confirmed the diagnosis of a massive prepatellar bursitis. Initially, the extreme and solid prepatellar swelling was suspected of being malignant; however, this could already be broadly excluded preoperatively. This article presents the rationale and the orthopedic rheumatologic approach for addressing unclear space-occupying lesions of the musculoskeletal system in patients with rheumatism. In the inflammatory systemic disease in the differential diagnosis periarticular swellings can ultimately also have benign causes, such as an organized bursitis.Weichteilschwellungen im Bereich der Extremitäten bedürfen einer sicheren Differenzierung zwischen benignen und malignen Entitäten. Die Bandbreite potenzieller Ursachen reicht von benignen Weichgewebetumoren über Weichteilsarkome bis hin zu Pseudotumoren. Aufgrund der niedrigen Inzidenz maligner Veränderungen und dem deutlichen Überwiegen benigner Raumforderungen sowie der ausgesprochenen Heterogenität aller Tumoren der Extremitäten bedarf es eines reproduzierbaren diagnostischen und therapeutischen Konzeptes bei der Behandlung. Im vorliegenden Case Report wird der Fall eines 59-jährigen Patienten mit rheumatoider Arthritis vorgestellt. In der orthopädisch-rheumatologischen Sprechstunde demonstrierte dieser eine massive Schwellung ventral des rechten Kniegelenkes. Die Vorgeschichte ergab eine bereits 5‑jährige langsame Größenprogredienz der auffälligen Veränderung. In der Stufendiagnostik (Anamnese, klinische Untersuchung, Labordiagnostik, Sonografie, Röntgen, MRT mit KM) ergab sich kein Hinweis auf eine Malignität, sodass eine vollständige chirurgische Exstirpation unter Einhaltung der tumorchirurgischen Handlungsempfehlungen erfolgte. Histopathologisch wurde die Diagnose einer ausgedehnten Bursitis praepatellaris gesichert. Die extreme, solide Schwellung präpatellar legte zunächst den Verdacht auf ein malignes Geschehen nahe, das bereits präoperativ jedoch weitgehend ausgeschlossen werden konnte. Wir stellen die Ratio und das orthopädisch-rheumatologische Vorgehen für die Adressierung unklarer Raumforderungen am muskuloskeletalen System beim „Rheumatiker“ vor. Bei den entzündlichen Systemerkrankungen können periartikuläre Schwellungen differenzialdiagnostisch zuletzt auch benigne Ursachen, wie z. B. eine organisierte Bursitis, aufweisen.

With an almost 3.5% manifestation rate in Germany, rheumatoid arthritis is a relatively frequent disease. Due to the involvement of diverse locations on the skeleton and often multiple comorbidities, treatment of these patients in cases of acute trauma potentially represents a substantial risk. The anti-inflammatory drug treatment harbors dangers, such as delayed wound healing and infections in the perioperative management of these patients. In an emergency a modification of the basic anti-inflammatory medication is hardly possible, so that the postoperative phase after trauma surgery is of special importance. If necessary, orthopedic or internist rheumatologists should be consulted for additional support. Absolute and urgent surgical interventions do not constitute a contraindication with respect to the antirheumatic medication but should be considered in the assessment of the perioperative risk profile. A close cooperation with anesthesia, the meticulous control of intraoperative positioning and postoperative management are of particular importance.

BackgroundIn rheumatoid arthritis (RA), osteoclasts are one of the most important mediators of bone erosion. In addition, RA synovial fibroblasts (RASF) have a major influence on joint erosion in RA. They affect osteoclast differentiation e.g. by increased RANKL production or secretion of other pro-osteoclastogenic factors such as IL-6. In addition to the pro-osteoclastogenic effect of soluble factors such as RANKL and IL-1, visfatin inhibits osteoclast differentiation. Furthermore, visfatin increases the secretion of pro-inflammatory factors by RASF, such as IL-6 or matrix degrading enzymes.ObjectivesIn this study, the effect of RASF with/without activation by visfatin and IL-1 on osteoclastogenesis was evaluated.MethodsBlood from healthy donors and RA patients was used for PBMC isolation. RANKL, TGF-β and hM-CSF were added to induce osteoclast differentiation. RASF-conditioned media (CM) were prepared from confluent RASF cultured for 48h. Differentiating PBMCs in monoculture were compared to PBMC cultured with CM from RASF (CM: 10%, 20%, 30%) as well as in direct co-culture with RASF with/without stimulation with IL-1 (0.05ng/ml), visfatin (25ng/ml). After two weeks in culture, cells were stained using TRAP staining. 3-5 images per well were used for quantification dependent on the variability of the wells. IL-6 was measured by ELISA in supernatants collected at day 14.ResultsIL-6 production increased by IL-1 (e.g. co-culture: 2,8-fold) and visfatin (CM-visfatin: 10%=4,3-fold, 20%=5,4-fold, 30%=4,2-fold; co-culture: 9,5-fold) compared to unstimulated control in all settings. In addition, IL-6 was increased with the addition of CM compared to unstimulated controls (healthy donors CM 30%: unstimulated p=0.0342, IL-1 p=0.0133, visfatin p=0,0133; RA: unstimulated p=0.0133, IL-1 p=0.0342, visfatin p=0.0133, n=3 each). Of note, baseline IL-6 concentrations were higher in PBMC from RA patients compared to healthy donors. Co-culture showed an additional increase in IL-6 levels in all settings (e.g. monoculture: IL-1 4.71±5.75pg/ml, visfatin 141.09±182.79pg/ml; co-culture: IL-1 7241±10398pg/ml, visfatin 24535±16994pg/ml;). During osteoclast differentiation, addition of CM showed similar osteoclastogenesis with similar proportion of osteoclasts with 2 and 3-5 vs. higher numbers of nuclei per cell compared to control. In coculture with RASF osteoclasts showed a stronger TRAP signal compared to monoculture especially for unstimulated and IL-1 stimulated co-cultures.ConclusionBoth, in monoculture with CM and in coculture, IL-6 levels were increased compared to control, whereas in RA patients the IL-6 levels were higher compared to healthy donors. The CM containing secreted factors of RASF did not have a prominent influence on osteoclastogenesis. However, the presence of RASF increased the TRAP signal showing an increased activity of differentiated osteoclasts especially in unstimulated and IL-1 stimulated co-cultures but not with addition of visfatin.ReferencesNone.Disclosure of InterestsNone declared.

Rheumatic diseases usually progress towards morphological and functional deficits and thus cause impairment of physical health and function. Based on this fact, physiotherapeutic options are elementary and indispensable. This article focuses on the significance and importance of physiotherapy in inflammatory and degenerative rheumatic diseases. Furthermore, an overview is presented on the consequences of rheumatic diseases, the reality of supply of physiotherapy, the principles and therapeutic options, and the evidence.

Background:Activin A and follistatin belong to an anti-inflammatory auto-regulatory cycle. Patients with rheumatoid arthritis (RA) have increased activin A levels in the synovial fluid and tissue. During inflammation, activin A is released systemically, then inducing its antagonist follistatin. This negative feedback is active in different cell types but not RA synovial fibroblasts (SF). Fibroblasts interact with endothelial cells in inflamed tissues inducing angiogenesis.Objectives:Evaluation of the role of activin A and follistatin on RASF and endothelial cell interactions.Methods:RA synovium was used for RASF isolation, HUVEC were commercially obtained. RASF and HUVEC were stimulated in mono- and coculture. Direct: RASF together with HUVEC; indirect: inserts with HUVEC separated by a membrane from RASF. Stimuli: activin A 15ng/ml, follistatin 500ng/ml, IL-1β 1ng/ml. Proliferation was analyzed by BrdU assay. RASF were Calcein-AM stained. Cells were transferred to 24-well plates after 18h stimulation. After adhesion for 1h, non-adherent cells were removed by shaking 3x for 5 min. Afterwards, fluorescent cells were quantified. For the flow-adhesion assay, HUVEC were cultured on rattail collagen coated capillary slides. HUVEC and RASF were stimulated for 4h with TNFα, TNFα+activin A or TNFα+follistatin. After stimulation, 2x10^6 RASF were resuspended in 20ml medium and sent through the capillaries. Two 1min videos were recorded (18.4ml/h, 30.5ml/h). Settings: TNFα-stimulated RASF on HUVEC stimulated wit TNFα or activin A+TNFα or follistatin+ TNFα. For migration assays, 2% FCS medium with 1x10^5 cells were placed in inserts (8µm membrane) into wells with 10% FCS (control: 2%FCS vs. 2%FCS) and stimulated with, IL-1, IL-1+activinA and IL-1+follistatin. After 16h, migrated cells were quantified. For scratch-assay 4x10^5 cells were cultured overnight, then cells were scratched and stimulated, afterwards 3 pictures per scratch were taken at start, after 10h and every 1.5h. Cells migrating into the scratch area were quantified.Results:IL-1 induced activin A in RASF and HUVEC in all settings. IL-1-induced activin A release was reduced by follistatin in HUVEC monoculture and both cocultures compared to IL-1 alone but not in RASF monoculture. IL-1-induced IL-6 release was reduced by activin A in HUVEC and indirect coculture but not in RASF monoculture and direct coculture. Follistatin did not alter IL-6 responses. IL-1 induced VEGF in RASF but not in HUVEC and was not altered by activin A. Short-term adhesion showed no significant influence of activin A or follistatin (n=4). Flow adhesion assay showed reduced adherence/rolling of RASF on HUVEC stimulated with TNFα and activin A (n=4). Migration assays showed that IL-1 decreased migration but without significant difference between the induced effects mediated by IL-1+activinA and IL-1+follistatin (n=4). Scratch assay showed increased migration in dicrect coculture with greater difference between stimulated and unstimulated cells in RASF monoculture and indirect coculture (n=4). Proliferation was not altered by activin A or follistatin.Conclusion:In direct and indirect coculture of HUVEC with RASF the effect on HUVEC was dominant leading to reduced IL-1-induced activin A release. However, the IL-1-induced IL-6 release in RASF or HUVECs was decreased by activin A in HUVEC monoculture and indirect coculture but not during cell-contact between both cell types. The direct interaction of RASF with HUVEC seems to prevent the reducing activin A effect on IL-6 release in HUVECs. Activin A seems to not to have an impact on short-term cell adhesion but first observations show, that activin A alters selectin-mediated adhesion under flow conditions. The migration assay shows that IL-1-induced effects on cell migration were enhanced by activin A and follistatin. Migration assay shows that IL-1-induced decrease on migration more prominent in indirect coculture and RASF monoculture than in direct coculture although in gap migration in the scratch assay was highest in direct coculture.Disclosure of Interests:None declared

Background:One of the key mechanisms in the pathogenesis of rheumatoid arthritis (RA) is the interaction of macrophages and synovial fibroblasts during joint inflammation. Increased synergistic proinflammatory activity of both cell types leads to the release of high levels of proinflammatory cytokines, especially of interleukin-6 (IL-6), and of matrix degrading enzymes. If this mechanism is uncontrolled, progressive destruction of articular cartilage and bone will take place.In active disease, immediate anti-inflammatory treatment with glucocorticoids is usually replaced by disease-modifying anti-rheumatic drugs (DMARDS), especially by methotrexate (MTX) and biologics such as TNF-α- or IL-6-inhibitors. This led to great improvements in prognosis and outcome for RA patients. However, about 40% of patients experience no remission or suffer from side effects of medication. To optimize established substances and to develop new treatment strategies, it is necessary to understand the mechanisms underlying the limited therapeutic effects.Objectives:Evaluation of the effect of prednisolone, MTX, adalimumab, tocilizumab on IL-6 secretion by RA synovial fibroblasts (RASF) and macrophages.Methods:RA synovium was used for RASF isolation. Peripheral blood mononuclear cells (PBMCs) were isolated from blood of healthy donors and RA patients by using Ficoll© medium followed by density gradient centrifugation. Mononuclear cells were seeded on six well plates (6x10^6/well) and incubated for one week. Then they were stimulated with Interferon-у (20 ng/ml) and LPS (50 ng/ml) for 48h to initiate differentiation into proinflammatory M1 macrophages. The M1 macrophages were co-cultured with RASF (100.000/well) and different treatments added (prednisolone: 10, 25, 50, 75, 100 nM, 1 µM; adalimumab: 100, 500 µg/ml; tocilizumab: 1, 5 µg/ml; MTX: 0,5, 1, 5, 10, 100 nM, 1µM). After 24h culture supernatants were collected and IL-6- and TNFα-ELISAs were performed.Results:IL-6 concentrations of untreated controls were comparable, regardless whether M1 macrophages from healthy donors or RA-patients were used for co-culture. Prednisolone reduced co-culture-induced IL-6 up to 56% (pConclusion:Prednisolone and adalimumab clearly decrease but do not eliminate proinflammatory synergistic activity of RASF and M1 macrophages. These results confirm the clinical observation, that there is a large number of RA-patients that independent of anti-inflammatory treatment still suffer from low-level joint inflammation.The synergistic proinflammatory activity of M1 macrophages and RASF seems to be a complex and multifactorial mechanism that is difficult to eliminate by a single treatment substance. Since it is one of the key mechanisms in RA pathogenesis, there is a critical need to investigate how therapy effects could be optimized. This study confirmed RASFs as one of the leading effector cells of increased synergistic proinflammatory activity, thus underlining their promising role as a treatment target in rheumatoid arthritis.Disclosure of Interests:None declared

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

Career situation of first and presenting author Student for a master or a PhD. Introduction Osteoporosis (OP) is the most common age-related disorder characterized by bone loss and correlates with increased bone marrow adiposity due to a shift of osteogenic towards adipogenic differentiation of bone marrow mesenchymal stem cells (MSC). Therefore, bone marrow adipocytes are in direct contact with the altered bone matrix in OP. Adipose tissue is metabolically active. Therefore, adipocyte-derived factors such as adipokines might influence MSC differentiation. Objectives We analyzed the presence of adipokines (visfatin, resistin and leptin) in bone tissue and their effects on MSC differentiation under standard culture vs. spongiosa. Methods RNA and MSC were isolated from spongiosa of femoral heads of osteoarthritis patients after hip replacement surgery, or after osteoporotic femoral neck fracture. Adipogenic MSC differentiation was performed with/without adipokines and visfatin inhibitor Apo866 as well as SB203580 p38-MAPK inhibitor. For the transfer and differentiation of MSC on cancellous bone, bone fragments were purified and sterilized. Gene expression was evaluated by Realtime PCR. Protein production was analyzed by ELISA. Results Visfatin and leptin levels were increased in OP bone vs. non-osteoporotic OA bone, however, resistin was reduced. Visfatin induced the secretion of proinflammatory factors during adipogenesis in standard cell culture as well as on cancellous bone. Visfatin-induced cytokine release was markedly reduced during differentiation on spongiosa (e.g. 14d IL6, x-fold: standard culture 151±110, spong. 40±30, n=7). Significantly elevated MMP13 mRNA as well as protein expression induced by visfatin could be observed during adipogenesis in standard cell culture as well as on spongiosa, however visfatin-mediated MMP13 expression was reduced on cancellous bone (e.g. 21d, x-fold,: standard culture 81±89, spong. 13±21, n=7). The visfatin inhibitor Apo866 inhibited the visfatin-induced cytokine release. However, the MMP13 expression was not influenced during adipogenesis in culture (n=4). In contrast to Apo866, the p38-MAPK inhibitor did not reduce cytokine release during adipogenesis. Conclusions Visfatin and leptin levels were elevated in osteoporotic bone. Therefore, visfatin-mediated increase of MMPs and proinflammatory cytokines during adipogenic differentiation might influence bone turnover at the adipose tissue/bone interface. Our results support the idea that the extracellular matrix attenuates visfatin-mediated detrimental effects during adipogenesis. The observed visfatin-mediated effects most likely depend on different signaling pathways. Disclosure of Interest None declared.

Career situation of first and presenting author Student for a master or a PhD. Introduction Osteoarthritis (OA) and osteoporosis are destructive bone diseases causing chronic pain and leading to disability. Mesenchymal stromal cells (MSC) are essential to bone health and tissue repair. Adipokines such as visfatin alter the osteogenic potential of MSCs and contribute to the loss of bone homeostasis. Long non-coding RNA H19 is one of the first lncRNAs discovered and relevant for distinct processes, e.g. during embryonic growth and tumor formation. lncRNAs interact directly with DNA, RNA as well as proteins, modulating transcription, protein expression and protein function. H19 upregulation was shown in osteogenic differentiation of MSCs.1 H19 increases the osteogenic potential via TGFβ1 and Wnt/β-catenin pathways.2 3 Objectives To investigate the influence of visfatin on H19 expression during osteogenesis. Methods Human MSCs from healthy donors (hMSC) and primary human MSCs from osteoarthritis patients (phMSC) after knee replacement surgery were treated with differentiation medium to induce osteogenic differentiation (OD). Matrix mineralization (MM) was quantified after 21 days by Alizarin Red. H19 expression by realtime PCR and IL-6 production by ELISA were measured. Results lncRNA H19 was up-regulated during OD. Although the H19 upregulation was not altered by co-stimulation with resistin, leptin or TNFα, visfatin co-stimulation during OD down-regulated H19 expression up to 10-fold as compared to unstimulated MSCs. The effect was significant in phMSCs at two of three measured time points (day 7 p=0.03; day 14 p=0.002, n=3) and in hMSCs at day 14 (p=0.0003, n=4). Visfatin co-stimulation of MSCs in OD increased MM, as well as IL-6 levels. However, TNF did not alter H19 expression or increase MM. Conclusions Visfatin co-stimulation during osteogenesis down-regulated lncRNA H19 expression, indicating a loss of the growthpromoting effects of lncRNA H19 in affected areas of destructive bone disease. This regulatory effect was specific to visfatin and did not occur upon co-stimulation with other adipokines or inflammatory stimuli such as TNF supporting a TNF-independent effect of visfatin. References Wang, L. Differential expression of long noncoding ribonucleic acids during osteogenic differentiation of human bone marrow mesenchymal stem cells. Int. Orthop. 2015;39:1013–1019. Huang, Y. Long Noncoding RNA H19 Promotes Osteoblast Differentiation Via TGF-?1/Smad3/HDAC Signaling Pathway by Deriving miR-675. Stem Cells 2015;33:3481–3492. Liang, W.-C. H19 activates Wnt signaling and promotes osteoblast differentiation by functioning as a competing endogenous RNA. Sci. Rep. 2012;6:20121. Disclosure of Interest None declared.

Career situation of first and presenting author Post-doctoral fellow. Introduction Rheumatoid arthritis (RA) and psoriatic arthritis (PsA) are both rheumatic autoimmune diseases, which share a number of similarities but also display differences. For example, the anti-IL17A biologic secukinumab turned out to be more effective in PsA than in RA. The anti-TNF biologic adalimumab on the other hand is equally indicated for both diseases. Synovial fibroblasts (SF) are one of the key effector cell types in the pathophysiology of RA and PsA. Objectives We therefore investigated whether the effect of the two cytokines IL-17A and TNF-α as well as the effect of their corresponding biologics differs between RASF and PsASF, thus contributing to the difference seen in the therapeutic response. The effect of the IL-17A homolog IL-17F was also analyzed. Methods SF were isolated from patients with PsA or RA, each undergoing surgery. SF from RA and PsA patients were stimulated with recombinant IL-17A, IL-17F and TNF-α alone or with respective combinations. Dose-response curve analysis was performed with IL-17A. The biologics secukinumab and adalimumab were used to block the effects on the SF. As a measure of the proinflammatory response, secretion of the cytokine IL–6 was quantified using an immunoassay. Results RASF as well as PsASF responded to IL-17A (IL-17A: 13.7-fold vs 6.9–fold; n=3), while IL-17F alone caused no induction of IL-6 secretion in either SF type. However, when used in combination with TNF-α, both IL-17 isoforms, IL–17A and IL-17F, increased IL-6 secretion due to a strong synergistic effect with TNF-α. Surprisingly, these effects were notably stronger for RASF than for PsASF (IL-17A: 544-fold vs 127-fold, IL-17F: 54-fold vs 27-fold; n=3). However, adalimumab and secukinumab were similarly effective in abolishing the synergistic effect of IL-17A and TNF-α in RASF as well as PsASF. Conclusions SF appear not to contribute to the differences in the therapeutic effectiveness of the anti-IL17A biologic secukinumab as the response to IL-17A alone and IL-17A together with TNF–α is not stronger for PsASF than for RASF. Furthermore, secukinumab was similarly effective for both SF types. The data also suggest that in a proinflammatory milieu with increased TNF levels IL-17A as well as IL-17F play a role in the SF-mediated pathophysiology of PsA and, therefore, approaches targeting TNF are effective in both diseases. Acknowledgements Supported by an unrestricted educational grant from Celgene GmbH. Disclosure of Interest K. Frommer Grant/research support from: unrestricted educational grant from Celgene GmbH, S. Rehart: None declared, U. Muller-Ladner: None declared, E. Neumann: None declared.

Career situation of first and presenting author Post-doctoral fellow. Introduction Tofacitinib and baricitinib are the first approved Janus kinase inhibitors (JAKi) in Europe for treatment of rheumatoid arthritis (RA). Other JAKi differing in the inhibition profile of the four isoforms JAK1, JAK2, JAK3 and TYK2 are currently examined in clinical trials. Especially filgotinib, inhibiting mainly JAK1/2, and the panJAKi peficitinib are well tolerated up to doses causing Cmax values higher than 1 µM. However, less is known about the effect of JAKi in RA on synovial fibroblasts (RASF) activated by IL-1β. RASF contribute to the growing pannus and develop an aggressive cartilage-destructive phenotype. Objectives The aim of the study was to examine the effect of JAKi on activated RASF and further characterize the most effective inhibitor. Methods Isolated human RASF were pretreated with JAKi for 2 hour and then stimulated with IL-1β and JAKi with/without soluble IL-6 receptor (sIL-6R). IL-6 and MMP-3 were measured in supernatants by ELISA. Stimulation with oncostatin M served as control. The proliferation of RASF was detected using a BrdU-incorporation assay. The effect of peficitinib on RASF migration was investigated by cell culture inserts using a FCS gradient. For adhesion assays, RASF were treated with JAKi, detached and seeded in culture plates. Then, plates were extensively shaken and adherent RASF quantified by counting crystal violet stained cells. Cell viability, cytotoxicity and apoptosis were measured using commercially available assays. Results Addition of the sIL-6R caused an additional release of IL-6 in RASF treated with IL-1β compared to IL-1β alone. This release was fully blocked by tofacitinib at 0.5 and 1 µM (both p Conclusions JAKi suppress the inflammatory response induced by transsignaling of IL-6 in RASF. Peficitinib appears to be superior to other JAKi in suppressing the IL-1β induced response and the proliferation of activated RASF. Thus, patients suffering specifically from severe synovial proliferation could benefit from treatment with peficitinib. Disclosure of Interest None declared.

Career situation of first and presenting author Student for a master or a PhD. Introduction The autoregulatory cycle of activin A and its antagonist follistatin is well known in the hypothalamic-pituitary-gonadal axis, but activins also play an important role in autoimmune diseases, such as rheumatoid arthritis (RA). Due to inflammation, activin A is released, then inducing its antagonist follistatin. This negative feedback mechanism has been primarily described in hepatocytes, but is inactive in synovial fibroblasts from patients with rheumatoid arthritis (RASF). Synovial fibroblasts are mediators of cartilage destruction in RA. In inflamed synovium, there is an interaction of RASF with endothelial cells. Due to tissue hyperplasia and inflammation, neoangiogenesis, mediated in part by local fibroblasts, is increased in RA synovium. The effect of activin and follistatin on the interaction of RASF and endothelial cells is still unknown. Objectives This study focuses on the effect of the activin A and follistatin on the interaction of RASF and endothelial cells. Methods RASF were isolated from synovial tissue of patients with RA undergoing joint replacement surgery. Endothelial cells (HUVEC) were commercially obtained. RASF and HUVEC were stimulated in mono-, or coculture with activin A (15 ng/ml), follistatin (500 ng/ml) or IL-1β (1 ng/ml). After 18 hour the supernatants were collected and the concentrations of activin A, VEGF and IL-6 were measured by ELISA. Results IL-1β induced activin A release in RASF and HUVECs alone as well as in direct coculture. The stimulation with follistatin and IL-1β at the same time reduced the activin A concentration in HUVECs as well as in cocultures in comparison to stimulation with IL-1β alone (p With respect to HUVECs, a significant reduction (p The release of VEGF, which plays an important role in inflammation-induced neoangiogenesis, was induced in RASF with IL-1β (89%), activin A (55%), activin A and IL-1β (148%), follistatin and IL-1β (84%). In coculture with HUVECs, the induction was less pronounced as in monoculture (IL-1β (75%), activin A (22%), activin A and IL-1β (101%), follistatin and IL-1β (67%)). Conclusions The autoregulatory cycle of activin A and follistatin is active in HUVECs, but not in RASF. In direct coculture of HUVECs and RASF, the effects of HUVECs appear to overweigh resulting in a significant reduction of IL-1β in the presence of follistatin. Disclosure of Interest None declared.

Background:Long non-coding (lnc-)RNA are regulatory molecules transcribed from DNA similar to mRNA and interact directly with DNA, RNA and proteins. Some lncRNAs have been shown to contain micro (mi-)RNAs in their sequence that can be released by splicing and lead to active miRNA molecules, e.g. lncRNA H19 includes two miRNAs 675-3p and -5p in its sequence.Adipose tissue derived factors (adipokines) are involved in inflammation processes and osteoarthritis (OA) development. The proinflammatory adipokine visfatin has been shown to alter osteogenic differentiation (OD) of pluripotent mesenchymal stem cells (MSCs) and reduces elastic fiber expression, increases matrix mineralization and proinflammatory cytokine and chemokine production(1).Objectives:We evaluated a novel effect of visfatin on lncRNA H19 in MSCs during OD. The goal was to explore the kinetics of the visfatin effect during OD with regard to H19 regulation and to investigate H19 downstream mechanisms leading to the observed altered MSC differentiation and osteoblast activity.Methods:MSCs isolated from OA hip or knee bone (phMSC) and commercially obtained healthy human (h-)MSCs were differentiated towards osteoblasts with/without visfatin, resistin, leptin, TNF and Wnt/TGFβ1 pathway inhibitors. Supernatants were collected at days 2, 7, 9, 14 and 21 of OD, cell lysates at day 2, 7, 9, 14 and matrix mineralization assays conducted at day 21. H19 and miRNA expression was evaluated by real-time PCR after mi-/RNA isolation. IL-6 was analyzed by ELISA.Results:H19 was continuously upregulated in unstimulated controls as expected during OD but also when stimulated with other adipokines. In contrast, stimulation with visfatin significantly decreased H19 (day 2 to 14 of OD, hip-phMSCs: p = 0.0097, knee-phMSCs: p=0.0075, h-MSC: p = 0.044). Visfatin increased matrix mineralization and IL-6 production as expected (hMSC: p = 0.03, phMSC: p = 0.013)(1). TNF stimulation during OD did not lead to a downregulation of H19 nor increased matrix mineralization, thus showing that the effects were visfatin-dependent. H19s endogenous miRNA 675-5p was changed in parallel with H19, increased during control OD and significantly down-regulated by visfatin (e.g. day 14 p = 0.015). However, H19s endogenous miRNA 675-3p was inversely regulated, downregulated during control OD while visfatin stimulation attenuated this effect (e.g. day 14 p = 0.025). Altered Wnt-signaling and involvement of the TGFβ1 pathway could not be observed.Conclusion:H19 is upregulated during OD and may therefore play a regulatory role in the process of osteogenesis. Visfatin stimulation of MSCs during OD showed pro-inflammatory effects, increased matrix mineralization while reducing elastic fiber production(1). These effects were associated with a downregulation of H19, a specific visfatin effect not triggered by other adipokines or TNF. The H19 sequence includes two endogenous micro-RNAs 675-3p and 5p. We demonstrated miRNA 675-5p to be regulated in parallel to H19, whereas miRNA 675-3p was inversely regulated and increased continuously upon visfatin stimulation. Based on these results, we hypothesize that visfatin provides a specific stimulus for the splicing of miRNA 675-3p from H19, in turn leading to H19 reduction. miRNA 675-3p thus represents an effector mechanism of visfatin that contributes to the observed functional effects in differentiating MSCs.References:[1]Tsiklauri, L.et al.Visfatin alters the cytokine and matrix-degrading enzyme profile during osteogenic and adipogenic MSC differentiation.Osteoarthr. Cartil.26, 1225–1235 (2018).Disclosure of Interests:Dennis Küppers: None declared, Lali Tsiklauri: None declared, Marie Hülser: None declared, Klaus Frommer: None declared, Stefan Rehart: None declared, Caroline Ospelt Consultant of: Consultancy fees from Gilead Sciences., Ulf Müller-Ladner Speakers bureau: Biogen, Elena Neumann: None declared

Orthopaedic and traumatologic involvement in patients with rheumatic diseases require extensive knowledge of these immunologically impairing illnesses. This concerns both the handling of medication and conservative treatment. The destructive processes of the joints and the spine follow established pathways. Various operating procedures are helpful depending on the stage of articular destruction. The special features of the entire perioperative management of affected persons has to be observed. Soft tissue surgical interventions are followed by arthrodesis or arthroplasty in later courses of destruction. In Germany, the orthopaedic rheumatologist specializes in the conservative and surgical treatment of inflammatory systemic diseases. Audited centres for operative interventions of the German Society for Orthopaedic Rheumatology (DGORh) seem to be the best fit for this purpose.

Rheumatic diseases usually progress towards morphological and functional deficits and thus cause impairment of physical health and function. Based on this fact, physiotherapeutic options are elementary and indispensable. This article focuses on the significance and importance of physiotherapy in inflammatory and degenerative rheumatic diseases. Furthermore, an overview is presented on the consequences of rheumatic diseases, the reality of supply of physiotherapy, the principles and therapeutic options, and the evidence.

The management of acute pain is of utmost importance in the treatment regimen of orthopedic and trauma patients. Pain perception is different for each patient and has to be individually addressed. Especially in a postoperative setting often with a very dynamic course of pain, it is optimal that the pain management is adapted to the individual course of pain. In this situation it makes sense to apply patient-controlled systems. By combining different analgesic substance classes and non-pharmaceutical therapy in the sense of a multimodal concept, the mechanisms of action complement each other and side effects can be reduced. Patient satisfaction is higher when they are actively involved in the (medicinal) pain therapy and in the decision making. This is particularly important for patient-controlled analgesia (PCA). In addition to invasive catheter administration procedures, there are also modern approaches for oral individual self-administered opioid treatment.

Background Although rheumatoid arthritis (RA) and psoriatic arthritis (PsA) have several features in common, they also possess distinct differences. We hypothesised that RA and PsA synovial fibroblasts (SF), known key effector cells in the pathophysiology of inflammatory arthritis, differentially respond to various stimuli including adipokines and cytokines and that this may contribute to those differences. For example, IL-17 (also found in synovial tissue) is of particular therapeutic significance in PsA but not as effective in RA. Thus far, IL-17 in its isoform IL-17A has been the major therapeutic target in PsA but IL-17F also plays a role in the IL-23/IL-17 axis of inflammatory diseases. Objectives Therefore, we analysed the responses of SF from patients with PsA, RA or no rheumatic disease to IL-17A/F±TNF-α and the adipokines visfatin and resistin, which show strong expression in the synovium of inflammatory arthritis. Methods SF were isolated from patients with PsA, RA or non-rheumatic disease controls (N), each undergoing joint surgery. PsASF, RASF and NSF were stimulated with human recombinant IL-17A/F, TNF-α, visfatin, and resistin. A neutralising anti-IL-17A antibody was used to verify specificity of the IL-17A effects. Secretion of the proinflammatory cytokine IL-6 was used as the initial readout parameter and was quantified using a commercial immunoassay. Results Stimulation with visfatin caused a strong increase in IL-6 secretion in all SF types (n=3 each), while resistin had no effect. Differences in responses were not statistically significant between the SF types studied. IL-17A at concentrations found in serum or synovial fluid did not induce IL-6 secretion in any of the SF. Dose-response curve analysis showed that considerably higher concentrations of IL–17A, which may occur locally in tissue, are required for the induction of IL-6 secretion. An anti-IL–17A antibody abolished the effect, thus showing that the effect is specific for IL-17A. The effects of IL-17A and IL–17F on IL-6 secretion by PsASF could be strongly amplified by a co–stimulation with TNF-a (IL-17A: 5-fold vs 113-fold; IL-17F: 1.7-fold vs 39-fold; TNF-α alone: 12-fold). The effects were stronger for IL-17A than for IL–17F with or without TNF co–stimulation. No effect of IL–17F alone was observed on NSF (n=1). Conclusions SF from RA and PsA patients were not differentially affected by the adipokines visfatin and resistin or IL-17A when used at serum or synovial fluid concentrations suggesting inflammatory cells to be the primary target of anti-IL-17 therapy. In its use as a therapeutic target, the attribute of IL-17F affecting PsASF would potentially increase the beneficial effects. Acknowledgements This work was supported by an unrestricted educational grant from Celgene GmbH. Disclosure of Interest K. Frommer Grant/research support from: unrestricted educational grant from Celgene GmbH, S. Rehart: None declared, M. Sauerbier: None declared, U. Muller-Ladner: None declared, E. Neumann: None declared

Background With the approval of the Janus kinase inhibitors (JAKi) Tofacitinib and Baricitinib for the treatment of rheumatoid arthritis (RA) in the European Union (EU), the opportunities for a successful therapy were extended by a new substance class. Other JAKi like Peficitinib and Filgotinib are currently examined in clinical trials. Peficitinib is a pan-JAKi, whereas the other substances differ clearly in the capability to block the four members of the Janus kinase family. It is unclear, if the new substances offer an additional benefit in RA treatment in comparison to the approved JAKi. Objectives This study characterised the effect of the different JAKi on inflammatory response of activated fibroblast-like synoviocytes from patients with RA (RA-FLS). Methods RA-FLS were isolated from synovial tissue of patients with RA undergoing joint replacement surgery. The cells were pretreated for 2 hour with different concentrations of JAKi or vehicle control and then stimulated with IL1-β (10 or 20 ng/ml) or Oncostatin M (OSM, 100 ng/ml). After the indicated time (17–24 hour), the supernatants were collected and the concentrations of IL-6 and MMP-3 were measured by ELISA. An assay combining the measurement of cell viability, cytotoxicity and apoptosis was performed to exclude effects of JAKi caused by cell toxicity. Results To detect the most effective JAKi in blocking the inflammatory response induced by IL1-β, RA-FLS were first pretreated with different JAKi for 2 hour with concentrations of 1 µM and 10 µM and then additionally stimulated with IL1-β (20 ng/ml) for 18 hour. Even at the highest concentration of 10 µM Tofacitinib and Baricitinib did not change the IL-6 levels, whereas Peficitinib and Filgotinib reduced the IL-6 release at 10 µM. Tofacitinib and Baricitinib reduced the cytokine release if the RA-FLS were stimulated with OSM, a factor directly inducing the JAK-dependent IL-6-pathway (n=3). To obtain a dose-response curve for the clinically relevant range of concentrations between 0.01 µM and 5 µM, RA-FLS were pretreated with Filgotinib and Peficitinib for 2 hour and then stimulated with IL1-β (10 ng/ml) for 17 hour. In contrast to Filgotinib, Peficitinib at 5 µM caused a reduction of IL-6 levels of 66% compared to control with IL1-β (p The treatment with Peficitinib did not affect the viability, cytotoxicity or apoptosis of RA-FLS (n=3). Therefore, the effects of Peficitinib on the inflammatory response were not caused by cell death. Conclusions Peficitinib reduced the release of proinflammatory cytokines and of matrix metalloproteinases after activation of RA-FLS with IL1-β and appeared to be superior to Tofacitinib and Baricitinib in targeting the pro-inflammatory and matrix destructive properties of RA-FLS. Disclosure of Interest None declared

Ein Befall der Hand- und Fingergelenke im Verlauf von rheumatischen Erkrankungen ist sehr haufig. Mit fortschreitender Dauer kommt es zu typischen pathologischen Veranderungen und Fehlstellungen. Die orthetische Versorgung ist ein wichtiger Bestandteil der konservativen Therapie und der postoperativen Versorgung zur Sicherung von OP-Ergebnissen. Handorthesen konnen eingesetzt werden Man unterscheidet statische, die vorwiegend zur Lagerung, Funktionsverbesserung oder Achskorrektur eingesetzt werden, von dynamischen Orthesen, die vor allem postoperativ zur Verbesserung des Bewegungsbildes und der Pravention von Sehnenadhasionen eingesetzt werden.

Background Cross-talk between synovial fibroblasts (SF) and immune cells is suggested to play a crucial role in inflammation and chronification of rheumatoid arthritis (RA). The contribution of B cells in this process is poorly defined. Methods Here, primary B cells from healthy donors were polyclonally activated and cocultured with SF of non-synovitic origin from patients with osteoarthritis. Results In B–SF cocultures the concentrations of interleukin 6 (IL-6) and IL-8 increased manifold compared with single cultures even under physical separation and remained stable for several days after B-cell removal. Intracellular staining confirmed SF as key producers of IL-6 and IL-8, and B cells as main producers of tumour necrosis factor alpha (TNFα) and IL-1s. Blocking experiments with a combination of anti-TNFα-antibodies and rIL-1RA significantly reduced SF cytokine production by up to 90%, suggesting that B-cell-derived TNFα and IL-1s were crucial mediators of SF activation. Interestingly, B-cell cytokine production, CD25 expression and proliferation decreased in cocultures by at least 50%, demonstrating a negative regulatory loop towards the activated B cells. Inhibition of activin receptor-like kinase 5, a crucial component of the tumour growth factor s (TGFs) signalling pathway, partly restored B-cell proliferation, suggesting a contribution of SF-derived TGFs in B-cell suppression. Besides cytokines, B-cell-activated SF also upregulated secretion of matrix metalloproteases such as MMP-3, thereby acquiring potential tissue destructive properties. This was confirmed by their invasion into human cartilage in the severe combined immunodeficiency mouse fibroblast invasion model in vivo. Conclusions Interaction with activated B cells leads to conversion of non-arthritic SF into SF with a proinflammatory and aggressive RA-like phenotype, thereby suggesting a new, so far unrecognised role for B cells in RA pathogenesis.

Introduction Osteoporosis predominantly affects elderly people and is characterised by bone loss, increased fracture risk and reduced regeneration ability. Age-related bone loss correlates with increased bone marrow adiposity due to a shift of osteogenic towards adipogenic differentiation of bone marrow-derived mesenchymal stem cells (MSC). Adipose tissue is metabolically active. Through the release of adipokines with immunomodulatory properties adipose tissue might influence differentiation of bone marrow-derived MSC and contribute to bone loss in osteoporosis. Objectives Thus we analysed the presence of adipokines (visfatin, resistin and leptin) in the bone marrow cavity and their effects on MSC differentiation. Methods MSC and RNA were isolated out of spongiosa from femoral heads (hip replacement surgery of osteoarthritis patients (OA) or after osteoporotic femoral neck fracture (FF). Adipogenic as well as osteogenic MSC differentiation was performed with/without adipokines. For the transfer and differentiation of MSC on cancellous bone, cell-free bone fragments were prepared and sterilised. Proinflammatory factors were measured by immunoassays. Gene expression was evaluated by Realtime PCR. Matrix mineralization was assayed using Alizarin red S staining. Results While resistin was reduced, visfatin and leptin levels were increased in FF bone vs. non-osteoporotic OA bone (FF mean visfatin 7.77±1.86, n=11; OA 2.25±0.36, n=13, p=0.002). In contrast to leptin and resistin, visfatin induced the secretion of proinflammatory factors (IL-6, IL-8, MCP-1) during both, osteogenic and adipogenic differentiation, (e.g. adipogenic differentiation IL-6, 21d; control: 270.3±140.2 pg/ml; visfatin: 3,223±600.4 pg/ml, p=0.0006, n=12). In osteogenically differentiated cells matrix mineralization was significantly increased, while collagen type 1 expression was downregulated (d21: −4.2-fold/p=0.0001; n=7) after visfatin stimulation. The expression of MMP2, −13, TIMP1 and −2 (e.g. d21: −2.4-fold; −3.2-fold; −3.2-fold; −4.3 fold, respectively) was also reduced by visfatin during osteogenesis. Interestingly, visfatin significantly induced MMP13 expression (e.g. d21: 104-fold) during adipogenic differentiation under cell culture conditions. However, when differentiated on autologous cancellous bone, visfatin-induced MMP13 expression, as well as IL-6 and IL-8 release was markedly reduced (e.g. MMP13 21d: 13.8-fold, p=0.0156, n=7). Conclusions Taken together, visfatin expression was not only elevated in osteoporotic bone, it induced release of proinflammatory factors and dysregulated the MMP/TIMP balance during MSC-differentiation. Therefore visfatin might influence bone remodelling specifically at the bone/adipose tissue interface. The visfatin-mediated increase of matrix mineralization and the observed reduction of organic component of ECM – Coll.1, essential for the bone plasticity might contribute to bone fragility and therefore to the pathogenesis of osteoporosis. Disclosure of interest None declared

Introduction In 2017, the Janus kinase inhibitors (JAKi) Tofacitinib and Baricitinib were approved for the treatment of Rheumatoid arthritis (RA) in the European Union (EU) by the European Medicines Agency (EMA). Other JAKi like Peficitinib, Filgotinib and Upadacitinib are currently examined in clinical trials. The effect of these substances is mainly based on blocking the IL-6 pathway in immune cells.1 However the effect of the different JAKi on activated fibroblast-like synoviocytes from patients with RA (RA-FLS) is not well characterised. Objectives This study compared the effect of different JAKi on the pro-inflammatory response of activated RA-FLS. Methods RA-FLS were isolated from synovial tissue of patients with known RA undergoing joint replacement surgery. The cells were pretreated with different concentrations of JAKi or vehicle control and then stimulated with IL1-β (10 or 20 ng/ml) or Oncostatin M (OSM, 100 ng/ml). After the indicated time (17–24 hour), the supernatants were collected and the concentrations of IL-6 were measured by ELISA. An assay combining the measurement of cell viability, cytotoxicity and apoptosis was performed to exclude effects of JAKi caused by cell toxicity. Results In a pretest-setting, RA-FLS were pretreated with JAKi for 2 hour with concentrations of 1 µM and 10 µM and then stimulated with IL1-β (20 ng/ml) for 18 hour. At the concentration of 10 µM, Peficitinib, Filgotinib and Upadacitinib reduced the IL-6 release by RA-FLS, whereas Tofacitinib and Baricitinib did not change the IL-6-levels. Tofacitinib and Baricitinib at 1 and 5 µM only reduced the cytokine release if the IL-6 pathway was activated selectively with OSM (n=3). In further analyses, RA-FLS were again pretreated with Filgotinib and Peficitinib for 2 hour with clinically relevant concentrations (range between 0.01 µM and 5 µM) and then stimulated with IL1-β (10 ng/ml) for 17 hour. At the concentration of 5 µM, Peficitinib caused a reduction of IL-6 levels of 66% compared to control with IL1-β (p Conclusions Peficitinib reduced the inflammatory response of RA-FLS after activation with IL1-β and appeared to be superior to Tofacitinib and Baricitinib in targeting RA-FLS. The lack of effect of Tofacitinib and Baricitinib on RA-FLS activated by IL1-β could explain the treatment failure in some patients. Reference . Schwartz, et al. Type I/II cytokines, JAKs, and new strategies for treating autoimmune diseases. Nat Rev Rheumatol2016January;12(1):25–36. Disclosure of interest None declared

Summary Objectives Age-related bone loss is associated with bone marrow adiposity. Adipokines (e.g., visfatin, resistin, leptin) are adipocyte-derived factors with immunomodulatory properties and might influence differentiation of bone marrow-derived mesenchymal stem cells (MSC) in osteoarthritis (OA) and osteoporosis (OP). Thus, the presence of adipokines and MMPs in bone marrow and their effects on MSC differentiation were analyzed. Methods MSC and ribonucleic acid (RNA) were isolated from femoral heads after hip replacement surgery of OA or osteoporotic femoral neck fracture (FF) patients. Bone structural parameters were evaluated by microcomputed tomography (μCT). MSC were differentiated towards adipocytes or osteoblasts with/without adipokines. Gene expression (adipokines, bone marker genes, MMPs, TIMPs) and cytokine production was evaluated by realtime-polymerase chain reaction (realtime-PCR) and enzyme-linked immunosorbent assay (ELISA). Matrix mineralization was quantified using Alizarin red S staining. Results μCT showed an osteoporotic phenotype of FF compared to OA bone (reduced trabecular thickness and increased ratio of bone surface vs volume of solid bone). Visfatin and leptin were increased in FF vs OA. Visfatin induced the secretion of IL-6, IL-8, and MCP-1 during osteogenic and adipogenic differentiation. In contrast to resistin and leptin, visfatin increased MMP2 and MMP13 during adipogenesis. In osteogenically differentiated cells, MMPs and TIMPs were reduced by visfatin. Visfatin significantly increased matrix mineralization during osteogenesis, whereas collagen type I expression was reduced. Conclusion Visfatin-mediated increase of matrix mineralization and reduced collagen type I expression could contribute to bone fragility. Visfatin is involved in impaired bone remodeling at the adipose tissue/bone interface through induction of proinflammatory factors and dysregulated MMP/TIMP balance during MSC differentiation.

Background Preventing synovial fibroblasts (SF) from migrating into the adjacent cartilage is a desirable therapeutic target in rheumatoid arthritis (RA) in order to avoid joint destruction and disability. In our previous studies we could show that RASF as well as SF from osteoarthritis (OA) patients express all dopamine receptor (DR) subtypes and dopamine stimulation alters pro-inflammatory cytokines (Capellino S et al, A&R 2014). Objectives Therefore, we aimed to elucidate a potential dopamine-mediated impact on joint invasion and destruction in arthritis. Methods SF from RA and OA patients were obtained from patients undergoing knee joint replacement surgery (mean age: 74.3±11.3yrs at OA and 73.7±10.3 yrs at RA patients) to investigate dopamine receptor (DR)-distribution within the RA synovium and in the invasion zone, immunohistochemistry was performed for all five DR-subtypes. Migration and motility assays were performed under D1-like (D1DR and D5DR) and D2-like (D2DR, D3DR and D4DR) receptor stimulation. Dopamine effects on MMP3 and proMMP1 were evaluated using ELISA. Results D1DR, D4DR and D5DR were found to be stronger expressed close to the invasion zone and more cells were expressing the respective DR. Migration of RASF and OASF was significantly correlated with patients9 age at surgery: younger patients (≤75years) showed an increase in migration up to 78% whereas older patients (≥75years) showed a reduced migration of up to 50% (OA n=8; RA n=7). There was no difference between RA and OA patients and between D1-like and D2-like receptor stimulation. The same effect could be observed in the motility assay (OA n=5; RA n=6). MMP3 levels are altered under DR activation (OA n=6; RA n=6). Conclusions The high DR expression close to the invasion zone suggests a direct role of dopamine on RASF aggressiveness and may contribute to cartilage invasion. This was confirmed in the in vitro assays, and supports the idea of a therapeutic potential of the dopamine pathway in RA. Disclosure of Interest None declared

Background Various inflammatory cardiovascular and metabolic diseases such as atherosclerosis, coronary heart diseases and type 2 diabetes are associated with chronically elevated free fatty acid (FFA) levels. With inflammation being a factor in pathological bone loss, FFA may also be contributors to bone loss in osteoarthritis (OA) and/or rheumatoid arthritis (RA). Objectives To investigate whether FFA have an influence on osteoblasts and osteoclasts from patients with RA or OA, in a way that may alter bone degradation in these diseases. Methods Primary osteoblasts (OB) were isolated from cancellous bone of OA and RA patients undergoing knee joint surgery. Osteoclasts (OC) were differentiated from peripheral blood mononuclear cells (PBMC). OB and OC were stimulated with the saturated FFA palmitic acid (PA) and the unsaturated FFA linoleic acid (LA) (100 μM each). Immunoassays were used to quantify protein secretion. mRNA expression levels were quantified by real-time PCR. Mineralization activity was quantified using Alizarin Red S staining, differentiated OC were quantified by counting TRAP-positive multinuclear cells (>2 nuclei). Toll-like receptor (TLR) 4 and TLR2 were blocked by neutralizing antibodies. Results When stimulated with FFA, OB from RA and OA patients secreted higher amounts of the proinflammatory cytokine IL-6 (up to 9-fold) and the chemokines IL-8 (up to 221-fold), GRO-a (from below detection level to detectable levels) and MCP-1 (up to 16-fold). Differences in the degree of response were more dependent on the patient than the disease. RANKL as well as OPG, OB-secreted modulators of OC differentiation, as well as OB differentiation markers (e.g. osterix, osteocalcin) were not influenced by FFA on mRNA or protein level. The effect of FFA on mineralization activity of OB varied between patients, yet overall there was no significant difference between FFA-treated and untreated OB. Expression of the two Wnt signaling molecules, axin-2 and b-catenin, was not changed by PA or LA, suggesting no involvement of the Wnt signaling pathway in the effects observed by FFA in OB. On the other hand, TLR4 blockade significantly reduced PA-induced IL-8 secretion by OB (by 93%), while blocking TLR2 had no effect. In both RA and OA OC, IL-8 secretion was significantly enhanced by PA and LA, with a clear time-dependency within the differentiation process for RA OC but not for OA OC. The number of TRAP positive multinuclear cells decreased for RA OC by approx. 50%, which was in agreement with the reduced TRAP secretion by a factor of 2–3 at d14. mRNA expression of various osteoclast activity markers (CLCN7, CTSK, TCIRG) was not altered. Conclusions Inflammation is promoted by FFA via both OB and OC from patients with RA or OA, thus possibly indirectly contributing to bone loss while no direct effect on OB/OC activity could be observed. In OB, these effects are probably mainly mediated by TLR4, while TLR2 and Wnt pathways do not play a role. Disclosure of Interest None declared

Background Osteoporosis (OP) and osteoarthritis (OA) are two common age-related disorders leading to chronic pain and disability in elderly people. Age-related bone loss and articular cartilage damage are associated with increased bone marrow adiposity due to a possible shift of osteogenic differentiation towards adipogenic differentiation of bone marrow mesenchymal stem cells (MSC). The differentiation of MSC into adipocytes or osteoblasts is an important determinant of bone structural integrity. Adipose tissue is an metabolically active tissue. Therefore adipocyte-derived factors -adipokines- might influence differentiation of bone marrow-derived MSC. Objectives The role of fat-bone interactions in the pathogenesis of OP is poorly understood. Therefore, we analyzed the presence of distinct adipokines (visfatin, resistin and leptin) in the bone marrow cavity and their effects on MSC differentiation. Methods Spongiosa from femoral heads was collected (hip replacement surgery of OA patients or after osteoporotic femoral neck fracture). MSC were cultured in adipogenic and osteogenic media with/without adipokines. For the transfer and differentiation of MSC on cancellous bone, bone fragments were purified and sterilized. mRNA expression of adipokines, bone marker genes, TIMPs and MMPs of stimulated MSC and bone samples were evaluated by realtime PCR. Matrix mineralization was assayed using Alizarin red S staining. Proinflammatory factors were measured by ELISA. Results Visfatin and leptin levels were increased in OP bone vs. non-osteoporotic bone (n=14). In contrast to leptin and resistin, visfatin induced the secretion of proinflammatory factors (IL-6, IL-8, MCP-1) during both, osteogenic and adipogenic differentiation. Visfatin significantly increased the matrix mineralization and downregulated collagen type 1-expression (e.g. d21: -4.6-fold) in osteogenic differentiated cells. Visfatin also reduced the expression of MMP2, MMP13, RunX2, TIMP1 and TIMP2 (e.g. d21: -2.4-fold/-3.18-fold/-5.85-fold/-3.2-fold/-4.3 fold respectively) during osteogenic differentiation, but not leptin and resistin. In contrast to osteogenesis, visfatin significantly induced MMP13 expression (e.g. d21: 104-fold) during adipogenic differentiation under standard cell culture conditions. However, visfatin-induced MMP13-expression was markedly reduced during differentiation on purified autologous cancellous bone. Conclusions Visfatin and leptin levels were elevated in osteoporotic bone tissue. Therefore, the visfatin-mediated increase of matrix mineralization and reduction of collagen type 1 expression might lead to enhanced bone fragility and contribute to the pathogenesis of OP. Visfatin induced release of proinflammatory cytokines and dysregulated expression of MMPs and TIMPs during osteogenic and adipogenic MSC-differentiation might influence bone turnover specifically at the adipose tissue/bone interface. Disclosure of Interest None declared

Der Sport gewinnt in unserer Gesellschaft zunehmend an Bedeutung. Durch das veranderte Altersspektrum mit einer groseren Zahl an alteren und wesentlich aktiveren Menschen finden sich immer mehr sportlich interessierte Menschen mit orthopadischen Grunderkrankungen. Der vorliegende Artikel beschaftigt sich mit den Moglichkeiten und Auswirkungen von sportlicher Betatigung bei rheumatoider Arthritis im Rahmen der konservativen Therapie. Die Literaturrecherche erfolgte einerseits uber medizinische Suchmaschinen (im Besonderen PubMed-Recherche), andererseits aber auch uber die Empfehlungen der Fachgesellschaften und der Patientenhilfegruppen. Die Lebensqualitat des Patienten mit rheumatoider Arthritis setzt sich aus physischen, psychischen und sozialen Komponenten zusammen. Sport als Mittel der Rehabilitation nimmt auf alle diese Komponenten einen positiven Einfluss. Sport sollte als Therapie verstanden und den Bedurfnissen des Patienten individuell angepasst werden. Die Bereitschaft sich zu bewegen ist zu jedem Zeitpunkt hoch anzurechnen und zu fordern. Sport ist damit ein wichtiger Therapiepfeiler in einem konservativen Gesamtkonzept. Hauptaspekte der sporttherapeutischen Arbeit sind hierbei funktionelle, padagogische und erlebnisorientierte Aspekte. Klinisches Erscheinungsbild, Ausmas der Schadigung und die korperliche Beeintrachtigung mussen jedoch evaluiert und in das therapeutische Konzept eingebracht werden. Die Datenlage zu dem Themenkomplex Sport und rheumatoide Arthritis ist insgesamt gering und bezieht sich im Wesentlichen auf retrospektive Ubersichtsdaten. Eine prospektiv-randomisierte Studienbasis fehlt. Ziel muss es daher sein, die aktuell vorhandenen Empfehlungen zu verschiedenen Sportarten auch in kontrollierten Studien zu bestatigen.

Hintergrund Der perioperative Einsatz antirheumatischer Arzneimittel kann zu einem erhohten Infektionsrisiko und zu einer Wundheilungsstorung bis zum manifesten Infekt fuhren, andererseits kann eine Unterbrechung der antirheumatischen Therapie einen Krankheitsschub zur Folge haben. Beides kann, insbesondere in der Endoprothetik, den Operationserfolg gefahrden.

Rheumatische Krankheitsbilder bedingen aufgrund ihres progredienten Verlaufs oft Einschrankungen der funktionellen und funktionalen Gesundheit. Gerade hierdurch ergibt sich ein elementarer Ansatzpunkt fur den Einsatz physikalisch-therapeutischer Optionen im internistisch- wie auch orthopadisch-rheumatologischen Praxisalltag. Der vorliegende Artikel fokussiert auf den Stellenwert und die Bedeutung der konservativen Therapie mittels physikalischer Medizin beim Rheumatiker. Ferner wird ein Uberblick uber die Grundlagen und therapeutischen Moglichkeiten, Krankheitsfolgen, die Versorgungsrealitat und zur Evidenz einzelner Physiotherapeutika gegeben.

Involvement of tendons and tendon sheaths is frequently found in the most common inflammatory systemic diseases, rheumatoid arthritis and spondyloarthritis. In rheumatoid arthritis tendon manifestations occur as tenosynovitis, with swelling and pain of the tendons mainly on the hands and feet. In spondyloarthritis the involvement of tendons presents as enthesitis with pain and swelling directly at the attachment points of tendons to the bony structures and more commonly in the lower extremities. Pathological alterations of tendons can be normally visualized by sonography and only sometimes with magnetic resonance imaging (MRI) or scintigraphy. Furthermore, it is important for diagnostics and effective therapy to detect all joints involved by means of clinical, sonographic and radiological examination as well as laboratory parameters of inflammation, antibody serology (e.g. anti-CCP antibodies) and HLA-B27. The histopathological alterations of tendinopathy in rheumatic diseases differ from degenerative/posttraumatic tendinopathy in their expression of the changes; however, a clear differentiation of the different rheumatic inflammatory systemic diseases is histopathologically not possible. Therapeutically, systemic medication is the most important part of treatment in rheumatic diseases. Local therapeutic measures can be employed in the treatment of tenosynovitis and enthesitis. In the case of failure or lack of efficacy of the medication and conservative therapy, tenosynovectomy is performed for persistent tenosynovitis and reconstructive surgical procedures are necessary for tendon ruptures.

Objective Osteophyte formation in osteoarthritis (OA) is mediated by increased osteoblast activity, which is -in turn- regulated by the Wnt signaling pathway. Obesity is regarded a risk factor in OA, yet little is known about the interaction between adipose tissue-derived factors, the adipokines, and bone formation, although adipokines are associated with the pathogenesis of OA. Therefore, the effect of adipokines on bone and cartilage forming cells and osteophyte development was analyzed. Methods Human OA osteophytes were histologically characterized and adipokine expression was evaluated by immunohistochemistry. Osteoblasts and chondrocytes were isolated from OA tissue and stimulated with adiponectin, resistin, or visfatin. Cytokine and osteoblast/chondrocyte markers were quantified and activation of Wnt and p38 MAPK signaling was analyzed. Results Adiponectin, resistin, and visfatin were expressed in OA osteophytes by various articular cell types. Stimulation of OA osteoblasts with adiponectin and of OA chondrocytes with visfatin led to an increased release of proinflammatory mediators but not to osteoblast differentiation or activation. Additionally, visfatin increased matrix degrading factors in chondrocytes. Wnt signaling was not altered by adipokines, but adiponectin induced p38 MAPK signaling in osteoblasts. Conclusion Adipokines are present in OA osteophytes, and adiponectin and visfatin increase the release of proinflammatory mediators by osteoblasts and chondrocytes. The effects of adiponectin were mediated by p38 MAPK but not Wnt signaling in osteoblasts. Therefore, the results support the idea that adipokines do not directly influence osteophyte development but the proinflammatory conditions in OA.

The management of patients with spondyloarthritis (SpA) has experienced a paradigm shift in recent years. This is true for the treatment of axial as well as peripheral manifestations. International treat to target (T2T) recommendations for SpA based on the T2T strategy have now also been published, which contain 5 higher level principles (A-E) in addition to the 15 recommendations. In order to make the recommendations known and to promote national distribution, German experts have now issued a translation of the T2T recommendations for SpA into German.

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

Die häufigste Erkrankung des rheumatischen Formenkreises ist die rheumatoide Arthritis. Sie befällt überwiegend die Gelenke des Bewegungsapparats und führt dort zu schmerzhaften Gelenkschwellungen mit Funktionseinschränkungen und im Verlauf zu typischen Deformierungen und Destruktionen. Als entzündliche Systemerkrankung kann die rheumatoide Arthritis aber auch Sehnenscheiden, Schleimbeutel, Gefäße, Augen und die inneren Organe betreffen.Dieser Artikel ist mit der Diagnostik befasst und beschreibt die medikamentösen und die begleitenden konservativen Therapieoptionen der rheumatoiden Arthritis. Versagt dieser konservative Ansatz, kommen operative Therapiemaßnahmen zum Einsatz. Ein weiterer Artikel, der zu einem späteren Zeitpunkt erscheinen wird, stellt diese chirurgischen Therapiemöglichkeiten dar.

ZusammenfassungDer primäre und sekundäre Entzündungsprozess bei der rheumatoiden Arthritis und bei der Arthrose ist verantwortlich für die Symptomatik, die Progression und die therapeutischen Möglichkeiten bei beiden Erkrankungen. Bei der rheumatoiden Arthritis kann die Entzündung im Frühstadium durch eine suffiziente medikamentöse Therapie aufgehalten werden, bei der Arthrose wurden die Bemügungen um ein besseres Verständnis der pathophysiologischen Vorgänge der sekundären Entzündungsreaktion intensiviert, kurative Therapieansätze fehlen jedoch nach wie vor. Bei beiden Krankheitsentitäten können lokale Therapiemaßnahmen die entzündliche Symptomatik positiv beeinflussen.

In many cases rheumatoid arthritis leads to functional disturbances and deformities of the hip joint despite intensive conservative treatment. Joint replacement becomes necessary to preserve mobility and independence. The choice of implant and fixation system depends on the results of clinical and radiological examinations and the individual patient situation (e.g. age, bone quality, deformities of adjacent joints). The procedure, pre-operative and postoperative treatment, all require special expertise. If possible surgical procedures should be carried out in specialized surgical institutions by surgeons experienced in rheumatology and orthopedics.