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ZusammenfassungDie Fortschritte der Rheumatologie haben aus fast regelhaft zu Invalidität und frühem Tod führenden chronischen entzündlich-rheumatischen Erkrankungen gut behandelbare Krankheitsbilder gemacht. Dieser Fortschritt bringt aber auch ein paar Herausforderungen mit sich. Diese CME-Arbeit fasst den aktuellen Stand der Rheumatologie prägnant und anhand der wesentlichen Erkrankungsbilder zusammen und beleuchtet ihre Schnittstellen.

Rheumatoid arthritis (RA) is a chronic inflammatory disorder marked by synovitis, ultimately leading to cartilage and bone destruction. In RA, adiponectin levels are increased in serum and synovial fluid. Adiponectin belongs to the adipokines, a group of highly bioactive substances secreted by adipocytes and other cell types. It has been shown to induce the production of proinflammatory and prodestructive factors by human RA synovial fibroblasts (RASF), suggesting a role in the pathophysiology of the disease. Although adenosine monophosphate-activated protein kinase (AMPK) and p38 mitogen-activated protein kinase (MAPK) are known to be involved in adiponectin signaling in RASF, no literature is available about whether the different adiponectin isoforms affect AMPK and p38 MAPK signaling in the same manner. In this study, we elucidated the signaling mechanisms in RASF, activated in response to selective stimulation with the 2 biologically most potent adiponectin isoforms, and possible approaches to inhibit adiponectin-mediated effects in RASF. All adiponectin isoforms induced p38 MAPK and AMPK phosphorylation to various degrees. Blocking AMPK activation increased p38 MAPK phosphorylation, while blocking p38 MAPK activation increased AMPK phosphorylation, both independent of the effect of adiponectin. Neither AMPKα1 nor AMPKα2 knockdown reduced interleukin (IL)-6/IL-8 release. Targeting transforming growth factor-activated kinase 1 (TAK1), a signaling molecule upstream of p38 MAPK, reduced the IL-6/IL-8 release. Taken together, our study showed that, in the case of adiponectin isoforms, inhibiting the p38 MAPK or the AMPK signaling pathway individually is not sufficient, probably due to compensatory interactions between these pathways. TAK1 might provide an alternative approach by ameliorating the proinflammatory effects of adiponectin in RA. Our results do not suggest that targeting individual adiponectin isoforms specifically in RA would provide a benefit over targeting adiponectin as a whole. However, whether targeting individual adiponectin isoforms would allow minimizing the loss of the beneficial effects of adiponectin within the metabolic and cardiovascular system still needs further investigation.

Rheumatoid arthritis (RA) is associated with systemic osteoporosis, which leads to severe disability and low quality of life. Current therapies target osteoclasts to reduce bone degradation, but more treatment options would be required to promote bone protection by acting directly on osteoblasts (OB). Recently, the local production of dopamine in inflamed joints of RA has been observed. Thus, in this project, we aimed to determine the implication of the neurotransmitter dopamine in the bone formation process in RA. Dopamine receptors (DR) in the human bone tissue of RA or osteoarthritis (OA) patients were examined by immunohistochemistry. DR in isolated human osteoblasts (OB) was analyzed by flow cytometry, and dopamine content was evaluated by ELISA. Osteoclasts (OC) were differentiated from the PBMCs of healthy controls (HC) and RA patients. Isolated cells were treated with specific dopamine agonists. The effect of dopamine on mineralization was evaluated by Alizarin red staining. Cytokine release in supernatants was measured by ELISA. Osteoclastogenesis was evaluated with TRAP staining. OC markers were analyzed via real-time PCR and bone resorption via staining of resorption pits with toluidine blue. All DR were observed in bone tissue, especially in the bone remodeling area. Isolated OB maintained DR expression, which allowed their study in vitro. Isolated OB expressed tyrosine hydroxylase, the rate-limiting enzyme for dopamine production, and contained dopamine. The activation of D2-like DR significantly increased bone mineralization in RA osteoblasts and increased osteoclastogenesis but did not alter the expression of OC markers nor bone resorption. DR were found in the bone remodeling area of human bone tissue and dopamine can be produced by osteoblasts themselves, thus suggesting a local autocrine/paracrine pathway of dopamine in the bone. D2-like DRs are responsible for bone mineralization in osteoblasts from RA patients without an increase in bone resorption, thus suggesting the D2-like DR pathway as a possible future therapeutic target to counteract bone resorption in arthritis.

ZusammenfassungDie Endoprothetik von Knie- und Hüftgelenk sind häufig auf eine primäre Arthrose zurückzuführen. Bei den sog. „kleinen“ Gelenken der oberen und unteren Extremität ist die Ätiologie meist eine andere – häufig treten hier sekundäre Destruktionen aufgrund einer Grunderkrankung des rheumatischen Formenkreises oder posttraumatische Arthrosen auf – primäre, degenerative Zerstörungen sind eher selten. Ausgedehnte Kenntnisse bezüglich optimaler Indikationen und des OP-Zeitpunkts, stellen für eine endoprothetische Versorgung eine Grundvoraussetzung für ein erfolgreiches Vorgehen dar. Neben der klinischen Untersuchung gehört die bildgebende Diagnostik zu den entscheidenden Informationen und ist damit für die Therapieplanung essentiell. Die Endoprothetik des Schultergelenkes hebt sich im Vergleich zu anderen „kleinen“ Gelenken ab, denn sie erreicht – trotz deutlich niedriger Fallzahlen als Knie- und Hüftendoprothetik – ähnlich gute Ergebnisse. Der aktuelle Goldstandard der Schulterendoprothetik ist die Hybrid-Totalendoprothese (mit zementfreier humeralen Komponente und zementierter Glenoidkomponente), die im Blick auf Patientenzufriedenheit und Schmerzreduktion der „Hemiprothese“ (ohne Glenoid-Komponente) überlegen ist. Die Hemiprothese kann tendenziell bei jüngeren Patienten mit gut erhaltener Pfanne als Primärimplantat indiziert sein, mit dem Risiko eines schmerzhaften sekundären Pfannenverschleißes im Verlauf. Bei Patienten im Alter über 70 Jahren mit Rotatorenmanschettendefektarthropatien aber auch nach Humeruskopffrakturen besteht die Möglichkeit einer Implantation einer inversen Prothese. Deren Standzeit liegt aktuell bei etwa 15 Jahren, sodass die Implantation auch dafür bei jungen Patienten eher kritisch zu bewerten ist. Bei Frakturversorgungen ist die inverse Prothese bezüglich der Revisionsrate der sog. „anatomischen“ Prothese überlegen. Die Ellenbogenprothetik bietet v. a. bei sekundärer Destruktion rheumatischer Genese den Vorteil einer raschen Schmerzreduktion und eines meist deutlichen Bewegungsgewinns, was für die eigenständige Pflege der Patienten wichtig ist. Eine dauerhafte Belastung des Ellenbogengelenkes ist jedoch bei den semigekoppelten Prothesen nur bis ca. 2–5 kg zu empfehlen und erfordert eine hohe Patienten-Compliance. Die Radiuskopfprothese, die bei traumatisch bedingter Radiuskopfdestruktion die Kongruenz des Ellenbogengelenkes wiederherstellt, erlaubt ebenso keine hohe Last. Goldstandard der endoprothetischen Versorgung von Fingergrund- und Fingermittelgelenken auch heute sind die seit den 1960iger Jahren verwendeten Silastic-Prothesen nach Swanson. Die Entwicklung von Oberflächenersatzimplantaten zeigt bisher am Fingermittelgelenk vielversprechende mittelfristige Ergebnisse. Auch am Daumensattelgelenk sind Implantate verfügbar, hier ist jedoch bei funktionell guten Alternativtechniken die Sinnhaftigkeit einer solchen Versorgung ernsthaft zu hinterfragen. Die Handgelenkendoprothetik bleibt Patienten mit geringer Beanspruchung und hoher Compliance und dann möglichst an der nicht-dominanten Hand vorbehalten. OSG-Prothesen der neuen Generation bestehen aus 3 Komponenten mit PE-Mittelkomponente ähnlich wie bei der Knie-Endoprothetik. Es werden dadurch im Gegensatz zur Arthrodese physiologischere Bewegungen und der weitgehende Erhalt eines physiologischen Gangbildes erreicht. Aktuelle Studienergebnisse aus Kohorten mit kleiner Fallzahl zeigen akzeptable 10–15 Jahres-Ergebnisse.

Nach schlechten Ergebnissen der ersten Prothesenmodelle in den 1970/-80er-Jahren mit kurzen Standzeiten und hohen Revisionsraten sind die aktuellen Langzeitergebnisse verschiedener Prothesentypen vielversprechend. Durch verbessertes Design und Implantationsmethoden erlauben „moderne“ Prothesen weitgehend physiologische Bewegungen, bei langeren Standzeiten. Mit im Mittel 20°–30° radiologisch gemessener Gesamtbewegung erreichen die sogenannten „Drei-Komponenten-Prothesen“ die fur den normalen Gang notwendige Bewegungsbreite. Aktuelle Diskussionen in der Literatur beziehen sich u. a. auf das Patientenalter als Einflussfaktor auf das Outcome. Aufgrund der verbesserten Revisionsoptionen und einer aktuell guten Studienlage dazu wird vielfach empfohlen, den Gelenkersatz des oberen Sprunggelenks auch bei jungeren Patienten als Therapieoption zu berucksichtigen. In der Literatur werden unabhangig vom Prothesenmodell ubereinstimmende Standzeiten von 78–94 % im 5-Jahres-Follow-up beschrieben. Untersuchungen mit groseren Fallzahlen und einer langeren Beobachtungszeit stehen noch aus. Trotz verbesserten Prothesendesigns sind die klinischen Ergebnisse der OSG-TEPs noch langst nicht so zufriedenstellend, wie die der Knie- und Huftendoprothetik. Hervorgehoben wird einheitlich, dass eine der Schwierigkeiten besonders in der sehr flachen Lernkurve liegt. In Deutschland werden jahrlich insgesamt nur ca. 2000 Prothesen implantiert. Daher sollte ein entsprechender Eingriff Zentren vorbehalten bleiben, die hohere Fallzahlen versorgen. While results of the first generations of implants in the 70/80th were rather poor due to short survivorship and high rates of revision current long-term results of different modern prostheses are more promising. Due to a progress in design and implantation modern prostheses enable a more physiological movement and survivorship. Modern three component models accomplish a radiological measured motion of 20°–30° and therefore the range of motion necessary for normal gait. Current discussions in literature are amongst others about the age of patients as influencing factor of the outcome. Due to facilitated options of revision and currently good results in literature it is stated that the procedure can be considered even in younger patients. Irrespective of the prosthesis there are described consistent survival rates between 78–94 % after 5 years. However, further research with higher case numbers and longer follow-ups must follow. Although implants improved clinical outcome of the total ankle replacement does not match those for knee and hip arthroplasty. It is consistently highlighted, that one of the main difficulties arising from a considerable learning curve. In Germany there are only about 2000 prosthesis implanted annually. Until case numbers increase total ankle replacement should remain reserved for specialized centres.

Background Activin A and follistatin exhibit immunomodulatory functions, thus affecting autoinflammatory processes as found in rheumatoid arthritis (RA). The impact of both proteins on the behavior of synovial fibroblasts (SF) in RA as well as in osteoarthritis (OA) is unknown. Methods Immunohistochemical analyses of synovial tissue for expression of activin A and follistatin were performed. The influence of RASF overexpressing activin A on cartilage invasion in a SCID mouse model was examined. RASF and OASF were stimulated with either IL-1β or TNFα in combination with or solely with activin A, activin AB, or follistatin. Protein secretion was measured by ELISA and mRNA expression by RT-PCR. Smad signaling was confirmed by western blot. Results In human RA synovial tissue, the number of activin A-positive cells as well as its extracellular presence was higher than in the OA synovium. Single cells within the tissue expressed follistatin in RA and OA synovial tissue. In the SCID mouse model, activin A overexpression reduced RASF invasion. In human RASF, activin A was induced by IL-1β and TNFα. Activin A slightly increased IL-6 release by unstimulated RASF, but decreased protein and mRNA levels of follistatin. Conclusion The observed decrease of cartilage invasion by RASF overexpressing activin A in the SCID mouse model appears to be mediated by an interaction between activin/follistatin and other local cells indirectly affecting RASF because activin A displayed certain pro-inflammatory effects on RASF. Activin A even inhibits production and release of follistatin in RASF and therefore prevents itself from being blocked by its inhibitory binding protein follistatin in the local inflammatory joint environment. Electronic supplementary material The online version of this article (10.1186/s13075-019-1926-7) contains supplementary material, which is available to authorized users.

Objective: The long-distance migration of rheumatoid arthritis synovial fibroblasts (RASFs) in the severe combined immunodeficiency (SCID) mouse model of rheumatoid arthritis (RA) suggests that an interaction between RASFs and endothelial cells (EC) is critical in this process. Our objective was to assess whether immunomodulatory factors such as adipokines and antirheumatic drugs affect the adhesion of RASFs to ECs or the expression of surface molecules. Methods: Primary ECs or human umbilical vein endothelial cell (HUVEC) and primary RASFs were stimulated with adiponectin (10 μg/mL), visfatin (100 ng/mL), and resistin (20 ng/mL) or treated with methotrexate (1.5 and 1,000 μM) and the glucocorticoids prednisolone (1 μM) and dexamethasone (1 μM), respectively. The expression of adhesion molecules was analyzed by real-time polymerase chain reaction. The interaction of both cell types was analyzed under static (cell-to-cell binding assay) and dynamic conditions (flow-adhesion assay). Results: Under static conditions, adipokines increased mostly binding of RASFs to EC (adiponectin: 40%, visfatin: 28%, tumor necrosis factor α: 49%). Under flow conditions, visfatin increased RASF adhesion to HUVEC (e.g., 0.5 dyn/cm2: 75.2%). Reduced adhesion of RASFs to E-selectin was observed after treatment with dexamethasone (e.g., 0.9 dyn/cm2: −40%). In ECs, tumor necrosis factor α (TNF-α) increased expression of intercellular adhesion molecule 1 (20-fold) and vascular cell adhesion molecule 1 (77-fold), whereas P-selectin was downregulated after stimulation with TNF-α (−6-fold). Conclusion: The adhesion of RASFs to EC was increased by visfatin under static and flow conditions, whereas glucocorticoids were able to decrease adhesion to E-selectin. The process of migration and adhesion of RASFs to ECs could be enhanced by adipokines via adhesion molecules and seems to be targeted by therapeutic intervention with glucocorticoids.

Die orthopadisch-unfallchirurgische Beschaftigung mit Patienten des rheumatischen Formenkreises erfordert eine umfangreiche Kenntnis der Besonderheiten dieser immunologisch induzierten Systemerkrankungen. Dazu gehoren die medikamentosen und die konservativen Vorgehensweisen. Die Zerstorungen an den Gelenken und der Wirbelsaule folgen einem typischen Muster. In Abhangigkeit von dem Stadium der Gelenkdestruktionen kommen verschiedene Operationsverfahren zum Einsatz, dabei ist das ganzheitliche perioperative Management zu beachten. Praventive und rekonstruktive OP-Verfahren konnen anhand der radiologischen Stadien abgeleitet werden. Bei fehlender oder beginnender Gelenkdestruktion sind vor allem Weichteileingriffe, bei fortgeschrittener Zerstorung Endoprothesen und Arthrodesen indiziert. Der orthopadische Rheumatologe ist spezialisiert auf die konservative und operative Behandlung der entzundlichen Systemerkrankungen. Es bietet sich an, entsprechende Eingriffe in den auditierten OP-Zentren der Deutschen Gesellschaft fur Orthopadische Rheumatologie (DGORh) durchzufuhren.

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 The aim of this retrospective study is to evaluate distal resection interposition arthroplasty of the wrist as a tool to restore mobility as well as to restore stability in severely destroyed wrist joints. Methods Thirty-four wrists in 28 rheumatoid arthritis patients were included. The mean follow-up time was 9 years after surgical treatment with clinical and radiological examination. The results were accessed based on a modification of Clayton ´s scoring system as well as a functional questionnaire. Results 71% patients were satisfied with pain, function and activities of daily life. Better results were reported by patients with a young age, early surgical intervention, a shorter duration of the disease, and lesser involvement of other joints. Conclusions The results for radiocarpal arthrodesis were comparable to those of synovectomy or arthrodesis of the wrist. The results after total wrist joint arthroplasty varies probably as the result of different patient groups, implant types and evolution of prosthetic designs, and are not comparable with the present study. Electronic supplementary material The online version of this article (10.1186/s12891-018-2172-x) contains supplementary material, which is available to authorized users.

ZusammenfassungDie orthopädische Rheumatologie befasst sich mit der Diagnostik und der konservativen sowie der operativen Behandlung von rheumatischen Erkrankungen am muskulo-skelettalen System. Um eine dauerhafte Remission der entzündlichen Aktivität einer rheumatischen Erkrankung zu erreichen, ist ein multidisziplinäres Therapiekonzept notwendig. Begleitend zur medikamentösen Therapie und angepasst an die Schwere der Erkrankung, bzw. die entzündliche Aktivität und den Grad der Destruktion von Gelenken, umfasst dieses verschiedene konservative und operative Maßnahmen. Die enge interdisziplinäre Kooperation mit internistischen Rheumatologen, Radiologen, Nuklearmedizinern, Anästhesisten und nicht zuletzt Ergo- und Physiotherapeuten sowie Orthopädietechnikern ist dabei unabdingbar. In der Therapie von rheumatischen Erkrankungen erfolgt in der Regel neben einer medikamentösen Basistherapie eine konservative Therapie an den Strukturen des muskulo-skelettalen Systems. Je nach Gelenk und Zustand umfasst diese alle lokalen Maßnahmen der physikalischen Therapie, Physiotherapie, Ergotherapie, Schienenversorgung, Einlagen- und Schuhversorgung, bzw. zuletzt Gelenkinfiltrationen. Erst, wenn mit diesen konservativen Maßnahmen keine ausreichende Wirkung erzielt wird, kommen operative Maßnahmen zum Einsatz. Ausnahmen hiervon sind absolute oder dringliche OP-Indikationen wie Nervenausfälle, ausgeprägte Achsabweichungen von Gelenken, ein rasches Fortschreiten der Destruktionen oder Sehnenrupturen. Je nach Gelenk und radiologischem Destruktionsgrad werden bei der operativen Therapie präventive/gelenkerhaltende von rekonstruktiven/gelenkersetzenden Verfahren unterschieden. Aufgrund des multilokulären Befalls sowohl artikulärer als auch ligamentärer Strukturen, v. a. aber der besonderen Medikation und deren potentiellen Nebenwirkungen gilt es, im operativen Bereich die Besonderheiten dieser Patientengruppe zu berücksichtigen.

Zusammenfassung„Rheumatiker“ haben ein erhöhtes Frakturrisiko. Die chirurgische Versorgung eines akuten Traumas bzw. der eingetretenen Traumafolgen ist aufgrund der schlechten ossären und weichteiligen Gewebestrukturen anspruchsvoll. Das Risiko für perioperative Komplikationen ist erhöht. Die Behandlung von „Rheumatikern“ nach Trauma ist komplex und erfordert eine individuelle multimodale Rehabilitation in spezialisierten Einrichtungen, welche die muskulo-skelettale und systemische Manifestation der Grunderkrankung und der additiv vorliegenden Traumafolgen adressieren kann.

ZusammenfassungTrotz verbesserter Therapiemöglichkeiten bedeutet die Diagnose „Rheumatoide Arthritis“ nach wie vor für den Patienten eine erhebliche physische und psychische Belastung. Zu den Krankheitssymptomen wie Schmerzen, lang anhaltende Morgensteifigkeit, Funktionsstörungen, Müdigkeit kommen die Notwendigkeit einer medikamentösen Dauertherapie und in vielen Fällen auch Operationen. Häufig leiden die Patienten unter Verunsicherung, Ängsten und Zweifeln, bei den jüngeren Patienten eher im Hinblick auf Berufswahl, Familienplanung oder Freizeitaktivitäten, bei den älteren Patienten im Hinblick auf Verlust von Mobilität und Selbstständigkeit. Hinsichtlich der Frage der operativen Intervention findet sich oft eine ambivalente Haltung der Patienten. Einerseits besteht bei persistierenden Schmerzen und Funktionseinschränkungen der Wunsch nach Besserung, andererseits bestehen Ängste hinsichtlich möglicher Komplikationen. Die meisten rheumaorthopädischen Operationen werden elektiv durchgeführt, sodass vor der geplanten Operation genügend Zeit bleibt, um den Patienten bestmöglich auf den Eingriff vorzubereiten. Schon bei der Indikationsstellung müssen zusätzliche Funktionsstörungen bei polyartikulärem Befall berücksichtigt werden, ggf. muss eine sinnvolle Reihenfolge von Operationen gemeinsam mit dem Patienten festgelegt werden. Risiken, individuelle Besonderheiten z.B. durch Voroperationen/Vorerkrankungen, der Umgang mit den Medikamenten, Alternativen zum Eingriff, postoperative Behandlung und das zu erwartende Ergebnis des Eingriffs sollten mit dem Patienten im Vorfeld ausführlich besprochen werden. Hilfreich für solche Gespräche ist es, wenn der Patient schriftlich entsprechende Informationen für den Arzt mit sich führt. Auch psychische Vorerkrankungen oder Belastungen sollten miteinbezogen werden, da das Outcome erheblich vom Vorhandensein positiver Copingmechanismen profitiert.

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.

Obesity—in which free fatty acid (FFA) levels are chronically elevated—is a known risk factor for different rheumatic diseases, and obese patients are more likely to develop osteoarthritis (OA) also in non-weight-bearing joints. These findings suggest that FFA may also play a role in inflammation-related joint damage and bone loss in rheumatoid arthritis (RA) and OA. Therefore, the objective of this study was to analyze if and how FFA influence cells of bone metabolism in rheumatic diseases. When stimulated with FFA, osteoblasts from RA and OA patients secreted higher amounts of the proinflammatory cytokine interleukin (IL)-6 and the chemokines IL-8, growth-related oncogene α, and monocyte chemotactic protein 1. Receptor activator of nuclear factor kappa B ligand (RANKL), osteoprotegerin, and osteoblast differentiation markers were not influenced by FFA. Mineralization activity of osteoblasts correlated inversely with the level of FFA-induced IL-6 secretion. Expression of the Wnt signaling molecules, axin-2 and β-catenin, was not changed by palmitic acid (PA) or linoleic acid (LA), suggesting no involvement of the Wnt signaling pathway in FFA signaling for osteoblasts. On the other hand, Toll-like receptor 4 blockade significantly reduced PA-induced IL-8 secretion by osteoblasts, while blocking Toll-like receptor 2 had no effect. In osteoclasts, IL-8 secretion was enhanced by PA and LA particularly at the earliest time point of differentiation. Differences were observed between the responses of RA and OA osteoclasts. FFA might therefore represent a new molecular factor by which adipose tissue contributes to subchondral bone damage in RA and OA. In this context, their mechanisms of action appear to be dependent on inflammation and innate immune system rather than Wnt-RANKL pathways.

Tuberculosis is a central global health problem with an incidence of 10 million new cases per year and more than one million deaths per year. Contrary to this, osseous tuberculosis represents an extremely rare entity of tuberculosis. Osseous tuberculosis is challenging beginning with the correct diagnosis, adequate surgical as well infectiological treatment as well as extremity reconstruction. Facing increased migration and therefore increasing numbers of cases of tuberculosis in western countries, the question of a reliable diagnosis, therapy and protective measures in dealing with those patients is becoming increasingly important for Central Europe.In the present case, a 49-year-old female patient from Pakistan, the first presented to our institution with a clinical picture of an exanthema at the level of the upper ankle joint with radiological signs of osteolysis. Pathological and molecular pathological diagnostics revealed the presence of an infection caused by Mycobacteria tuberculosis complex. In the initial phase over 6 weeks, a 4-fold therapy with isoniazid (INH), rifampicin (RMP), pyrazinamide (PZA) and ethambutol (EMB) was administered in accordance with the WHO guidelines, followed by 2-fold therapy with INH and RMP for 12 months in the subsequent continuity phase.14 months later, the patient was re-admitted to hospital because of a recurrent abscess. Therefore tuberculostatic therapy as a quadruple combination of INH, RMP, PZA and EMB was initiated for 6 weeks and as a double combination of INH and RMP for a total of one year.After the abscess had been eradicated, the joint was immobilized by ankle arthrodesis and the deep necrosis of the right ankle was finally reconstructed with allergenic bone grafts and a free microvascular M. gracilis flap.In the case presented here, successful treatment was possible via an interdisciplinary treatment consisiting of infectiology, orthopaedic surgery as well as plastic surgery specialists. Osseous tuberculosis could be eradicated and the bony defect could be reconstructed together with resulting soft tissue defect ultimately preserving of the extremity. In the context of this case study, a comprehensive overview of the current literature is described and a therapy algorithm is proposed due to the increasing relevance of this entity.Die Tuberkulose stellt mit jährlich 10 Millionen neuen Fällen und über einer Million Toten im Jahr ein zentrales globales Problem dar. Eine Knochentuberkulose stellt dem gegenüber als extrem selten auftretende Form der Tuberkulose eine besondere Herausforderung hinsichtlich der Diagnosestellung sowie der Sanierung und Defektdeckung von tiefgreifenden Defekten im Bereich der Extremitäten dar. Für Mitteleuropa stellt sich vor dem Hintergrund vermehrter Migration und ansteigender Zahlen von Tuberkulosefällen verstärkt die Frage nach einer sicheren Diagnose, Therapie und Schutzmaßnahmen im Umgang mit dem Patienten.Im vorliegenden Fall, einer 49-jährigen Frau aus Pakistan, erfolgte eine erstmalige Vorstellung mit dem klinischen Bild eines Exanthems auf Höhe des oberen Sprunggelenkes mit radiologischen Zeichen einer Osteolyse. Die pathologische und molekularpathologische Diagnostik erbrachte den Nachweis einer Infektion durch einen Erreger des M. tuberculosis-Komplexes. In der Initialphase über 6 Wochen erfolgte die leitliniengerechte 4fach-Therapie mit Isoniazid (INH), Rifampicin (RMP), Pyrazinamid (PZA) und Ethambutol (EMB) und in der anschließenden Kontinuitätsphase die 2fach-Therapie mit INH und RMP für 12 Monate.14 Monate später, erfolgte bei Rezidiv-Abszess die erneute stationäre Aufnahme, mit der Fortführung der tuberkulostatischen Therapie als Vierfach-Kombination aus INH, RMP, PZA und EMB für 6 Wochen und als Zweifachkombination INH und RMP für insgesamt ein Jahr.Nach Sanierung des Abszesses erfolgte die Ruhigstellung des Gelenkes mittels Sprunggelenks-Arthrodese und schließlich die Defektdeckung der tiefgreifenden Nekrose am rechten Sprunggelenk durch einen freien M. gracilis-Lappenplastik durch die Plastische Chirurgie.In dem hier beschriebenen Fall erfolgte die suffiziente ossäre Versorgung sowie Weichgewebsdeckung in einem Schwerpunktkrankenhaus durch die Zusammenarbeit der Infektiologie, der orthopädisch-unfallchirurgischen und der plastisch-chirurgischen Abteilung. Der knöcherne Defekt konnte so saniert, der Weichgewebsdefekt gedeckt und letztlich der Extremitätenerhalt gesichert werden. Im Rahmen dieses Fallbeispiels soll aufgrund der zunehmenden Relevanz dieser Entität ein umfassender Überblick über die relevante aktuelle Literatur gegeben werden und ein Therapie-Algorithmus abgeleitet werden.

Obesity—in which free fatty acid (FFA) levels are chronically elevated—is a known risk factor for different rheumatic diseases, and obese patients are more likely to develop osteoarthritis (OA) also in non-weight-bearing joints. These findings suggest that FFA may also play a role in inflammation-related joint damage and bone loss in rheumatoid arthritis (RA) and OA. Therefore, the objective of this study was to analyze if and how FFA influence cells of bone metabolism in rheumatic diseases. When stimulated with FFA, osteoblasts from RA and OA patients secreted higher amounts of the proinflammatory cytokine interleukin (IL)-6 and the chemokines IL-8, growth-related oncogene α, and monocyte chemotactic protein 1. Receptor activator of nuclear factor kappa B ligand (RANKL), osteoprotegerin, and osteoblast differentiation markers were not influenced by FFA. Mineralization activity of osteoblasts correlated inversely with the level of FFA-induced IL-6 secretion. Expression of the Wnt signaling molecules, axin-2 and β-catenin, was not changed by palmitic acid (PA) or linoleic acid (LA), suggesting no involvement of the Wnt signaling pathway in FFA signaling for osteoblasts. On the other hand, Toll-like receptor 4 blockade significantly reduced PA-induced IL-8 secretion by osteoblasts, while blocking Toll-like receptor 2 had no effect. In osteoclasts, IL-8 secretion was enhanced by PA and LA particularly at the earliest time point of differentiation. Differences were observed between the responses of RA and OA osteoclasts. FFA might therefore represent a new molecular factor by which adipose tissue contributes to subchondral bone damage in RA and OA. In this context, their mechanisms of action appear to be dependent on inflammation and innate immune system rather than Wnt-RANKL pathways.

Background The Janus kinase inhibitors (JAKi) peficitinib and filgotinib are currently examined in clinical trials for treatment of rheumatoid arthritis. Both inhibitors are well tolerated up to doses causing Cmax values higher than 1 µM [1,2]. This is in contrast to the approved dosages of tofacitinib and baricitinib reaching Cmax values below 0.5 µM [3,4]. However, it is not known if the higher concentrations of peficitinib or filgotinib offer a benefit in treatment of rheumatoid arthritis. Objectives The aim of the study compared the effect of different JAKi on inflammatory response and functional behavior of fibroblast-like synoviocytes from patients with RA (RASF). Methods Human RASF were isolated and pretreated with JAKi. After stimulation with IL-1β and JAKi with/without soluble IL-6 receptor (sIL-6R) the levels of IL-6 and MMP-3 were measured in supernatants by ELISA. The effect of different JAKi on proliferation of RASF was determined by a BrdU-incorporation assay. The influence of peficitinib on migration of RASF towards a FCS gradient was examined. For short-term adhesion assays, cells were treated with JAKi, detached and seeded in culture plates. The 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 The IL-1β (10 ng/ml) dependant IL-6 release of RASF was decreased by peficitinib (62%, p The proliferation of RASF was attenuated by tofacitinib, baricitinib and peficitinib at 5 µM. Peficitinib exerted the strongest decrease of about 70% (p Conclusion Peficitinib and filgotinib modulated the IL-1β-induced response of RASF. Peficitinib also inhibited the proliferation and the migration of RASF. Therefore, especially peficitinib could be able to reduce the aggressive pannus formation in RA patients. References [1] Cao YJ, et al.: Pharmacokinetics, Pharmacodynamics, and Safety of ASP015K (Peficitinib), a New Janus Kinase Inhibitor, in Healthy Subjects. Clin Pharmacol Drug Dev 2016;5:435-449. [2] Vanhoutte F, et al.: Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Filgotinib, a Selective JAK-1 Inhibitor, After Short-Term Treatment of Rheumatoid Arthritis: Results of Two Randomized Phase IIa Trials. Arthritis Rheumatol 2017;69:1949-1959. [3] Lamba M, et al.: Evaluation of Pharmacokinetics Compared With Immediate-Release Tofacitinib and Impact of Food. J Clin Pharmacol 2016;56:1362-1371. [4] Shi JG, et al.: The pharmacokinetics, pharmacodynamics, and safety of baricitinib, an oral JAK 1/2 inhibitor, in healthy volunteers. J Clin Pharmacol 2014;54:1354-1361. Disclosure of Interests Magnus Diller: None declared, Rebecca Hasseli: None declared, Iris Aykara: None declared, Marie Hulser: None declared, Stefan Rehart: None declared, Ulf Muller-Ladner Grant/research support from: Projekt supported by an unrestricted educational grant from Celgene GmbH., Elena Neumann: None declared

Background Rheumatoid arthritis (RA) and psoriatic arthritis (PsA), although similar in several respects, display clinical as well as therapeutic differences. This includes, for example, the higher effectiveness of the anti-IL17A biologic secukinumab in PsA than in RA patients. Synovial fibroblasts (SF) are one of the key effector cell types in the pathophysiology of RA and PsA. We hypothesized that RASF and PsASF respond differentially to IL-17A and its biologic secukinumab and that this might contribute to the difference seen in the therapeutic response. Objectives To examine the effect of the two cytokines IL-17A and TNF-α on RASF in comparison to PsASF as well as the effect of their corresponding biologics. To analyze the effect of the IL-17A homolog IL-17F. Methods SF were isolated from synovium from PsA or RA patients 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 IL-6 secretion was induced by IL-17A in RASF as well as PsASF (IL-17A: 13.7-fold ↑ vs 6.9–fold ↑; n=3). Although sharing the same receptor, the IL-17A homolog IL-17F alone caused no induction of IL-6 secretion in SF. However, when combined 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. RASF (n=3) responded more strongly than PsASF (n=3) to the combined stimulation (IL-17A: 544-fold ↑ vs 127-fold ↑, IL-17F: 54-fold ↑ vs 27-fold ↑). Adalimumab and secukinumab were similarly effective in abolishing the synergistic effect of IL-17A + TNF-α in RASF and PsASF. Conclusion According to our data, the differences in the therapeutic effectiveness of the anti-IL17A biologic secukinumab cannot be attributed to differential SF responses since the response to IL-17A alone and IL-17A together with TNF–α is not stronger for PsASF than for RASF and since secukinumab was similarly effective for both SF types. Furthermore, in a proinflammatory milieu with increased TNF levels, both IL-17A and IL-17F can contribute to promoting inflammation in the pathophysiology of PsA and RA. Acknowledgement Supported by an unrestricted educational grant from Celgene GmbH. Disclosure of Interests Klaus Frommer: None declared, Stefan Rehart: None declared, Ulf Muller-Ladner Grant/research support from: Projekt supported by an unrestricted educational grant from Celgene GmbH., Elena Neumann: None declared

Background: Psoriatic arthritis (PsA) is frequently associated with enthesitis. It has been proposed that inflammatory processes at the synovio-enthesal complex are involved in the pathogenesis of inflammatory arthritides including especially PsA. Besides IL-1β and TNF-α, IL-15, IL-23 and IFN-γ are cytokines expressed within the synovium, tendons and entheses and some of which are already used as therapeutic targets. While synovial fibroblasts (SF) are known key effector cells of cartilage destruction in inflammatory arthritides such as RA, tenocytes are a major component of tendons and entheses and play a central role in tendon inflammation observed in PsA. Objectives: To investigate whether PsASF and tenocytes show significant interactions while being stimulated with the above cytokines alone as well as in combination with the aim to find out whether these may contribute to the pathogenesis of PsA. Methods: SF were isolated from patients with PsA undergoing joint surgery. Human tenocytes were acquired commercially and isolated from hamstring tendon tissue of patients undergoing hamstring tendon ACL reconstruction. PsASF and tenocytes were stimulated with IL-1β, TNF-α, IFN-γ, IL-15 and IL-23 alone and in combination. Direct cell co-culture experiments were performed at a 1:1 ratio of both cell types in parallel to experiments with single cell type cultures. IL-6 levels were measured by ELISA to quantify the immunological activation of the cells. Results: PsASF as well as tenocytes showed strong responses to IL-1β (tenocytes ↑173-fold, n=3; PsASF ↑56-fold, n=3) and TNF-α (tenocytes ↑10-fold, n=3; PsASF ↑9-fold, n=3) stimulation regarding IL-6 secretion. IFN-γ alone had only minimal effects on both cell types but acted synergistically when applied together with IL-1β (tenocytes ↑218-fold, n=3; PsASF ↑129-fold, n=3) and TNF-α (tenocytes ↑24-fold, n=3; PsASF ↑19-fold, n=3). IL-15 and IL-23 alone showed no effect but the data suggest a small antagonistic effect against IL-1β (tenocytes IL-15 ↓21%/IL-23 ↓27%, n=3; PsASF IL-23 ↓19%, n=3) and TNF-α induced IL-6 secretion. Overall, PsASF and tenocytes showed similar responses in the single cell type stimulation experiments. Co-culturing PsASF and tenocytes did not reveal any synergistic or antagonistic interactions in regards to any of the cytokines used. Conclusion: Our data suggest that tenocytes and PsASF do not interact in a way that would promote inflammation within the synovio-enthesal complex. Also, as far as the induction of IL-6 is concerned, PsASF and tenocytes are not major target cells of IL-15 and IL-23. IFN-γ, however, may be able to promote inflammation in combination with other cytokines in both cell types. Disclosure of Interests: Felix Dechant: None declared, Klaus Frommer: None declared, Neal L Millar: None declared, Iain McInnes Grant/research support from: AstraZeneca, Celgene, Compugen, Novartis, Roche, UCB Pharma, Consultant for: AbbVie, Celgene, Galvani, Lilly, Novartis, Pfizer, UCB Pharma, Stefan Rehart: None declared, Ulf Muller-Ladner Grant/research support from: Projekt supported by an unrestricted educational grant from Celgene GmbH., Elena Neumann: None declared

Background: The spleen tyrosine kinase (syk) is an intracellular protein kinase involved in signal transmission processes of immune cells and non-hematopoietic cells, such as fibroblasts. Various syk-inhibitors are therefore currently being tested in preclinical and clinical studies, e.g. for the treatment of different types of cancer as well as autoimmune diseases. In preclinical studies, the syk inhibitor fostamatinib showed a pronounced anti-inflammatory effect on synovial fibroblasts (SF) from patients with rheumatoid arthritis (RA). These cells play an important role in the pathogenesis of RA by mediating matrix destructive processes. On the other hand, clinical trials have been only moderately successful due to the side effects and the limitation regarding increase in dosage. However, further inhibitors such as RO9021 or TAK-659 have been developed. They are characterized by a more specific kinase profile and therefore side effects could potentially be less severe. Whether these inhibitors also convey an anti-inflammatory effect on RASF has not yet been investigated. Objectives: This study examines the effect of syk-inhibitors on the inflammatory response and functional behavior of activated RASF. Methods: RASF were isolated from synovial tissue of patients with known rheumatoid arthritis during joint replacement surgery. RASF were pretreated with different concentrations of RO9021 and TAK-659 and their vehicle control for 2h and additionally stimulated with IL-1β (10 ng/ml) for 17h or with oncostatin M (OSM, 100 ng/ml) for 24h. Supernatants were collected and the concentration of IL-6 and MMP3 were determinate by ELISA. The measurement of cell viability, cytotoxicity and apoptosis was performed to exclude possible cytotoxic or apoptotic effects of the syk-inhibitors. The RASF proliferation was detected by a BrdU-incorporation assay. The effect of syk-inhibitors on cell migration towards a FCS-gradient was measured by cell culture inserts. Results: Both TAK-659 and RO9021 showed a significant reduction of the release of the pro-inflammatory cytokine IL-6 and the production of MMP3 in IL-1β stimulated RASF. However TAK-659 showed a stronger effect on IL-6 reduction (48%, p Conclusion: The syk-inhibitors TAK-659 und RO9021 at concentrations above 5µM reduce the inflammatory response, the migration and proliferation of RASF. If appropriate concentrations can be reached in vivo, these syk-inhibitors could offer a possibility to modulate the aggressive phenotype of RASF. Disclosure of Interests: Jeanne Pierrette Lallah Missimana: None declared, Magnus Diller: None declared, Rebecca Hasseli: None declared, Stefan Rehart: None declared, Ulf Muller-Ladner Grant/research support from: Projekt supported by an unrestricted educational grant from Celgene GmbH., Elena Neumann: None declared

Background Osteoporosis (OP), as an age-related disease, is characterized by bone loss, increased fracture risk and poor regeneration. During aging and OP bone marrow adiposity is increased due to a shift of osteogenic 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. It is known, that fatty tissue not simply functions as energy storage but is metabolically highly active. Therefore, adipocyte-derived factors such as adipokines might influence MSC differentiation. Objectives The role of interactions between adipocyte-derived factors and MSC in the pathogenesis of OP is not fully elucidated. Thus, we analyzed the presence of the adipokine visfatin in bone tissue and its effects on MSC differentiation in standard culture vs. spongiosa. Methods The spongiosa of femoral heads of patients with osteoarthritis (OA) after hip replacement surgery, or after osteoporotic femoral neck fracture were used for RNA- and MSC-isolation. Adipogenic MSC differentiation was performed with/without visfatin and its 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 measured by Realtime PCR. Protein production was evaluated by ELISA. Results Elevated visfatin-level were observed in OP compared to non-osteoporotic OA bone. Visfatin-induced secretion of proinflammatory factors was lower during adipogenesis on cancellous bone then in standard cell culture (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 detected during adipogenesis on spongiosa as well as in standard cell culture. However visfatin-mediated MMP13 expression was markedly reduced in the presence of cancellous bone (e.g. 21d, x-fold: standard culture 81±89, spong. 13±21, n=7). Inhibition of visfatin by Apo866 decreased the visfatin-induced cytokine release but not the MMP13 expression during adipogenesis in culture (n=4). In contrast to Apo866, the p38-MAPK inhibitor did not influence cytokine release but reduced MMP13 expression in a time dependent manner. Conclusion Visfatin level was elevated in osteoporotic vs OA 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 Interests Lali Tsiklauri: None declared, Janina Werner: None declared, Klaus Frommer: None declared, Stefan Rehart: None declared, Sabine Wenisch: None declared, Ulf Muller-Ladner Grant/research support from: supported by an unrestricted educational grant from Celgene GmbH., Elena Neumann: None declared

Background: Activin A and its antagonist follistatin are part of an autoregulatory cycle, which is well known in the hypothalamic-pituitary-gonadal axis. Activins also have an important function in autoimmune diseases, such as rheumatoid arthritis (RA). Due to inflammation, activin A is released systemically, causing an induction of its antagonist follistatin. The negative feedback mechanism is well described for hepatocytes, but seems to be inactive in synovial fibroblasts from patients with rheumatoid arthritis (RASF). Neoangiogenesis, which is mediated partially by local fibroblasts, is increased due to inflammation and tissue hyperplasia in RA synovium. Despite the fact that RASF contribute to cartilage destruction in RA and RASF are able to interact with endothelial cells, less is known about the effect of activin and follistatin in this context. Objectives: The aim of this study was to examine the effect of activin A and follistatin on the interaction of RASF and endothelial cells. Methods: Endothelial cells (HUVEC) were commercially obtained and RASF were isolated from synovial tissue of patients with RA undergoing joint replacement surgery, RASF and HUVEC were stimulated in mono-, or coculture with activin A (15ng/ml), follistatin (500ng/ml) and/or IL-1β (1ng/ml). The concentrations of activin A, follistatin, VEGF and IL-6 were measured by ELISA. Results: IL-1β induced the release of activin A 8-fold in RASF alone (p In HUVECs, the IL-6 release was reduced by 37.6% after stimulation with activin A and IL-1β (n=5,p The release of VEGF was induced in RASF with IL-1β (89%), activin A (55%), activin A combined with IL-1β (148%), follistatin and IL-1β (84%) compared to unstimulated control. In coculture with HUVECs, the induction was less distinct than in monoculture (IL-1β: 75%, activin A: 22%, activin A and IL-1β: 101%, follistatin and IL-1β: 67%, n=4). Conclusion: The autoregulatory cycle of activin A and follistatin is active in endothelial cells and inactive in RASF. Due to the interaction of endothelial cells and RASF, the proinflammatory response of the RASF is weakened. This was shown in direct coculture with no induction in coculture compared to stimulation with activin A and IL-1β in RASF monoculture. Interestingly, in direct coculture, the effects of HUVECs appear to dominate resulting in a significant reduction of the activin A concentration in the presence of follistatin and IL-1β in comparison to RASF monoculture. References [1] de Jong FH, Grootenhuis AJ, Klaij IA, Van Beurden WM: Inhibin and related proteins: localization, regulation, and effects. Adv Exp Med Biol1990;274:271-293. [2] de Kretser DM, O’Hehir RE, Hardy CL, Hedger MP: The roles of activin A and its binding protein, follistatin, in inflammation and tissue repair. Mol Cell Endocrinol2012;359:101-106 Disclosure of Interests: Iris Aykara: None declared, Magnus Diller: None declared, Stefan Rehart: None declared, Ulf Muller-Ladner Grant/research support from: Projekt supported by an unrestricted educational grant from Celgene GmbH., Elena Neumann: None declared

Die operative Versorgung von Patienten mit rheumatoider Arthritis setzt grose Erfahrung voraus, daher sollte die Indikation zur Operation interdisziplinar von einem Rheumaorthopaden in Zusammenarbeit mit seinem internistischen Kollegen getroffen werden. Im Rahmen der Operation mussen bestimmte Strategien verfolgt werden, da die Erkrankung aufgrund ihres systemischen Charakters das perioperative Management durch zahlreichen Komorbiditaten, aber auch durch notige medikamentose Therapien und gleichzeitig bestehenden Defektsituationen an mehreren Gelenken, deutlich erschwert. Fur die Durchfuhrung der Operation ist daher eine enge Zusammenarbeit zwischen Anasthesie und Chirurgie unerlasslich. Auch die postoperative Nachbehandlung gestaltet sich durch bestehende Defektsituationen an anderen, nicht frisch operierten Gelenken mit ihrer oft stark reduzierten Belastbarkeit schwierig. Zusatzlich konnen die Erkrankung selbst und ihre medikamentose Therapie zu Immundepressionen mit schweren Komplikationen fuhren.

Grundlegende Bausteine bei der Differenzialdiagnostik des Gelenkergusses sind Anamnese und klinische Untersuchung. Bei unklaren Befunden kann die Arthrosonographie Aufschluss fur die Unterscheidung zwischen intra- und extraartikularen Pathologien geben. Bei atraumatischen Gelenkergussen ist die Bestimmung der Entzundungsparameter im Blut zur Differenzierung zwischen systemisch entzundlichen oder lokal entzundlichen Situationen hilfreich. Bei normwertigen Laborparametern erfolgt die weitere Diagnostik mittels Bildgebung. Bei einer Erhohung der Entzundungslaborwerte bestehen die wichtigsten Differenzialdiagnosen in der Arthritis urica, den autoimmunologischen Gelenkprozessen und der septischen Arthritis. Im Zweifel ist eine Gelenkpunktion mit Synoviaanalyse zum Ausschluss einer septischen Arthritis oder der evtl. Bestatigung einer Kristallarthritis durchzufuhren.

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.

Der Fus ist im Laufe einer chronisch-entzundlichen Erkrankung fast immer und meist von Anfang an mitbetroffen, die entsprechenden Affektionen durfen nicht ubersehen werden. Nach ausgereizter konservativer Behandlung ist eine prazise perioperative Planung inklusive des Umgangs mit der Basistherapie erforderlich, dann profitieren die Patienten auch mit hoher Wahrscheinlichkeit deutlich von operativen Eingriffen. Obwohl gelenkerhaltende Eingriffe immer mehr mit Erfolg durchgefuhrt werden konnen, stellen die rheumaspezifischen Operationsverfahren weiterhin den Hauptanteil. Arthroskopien haben einen hohen Stellenwert am oberen Sprunggelenk. Ein endoprothetischer Ersatz kann an OSG und am Metatarsophalangealgelenk nach sorgfaltiger Abwagung durchgefuhrt werden. Es besteht ein erhohtes perioperatives Risiko, deshalb empfiehlt es sich, rheumatisch-destruierte Fuse von speziell fur diese Problematik ausgebildeten orthopadischen Rheumatologen versorgen zu lassen.

In a joint initiative by the boards of the German Society for Rheumatology (DGRh) and the Association of Rheumatology Clinics (VRA) the European aEurostandards of care" for rheumatoid arthritis, recently suggested by the European Musculoskeletal Conditions Surveillance and Information Network (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.

Objective Osteoarthritis is not only characterized by cartilage degradation but also involves subchondral bone remodeling and osteophyte formation. Osteophytes are fibrocartilage-capped bony outgrowths originating from the periosteum. The pathophysiology of osteophyte formation is not completely understood. Yet, different research approaches are under way. Therefore, a histological osteophyte classification to achieve comparable results in osteophyte research was established for application to basic science research questions. Methods The osteophytes were collected from knee joints of osteoarthritis patients ( n = 10, 94 osteophytes in total) after joint replacement surgery. Their size and origin in the respective joint were photo-documented. To develop an osteophyte classification, serial tissue sections were evaluated using histological (hematoxylin and eosin, Masson's trichrome, toluidine blue) and immunohistochemical staining (collagen type II). Results Based on the histological and immunohistochemical evaluation, osteophytes were categorized into four different types depending on the degree of ossification and the percentage of mesenchymal connective tissue. Size and localization of osteophytes were independent from the histological stages. Conclusion This histological classification system of osteoarthritis osteophytes provides a helpful tool for analyzing and monitoring osteophyte development and for characterizing osteophyte types within a single human joint and may therefore contribute to achieve comparable results when analyzing histological findings in osteophytes.

Tetraspanins function as membrane adaptors altering cell-cell fusion, antigen presentation, receptor-mediated signal transduction and cell motility via interaction with membrane proteins including other tetraspanins and adhesion molecules such as integrins. CD82 is expressed in several malignant cells and well described as tumour metastasis suppressor. Rheumatoid arthritis (RA) is based on persistent synovial inflammation and joint destruction driven to a large extent by transformed-appearing activated synovial fibroblasts (SF) with an increased migratory potential.ObjectiveCD82 is upregulated in RA synovial fibroblasts (RASF) compared with osteoarthritis (OA) SF as well as within RA compared with OA synovial lining layer (LL) and the role of CD82 in RASF was evaluated.MethodsCD82 and integrin immunofluorescence was performed. Lentiviral CD82 overexpression and siRNA-mediated knockdown was confirmed (realtime-PCR, Western blot, immunocytochemistry). RASF migration (Boyden chamber, scrape assay), attachment towards plastic/Matrigel, RASF-binding to endothelial cells (EC) and CD82 expression during long-term invasion in the SCID-mouse-model were evaluated.ResultsCD82 was induced by proinflammatory stimuli in SF. In RA-synovium, CD82 was expressed in RASF close to blood vessels, LL, sites of cartilage invasion and colocalised with distinct integrins involved in tumour metastasis suppression but also in RA-synovium by RASF. CD82 overexpression led to reduced RASF migration, cell-matrix and RASF-EC adhesion. Reduced CD82 expression (observed in the sublining) increased RASF migration and matrix adhesion whereas RASF-EC-interaction was reduced. In SCID mice, the presence of CD82 on cartilage-invading RASF was confirmed.ConclusionCD82 could contribute to RASF migration to sites of inflammation and tissue damage, where CD82 keeps aggressive RASF on site.

Background Dysfunction of either osteoclastic bone resorption or osteoblastic bone formation leads to bone disorders such in rheumatoid arthritis (RA). Several therapies target osteoclasts to reduce bone degradation, but treatments able to induce bone formation are still required. Recently, local production of dopamine in inflamed joints of RA has been described. Thus, we aimed to determine the implication of dopamine in the bone remodeling process. Methods Dopamine receptors (DR) presence in human bone tissue of RA or osteoarthritis (OA) patients, as well as in bone tissue of a murine model of arthritis was determined by immunohistochemistry. DR in isolated human osteoblasts (OB) was analyzed by flow cytometry. The influence of dopamine agonists (DA) on human OB was tested in vitro, supplementing the medium with DA for 24 h. Then, supernatants were collected for cytokine quantification. The effect of DA on mineralization was evaluated by including DA for 14 days in differentiation medium. Results All DR were observed in mouse and human bone tissue, especially in the bone-remodeling zone. Moreover, isolated OB maintained the presence of DR. DA stimulation lead to a significantly increase of proinflammatory cytokines, such as IL6 and CCL2. Furthermore, mineralization was altered after stimulation of OB with DA. Conclusion Dopamine receptors are present in the bone remodeling area and their activation on osteoblast seems to have a modulatory effect on bone homeostasis.

Unglaublich aber wahr: Patienten mit Erkrankungen des rheumatischen Formenkreises können genauso Traumata erleiden, wie „normale“ Menschen… Das erscheint deshalb so verwunderlich, weil „Rheumatiker“ durch die regelmäßige medizinische Supervision gewissermaßen gefeit zu sein haben, vor negativen Erlebnissen im Sinne von Verletzungen, die andere durchmachen. Auch erscheint es möglich, dass die Überzeugung von Betroffenen und medizinisch Betreuenden, entzündlich-systemisch Erkrankte gingen so vorsichtig mit sich um, dass Verletzung praktisch ausgeschlossen sind, einer gründlichen Revision bedarf! Aktive Teilnahme am Straßenverkehr oder gefährliche Betätigungen im Haushalt, sportliche Betätigung mit der Möglichkeit von Stürzen im höheren Lebensalter sollten bei diesen Patienten doch tabu sein… Zumindest war das die vorherrschende Meinung noch vor 2 Dekaden und fest verankerte Überzeugungen brauchen bekanntlich sehr lange, um zu verschwinden.

Die Probleme bei Rheumapatienten betreffen in vielen Fallen den Fus und das Sprunggelenk. Dies hat besondere Auswirkungen auf die Aktivitaten des taglichen Lebens. Die Mobilitat der Patienten ist bei einem Befall der unteren Extremitat haufig sehr stark vermindert, so dass eine eigenstandige Versorgung der Patienten erschwert ist. Insbesondere weil oft auch Handdeformitaten vorliegen, die eine Nutzung von Gehstutzen oder Rollatoren erschweren. Trotz verbesserter medikamentoser Therapiemoglichkeiten finden in diesem belastungsabhangigen Korperabschnitt sukzessive Veranderungen statt, die eine zusatzliche Versorgung mit Hilfsmitteln oder sogar operative Interventionen notwendig machen. Hier gilt es, gerade in den fruhen Stadien der Destruktionen und Deformierungen, eine optimale Hilfestellung zu geben, um vor allem eine Schmerzlinderung zu erreichen. In spateren Stadien ist meist eine Stabilisierung erforderlich, welche sowohl operativ als auch mit Masschuhen oder Orthesen erfolgen kann. Hier ist fur jeden Patienten das richtige Vorgehen zu erarbeiten. Die Entscheidung, ob eine operative oder konservative Therapie erfolgt, hangt von vielen Parametern ab. Hier spielen Patientenalter, Komorbiditaten, anatomische Voraussetzungen und schlieslich der Patientenwunsch eine entscheidende Rolle in der Entscheidungsfindung. In allen Fallen ist es jedoch wichtig eine fur den Patienten optimale Therapie zu finden, die auch umgesetzt werden kann. Hierzu ist eine enge Absprache mit internistischen Rheumatologen, orthopadischen Rheumatologen, Orthopadieschuhmacher und naturlich dem Patienten selbst erforderlich. Die speziellen Erfordernisse beim Rheumapatienten sollten in allen ihren Belangen berucksichtigt werden. Hier ist unter anderem die Hautsituation und die Schmerzen und Beschwerden in anderen Gelenken zu berucksichtigen. Ahnlich zu den Patienten mit diabetischer neuropathischer Osteoarthropathie ist auf eine spezielle Weichbettung der druckbelasteten Stellen zu achten. Dies kann nur durch individualisierte Anfertigungen von Einlagen und Schuhen gelingen. Pauschale Therapievorschlage sind bei der grosen Diversitat der Begleiterkrankungen und -behinderungen nicht moglich. Ein patientenindividuelles Vorgehen ist auf jeden Fall erforderlich. Hier bietet die Orthopadietechnik vielfaltige Moglichkeiten, um eine optimale Therapie zu bewerkstelligen. Zusatzlich sollte die medikamentose Therapie bei entsprechenden Veranderungen der anatomischen Situation bedacht werden.

Resume Objectif L’arthrose est non seulement caracterisee par une degradation du cartilage, mais comporte egalement un remodelage de l’os sous-chondral et la formation d’osteophytes. Les osteophytes sont des excroissances osseuses coiffees de fibrocartilage provenant du perioste. La physiopathologie de la formation d’osteophytes n’est pas completement comprise. Pourtant, differentes voies de recherche sont en cours. Par consequent, une classification histologique des osteophytes en vue d’obtenir des resultats comparables de la recherche sur les osteophytes a ete creee en vue d’une application aux questions de recherche fondamentale. Methodes Les osteophytes ont ete recueillis sur des genoux de patients souffrant d’arthrose ( n = 10 ; 94 osteophytes au total) apres mise en place d’une prothese. Leur taille et origine dans leur articulation respective furent documentees par photographies. Afin de developper une classification des osteophytes, des coupes seriees de tissus furent effectuees en utilisant des colorations histologiques (hematoxyline-eosine, trichrome de Masson, bleu de toluidine) et immunohistochimiques (collagene de type II). Resultats En fonction d’une evaluation histologique et immunohistochimique, les osteophytes furent classes en quatre types differents selon leur degre d’ossification et le pourcentage de tissu conjonctif mesenchymateux. La taille et la situation des osteophytes etaient independantes des stades histologiques. Conclusion Ce systeme de classification histologique des osteophytes arthrosiques fournit un outil utile pour l’analyse et le suivi du developpement des osteophytes et pour caracteriser le type d’osteophyte dans une seule articulation humaine. Il peut donc contribuer a obtenir des resultats comparables lors de l’analyse histologique des osteophytes.

Beschwerden im Bereich der Halswirbelsaule gehen haufig mit Einschrankungen der Lebensqualitat der Patienten einher. Nach Ausschluss eines gefahrlichen Verlaufes (z. B. Tumore, Bandscheibenvorfall) stellen das „HWS“-Syndrom, die „Zervikale Radikulopathie“ sowie eine rheumatische Grunderkrankung haufige Diagnosen dar. Die Patienten profitieren im Rahmen der Multimodalen Schmerztherapie (MMS) von den angebotenen Therapiemoglichkeiten in einem interdisziplinaren Team. Dieser Artikel stellt im Besonderen die Aspekte aus schmerztherapeutischer Sicht (Score- Systeme) sowie aus orthopadischer Sicht dar.

Septische Arthritiden treten in der Allgemeinbevolkerung selten auf. Patienten mit rheumatischen Erkrankungen haben durch die Erkrankung selbst, durch die immunsuppressive Therapie und durch das haufige Vorhandensein von Gelenkendoprothesen ein deutlich erhohtes Risiko fur septische Arthritiden. Haufigster Erreger ist nach wie vor Staphylococcus aureus. Problematisch ist die weltweit zunehmende Resistenzentwicklung, vor allem im Hinblick auf methicillinresistente Staph. aureus und vancomycinresistente Enterokokken, die jedoch im Moment noch nur bei einem geringen Teil der Infektionen nachgewiesen werden. Unter der Therapie mit TNF-α-Antikorpern wird eine ansteigende Inzidenz von gramnegativen und intrazellularen Erregern beobachtet. Zur Prophylaxe septischer Arthritiden sind mogliche Infektionsherde zu sanieren. Perioperativ sind gegebenenfalls Medikamente zu pausieren und eine Antibiotikumprophylaxe durchzufuhren. Diagnostisch kommt neben Anamnese, Klinik und Laborparametern, dem Gelenkpunktat mit Synoviaanalyse, Grampraparat und der Kultur besondere Bedeutung zu. Die Therapie von septischen Arthritiden und periprothetischen Gelenkinfekten ist in erster Linie operativ, kombiniert mit einer systemischen Antibiotikatherapie. Uber das chirurgische Vorgehen muss im Einzelfall entschieden werden. Bei nativen Infekten sind oft arthroskopische Gelenkspulungen mit Entfernen von Fibrinbelagen und der Synovialis ausreichend. Bei periprothetischen Infekten entscheiden eine ganze Reihe von Faktoren, ob gelenkerhaltend vorgegangen werden kann oder ein 1-, bzw. 2-zeitiger Prothesenwechsel angezeigt ist. Grundsatzlich halten wir bei Patienten des rheumatischen Formenkreises den operativ ausgewiesenen orthopadischen Rheumatologen als Hauptansprechpartner fur die Sanierung von Infekten am muskulo-skelettalen System fur geeignet. Flankiert wird die operative Therapie durch eine antibiotische Therapie, die als kalkulierte Initialtherapie begonnen wird und dann an den jeweiligen Erreger angepasst wird. Insbesondere bei seltenen oder multiresistenten Erregern ist die Zusammenarbeit mit Mikrobiologen und Hygienikern unabdingbar. Nach stattgehabtem, (vermeintlich) ausgeheiltem Gelenkinfekt besteht lebenslang ein erhohtes Risiko fur weitere Gelenkinfekte.

Bei Patienten mit juveniler idiopathischer Arthritis (JIA) besteht haufig ein Befall der Huftgelenke mit Gelenkdestruktion und entsprechenden Funktionseinschrankungen. Die Indikation zur Implantation einer Huftendoprothese muss dann nicht selten gestellt werden. Welche Besonderheiten sind bei Patienten mit JIA bei einer Prothesenversorgung zu erwarten und was bedeutet diese im Hinblick auf OP-Indikation, Implantatwahl und Technik. Selektive Literaturrecherche sowie Auswertung des eigenen Patientenkollektivs. Im Vergleich zu Arthrosepatienten sind Patienten mit JIA zum Zeitpunkt der Prothesenimplantation im Schnitt deutlich junger. Durch Beginn der Erkrankung im Kindes- bzw. Jugendalter und der haufigen Glukokortikoidtherapie sind bei den Patienten nicht selten Wachstumsstorungen oder anatomische Formveranderungen zu finden. Auch die Knochendichte ist bei dieser Patientengruppe haufig schon in jungen Jahren gemindert. Der perioperative Umgang mit der besonderen Medikation ist zu planen. Spezielle Implantate fur „Rheumatiker“ existieren nicht, aber die oben genannten Besonderheiten dieser Patientengruppe sollte beim operativen Vorgehen, der Implantat- bzw. Materialwahl berucksichtigt werden. Insgesamt sind die Ergebnisse der Huftendoprothetik bei juvenilen rheumatischen Erkrankungen im Hinblick auf Schmerzlinderung und Funktionsverbesserung gut. Problematisch ist die begrenzte Standzeit der Prothesen. Durch Schmerzlinderung, Verbesserung der Beweglichkeit und des Aktivitatslevels wird nach Huftendoprothesenimplantation bei JIA-Patienten meist eine sehr hohe Patientenzufriedenheit erreicht. Bei Befall des kontralateralen Huftgelenkes oder des ipsilateralen Kniegelenkes kann ein simultaner einzeitiger Gelenkersatz beider Gelenke sinnvoll sein.

Results of surgical synovectomy and radiation synovectomy (radiosynoviorthesis) of the tibiotalar joint in rheumatoid patients are reported. The staged concept for management of the rheumatoid ankle joint is presented which is based on the radiographic appearance of disease progression. Results of 16 rheumatoid patients with disease to the ankle joint suggest that pain and walking capability is positively influenced by synovectomy and radiosynoviorthesis. Follow-up of 30 months revealed no deterioration of postoperative clinical improvement. In the absence of contraindications to radiosynoviorthesis it is suggested to combine arthroscopic synovectomy with radiosynoviorthesis for the treatment of early stages of rheumatoid disease of the ankle joint. Open synovectomy is preferred to arthroscopic synovectomy, if tenosynovectomy is simultaneously required.

Background To keep synovial fibroblasts (SF) from migrating into the adjacent cartilage is a desirable therapeutic target in rheumatoid arthritis (RA). Using this approach, both joint destruction and disability could be prevented. Moreover, our previous studies could show a significant decrease of IL-6 and IL-8 in RASF under dopamine receptor activation ( Capellino S et al, Arthritis Rheumatol 2014 ). Based on these results, we suggest a potential impact of RASF on joint invasion and destruction in RA. Materials and methods RA and osteoarthritis (OA) SF were obtained from patients undergoing knee joint replacement surgery (mean age: OA: 74.3±11.3 years; RA: 73.7±10.3 years).In order to investigate the dopamine receptor (DR) distribution in the synovium, we performed immunohistochemistry and evaluated all DR 5 receptor subtypes. Here, the DR-expression in the lining layer and especially in the invasion zone between was of special interest. SF migration and motility assays as well as ELISAs for MMP3 and proMMP1 were performed under D1-like (D1DR and D5DR) and D2-like (D2DR, D3DR and D4DR) receptor stimulation, each in different concentrations, respectively. Results D1DR, D4DR and D5DR were higher expressed on SF nearby the invasion zone. Also, migration of RASF and OASF were found to be correlated with age of the patient at surgery. While younger patients (≤75 years) showed an increase in migration up to 78%, the older patients (≥75 years) show a reduced migration of less than 50% (p=0.0009; r=0.69, OA n=8; RA n=7). No difference could be observed between RA and OA patients and between the D1-like and D2-like receptor stimulation. The same impact on the RASF and OASF could be seen in the motility assay (OA n=6; RA n=6). MMP3 and proMMP1 level were altered in both directions under DR activation (OA n=3; RA n=3). Conclusion DRs are highly expressed in the invasion zone, which suggests a direct role for dopamine on the aggressive phenotype of the synovial fibroblasts, as confirmed in the in vitro assays. As RASF migration is significantly altered under DR activation, the synovial dopamine pathway can be regarded as a potential therapeutic target of RA.

Background Increased amounts of visceral fat are often associated with lower bone density. Also, in obese patients an increased risk of osteoarthritis can be seen in non-weight bearing joints. Chronically elevated free fatty acid (FFA) levels as occurring in obesity may therefore also play a role in bone loss. We hence analysed if and how FFA influence cells of bone metabolism in rheumatic 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). Protein secretion was quantified by immunoassays, mRNA expression by real-time PCR. Mineralization activity was quantified using Alizarin Red S staining, differentiated OC were quantified by counting TRAP-positive multinuclear cells. Toll-like receptor (TLR) 4 and TLR2 were blocked by neutralising antibodies. Results Stimulation with PA or LA increased OB secretion of the proinflammatory cytokine IL6 (up to 9-fold ↑) and the chemokines IL-8 (up to 221-fold ↑), GRO-α (from below detection level to detectable levels) and MCP1 (up to 16-fold ↑). RANKL and OPG were not influenced by FFA on protein and mRNA level. In osteoblasts, activity (ALP/collagen type I) and differentiation markers (e.g. osteocalcin) as well as production of inorganic matrix were not altered by FFA stimulation. TLR4 but not TLR2 blockade significantly reduced PA-induced IL-8 secretion by OB. Secretion of IL-8 by RA OC was increased by FFA, while MMP-9 was reduced. The mRNA expression of osteoclast activity markers (CLCN7, CTSK, TCIRG) remained unchanged. However, the number of TRAP positive multinuclear cells formed from RA PBMC was decreased (by around 50%). Conclusions The pro-inflammatory effect of certain FFA on osteoblasts and osteoclasts may indirectly contribute to bone loss, while the reduction of mature OC after FFA stimulation suggests an inhibitory effect on bone resorption. In osteoblasts, FFA signalling is at least in part mediated by TLR4, but not by TLR2.