Diss. (sammanfattning) Stockholm : Karolinska institutet, 2010.

Submitted by ALLINE MARDEGAN MIOTO (allinefisio@gmail.com) on 2018-07-27T15:46:26Z No. of bitstreams: 1 DEFINITIVO 1.pdf: 974826 bytes, checksum: c58be54a25aa5395ad0f19a218ebb9bd (MD5) / Approved for entry into archive by Claudia Adriana Spindola null (claudia@fct.unesp.br) on 2018-07-27T17:17:48Z (GMT) No. of bitstreams: 1 mioto_am_me_prud.pdf: 974826 bytes, checksum: c58be54a25aa5395ad0f19a218ebb9bd (MD5) / Made available in DSpace on 2018-07-27T17:17:48Z (GMT). No. of bitstreams: 1 mioto_am_me_prud.pdf: 974826 bytes, checksum: c58be54a25aa5395ad0f19a218ebb9bd (MD5) Previous issue date: 2018-05-30 / A artrite reumatoide (AR) é uma doença inflamatória crônica, autoimune e de etiologia e patogênese desconhecidas que afeta o sistema musculoesquelético. O exercício físico é indicado como meio de auxiliar a retardar a incapacidade funcional, ajudando a melhorar a função articular. OBJETIVO: O objetivo desse estudo foi analisar os efeitos que exercício físico aquático ─ nas intensidades baixa, média e alta ─ provocam na inflamação articular, nas propriedades dos ossos, fêmur e tíbia, na artrite induzida em joelhos de ratos. MÉTODOS: Foram utilizados 20 ratos machos Wistar com 60 dias de idade, divididos em 5 grupos: Grupo Controle Artrite (GCA) n= 4, Grupo Controle Placebo (GCP) n=4, Grupo Atividade física baixa (GB) n=4, grupo Atividade Física Moderada (GM) n=4 e grupo Atividade Física Intensa (GI) n=4. Os grupos de atividade física foram submetidos à injeção intraarticular (ia) de 0,05 ml/100g Zymosam (1mg/50µL) no joelho direito. Os animais do grupo controle artrite (GCA) receberam solução salina no joelho direito ao invés do Zymosan, e os animais do grupo controle placebo (GCP) foram submetidos somente ao estresse da agulha. Os animais foram submetidos à atividade aquática durante 30 minutos, 4 vezes na semana, durante 5 semanas, sendo a intensidade do exercício determinada por meio da sobrecarga colocada no dorso de cada animal em seus respectivos grupos: GB 1%, GM 5%, GI 15% do peso do rato, no grupo GCA não foi adicionada sobrecarga. Os animais foram eutanasiados após 5 semanas de treinamento. RESULTADOS: Observou-se que o grupo de baixa intensidade, e os grupos que não fizeram exercício GCA e GCP, ganharam mais peso comparado ao grupo de média intensidade GM. Em relação ao edema articular houve diminuição do mesmo no grupo GI após a terceira semana de treino e no grupo GM após a 4º semana de exercício, já em relação ao conteúdo mineral ósseo (CMO) da tíbia houve diminuição do grupo GM quando comparado ao grupo GCP (p=0,026), já na densidade mineral óssea da tíbia houve diminuição do grupo GM comparado aos grupos GCP (p=0,001), GCA (p=0,002), GB (p=0,026). Para Área do fêmur, o grupo GI apresentou aumento comparado aos grupos GB (p=0,014) e GM (p=0,008). CONCLUSÃO: conclui-se que os exercício de intensidade moderada e alta intensidade promovem melhores resultados que os exercícios de baixa intensidade. / Rheumatoid arthritis (RA) is a chronic inflammatory, autoimmune disease, its etiology and pathogenesis are unknown and it affects the musculoskeletal system. Based on this argument, physical exercise is indicated as it may help to delay functional disability, which can improve joint function. OBJECTIVE: The aim of this study was to analyze the effects of aquatic physical exercise on the low, medium and high intensity on the joint inflammation and on the properties of femoral and tibial bones of the rats in which knee arthritis was induced. METHODS: Twenty male Wistar rats aged 60 days were divided into 5 groups: Group Control Arthritis (GCA) n = 4, Group Control Placebo (GCP) n = 4, Group Low physical activity (GL) n = 4, Group Moderate physical activity (GM) n = 4 and Group Intense Physical activity (GI) n = 4. The physical activity groups were submitted to intra-articular injection (ai) of 0.05 ml / 100g Zymosam (1mg / 50μL) in the right knee. The animals in the control group arthritis (GCA) received saline solution in the right knee instead of Zymosan, and the animals in the placebo control group (GCP) were submitted only to the stress of the needle. The animals were submitted to aquatic activity for 30 minutes, 4 times a week for 5 weeks, and the intensity of the exercise was determined by the overload placed on the back of each animal in their respective groups: GL 1%, GM 5%, GI 15 % of their weight, no overload was added in the GCA group. The animals were euthanized after 5 weeks of training RESULTS:It was observed that the low intensity group GL, and the groups that did not exercise GCA and GCP, gained more weight compared to the group GM. In relation to the joint edema, there was a decrease in the GI (p = 0.200) after the third week of training and in the GM group (p= 0.39) after In the 4th week of exercise; in relation to the bone mineral content (BMC) of the tibia, there was a decrease in the GM group when compared to the GCP group (p = 0.026), whereas in the tibial bone mineral density (BMD) there was a decrease in the GM group compared to the GCP (p = 0.001), GCA (p = 0.002), GB (p = 0.026). As for the area of the femur, the GI group presented an increase of it compared to the GB (p = 0.014) and GM (p = 0.008) groups;. CONCLUSION: Therefore, it is concluded that the exercises of moderate intensity and high intensity promote better results than the exercises of low intensity.

A artrite reumatóide (AR) representa uma doença inflamatória crônica de alta prevalência, para a qual ainda não foi estabelecido um tratamento satisfatório. Os objetivos deste estudo foram: 1) investigar o efeito terapêutico da hemopressina e da depleção de neuropeptídeos sobre a artrite induzida por antígeno (AIA); 2) padronizar este modelo em duas linhagens de ratos: Wistar e Sprague Dawley (SD). Ambas as linhagens, exibiram sinais equipotententes de edema e dor; entretanto, a perda de peso, o infiltrado celular e a produção de citocinas foi maior no rato SD, sugerindo uma maior susceptibilidade do SD. O tratamento com hemopressina inibiu esses sinais inflamatórios, mas não preveniu a perda de peso e a gênese de citocinas. Em contraste, a depleção de neuropeptídeos falhou em suprimir os sinais da AIA, excluindo a participação de mecanismos neurovasculares na ação da hemopressina. Embora ainda não estabelecido o mecanismo de ação do efeito anti-artrítico da hemopressina, este achado inédito sugere uma alternativa promissora para o tratamento dessa doença. / Arthritis and other rheumatic conditions are among the most prevalent diseases worldwide and the most frequent cause of disability. There are many treatment options, but an effective treatment has not been established. Our aims were to investigate a possible anti-inflammatory effect of hemopressin and neuropeptide depletion on Met-BSA induced arthritis (AIA); and to establish a suitable rat strain between Wistar and Sprague Dawley (SD) for the study. The classical signs of AIA such as oedema and pain were similar in both strains. But, the cell influx and cytokines production were higher in SD, thus suggesting a higher susceptibility for this strain. The treatment of rats with hemopressin greatly reduced the oedema, pain and cell influx, but did not prevent the body weight loss and cytokines. Depletion of neuropeptides failed to reduce the AIA signs, thus excluding a neurogenic component on hemopressin-induced effect. In conclusion, our findings reveal a potential alternative treatment for arthritis, although the mechanism of action for this peptide is not clear.

La cryothérapie est utilisée de manière large et empirique à visée adjuvante dans les rhumatismes inflammatoires, avec un niveau de preuve faible. Dans une revue systématique de la littérature, en poolant les données de 6 études non contrôlées, nous avons pu démontrer que la cryothérapie (locale ou corps entier) appliquée deux fois par jour pendant 7 à 15 jours réduisait significativement l'EVA douleur et le score d'activité DAS25 dans la polyarthrite rhumatoïde. La cryothérapie locale (glace ou gaz froide) montrait par ailleurs des effets taille intra-classes supérieurs à ceux obtenus en utilisant la cryothérapie corps entier. L'objectif de ce travail était de mesurer les effets de la cryothérapie locale sur al douleur, l'inflammation synoviale et systémique chez les patients arthritiques et dans le modèle murin d'arthrite à l'adjuvant. Dans les études randomisées CDRI et ALGGAR, nous avons évalué les effets de deux applications locales de froid (glace versus gaz froid) sur la douleur, l'activité Doppler et les taux protéiques de cytokines intra-articulaires controlatéraux non souffrant d'arthrites de genou non septiques. Les genoux arthritiques controlatéraux non traités étaient utilisés comme contrôles. Nous avons par ailleurs étudié in vitro les effets de l'hypothermie modérée (30°C pendant 2heures) sur l'expression protéique des cytokines dans un modèle de culture de rotules de rats arthritiques. Nous avons enfin étudié in vitro dans l'arthrite à l'adjuvant les effets de l'application sub-chronique de glace ou de gaz froid (2 fois par jour pendant 14 jours versus contrôles arthritiques non traités) sur le score d'arthrite, le diamètre de cheville, la transcription des gènes codant pour les cytokines pro-inflammatoires dans les pattes arrières (Q-RT-PCR) et l'expression protéique des cytokines dans le plasma (Multiplex et ELISA) après 14 jours de traitement. Dans l'étude CDRI, la cryothérapie locale (glace et gaz froid) réduisait significativement l'EVA douleur ainsi que le score Doppler dans les genoux traités, ces effets persistant le lendemain des deux applications. Dans une analyse intermédiaire des résultats de l'étude ALGGAR, en combinant les deux groupes de traitement (glace et gaz de froid), nous avons observé une baisse des taux d'IL-6, d'IL-1β et de VEGF dans le liquide articulaire arès deux applications. dans les cultures d'explants de rotules de rats arthritiques, l'hypothermie ponctuelle réduisait significativement les taux d'IL-6, IL-17A et IL-1β dans les pattes arrières après 14 jours de traitement. Les deux modalités réduisaient significativement les niveaux plasmatiques d'IL-17A et la glace réduisait en outre les taux d'IL-6 et de VEGF. Nous n'avons observé aucun effet de la cryothérapie locale sur le voie du TNF-α chez l'homme ni chez l'animal. Nos résultats démontrent pour la première fois un effet thérapeutique et anti-inflammatoire de la cryothérapie locale dans l'arthrite. Les effets biologiques était IL-6/IL-147 dépendants et TNF-α indépendants. Des études complémentaires permettront de mieux caractériser les mécanismes moléculaires sous-jacents et de déterminer su la cryothérapie locale pourrait être une alternative aux AINS et corticoïdes dans les rhumatismes inflammatoires. / Cryotheapy i widely and empirically used in an adjuvant setting in inflammatory rheumatic diseases, with a low level of evidence. We performed a systematic review of the literature and, by pooling data from 6 non-controlled studies, we could show that local cryotherapy (local or whole-body cryotherapy) applaied twice a day for 7-15 days significantly reduced the pain VAS and the DAS28 activity score in rheumatoid arthritis. Furthermore, local cryotherapy (ice packs or cold gas) showed significantly greater intra)class effect-sizes compared to whole-body cryotherapy. The aim of this work was to measure the effects of local cryotherapy on pain, synovial and systemic inflammation in arthrici patients and in the murine model of adjuvant-induced arthritis. First, in the CDRI and ALGGAR randomized studies, we evaluated the effects of 2 local cold applications (ice versus cold gas) on pain, power Doppler activity and intra-joint cytokine protein levels in 46 patients suffering from non-septic knee arthritides. Contralateral arthritic knee were used as control. Secondly, we studied the in vitro effects of mild hypothermia (30°C for 2 hours) on cytokine protein expression in a model of cultured arthritic rat patellae. Thidly, we studied the in vitro effects of sub-chronically applied ice or cold gas (twice a day for 14 days versus non-treated arthritic controls) on the arthritis score, the ankle diameter, pro-inflammatory cytokine gene transcription levelsin hind paws (Q-RT-PCR) and cytokine plasma protein levelx (Multiplex and ELISA) after 14 days of treatment. In the CDRI study, local cryotherapy (ice and cold gas) significantly reduced the pain VAS and the power Doppler score in treated kness, and these effects remained significant the day afetr 2 cold applicaitions. In an intermediate analysis of the ALGGAR study results, by pooling the 2 treatment groups, we could show significant decreases in IL-6 protein, IL-1β and VEGF synovial fluid protein levels after 2 cold applicatios. In arthritic rat patella explangt culture experiments, punctual hypothermia significantly reduced IL-6 protein levels. In vivon ice was more efficient on the clinical parameters and better tolerated compared to cold gas. Both techniques significantly reduced IL-6, IL-17A ans IL-1β gene transcription levels in hind paws after 14 days of treatment. Both techniques redcued IL-17A plasma protein levles, while ice also reduced IL-6 and VEGF plasma protein levels. Conversely, we observed no effect of local cryotherapy on the TNF-α pathway, neither in patients nor in our animal model. Here we demonstrate for the first time therapeutic and anti-inflammatory effet-cts of local cryothepary in arthritis. The biological effects were IL-6/IL-17-driven and TNF-α independent. Further studies will help elucidate the underlying molecular mlechanisms involved and detemrine whether local cryotherapy might be a safer alternative to NSAIDs ans corticosteroids in inflammatory rheumatic diseases.

This study was designed to investigate the experience of having arthritic pain from the children's perspective. Previous research on how Canadian children perceive and manage arthritic pain and how it affects their daily lives is nonexistent. Therefore the purpose of this qualitative descriptive study was to explore and describe the arthritic pain experience of school age children with juvenile rheumatoid arthritis (JRA) and to understand the impact/influence of various factors on the construction of that experience. Ten children, aged 10 to 13 years, with either early (at 2 to 4 years) or late (at 7 to 11 years) onset arthritis participated in this study. Descriptive data were obtained during two open-ended in depth interviews with the children in their homes. Using content analysis, data were analyzed for themes and their elements. An analytical framework of themes and their elements was developed that reflected the children's descriptions of and explanations for arthritic pain in the context of their day to day in the context of their day to day living with arthritis, both in the past and currently. The children perceived pain to be synonymous with arthritis and the mediating factor in how they functioned. They described arthritic pain in relation to distinguishing factors: intensity, duration, and frequency. Intermittent arthritic pain was attributed to cessation of medications, arthritis "flare-ups," inactivity, and activity. A current concern for most children was pain attributed to activity because it meant limitations in activities with peers. The children identified strategies they used to manage pain and cope with pain's unpredictability. The findings of this study were discussed in relation to selected research studies that either supported or refuted the findings of this study. Implications for nursing practice and research were addressed. / Applied Science, Faculty of / Nursing, School of / Graduate

Balb/c normal mice were used to study the effects of gold sodium thiomalate (GST) on intact, nonadherent, and adherent mononuclear spleen cells. The three populations were tested for the following aspects: in vitro effects of GST on the mitogen-triggered DNA synthesis; intracellular levels of cyclic AMP; and chemotaxis ability. These studies showed that GST inhibited the proliferative responses of all three populations as the concentration of GST increased. Cyclic AMP levels in the nonadherent population increased as the GST concentration increased. GST had a biphasic effect on the adherent population. At concentrations of 5 and 10 jag/ml, GST suppressed the cyclic AMP levels, and at concentration of 50 pg/ml it enhanced the cyclic AMP levels. GST had no effect on the cyclic AMP levels in the intact mononuclear spleen cells. GST appeared to have an inhibitory effect on the chemotaxis ability of all three populations of spleen cells.

Monocytes are no longer regarded as a homogenous cell population but can be divided, both phenotypically and functionally, into different subsets. In rheumatoid arthritis, the subpopulation of CD14bright/CD16+ monocytes is expanded and prone towards generation of Th17 cells. CD56+ monocytes represent a different subpopulation, which is also expanded in conditions associated with autoimmunity like inflammatory bowel diseases. The aim of the study was the quantification and functional characterization of the CD56+ monocyte subset in rheumatoid arthritis (RA). The work at hand shows that the frequency of CD56+ monocytes is also expanded in RA; moreover, this subpopulation seems to increase with age in healthy controls. This age association is completely lost in patients suffering from RA. Further functional investigations could demonstrate a dysregulated cytokine response to lipopolysaccharide (LPS) with an increased production of pro-inflammatory cytokines like TNFα as well as an increased spontaneous reactive oxygen intermediate (ROI) production. A longitudinal treatment study using Etanercept as an established TNFα-blocking agent revealed a decrease of the frequency of that cell population under therapy. This decrease was more pronounced in patients with a good treatment response as judged by the reduction of the disease activity score (DAS) 28. Summing up those results, the CD56+ monocyte subset might be involved in immunosenescence as well as in the pathogenesis of RA.

Katecholamine beeinflussen durch direkte Stimulation über adrenerge Rezeptoren die Funktion von Immunzellen. Ziel der Untersuchungen an Patienten mit Rheumatoider Arthritis war es, das Expressionsprofil unterschiedlicher adrenerger Rezeptorsubtypen in CD4(+)T-Lymphozyten dieser Patienten zu bestimmen. Zur Quantifizierung der Expression wurden semiquantitative RT-PCR-Analysen durchgeführt. Die Untersuchung zeigte, dass alpha1-adrenerge Rezeptoren in CD4(+)-T-Lymphozyten von RA-Patienten exprimiert werden. Es scheint eine Korrelation zwischen bestimmten extraartikulären Organmanifestationen (z.B. Sicca-Sydrom und Tenosynovitis) und der Expression alpha1-adrenerger Rezeptoren zu bestehen. Die gefundene differenzielle Expression der Rezeptoren in CD4(+)-T-Lymphozyten von RA-Patienten legen vertiefende Untersuchungen zur Relevanz des adrenergen Systems bei der Lymphozytenfunktionsmodulation nahe.

Das Ziel dieser Studie war es, die mundgesundheitsbezogene Lebensqualität (MLQ) bei Patienten mit rheumatoider Arthritis (RA) unter Berücksichtigung krank- heitsspezifischer Parameter zu bewerten. Dabei sollte eine Analyse der verschiedenen Dimensionen der MLQ, wie Funktionseinschränkungen des Kausystems, psychosozialer Einfluss, orofaziale Schmerzen sowie dentofaziale Ästhetik, durchgeführt werden.

Die Rheumatoide Arthritis (RA) ist eine multifaktoriell bedingte Autoimmunerkrankung, die durch entzündlichen Gelenksbefall charakterisiert ist. Unter fehlender oder ungenügender therapeutischer Intervention nimmt die Erkrankung einen progressiven Verlauf, der zu Gelenkdestruktionen und damit zu zunehmender Behinderung, sowie Arbeitsunfähigkeit führt. Neben den Einschränkungen in der Gelenkfunktion können in jedem Krankheitsstadium Allgemeinsymptome und vielfältige extraartikuläre Manifestationen auftreten, sodass die Erkrankung mit einer verkürzten Lebenserwartung bzw. erhöhter Mortalität assoziiert ist. Obwohl in den letzten Jahren deutliche Fortschritte in der Therapie erzielt wurden, ist eine definitive Heilung nicht möglich. Gemäß der EULAR-Guidelines von 2019 ist Methotrexat (MTX) weiterhin als „anchor drug“ in der RA das Erstlinienmedikament der Wahl. Bei Therapieversagen von MTX und dem Fehlen von negativen Prognoseparametern kann als Zweitlinientherapie ein anderes konventionelles DMARD (csDMARD) in Monotherapie oder Kombination eingesetzt werden. Eine der Optionen ist Leflunomid (LEF), das in Studien seine Wirksamkeit als DMARD und seine Überlegenheit gegenüber Placebo bewiesen hat. Es ist aber nach wie vor nicht wirklich geklärt, ob Patienten im klinischen Alltag tatsächlich von einer Therapie mit LEF oder LEF/MTX profitieren, insbesondere nach dem Versagen einer Erstlinientherapie mit MTX. Dazu wurde in der vorliegenden Untersuchung der Alltagseinsatz und Nutzen von LEF sowohl in Monotherapie als auch in Kombination mit MTX analysiert. Es handelt sich um eine historisch prospektive Kohortenstudie mit Patienten der Rheumatologischen Ambulanz des Universitätsklinikums Dresden. Es erfolgte die Einteilung der Studienkohorte (n=158) in zwei Untergruppen. In der erweiterten LEF-Kohorte (eLEF) befanden sich alle Patienten, welche zu einem beliebigen Zeitpunkt zwischen 2007 und 2015 mit LEF (n=103) oder mit LEF/MTX (n=49) behandelt worden waren. In der post MTX-Kohorte (pMTX-Gruppe) befanden sich alle Patienten, die nach dem Versagen einer Erstlinientherapie mit MTX zwischen 2007 und 2015 mit LEF (n=39) oder LEF/MTX (n=16) als Zweitlinientherapie behandelt worden waren. Es wurde das Therapieüberleben mittels Kaplan-Meier-Kurven, sowie der klinische Verlauf im ersten Jahr mittels Scoresystemen (CDAI) erfasst. Zudem wurden Nebenwirkungen, Absetzgründe und radiographischer Progress analysiert. Sowohl in der eLEF-Gruppe als auch in der pMTX-Gruppe lag ein signifikant schlechteres Gesamttherapieüberleben in Kombinationstherapie von LEF/MTX im Vergleich zur Monotherapie mit LEF vor (eLEF p=0,004; pMTX p=0,002; Signifikanzniveau p=0,05). Im klinischen Verlauf zeigten sich keine signifikanten Unterschiede, lediglich der Startscorewert der Kombinationstherapie war signifikant höher als unter Monotherapie. Beide Therapieregime konnten eine durchschnittliche Verbesserung von moderater zu niedriger Krankheitsaktivität, aber nicht bis in Remission erreichen. Insgesamt lag eine hohe Abbrecherzahl innerhalb des ersten Behandlungsjahres unabhängig vom Therapieregime vor. Der wichtigste Absetzgrund war (außer in der pMTX-Gruppe unter LEF/MTX) Wirkversagen, von dem etwa jeder zweite Patient betroffen war. Der andere wesentliche Absetzgrund waren Nebenwirkungen, hier war etwa jeder vierte bis fünfte Patient betroffen. Zudem traten unter Kombinationstherapie mehr Nebenwirkungen als unter Monotherapie auf. Radiographischer Progress spielte in der vorliegenden Kohorte keine relevante Rolle. Zusammenfassend zeigt die vorliegende Studie Hinweise, dass die Kombinationstherapie der Monotherapie nicht überlegen ist. Daher wäre durchaus vertretbar, bei einem Therapiewechsel primär eine Monotherapie anzustreben, was sich unter Berücksichtigung des langjährigen Therapiebedarfs und des höheren Patientenalters positiv auf Interaktionen mit anderen Medikamenten, auf Nebenwirkungen und auf die Compliance der Patienten auswirken könnte. Zugleich könnten Kosten gespart werden. Aufgrund des längerfristig nicht überzeugenden Verlaufes, sollte ein Wechsel auf ein zweites csDMARD (oder die Etablierung einer Kombinationstherapie) nach Versagen von MTX entsprechend der Leitlinien der EULAR nur bei Fehlen negativer Prognosefaktoren und in höherem Lebensalter, sowie mit einem engmaschigen Therapiemonitoring (klinisch, laborchemisch, radiologisch) erfolgen. Dennoch ist bei weltweitem Auftreten der Erkrankung die Medikation mit LEF weiterhin eine preisgünstigere Alternative für die Länder, wo zusätzliche Ressourcen knapp sind.:Inhaltsverzeichnis V Abbildungen VIII Tabellen X Glossar XII Akürzungsverzeichnis XIX 1 Einleitung und Fragestellung 1 2 Die Rheumatoide Arthritis (RA) 3 2.1 Epidemiologie 3 2.2 Ätiologie 4 2.2.1 Genetische Veränderungen 4 2.2.2 Epigenetische Veränderungen 5 2.2.3 Nicht genetische Faktoren/Umwelt 5 2.3 Pathophysiologie/Pathogenese 8 2.3.1 Synovium 8 2.3.2 Weitere Antikörper 12 2.3.3 Krankheitsverlauf 12 2.4 Klinisches Bild 14 2.4.1 Gelenkbefall 14 2.4.2 Differentialdiagnosen 16 2.4.3 Extraartikuläre Manifestationen 19 2.4.4 Sonderformen 23 2.5 Diagnostik 23 2.5.1 Labor 24 2.5.2 Bildgebung 25 2.6 Therapie 27 2.6.1 Medikamentöse Basistherapie 27 2.6.2 Weitere Aspekte zum Einsatz von bDMARDs/ tsDMARDs 32 2.6.3 Einschätzung der Krankheitsaktivität 33 2.6.4 Ko-Medikation und begleitende nichtmedikamentöse Therapien 36 2.7 Prognose 37 2.7.1 Komorbiditäten 39 2.7.2 Mortalität 40 3 Leflunomid (LEF) 42 3.1 Wirkmechanismus 42 3.2 Pharmakologische Aspekte 43 3.3 Arzneimittelinteraktionen 44 3.4 Wirksamkeit 45 3.4.1 Klinisch 45 3.4.2 Radiologischer Progress 46 3.4.3 Kombinationstherapien 47 3.5 Nebenwirkungen 48 3.5.1 Spezielle Nebenwirkungen 49 3.6 Praktische Anwendung 55 3.7 Kontraindikationen 56 4 Studienergebnisse 58 4.1 Material und Methoden 58 4.2 Patientenpool und Vergleichsgruppen 59 4.2.1 Weitere Subgruppen 64 4.2.2 Patientencharakteristika 66 4.2.3 Nachverfolgung 67 4.3 Therapieüberleben 68 4.3.1 Ergebnisübersicht: Therapie- und Patientengruppen 68 4.3.2 Ergebnisübersicht möglicher Einflussfaktoren 69 4.4 Therapieverlauf im ersten Jahr 78 4.4.1 Ergebnisübersicht CDAI 78 4.4.2 Ergebnisübersicht SDAI 80 4.4.3 Ergebnisübersicht DAS28 81 4.4.4 Entzündungsparameter 83 4.4.5 Therapiewirksamkeit und Therapieabbruch 87 4.4.6 Vorliegen von Prognosefaktoren 89 4.5 Nebenwirkungen 93 4.5.1 Ergebnisübersicht eLEF-Gruppe 93 4.5.2 Ergebnisübersicht pMTX 96 4.6 Absetzgründe 100 4.6.1 Ergebnisübersicht 100 4.7 Röntgenprogress 103 4.7.1 Ergebnisübersicht 103 5 Interpretation und Diskussion 105 5.1 Therapieüberleben 105 5.2 Therapieverlauf im ersten Jahr 108 5.3 Nebenwirkungen 111 5.4 Therapievergleiche 113 5.5 Röntgenprogress 115 6 Schlussfolgerung 117 7 Anhang 120 7.1 Zusäzliche Abbildungen zu Kapitel 2 120 7.2 Zusäzliche Analysen zu Kapitel 4 122 7.2.1 LEF-Erstlinie 122 7.2.2 Therapieüberleben: Zusätzliche Vergleiche in Abhängigkeit der Therapie 123 7.2.3 Therapieüberleben in Abhängigkeit vom Zeitpunkt der Kombinationstherapie 126 7.2.4 Therapieverlauf im ersten Jahr: Statistische Tests 128 7.2.5 Zusammenhang zwischen CRP bzw. BSG und CDAI für pMTX 133 7.2.6 Nebenwirkungen in Abhängigkeit vom Serostatus 134 7.2.7 pMTX-LM-L-Gruppe 135 7.3 Zusäzliche Analysen zu Kapitel 5 136 7.3.1 LEF und Prednisolon 136 8 Literaturverzeichnis 139 / Rheumatoid arthritis (RA) is a multifactorial autoimmune disease characterized by inflammatory joint involvement. In the absence or inadequacy of therapeutic intervention, the disease takes a progressive course, leading to joint destruction, increasing disability, and incapacity to work. In addition to limitations in joint function, general symptoms and multiple extra-articular manifestations may occur at any stage of the disease, so that the disease is associated with a shortened life expectancy and increased mortality. Although significant advances in therapy have been made in recent years, a definitive cure is not possible. According to the 2019 EULAR guidelines, Methotrexate (MTX) remains the first-line drug of choice as the 'anchor drug' in RA. In case of treatment failure of MTX and the absence of poor prognostic factors, another conventional DMARD (csDMARD) can be used as second-line therapy in monotherapy or combination. One of the options is Leflunomide (LEF), which has demonstrated its efficacy as a DMARD and its superiority to placebo in trials. However, it is still not really clear whether patients actually benefit from therapy with LEF or LEF/MTX in daily clinical practice, especially after failure of first-line therapy with MTX. To this end, the present study analyzed the everyday use and benefit of LEF both in monotherapy and in combination with MTX. It is a historical prospective cohort study with patients of the Rheumatologic Outpatient Clinic of the University Hospital of Dresden. The study cohort (n=158) was divided into two subgroups. The extended LEF cohort (eLEF) included all patients who had been treated with LEF (n=103) or with LEF/MTX (n=49) at any time between 2007 and 2015. The post MTX cohort (pMTX group) included all patients who had been treated with LEF (n=39) or LEF/MTX (n=16) as second-line therapy after failure of first-line MTX between 2007 and 2015. Treatment survival was assessed using Kaplan-Meier curves, and clinical outcome in the first year was assessed using scoring systems (CDAI). In addition, side effects, discontinuation reasons, and radiographic progression were analyzed. In both the eLEF group and the pMTX group, there was a significantly worse overall therapy survival in combination therapy of LEF/MTX compared to monotherapy with LEF (eLEF p=0.004; pMTX p=0.002; significance level p=0.05). There were no significant differences in the clinical course, only the start score of the combination therapy was significantly higher than under monotherapy. Both therapy regimens were able to achieve an average improvement from moderate to low disease activity, but not to remission. Overall, a high dropout rate was present within the first year of treatment regardless of the therapy regimen. The main discontinuation reason (except in the pMTX group on LEF/MTX) was efficacy failure, affecting approximately one in two patients. The other major reason for discontinuation was side effects, affecting approximately one in four to five patients. In addition, more side effects occurred with combination therapy than with monotherapy. Radiographic progression did not play a relevant role in the present cohort. In summary, the present study shows some evidence that combination therapy is not superior to monotherapy. Therefore, it would be quite justifiable to aim primarily for monotherapy when changing therapy, which could have a positive effect on interactions with other drugs, on side effects, and on patient compliance, taking into account the long-term need for therapy and the higher patient age. At the same time, costs could be saved. Due to the unconvincing course in the longer term, a switch to a second csDMARD (or the establishment of a combination therapy) after failure of MTX should, according to the EULAR guidelines, only be made in the absence of poor prognostic factors and at an higher age, as well as with close-meshed therapy monitoring (clinical, laboratory, radiological). Nevertheless, with worldwide occurrence of the disease, medication with LEF continues to be a less expensive alternative for countries where additional resources are scarce.:Inhaltsverzeichnis V Abbildungen VIII Tabellen X Glossar XII Akürzungsverzeichnis XIX 1 Einleitung und Fragestellung 1 2 Die Rheumatoide Arthritis (RA) 3 2.1 Epidemiologie 3 2.2 Ätiologie 4 2.2.1 Genetische Veränderungen 4 2.2.2 Epigenetische Veränderungen 5 2.2.3 Nicht genetische Faktoren/Umwelt 5 2.3 Pathophysiologie/Pathogenese 8 2.3.1 Synovium 8 2.3.2 Weitere Antikörper 12 2.3.3 Krankheitsverlauf 12 2.4 Klinisches Bild 14 2.4.1 Gelenkbefall 14 2.4.2 Differentialdiagnosen 16 2.4.3 Extraartikuläre Manifestationen 19 2.4.4 Sonderformen 23 2.5 Diagnostik 23 2.5.1 Labor 24 2.5.2 Bildgebung 25 2.6 Therapie 27 2.6.1 Medikamentöse Basistherapie 27 2.6.2 Weitere Aspekte zum Einsatz von bDMARDs/ tsDMARDs 32 2.6.3 Einschätzung der Krankheitsaktivität 33 2.6.4 Ko-Medikation und begleitende nichtmedikamentöse Therapien 36 2.7 Prognose 37 2.7.1 Komorbiditäten 39 2.7.2 Mortalität 40 3 Leflunomid (LEF) 42 3.1 Wirkmechanismus 42 3.2 Pharmakologische Aspekte 43 3.3 Arzneimittelinteraktionen 44 3.4 Wirksamkeit 45 3.4.1 Klinisch 45 3.4.2 Radiologischer Progress 46 3.4.3 Kombinationstherapien 47 3.5 Nebenwirkungen 48 3.5.1 Spezielle Nebenwirkungen 49 3.6 Praktische Anwendung 55 3.7 Kontraindikationen 56 4 Studienergebnisse 58 4.1 Material und Methoden 58 4.2 Patientenpool und Vergleichsgruppen 59 4.2.1 Weitere Subgruppen 64 4.2.2 Patientencharakteristika 66 4.2.3 Nachverfolgung 67 4.3 Therapieüberleben 68 4.3.1 Ergebnisübersicht: Therapie- und Patientengruppen 68 4.3.2 Ergebnisübersicht möglicher Einflussfaktoren 69 4.4 Therapieverlauf im ersten Jahr 78 4.4.1 Ergebnisübersicht CDAI 78 4.4.2 Ergebnisübersicht SDAI 80 4.4.3 Ergebnisübersicht DAS28 81 4.4.4 Entzündungsparameter 83 4.4.5 Therapiewirksamkeit und Therapieabbruch 87 4.4.6 Vorliegen von Prognosefaktoren 89 4.5 Nebenwirkungen 93 4.5.1 Ergebnisübersicht eLEF-Gruppe 93 4.5.2 Ergebnisübersicht pMTX 96 4.6 Absetzgründe 100 4.6.1 Ergebnisübersicht 100 4.7 Röntgenprogress 103 4.7.1 Ergebnisübersicht 103 5 Interpretation und Diskussion 105 5.1 Therapieüberleben 105 5.2 Therapieverlauf im ersten Jahr 108 5.3 Nebenwirkungen 111 5.4 Therapievergleiche 113 5.5 Röntgenprogress 115 6 Schlussfolgerung 117 7 Anhang 120 7.1 Zusäzliche Abbildungen zu Kapitel 2 120 7.2 Zusäzliche Analysen zu Kapitel 4 122 7.2.1 LEF-Erstlinie 122 7.2.2 Therapieüberleben: Zusätzliche Vergleiche in Abhängigkeit der Therapie 123 7.2.3 Therapieüberleben in Abhängigkeit vom Zeitpunkt der Kombinationstherapie 126 7.2.4 Therapieverlauf im ersten Jahr: Statistische Tests 128 7.2.5 Zusammenhang zwischen CRP bzw. BSG und CDAI für pMTX 133 7.2.6 Nebenwirkungen in Abhängigkeit vom Serostatus 134 7.2.7 pMTX-LM-L-Gruppe 135 7.3 Zusäzliche Analysen zu Kapitel 5 136 7.3.1 LEF und Prednisolon 136 8 Literaturverzeichnis 139