Medizinische Klinik

, Volume 94, Issue 12, pp 673–680 | Cite as

Rheumatoide Arthritis: Neue molekulare und zelluläre Aspekte

  • Oliver Distler
  • Ulf Müller-Ladner
  • Jürgen Schölmerich
  • Renate E. Gay
  • Steffen Gay
Übersicht

Zusammenfassung

□ Hintergrund

Die rheumatoide Arthritis ist eine chronische systemische Erkrankung bislang ungeklärter Ätiologie, bei det es in den betroffenen Gelenken zu entzündlichen Veränderungen, synovialer Hyperplasie und einer Destruktion des angrenzenden Knorpel- und Knochengerüstes kommt. Mit neu entwickelten molekularbiologischen Methoden konnten in den letzten Jahren wichtige zulluläre und molekulare Abläufe in der Pathogenese der rheumatoiden Arthritis aufgeklärt werden.

□ Ergebnisse

Eines der Schlüsselereignisse in der Pathogenese der rheumatoiden Arthritis ist die zelluläre Aktivierung aggressiv wachsender, matrixabbauender synovialer Fibroblasten. Diese zelluläre Aktivierung ist unter anderem durch eine veränderte Expression apoptoseregulierender Moleküle (zum Beispiel CD 95 und Sentrin) und von Protoonkogenen (zum Beispiel RAS und MYC) gekennzeichnet. Wichtige externe Stimuli sind proinflammatorische Zytokine, die bei der rheumatoiden Arthritis in einem unausgewogenen Verhältnis synthetisiert werden. Erste therapeutische Studien mit zytokinhemmenden Molekülen (Interleukin-1-Rezeptor-Antagonist, rekombinanter löslicher TNF-α-Rezeptor/Etanercept und monoklonale TNF-α Antikörper/Remicade) zeigten vielversprechende Ergebnisse. Etanercept ist seit kurzem in den USA zur Therapie der rheumatoiden Arthritis zugelassen. Das pharmakokinetische Problem einer kontinuierlichen Expression der therapeutischen Moleküle im Gelenk könnte durch Gentransfermethoden gelöst werden; auch hier ist eine erste Studie mit dem Interleukin-1-Rezeptor-Antagonisten durchgeführt worden. Die gelenkdestruktiven Effekte der aktivierten synovialen Fibroblasten werden über matrixabbauende Enzyme, wie die Familie der Matrixmetalloproteasen, vermittelt, deren Beeinflussung ein weiteres therapeutisches Prinzip darstellen könnte.

□ Schlußfolgerung

Die Aufklärung pathophysiologisch wichtiger Stoffwechselwege in der rheumatoiden Arthritis hat zu neuen Ansätzen in der Therapie der Erkrankung geführt. Gentransfermethoden sind für die Erforschung der Pathophysiologie der rheumatoiden Arthritis von großer Bedeutung, die Möglichkeit und Sicherheit eines klinischen Einsatzes sind aber noch durch weitere Studien zu belegen.

Schlüsselwörter

Rheumatoide Arthritis Pathogenese Gentherapie Interleukin-1 TNF-α 

Rheumatoid arthritis: New molecular and cellular aspects

Abstract

□ Background

Rheumatoid arthritis is a chronic systemic disorder of unknown etiology, that is characterized by inflammation, synovial hyperplasia and destruction of the affected joints. Novel molecular biology techniques have identified important cellular and molecular pathways in the pathogenesis of rheumatoid arthritis during the last years.

□ Results

The cellular activation of aggressively growing, matrix-degrading synovial fibroblasts is a key event in the pathogenesis of rheumatoid arthritis. The cellular activation results in an altered expression of apoptosis regulating molecules (for example CD 95 and Sentrin) as well as of protooncogenes (for example RAS and MYC). Important extracellular stimuli such as the pro-inflammatory cytokines interleukin-1 and TNF-α are overexpressed in the rheumatoid arthritis synovium. First clinical trials with cytokine inhibiting molecules (interleukin-1 receptor antagonist, recombinant soluble TNF-α receptor/Etanercept and monoclonal TNF-α antibodies/Remicade) revealed promising results. Etanercept is now available for the treatment of rheumatoid arthritis in the USA. In addition, gene transfer methods could help to overcome the problem of a continuous expression of therapeutic molecules in the affected joints; gene delivery of the interleukin-1 receptor antagonist is currently tested in a human trial. Finally, the inhibition of matrix degrading enzymes such as matrix metalloproteinases, that mediate the joint destructive features of the activated synovial fibroblasts, could be another therapeutic approach.

□ Conclusions

The elucidation of important molecular and cellular pathways in the pathogenesis resulted in novel concepts in the therapy of rheumatoid arthritis. Gene transfer methods are of importance in studying the pathogenesis of the disease, however, their clinical safety and usefulness have to be proven in additional studies.

Key Words

Rheumatoid arthritis Pathogenesis Gene therapy Interleukin-1 TNF-α 

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Copyright information

© Urban & Vogel 1999

Authors and Affiliations

  • Oliver Distler
    • 1
    • 2
  • Ulf Müller-Ladner
    • 1
    • 2
  • Jürgen Schölmerich
    • 1
  • Renate E. Gay
    • 2
  • Steffen Gay
    • 2
  1. 1.Klinik und Poliklinik für Innere Medizin IUniversität RegensburgRegensburgDeutschland
  2. 2.WHO Collaborating Center for Molecular Biology and Novel Therapeutic Strategies for Rheumatic Diseases, RheumaklinikUniversitätsspital ZürichZürichSchweiz

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