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Januskinase-Inhibitoren

State of the Art im klinischen Einsatz und Zukunftsperspektiven

Janus kinase inhibitors

State of the art in clinical use and future perspectives

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Zeitschrift für Rheumatologie Aims and scope Submit manuscript

Zusammenfassung

Hintergrund

In der Pathogenese von Autoimmunerkrankungen spielen Zytokine und deren intrazelluläre Signalkaskaden eine zentrale Rolle. An dieser intrazellulären Signalübertragung sind auch sog. Januskinasen (JAK) beteiligt. Die zur Gruppe der „targeted synthetic disease-modifying antirheumatic drugs“ (tsDMARDs) zählenden Januskinase-Inhibitoren (JAKi) sind eine relativ junge und vielversprechende Wirkstoffklasse in der Therapie autoimmuner Krankheitsbilder.

Wirksamkeit

Mittlerweile sind für die Behandlung der rheumatoiden Arthritis (RA) drei Wirkstoffe, Tofacitinib, Baricitinib und Upadacitinib, in den USA, der Schweiz und der EU zugelassen. Auch Filgotinib, ein weiterer JAKi, zeigt vielversprechende Ergebnisse in der Therapie der RA. Darüber hinaus wurde Tofacitinib auch für die Therapie der ulzerativen Kolitis und der Psoriasisarthritis zugelassen. Zusätzlich zu den bereits genannten wurden und werden weitere JAKi wie Filgotinib oder Peficitinib in zahlreichen Studien zu Indikationen wie atopische Dermatitis, ankylosierende Spondylitis oder systemischer Lupus erythematodes untersucht.

Sicherheit

Als Immunsuppressiva weisen JAKi eine mit Biologika vergleichbare erhöhte Inzidenz für schwere Infekte auf. Bemerkenswert ist die erhöhte Reaktivierung des Varicella-Zoster-Virus. Auch Zytopenien treten unter JAKi-Therapie überhäufig auf. Klinisch relevant ist hierbei v. a. die beobachtete Lymphopenie, die mit einem erhöhten Auftreten von schweren Infekten assoziiert ist. Ein erhöhtes Risiko besteht weiterhin für thromboembolische Ereignisse, insbesondere Lungenembolien. Die Risiken hinsichtlich metabolischer Veränderungen und des Auftretens maligner Neoplasien sind vergleichbar mit denen unter Biologikatherapie.

Abstract

Background

Cytokines and associated intracellular signal cascades play a major role in the pathogenesis of autoimmune diseases. Janus kinases (JAK) are part of these intracellular signal transduction processes. A relatively new drug group of targeted synthetic disease-modifying antirheumatic drugs (tsDMARD) are JAK inhibitors (JAKi) and are a promising treatment approach for autoimmune diseases.

Efficacy

Hitherto, three JAKis, Tofacitinib, Baricitinib and Upadacitinib, have been approved for treatment of Rheumatoid Arthritis (RA) in the USA, Switzerland and the EU. Filgotinib, another JAKi, also showed promising results in the treatment of RA. Furthermore, tofacitinib received approval for the treatment of ulcerative colitis and psoriatic arthritis. In addition to the JAKis already mentioned, several other JAKis, e.g. filgotinib and peficitinib, are being and were investigated in various studies on indications, such as atopic dermatitis, ankylosing spondylitis and systemic lupus erythematosus.

Safety

Being immunosuppressants, JAKis show an elevated incidence of severe infections, comparable to biologics. The increased reactivation of varicella zoster virus is especially noteworthy. Under JAKi treatment cytopenia is also more frequent. Lymphopenia under JAKi treatment is of particular clinical relevance because of its association with an increase in the number of severe infections. Furthermore, an elevated risk of thromboembolic events, particularly pulmonary embolism has been noted. The risks concerning metabolic alterations and the occurrence of malignant neoplasms are comparable to those under treatment with biologics.

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Correspondence to R. Alten.

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Interessenkonflikt

R. Alten gibt an, von AbbVie Vortragshonorare, von Gilead Sciences, Eli Lilly und Pfizer Vortrags- und Beraterhonorare erhalten zu haben. Weiterhin erhielt sie Forschungsunterstützung von Gilead Sciences, Eli Lilly und Pfizer. T. Dörner gibt an, von Gilead Sciences Beraterhonorare und von AbbVie und Eli Lilly Vortrags- und Beraterhonorare erhalten zu haben. Weiterhin erhielt er Forschungsunterstützung von AbbVie und Eli Lilly. M. Mischkewitz und A.‑L. Stefanski geben an, dass kein Interessenkonflikt besteht.

Für diesen Beitrag wurden von den Autoren keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien.

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Alten, R., Mischkewitz, M., Stefanski, AL. et al. Januskinase-Inhibitoren. Z Rheumatol 79, 241–254 (2020). https://doi.org/10.1007/s00393-020-00768-5

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