Risk of cancer and opportunistic infections: JAK inhibitors versus biologics
Autor: M. Röcken
Department of Dermatology, Eberhard Karls University Tübingen, Germany
Many immune responses, such as the control of viral infections are critically controlled by cytotoxic T cells (CTL) and by natural killer cells. Because of this, it was long believed that inflammatory and autoimmune diseases are also mainly caused by cytotoxic T cells. For some diseases, like alopecia areata, this is still the prevailing concept.
The identification of first the innate cytokines interleukin (IL-) 1 and tumor necrosis factor (TNF) and then of the T cell cytokines IL-2, interferon (IFN-) g, IL-4, IL-5 and IL-13 strongly suggested that these cytokines critically determine the outcome of both, innate and adaptive immune responses.
The proof-of-concept experiment for the relevance of T cell cytokines in inflammatory diseases was first provided in a model disease for multiple sclerosis, the experimental autoimmune encephalitis (EAE) in mice. In this model disease it was first shown that autoreactive, pro-inflammatory CD4+ T helper cells can cause this autoimmune disease. Moreover, it was shown in vivo that it is possible to deviate the autoreactive proinflammatory CD4+ T helper cells, that produce IFN-g and IL-17, into autoreactive Th2 cells that produce IL-4. This immune-deviation, the induction of autoreactive Th2 cells is a highly efficient therapy of EAE.
Later this IL-4 based therapy of EAE in mice was translated into an IL-4 based therapy of psoriasis. This study provided the proof of concept, that modulation of T cell cytokines can be highly efficient as therapy for human autoimmune diseases. As most cytokines have a short half live in vivo, the industry focused on the modulation of T cell cytokine responses not with cytokines but with antagonistic monoclonal antibodies. Today, many of these novel antibody-therapies were first developed for the treatment for either psoriasis or atopic dermatitis. Now, they have been approved for a large spectrum of inflammatory diseases. The safety concerns depend on the actions of the cytokine that are attenuated. They are well predictable as they affect a well described spectrum of signaling pathways. When used correctly, most cytokine antagonists can safely be used.
As it became clear that many cytokines signal their message to the nucleus through Janus kinases (JAK), JAK inhibitors (JAKi) were developed. JAKi have the advantage of being orally applicable small molecules. JAKi initiated a second revolution in the therapy of autoimmune and inflammatory diseases, with a profound impact on dermatology and rheumatology. However, their clinical success has been accompanied by an increasing number of safety concerns, that warrant careful consideration. This is at least in part due to the effect that more than 20 cytokines mediate their message to the nucleus through as little as four JAK molecules. In consequence, JAKi are never as specific as cytokine antagonists., like monoclonal antibodies. Importantly, three of the four JAK are critically involved in the signaling of the various IFN molecules – cytokines that are essential for the immune responses against viruses, intracellular pathogens and tumors. In consequence, the safety concerns associated with JAKi include a greater susceptibility to viral diseases, mycobacterial infections, and cancer, a potential association with thrombosis, and, in certain patient populations, increased mortality. As a response to these concerns, regulatory agencies, like the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have published warnings, jointly with important pharma companies.
Treating inflammatory skin diseases under financial restrictions
Autor: M. Röcken
Department of Dermatology, Eberhard Karls University Tübingen, Germany
In 2002 it was first shown that psoriasis can efficiently be treated by modifying potentially harmful cytokines produced by T lymphocytes or by antigen presenting cells. In this proof of concept manuscript psoriasis was successfully treated with interleukin 4, a cytokine that impairs the production of IL-23p19 in antigen presenting cells (Ghoreschi K et al. Nature Medicine 2002). Since this proof of concept showing that soluble mediators produced by immune cells can cause inflammatory and autoimmune diseases, multiple therapies were developed to attenuate or block the functions of cytokines. Psoriasis and atopic dermatitis were frequently the first diseases where such cytokine antagonist have been shown to be effective, and they are currently heavily propagated during medical society meetings, in guidelines, and by the industry. While efficient for many diseases, these treatments are marketed at extraordinary high prices and are a major burden for those affected or health care systems. It is therefore time to re-evaluate the efficacy, safety and availability of less expensive drugs, two being methotrexate and glucocorticosteroids.
Controlled trials published over the past 25 years demonstrate that methotrexate is as efficient as cyclosporin A in treating either psoriasis or atopic dermatitis. Methotrexate should not be given to pregnant women and not taken while planning to get children. Otherwise, if applied correctly, 15 mg to 20 mg methotrexate per week are not associated with the metabolic side effects of cyclosporin A and does not sensitize for UV-induced skin cancers. There some few and severe disease conditions where defined cytokine antagonists are much more efficient than methotrexate, such as Hallopeau type or joint psoriasis. Yet, under most conditions, methotrexate seems to be similar effective as the most expensive novel therapies – and in case of very severe atopic dermatitis a short comedication for 2-4 weeks of methotrexate and glucocorticosteroids also strongly improves the most severe manifestations. Importantly, systemic glucocorticosteroids have to be strictly limited to this time. As, in addition methotrexate has an excellent long-term safety, most severe inflammatory skin disease can efficiently and safely be treated at relatively low costs – independent of whether patients are wealthy or have financial restritions.
Scurt CV
Education and academic career
1976 – 1983 Medical Studies, Freie Universität Berlin (Germany), Université Libre de Bruxelles (Belgium, 1976 – 1977), Université de Lausanne (Switzerland, 1980 – 1981) and Universität Bern (Switzerland, 1982 – 1983)
1984 – 1988 Medical training and Consultant, Department of Dermatology and Allergology, City Hospital Munich Schwabing, Teaching Unit of the Ludwig-Maximilians-Universität München (Germany)
1988 – 1991 Research grant of the Deutsche Forschungsgemeinschaft, Department of Dermatology, Université de Genève (Switzerland)
1991 – 1993 Visiting Associate, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland (USA)
1993 – 1998 Assistant Professor, Medical Faculty, Department of Dermatology and Allergology, Ludwig-Maximilians-Universität München (Germany)
1998 – 2002 C3 Professor for Dermatology and Venereology, Medical Faculty, Department of Dermatology and Allergology, Ludwig-Maximilians-Universität München (Germany)
2002 – 2024 C4 Professor for Dermatology and Venereology and Chairman, Medical Faculty, Department of Dermatology, Eberhard Karls Universität Tübingen (Germany)
Clinical and experimental focus
● Tumor immune therapy, tumor immunology
● Autoimmune diseases of the skin and psoriasis: Pathogenesis and novel therapies
● Allergology
● Pathogen-host-interactions during infectious diseases in immune-competent and
immune-compromised hosts, HIV-infection
● Immunology
● Translational medicine
Memberships, faculty positions and editorial boards
JDDG, British Journal of Dermatology, Journal of Investigative Dermatology, Acta Dermatovenerologica (Scandinavia)
Arbeitsgemeinschaft Dermatologische Forschung (ADF), Board of Directors and Secretary Treasurer
European Dermatology Forum (EDF)
European Society for Dermatological Research (ESDR), Board of Directors, President and Secretary Treasurer
Deutsche Dermatologische Gesellschaft (DDG, German Dermatological Society), Board of Directors, Executive Council and Secretary Treasurer
Deutsche Forschungsgemeinschaft (DFG), Vice Chairman of Review Board „Sektion 1: Entzündungsforschung“ (inflammation research)
The German Academy of Sciences Leopoldina
Alfred-Marchionini-Stiftung zur Förderung der medizinischen Wissenschaft
European Skin Research Foundation (ESRF), Board of Trustees
European Academy of Dermatology and Venereology (EADV), Board of Directors,
Executive Committee, Representative of the Board (2012 – 2014),
Chairperson Scientific Programming Committee (2013 – 2018),
President Elect (2020 – 2022), President (since 09/2022)
Honorary Member of the French Society for Dermatology
Academia Europaea (The Academy of Europe)
Honorary Member of the Austrian Society of Dermatology and Venereology
Corresponding Member of the Swiss Society of Dermatology and Venereology
International League of Dermatological Societies (ILDS), Board of Directors,
Chair of the Scientific Programme Committee „World Congress of Dermatology 2023“
Honorary Member of the Società Italiana di Dermatologia
Honorary Member of the European Society for Dermatological Research
Honorary Member of the Sociedade Portuguesa de Dermatologia e Venereologia
Honorary Member of the Swiss Society of Dermatology and Venereology
Honorary Member of the Colegio Ibero Latino Americano de Dermatología
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