How the action of Cyclosporine helps in understanding anti-Il17 and anti-Il23 biologics

• When looking at psoriasis lesions, numerous T cells are present.
• In 1979, cyclosporine was shown to act on psoriasis as a T cell suppressor. Nevertheless, at that time but it was also shown to have an antiproliferative action on keratinocytes. Result: the biological action (cytokine inhibition) was overlooked.

• T cells are stimulated by antigen presenting cells (APC), which are dendritic cells
• In psoriasis lesions, dendritic cells activate T cells which in turn activate cytokines which then activate dendritic cells…ever perpetuating the cycle.
  • Th1 produces interferon gamma (Ifn g)
  • Th2 produces Il4 and Il14 humoral. It is involved in immunity, anti parasitic activity and against allergies
  • In the past high levels of Ifn g and low levels of Il4  were found leading to the conclusion that psoriasis was a Th1 disease

• Th17 T-cells play a key role in the pathogenesis of psoriasis. The have a role to play in autoimmunity, inflammation and against parasites.
• Il-23 is key to generation of Th17 cells
• Cyclosporine also shows an action against Th17 cells

• Il-23 is also highly expressed in T cells of psoriatiic cells and keratinocytes express receptors for Il17 and Il23. Il17 and Il-22 produced by
• T cells induce keratinocytes to produce chemokines. Also Il-22 produced by T cells induces epidermal hyperplasia

• To be activated by antigen presenting cells (APC):
  • Th17 needs Il23 needs to be combined with p30 subunit
  • (Th2 needs Il23 combined with p19 and p40)
  • (Th1 needs Il12 combined with the p35 subunit)

• To conclude biologics are an additional non-negligible therapeutic tool in the treatment of psoriasis:
  • Indeed treatment with topicals is not only impractable when extensive but compliance issues can be raised when applying creams and ointments impairs professional activities (as manipulating a knife for a sushi chef – in Japan where these notes were taken !)
  • Systemic drugs can also pose a problem:
    • etretinate: doesn’t always work and remains teratogenic for a long undetermined time after it is stopped (for acitretin, another vitamin A derivative, pregnancy cannot be strated for at least a year after the treatment is discontinued)pregnancy problems
    • Phototherapy is difficult to use in teenagers as time restraints to come to do the treatment several times a week
    • On the other hand and contrarily to topicals, regular skin visits are needed for biologics, phototherapy and etretintate; slightly less often for cyclosporine

• The problem for cyclosporine: renal failure, high blood pressure…and to a lesser extent increased risk of skin and squamous cell carcinoma, infections as well as gingival hypertrophy.

Contributors

Dr Christophe Hsu – dermatologist. Geneva, Switzerland

Source of information: Yamasaki K. The strategies of psoriasis treatments from the viewpoint of patients’ lifestyle in the era of biologics & Fujita H. Cyclosporine for psoriasis. Novartis Seminar. JSID Annual Meeting (Japanese Society of Investigative Dermatology, 日本研究皮膚科学会) 2014 – Osaka, Japan