Calcineurin inhibitors

Group of immunosuppressive drugs that bind in complexes to specific mediators ( cyclophilin to cyclosporin A, tacrolimus to the protein FKBP12). These complexes in turn bind to calcineurin and thus prevent the activation of transcription factors (NFAT, NFKB), which leads to a reduced synthesis of interleukin-2 in the T helper cells.

The cell cycle remains in the G0 phase, without transition to the G1 phase of the cell cycle; T cell activation is thus inhibited.

See also Tacrolimus (^Protopic®), Pimecrolimus (^Elidel®), Ciclosporin A (^{Immunosporin®}).

Furthermore, calcineurin inhibitors bind to the capsaicin receptor and thus trigger neurogenic inflammation. On the one hand, this explains the initial burning sensation of the therapy and, on the other, its antipruritic effect.

In addition to the known indications for Ciclosporin A (systemic: autoimmune diseases and diseases with impaired keratinization), Tacrolimus (systemic: autoimmune diseases, psoriasis vulgaris), Pimecrolimus and Tacrolimus (topical: atopic eczema), the use of calcineurin inhibitors for the topical treatment of psoriasis vulgaris is also discussed in the literature. In principle, all of the drugs mentioned in this group are considered to have antipsoriatic potency.

Ciclosporin, topical: The topical application of Ciclosporin, however, is inadequate due to the galenic preparation. Ciclosporin is characterized by lipophilicity, high molecular weight and a ring structure, which impair penetration through the skin.

Tacrolimus, topical: Tacrolimus is currently approved in a 0.1% or 0.03% lipophilic ointment for the topical treatment of atopic eczema. Previous applications in the form of a 0.3% ointment for the treatment of psoriasis have not yet shown any efficacy. To date, efficacy has only been observed in inverse psoriasis (apply tacrolimus ointment 0.1% twice a day).

Pimecrolimus, topical: Similar experience is available for pimecrolimus; clinical effects have been observed with occlusive application of a 0.1% lipophilic cream. Successes in psoriasis inversa and in children have been described in individual cases. In summary, the individual galenic systems must be optimally developed for efficient topical applications. The evaluation of the antipsoriatic potency in controlled studies remains to be seen.

Tacrolimus (^Protopic®)

Pimecrolimus (^Elidel®)

Ciclosporin A (^{Immunosporin®}; ^Ikervis®)

In children, most topical calcineurin inhibitors represent an off-label use.

The safety of topical calcineurin inhibitors and thus their use was called into question in 2006 by a "black box warning" issued by the FDA. A cautious prescription of calcineurin inhibitors was recommended, particularly in children, due to a possible increased risk of skin cancer and lymphoma. However, a systematic analysis of the study situation by various However, a systematic analysis of the study situation of various authors could not prove an increased incidence of lymphoma or skin cancer compared to the normal population.

Leading European dermatologists and the American Academy of Dermatology (AAD) also believe that the fears are no longer justified.

Satisfactory to good results were obtained for Pimecrolimus (10mg/g cream - twice daily) in 2439 children (PETITE study) from 3 months of age. It was applied twice daily at the first signs of itching or eczema. Pimecrolimus had no effect on the child's growth and no increase in infections was observed.

An algorithm developed by an international group of experts recommends the short-term (3-4 days) use of mild topical glucocorticoids (class I according to Niedner) for acute symptoms of mild to moderate atopic eczema, followed by a combination with local calcineurin inhibitors and continued monotherapy with calcineurin inhibitors as required.

1. Huang C et al. (2014) Pimecrolimus cream 1% in the management of atopic dermatitis in pediatric patients: a meta-analysis. PLoS One doi: 10.1371/journal.pone.0093095

2. Lee SJ et al. (2014) Functional interpretation of metabolomics data as a new method for predicting long-term side effects: treatment of atopic dermatitis in infants. Sci Rep. doi: 10.1038/srep07408

3. Luger T et al. (2013) Recommendations for pimecrolimus 1% cream in the treatment of mild-to-moderate atopic dermatitis: from medical needs to a new treatment algorithm. Eur J Dermatol 23:758-66

4. Po-Chien Wu et al. (2021) Topical calcineurin inhibitors and the risk of lymphoma: a systematic review and meta-analysis. JDDG 19:1265-1270

5. Salgo R (2011) Difficult decisions in dermatotherapy in children: topical calcineurin inhibitors in children: often off label, very carefully or not at all? Abstract-CD 46th DDG-Conference: AKS17/04.