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Published on 27 January 2010

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Topical calcineurin inhibitors: where do they fit?

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Tacrolimus and pimecrolimus offer hope to eczema patients at risk of skin atrophy from long-term topical corticosteroid treatment, provided there is careful prescribing and monitoring

Christine Clark
BSx MSc PhD FRPharmS
FCPP(Hon)
Editor
HPE

Tacrolimus and pimecrolimus are calcineurin inhibitors. This class of drugs was first used as systemic immunosuppressants, for example, to prevent graft rejection in transplant patients. Subsequently it was discovered that they were also active topically and trials showed that they were helpful in the treatment of atopic eczema. The first of these agents to reach the marketplace was tacrolimus (Protopic) and pimecrolimus (Elidel) followed some time later. Both drugs have a useful place in the management of atopic eczema but their licensed indications differ slightly.

Eczema is not a trivial problem. Atopic eczema affects one in five children in the UK and 2-10% of adults. It accounts for one in 30 consultations in community care. It should not be forgotten that skin diseases invade every aspect of people’s lives making it difficult to work, sleep and function generally. For this reason treatments that offer the hope of relief are eagerly grasped and it makes sense for health care professionals to work out how they can be used safely and effectively.

Topical calcineurin inhibitors
Tacrolimus and pimecrolimus both inhibit the calcium-dependent phosphatase calcineurin, which is involved in cytokine regulation. Tacrolimus is a macrolide antibiotic produced by the bacterium Streptomyces tsukubaensis and pimecrolimus is a synthetic derivative of ascomycin — an antibiotic produced by Streptomyces hygroscopicus var ascomyceticus. When used in the treatment of atopic dermatitis these drugs are often described as having an immunomodulatory action rather than immunosuppressant action.

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Topical calcineurin inhibitors in atopic eczema
The topical calcineurin inhibitors (TCIs) tacrolimus and pimecrolimus block the synthesis of pro-inflammatory cytokines in T-cells. In this way they are believed to block part of the inflammatory process that underlies the pathology of eczema. These agents penetrate the skin but absorption through the skin into the systemic circulation is very low. Blood concentrations for tacrolimus are typically below 1ng/ml.[1] Similarly, Pimecrolimus blood concentrations of less than 1ng/ml have been recorded in adults and children with atopic dermatitis.[2]

There is now experience of the use of tacrolimus and pimecrolimus in many thousands of children and adults with atopic dermatitis.[3,4] Short-term studies have examined the effectiveness of TCIs in treating atopic dermatitis [5,6] and long-term studies have examined their effectiveness in preventing flares of the condition.[7,8] The licensed indications for tacrolimus and pimecrolimus are shown in Box 2.

Pimecrolimus (Elidel) should be applied only to the areas of active disease and not to uninvolved skin, much like topical corticosteroids. Tacrolimus (Protopic), is used in the same way but it can also be used for maintenance treatment. In this case it is applied to areas of uninvolved skin that are commonly affected by eczema twice weekly (eg, Monday and Thursday).
The efficacy and tolerability of tacrolimus and pimecrolimus were summarized in a recent systematic review.9 Key points were that:

  • Tacrolimus ointment (both 0.03% and 0.1%), used for three weeks was more effective than hydrocortisone acetate.
  • Tacrolimus ointment 0.1% was as effective as potent topical corticosteroids at three weeks.
  • Tacrolimus ointment 0.1% was more effective than combined treatment with hydrocortisone butyrate 0.1% (potent, used on trunk) and hydrocortisone acetate 1% (weak, used on face) at 12 weeks.

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  • Pimecrolimus was significantly less effective after three weeks than betamethasone valerate 0.1% (a potent corticosteroid).
  • Pimecrolimus cream 1% has not been compared directly with hydrocortisone in any published studies.

Tacrolimus was more effective than pimecrolimus in a six-week study of moderate atopic dermatitis in adults showed that but the frequency of adverse events was similar in the two groups.[10] In a study comparing the two agents in the treatment of moderate to very severe atopic dermatitis in adults, tacrolimus was significantly more effective.[11] However, it should be noted that pimecrolimus is not indicated for treatment of severe atopic dermatitis.

In a one-year open-label study of adults with atopic eczema, tacrolimus ointment 0.1% applied twice daily to areas of actively diseased skin was shown to be safe and effective.[7]

Two studies have shown that early treatment with pimecrolimus cream 1% significantly increases the time between flares (defined as disease that requires treatment with a topical corticosteroid), and reduces the need for topical corticosteroids.[8,12]

Adverse events
The overall adverse-event profiles of tacrolimus and pimecrolimus are similar. The most commonly reported side effect is a sensation of burning on the skin. Other local (application site) reactions such as irritation, pruritus and erythema and folliculitis occur a little less frequently.

Unlike topical corticosteroids, TCIs do not induce skin atrophy or hypothalamic-pituitary-adrenal (HPA) axis suppression. In addition, TCIs can be applied to the skin in all areas, including the neck, face and flexures.

In February 2005 the US Food and Drug Administration (FDA) recommended ‘black box’ warnings for pimecrolimus (Elidel) and tacrolimus (Protopic). The reason for this was the theoretical risk of cancer based on animal studies and a small number of case reports in adults and children treated with Elidel or Protopic. The European Medicines Evaluation Agency (EMEA) followed by launching a safety review to examine the potential risk of skin cancer and lymphoma with TCI treatment.

So far, no causal link between TCI use and malignancy has been identified. Many dermatologists felt that the FDA action was not justified and their views were set out in a consensus statement.[13] A recent review[14] of the safety of tacrolimus pointed out that:

  • TCIs are not associated with reduced immunocompetence in the skin and there is no increase in the incidence of infections with long-term treatment.
  • More than 5.4 million prescriptions for tacrolimus ointment have been issued worldwide, with no evidence of an increased risk of malignancy in adults or children compared with the general population.

TCIs in clinical practice
TCIs fit into the stepped care approach that is currently recommended by many dermatologists and described in recent NICE guidance.[15] Although the guidance is specifically designed for childhood eczema the approach works equally well for adults. Stepped care involves tailoring treatment to the severity of the disease and then stepping up or down according to response. In this scheme, TCIs are placed at the third step that is, after emollients and topical corticosteroids, but before phototherapy or systemic therapy.

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NICE makes the following recommendations about TCIs:

  • Topical tacrolimus and pimecrolimus are not recommended for the treatment of mild atopic eczema or as first-line treatments for atopic eczema of any severity.[16]
  • Topical tacrolimus is recommended, within its licensed indications, as an option for the second-line treatment of moderate to severe atopic eczema in adults and children aged two years and older that has not been controlled by topical corticosteroids, where there is a serious risk of important adverse effects from further topical corticosteroid use, particularly irreversible skin atrophy.[15]

 

  • Pimecrolimus is recommended, within its licensed indications, as an option for the second-line treatment of moderate atopic eczema on the face and neck in children aged two to 16 years that has not been controlled by topical corticosteroids, where there is a serious risk of important adverse effects from further topical corticosteroid use, particularly irreversible skin atrophy.[15]

In practice, what this means it is suitable for patients aged two years and over with mild or moderate atopic dermatitis in whom treatment with topical corticosteroids is either inadvisable or not possible. This would therefore apply to patients who have eczema affecting the face and neck where prolonged intermittent treatment with topical steroids would be undesirable because of the risks of skin atrophy. It would also apply to patients in whom steroids do not work and for those who are intolerant to topical steroids. It should not be forgotten that there is a small group of patients who have allergies to one or more topical steroid products.

Conclusions
Tacrolimus and pimecrolimus have a more selective action on skin than topical corticosteroids and they are generally well-tolerated. Current knowledge suggests that they should be used in the management of atopic eczema when the condition has not been controlled by adequate use of appropriate strength topical corticosteroids or where there is a risk of adverse effects with continued use of topical corticosteroids.

References
1. (Protopic 0.03% and 0.1% Summary of Product Characteristics [SPC], updated 30 April, 2009).
2. (Elidel 1% SPC, updated 26 January, 2009).
3. Alomar A, Berth-Jones J, et al. Br J Dermatol 2004;151(Suppl 70):3–27.
4. Drug Regulatory Affairs. Elidel (pimecrolimus) Cream 1%. NDA 21-302 briefing document: www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4089b2_03_04_Elidel%20Novartis%20Briefing%20Bookredacted.pdf.
5. Ruzicka T, Bieber T, et al. N Engl J Med 1997;337:816–21.
6. Luger T, Van Leent EJ, et al. Br J Dermatol 2001;144:788–94.
7. Reitamo S, Wollenberg A, et al. Arch Dermatol 2000;136:999–1006.
8. Wahn U, Bos JD, et al. Pediatrics 110:e2.
9. Ashcroft DM, Dimmock P, et al. Br Med J 2005;330:516.
10.
Abramovits W, Fleischer AB, et al. Journal of Drugs in Dermatology 2008;7:1153–8.
11. Fleischer AB, Abramovits W, et al. Journal of Dermatological Treatment 2007;18:151–157.
12. Meurer M, Folster-Holst R, et al. Dermatology 2002;205:271–7.
13. Bieber T, Cork M, et al. Dermatology 2005;211:77–78.
14. Rustin MHA. BJD 2007;157:861–873.
15. National Institute for Health and Clinical Excellence (2004) Atopic eczema in children: Management of atopic eczema in children from birth up to the age of 12 years. NICE clinical guideline 57. NICE, London.
16. National Institute for Health and Clinical Excellence. Tacrolimus and pimecrolimus for atopic eczema. Technology Appraisal 82. August 2004. www.nice.nhs.



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