If topical corticosteroids and moisturisers fail in the treatment of atopic dermatitis, short-term treatment with topical calcineurin inhibitors such as tacrolimus or pimecrolimus may be tried. Both tacrolimus and pimecrolimus are effective and safe to use in AD.[9][10]
In January 2006, the United States Food and Drug Administration (FDA) announced that Elidel packaging would be required to carry a black box warning regarding the potential increased risk of lymph node or skin cancer, as for the similar drug tacrolimus, whereas current practice by UK dermatologists is not to consider this a significant real concern and they are increasingly recommending the use of such new drugs.[11]
Importantly, although the FDA has approved updated black-box warning for tacrolimus and pimecrolimus, the recent report of the American Academy of Dermatology Association Task Force finds that there is no causal proof that topical immunomodulators cause lymphoma or nonmelanoma skin cancer, and systemic immunosuppression after short-term or intermittent long-term topical application seems an unlikely mechanism.[12]
Another recent review of evidence concluded that postmarketing surveillance shows no evidence for this systemic immunosuppression or increased risk for any malignancy.[13]
A 2023 systematic review and meta-analysis published in The Lancet Child & Adolescent Health further concluded with moderate-certainty evidence that the two drugs were not associated with any increased risk of cancer.[14]
However, strong debates and controversies continue regarding the exact indications of immunomodulators and their duration of use in the absence of active controlled trials.[15]
Dermatologists' and allergists' professional societies, the American Academy of Dermatology,[16]
and the American Academy of Allergy, Asthma, and Immunology, have protested the inclusion of the black box warning. The AAAAI states "None of the information provided for the cases of lymphoma associated with the use of topical pimecrolimus or tacrolimus in AD indicate or suggest a causal relationship."[17]
Pharmacology
Pimecrolimus is an ascomycin macrolactam derivative. It has been shown in vitro that pimecrolimus binds to FKBP1A and also inhibits calcineurin.[citation needed] Thus pimecrolimus inhibits T-cell activation by inhibiting the synthesis and release of cytokines from T-cells. Pimecrolimus also prevents the release of inflammatory cytokines and mediators from mast cells.[citation needed]
Pimecrolimus, like tacrolimus, belongs to the ascomycin class of macrolactam immunosuppressives, acting by the inhibition of T-cell activation by the calcineurin pathway and inhibition of the release of numerous inflammatory cytokines, thereby preventing the cascade of immune and inflammatory signals.[18]
Pimecrolimus has a similar mode of action to that of tacrolimus but is more selective, with no effect on dendritic (Langerhans) cells.[19]
It has lower permeation through the skin than topical steroids or topical tacrolimus[20] although they have not been compared with each other for their permeation ability through mucosa. In addition, in contrast with topical steroids, pimecrolimus does not produce skin atrophy.[21]
Development and production
Pimecrolimus was developed by Novartis. Its development number was ascomycin derivative ASM 981.[22]
The New Drug Application (NDA) was filed December 15, 2000. It received US FDA approval on December 13, 2001.[23]
At its US approval, it was one of the first new eczema treatments introduced since the topical corticosteroids of the 1950s.[24]
It is available as a topical cream, once marketed by Novartis. Since early 2007, Galderma has been promoting the compound in Canada. The trade name is Elidel.
^Firooz A, Solhpour A, Gorouhi F, Daneshpazhooh M, Balighi K, Farsinejad K, et al. (August 2006). "Pimecrolimus cream, 1%, vs hydrocortisone acetate cream, 1%, in the treatment of facial seborrheic dermatitis: a randomized, investigator-blind, clinical trial". Archives of Dermatology. 142 (8): 1066–1067. doi:10.1001/archderm.142.8.1066. PMID16924062.
^Kreuter A, Gambichler T, Breuckmann F, Pawlak FM, Stücker M, Bader A, et al. (September 2004). "Pimecrolimus 1% cream for cutaneous lupus erythematosus". Journal of the American Academy of Dermatology. 51 (3): 407–410. doi:10.1016/j.jaad.2004.01.044. PMID15337984.
^Gorouhi F, Solhpour A, Beitollahi JM, Afshar S, Davari P, Hashemi P, et al. (November 2007). "Randomized trial of pimecrolimus cream versus triamcinolone acetonide paste in the treatment of oral lichen planus". Journal of the American Academy of Dermatology. 57 (5): 806–813. doi:10.1016/j.jaad.2007.06.022. PMID17658663.
^Boone B, Ongenae K, Van Geel N, Vernijns S, De Keyser S, Naeyaert JM (2007). "Topical pimecrolimus in the treatment of vitiligo". European Journal of Dermatology. 17 (1): 55–61. doi:10.1684/ejd.2007.0093 (inactive 1 November 2024). PMID17324829.{{cite journal}}: CS1 maint: DOI inactive as of November 2024 (link)
^Jacobi A, Braeutigam M, Mahler V, Schultz E, Hertl M (2008). "Pimecrolimus 1% cream in the treatment of facial psoriasis: a 16-week open-label study". Dermatology. 216 (2): 133–136. doi:10.1159/000111510. PMID18216475. S2CID35741213.
^Scheinfeld N (July 2004). "The use of topical tacrolimus and pimecrolimus to treat psoriasis: a review". Dermatology Online Journal. 10 (1): 3. doi:10.5070/D35ZK7V6CS. PMID15347485.
^Devasenapathy N, Chu A, Wong M, Srivastava A, Ceccacci R, Lin C, et al. (January 2023). "Cancer risk with topical calcineurin inhibitors, pimecrolimus and tacrolimus, for atopic dermatitis: a systematic review and meta-analysis". The Lancet. Child & Adolescent Health. 7 (1): 13–25. doi:10.1016/S2352-4642(22)00283-8. PMID36370744. S2CID253470127.
^Berger TG, Duvic M, Van Voorhees AS, VanBeek MJ, Frieden IJ (May 2006). "The use of topical calcineurin inhibitors in dermatology: safety concerns. Report of the American Academy of Dermatology Association Task Force". Journal of the American Academy of Dermatology. 54 (5): 818–823. doi:10.1016/j.jaad.2006.01.054. PMID16635663.
^Spergel JM, Leung DY (July 2006). "Safety of topical calcineurin inhibitors in atopic dermatitis: evaluation of the evidence". Current Allergy and Asthma Reports. 6 (4): 270–274. doi:10.1007/s11882-006-0059-7. PMID16822378. S2CID40761750.
^Devasenapathy N, Chu A, Wong M, Srivastava A, Ceccacci R, Lin C, et al. (January 2023). "Cancer risk with topical calcineurin inhibitors, pimecrolimus and tacrolimus, for atopic dermatitis: a systematic review and meta-analysis". The Lancet. Child & Adolescent Health. 7 (1): 13–25. doi:10.1016/S2352-4642(22)00283-8. PMID36370744. S2CID253470127.
^Stern RS (September 2006). "Topical calcineurin inhibitors labeling: putting the "box" in perspective". Archives of Dermatology. 142 (9): 1233–1235. doi:10.1001/archderm.142.9.1233. PMID16983018.
^Meingassner JG, Kowalsky E, Schwendinger H, Elbe-Bürger A, Stütz A (October 2003). "Pimecrolimus does not affect Langerhans cells in murine epidermis". The British Journal of Dermatology. 149 (4): 853–857. doi:10.1046/j.1365-2133.2003.05559.x. PMID14616380. S2CID26517363.
^Billich A, Aschauer H, Aszódi A, Stuetz A (January 2004). "Percutaneous absorption of drugs used in atopic eczema: pimecrolimus permeates less through skin than corticosteroids and tacrolimus". International Journal of Pharmaceutics. 269 (1): 29–35. doi:10.1016/j.ijpharm.2003.07.013. PMID14698574.
^Murrell DF, Calvieri S, Ortonne JP, Ho VC, Weise-Riccardi S, Barbier N, Paul CF (November 2007). "A randomized controlled trial of pimecrolimus cream 1% in adolescents and adults with head and neck atopic dermatitis and intolerant of, or dependent on, topical corticosteroids". The British Journal of Dermatology. 157 (5): 954–959. doi:10.1111/j.1365-2133.2007.08192.x. PMID17935515. S2CID34706897.
