Correspondence
Tacrolimus Ointment for Atopic Dermatitis
N Engl J Med 1998; 339:1788-1789December 10, 1998
- Article
To the Editor:
Ruzicka et al. (Sept. 18, 1997, issue)1 reported that tacrolimus (FK 506) ointment is beneficial in the treatment of atopic dermatitis. It is remarkable that an immunosuppressant agent produced a significant improvement in the symptoms of an inflammatory disease after three days of treatment. I suggest that in this disorder, which is characterized by the activation of skin mast cells and infiltrating basophils,2 tacrolimus acts as an antiinflammatory agent by modulating the release of inflammatory mediators. Mast cells and basophils act as both immunoregulators and proinflammatory cells through the release of vasoactive mediators and cytokines (e.g., interleukin-4). Basophils from patients with atopic dermatitis have an increase in the release of histamine after exposure to immunologic and nonimmunologic stimuli.3 Pharmacologic concentrations of tacrolimus exert antiinflammatory effects by inhibiting the immunologically stimulated release of histamine and other proinflammatory agents from basophils4 and skin mast cells.5 Recently, my colleagues and I found that tacrolimus also inhibits the immunologically mediated generation of interleukin-4 from basophils.6 These results, together with the finding that cyclosporine, which also acts on the calcium–calcineurin pathway that regulates the secretion of basophils and mast cells,4,5 suggest that immunophilin-binding drugs are potent antiinflammatory agents.5 Therefore, although tacrolimus has remarkable properties of immunosuppression, its rapid antiinflammatory effect in patients with atopic dermatitis1 is most likely mediated by its effects on the release of proinflammatory and vasoactive mediators from skin mast cells and infiltrating basophils.2 Therefore, patients with other inflammatory skin disorders involving these cells might also benefit from treatment with these compounds.
6 ReferencesGianni Marone, M.D.
University of Naples Federico II School of Medicine, Naples 80131, Italy1
Ruzicka T ,Bieber T ,Schopf E , et al. A short-term trial of tacrolimus ointment for atopic dermatitis. N Engl J Med 1997;337:816-821
Full Text | Web of Science | Medline2
Mitchell EB ,Crow J ,Chapman MD ,Jouhal SS ,Pope FM ,Platts-Mills TA . Basophils in allergen-induced patch test sites in atopic dermatitis. Lancet 1982;1:127-130
CrossRef | Web of Science | Medline3
Marone G ,Giugliano R ,Lembo G ,Ayala F . Human basophil releasability. II. Changes in basophil releasability in patients with atopic dermatitis. J Invest Dermatol 1986;87:19-23
CrossRef | Web of Science | Medline4
de Paulis A ,Cirillo R ,Ciccarelli A ,de Crescenzo G ,Oriente A ,Marone G . Characterization of the anti-inflammatory effect of FK-506 on human mast cells. J Immunol 1991;147:4278-4285
Web of Science | Medline5
de Paulis A ,Stellato C ,Cirillo R ,Ciccarelli A ,Oriente A ,Marone G . Anti-inflammatory effect of FK-506 on human skin mast cells. J Invest Dermatol 1992;99:723-728
CrossRef | Web of Science | Medline6
Patella V ,Giuliano A ,Bouvet J-P ,Marone G . Endogenous superallergen protein Fv induces IL-4 secretion from Human FcεRI+ cells through interaction with the VH3 region of IgE1. J Immunol 1998;161:5647-5655
Web of Science | Medline
To the Editor:
The findings of Ruzicka et al. of the effectiveness of topical tacrolimus in patients with atopic dermatitis, with a trend toward a greater benefit with use of the 0.1 percent concentration as compared with the 0.03 percent concentration, are consistent with the findings of Nakagawa,1 who reported that the 0.1 percent (1 μg per gram) concentration of tacrolimus was optimal. However, I am concerned about the adequacy of the use of vehicle alone (the ointment base) as a control in the study by Ruzicka et al., since 39 percent of the patients who received vehicle withdrew from the study, almost three times as many as in the other groups. Are patients who did not comply with treatment overrepresented in this group, or was compliance not adequately assessed in the other groups? Is this a failure of randomization? There are also no data on the duration of treatment for the patients who withdrew from the study. On average, the vehicle group may have had a shorter duration of treatment, and if the data are analyzed according to the intention to treat, the benefit of the vehicle alone may have been underestimated.
1 ReferencesColin S. Ong, M.B., B.S.
University of Sydney, Sydney, NSW 2050, AustraliaAuthor/Editor Response
The authors reply:
To the Editor: Marone and others have shown that tacrolimus inhibits IgE-induced release of histamine and inflammatory mediators from mast cells and basophils and that this activity is dependent on FK-binding proteins (a class of immunophilins). We have shown that tacrolimus can partially reverse interleukin-3–mediated enhancement of IgE-induced histamine release in peripheral-blood leukocytes in humans, but only if it is present before interleukin-3.1 Mast cells and basophils probably play a part in the pathogenesis of atopic dermatitis; however, tacrolimus has discrete effects on other types of cells of the skin immune system,2 and these seem to be critical in atopic dermatitis. Current knowledge suggests that atopic dermatitis involves a cell-mediated immune reaction in the skin, with infiltrating T cells having a crucial role.3 Thus, the inhibition of T-cell activation by tacrolimus4 must also make a large contribution to the observed efficacy of the drug. Tacrolimus also down-regulates the expression of the high-affinity IgE receptor on Langerhans cells and related antigen-presenting cells in the skin and inhibits their stimulatory activity in vivo.5 One of these factors may predominate; however, it seems likely that they function synergistically in patients with atopic dermatitis. Certainly, the encouraging results of tacrolimus therapy in patients with atopic dermatitis suggest that it would be worthwhile to investigate the use of this drug in patients with other inflammatory diseases and autoimmune diseases.
Dr. Ong was correct in pointing out that more patients withdrew from the vehicle group than from the tacrolimus groups, but this had nothing to do with inadequate randomization or inadequate assessment of compliance. The patients in the vehicle group withdrew from the study because they were not benefiting from the assigned treatment. The use of prohibited therapies (i.e., topical and systemic steroids) was the main reason for withdrawal (13 of 54 patients; 24 percent), followed by adverse events (5 patients; 9 percent), all of which were related to exacerbation of disease. Most of the patients who received vehicle (49 of 54 patients; 91 percent) remained in the study for the first week of treatment. Since the greatest clinical improvement was observed after three days of treatment (P<0.01), with improvement maintained after one week of treatment, the patients who withdrew from the study would have had only a minor effect on the intention-to-treat analysis (a last-value-carried-forward method was used in the analysis). The results were similar when the data were analyzed per protocol.
We would like to apologize to our coauthor Dr. Imtiaz Ahmed for the misspelling of his first name in our report.
5 ReferencesThomas Ruzicka, M.D.
Heinrich Heine University, D-40225 Düsseldorf, GermanySakari Reitamo, M.D.
Helsinki University Central Hospital, FIN-00250 Helsinki, FinlandThomas Bieber, M.D., Ph.D.
Rheinische Friedrich-Wilhelms University, Bonn, Germany1
Eberlein-Konig B ,Michel G ,Ruzicka T ,Przybilla B . Modulation of histamine release in vitro by FK506 and interleukin-3 is determined by sequence of incubation. Arch Dermatol Res 1997;289:606-608
CrossRef | Web of Science | Medline2
Ruzicka T, et al. Tacrolimus: the drug for the turn of the millennium. Arch Dermatol (in press).
3
Thepen T ,Langeveld-Wildschut EG ,Bihari IC , et al. Biphasic response against aeroallergen in atopic dermatitis showing a switch from an initial TH2 response to a TH1 response in situ: an immunocytochemical study. J Allergy Clin Immunol 1996;97:828-837
CrossRef | Web of Science | Medline4
Goto T ,Kino T ,Hatanaka H , et al. FK 506: historical perspectives. Transplant Proc 1991;23:2713-2717
Web of Science | Medline5
Wollenberg A ,Regele D ,Sharma S ,Haberstok J ,Panhans A ,Bieber T . Topical tacrolimus treatment leads to profound alterations of the antigen presenting cells in lesional atopic dermatitis skin. J Invest Dermatol 1996;107:468-468
- Citing Articles (8)
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ANNALISA PATRIZI, IRIA NERI, FEDERICA BIANCHI, BEATRICE PASSARINI, GIAMPAOLO RICCI. (2007) Facial Eruption of Viral Warts in a Child Treated with 0.03% Tacrolimus Ointment for Atopic Dermatitis. Pediatric Dermatology 24:4, 445-447
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Akane Tanaka, Susumu Muto, Kyungsook Jung, Akiko Itai, Hiroshi Matsuda. (2007) Topical Application with a New NF-κB Inhibitor Improves Atopic Dermatitis in NC/NgaTnd Mice. Journal of Investigative Dermatology 127:4, 855-863
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Keung Yeung Chi, Chiu Ma Kwok, Hin Lee Chan Henry. (2006) Efficacy and Safety of Tacrolimus Ointment Monotherapy in Chinese Children With Atopic Dermatitis. SKINmed 5:1, 12-17
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Dene Simpson, Stuart Noble. (2005) Tacrolimus Ointment. Drugs 65:6, 827-858
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Leah M Wilson, Catherine M Reid. (2004) Molluscum contagiosum in atopic dermatitis treated with 0.1% tacrolimus ointment. Australasian Journal of Dermatology 45:3, 184-185
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G. Marone, A. Genovese, F. Granata, V. Forte, A. Detoraki, A. de Paulis, M. Triggiani. (2002) Pharmacological modulation of human mast cells and basophils. Clinical <html_ent glyph="@amp;" ascii="&"/> Experimental Allergy 32:12, 1682-1689
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Fulvio Mastrandrea. (2001) Immunotherapy in atopic dermatitis. Expert Opinion on Investigational Drugs 10:1, 49-63
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Remitz, Reitamo, Erkko, Granlund, Lauerma. (1999) Tacrolimus ointment improves psoriasis in a microplaque assay. British Journal of Dermatology 141:1, 103-107
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