Therapy

Alexandra KATSAROU1 Manolis MAKRIS2 Konstantina PAPAGIANNAKI1 Eirini LAGOGIANNI1 Anna TAGKA1 Dimitrios KALOGEROMITROS2
Department of Dermatology, A. Sygros Hospital, 5 I.Dragoumi Str, Kesariani, Athens, 11621, Greece 2 Allergy Unit, Attikon University Hospital, University of Athens, Greece
1

Eur J Dermatol 2012; 22(2): 192-6

Tacrolimus 0.1% vs mometasone furoate topical treatment in allergic contact hand eczema: a prospective randomized clinical study
Background: Tacrolimus is a macrolide immunosuppressant that has been demonstrated to inhibit T-lymphocyte activation without the sideeffects of corticosteroids. The safety prole of tacrolimus makes it a promising therapeutic option for dermatitis. Objectives: To evaluate and compare the therapeutic ability of tacrolimus 0.1% ointment and mometasone furoate 0.1% ointment in patients with chronic hand eczema and positive patch tests. Methods: Thirty adults with chronic hand eczema and positive patch test reaction to relevant contact allergens were treated with tacrolimus 0.1% ointment or mometasone furoate 0.1% ointment in a single-centre, randomized comparative study. Results: The scores of the evaluated clinical parameters (erythema, inltration, vesiculation, desquamation, presence of cracks and itching) did not differ between Groups A and B at any of the four time points (p>0.05).On the other hand, in both groups, a signicant difference was detected in all parameters between baseline and Day 90 recorded values. Conclusions: Tacrolimus is a promising alternative therapy for contact dermatitis patients as it is effective from the rst month of treatment, well tolerated and offers similar therapeutic results to topical corticosteroid therapy. Key words: allergic contact dermatitis, hand eczema, mometasone furoate, tacrolimus

Reprints: A. Katsarou <alkats.duoa@yahoo.gr>

Article accepted on 11/27/2011

and dermatitis (HD) is a common, chronic relapsing skin condition. The management of HD can sometimes be very difcult because both endogenous and environmental factors are involved. Allergic contact dermatitis (ACD) represents a unique and large proportion of HD cases. In an interesting study by Li and Wang [1], patch testing, the key diagnostic tool for ACD diagnosis, revealed 55% positive reactions to different sensitizers in a population with vesicular hand eczema. Besides, the North American Contact Dermatitis Group reported that 13.8% of eczema patients with hand involvement suffered from ACD as the only underlying diagnosis [2]. Treatment of allergic HD is a difcult procedure that sometimes may last lifelong; avoidance of the responsible allergens is difcult, even impossible in certain cases, thus relapses of clinical manifestations are very frequent. Topical corticosteroids represent the main therapeutic choice for ACD but the commonly observed side effects [3], especially after long term use, make the need for alternative topical treatment very important. Tacrolimus (TAC), a macrolide immunosuppressant, has been demonstrated to inhibit T-lymphocyte activation [4]. Topical tacrolimus has been reported to exert benecial results in many immunologically-mediated dermatoses, including ACD [5-7] and irritant eczema. Mometasone furoate 0.1% (MF) is a strong corticosteroid, widely prescribed nowadays with a satisfying therapeutic ratio. Recent

studies have been performed in order to compare MF with TAC in the suppression of nickel elicited ACD [5] and in the treatment of dyshidrotic palmar eczema [8]. The aim of this open-label study was to evaluate and compare the therapeutic ability of topical tacrolimus 0.1% ointment in patients with chronic hand eczema and positive patch tests, in a randomized mometasone furoate 0.1% ointment controlled study.

Materials and Methods

Patients
The study was designed as a single-centre, randomized comparative protocol. Study participants were recruited from patients suffering from chronic hand eczema who were referred to the Contact Dermatitis Clinic, a specic Unit of the Department of Dermatology in Andreas Sygros Hospital (Medical School, Athens University) and were selected arbitrarily. Two patients refused to participate because of their inability to be present at the subsequent follow-ups due to long distance. Inclusion criteria were: a) age 18 years, b) chronic hand eczema present at least 6 months before referral to our Clinic,
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doi:10.1684/ejd.2011.1615

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To cite this article: Katsarou A, Makris M, Papagiannaki K, Lagogianni E, Tagka A, Kalogeromitros D. Tacrolimus 0.1% vs mometasone furoate topical treatment in allergic contact hand eczema: a prospective randomized clinical study. Eur J Dermatol 2012; 22(2): 192-6 doi:10.1684/ejd.2011.1615

c) positive patch testing reactions relevant to patient records (patients history and occupation) of HD, d) absence of atopy documented with a negative personal and family atopic history and total serum IgE concentration 100 IU/mL, e) avoidance of topical and systemic corticosteroids and/or immunosuppressants for the preceding two weeks before study onset.

Any adverse effect due to the therapy was recorded. All patients signed an informed consent while the study protocol was approved by the Andreas Sygros ethical Committee. All the patients were given a detailed instruction sheet outlining the allergens that should be avoided.

Statistical analysis
The Friedman test for k related samples was used for the evaluation of VAS values of all parameters at different time points in each study Group. Wilcoxon non-parametric test for 2 related samples was carried out in order to estimate statistical signicance in the recorded VAS values at the baseline visit and the Day 90 visit. The Mann-Whitney test was used for the comparison of VAS scoring at each of the four time points according to treatment (Group A vs Group B). A p value <0.05 was considered as statistically signicant.

Study design
According to the study design, patients were randomized according to random numbers in a computerized way. Two Groups were formed, each consisting of fteen individuals. Group A included 7 males (mean age 34) and 8 females (mean age 39) and Group B consisted of 6 males (mean age 32) and 9 females (mean age 40). Most of the patients had a diffuse type of hand eczema affecting palmar and nger sides as well as the back of the hands. Both groups, before clinical evaluation, were treated for 3 days morning and night with clobetasol proprionate 0.05% cream. Afterwards, Group A used TAC ointment 0.1% twice daily (morning and evening) topically on hand lesions for the rst 30 days and once daily (evening) during the following two months (31st to 90th day), and Group B used MF ointment 0.1% twice daily (morning and evening) for the 1st week, once daily (evening) during 2nd and 3rd week, once daily three times per week for 2 weeks and two times per week once daily until the 90th day of the study period. Besides this, emollients were used in both groups, several times per day but with a two-hour interval from the use of the above mentioned treatments. In Group B the intermittent use of mometasone after the 3rd week was chosen in order to eliminate adverse effects of topical steroids [8]. An investigators assistant enrolled and assigned the treatment of the participants while the clinical evaluation was performed by a group of three investigators, in order to make the assessments more objective as the investigators were unaware of the patients group. The clinical evaluation took place by the same investigator group for each patient at four time points: Day 0: after three days treatment with clobetasole proprionate 0.05% (baseline visit), Day 30, Day 60 and Day 90 after 30, 60 and 90 days of treatment respectively. As far as the clinical evaluation was concerned the two groups were mixed and at each visit the Visual Assessment Score (VAS) was recorded for each of the following clinical manifestations: (a) erythema, (b) inltration, (c) vesiculation, (d) desquamation, (e) presence of cracks and (f) itching. A ve point scoring system was used for each parameter: 0 no signs of disease 0.5 extension of the symptom <10 cm2 and slight intensity of the symptoms 1.0 extension of the symptom <10 cm2 and well dened symptoms or extension >10 cm2 and slight intensity of symptoms 2.0 extension of the symptom<10 cm2 and moderate intensity of symptoms or extension >10 cm2 and well dened symptoms. 3.0 extension of the symptom >10 cm2 and moderate to severe symptoms
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Results
The prole of contact allergen sensitizations in the study population, according to patch testing, is presented in Table 1. The recorded values of the examined parameters at each time point for both Groups are presented in Table 2. The scores of the evaluated clinical parameters did not differ between the Group A and B at any of the four time points (P>0.05). In both groups a signicant difference was detected in all parameters between baseline and Day 90 recorded values (gure 1). One patient from group A as well as one patient from group B relapsed even though they responded to the therapy for the rst 2 months. The estimated p values were: erythema 0.001 in group A and 0.001 in group B, inltration 0.004 in both groups, vesiculation 0.013 in both groups, desquamation 0.001 in both groups also, cracks 0.002 in the tacrolimus group and 0.003 in the mometasone group respectively and itching 0.001 in both groups. The decrease in the recorded values in each parameter after treatment reached statistical signicance in both groups from the Day 30 assessment for erythema, desquamation, cracks and itching (gure 2). On the contrary, while in the mometasone group the p value referring to inltration
Table 1. Allergen contact sensitization in Study population
Thiuram Mix Group A (tacrolimus) 6 Group B (mometasone) 4

Nickel Sulfate Potassium Dichromate Fragrance Mix Balsam of Peru Cobalt Chloride Colophony PPD black rubber Total (No of reactions)

11 4 4 3 1 1 2 32 in 15 patients

10 2 2 2 2 2 1 24 in 15 patients

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Table 2. Visual assessment Scores (total score and mean value) in study population at different time points
Group A (tacrolimus) Baseline Day 30 Day 60 Day 90 Group B (mometasone) Baseline Day 30 Day 60 Day 90

Erythema Inltration Vesiculation Desquamation Cracks Itching

38.0 1.90 19.5 0.97 12.0 0.60 30.0 1.5 22.5 1.12 41.5 2.07

25.5 1.27 13.5 0.67 8.0 0.40 11.0 0.55 5.5 0.27 19.5 0.97

17.5 0.87 9.5 0.47 3.5 0.17 5.5 0.27 3.5 0.17 14.5 0,72

16.5 0.82 10.0 0.5 4.5 0.22 6.0 0.3 4.0 0.20 12.0 0.6

26.0 1.74 12.5 0.84 9.5 0.64 20.5 1.37 13.0 0.87 30.0 2.00

13.0 0.87 6.0 0.40 3.0 0.20 5.0 0.34 4.0 0.27 10.5 0.70

10.0 0.67 4.5 0.30 2.5 0.17 2.5 0.17 2.0 0.13 9.5 0.63

9.0 0.60 5.5 0.37 4.0 0.27 2.0 0.13 3.0 0.20 7.0 0.47

Figure 1. A) Photo of the same patient from group A (tacrolimus) at Day 0 and (B) Day 30 of the clinical study.

(Day 30 vs Baseline) was 0.003 (statistically signicant), in the tacrolimus patients it was not signicant (p=0.084); vesiculation scores also differed between the two Groups. In Group A, the p value referring to vesiculation was not statistically signicant (p=0.057) while in Group B it was statistically signicant (p=0.008). We should mention that neither the topical corticosteroid therapy nor the treatment with tacrolimus ointment 0.1% succeded in the elimination of all parameters at the same time.

Discussion
The treatment of allergic contact hand dermatitis over the years has been frustrating, with few safe and effective

Figure 2. A) Photo of a patient from group A (tacrolimus) at Day 0 and (B) Day 30 of the clinical study.

long-term options. Topical corticosteroids are nowadays the mainstay of therapy for allergic contact dermatitis but the need for long-term therapy with potent corticosteroids is associated with multiple side effects including atrophy, telangiectasia, striae, acne, folliculitis, other local adverse effects and systemic absorption. In addition, the development of tachyphylaxis or tolerance to their therapeutic effects and the potential for delay in epidermal regeneration are signicant drawbacks to the use of topical corticosteroids that have forced scientists to search for better therapeutic alternatives [5, 9]. Tacrolimus is a topical macrolactam immunosuppressant that inhibits not only calcineurin and the expression of genes for cytokine production but also inhibits T lymphocyte activation and dermal skin Langerhans cells [10]. Mometasone furoate 0.1% belongs to a class of corticosteroids characterized by their intrinsic potency and their improved therapeutic ratio [5]. A recent study has shown mometasone furoate 0.1% and tacrolimus 0.1% to be approximately equipotent in the treatment of dyshidrotic palmar eczema [8]. According to Fujii et al topical tacrolimus demonstrated suppressive effects as potent as those of betamethasone valerate when used as treatment to a rats ear with chronic allergic contact dermatitis induced by repeated application of oxazolone [11]. Our ndings complement those of our previous study which showed the efcacy of tacrolimus ointment 0.1% in the treatment of allergic contact dermatitis [12] and that of Saripalli et al, who showed that tacrolimus 0.1% appeared
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Table 3. P values of visual assessment scores in groups A and B between different time points
Group A (tacrolimus) D0-3rd month D0-1st month D0-2nd month 2nd -3rd month Group B (mometasone) D0-3rd month D0-1st month D02nd month 2nd -3rd month

Erythema Inltration Vesiculation Desquamation Cracks Itching

0.001 0.004 0.013 0.001 0.002 0.001

0.002 0.084 0.057 0.001 0.002 0.001

<0.001 0.002 0.007 0.001 0.003 0.001

0.405 NS 0.366 NS 0.083 NS 0.655 NS 0.739 NS 0.593 NS

<0.001 0.004 0.013 <0.001 0.003 <0.001

<0.001 0.003 0.008 <0.001 0.003 <0.001

<0.001 0.005 0.011 <0.001 0.002 <0.001

0.713 NS 0.366 NS 0.275 NS 0.564 NS 0.317 NS 0.096 NS

to be both safe and effective for the treatment of nickelinduced contact dermatitis [7]. Furthermore, Lauerma et al found that pre-treatment with topical tacrolimus in concentrations ranging from 0.01% to 0.1% inhibited the elicitation of an allergic response within a 5 day period when compared with the placebo [13]. Animal models of contact dermatitis have also been employed. Meingassner et al studied the effect of topically applied tacrolimus ointment 0.4% and 0.04% in comparison with rapamycin, cyclosporine, dexamethasone and clobetasole proprionate. Their study revealed that tacrolimus caused a pronounced inhibition of inammatory skin reactions of hypersensitivity to DNFB; dexamethasone was less effective than clobetasol, whereas rapamycin and cyclosporine were inactive at concentrations of 1.2% and 10% respectively [14]. In addition, Dunkan et al showed that in vivo only tacrolimus suppressed T cell inltration and erythema in comparison with cyclosporine and rapamycin but it did not have effects on keratinocyte growth, which the other agents inhibited [15]. According to Nakada et al, tacrolimus may be effective for allergic contact dermatitis patients who cannot avoid repeated allergen exposure as it may not only reduce inammation but inhibit recurrences [16]. In addition, pimecrolimus is another topical calcineurin inhibitor that has been used as an alternative therapy for chronic hand eczema as well as for contact dermatitis [17, 18]. Topical application of the drugs to the affected areas of the skin was well tolerated in both groups. None of the patients in either group reported any adverse events. In this study we tried hard to exclude patients with atopic dermatitis. We studied only patients in whom allergic contact dermatitis was supported by a positive history of contact reactions to relevant patch test allergens. Furthermore, patients with an ambiguous history of contact reactions and with positive patch tests were excluded from the study. The use of a very potent topical corticosteroid for three days before the clinical evaluation aimed at a fast clinical response and at better patient compliance. In our study, the application of topical tacrolimus or mometasone furoate caused a signicant decrease in the mean visual scores of all parameters between baseline and day 90, although there was no statistically signicant difference between the latter in this period. The decrease of the recorded values in each parameter reached statistical signicance in both groups from day 30 of assessment, except for the p value referring to inltration, which did not reach statistical signicance in group A.

In conclusion, tacrolimus may be considered as a useful alternative therapy for contact allergic dermatitis and as a maintenance therapy for the long-term management of the disease, as it is effective, well tolerated and offers similar therapeutic results to topical corticosteroid therapy. Finally, according to our study, in cases of contact allergic dermatitis characterized by vesiculation and inltration, we should rst apply a topical corticosteroid therapy and use tacrolimus ointment 0.1% as a maintenance therapy (table 3).

Disclosure
Financial support: none. Conict of interest: none.

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