Tacrolimus 0.1% vs mometasone furoate topical treatment in allergic contact hand eczema: a prospective randomized clinical study

Tacrolimus is a macrolide immunosuppressant that has been demonstrated to inhibit T-lymphocyte activation without the side-effects of corticosteroids. The safety profile of tacrolimus makes it a promising therapeutic option for dermatitis.

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.

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.

The scores of the evaluated clinical parameters (erythema, infiltration, 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 significant difference was detected in all parameters between baseline and Day 90 recorded values.

Tacrolimus is a promising alternative therapy for contact dermatitis patients as it is effective from the first month of treatment, well tolerated and offers similar therapeutic results to topical corticosteroid therapy.

ARTICLE

ejd.2011.1615

Auteur(s) : Alexandra Katsarou¹ alkats.duoa@yahoo.gr, Manolis Makris², Konstantina Papagiannaki¹, Eirini Lagogianni¹, Anna Tagka¹, Dimitrios Kalogeromitros²

¹ Department of Dermatology, “A. Sygros” Hospital, 5 I.Dragoumi Str, Kesariani, Athens, 11621, Greece

² Allergy Unit, “Attikon” University Hospital, University of Athens, Greece

Reprints: A. Katsarou

Hand dermatitis (HD) is a common, chronic relapsing skin condition. The management of HD can sometimes be very difficult 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 difficult procedure that sometimes may last lifelong; avoidance of the responsible allergens is difficult, 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 beneficial 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 specific 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,
• c). positive patch testing reactions relevant to patient records (patient's 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.

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 fifteen 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 finger 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 first 30 days and once daily (evening) during the following two months (31^st to 90^th day), and Group B used MF ointment 0.1% twice daily (morning and evening) for the 1^st week, once daily (evening) during 2^nd and 3^rd 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 3^rd week was chosen in order to eliminate adverse effects of topical steroids [8]. An investigator's 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 patient's 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) infiltration, (c) vesiculation, (d) desquamation, (e) presence of cracks and (f) itching.

A five 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 defined 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 defined symptoms.
• 3.0 extension of the symptom >10 cm² and moderate to severe symptoms

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 significance 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 significant.

Results

The profile 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.

Table 1 Allergen contact sensitization in Study population

Table 2 Visual assessment Scores (total score and mean value) in study population at different time points

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 significant difference was detected in all parameters between baseline and Day 90 recorded values (figure 1). One patient from group A as well as one patient from group B relapsed even though they responded to the therapy for the first 2 months. The estimated p values were: erythema 0.001 in group A and 0.001 in group B, infiltration 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 significance in both groups from the Day 30 assessment for erythema, desquamation, cracks and itching (figure 2). On the contrary, while in the mometasone group the p value referring to infiltration (Day 30 vs Baseline) was 0.003 (statistically significant), in the tacrolimus patients it was not significant (p=0.084); vesiculation scores also differed between the two Groups. In Group A, the p value referring to vesiculation was not statistically significant (p=0.057) while in Group B it was statistically significant (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 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 significant 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 rat's ear with chronic allergic contact dermatitis induced by repeated application of oxazolone [11].

Our findings complement those of our previous study which showed the efficacy 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 to be both safe and effective for the treatment of nickel-induced 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 inflammatory 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 infiltration 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 inflammation 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 significant decrease in the mean visual scores of all parameters between baseline and day 90, although there was no statistically significant difference between the latter in this period. The decrease of the recorded values in each parameter reached statistical significance in both groups from day 30 of assessment, except for the p value referring to infiltration, which did not reach statistical significance 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 infiltration, we should first apply a topical corticosteroid therapy and use tacrolimus ointment 0.1% as a maintenance therapy (table 3).

Table 3 P values of visual assessment scores in groups A and B between different time points

Disclosure

Financial support: none. Conflict of interest: none.

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