Skin susceptibility to dithranol: contact allergy or irritation?

ARTICLE

In 1916, Eugen Galewsky introduced dithranol as a treatment for psoriasis [1]. This drug has been one of the most effective antipsoriatic agents to date. Dithranol (anthralin) is 1,8,9-trihydroxyanthranol [2]; its mode of action in psoriasis is not completely understood. One difficulty is skin irritation, resulting in erythema and/or edema especially in the area surrounding the treated psoriatic plaque. This irritant effect has led to dithranol being used as a model irritant in experimental studies comparing irritant and allergic reactions [3-6].

The irritant effect of dithranol can be overcome using a variety of approaches: reducing the number of applications, combination with glucocorticosteroids, UV-irradiation or tar. Occasionally one comes across patients who suddenly can no longer tolerate dithranol, although the treatment had not caused any problem for years. In the literature two dozen case reports of this type can be found [7-10]. The question as to whether it is an irritant or an allergic reaction to dithranol has not yet been answered [9].

While studying a possible case of dithranol intolerance, we performed patch testing with dithranol in 15 psoriatic patients and 39 healthy volunteers. In order to evaluate individual skin susceptibility, we compared these results to those obtained with a simultaneously conducted irritant test with sodium lauryl sulphate [11].

Patients and method

Patients

The present study was initiated because one of our psoriatic patients had shown an unusual response to dithranol. He had suffered from psoriasis for almost 25 years. For decades he had been treated with dithranol, which was tolerated in concentrations of up to 2%. However, five years earlier, the patient showed a severe reaction to dithranol at a very low concentration (0.06%), resulting in eczematous skin lesions. Since that time the patient no longer tolerated dithranol treament. Additionally, the patient suffered from a chronic, irritative contact dermatitis of the interdigital spaces of his hands.

Fourteen psoriatic individuals, with no history of dithranol incompatibility, as well as 39 healthy volunteers, were patch tested with dithranol ointment. Psoriatics showing skin lesions at the test area were excluded as well as patients receiving systemic antipsoriatic UV treatment. Moreover, volunteers with an atopy score > 7 (calculated using the "Erlanger Atopy-Score" [12, 13]) were not enrolled in the study, because of the risk of an increased irritant skin reaction. The age of the patients was between 18 and 60 years.

Methods

Dithranol in petrolatum was patch tested at different concentrations (0.01%; 0.005%; 0.001% and 0.0005%). No salicylic acid was added and the test substances were used for one day only. In addition, the sodium lauryl sulphate (SLS) test with aqueous 0.5% SLS, was performed as previously described [11]. All test substances were applied for 48 hrs in Large Finn Chambers^® to the medial part of the volar forearm. The tests were double blind and randomized. After 48 hrs, the patches were removed and the skin reaction was evaluated by use of a 4-point scale: 0 = no reaction; 1 = slight erythema, no edema; 2 = moderate erythema, slight edema; 3 = strong erythema, strong edema; 4 = additional: vesicles or necrosis.

Evaluation

Differences in clinical scores between the two test groups were calculated for significance (P < 0.05) using the Mann-Whitney-U-test. The test reaction to dithranol and to SLS was compared using the Pearson correlations-coefficient. The results were further analyzed with descriptive statistics.

Results

Table I, Figures 1 and 2 show the frequency of the positive reactions to dithranol in each test group at two time points. The vehicle alone did not cause a skin reaction. The differences in the degree of the test reaction between psoriatics and healthy controls were not significant. Skin reactions were seen in both groups at a very low concentrations (0.001%). At a concentration between 0.005% and 0.01%, half of all tested persons showed a distinct reaction.

The patient who had prompted the study showed definite skin reactions to dithranol at concentrations as low as 0.001%. Remarkably, he also reacted strongly to SLS 0.5% (Table II).

A slight post-inflammatory hyperpigmentation could be observed after strong reactions to the dithranol test (especially at high concentrations) as well as for the SLS test.

Correlation between reactions to dithranol and SLS

The correlation between dithranol and SLS test results was statistically significant: a strong reaction to dithranol usually paralleled a strong response to SLS (p < 0.01).

Discussion

The question of the existence of a contact allergy to dithranol is a very old one [2, 9]. In the dermatological literature reports on dithranol allergy can be found frequently. However, the proof of such an allergy is problematic. In 1992, an elaborate literature survey was published by Burden et al. [7]. In this survey, most of these reports were anecdotal, no standardized patch testing was performed. A pivotal point appears to be the test concentration of dithranol. Usually, concentrations higher 0.001% have been applied. Such concentrations have been considered as a minimal dithranol concentration causing irritation in individuals with sensitive skin [14, 15].

In our study, both psoriatics and healthy controls showed similar reactions to dithranol and SLS, a widely used irritant. This result confirms the findings of Kingston & Mark [16]. It is noteworthy that 15% of our healthy probands (who had not had any contact with dithranol) had a distinct response to dithranol at a concentration as low as 0.001% after 72 hrs (Table I). Hence, any patch testing regarding the question of sensitization to dithranol should be performed with concentrations lower than 0.001%. Furthermore, the test substances should not contain salicylic acid and should be freshly prepared. Such requirements were not fulfilled in most of the previous studies. Table III provides a survey of dithranol concentrations used and the results obtained. Our results indicate that positive test reactions to dithranol of concentrations higher than 0.001% cannot automatically be classified as an allergic reaction. With this evaluation system, the number of patients with a suspected dithranol allergy would decrease considerably.

There is a trend towards a stronger irritant reaction with the dithranol and SLS tests in psoriatic patients when compared to healthy controls. These values which are not statistically significant may be the result of the predisposition of psoriatic patients to unusual skin reactions to external irritation, such as the Koebner phenomenon.

When a dithranol patch test is performed, a simultaneous patch test with another irritant can be helpful, because additional information regarding genuine skin irritability can be achieved [11]. The present patient with a dithranol intolerance simultaneously showed a strong reaction to the irritant SLS. This result suggests that the pronounced skin reaction to 0.001% dithranol is most likely an irritant effect. Moreover, some healthy controls who showed a pronounced reaction to SLS had likewise a distinct reaction to 0.001% dithranol. Skin reactions to this dithranol concentration seem to represent an irritant effect reflecting genuine skin irritability.

A final answer to the question of possible dithranol allergy cannot be derived from the present study. We can ascertain, however, that dithranol at a concentration of 0.001% can certainly induce an irritant reaction. Patch testing to rule out or to prove a dithranol allergy should, in our opinion, be performed with concentrations lower than 0.001% (e.g., 0.0005%). No salicylic acid should be added to the test ointment as it has been shown that dithranol ointments with salicylic acid among their stabilizers lead to increased skin irritation [17]. In particular, another irritant, e.g., SLS [18, 19] should be tested simultaneously, in order to distinguish between increased skin susceptibility and a delayed-type hypersensitivity.

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