34 Dithranol

317 34 Dithranol M. Kucharekova, PC.M. van de Kerkhof, J. Schalkwijk, P.G.M. van der Valk Contents at the C9, and a methylene group at the C10 position (Fig. 1). It is easily oxidized at the C10 methylene 34.1 Introduction . 317 group by air, light, water, high temperature, and al- 34.2 Mechanism of Action . 317 kali and it is also quickly oxidized when it comes into 34.3 Factors Influencing Dithranol Irritation . 318 contact with the skin. Trace metals, enzymes, proteins, 34.4 Relation Between the Concentration of and also coal tar enhance oxidation. In the oxidiza- Dithranol and Dithranol Irritation . 319 tion process free radicals are formed, which are essen- 34.5 Dithranol Irritation and Skin Bar- tial for the antipsoriatic activity. The free radicals are rier Function . 319 34.6 Dithranol Irritation and Treat- cytotoxic and responsible for the therapeutic action ment Results . 319 on lesional skin and irritation of (peri)lesional skin. 34.7 Concomitant Treatment and Di- These reactive agents damage cell membranes and thranol Irritation . 319 mitochondria, causing antirespiratory and antipro- 34.8 Treatment of Dithranol Irritation . 320 liferative effects in lesional skin. The oxidation prod- 34.9 Histopathology of Dithranol Irritation . 320 ucts (danthron, dithranol dimers and anthraquinone 34.10 Electron Microscopy . 320 dimers) have minimal or no effect on psoriasis. The 34.11 How to Avoid Dithranol Irritation . 321 anthraquinone dimers are responsible for the purple References . 321 brown staining. 34.1 Introduction Dithranol (1,8-dihydroxy-9-anthrone), also known as cignolin and anthralin, is a very effective topical antipsoriatic therapy [1]. It has no serious side effects and offers a very good systemic and cutaneous safety profile. Because of its high efficacy, long-term remission times, and safety it may be considered as a time- honored principle. Dithranol has two drawbacks: skin irritation and temporary discoloration of the skin, as well as permanent discoloration of garments, furni- ture, and sanitary. To avoid this permanent discolor- Fig. 1. Chemical structure of antipsoriatic anthrones ation, precautions have to be taken to avoid contact between dithranol and these materials. Without a mild inflammation there is no therapeutic action. Because the skin adapts to dithranol exposure, the concentration or contact time has to 34.2 Mechanism of Action be increased every 3–4 days to obtain a maximal therapeutic effect. The dose and time increments are Dithranol is an aromatic compound consisting of no goal in itself. As long as a mild erythematous re- three benzene rings (anthracene derivative) with two sponse ensues, no adjustments are needed. However, hydroxyl groups at the C1 and C8, a carboxyl group if the skin comes into contact with concentrations 318 M. Kucharekova, PC.M. van de Kerkhof, J. Schalkwijk, P.G.M. van der Valk Fig. 2. Dithranol irritation of uninvolved skin that are too high, skin irritation may result (Fig. 2). dose (MID) may optimize finding of the starting dose The erythematous response has its maximum after [2]. We could, however, not detect a positive dose re- 48–72 h and subsides in 4–7 days after discontinua- lationship between the severity of the irritation and tion of treatment although in serious cases it may last concentrations varying from 0.05% to 0.6% in an ex- for weeks. Because of such painful irritation, but also perimental patch test design in 13 healthy volunteers because of the possibly negative effect on treatment (own observation, unpublished data). Other factors duration, increments in time or concentration have could be a subject of research to predict susceptibility to be fine-tuned [2–5]. to dithranol. A polymorphism of TNF-α gene is the first demonstrated genetic marker for irritant susceptibility in normal individuals [9]. Whether or not this 34.3 Factors Influencing Dithranol marker may contribute to screening of individuals Irritation deemed at risk of increased susceptibility to dithranol remains to be seen. The sensitivity of the skin to dithranol displays large In contrast with detergent-induced irritation (SDS), variations from time to time, but also between in- there seems to be no association between dithranol dividuals. Some patients are extremely sensitive; irritation and gender, age, horny layer thickness, and even positive reactions to concentrations as low as season of the year [2]. Nevertheless, there are other 0.00025% if patch tested can be observed [6]. It still factors relevant to dithranol irritation like the vehi- remains an issue of discussion whether dithranol sen- cle, [6, 10] application frequency [11], and skin type sitivity represents a delayed-type allergy or a nonim- [2]. Sensitivity to dithranol varies with location; the munological phenomenon. Dithranol probably has a face, body flexures, axillae, scrotum, breasts, and in- minor contact sensitivity potential and therefore an ner sides of the thighs are the most vulnerable parts increased reactivity to dithranol most likely reflect- of the body. The psoriasis lesions are less sensitive to ing increased susceptibility rather than an allergic the oxidative dithranol irritation than the surround- response [7, 8]. The question arises whether it is pos- ing skin [12, 13]. Dithranol sensitivity is dependent sible to predict susceptibility to dithranol. In analogy on the status of the skin. Inflammatory conditions as to the minimal erythema dose (MED) for ultraviolet well as damage to the horny layer make the skin more light, the determination of the minimal irritation vulnerable. Pretreatment with corticosteroids, which 34 Dithranol 319 Fig. 3. Frequency of irritant reactions during the treatment of 68 inpatients with dithranol in relation to the concentration of Fig. 4. The number of day’s patients have to interrupt the ther- dithranol. Dithranol (in petrolatum) is applied diffusely (in- apy with dithranol because of irritation volved and uninvolved skin) for 24 h make the horny layer thinner, may make the skin rolatum. Pronounced erythema occurred but an in- more vulnerable and phototherapy (UVB radiation or creased of transepidermal water loss, an indicator for PUVA), which makes the horny layer thicker, renders damage to the skin barrier, was not observed [15]. the skin less vulnerable [14]. 34.6 Dithranol Irritation and 34.4 Relation Between the Treatment Results Concentration of Dithranol and Dithranol Irritation Strong responses to dithranol may result in cessation of treatment for 1 or more days because of the We studied dithranol skin irritation in 68 patients redness and pain of uninvolved skin. An interesting visiting our inpatient department for psoriasis treat- question is whether skin irritation and consequent ment from 1999 till March 2001. At the inpatient de- cessation of treatment results in a shorter or longer partment the patients are treated with dithranol in treatment period. In other words, is dithranol irrita- petrolatum and the ointment is applied diffusely over tion beneficial in terms of treatment duration, or is it the skin (both involved and uninvolved skin). Dose not beneficial because of the days the treatment has to increments are done every 3–4 days. Figure 3 shows be stopped? Recently, we found a significant negative the frequency of irritation-episodes in relation to the correlation between the number of days of stopped concentration of dithranol in the vehicle. Only the treatment due to dithranol irritation and the num- episodes when patients experienced irritation that ber of days of treatment needed to achieve clearance caused temporary cessation of treatment are shown. of skin in a population of patients with moderate to It is remarkable that most episodes occur at the start severe plaque psoriasis. This suggests that avoidance of the therapy with relatively low concentrations. Fig- of dithranol irritation is to be preferred for optimal ure 4 shows the number of days patients were not treatment results [16. treated because of irritation per episode. Mostly the irritation was mild and short lasting, but apparently it may be more serious in some cases. 34.7 Concomitant Treatment and Dithranol Irritation 34.5 Dithranol Irritation and Skin Combined topical treatment with skin irritants like, Barrier Function e.g., vitamin D analogs may be beneficial but may increase the susceptibility to dithranol. Phototherapy In an experimental design we exposed the skin dur- combined with dithranol treatment may have an ad- ing 1 h using a patch test technique and studied skin ditional/synergistic effect on the rate of clearance and irritation by dithranol 3% in cream, paste, and pet- duration of remission of the psoriasis lesions if cor- 320 M. Kucharekova, PC.M. van de Kerkhof, J. Schalkwijk, P.G.M. van der Valk rectly dosed. However, the dose increments must be filtrate in the dermis [29]. Models in which dithranol carefully tuned, because both modalities can cause irritation is experimentally induced in skin of non- erythematous reactions [17–19]. psoriatics and uninvolved skin of psoriasis patients Tar, although an irritant in itself under certain con- may be helpful to assess the dynamics of clinical and ditions, may have an additional effect on the clear- (immuno)histopathological changes and the effects of ance of lesions and may be helpful in avoiding but not therapeutic agents. in the treatment of dithranol irritation [20 21]. The We studied the response of the skin of healthy vol- latter may be at least in part due to inactivation of di- unteers to single and repeated applications of dithra- thranol [22]. nol cream. We applied the cream on a 2-cm diameter of the lower back for 1 h, after which the dithranol cream was removed with water. For a single applica- 34.8 Treatment of Dithranol tion we applied dithranol only once and for repeated Irritation applications we applied it once daily during 12 con- secutive days [30]. Secondly, we studied the response Dithranol irritation can be treated by topical corti- of uninvolved skin of patients with psoriasis to single costeroids, although some authors state that it would and repeated application of dithranol cream [31].

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