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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 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 . 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 remis- sion 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 thera- peutic 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 ( 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 suscep- tibility 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 cessa- tion 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., 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]. In be ineffective [14, 23]. Topical corticosteroids sup- addition to a clinical evaluation, we studied aspects press inflammation and symptoms like redness and of epidermal proliferation, differentiation, and in- pain. However, steroids may also make the epidermis flammation. A marked erythema appeared 48 h after thinner and may make the skin more vulnerable to application of dithranol in both models in psoriasis dithranol irritation. Consequently, the use of topical patients and healthy subjects. corticosteroids may increase dithranol irritation in After single challenge we observed an induction the long run and may influence the effectiveness of of the cornified envelope precursor protein involu- dithranol therapy. It is generally accepted that corti- crin and the cross-linking enzyme transglutaminase costeroid monotherapy gives shorter remission times I followed by hyperproliferation in the epidermis. It as compared with dithranol treatment, and combined is remarkable that dithranol increases the number of treatment may therefore shorten remission times. On cycling cells in nonlesional skin and decreases the the other hand, Munro et al. showed, using a left-right number of cycling cells in the psoriasis lesions. The comparison, that dithranol-treated sides have shorter expression of the protein filaggrin in the stratum remissions as compared to the sides treated with po- granulosum was significantly decreased after 4 days. tent corticosteroid [24]. Recently, we showed a syn- Langerhans cells decreased early after application. T ergistic action of combined treatment on psoriatic lymphocytes and to a lesser extent polymorphonu- lesions in terms of treatment duration with equal re- clear granulocytes (PMN) were found to be signifi- mission times; however, extra care may be needed to cantly increased. The dynamics as observed in these avoid (serious) irritation [25]. Clinical trials, however, studies suggests the importance of the suprabasal must be carried out to study the effect of combined compartment in the hyperproliferative reaction to treatment of psoriasis with topical corticosteroids dithranol irritation. The response in skin of healthy and dithranol on treatment duration and remission subjects resembled the response in uninvolved skin times. Emollients are useful to cool and soothe the of psoriasis patients; however, the response was much skin in case of irritation. Anti-inflammatory effects more pronounced in the latter group. with emollients and other modalities like tar and The dynamics in changes after repeated challenge nonsteroidal anti-inflammatory drugs (indometha- are comparable with those after single application. In cin, scopolamine) in dithranol irritation are not to be view of the differences between skin of healthy volun- expected [23, 26–28]. teers and uninvolved skin of patients with psoriasis it may be advisable to use uninvolved skin of patients in studies on the interference of dithranol irritation by 34.9 Histopathology of Dithranol various therapeutic agents. Irritation

Histopathological changes observed in dithranol are 34.10 Electron Microscopy intercellular edema, intracellular vacuolation, and hydropic degeneration in the epidermis followed by In a study of dithranol irritation of the skin, the full a hyperproliferative response and a mononuclear in- sequence of events characteristic for apoptosis has 34 Dithranol 321 been shown. The formation of colloid bodies in the 8. Viluksela M. Characteristics and modulation of dithranol upper dermis was observed. Dithranol also caused fi- (anthralin)-induced skin irritation in the mouse ear model. brillar degeneration of melanocytes and Langerhans Arch Dermatol Res 1991; 283:262–268 cells, indicating that colloid bodies in the upper der- 9. Allen MH, Wakelin SH, Holloway D, Lisby S, Baadsgaard mis could partly derived from these cell types [32]. O, Barker JN, et al. Association of TNFA gene polymor- phism at position -308 with susceptibility to irritant con- tact dermatitis. Immunogenetics 2000; 51:201–205 34.11 How to Avoid Dithranol 10. Prins M, Swinkels OQ, Kolkman EG, Wuis EW, Hekster. Irritation YA,van der Valk PG. Skin irritation by dithranol cream. A blind study to assess the role of the cream formulation. Although dithranol is a very effective topical treat- Acta Derm Venereol 1998; 78:262–265 11. Lawrence CM, Howel D, Shuster S. The inflammatory re- ment for psoriasis, it should be used in experienced sponse to anthralin. Clin Exp Dermatol 1983; 9:336–341 hands. Proper patient selection is mandatory. Instable, 12. Paramsothy Y, Lawrence CM. Time course and intensity of pustular, or erythrodermic psoriasis should not be anthralin inflammation on involved and uninvolved psori- treated with dithranol. Patients must be thoroughly atic skin. Br J Dermatol 1987; 116:517–519 guided, instructed, and monitored during therapy 13. Schallreuter KU, Pittelkow MR. Anthralin inhibits elevated to ensure proper concentration and, if relevant, ap- levels of thioredoxin reductase in psoriasis. A new mode of plication time adjustments. The preparation must be action for this drug. Arch Dermatol 1987; 123:1494–1498 of the highest quality to ensure constant potency. De- 14. Juhlin L. Factors influencing anthralin erythema. Br J Der- composition by, e.g., light should be avoided and the matol 1981; 105(Suppl.):20 stability should be guaranteed by proper selection of 15. Snater E, Janssen EA, van der Valk PG, van de kerkhof PC. the vehicle and limited storage times. Transepidermal water vapour loss is not increased during Concomitant topical treatment, especially with and following dithranol irritation. Br J Dermatol 1995; potentially irritating modalities like, e.g., vitamin D- 132:908–912 derivatives or salicylic acid should be carried out with 16. Swinkels OQ, Prins M, Veenhuis RT de Boo MJP, Gerrit- care. Also oral or systemic treatment may make the sen GJ, van der Wilt PCM. Effectiveness and side effects skin more vulnerable to dithranol irritation. of UVB-phototherapy, dithranol inpatients therapy and a care instruction programme of short contact dithranol in moderate to severe psoriasis. An open randomised trial. References Eur J Dermatol 2004; 14:159–165 17. Carrozza P, Hausermann P, Nestle FO Burg G, Boni R. 1. van de Kerkhof PC. Dithranol treatment in psoriasis: after Clinical efficacy of narrow-band UVB (311 nm) combined 75 years, still going strong. Eur J Dermatol 1991; 1:79–88 with dithranol in psoriasis. An open pilot study. Dermatol- 2. Kingston T, Marks R. Irritant reactions to dithranol in nor- ogy 2000; 200:35–39 mal subjects and psoriatic patients. Br J Dermatol 1983; 18. van der Vleuten CJ, Gerritsen MJ, de Jong EM et al. A novel 108:307–13 dithranol formulation (Micanol): the effects of mono- 3. Lawrence CM, Shuster S. 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Skin Pharmacol 1990; 3:1–20 1988; 118:429–434 6. Prins M, Swinknels OQ, Bouwhuis S, de Gast MJ, Bouw- 21. Bratzke B, Albrecht G, Orfanos CE. [Skin reaction to di- man-Boer Y, van der Valk PG, et al. Dithranol in a cream thranol and its modification by the addition of tar (LCD)] preparation: disperse or dissolve? Skin Pharmacol Appl Hautreaktion auf Dithranol und ihre Beeinflussung durch Skin Physiol 2000; 13:273–279 Teerzusatz (LCD). Hautarzt 1987; 38:356–360 7. Loffler H, Effendy I, Happle R. Skin susceptibility to di- 22. Whitefield M. Degradation of anthralin by coal tar [letter]. thranol: contact allergy or irritation? Eur J Dermatol 1999; J Am Acad Dermatol 1987; 16:629 9:32–34 23. Misch K, Davies M, Greaves M et al. Pharmacological stud- ies of anthralin erythema. Br J Dermatol 1981; 105 (Suppl) 20 322 M. Kucharekova, PC.M. van de Kerkhof, J. Schalkwijk, P.G.M. van der Valk

24. Munro DD, Rustin MHA. Corticosteroids. In: Mier PD, 29. Willis CM, Stephens CJ, Wilkinson JD. Epidermal damage van de Kerkhof PC (eds) Textbook of psoriasis, 1st edn. induced by irritants in man: a light and electron micro- Churchill Livingstone, Edinburgh, 1986; pp 168–177 scopic study. J Invest Dermatol 1989; 93:695–699 25. Swinkels OQ, Prins M, Kucharekova M Gerritsen MJ, van 30. Swinkels OQ, Prins M, Birker L, Gerritsen MJ, van der Valk der Valk PG, van de Kerkhof PC. Combining lesional short- PG, van de Kerkhof PC. The response of normal human contact dithranol therapy of psoriasis with a potent topical skin single and repeated application of dithranol cream: an corticosteroid. Br J Dermatol 2002; 146:621–626 immunohistochemical assessment. Skin Pharmacol Appl 26. van de Kerkhof PC, Timmerman MG. The effect of clo- Skin Physiol 2002; 15(4):262–269 betasol-17-propionate and crude coal tar on dithranol- 31. Swinkels OQ, Prins M, van Vlijmen-Willems IMJJ, Gerrit- induced inflammation. A clinical and biochemical study. sen MJ, van der Valk PG, van de Kerkhof PC. The response Acta Derm Venereol 1990; 70:434–437 of uninvolved skin of patient with psoriasis to single and 27. Swinkels OQ, Kucharekova M, Prins M, Gerritsen MJ, van repeated application of dithranol cream: an immunohis- der Valk PG, van de Kerkhof PC. The effects of topical tochemical assessment. Skin Pharmacol Appl Skin Physiol corticosteroids and a coal tar preparation on dithranol in- 2002; 15(6):385–392 duced irritation in patients with psoriasis. Skin Pharmacol 32. Kanerva L. Electron microscopic observations of dyskera- Appl Skin Physiol 2003; 16(1):12–17 tosis, apoptosis, colloid bodies and fibrillar degeneration 28. Duhra P, Ryatt KS. Lack of additive effect of coal tar com- after skin irritation with dithranol. J Cutan Pathol 1990; bined with dithranol for psoriasis. Clin Exp Dermatol 17:37 1988; 13:72–73