The impact of the frequency of short contact dithranol treatment

ARTICLE

Daily application is the well-established approach in the topical treatment of psoriasis. However, twice-daily applications proved to be more effective as compared to once daily applications in topical vitamin D₃ treatment [1]. On the other hand intermittent treatments have been advocated in topical treatment with corticosteroids [2, 3], an approach which reduces the toxicity potential, without reducing efficacy too much, whilst enhancing compliance.

Dithranol short contact treatment is applied by many dermatologists, mostly in a protocollised treatment regimen in which patients are treated daily. In the department of dermatology of the University Medical Centre St. Radboud at Nijmegen in the Netherlands, dithranol short contact therapy is performed in the day-care unit. The treatment protocol consists of 15-45 min of dithranol application daily. Patients are treated in a care-instruction program. They visit the day-care centre twice a week to be treated and are instructed how to treat themselves at home the other five days of the week. Instruction also includes how to descale, how to treat the scalp if this is not treated with dithranol, how to avoid dithranol staining at home as much as possible, how to apply and wash off the dithranol cream, and how to recognise and react to dithranol irritation. The treatment protocol suits many patients, certainly when it is applied with the necessary flexibility, i.e. lowering the starting concentration or treatment time when a patient is known to be very sensitive to dithranol irritation.

So far, few data are available on the efficacy of dithranol treatment regimens, which deviate from the gold standard of once daily dithranol applications. There are studies which indicate that diminishing the application frequency would significantly lengthen the time needed until clearance [4]. Others studied a twice daily application frequency of dithranol in pasta Lassar and found no shortening of clearance time [5]. We wanted to investigate if increasing the application frequency of short contact dithranol therapy from once to twice daily would enhance the efficacy. Besides that we investigated if decreasing the application frequency to a thrice-weekly schedule, would still be efficacious, as such a schedule might be more feasible for those patients who cannot afford the time for daily applications of dithranol.

Before designing large comparative studies we set out a small-scale trial to find out the efficacy of a twice daily treatment schedule in order to maximise dithranol efficacy and a thrice-weekly treatment regimen in order to maximise compliance of dithranol treatment.

Patients and methods

All patients with plaque psoriasis who were referred to the day-care unit were asked to participate in this study. Patients were not allowed to use oral anti-psoriatics, corticosteroids or immunosuppressives. There were no age limits; patients had to be fit-for-his/her-age. Patients were not included if they had recently (within one month) used oral anti-psoriatics or if they had recently (within two months) been treated in the day-care unit or the dermatological inpatient ward. There was no real rule-out period for topical treatments. When patients visit the outpatient clinic and are referred to the day-care unit, they are instructed only to use indifferent moisturisers until instruction on the day-care unit.

The Psoriasis Area and Severity Index (PASI) was used to monitor the severity of the psoriasis [6]. The "Area of involved skin" expressed the extensiveness of the psoriasis plaques [7]. The PASI and Area were registered weekly. Patients were treated until 90% clearance of the area had occurred. If they wanted to continue treatment at 90% clearance, this was tolerated as long as progress in the treatment result was seen. There was no time limitation, but if clearing of the lesions stagnated, treatment was stopped.

The treatment protocol for twice daily application was essentially comparable with that of once daily application. We used dithranolcream according to the prescription of the Scientific Institute of Dutch Pharmacists (dithranolcream FNA). This cream has a shelf life of 2 to 6 months (depending on dithranol concentration) and was prepared freshly by the patient's pharmacist every time a concentration adjustment was made. Dithranol is dispersed in this cream and it is known to have a clinical efficacy comparable to the cream according to Ros [8, 9]. Table I shows the prescription of the cream.

Treatment was started with a "diffuse application" of dithranolcream 0.1% for 15 min, covering lesional and non-lesional skin. The application time and concentration were kept the same for three days. If no irritation occurred, the application time was lengthened to 30 min for another three days, after which the time was lengthened again to 45 min for three days. If there were no side effects, the dithranol concentration rose to 0.2% and the application time returned to 15 min for three days. This way the dithranol concentration rose every nine days and the application scheme could be applied over and over. If irritation occurred the application time and/or dithranol concentration was lowered. If patients were known or appeared to be sensitive to dithranol irritation, a lower concentration or shorter application time was chosen. Dithranol cream was prescribed in the following concentrations: 0.1%, 0.2%, 0.3%, 0.4%, 0.6%, 0.8%, 1.0%, 2.0%, 3.0% and 5.0%. If a lower concentration was necessary 0.01%, 0.03% or 0.05% could be used. The treatment was performed in the morning and in the evening. The evening application had a fixed duration of 15 min, and was shortened in the case of irritation. This application was diffuse or restricted to lesional skin, depending on the patients' skin reactions and the severity and location of the psoriasis. The dithranol concentrations of the morning- and evening applications were allowed to rise independently. Patients visited the day-care unit daily during the first week of treatment to be instructed and to get used to the treatment. Following the first week, the visits to the day-care unit were limited to twice weekly. The patients treated themselves the remaining five days. Besides dithranol creams, they were allowed to use descaling ointments (10% salicylic acid in vaseline for the skin and 10% salicylic acid in ung. Cetomacrogolis for the scalp), moisturising ointments and, if necessary, intermittent topical corticosteroid lotion (desoximetasone) to treat their scalp.

In the treatment protocol for thrice-weekly treatment it was aimed to keep the speed of increase of dithranol concentration comparable to that during the daily treatment (approximately every 9 days a higher concentration). Application times were lowered to minimise irritation and applications did not exceed 20 min. The dithranol concentration or application time was adjusted every two applications. Dithranol cream was prescribed in the same concentrations as in twice daily treatment. Treatment was started diffusely with a 10 minute application of 0.1% dithranol cream. If no irritation occurred after two applications, the application was lengthened to 20 min. After two applications the dithranol concentration was increased to 0.2% and the application time returned to 10 min. Patients were treated in the day-care unit on Monday, Wednesday and Friday. Dithranol treatment was not performed at home, which makes this treatment suited for patients who are unable to treat at home because of age, immobility or lack of help. Dithranol was prescribed in the same concentrations as in twice daily treatment. At home patients were allowed to use descaling ointments (10% salicylic acid in vaseline for the skin and 10% salicylic acid in ung. Cetomacrogolis for the scalp), moisturising ointments and, if necessary, intermittent topical corticosteroid lotion (desoximetasone) to treat their scalp.

Results

Eight patients (4 men, 4 women, mean age 45.3 years, spread 33-68 years) were treated twice daily and 9 patients (5 men, 4 women, mean age 57.1 years, spread 32-74 years) thrice weekly. The courses of the area during both treatments are figured out for every patient separately in Figure 1 and 2. At the start of treatment a large variation in severity of psoriasis was observed in both treatment groups. However, generally the "twice-daily group" and the "thrice-weekly group" were comparable although patients in the thrice-weekly group tended to have a more widespread psoriasis. One patient from the thrice-weekly group developed a psoriatic erythroderma during the second week of treatment and was left out of the analysis (Fig. 2, pt6). Mean treatment results are illustrated in Table II.

The twice-daily group showed a pronounced improvement. The mean area was reduced by 96.3% and the mean PASI by 94.2% following a treatment time of 12.3 ± 1.6 (mean ± SD). All patients in this group achieved at least 90% clearance.

The thrice-weekly group also showed an impressive improvement. The mean area was reduced by 87.0% and the mean PASI by 82.3% following a treatment period of 13.1 ± 4.2 weeks (mean ± SD). In this group 6 out of 8 patients achieved a clearance of 90% or more. One patient had to stop because of an operation on an aneurysm of the iliac artery (Fig. 2, pt5). This patient had a reduction of the area of 81.5% after 13 weeks of treatment. Another patient wanted to stop treatment because no significant improvement appeared beyond a 72.4% reduction of the area after 15 weeks (Fig. 2, pt.7).

Comparing the twice-daily schedule with the thrice-weekly schedule no meaningful statistical analysis can be given at these sizes of study groups. However these preliminary results provide evidence that the length of treatment is comparable and that the improvement in the thrice weekly group is only slightly inferior to the twice-daily group.

The occurrence of irritation was comparable in both groups. In both treatments 4 patients had to lower the starting dithranol concentration to 0.05% or lower (once 0.03% and once 0.01%) because of irritation. During treatment irritation occurred in five patients of the twice-daily group and in four of the thrice weekly group. To avoid irritation and promote therapy result, the second application in the twice-daily group was performed locally in 5 patients. This way the dithranol concentration of the second application could rise, while the first application could be adjusted to the patient's skin reaction.

Discussion

Since the introduction of short contact therapy in 1980 different contact times and application schemes have been described [4, 10-15]. Runne and Kunze [4] studied the influence of dithranol application, with dithranol in a salicylic acid/ vaseline base, every second or third day and found that it lengthened the treatment time necessary. We also saw a lengthening of treatment time when treatment was performed thrice weekly instead of daily. They also state that patients who treated themselves at home took longer to achieve the same clinical results compared to patients who were treated at the day-care centre. In the twice-daily treatment, patients were expected to treat themselves at home five days a week. The quality and regularity of the treatment in a day care center is not superior per se over home treatment, but it is known that patients' compliance is variable in home treatment. With the treatments performed at the day-care centre one can be sure that they are performed correctly.

Recently a large study was carried out on the cost effectiveness of a care instruction program for short contact dithranol treatment. This approach was a further popularisation of day-care by instructing the patients to carry out the treatment themselves at home. The results of once daily applications in 100 patients will be published soon. The outcome parameters "treatment time", "area at start", "PASI at start" and success-rate (percentage of patients with 90% clearance of the area of involved skin) are summarised in Table III. We cannot really compare the results of our pilot twice daily and thrice weekly study with the outcomes of this large study. The study groups differ too much in size and in the way the studies were set up. But the results of the large once daily application study can function as a standard for the outcomes of the two pilot groups. In a future study it would be possible to overcome the effect of interpersonal variation in reaction to dithranol and the lack of a control group by designing a left-right comparing study. This would also make it possible to study the efficacy of different treatment regimens in relatively small patient groups.

If we compare the twice daily modification with the standard group of the care instruction program for short contact dithranol treatment, we can cautiously state that twice daily dithranol application did not shorten the duration of the treatment as we hoped it would do. Others were also unable to find a benefit from twice daily application. Statham [5] studied the effect of local application of Lassar's paste for two hours twice daily and found no quicker clearance. Still, in our 8 patients, there seemed to be some benefit in clearing the persistent lesions when dithranol was applied twice daily. Also twice daily therapy seemed to be more effective as it did lead to 90% clearance of the psoriasis in all patients. Therefore the twice daily application schedule could be useful in patients having a poor improvement, as an attempt to enhance efficacy.

If we compare the thrice-weekly modification with the standard group, we see an indication that the thrice-weekly treatment regimen can be an effective regimen for patients who are unable to treat at home or every day. Patients and doctors should however be aware that thrice weekly treatment with dithranol takes longer compared to daily treatment and is not a treatment regimen of first choice. Therefore we may offer this intermittent schedule as a treatment approach for those patients for whom daily treatments are not practical. Thrice weekly treatment with short contact dithranol applications might also be used as an additional treatment in combination with UVB-phototherapy [16, 17] or corticosteroids [18]. An intermittent short contact dithranol treatment combined with calcipotriol might prove to be effective as well.

This study was a pilot set up to investigate if there are differences in effectiveness between different treatment regimens and to evaluate if a larger study should be performed to find the best treatment option. Because the two groups we studied are small and heterogeneous in PASI and area, especially in comparison with our reference group, the preliminary conclusion can be that although twice daily and thrice weekly dithranol treatment can be useful for specific patients, once daily dithranol treatment remains the "gold standard". Further studies in larger patient groups are certainly indicated to find out the possibilities of modification of the frequency of dithranol application.

Article accepted on 22/1/01

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