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The management of psoriasis
Netherlands Journal of Medicine 52 Ž1998. 40–45
Review
The management of psoriasis P.C.M. van de Kerkhof
)
Department of Dermatology, UniÕersity Hospital Nijmegen, PO Box 9101, 6500 HB Nijmegen, Netherlands Received 3 April 1997; revised 24 September 1997; accepted 30 September 1997
Abstract A spectrum of treatments is available for patients with psoriasis. It is of utmost importance to individualize the selection of treatment for the individual patient at the very moment of consultation. The manifestation of psoriasis, the extent of the lesions and the subjective discomfort of psoriasis are important factors which denominate the selection of treatment. The most important topical treatments are calcipotriol, dithranol, tar and corticosteroids. If topical treatments are unsuccessful, phototherapy with UVB, photochemotherapy ŽPUVA., methotrexate, cyclosporin and acitretin are the most important therapeutical options. The possibilities and limitations of these treatments will be presented in this review. In particular, the question will be addressed to what extent treatments of psoriasis may have systemic complications. q 1998 Elsevier Science B.V. Keywords: Acitretin; Cyclosporin; Corticosteroid; Dithranol; Methotrexate; Phototherapy; Psoriasis; Treatment; Vitamin D 3
1. Introduction Various treatments are available for patients with psoriasis. Over the last decade, the spectrum of treatments has expanded with the introduction of calcipotriol and cyclosporin. In the present review, a description of the topical and systemic treatments will be provided as well as a comparative analysis of these treatments. Systemic treatments and some topical treatments may have systemic complications. Therefore, insight into these treatments is of value for general medicine. Treatment of psoriasis has to be individualized as every case of psoriasis is different.
)
Tel.: q31 24 3613247; fax: q31 24 3541184.
2. Vitamin D 3 analogues In 1992, calcipotriol was introduced as a treatment of psoriasis. In view of the excellent therapeutic efficacy and the limited toxicity, calcipotriol became a frequently used treatment in chronic plaque psoriasis. In a placebo-controlled study, calcipotriol 50 mgrg in ointment, applied twice daily, proved to result in an impressive improvement in more than 74% of the patients w1x. This response was far better compared to the placebo ointment only. A long-term efficacy and toxicity study was carried out over 12 months involving 161 patients with chronic plaque psoriasis w2x. During the first 8 weeks, the most impressive improvement occurred. Continuation of the treatment did not result in a habituation. The total quantity of 100 g of calcipotriol ointment did not
0300-2977r98r$19.00 q 1998 Elsevier Science B.V. All rights reserved. PII S 0 3 0 0 - 2 9 7 7 Ž 9 7 . 0 0 0 8 1 - 8
P.C.M. Õan de Kerkhofr Netherlands Journal of Medicine 52 (1998) 40–45
induce a significant effect on systemic calcium metabolism. Calcipotriol ointment resulted in irritation of the skin in 20% of the patients, which required discontinuation of the treatment in 5% of them w2x. Comparative studies between calcipotriol and other treatments revealed that calcipotriol was at least as effective as betamethasone and dithranol w3–5x. Combination treatments of calcipotriol and phototherapy with UVB proved to be effective and safe w6,7x. The combination of calcipotriol and photochemotherapy resulted in a significant reduction of the cumulative doses of UVA needed to induce a satisfactory response. The combination of calcipotriol and cyclosporin proved to be a very effective combination w8x. A dose of 2 mgrkgrday of cyclosporin in combination with calcipotriol ointment resulted in a substantial improvement in 50% of the patients, in contrast to the significant improvement in only 11% of the patients treated with 2 mgrkg cyclosporin in combination with the placebo ointment. In other forms of psoriasis, such as pustular, guttate and erythrodermic psoriasis, calcipotriol ointment is not a first-line treatment in view of the potential irritative facts andror the large surface area of involvement resulting in substantial transdermal absorption of calcipotriol. Application of calcipotriol to the face and flexures should be avoided in view of the irritative potential of the drug. In the case of irritation, a topical corticosteroid is indicated. Recently, the combination of calcipotriol and acitretin was proved to result in a reduced treatment time, with an increased number of patients showing a substantial improvement or clearing. Occasionally, hypercalcaemia may occur in patients treated with calcipotriol. Although the usage of more than 100 g of calcipotriol ointment may be the cause of hypercalcaemia, in some patients with systemic disorders of calcium metabolism Žsarcoidosis, metastasized mammary carcinoma. and in patients with renal insufficiency, the use of smaller doses of calcipotriol has been reported to increase serum calcium w9,10x. Although the reported increases following calcipotriol treatment are not alarming, the hazards of long-term hypercalcaemia should not be underestimated.
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3. Tar Probably the oldest treatment of psoriasis is tar. Hippocrates already prepared tar from the ceder tree. In psoriasis, crude coal tar proved to have a substantial therapeutic effect. The variability of the composition of coal tar makes standardization of this treatment virtually impossible w11,12x. Treatment with tar was popularized by Goeckerman, who developed a combined treatment approach of crude coal tar with ultraviolet radiation w13x. The efficacy of tar in psoriasis has been clearly demonstrated. Especially in itchy psoriasis Žinstable psoriasis, guttate psoriasis., tar treatment causes a major reduction of itch. Apart from tar folliculitis and occasional sensitization, no substantial side effects have been reported. Although tar is a carcinogen in animal experiments and is a well-established carcinogen in dermatological treatment, tar can be regarded as a safe therapeutic principal w13–16x. Solutio carbonis detergent is an alcoholic extract of crude coal tar. In contrast to crude coal tar, staining is minimal. The efficacy of this extract, however, is substantially inferior to crude coal tar. Crude coal tar is manufactured in pastes or ointments in a concentration of 1–5%. Solutio carbonis detergent can be manufactured in a cream in concentrations between 10 and 20%. 4. Dithranol In 1916, dithranol was introduced as a treatment of chronic plaque psoriasis w17x. The mode of action proved to be the induction of free radicals in the skin. A slight irritative response is obligatory for a therapeutic response. Dithranol is an unstable product which can be inactivated by oxidation. Oxidation can be recognized by a yellowrbrown discolouration of the preparation. Dithranol can be applied during 24 h a day, or as a short-contact treatment during 5–15 min only. The reduced application time results in a relative decrease of the accumulation of dithranol through the intact skin. Therefore, short-contact dithranol treatment permits a more aggressive treatment of the lesional skin, with relative sparing of the symptomfree skin.
42
P.C.M. Õan de Kerkhofr Netherlands Journal of Medicine 52 (1998) 40–45
The efficacy of dithranol treatment is highly dependent on the intensity of the patient supervision. Treatment at a day-care centre or in-patient department has the highest efficacy. Home treatment with supervision at the day care department once every 2 weeks, has a rather poor therapeutic response w18x. An alternative approach is the care instruction programme where patients are treated and instructed once daily during the first week. Later the patient carries out the treatment at home and is seen twice weekly at the treatment unit. For further information, the reader is referred to a review on dithranol w18x.
5. Corticosteroids Systemic corticosteroids are no longer indicated in psoriasis. If systemic corticosteroids are indicated for other reasons, the dose reduction should be careful as aggravation of psoriasis may occur. Since 1963, topical corticosteroids are a most important treatment modality in psoriasis w19x. The advantage of topical corticosteroids is that they are cosmetically acceptable formulations. Potent topical corticosteroids are very effective in patients with psoriasis. Potent topical corticosteroids should be reserved for crisis intervention. Corticosteroid treatment may relieve patients of psoriasis within a short period of time. In general, patients should be treated once daily, although intermittent treatment Žoncertwice weekly. has been claimed to be very effective w20x. A hazard of long-term treatment is atrophy of the skin: striae, telangiectasias and purpura. Other side effects of topical corticosteroids are hypertrichosis, perioral dermatitis and allergic contact dermatitis. These potent topical corticosteroids may suppress plasma cortisol levels w21x. The application over larger surface areas of skin should be avoided. Prolonged treatment with topical corticosteroids reduces the therapeutic efficacy. It is a well-established fact that the efficacy of a corticosteroid is enhanced considerably by using occlusion. A new approach in recalcitrant chronic plaque psoriasis is the application of topical corticosteroids under a ‘hydrocolloid occlusive’ w22x. Once weekly, the corticosteroids Žeither a lotion or a cream. can be applied to therapy-resistant
plaques, which subsequently are covered by a ‘hydrocolloid’ dressing. ‘Hydrocolloid occlusion’ is well tolerated by the patient. It is of importance that non-dermatologists become aware that a patient using fluorinated topical corticosteroids over large areas for more than 1 month, should be seen by a dermatologist for the institution of another treatment.
6. Photo(chemo)therapy Ultraviolet radiation has an important therapeutic effect in psoriasis. Ultra-violet B ŽUVB. radiation Ž290–320 nm. has a substantial photodynamic effect, whilst the radiation penetrates into the dermal–epidermal transition zone. The therapeutic efficacy of UVB phototherapy in psoriasis is satisfactory in the majority of patients w23,24x. The therapeutic effect of UVA Ž320–400 nm. is limited. Although the radiation penetrates into the deeper layers of the skin, the quantum energy of the radiation is too low for a substantial anti-psoriatic effect. With the combination of ultraviolet A and the ingestion or topical application of a psoralen, a substantial photodynamic and anti-psoriatic effect can be achieved. Both phototherapy with UVB and photochemotherapy require dose management resulting in a slight irritation of the skin. Phototherapy with UVB is indicated in extensive chronic plaque psoriasis and guttate psoriasis. In generalized pustular psoriasis and erythrodermic psoriasis, a restrictive attitude with respect to phototherapy is indicated. Although several studies have demonstrated the carcinogenic potential of phototherapy in humans, treatment with UVB has only a minimal risk of inducing cancer of the skin w25,26x. Contraindications for phototherapy are photodermatoses, the ingestion of phototoxic medication, a previous history of skin cancer and actinic keratoses as well as previous treatments with X-rays, or arsenic ingestion. A family history of melanoma is also regarded as a contraindication for phototherapy. Photochemotherapy ŽPUVA. has a substantially increased anti-psoriatic potential compared to phototherapy with UVB. Side effects of photochemotherapy are erythema, bullae, burning, nausea, itching, pigmentations, PUVA-lentigines, hyper-
P.C.M. Õan de Kerkhofr Netherlands Journal of Medicine 52 (1998) 40–45
trichosis and pain. On long-term treatment with PUVA, multiple squamous cell carcinomas have been induced w26,27x. Contraindications for PUVA are the same as for UVB. Therefore the side effects of PUVA are more severe compared to UVB. Chronic side effects are cataract and hepatotoxicity. PUVA treatment may be considered in case UVB treatment has had insufficient effects. PUVA treatment is indicated in extensive psoriasis, including generalized pustular psoriasis, pustulosis palmoplantaris and erythrodermic psoriasis. In the Scandinavian countries, bath-PUVA has already been applied for years w26–28x. The psoralen is applied via a bath and subsequently the patients are treated with UVA. The advantage of bath-PUVA is the reduced occurrence of nausea. The long-term risk with respect to the induction of squamous cell carcinomata has been reported to be reduced in the case of bath-PUVA as compared to systemic PUVA treatment w26x. It is of practical relevance that patients using systemic medication with a phototoxic potential should refrain from photoŽchemo.therapy or alternatively should discontinue the phototoxic medication. Patients using immunosuppressive treatment should refrain from photochemotherapy as this combination can have a carcinogenic effect w29x. Recently, it was demonstrated that patients receiving 250 PUVA treatments or more had an increased risk of malignant melanoma. Therefore, the cumulative carcinogenic risk of PUVA treatment should not be underestimated w30x.
7. Systemic treatments In recalcitrant manifestations of chronic plaque psoriasis, erythrodermic psoriasis and generalized pustular psoriasis, a systemic treatment may be indicated. Methotrexate, acitretin and cyclosporin are the well-established treatments for psoriasis w31–34x. As these treatments may have serious systemic complications, it is of importance that the departments of general medicine are aware of these complications and that guidelines are formulated in each centre on how to handle the side effects.
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7.1. Methotrexate Methotrexate is very effective in nearly all forms of psoriasis. Intermittent treatment is indicated in order to reduce the toxic potential of this drug. In general, the treatment is prescribed according to the Weinstein scheme Žthree ingestions at 12-h intervals per week.. The Nijmegen centre advises a maximum dose of 15 mg methotrexate per week. According to the literature, doses between 22.5 and 30 mg are accepted, however. Side effects include anorexia, nausea, alopecia, leucopenia, thrombopenia, megaloblastic anaemia. Methotrexate may induce fibrosis and cirrhosis of the liver. In women and men who want to produce children in the short-term, the mutagenic effect of methotrexate has to be considered as males and females must use continuous contraception for at least 6 months after discontinuing methotrexate treatment. Contraindications for methotrexate treatment are substantial liver and kidney disease, pregnancy, a desire to procreate in the short-term, active infections, interaction with other medication, bone marrow hypoplasia, peptic ulceration, ulcerative colitis and patient non-cooperation. During treatment, patients are advised not to take alcohol during the days of methotrexate ingestion. Patients are seen at the out-patient department at 4- to 6-week intervals. Before treatment and after the cumulative dose of 1.5 g methotrexate, a liver biopsy is indicated in order to assess the histological appearance of the liver. This recommendation is in contrast to the approach for methotrexate treatment at the departments of rheumatology for the treatment of rheumatoid arthritis. The side effects of methotrexate proved to be highly dependent on the conditions which indicated the installation of methotrexate treatment. Liver biopsy-controlled patient surveys revealed that the occurrence of serious liver impairment in patients with rheumatoid arthritis treated with methotrexate is very seldom. w35x 7.2. Acitretin Acitretin is a retinoic acid derivative which is indicated as a monotherapy in erythrodermic and pustular psoriasis. In the case of chronic plaque psoriasis, this treatment is very effective in combina-
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P.C.M. Õan de Kerkhofr Netherlands Journal of Medicine 52 (1998) 40–45
tion with phototherapy ŽUVB. or photochemotherapy ŽPUVA.. The dose of acitretin varies between 25 and 75 mgrday. Side effect include dry lips, epistaxis, conjunctivitis, pruritus, skin atrophy, alopecia, dermatitis, decreased visual perception at night, colour blindness and hyperlipidaemia. Incidentally, hepatitis and increased osteophyte formation have been recorded. Women, wishing to become pregnant, must refrain from acitretin as acitretin is teratogenic. Pregnancy should be excluded before initiation of acitretin treatment and for a period of at least 2 years following discontinuation of treatment. No restrictions with respect to male patients should be given. Contraindications for treatment with acitretin are liver disease, hyperlipidaemia, pregnancy and the desire to become pregnant. Before treatment and at monthly intervals, patients are seen at the out-patient department, and serum triglycerides, serum cholesterol and liver function tests are carried out. Before treatment and at yearly intervals, X-ray examination of the spine is advised. Active questioning of the patients with respect to joint complaints is indicated.
calcipotriol as an effective and safe principle. If rapid clearing of lesions is required, a topical corticosteroid can be given for a limited period of time. In case the condition cannot be controlled efficiently with a short course of these treatments, the patient may be treated with tar or dithranol. Tar treatment is, in particular, indicated for patients with itchy psoriasis. The next possibility is the treatment with phototherapy with UVB or, alternatively, photochemotherapy. These treatments are indicated for widespread psoriasis with lesions over an extent of the body surface which would require very elaborate applications of topical drugs. Should the desired effect not be achieved with topical treatment or photochemotherapy, systemic treatments are indicated. The choice of which systemic treatment to select is highly dependent on the manifestation of psoriasis and whether contraindications for one of these treatments exist. The spectrum of treatments available for patients with psoriasis provides an adequate possibility to manage psoriasis.
7.3. Cyclosporin
9. Experimental treatments for psoriasis
Cyclosporin is effective in nearly all forms of psoriasis. The dose is between 3 and 5 mgrkgrday. Side effects are nephrotoxicity, hypertension, gingiva hyperplasia, tremors, hypertrichoses, headache, diarrhoea, general feeling of discomfort and nausea. Contraindications are nephrotoxicity, cytotoxicity, and immunosuppressive co-medication, X-ray exposure, concurrent photo-Žchemo.therapy, malignancies, active infections, immunodeficiency, organ defects, drug abuse, alcohol abuse, epilepsy, pregnancy, kidney dysfunctions and unmanageable hypertension. The patient is seen once in 4–6 weeks. Kidney functions, blood pressure, liver functions and haematological investigations are carried out during each visit.
Although not yet available for the patient of today, various experimental treatments can be expected in the next decade. For topical treatment, new Vitamin D 3 analogues and retinoic acid derivatives are being investigated. For systemic treatment, cytochrome P-450 inhibition and immunomodulation are effective antipsoriatic approaches w36x.
Acknowledgements Sandra Pastoor and Anke den Brok are acknowledged for their proficient secretarial assistance.
References 8. Management of the individual patient A spectrum of treatments is available for patients with psoriasis. The first line of treatment is the topical treatment of psoriasis. The first choice is
w1x Dubertret L, Wallach D, Sonteyrand P, et al. Efficacy and safety of calcipotriol ŽMC 903. ointment in psoriasis vulgaris. J Am Acad Dermatol 1992;27:983–988. w2x Ramsay CA, Berth-Jones J, Brudin G, et al. Long-term use of topical calcipotriol in chronic plaque psoriasis. Dermatology 1994;189:260–264.
P.C.M. Õan de Kerkhofr Netherlands Journal of Medicine 52 (1998) 40–45 w3x Kragballe K, Tore Gjertzen B, de Hoop D, et al. Double blind, rightrleft comparison of calcipotriol and betamethasone valerate in treatment of psoriasis vulgaris. Lancet 1991;337:193–196. w4x Cunliffe WJ, Berth-Jones J, Claudy A, et al. Comparative study of calcipotriol ŽMC 903. ointment and betamethasone 17-valerate ointment in patients with psoriasis vulgaris. J Am Acad Dermatol 1992;26:736–743. w5x Berth-Jones J, Chu AC, Dodd WAH, et al. A multicenter, parallel-group comparison of calcipotriol ointment and short contact dithranol therapy in chronic plaque psoriasis. Br J Dermatol 1992;127:266–271. w6x Molin L. Does UVB improve the effect of calcipotriol in psoriasis? Žabstract.. Presented at the 2nd International Symposium on Calcipotriol; Monte Carlo, March 1993. w7x Guilhou JJ, Thivolet J, Bazex JA, et al. Efficacy, safety and tolerability of calcipotriol combined with PUVA therapy Žabstract.. Presented at the 2nd International Symposium on Calcipotriol; Monte Carlo, March 1993. w8x Grossmann RM, Thivolet J, Claudy A, et al. A novel therapeutic approach to psoriasis with combination calcipotriol ointment and very low-dose cyclosporin: results of a multicenter placebo-controlled study. J Am Acad Dermatol 1994;31:68–74. w9x Hardman KH, Heath DA. Hypercalcaemia associated with calcipotriol ŽDovonex. treatment. Br Med J 1993;306:896. w10x Russell S, Young MJ. Hypercalcaemia during treatment of psoriasis with calcipotriol. Br J Dermatol 1994;130:795–796. w11x van de Kerkhof PCM. Teerbehandeling in de dermatologie. Ned Tijdschr Geneeskd 1989;133:2067–2070. w12x Lowe NJ, Breeding J, Wortzmann MS. The pharmacological variability of crude coal tar. Br J Dermatol 1982;107:475. w13x Goeckerman WH. Treatment of psoriasis. Arch Dermatol Syphil 1931;24:446–450. w14x Stern RS, Zierler S, Parrish JA. Skin carcinoma in patients with psoriasis treated with topical tar and artificial ultraviolet radiation. Lancet 1980;i:732–735. w15x Muller SA. Coal tar, ultraviolet light and cancer. J Am Acad Dermatol 1981;4:234–235. w16x Pittelkow MR, Perry HA, Muller SA, Maughan WZ, O’Brien PC. Skin cancer in patients with psoriasis treated with coal tar. Arch Dermatol 1981;117:465–468. w17x Baker H. Psoriasis. In: Rook A, Wilkinson DS, Ebin FJG, Champion RH, Burton, JL, eds. Textbook of dermatology, 5th ed. Oxford: Blackwell Scientific Publications, 1469– 1532. w18x van de Kerkhof PCM. Dithranol treatment for psoriasis. After 75 years, still going strong. Eur J Dermatol 1991;1:79– 89. w19x Sarett LH, Patchett AA, Steelman S. The effects of structural alteration on the anti-inflammatory properties of hydrocortisone. Prog Drug Res 1963;5:111–153.
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w20x Munro DD, Rustin MHA. Corticosteroids. In: Texbook of psoriasis. Edinburgh: Churchill Livingstone, 1986;168–177. w21x Munro DD, Clift DC. Pituitary–adrenal function after prolonged use of topical corticosteroids. Br J Dermatol 1973;88:381–385. w22x van de Kerkhof PCM, van der Walle HB, Bolluyt A, et al. Weekly treatment of psoriasis with a hydrocolloid dressing ŽDuoderm E. in combination with triamcinolone acetonide: a controlled comparative study. Acta Derm-Venereol 1994;74:143–147. w23x Adrian RM, Parrish JA, Khosrow Momtaz T, Karlin MJ. Outpatient phototherapy of psoriasis. Arch Dermatol 1981;117:623–626. w24x le Vine MJ, Parish JA. Outpatient phototherapy of psoriasis. Arch Dermatol 1980;116:552–554. w25x van Weelden H. FotoŽchemo.therapie bij psoriasis. Ned Tijdschr Derm Venereol 1994;4:74–76. w26x Lindelof ¨ B, Sigurgeirson B, Tegner E, Larko¨ O, Berne B. Comparison of the carcinogenic potential of trioxsalen both PUVA and oral methoxsalen PUVA. Arch Dermatol 1992;128:1341–1344. w27x Fischer T, Aslins J. Treatment of psoriasis with trioxsalen baths and dysprosium lamps. Acta Derm-Venereol 1976;56:383–390. w28x Mali-Gerrits MGH, Gaasbeek D, Boezeman J, van de Kerkhof PCM. Psoriasis therapy and the risk of skin cancers. Clin Exp Dermatol 1991;16:85–89. w29x van de Kerkhof PCM, de Rooij MJP. Multiple squamous cell carcinomas in a psoriatic patient following high dose photochemotherapy and cyclosporin treatment; response to long term acitretin maintenance. Br J Dermatol 1997;136:275–279. w30x Stern RS, Nichols KT, Vakeva ¨ ¨ LH. Malignant melanoma in patients treated for psoriasis with methoxsalen ŽPsoralen. and ultraviolet A radiation ŽPUVA .. N Engl J Med 1997;336:1041–1045. w31x Meinardi MMHM, Spuls PhL, Witkamp L. Protocollen voor systemische behandelingen van psoriasis met Acitretine, Methotrexaat, Fumaarzuur en Cyclosporine A. Ned Tijdschr Derm Venereol 1994;4:65–71. w32x van de Kerkhof PCM. Methotrexaat ter behandeling van psoriasis. Ned Tijdschr Geneeskd 1987;131:2345–2348. w33x van de Kerkhof PCM, van Dooren-Greebe RJ. Acitretine en Methotrexaat bij de behandeling van psoriasis. Ned Tijdschr Derm Venereol 1992;2:18–23. w34x van Dooren-Greebe RJ, van de Kerkhof PCM, Steijlen PM, Happle R. Orale retinoiden bij verhoorningsstoornissen van de huid. Ned Tijdschr Derm Venereol 1990;134:1995–2000. w35x Weinblatt ME, Coblyn JS, Fox DA, et al. Efficacy of lowdose methotrexate in rheumatoid arthritis. N Engl J Med 1985;312:818–822. w36x Van de Kerkhof PCM. What is new in the treatment of psoriasis? J. Dermatol. Treat., in press.
Review
The management of psoriasis P.C.M. van de Kerkhof
)
Department of Dermatology, UniÕersity Hospital Nijmegen, PO Box 9101, 6500 HB Nijmegen, Netherlands Received 3 April 1997; revised 24 September 1997; accepted 30 September 1997
Abstract A spectrum of treatments is available for patients with psoriasis. It is of utmost importance to individualize the selection of treatment for the individual patient at the very moment of consultation. The manifestation of psoriasis, the extent of the lesions and the subjective discomfort of psoriasis are important factors which denominate the selection of treatment. The most important topical treatments are calcipotriol, dithranol, tar and corticosteroids. If topical treatments are unsuccessful, phototherapy with UVB, photochemotherapy ŽPUVA., methotrexate, cyclosporin and acitretin are the most important therapeutical options. The possibilities and limitations of these treatments will be presented in this review. In particular, the question will be addressed to what extent treatments of psoriasis may have systemic complications. q 1998 Elsevier Science B.V. Keywords: Acitretin; Cyclosporin; Corticosteroid; Dithranol; Methotrexate; Phototherapy; Psoriasis; Treatment; Vitamin D 3
1. Introduction Various treatments are available for patients with psoriasis. Over the last decade, the spectrum of treatments has expanded with the introduction of calcipotriol and cyclosporin. In the present review, a description of the topical and systemic treatments will be provided as well as a comparative analysis of these treatments. Systemic treatments and some topical treatments may have systemic complications. Therefore, insight into these treatments is of value for general medicine. Treatment of psoriasis has to be individualized as every case of psoriasis is different.
)
Tel.: q31 24 3613247; fax: q31 24 3541184.
2. Vitamin D 3 analogues In 1992, calcipotriol was introduced as a treatment of psoriasis. In view of the excellent therapeutic efficacy and the limited toxicity, calcipotriol became a frequently used treatment in chronic plaque psoriasis. In a placebo-controlled study, calcipotriol 50 mgrg in ointment, applied twice daily, proved to result in an impressive improvement in more than 74% of the patients w1x. This response was far better compared to the placebo ointment only. A long-term efficacy and toxicity study was carried out over 12 months involving 161 patients with chronic plaque psoriasis w2x. During the first 8 weeks, the most impressive improvement occurred. Continuation of the treatment did not result in a habituation. The total quantity of 100 g of calcipotriol ointment did not
0300-2977r98r$19.00 q 1998 Elsevier Science B.V. All rights reserved. PII S 0 3 0 0 - 2 9 7 7 Ž 9 7 . 0 0 0 8 1 - 8
P.C.M. Õan de Kerkhofr Netherlands Journal of Medicine 52 (1998) 40–45
induce a significant effect on systemic calcium metabolism. Calcipotriol ointment resulted in irritation of the skin in 20% of the patients, which required discontinuation of the treatment in 5% of them w2x. Comparative studies between calcipotriol and other treatments revealed that calcipotriol was at least as effective as betamethasone and dithranol w3–5x. Combination treatments of calcipotriol and phototherapy with UVB proved to be effective and safe w6,7x. The combination of calcipotriol and photochemotherapy resulted in a significant reduction of the cumulative doses of UVA needed to induce a satisfactory response. The combination of calcipotriol and cyclosporin proved to be a very effective combination w8x. A dose of 2 mgrkgrday of cyclosporin in combination with calcipotriol ointment resulted in a substantial improvement in 50% of the patients, in contrast to the significant improvement in only 11% of the patients treated with 2 mgrkg cyclosporin in combination with the placebo ointment. In other forms of psoriasis, such as pustular, guttate and erythrodermic psoriasis, calcipotriol ointment is not a first-line treatment in view of the potential irritative facts andror the large surface area of involvement resulting in substantial transdermal absorption of calcipotriol. Application of calcipotriol to the face and flexures should be avoided in view of the irritative potential of the drug. In the case of irritation, a topical corticosteroid is indicated. Recently, the combination of calcipotriol and acitretin was proved to result in a reduced treatment time, with an increased number of patients showing a substantial improvement or clearing. Occasionally, hypercalcaemia may occur in patients treated with calcipotriol. Although the usage of more than 100 g of calcipotriol ointment may be the cause of hypercalcaemia, in some patients with systemic disorders of calcium metabolism Žsarcoidosis, metastasized mammary carcinoma. and in patients with renal insufficiency, the use of smaller doses of calcipotriol has been reported to increase serum calcium w9,10x. Although the reported increases following calcipotriol treatment are not alarming, the hazards of long-term hypercalcaemia should not be underestimated.
41
3. Tar Probably the oldest treatment of psoriasis is tar. Hippocrates already prepared tar from the ceder tree. In psoriasis, crude coal tar proved to have a substantial therapeutic effect. The variability of the composition of coal tar makes standardization of this treatment virtually impossible w11,12x. Treatment with tar was popularized by Goeckerman, who developed a combined treatment approach of crude coal tar with ultraviolet radiation w13x. The efficacy of tar in psoriasis has been clearly demonstrated. Especially in itchy psoriasis Žinstable psoriasis, guttate psoriasis., tar treatment causes a major reduction of itch. Apart from tar folliculitis and occasional sensitization, no substantial side effects have been reported. Although tar is a carcinogen in animal experiments and is a well-established carcinogen in dermatological treatment, tar can be regarded as a safe therapeutic principal w13–16x. Solutio carbonis detergent is an alcoholic extract of crude coal tar. In contrast to crude coal tar, staining is minimal. The efficacy of this extract, however, is substantially inferior to crude coal tar. Crude coal tar is manufactured in pastes or ointments in a concentration of 1–5%. Solutio carbonis detergent can be manufactured in a cream in concentrations between 10 and 20%. 4. Dithranol In 1916, dithranol was introduced as a treatment of chronic plaque psoriasis w17x. The mode of action proved to be the induction of free radicals in the skin. A slight irritative response is obligatory for a therapeutic response. Dithranol is an unstable product which can be inactivated by oxidation. Oxidation can be recognized by a yellowrbrown discolouration of the preparation. Dithranol can be applied during 24 h a day, or as a short-contact treatment during 5–15 min only. The reduced application time results in a relative decrease of the accumulation of dithranol through the intact skin. Therefore, short-contact dithranol treatment permits a more aggressive treatment of the lesional skin, with relative sparing of the symptomfree skin.
42
P.C.M. Õan de Kerkhofr Netherlands Journal of Medicine 52 (1998) 40–45
The efficacy of dithranol treatment is highly dependent on the intensity of the patient supervision. Treatment at a day-care centre or in-patient department has the highest efficacy. Home treatment with supervision at the day care department once every 2 weeks, has a rather poor therapeutic response w18x. An alternative approach is the care instruction programme where patients are treated and instructed once daily during the first week. Later the patient carries out the treatment at home and is seen twice weekly at the treatment unit. For further information, the reader is referred to a review on dithranol w18x.
5. Corticosteroids Systemic corticosteroids are no longer indicated in psoriasis. If systemic corticosteroids are indicated for other reasons, the dose reduction should be careful as aggravation of psoriasis may occur. Since 1963, topical corticosteroids are a most important treatment modality in psoriasis w19x. The advantage of topical corticosteroids is that they are cosmetically acceptable formulations. Potent topical corticosteroids are very effective in patients with psoriasis. Potent topical corticosteroids should be reserved for crisis intervention. Corticosteroid treatment may relieve patients of psoriasis within a short period of time. In general, patients should be treated once daily, although intermittent treatment Žoncertwice weekly. has been claimed to be very effective w20x. A hazard of long-term treatment is atrophy of the skin: striae, telangiectasias and purpura. Other side effects of topical corticosteroids are hypertrichosis, perioral dermatitis and allergic contact dermatitis. These potent topical corticosteroids may suppress plasma cortisol levels w21x. The application over larger surface areas of skin should be avoided. Prolonged treatment with topical corticosteroids reduces the therapeutic efficacy. It is a well-established fact that the efficacy of a corticosteroid is enhanced considerably by using occlusion. A new approach in recalcitrant chronic plaque psoriasis is the application of topical corticosteroids under a ‘hydrocolloid occlusive’ w22x. Once weekly, the corticosteroids Žeither a lotion or a cream. can be applied to therapy-resistant
plaques, which subsequently are covered by a ‘hydrocolloid’ dressing. ‘Hydrocolloid occlusion’ is well tolerated by the patient. It is of importance that non-dermatologists become aware that a patient using fluorinated topical corticosteroids over large areas for more than 1 month, should be seen by a dermatologist for the institution of another treatment.
6. Photo(chemo)therapy Ultraviolet radiation has an important therapeutic effect in psoriasis. Ultra-violet B ŽUVB. radiation Ž290–320 nm. has a substantial photodynamic effect, whilst the radiation penetrates into the dermal–epidermal transition zone. The therapeutic efficacy of UVB phototherapy in psoriasis is satisfactory in the majority of patients w23,24x. The therapeutic effect of UVA Ž320–400 nm. is limited. Although the radiation penetrates into the deeper layers of the skin, the quantum energy of the radiation is too low for a substantial anti-psoriatic effect. With the combination of ultraviolet A and the ingestion or topical application of a psoralen, a substantial photodynamic and anti-psoriatic effect can be achieved. Both phototherapy with UVB and photochemotherapy require dose management resulting in a slight irritation of the skin. Phototherapy with UVB is indicated in extensive chronic plaque psoriasis and guttate psoriasis. In generalized pustular psoriasis and erythrodermic psoriasis, a restrictive attitude with respect to phototherapy is indicated. Although several studies have demonstrated the carcinogenic potential of phototherapy in humans, treatment with UVB has only a minimal risk of inducing cancer of the skin w25,26x. Contraindications for phototherapy are photodermatoses, the ingestion of phototoxic medication, a previous history of skin cancer and actinic keratoses as well as previous treatments with X-rays, or arsenic ingestion. A family history of melanoma is also regarded as a contraindication for phototherapy. Photochemotherapy ŽPUVA. has a substantially increased anti-psoriatic potential compared to phototherapy with UVB. Side effects of photochemotherapy are erythema, bullae, burning, nausea, itching, pigmentations, PUVA-lentigines, hyper-
P.C.M. Õan de Kerkhofr Netherlands Journal of Medicine 52 (1998) 40–45
trichosis and pain. On long-term treatment with PUVA, multiple squamous cell carcinomas have been induced w26,27x. Contraindications for PUVA are the same as for UVB. Therefore the side effects of PUVA are more severe compared to UVB. Chronic side effects are cataract and hepatotoxicity. PUVA treatment may be considered in case UVB treatment has had insufficient effects. PUVA treatment is indicated in extensive psoriasis, including generalized pustular psoriasis, pustulosis palmoplantaris and erythrodermic psoriasis. In the Scandinavian countries, bath-PUVA has already been applied for years w26–28x. The psoralen is applied via a bath and subsequently the patients are treated with UVA. The advantage of bath-PUVA is the reduced occurrence of nausea. The long-term risk with respect to the induction of squamous cell carcinomata has been reported to be reduced in the case of bath-PUVA as compared to systemic PUVA treatment w26x. It is of practical relevance that patients using systemic medication with a phototoxic potential should refrain from photoŽchemo.therapy or alternatively should discontinue the phototoxic medication. Patients using immunosuppressive treatment should refrain from photochemotherapy as this combination can have a carcinogenic effect w29x. Recently, it was demonstrated that patients receiving 250 PUVA treatments or more had an increased risk of malignant melanoma. Therefore, the cumulative carcinogenic risk of PUVA treatment should not be underestimated w30x.
7. Systemic treatments In recalcitrant manifestations of chronic plaque psoriasis, erythrodermic psoriasis and generalized pustular psoriasis, a systemic treatment may be indicated. Methotrexate, acitretin and cyclosporin are the well-established treatments for psoriasis w31–34x. As these treatments may have serious systemic complications, it is of importance that the departments of general medicine are aware of these complications and that guidelines are formulated in each centre on how to handle the side effects.
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7.1. Methotrexate Methotrexate is very effective in nearly all forms of psoriasis. Intermittent treatment is indicated in order to reduce the toxic potential of this drug. In general, the treatment is prescribed according to the Weinstein scheme Žthree ingestions at 12-h intervals per week.. The Nijmegen centre advises a maximum dose of 15 mg methotrexate per week. According to the literature, doses between 22.5 and 30 mg are accepted, however. Side effects include anorexia, nausea, alopecia, leucopenia, thrombopenia, megaloblastic anaemia. Methotrexate may induce fibrosis and cirrhosis of the liver. In women and men who want to produce children in the short-term, the mutagenic effect of methotrexate has to be considered as males and females must use continuous contraception for at least 6 months after discontinuing methotrexate treatment. Contraindications for methotrexate treatment are substantial liver and kidney disease, pregnancy, a desire to procreate in the short-term, active infections, interaction with other medication, bone marrow hypoplasia, peptic ulceration, ulcerative colitis and patient non-cooperation. During treatment, patients are advised not to take alcohol during the days of methotrexate ingestion. Patients are seen at the out-patient department at 4- to 6-week intervals. Before treatment and after the cumulative dose of 1.5 g methotrexate, a liver biopsy is indicated in order to assess the histological appearance of the liver. This recommendation is in contrast to the approach for methotrexate treatment at the departments of rheumatology for the treatment of rheumatoid arthritis. The side effects of methotrexate proved to be highly dependent on the conditions which indicated the installation of methotrexate treatment. Liver biopsy-controlled patient surveys revealed that the occurrence of serious liver impairment in patients with rheumatoid arthritis treated with methotrexate is very seldom. w35x 7.2. Acitretin Acitretin is a retinoic acid derivative which is indicated as a monotherapy in erythrodermic and pustular psoriasis. In the case of chronic plaque psoriasis, this treatment is very effective in combina-
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P.C.M. Õan de Kerkhofr Netherlands Journal of Medicine 52 (1998) 40–45
tion with phototherapy ŽUVB. or photochemotherapy ŽPUVA.. The dose of acitretin varies between 25 and 75 mgrday. Side effect include dry lips, epistaxis, conjunctivitis, pruritus, skin atrophy, alopecia, dermatitis, decreased visual perception at night, colour blindness and hyperlipidaemia. Incidentally, hepatitis and increased osteophyte formation have been recorded. Women, wishing to become pregnant, must refrain from acitretin as acitretin is teratogenic. Pregnancy should be excluded before initiation of acitretin treatment and for a period of at least 2 years following discontinuation of treatment. No restrictions with respect to male patients should be given. Contraindications for treatment with acitretin are liver disease, hyperlipidaemia, pregnancy and the desire to become pregnant. Before treatment and at monthly intervals, patients are seen at the out-patient department, and serum triglycerides, serum cholesterol and liver function tests are carried out. Before treatment and at yearly intervals, X-ray examination of the spine is advised. Active questioning of the patients with respect to joint complaints is indicated.
calcipotriol as an effective and safe principle. If rapid clearing of lesions is required, a topical corticosteroid can be given for a limited period of time. In case the condition cannot be controlled efficiently with a short course of these treatments, the patient may be treated with tar or dithranol. Tar treatment is, in particular, indicated for patients with itchy psoriasis. The next possibility is the treatment with phototherapy with UVB or, alternatively, photochemotherapy. These treatments are indicated for widespread psoriasis with lesions over an extent of the body surface which would require very elaborate applications of topical drugs. Should the desired effect not be achieved with topical treatment or photochemotherapy, systemic treatments are indicated. The choice of which systemic treatment to select is highly dependent on the manifestation of psoriasis and whether contraindications for one of these treatments exist. The spectrum of treatments available for patients with psoriasis provides an adequate possibility to manage psoriasis.
7.3. Cyclosporin
9. Experimental treatments for psoriasis
Cyclosporin is effective in nearly all forms of psoriasis. The dose is between 3 and 5 mgrkgrday. Side effects are nephrotoxicity, hypertension, gingiva hyperplasia, tremors, hypertrichoses, headache, diarrhoea, general feeling of discomfort and nausea. Contraindications are nephrotoxicity, cytotoxicity, and immunosuppressive co-medication, X-ray exposure, concurrent photo-Žchemo.therapy, malignancies, active infections, immunodeficiency, organ defects, drug abuse, alcohol abuse, epilepsy, pregnancy, kidney dysfunctions and unmanageable hypertension. The patient is seen once in 4–6 weeks. Kidney functions, blood pressure, liver functions and haematological investigations are carried out during each visit.
Although not yet available for the patient of today, various experimental treatments can be expected in the next decade. For topical treatment, new Vitamin D 3 analogues and retinoic acid derivatives are being investigated. For systemic treatment, cytochrome P-450 inhibition and immunomodulation are effective antipsoriatic approaches w36x.
Acknowledgements Sandra Pastoor and Anke den Brok are acknowledged for their proficient secretarial assistance.
References 8. Management of the individual patient A spectrum of treatments is available for patients with psoriasis. The first line of treatment is the topical treatment of psoriasis. The first choice is
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P.C.M. Õan de Kerkhofr Netherlands Journal of Medicine 52 (1998) 40–45 w3x Kragballe K, Tore Gjertzen B, de Hoop D, et al. Double blind, rightrleft comparison of calcipotriol and betamethasone valerate in treatment of psoriasis vulgaris. Lancet 1991;337:193–196. w4x Cunliffe WJ, Berth-Jones J, Claudy A, et al. Comparative study of calcipotriol ŽMC 903. ointment and betamethasone 17-valerate ointment in patients with psoriasis vulgaris. J Am Acad Dermatol 1992;26:736–743. w5x Berth-Jones J, Chu AC, Dodd WAH, et al. A multicenter, parallel-group comparison of calcipotriol ointment and short contact dithranol therapy in chronic plaque psoriasis. Br J Dermatol 1992;127:266–271. w6x Molin L. Does UVB improve the effect of calcipotriol in psoriasis? Žabstract.. Presented at the 2nd International Symposium on Calcipotriol; Monte Carlo, March 1993. w7x Guilhou JJ, Thivolet J, Bazex JA, et al. Efficacy, safety and tolerability of calcipotriol combined with PUVA therapy Žabstract.. Presented at the 2nd International Symposium on Calcipotriol; Monte Carlo, March 1993. w8x Grossmann RM, Thivolet J, Claudy A, et al. A novel therapeutic approach to psoriasis with combination calcipotriol ointment and very low-dose cyclosporin: results of a multicenter placebo-controlled study. J Am Acad Dermatol 1994;31:68–74. w9x Hardman KH, Heath DA. Hypercalcaemia associated with calcipotriol ŽDovonex. treatment. Br Med J 1993;306:896. w10x Russell S, Young MJ. Hypercalcaemia during treatment of psoriasis with calcipotriol. Br J Dermatol 1994;130:795–796. w11x van de Kerkhof PCM. Teerbehandeling in de dermatologie. Ned Tijdschr Geneeskd 1989;133:2067–2070. w12x Lowe NJ, Breeding J, Wortzmann MS. The pharmacological variability of crude coal tar. Br J Dermatol 1982;107:475. w13x Goeckerman WH. Treatment of psoriasis. Arch Dermatol Syphil 1931;24:446–450. w14x Stern RS, Zierler S, Parrish JA. Skin carcinoma in patients with psoriasis treated with topical tar and artificial ultraviolet radiation. Lancet 1980;i:732–735. w15x Muller SA. Coal tar, ultraviolet light and cancer. J Am Acad Dermatol 1981;4:234–235. w16x Pittelkow MR, Perry HA, Muller SA, Maughan WZ, O’Brien PC. Skin cancer in patients with psoriasis treated with coal tar. Arch Dermatol 1981;117:465–468. w17x Baker H. Psoriasis. In: Rook A, Wilkinson DS, Ebin FJG, Champion RH, Burton, JL, eds. Textbook of dermatology, 5th ed. Oxford: Blackwell Scientific Publications, 1469– 1532. w18x van de Kerkhof PCM. Dithranol treatment for psoriasis. After 75 years, still going strong. Eur J Dermatol 1991;1:79– 89. w19x Sarett LH, Patchett AA, Steelman S. The effects of structural alteration on the anti-inflammatory properties of hydrocortisone. Prog Drug Res 1963;5:111–153.
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w20x Munro DD, Rustin MHA. Corticosteroids. In: Texbook of psoriasis. Edinburgh: Churchill Livingstone, 1986;168–177. w21x Munro DD, Clift DC. Pituitary–adrenal function after prolonged use of topical corticosteroids. Br J Dermatol 1973;88:381–385. w22x van de Kerkhof PCM, van der Walle HB, Bolluyt A, et al. Weekly treatment of psoriasis with a hydrocolloid dressing ŽDuoderm E. in combination with triamcinolone acetonide: a controlled comparative study. Acta Derm-Venereol 1994;74:143–147. w23x Adrian RM, Parrish JA, Khosrow Momtaz T, Karlin MJ. Outpatient phototherapy of psoriasis. Arch Dermatol 1981;117:623–626. w24x le Vine MJ, Parish JA. Outpatient phototherapy of psoriasis. Arch Dermatol 1980;116:552–554. w25x van Weelden H. FotoŽchemo.therapie bij psoriasis. Ned Tijdschr Derm Venereol 1994;4:74–76. w26x Lindelof ¨ B, Sigurgeirson B, Tegner E, Larko¨ O, Berne B. Comparison of the carcinogenic potential of trioxsalen both PUVA and oral methoxsalen PUVA. Arch Dermatol 1992;128:1341–1344. w27x Fischer T, Aslins J. Treatment of psoriasis with trioxsalen baths and dysprosium lamps. Acta Derm-Venereol 1976;56:383–390. w28x Mali-Gerrits MGH, Gaasbeek D, Boezeman J, van de Kerkhof PCM. Psoriasis therapy and the risk of skin cancers. Clin Exp Dermatol 1991;16:85–89. w29x van de Kerkhof PCM, de Rooij MJP. Multiple squamous cell carcinomas in a psoriatic patient following high dose photochemotherapy and cyclosporin treatment; response to long term acitretin maintenance. Br J Dermatol 1997;136:275–279. w30x Stern RS, Nichols KT, Vakeva ¨ ¨ LH. Malignant melanoma in patients treated for psoriasis with methoxsalen ŽPsoralen. and ultraviolet A radiation ŽPUVA .. N Engl J Med 1997;336:1041–1045. w31x Meinardi MMHM, Spuls PhL, Witkamp L. Protocollen voor systemische behandelingen van psoriasis met Acitretine, Methotrexaat, Fumaarzuur en Cyclosporine A. Ned Tijdschr Derm Venereol 1994;4:65–71. w32x van de Kerkhof PCM. Methotrexaat ter behandeling van psoriasis. Ned Tijdschr Geneeskd 1987;131:2345–2348. w33x van de Kerkhof PCM, van Dooren-Greebe RJ. Acitretine en Methotrexaat bij de behandeling van psoriasis. Ned Tijdschr Derm Venereol 1992;2:18–23. w34x van Dooren-Greebe RJ, van de Kerkhof PCM, Steijlen PM, Happle R. Orale retinoiden bij verhoorningsstoornissen van de huid. Ned Tijdschr Derm Venereol 1990;134:1995–2000. w35x Weinblatt ME, Coblyn JS, Fox DA, et al. Efficacy of lowdose methotrexate in rheumatoid arthritis. N Engl J Med 1985;312:818–822. w36x Van de Kerkhof PCM. What is new in the treatment of psoriasis? J. Dermatol. Treat., in press.