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Hydroxyurea

Hydroxyurea is a second line modality for the treatment of psoriasis and has been used since 1965. It is usually reserved for cases where other second line agents have failed or are contraindicated. The dose used has generally been 0.5 to 1.5g daily, give orally either as a single dose, or divided into two doses (morning and evening). Although only a single controlled trial has been performed, it is generally considered to be effective. Hydroxyurea avoids the hepatotoxicity associated with methotrexate, and the nephrotoxicity associated with cyclosporin, and can therefore often be useful when other drugs are contraindicated, although it should be avoided, if possible, when renal function is markedly impaired. The main hazard is myelosuppression and careful monitoring of the full blood count is therefore required. It is recommended that the initial dose in adults should usually be 1g daily and this can be titrated, according to efficacy and toxicity, up to a maximum of 2g daily. Full blood count, including platelet and differential white cell counts, should be performed at least weekly for the first two months.

Efficacy

The use of hydroxyurea in the treatment of psoriasis was first reported in 1969, when Yarbro reported a response in 2 patients treated with a dose of 40mg/kg/day, which was halved after 6 - 10 days ¹. Yarbro and Leavell reported another patient showing a particularly rapid response to hydroxyurea, at the dose of 1g three times daily for the first 8 days of treatment ² . These observations were followed by a double-blind, placebo controlled crossover trial. Each treatment period was 4 weeks, and the dose of hydroxyurea was 0.5g twice daily ³ . Twelve subjects were included and 10 completed the protocol. Subjects and investigators considered that improvement had occurred during active therapy in 9 and 7 out of 10 cases repectively. Only one patient improved by either assessment during placebo treatment. The level of response was not quantified and no statistical analysis was presented.

Rosten reported treatment of 12 patients with initial doses of 500 mg twice daily increased to 1g twice daily if required ⁴. Six of the patients showed a considerable improvement after 4 - 8 weeks. Four discontinued the drug due to side effects and, in two, no response was seen after 8 weeks of treatment. Subsequently, a number of uncontrolled studies have been performed. Hunter et al. reported treatment of 24 patients mostly with severe refactory psoriasis, using 1g of hydroxyurea daily ⁵. Sixteen showed substantial improvement, although the response was considered somewhat slow relative to methotrexate, often taking 6 to 8 weeks to become established.

Moschella and Greenwald reported a study in which 60 patients were treated intermittently with hydroxyurea, starting at the dose of 500mg twice daily⁶. Patients who failed to respond to the initial dose were treated with 1.5g daily. During the first 6 weeks of treatment, 63% of the patients showed a good or excellent response, including some with erythrodermic and pustular psoriasis; a fair response was seen in another 10%. Patients in whom the drug was effective generally began to show some improvement within 2 to 3 weeks. In the majority of these patients the response was able to be successfully maintained by subsequent courses of treatment.

A survey of 54 dermatologists, published in 1973, revealed that 33 had used hydroxyurea for a total of 614 patients. Of these patients, 65 had cleared, 350 improved, 188 did not improve and 11 worsened⁷ . Layton et al. reported their experience of treating 85 patients, at doses of 0.5 -1.5g daily, over a period of eight years ⁸ . Sixty percent of these patients cleared completely or nearly completely, and a further 20% showed partial clearance. The response was maintained in 52 by continuous therapy, for a mean of 16 months at the time of reporting. The reported duration of remission following cessation of hydroxyurea has varied from 24 hours⁹ to several months3-5 . Rebound of psoriasis after discontinuation has been reported occasionally^6-8.

Generalised pustular psoriasis: Stein et al. reported 4 patients with generalised pustular psoriasis who responded to hydroxyurea 1 - 2 g daily⁹. Somewhat less consistent results were obtained by Lingren and Groth, who treated 12 episodes of generalised pustular psoriasis in 6 patients, and induced remission in six episodes using hydroxyurea 1.5 - 2 g daily¹⁰.

Synergy with other treatments

There has been a single report on treatment of 14 patients with severe psoriasis using a combination of hydroxyurea (500 mg daily) with methotrexate (12.5 - 15mg weekly)¹¹ . An adequate response was obtained in 13 patients, and the hydroxyurea appeared to reduce the quantity of methotrexate required.

Safety, side-effects and patient acceptability

The main concern regarding toxicity of hydroxyurea has been over myelosuppression which may manifest as megaloblastic anaemia, thrombocytopenia or leukopenia ^1,6,8,10,12 . Haematological abnormalities are particularly frequent with this drug. Layton et al reported significant blood changes in 35% of their patients ⁸ and, in one report, macrocytosis and a reduced red cell count, although not anaemia, were seen in 4 of 5 patients treated ¹³. These side effects may develop after several months of treatment⁶ . They have generally been reversible after discontinuation of the drug. Since hydroxyurea is largely excreted in the urine, extra caution is required if renal function is impaired. It may occasionally cause fever^6,14. Cutaneous side effects of hydroxyurea include partial alopecia, increased pigmentation, scaling, atrophy, nail changes, erythema of the face and hands, and a lichenoid eruption¹⁵. Hydroxyurea is a cytotoxic drug with potential for teratogenic effects and is best avoided in women of child-bearing age.

Monitoring: As in the case of azathioprine, it is recommended that patients should have their full blood count, including platelet count and differential white cell count, checked prior to commencing the drug and, at least, weekly intervals for at least the first six weeks. Subsequently, the intervals between haematological assessments may be gradually extended, provided there is no cause for concern. The maximal interval should not exceed three months. Serum creatinine and liver function tests should also be monitored. It would also seem prudent to examine patients every six months for evidence of malignancy and to advise females to attend, when called, for routine cervical smears.

Cost implications

In a published cost analysis of psoriasis treatment hydroxyurea had the distinction of being the cheapest treatment¹⁶.

References

1 Yarbro JW. Hydroxyurea in the treatment of refactory psoriasis. Lancet 1969; 2: 846-7.

2 Yarbro JW, Leavell UW. Hydroxyurea: a new agent for the management of refractory psoriasis. Journal of the Kentucky Medical Association 1969; 67: 899-901.

3 Leavell UW, Yarbro JW. Hydroxyurea. A new treatment for psoriasis. Arch Dermatol 1970; 102: 144- 50.

4 Rosten M. Hydroxyurea: a new antimetabolite in the treatment of psoriasis. Br J Dermatol 1971; 85: 177-81

5 Hunter GA, Simmons IJ, Thomas BM. A clinical trial of hydroxyurea for psoriasis. Australas J Dermatol 1972; 13:93-9.

6 Moschella SL, Greenwald MA. Psoriasis with hydroxyurea. An 18-month study of 60 patients. Arch Dermatol 1973; 107: 363-8.

7 Leavell UW, Mersack IP, Smith C. Survey of the treatment of psoriasis with hydroxyurea. Arch Dermatol 1973; 107:467.

8 Layton AM, Sheehan-Dare RA, Goodfield MJ, Cotterill JA. Hydroxyurea in the management of therapy resistant psoriasis. Br J Dermatol 1989; 121: 647-53.

9 Stein KM, Shelley WB, Weinberg RA. Hydroxyurea in the treatment of pustular psoriasis. Br J Dermatol 1971; 85: 81-5.

10 Lingren S, Groth O. Generalised pustular psoriasis. A report on thirteen patients. Acta Derm Venereol (Stockh) 1976; 56: 139-47.

11 Sauer GC. Combined methotrexate and hydroxyurea therapy for psoriasis. Arch Dermatol 1973; 107: 369-70

12 Dahl MG, Comaish JS. Long-term effects of hydroxurea in psoriasis. Br Med J 1972; 1: 585-8.

13 Touraine R, Revuz J, Tulliez M. Psoriasis and hydroxyurea. Br J Dermatol 1972; 86: 102.

14 Bauman JL, Shulruff S, Hasegawa GR, et al. Fever caused by hydroxyurea. Arch Int Med 1981; 141:260-1.

15 Kennedy BJ, Smith LR, Goltz RW. Skin changes secondary to hydroxyurea therapy. Arch Dermatol 1975; 111:183-7.

16 Sander HM, Morris LF, Phillips CM, et al . The annual cost of psoriasis. J Am Acad Dermatol 1993; 28: 422-5.