Mucocutaneous adverse effects of hydroxyurea: a prospective study of 30 psoriasis patients

Hydroxyurea is an anti-tumour agent most commonly used to treat chronic myeloproliferative disorders in doses up to 4 g per day. Dermatological adverse effects reported so far have been observed predominantly in these patients. As we are treating selected psoriasis patients with low dose hydroxyurea we attempted to define the spectrum and chronology of dermatological adverse effects in this group of patients prospectively. Of the 29 evaluable patients, 19 (65.5%) developed a mucocutaneous adverse reaction after a mean duration of 6.4 weeks of treatment. Pigmentation of nails, skin or mucosa was the most common observation and was seen in 17 (58.6%) patients. Other less common findings were xerosis, diffuse alopecia, oedema of the legs, oral ulcers and actinic psoriasis. Adverse effects subsided in 11 (57.9%) patients during a mean follow up of 18 weeks. Three hitherto unreported side-effects - scleral pigmentation, acquired ichthyosis and pigmentation of lunula of the nails - were noted. This first study of dermatological adverse effects of hydroxyurea therapy on Asian psoriatic patients reveals several new findings. Pigmentation of skin, nails and mucosa appears to be very common and occurs early. Serious dermatological side-effects probably do not occur with low dose (up to 1.5 g per day) hydroxyurea in patients with psoriasis.     

Hydroxyurea in the management of therapy resistant psoriasis

Eighty-five patients with extensive chronic plaque psoriasis, unresponsive to conventional topical therapy, were treated with long-term hydroxyurea in a dose of 0.5-1.5 g daily. Fifty-two (61%) had a satisfactory remission during treatment without significant adverse effects. Treatment was discontinued in 33 patients (39%), due to an inadequate response or significant relapse during treatment and because of adverse reactions (19%). Four (4.7%) patients on hydroxyurea developed actinic psoriasis. Significant haematological abnormalities occurred in 30 patients (35%), but these became normal following a reduction in the dose of hydroxyurea or temporarily stopping the drug. In only six was it considered necessary to discontinue treatment because of bone marrow suppression. Our experience suggests that hydroxyurea is an effective long-term treatment for psoriasis that is refractory to conventional topical therapy and that the incidence of serious adverse effects compares favourably with other cytotoxic drugs.     

Dermatomyositis-like eruption and leg ulceration caused by hydroxyurea in a patient with psoriasis

We report the case of an elderly woman who had been on hydroxyurea for long-standing widespread psoriasis. After approximately 5 years's treatment with hydroxyurea, she developed a symmetrical dermatomyositis-like eruption on her hands, together with bilateral leg ulceration. Although similar skin eruptions have been reported after long-term hydroxyurea treatment, all of the previous patients were being treated for myeloproliferative disorders. A dermatomyositis-like eruption has not previously been reported to occur as a consequence of hydroxyurea treatment for psoriasis. Its recognition is important to prevent unnecessary investigation or treatment withdrawal.     

Fumaric acid esters in severe psoriasis, including experience of use in combination with other systemic modalities

BACKGROUND: Fumaric acid esters (FAE) are used as a systemic treatment for severe psoriasis in Germany but there has been only very little published experience from the U.K. The potential for use in combination with other systemic drugs has not been explored. OBJECTIVES: To present data relating to the efficacy of FAE in severe psoriasis and to examine the potential dose-sparing effect and safety issues when FAE are combined with other systemic agents. METHODS: We retrospectively analysed the records of patients who had received FAE for severe psoriasis either alone (in two cases) or along with other systemic medications (in 10 cases). We reviewed the efficacy of FAE and assessed whether dose reductions were achieved for other systemic drugs. Patients were monitored carefully for possible adverse effects. RESULTS: Of 12 patients treated with FAE one discontinued the drug very early, due to flushing, while on a very low dose. The other 11 patients all demonstrated an improvement in psoriasis after starting FAE. Nine patients received FAE in combination with other systemic therapies including ciclosporin, acitretin, hydroxyurea and methotrexate. Seven achieved useful overall reductions in the dose of the other drugs. In two patients severe psoriasis was controlled using FAE alone. The side-effect profile of FAE was similar to that previously reported. There was no evidence of drug interactions. CONCLUSIONS: FAE appear effective and less toxic than other systemic treatments for psoriasis. FAE were used successfully in combination with other systemic agents and generally enabled the doses of the more hazardous drugs to be reduced. Extremely careful monitoring is required when using FAE in such combined regimens as experience is currently very limited.     

Nonstandard and off-label therapies for psoriasis

Although most psoriasis patients respond to standard therapies, many circumstances warrant the use of nonstandard or off-label treatments. For instance, patients with treatment-resistant psoriasis or those who have had multiple adverse effects to other therapies may be good candidates for off-label treatments. Similarly, patients with unusual and hard-to-treat forms of psoriasis such as pustular psoriasis and palmoplantar psoriasis or specific comorbidities may benefit from certain nonstandard therapies. Drugs that may be used as alternatives to standard therapies include mycophenolate mofetil, tacrolimus or pimecrolimus, isotretinoin, colchicine, sulfasalazine, paclitaxel, dapsone, azathioprine, and hydroxyurea. Other unconventional therapies include climatotherapy at the Dead Sea and grenz ray therapy.     

Combined treatment of psoriasis with etretinate plus hydroxyurea

Nineteen patients with extensive, therapy-resistant psoriasis received combined treatment with etretinate plus hydroxyurea. The individual components were given at a reduced dosage and hydroxyurea was administered intermittently. During 12 weeks of treatment, complete remission or marked improvement was observed in 16 patients (84%). The combination of etretinate and hydroxyurea in the above-mentioned regimen was both effective and well-tolerated.     

Cutaneous adverse reactions to hydroxyurea in patients with intermediate thalassemia

Although the cutaneous effects of hydroxyurea have been described for patients with sickle cell anemia, myeloproliferative disorders, and psoriasis, there are no reports of cutaneous adverse effects from hydroxyurea when used for patients with intermediate thalassemia. Therefore 43 patients with intermediate thalassemia treated with hydroxyurea were examined by a dermatologist, and pertinent cutaneous findings were recorded. These patients had received hydroxyurea for a mean of 15.5 months. Nineteen had cutaneous hyperpigmentation, eight had xerosis, and three were found to have one cafe au lait macule each. Eleven patients had nail abnormalities, including nail ridging, partial leukonychia, and longitudinal melanonychia. There were no cases of leg ulceration. It was concluded that the risk of developing leg ulcers and pigmentary disorders appears to be related to the underlying disease being treated, as well as to a patient's age, gender, and pigmentation.     

Use of recombinant interferon gamma administered intramuscularly for the treatment of psoriasis

Twenty-three patients with chronic plaque-type psoriasis were treated with intramuscular administration of human recombinant interferon gamma. Patients were treated with doses of 0.01 to 0.25 mg/m2 daily (five out of seven days) for four weeks, or 0.25 mg/m2 three times weekly for one week with escalation to 0.5 mg/m2 for the subsequent seven weeks. Some patients treated with the 0.25-mg/m2 dose showed improvement coincident with their therapy. Although recombinant interferon gamma may have some therapeutic activity in certain patients' psoriasis, the magnitude of this effect is at best small. This result is in contrast to interferon alfa, which has been reported to cause an exacerbation of this disease. Staining of posttreatment biopsy specimens with a monoclonal antibody against HLA-DR antigen using an immunoperoxidase technique demonstrated HLA-DR expression by keratinocytes in some of the patients treated at the higher doses. No obvious correlation was seen between clinical improvement of the psoriasis and intensity or extent of HLA-DR antigen expression by keratinocytes in the skin biopsy specimens.     

Hydroxyurea therapy

Hydroxyurea's place in the scheme of psoriasis therapy has diminished in recent years. Some practitioners mistakenly believe that it is used only in desperate situations, is of little or no benefit in patients unresponsive to more conventional systemic therapies, and may predispose patients to the development of secondary malignancies. Moreover, a legitimate argument against the use of this drug may be made by physicians concerned about the proliferation of systemic therapies for what is a benign, albeit unsightly, eruption. However, hydroxyurea therapy is not without advantages. It is easily dosed, relatively inexpensive, and has few contraindications or subjective side effects. In addition, patients with common systemic disorders such as hyperlipidemia, mild renal insufficiency, and cardiopulmonary disease who may not be potential candidates for other medications may be managed with hydroxyurea.     

HYDROXYUREA IN THE TREATMENT OF PUSTULAR PSORIASIS

SUMMARY.— Four patients with generalized pustular psoriasis of von Zumbusch were treated with hydroxyurea in an oral dosage of 1–2 g daily. In each instance the pustular, the febrile, the leucocytic and toxic responses were significantly suppressed.
It is suggested that the effectiveness of this new treatment reflects the known selective suppressant effect of hydroxyurea on the polymorphonuclear leucocytes, which apparently play a central role in this disease.     

Administration of DAB389IL-2 to patients with recalcitrant psoriasis: A double-blind, phase II multicenter trial

Background: Current therapies for recalcitrant psoriasis focus on immunoregulation and targeting of activated T-lymphocytes rather than keratinocytes. Previous studies with low doses of the lymphocyte-selective fusion protein DAB₃₈₉IL-2 have shown benefit to patients with psoriasis. Objective: We examined the safety and efficacy of DAB₃₈₉IL-2 in 41 volunteers receiving more frequent and higher doses than in a previous trial. Methods: Patients were randomized to receive either placebo or 5, 10, or 15 mg/kg daily of DAB₃₈₉IL-2 intravenously for 3 consecutive days each week for 4 consecutive weeks with a subsequent 4-week observation period. Results: Of the placebo group, 17% (2 of 12) exhibited at least 50% improvement from baseline Psoriasis Area and Severity Index scores at the end of the study, whereas 24% of all treated patients (7 of 29) showed the same improvement. Overall, 3 of 12 (25%) patients given placebo as opposed to 12 of 29 (41%) patients treated with DAB₃₈₉IL-2 improved to this same extent at some point during the study. The rate of improvement for treated patients was significantly greater than for placebo patients (p = 0.04; repeated measures ANOVA). Among treated patients, decreases in Psoriasis Area and Severity Index scores were paralleled by changes in the Physician’s Global Assessment and the Dermatology Life Quality Index. Treatment in ten patients was discontinued because of adverse events. Flu-like symptoms were the most common with severity increasing at the two higher doses. Only one serious adverse event was reported. This occurred in a patient receiving 5 mg/kg daily who experienced vasospasm and a coagulopathy resulting in arterial thrombosis. Conclusion: Our findings are consistent with the potential antipsoriatic activity of DAB₃₈₉IL-2 demonstrated in an earlier study. However, DAB₃₈₉IL-2 was less well tolerated at this dosing regimen, particularly at the highest dose, and it was too toxic at these doses and schedules to be considered in the routine treatment of psoriasis. (J Am Acad Dermatol 1998;38:938-44.)     

Oral pimecrolimus in the treatment of moderate to severe chronic plaque-type psoriasis: a double-blind, multicentre, randomized, dose-finding trial

BACKGROUND: There is a need for safe and effective alternative treatments for patients with moderate to severe psoriasis. OBJECTIVES: Pimecrolimus is a calcineurin inhibitor that is being investigated in oral form for the treatment of psoriasis. PATIENTS AND METHODS: A double-blind, randomized, parallel-group, dose-finding study was performed. Healthy adult outpatients with moderate to severe chronic plaque-type psoriasis (n = 143) were randomized to receive oral placebo or pimecrolimus 10 mg, 20 mg or 30 mg twice daily (b.d.) for 12 weeks. Main outcome measures: The Psoriasis Area and Severity Index (PASI) was used to assess clinical severity of psoriasis. Results were analysed at weeks 7 (primary endpoint) and 13. Safety was assessed by monitoring all adverse events, laboratory investigations (blood chemistry, urinalysis, haematology) and physical examinations. RESULTS: The change from baseline in PASI at week 7 showed a dose-dependent effect. The differences between each of the two higher doses of pimecrolimus and placebo were statistically significant (P < 0.001; ANOVA). The mean percentage decreases from baseline in PASI in the placebo group and pimecrolimus 10 mg, 20 mg and 30 mg b.d. groups at week 7 were 3.1%, 22.2%, 51.3% and 54.0%, respectively. Most adverse events were of mild or moderate severity. The only adverse event to show a dose-response relationship was a transient feeling of warmth. No clinically relevant effects on laboratory parameters were observed, and no increase in skin infection with pimecrolimus was seen. CONCLUSIONS: Oral pimecrolimus produces a dose-dependent reduction in psoriasis severity, with doses of 20 mg and 30 mg b.d. being the most effective and well tolerated.     

Blue lunula due to hydroxyurea

Alteration in the color of lunula can be an indication of either a cutaneous or systemic disorder or a systemic drug side effect. Hydroxyurea, an antitumor systemic agent (a ribonucleoside diphosphate reductase inhibitor) used in the treatment of refractory psoriasis as well as in the variety of neoplastic disorders is known to cause brownish pigmentation of the nails but hydroxyurea induced blue lunula is very rare. It is being reported in a 45-year-old man with chronic recalcitrant plaque psoriasis on oral hydroxyurea 500 mg twice daily. Lunular pigmentation in finger and toenails developed two weeks later. During follow up, pigmentation remained localized to the proximal portion of nails.     

Combined mycophenolate mofetil and cyclosporin therapy for severe recalcitrant psoriasis

The use of combination oral therapies in the management of severe psoriasis is gaining increasing acceptance. We report the concurrent use of mycophenolate mofetil (MMF) (maximum dose 3.0 g daily) with low-dose cyclosporin (mean dose 2.5 mg/kg/day) in nine patients with severe psoriasis. All had previously failed on other systemic therapies. They were all initially on treatment with cyclosporin alone which had either failed to clear their psoriasis or they were unable to tolerate higher doses. After the addition of MMF there was good clinical improvement in three patients and moderate disease control in a further four patients after a follow-up period of 3-11 months, with no additional evidence of toxicity at the doses used. We believe that MMF may be useful in some psoriatic patients unresponsive to or intolerant of other treatments or who are at risk of developing nephrotoxicity at higher doses of cyclosporin.     

Long‐term efficacy of psoriasis vulgaris treatments: Analysis of treatment with topical corticosteroid and/or vitamin D3 analog,oral cyclosporin,etretinate and phototherapy over a 35‐year period, 1975–2010

Various therapies have been tried for psoriasis. In Japan, biologics began to be used for psoriasis treatment in January 2010. Their clinical efficacy is well known, but biologics cannot be used in all psoriasis patients for reasons such as side‐effects and cost. It is necessary to evaluate the effect of long‐term psoriasis treatment, but there have been no reports evaluating long‐term treatment. Therefore, the outcomes of patients who had been treated at the Tokai University Hospital for more than 5 years, before biological agents were released, were examined. Three categories, classified by initial severity, changes in severity by method of treatment and background characteristics, were investigated. In conclusion, cases of long‐term treatment with a combination of topical corticosteroid and topical vitamin D₃ analog or oral cyclosporin were found to be effective therapies. Patients with a history of diabetes mellitus or cardiovascular disease of psoriasis were likely to be treatment resistant.     

Acral keratoses and leucocytoclastic vasculitis occurring during treatment of essential thrombocythaemia with hydroxyurea

Hydroxyurea is used in essential thrombocythaemia to lower thromboembolic risk. Cutaneous adverse effects from hydroxyurea are diverse. Small vessel vasculitis has been rarely reported, and the coexistence of several different morphologies has not been described. We report a case of acral keratoses, psoriasiform plaques and leucocytoclastic vasculitis (LCV) in a patient with essential thrombocythaemia. A 69‐year‐old woman developed a confusing array of skin lesions including keratotic papules, psoriasiform plaques and keratoderma 4 years after commencing hydroxyurea therapy. The initial diagnosis was hand and foot psoriasis, but lesions were resistant to therapy. With an increase in the dose of hydroxyurea, the lesions ulcerated. Skin biopsies taken from different sites indicated different diagnoses, including LCV. Discontinuation of hydroxyurea yielded rapid improvement. Although the most commonly reported cutaneous adverse effect from hydroxyurea is leg ulceration, this can be preceded or accompanied by less dramatic skin lesions. Unless recognized, delayed diagnosis and lesion progression can occur.     

Low Dose Cyclosporin A Treatment in Generalized Pustular Psoriasis

Generalized pustular psoriasis is a rare form of psoriasis, seldom seen in children. Three patients with generalized pustular psoriasis are presented, two of whom were a sister and brother and whose grandfather also had pustular psoriasis. Lesions consisted of pustular, erythematous, scaly, follicular papules located on the trunk, scalp, and extremities. The pustules in some areas coalesced to form lakes. Histologic examination of several biopsy specimens revealed the changes of pustular psoriasis, which were parakeratosis, elongation of the rete ridges, and deep spongioform pustules and Munro abscesses. All patients were treated with cyclosporin A for periods of 2-12 months. The doses ranged from 1 to 2 mg/kg/day. Clearance of psoriatic lesions occurred after 2-4 weeks of therapy.     

Safety and Efficacy of Subcutaneously Administered Efalizumab in Adults with Moderate-to-Severe Hand and Foot Psoriasis

Introduction: Hand and foot psoriasis may be more disabling than psoriasis at other body locations because of its interference with daily functional activities. Most treatment options have limited efficacy, short duration of response, toxicity, intolerability, or inconvenience. Objective: To investigate whether efalizumab (Raptiva®) is efficacious and safe for the treatment of patients with hand and foot psoriasis. Method: Adult patients with moderate-to-severe hand and/or foot psoriasis received a conditioning dose of efalizumab 0.7 mg/kg at week 0 with subsequent doses of efalizumab 1 mg/kg given weekly for 11 additional weeks (total of 12 doses). Patients were followed until week 24 (12 weeks after the last treatment) to monitor safety and efficacy. Static Physician’s Global Assessment (PGA) scores were used to measure efficacy. The primary efficacy endpoint was the number of patients achieving a 50% reduction in the global evaluation by static PGA from baseline at week 12. Results: Ten patients enrolled, six of whom completed the study. Of these six patients, four patients showed overall improvement at 12 weeks, including two patients that achieved 50% improvement overall. At 12 weeks, the hands of two patients and the feet of two patients showed at least 50% improvement from baseline. Efalizumab was well tolerated and there were no serious adverse events. Conclusion: Continuous treatment with efalizumab for 12 weeks was safe and efficacious in this open-label study of patients with hand and foot psoriasis.     

Deposits of Immunoglobulin and Complement in Psoriatic Lesions

Biopsy specimens from 43 patients with psoriasis were studied by immunofluorescence microscopy. Deposits of complement C3 and/or immunoglobulins were seen in the vessel walls and/or in the dermal-epidermal junction of all of 21 patients with pustular psoriasis, acute guttate psoriasis, psoriatic arthropathy and erythroderma. similar deposits were seen in nine out of 22 patients with psoriasis vulgaris. Deposits were found in clinically uninvolved skin in only one of 37 patients. The results might suggest that the deposition of immune complexes in the vessel walls are of importance for the development of psoriatic lesions.