British

Journal of Dermatolofiii

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124. 4 3 - 4 8 .

Cyclosporin A in atopic dermatitis: therapeutic response is dissociated from effects on allergic reactions C.S.MUNRO. ELIZABETH M.HIGGINS. lANKT M.MARKS. B.MARTINA DALY. P.S.FRIEDMANN AND S.SHUSTER Department of Dermatology, Royal Victoria Infirmary, Newcastle UIKHI Tipie ,\7:'I 4iP, O.K, Accepted for puhlicittioii 1 3 August

Summary

Fourteen patients with severe chronic atopic dermatitis were treated with cyclosporin A (CyA. Sandimmun®: 5 mg/kg/day) ibr 7-1 f) weeks. All showed a marked clinical improvement and half could omit topical corticosteroid treatment during therapy. Adverse effects were minor, but two patients relapsed despite continued treatment. In the others, the disease recurred soon after stopping CyA. Serum IgE levels and prick-test responses were unchanged by CyA. Immediate and late-phase cutaneous responses to intradermal house dust mite antigen (HDM) were significantly increased during treatment: hut a delayed response, present at 24 and 48 h. was unaffected. Four of six patients challenged with HDM patch tests to tape-stripped skin during treatment showed eczematous reactions at 48 h. Thus, cyclosporin A has a powerful therapeutic effect in atopic dermatitis hut does not reduce allergic responses to inhalant antigens.

Cyclosporin A (CyA), an immunosuppressive agent, has been found to be effective in various dermatoses.' '' Recent reports of a few patients indicate that atopic dermatitis also responds to this drug.' '* We have treated a larger group of patients with severe chronic atopic dermatitis with CyA. in order to explore its efficacy further. We have also explored its possible mechanism of action in the disease by examining the effect of CyA on the abnormal allergic responses to environmental antigens, such as house-dust-mite antigen (HDM). characteristic of atopic individuals. A causal link between such hypersensitivity reactions and atopic dermatitis has long been suspected but is not proven.""' If they are indeed relevant to dermatitis, drugs which improve the disease might be expected also to reduce hypersensitivity reactions. We therefore measured the effect of CyA treatment on the response to HDM. using both intradermal tests to follow immediate, late-phase (6 h) and delayed (48 h) reactions, and epicutaneous patch tests on tape-stripped skin, which were read at 48 h. While CyA greatly improved atopic dermatitis, we found no reduction in any component of the response to HDM, and immediate and late-phase responses were paradoxically increased.

Correspondence: Dr C.S.Muiiro.

Methods Fourteen patients with chronic atopic dermatitis, severe enough to require continuous use of potent topical corticosteroids. were recruited in an open therapeutic trial of cyclosporin A (Sandiman. Sandoz), All patients gave informed consent. Patients with abnormal renal or hepatic function were excluded. There were eight male and six female patients, and the mean age was 28-6 (range 1 7-56) years. Bach patient was treated with CyA at a dose of 5 mg/kg/day. given as a single evening dose, for periods of up to lf> weeks, at the end of which time the drug was either discontinued abruptly (in nine patients) or reduced gradually (in five). Patients were allowed to continue using topical steroid treatment as necessary, and no other changes were made. Two additional atopic patients (one male, one female, ages 18 and 25) were studied from a group being treated with CyA (5 mg/kg/ day) for alopecia areata: they had no history of dermatitis but were sensitive to HDM in skin prick tests. Blood pressure, and standard biochemical indicators of renal and hepatic function were monitored throughout. Whole blood cyclosporin levels were measured 12-14 h after the oral dose, using the speciHc monoclonal antibody RIA kit (Sandoz). The response to treatment was evaluated by clinical assessment of erythema, weeping, scale, excoration and 43

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C.S.MlJNROt'ffl/.

lichenification. Severity of itching and requirement for topical steroids were reported by the patients, In 11 of the 14 patients, the area involved by active dermatitis was assessed at each clinic visit using the rule of nines. In eight patients, severity of lesional erythema, scale, and excoriation was scored on a 0-3 scale in each of four areas (head and neck, trunk, arms, and legs), giving a maximum score of 12 for each parameter. Components of the atopic allergic response were measured before treatment, and again after 4-6 weeks of treatment. In 10 patients, total serum IgE levels were measured by routine laboratory HLISA before and after 6 weeks of treatment with CyA. Skin testing of patients was approved by the hospital ethical committee, immediate hypersensitivity responses were elicited with a range of common antigens (Bencard) as prick tests. Responses were considered positive if the weal diameter was more than 3 mm greater than the control at 1 5 min. The full time course of the response to intradermal injection of HDM was followed in six patients with dermatitis and the two with alopecia areata. all of whom displayed immediate hypersensitivity to the antigen. HDM antigen (Pharmacia) was injected at doses of 1. 5. and 2 5 tmits in OOS ml saline and the response was measured as the change in skinfold thickness with Harpenden callipers^^" at intervals of 15 min for an hour, then at 6. 24 and 48 h. In six patients, these measurements were repeated on a third occasion. 6 weeks after treatment had been discontinued. Epicutaneous challenges with HDM (1-25 x 10"* units in 25 /il) and diluent control were made in six patients during CyA treatment. Solutions were applied, on patch test felts (Al-test). to clinically normal back skin which had been stripped with cellophane tape until the first glistening points appeared. After removal of patch tests at 48 h. the responses were assessed according to conventional patch-testing criteria.'"^

Statistics The difference between individual measurements in paired data was compared using f-tests. Two-way within-patient analysis of variance was used to compare responses to intradermal HDM. In order to avoid multiple comparisons of related data, the immediate response was characterized by deriving a single statistic. the area under the curve, from measurements between 15 and 60 min. The measurements at f). 24 and 48 h. which may represent distinct responses, were analysed individually.

100 80-

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Weeks ot treatmenl l-'igure 1. The effect nf cyclospiiriii A treatment on the extent of active eczema, as a percentage of body surface urea, in 11 patients.

Results Clinical effects

All patients showed clinical benefit within 5 weeks. The earliest changes, often apparent within the tirst week, were lessening of itching and erythema of the lesions. Improvement in weeping, excoriation and scaling followed. Lichenification. when present, showed a more gradual response over the period of the study (up to I 6 weeks). All patients reported a marked reduction in their requirement for topical steroid application during CyA treatment. Seven patients required emollients only after remission was induced, and the other patients reported that they could use less potent steroids, or apply them less frequently or to smaller areas, than before treatment. The effect of CyA treatment on the area involved in 11 individual patients, assessed hy the rule of nines, is shown in Figure 1. The mean body area involved at start of treatment was 50-3% (range 6-81%); at 6 weeks the mean area was 9-9% (range 2-55%). a significant reduction ( P < 0 01). Scores for erythema, scale and excoriation in eight patients, who included two undergoing relapse at 6 weeks, are shown in Table 1. Mild fluctuations in the activity of the dermatitis occurred during CyA treatment in several patients, but in two patients the rash worsened and. because of the possibility that CyA was aggravating the disease, treatment was stopped after 7 and 8 weeks. In one of these patients the relapse was on the face and upper chest and resembled seborrhoeic dermatitis. It resolved on stopping CyA treatment (see below), but the atopic dermatitis worsened, as it did also on stopping CyA in the second patient. In five of the patients who responded well to the

CYA TREATMENT OF ATOPIC DERMATITIS

Table 1. Clinical effects of CyA Irealment in eight patients

Weeks Pre-CyA 2

Erylhema

Scale

Kxcoriation

6-4±()-S 4 - 3 ± l 4** 4()± M r

3i±t 9 l-5±l-5' 2-2±2-()

2 i±2 r*

Values given as mean and standard deviation, *P

Cyclosporin A in atopic dermatitis: therapeutic response is dissociated from effects on allergic reactions.

Fourteen patients with severe chronic atopic dermatitis were treated with cyclosporin A (CyA, Sandimmun; 5 mg/kg/day) for 7-16 weeks. All showed a mar...
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