Background

Atopic dermatitis is a chronic relapsing inflammatory disorder, which affects around 15-20% of UK children at some stage (often presenting before the age of 5 years) and 2-3% of adults.3^,4 Its pathophysiology is not fully understood, but abnormal secretion of cytokines from T-lymphocytes is thought to be important in the genesis of skin lesions. Characteristic clinical features include dryness of the skin, and flares in which affected skin becomes reddened, sore and very itchy. Scratching often leads to excoriation and lichenification. Secondary bacterial infection, manifesting as exudation and crusting, is common. The distress caused by these symptoms is often considerable.

In most patients, atopic dermatitis is mild or moderate in severity and, with careful explanation, can be managed successfully in primary care.5 It can usually be kept under control by minimising exposure to aggravating factors (e.g. soaps, detergents, animal fur, woollen fabrics), by daily use of emollients, and, during flares, topical treatment with short courses of a mild or moderately potent corticosteroid.5 Patients and parents can be reassured that it is very rare for such corticosteroid regimens to cause serious unwanted effects (e.g. skin atrophy, growth suppression), reports of which alarm and deter many people from using corticosteroid creams and ointments.5^,6 The risk is higher for patients who need frequent or prolonged courses of potent corticosteroids to control severe or chronic atopic dermatitis, for whom management will usually require the advice of a dermatologist.

What is pimecrolimus?

Pimecrolimus is a topically active immunosuppressant derived from the naturally occurring macrolactam, ascomycin. Its chemical structure closely resembles that of tacrolimus, which we concluded was an effective topical treatment, appropriate for use under the guidance of a specialist.1 In vitro, pimecrolimus inhibits the synthesis and release of inflammatory cytokines from T-lymphocytes, and the release of inflammatory mediators from mast cells.7 Unlike corticosteroids, it does not appear to affect other cell types such as fibroblasts and keratinocytes. When applied topically, pimecrolimus reduces skin inflammation in dose-dependent fashion in animal models of dermatitis, and has similar potency to topical tacrolimus.7 However, when administered systemically, pimecrolimus appears far weaker than tacrolimus in suppressing systemic immune responses.7 During regular application of pimecrolimus to the skin in adults and children with extensive atopic dermatitis, concentrations in the blood are reported to be, at most, only just measurable.8–10

Licensed use

Pimecrolimus is available as a 1% cream in tubes of 30g, 60g and 100g. Unlike topical tacrolimus, licensed use of pimecrolimus in the UK is not restricted to patients who are unresponsive to, or intolerant of, conventional therapy (a restriction which applies in the USA11). For short-term treatment of active mild or moderate atopic dermatitis, the company recommends twice-daily application to all affected areas, including the face, neck and skin creases, until lesions clear.2 For the long-term prevention of flares, the company recommends intermittent use, starting at first appearance of symptoms or signs, continuing until clearance, and resuming treatment at first symptoms or signs of a recurrence.2 There is no restriction either in the total daily dose, duration of treatment, or the area of skin that may be treated.2 Pimecrolimus should be stopped "and further therapeutic options considered" if there has been no improvement after 6 weeks, or if a flare occurs while pimecrolimus cream is being used.2

Clinical efficacy

Short-term treatment

Children

Three randomised double-blind trials, each lasting 6 weeks, have compared twice-daily application of 1% pimecrolimus cream with a vehicle cream in children with atopic dermatitis of mainly mild or moderate severity (a score of 2-3 out of 5 on the Investigator's Global Assessment [IGA]). The pooled results from two of these studies, involving in all 403 children aged 1-17 years (mean 6.7 years), showed that pimecrolimus cleared or almost cleared dermatitis (IGA score of 0 or 1, the primary outcome) in 35% of children (vs. 18% with vehicle; p<.05), with significant improvement in all treated areas, including the head and neck, by 8 days.12 The findings of a third study, in 186 infants aged 3 months to 2 years (for whom pimecrolimus is unlicensed), were similar: pimecrolimus cleared or almost cleared dermatitis in 55% of children by 6 weeks (vs. 24% with vehicle; p<.001).13 Improvement, relative to vehicle, was reported to be especially noticeable on the head and neck (a secondary outcome).

No published study has compared short-term use of pimecrolimus with a mild or moderately potent topical corticosteroid in children with mild or moderate atopic dermatitis - the standard treatment for flares in this group. Nor are there any published comparisons with tacrolimus ointment.

Adults

In a 3-week double-blind study, 34 adults with moderately severe atopic dermatitis applied 1% pimecrolimus cream to a small area of dermatitis on one forearm, and placebo base to a similarly affected area on the opposite forearm.8 Treatment was applied either once daily (18 patients) or twice daily (16 patients). In the twice-daily treatment group, pimecrolimus improved the Atopic Dermatitis Severity Index by 72% (vs. 10% with placebo; p<.001), the primary outcome measure. Once-daily pimecrolimus was much less effective.

In a dose-finding study, 260 patients with mainly moderate atopic dermatitis, were randomised to one of six twice-daily regimens: 0.05%, 0.2%, 0.6% or 1.0% pimecrolimus cream, 0.1% betamethasone valerate cream, or vehicle cream, applied for 3 weeks to all areas except the face.14 All but the lowest strength of pimecrolimus was significantly more effective than vehicle, as assessed by the Eczema Area and Severity Index (EASI), the primary outcome measure, with an apparent dose-response relationship. Improvement appeared to be much less with pimecrolimus than with betamethasone valerate (but significance levels were not reported). In patients with mild atopic dermatitis, the severity score decreased by 48% with pimecrolimus, and by 88% with betamethasone valerate; in those with moderately severe disease, it decreased by 38% and 64%, respectively.

As in children, there are no published trials comparing pimecrolimus cream with tacrolimus ointment in adults.

Prevention of 'flares'

Children

In a 1-year double-blind multicentre study, 713 children (age 2-17 years) with mainly mild or moderate atopic dermatitis (IGA score 2 or 3) were randomised in a 2:1 ratio to early treatment with either pimecrolimus cream or vehicle, applied twice daily at the first sign (i.e. redness) or symptom (i.e. pruritus) of atopic dermatitis.15 Once started, the study treatment was continued until complete clearance of symptoms and signs. In the event of a flare developing ("at least severe erythema and severe infiltration/papulation"; IGA 4 or 5), treatment with a moderately potent topical corticosteroid was given, instead of study medication, until clearance of the flare. All patients used emollients to treat dry skin.

The incidence of flares requiring treatment with corticosteroid in the first 6 months of the study, the primary outcome measure, was reported to be significantly lower in the pimecrolimus group (p<.001), regardless of the baseline severity of atopic dermatitis, but the absolute figures were not given. Instead, data were given for the proportion of patients completing 6 months (61% with pimecrolimus vs. 34% with vehicle) or 12 months (51% vs. 28%) without a flare, but no significance levels were provided for these data. Of those remaining in the study for 12 months, 14% used pimecrolimus continuously and 7% used vehicle continuously.15

In a double-blind study of similar design, 251 children (age 2-23 months) with mainly mild or moderate atopic dermatitis were randomised in a 4:1 ratio to early application of pimecrolimus or vehicle cream twice daily at the first symptom or sign of active dermatitis.16 A moderately potent corticosteroid was started if atopic dermatitis flared (IGA score 4 or 5, i.e. severe or very severe). Caregivers applied emollients regularly in all children. During the first 6 months, the incidence of such flares (averaged over 12 months), the primary outcome measure, was lower in those receiving pimecrolimus (1.0 vs. 2.2 with vehicle; p<.001). Topical corticosteroid was used on 3.2% and 6.2% of study days in the pimecrolimus and vehicle groups, respectively. Pimecrolimus was used on average on 75% of days in the first month, and thereafter on around 50% of days.

Adults

In a randomised double-blind study lasting 6 months, 192 adults with moderate (IGA score of 3) or severe (IGA score 4) atopic dermatitis, involving on average 17% of body surface area, applied 1% pimecrolimus or vehicle cream twice daily to affected areas at the first symptom or sign of atopic dermatitis, until clearance.17 All used emollients throughout the study. Patients with uncontrolled itching and clinical signs of atopic dermatitis (excoriation, oozing, crusting or severe erythema) despite study medication, were treated with a moderately potent topical corticosteroid, applied twice daily for a maximum of 7 days, then once daily for 7 days or until marked improvement. Patients in the intermittent-pimecrolimus group required corticosteroid on fewer days (14.2% of days; 95% CI 8.3-21.1%) than those on vehicle (37.2%; 95% CI 30-44%), the primary outcome measure. The incidence of flares (defined as atopic dermatitis needing at least 3 days of corticosteroid - a secondary endpoint) was lower with pimecrolimus (1.1 vs. 2.4 per 24 weeks with vehicle; p<.001).

Questions about the prevention studies

All of these studies are presented as assessing emollient plus intermittent 'flare-preventive' therapy with pimecrolimus against a 'conventional' regimen of emollient plus topical corticosteroid treatment for established flares. They show that pimecrolimus is superior to vehicle for preventing early inflammation progressing to flares, when defined as severe grades of atopic dermatitis requiring moderately potent topical corticosteroid therapy. However, no study has compared pimecrolimus to the usual first-line therapy for exacerbations of mild or moderate atopic dermatitis, which is treatment with a mild corticosteroid (such as 1.0% hydrocortisone acetate), customarily starting before the flare has become severe and given for the shortest time necessary. Waiting for atopic dermatitis to become severe or very severe is not, in our opinion, a conventional way of managing a flare, particularly in children. Hence it is difficult to assess the real clinical relevance of any corticosteroid-sparing effect of pimecrolimus. Furthermore, to achieve the observed benefits, some patients needed to use pimecrolimus for much of the time.

Unwanted effects

Around 19% of patients using pimecrolimus cream experience transient mild local reactions, including burning sensation, irritation, pruritus or erythema.2 Treatment with pimecrolimus cream for 4 weeks caused no thinning of forearm skin in healthy adults, as assessed by ultrasound and histology.18 However, we know of no studies investigating the effects of pimecrolimus on skin thickness when used long term in patients with atopic dermatitis. The company advises that skin infections such as impetigo, herpes simplex, herpes zoster, molluscum contagiosum and skin papilloma are uncommon unwanted effects of topical pimecrolimus, occurring in around 1 in 100-1,000 patients.2 In a 1-year study, the overall incidence of viral (but not bacterial) skin infections was higher in children treated with pimecrolimus than in those treated with vehicle (12.4% vs. 6.3%; p=0.038).15 However, the incidence of individual infections such as herpes simplex did not differ in the two groups. Cough was also more common in the pimecrolimus group (19.3% vs. 11.8%; p=0.045).15 In a recent 6-week study in infants, the incidence of pyrexia (31.7% vs. 12.7%; p<.05) and diarrhoea (8.1% vs. 0%; p<.05) was higher with pimecrolimus than with vehicle.13 However, study treatment was stopped early (mainly for inefficacy) in more infants receiving vehicle than pimecrolimus (48% vs. 11%)13 and the figures were not adjusted for this factor, so are difficult to interpret.

Contraindications and precautions

Pimecrolimus cream should not be applied to skin affected by acute cutaneous viral infections.2 Sites clinically infected with bacteria or fungi should be treated appropriately before starting pimecrolimus. Pimecrolimus is contraindicated in patients with known hypersensitivity to macrolactams. Given the absence of adequate safety data, it should not be used during pregnancy. Women who are breast-feeding should not apply pimecrolimus to the breast.2 No clinically significant interactions with systemically administered drugs or vaccines have been identified. As a precaution, the company recommends that, in patients with extensive atopic dermatitis, vaccinations should be given during treatment-free periods.2

Pimecrolimus cream has not been studied in immunocompromised patients or people with skin cancers. The long-term effect of pimecrolimus on the local immune response in the skin or on the incidence of skin malignancies is unknown.2 Animal studies have found an increased risk for lymphoma, thyroid adenoma and photocarcinogenicity with high doses of oral pimecrolimus, leading the US licensing authority to request long-term safety studies in children and adults.11 No systemic or cutaneous malignancies have been reported in humans. As with tacrolimus, patients using pimecrolimus should avoid excessive exposure of their skin to bright sunlight and use effective sunscreens, and should not be undergoing any form of phototherapy.2 The summary of product characteristics warns that pimecrolimus should not be applied to the eyes or mucous membranes.2 No explanation for this is given.

Cost

The basic cost to the NHS of 100g pimecrolimus cream is around £59. This is around 25 times the cost of 100g 1.0% hydrocortisone acetate cream (£2.40) and around 14 times that of 100g 0.1% betamethasone valerate cream or ointment (£4.35). The cost of 100g tacrolimus ointment is around £62-£68.

Conclusion

▼Pimecrolimus cream, a new topical immunosuppressant, is moderately effective for the short-term treatment of active mild or moderate atopic dermatitis, but has not been compared with the standard therapy in children, which is brief treatment with a mild or moderately potent corticosteroid. In adults, it has been compared to the potent corticosteroid, 0.1% betamethasone valerate, to which its efficacy is inferior.

Long-term intermittent use of pimecrolimus cream to prevent progression from early symptoms and signs of atopic dermatitis to flares, has not been compared with the most appropriate conventional therapy for patients with mild or moderate disease, that is, brief treatment with a mild or moderately potent corticosteroid commencing before the flare has become severe or very severe. Pimecrolimus is better than vehicle in preventing progression to severe grades of flare, if topical corticosteroid is withheld until this point, and can reduce the number of days for which a moderately potent corticosteroid is needed. However, such an approach could substantially increase the cost of managing mild or moderate atopic dermatitis, and is unnecessary since conventional therapy is generally effective, safe and cheap. The safety of long-term use of pimecrolimus, in terms of any potential to increase susceptibility to infection or malignancy, needs to be clearly established.

Overall, we can find no convincing evidence to justify the use of pimecrolimus in the first-line management of atopic dermatitis. An advertisement for pimecrolimus cream shows a child clearly aged under 2 years - so implying its use in this age group. This message breaches the licence and should be withdrawn and a corrective statement published.