Using topical immunomodulators

February 2004

Atopic dermatitis (AD) is a chronic dermatosis, with recurrent flares, resulting in pruritus, excoriation, erythema, scaling, and lichenification. AD usually begins in the first years of life. Therapy includes nonpharmacologic and pharmacologic treatments.

Topical corticosteroids are a main treatment consideration because of their anti-inflammatory and immunosuppressant effects, but an additional therapeutic choice has been introduced – topical immunomodulators. The available immunomodulators include tacrolimus (Protopic, Fujisawa) and pimecrolimus (Elidel, Novartis).

Maintenance of skin hydration is an important long-term therapy of AD, as dry skin exacerbates pruritus. Application of moisturizers within three minutes of bathing is recommended. The most beneficial moisturizers are occlusive agents and ointments such as petrolatum. However, petrolatum is messy and patient acceptance is low. Creams and lotions are classified as oil-in-water or water-in-oil emulsions. Oil-in-water emulsions are less occlusive, yet are generally more acceptable by patients.

Products with a greater lipid content (eg, petrolatum, mineral oil) are more occlusive and are better moisturizers. Products patients are more likely to accept include Eucerin cream, Jergens Advanced Therapy Ultra Healing Lotion or Keri Original Formula Therapeutic Dry Skin Lotion. Other effective ingredients include dimethicone and glycerin. Numerous other moisturizing products are available over-the-counter.

Topical corticosteroids are a mainstay of treatment for atopic dermatitis. They function as anti-inflammatories and have immunosuppressant effects. Topical corticosteroids differ by potency and may be classified as low (eg, hydrocortisone), low-intermediate (eg, triamcinolone acetonide), high-intermediate (eg, betamethasone valerate), and high potency (eg, fluocinonide).

Topical corticosteroids should be used with scheduled dosing, daily or twice daily, and not PRN. It is recommended that potent topical corticosteroids not be applied to areas where the stratum corneum is thinner, such as the face and intertriginous areas, as systemic absorption may be increased. Courses are indicated for resolution of acute flares and should not be used continuously. High potency topical corticosteroids should used for two weeks or less.

The benefit of topical steroid use must be considered against its adverse effect profile. Clinically significant adverse effects may include cutaneous atrophy, striae, or pigment changes. Cutaneous atrophy may occur after just three to four weeks of scheduled application. Systemic absorption may also become clinically important, especially as application area and corticosteroid potency increases, and especially in children, due to higher body surface areas. Systemic absorption resulting in hypthalamic-pituitary-adrenal axis suppression is a concern, and has been reported in the literature. Other systemic adverse effects have also been reported from steroid use (Ruiz-Maldonado, 1982; McLean, 1995). Concerns about adverse effects may affect compliance, according to a recent survey (Charman, 2000).

Topical immunomodulators

Because of their adverse effect profile, topical corticosteroids remain less than optimal. An additional concern with their use includes the potential for tachyphylaxis and reduced benefit with continued treatment. Two immunomodulators, tacrolimus and pimecrolimus have been approved for use in AD. Tacrolimus is approved for children 2 to 15 years of age with moderate to severe AD; pimecrolimus is approved for children 2 years of age and older with mild to moderate AD. Both are approved for short-term and intermittent long-term use.

Tacrolimus and pimecrolimus function as immunomodulators by binding to a cytosolic receptor, immunophilin, leading to inhibition of calcineurin. Calcineurin affects a cytosolic transcription factor, resulting in T-lymphocyte activation. Inhibition of T-lymphocyte activation results in reduced production of various proinflammatory mediators, including several interleukins and tumor necrosis factor. Neither drug affects collagen synthesis and will not result in cutaneous atrophy like topical steroids.

Tacrolimus became available for use in 2001, having shown efficacy from several clinical studies. Paller evaluated tacrolimus in a randomized, double-blind, placebo-controlled manner in 351 children aged 2-15 years with moderate to severe AD. Patients were treated for 12 weeks. Of those treated with tacrolimus, 38% (90/235) reported excellent clearing compared with 6.9% of patients receiving placebo. More children receiving tacrolimus had >90% improvement in the physician’s global evaluation of clinical response, the primary end point (P<.001). Adverse effects of tacrolimus application included skin burning and pruritus, which diminished after one week. There was no difference in efficacy among children receiving 0.03% or 0.1% ointment. Only the 0.03% ointment is approved for use in children, while both the 0.03% and 0.1% strengths are approved for use in adults.

Kang evaluated the safety and efficacy of tacrolimus 0.1% in an open-label study of 255 children, 2 to 15 years old, with moderate to severe AD for up to 12 months. The average treatment duration was 279 days. Transient skin burning and pruritus were the most common adverse events, but decreased within the first week of therapy. An increased incidence of infections was not found. Most patients demonstrated continued improvement throughout the study, without evidence of diminished efficacy.

Pimecrolimus

Pimecrolimus has been evaluated in 1,335 children aged 3 months to 17 years of age in phase-3 clinical studies. However, only data supporting the use of pimecrolimus in children 2 years of age and older have been used by the manufacturer for labeled indications. Eichenfield evaluated pimecrolimus in 267 children (2-17 years of age) and 136 children receiving placebo in a randomized, double-blind manner for six weeks of therapy. Most children evaluated had moderate AD. Efficacy monitoring para- meters included the Investigator’s Global Assessment and Eczema Area and Severity Index scales. At study conclusion, 35% of children receiving pimecrolimus were assessed as “clear or almost clear,” compared with 18% of children receiving placebo (P<.05). Additionally, 57% of children receiving pimecrolimus and 34% of children receiving placebo reported no or mild pruritus (P<.001). Adverse effects among treatment groups did not differ. Burning after application was reported by 10.5% of children receiving pimecrolimus.

Wahn compared pimecrolimus to placebo in 713 children 2 to 17 years old in a 2:1 randomized, double-blind manner for up to 12 months. Both groups used emollients and study drug to prevent progression to flares. When flares did occur, patients applied moderately potent topical corticosteroids as necessary to treat flares. Most patients had moderate AD. The primary endpoint was ranked flares at six months. The number of patients who completed therapy with no flares was significantly lower with pimecrolimus. At 12 months 50.8% vs. 28.3% of patients reported no flares when receiving pimecrolimus and placebo, respectively (P<.001). Significantly fewer patients receiving pimecrolimus required topical steroids to control flares than patients receiving vehicle, and children receiving pimecrolimus spent significantly fewer days in total receiving steroids. There was no difference between groups for bacterial skin infections or specific viral skin infections. However, the incidence of viral infections was higher in the pimecrolimus group (P<.05).

Although pimecrolimus is not labeled for use in children younger than 2 years of age, it has been studied in infants as young as 3 months, with evidence for its efficacy and safety. The manufacturer has decided not pursue this age indication. Kapp compared pimecrolimus to conventional therapy (emollient and topical corticosteroids as needed) in 251 infants (3 to 23 months of age) for up to 12 months. Infants receiving pimecrolimus had significantly less flares, less pruritus and required fewer topical corticosteroids than infants receiving emollients. There was no difference in the skin viral infections in infants receiving pimecrolimus. The package labeling for pimecrolimus describes two additional randomized, double-blind studies of 436 infants (3 to 23 months of age) with significantly greater resolution of symptoms in those receiving pimecrolimus.

Tacrolimus and pimecrolimus represent new therapeutic entities for the treatment of AD in children and adults. While topical corticosteroids can effectively treat disease flares, their long-term use is limited by significant adverse effects. Unlike steroids, tacrolimus and pimecrolimus may be applied to the face and other areas where the stratum corneum is thinner. Tacrolimus and pimecrolimus have been shown in clinical studies to be effective and safe for treatment periods of up to 12 months. Studies evaluating the most efficacious use of tacrolimus or pimecrolimus with topical corticosteroids are not available. However, published recommendations exist for combining topical immunomodulators and topical corticosteroids to induce remission for severe disease, and alternating topical immunomodulators with intermittent low potency topical corticosteroids for maintenance therapy (Abramovits). Despite an immunosuppressive mechanism of action of these topical immunomodulators, studies have not revealed increased topical bacterial or viral skin infections. Systemic absorption has been evaluated for both agents and is minimal. Measured blood concentrations of tacrolimus and pimecrolimus from studies have been less than 2 ng/ml in children, which is approximately 16 to 30-fold less than blood concentrations from orally administrated drug in adults. No evidence of accumulation exists for treatment durations of up to 12 months. The most common adverse effects of both drugs is application site burning, which appears to be greater with tacrolimus than pimecrolimus. Both agents have shortened the time to skin tumor formation in animal photocarcinogenicity studies. The manufacturers recommend that sunlight exposure be minimized with application. Information from additional studies comparing tacrolimus to pimecrolimus, long-term efficacy and safety studies, and optimal treatment regimens with topical corticosteroids would be helpful.

For more information:

• Ellison JA. Hypothalamic-pituitary-adrenal function and glucocorticoid sensitivity in atopic dermatitis. Pediatrics. 2000;105:794-799.
• Charman CR. Topical corticosteroid phobia in patients with atopic eczema. Br J Dermatol. 2000;142;931-936.
• McLean C. Cataracts, glaucoma, femoral avascular necrosis caused by topical corticosteroid ointment. Lancet. 1995;345:3330.
• Ruiz-Maldonado R. Cushing’s syndrome after topical application of corticosteroids. Amer J Dis Child. 1982;136:274-275.
• Paller A. A 12-week study of tacrolimus ointment for the treatment for atopic dermatitis in pediatric patients. J Am Acad Dermatol. 2001;44(1 Suppl):S47-S57.
• Kang S. Long-term safety and efficacy of tacrolimus ointment for the treatment of atopic dermatitis in children. J Am Acad Dermatol. 2001;44(1 Suppl):S58-S64.
• Eichenfield LF. Safety and efficacy of pimecrolimus (ASM 981) cream 1% in the treatment of mild and moderate atopic dermatitis in children and adolescents. J Am Acad Dermatol. 2002;46:495-504.
• Wahn U. Efficacy and safety of pimecrolimus cream in the long-term management of atopic dermatitis in children. Pediatrics. 2002;110:158-159.
• Kapp A. Long-term management of atopic dermatitis in infants with topical pimecrolimus, a nonsteroid anti-inflammatory drug. J All Clin Imm. 2002;110:277-284.