Latest treatments for atopic dermatitis

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José Carlos Pascual
MD
Department of Dermatology
Hospital General de Elche
Alicante
Spain
E:[email protected]

Atopic dermatitis (AD) is a common chronic inflammatory skin disease affecting up to 20% of school children.(1) This condition has a relapsing and remitting course. The pruritus characteristic of the disease usually leads to scratching. Other important features include a family or personal history of atopy, a characteristic distribution of lesions and a higher frequency of cutaneous bacterial and viral infections. Preventing and modulating trigger factors should be a lifelong goal. A major factor that exacerbates AD is dry skin. Moisturisers are critical in the management of AD and should be used regularly.(2) Although the exact aetiology of AD is unclear, it is thought to occur as a result of a combination of unknown genetic factors and interactions between the environment and the immune system.(3,4) AD is characterised by several immunological abnormalities; aberrant T-cell activation plays a pivotal role in disease pathogenesis, by producing cytokines that trigger immunological and inflammatory processes.(5)

Topical corticosteroids have been the mainstay of therapy for AD for many years. Their effectiveness is supported by randomised controlled trials.(5,6) However, their nonspecific mechanism of action can cause local and systemic side-effects, such as skin atrophy, striae distensae, telangiectasia and, rarely, hypothalamic–pituitary–adrenal axis suppression. The risk of steroidal side-effects is greater with long-term treatment and the use of potent corticosteroids.(7) Steroid-free topical calcineurin inhibitors (TCIs) are a new class of topical preparations available for the treatment of AD and other inflammatory dermatoses. Two drugs in this class are now widely available: tacrolimus ointment (Protopic(®) 0.03% and 0.1%; Fujisawa) and pimecrolimus cream (Elidel(®) 1%; Novartis). TCIs are more selective than corticosteroids. Tacrolimus and pimecrolimus both block T-cell activation by binding to the cytosolic FK-506 binding protein (FKBP)-12 to form a complex that inhibits the activity of the enzyme calcineurin. This binding phenomenon inhibits the ability of calcineurin to dephosphorylate transcriptor factor NFAT (nuclear factor of activated T-cells). This transcriptor factor activates the promoter region of the gene for various inflammatory cytokines that participate in the early immune response and are postulated to play a role in AD pathogenesis.(8,9)

Tacrolimus ointment
With over 16,000 adult and paediatric patients, the clinical development programme for tacrolimus ointment is the most extensive ever conducted in dermatology. In total, 11 phase III studies with tacrolimus have been carried out in Europe and North America.(10) The tacrolimus studies included almost exclusively patients with moderate-to-severe AD. Two concentrations of tacrolimus ointment (0.03% and 0.1%) are now available. The 0.03% concentration is the only one approved in children. Tacrolimus is indicated twice daily in mild, moderate or severe AD. In the first definitive, randomised, double-blind, multicentre study, 0.03%, 0.1% and 0.3% tacrolimus ointments were compared with vehicle alone in patients with moderate-to-severe AD. After three days of treatment, statistically significant changes occurred in all three treatment groups when compared with the vehicle.(11) Hanifin et al found tacrolimus 0.03% and 0.1% to be more effective in treating moderate-to-severe AD than the vehicle.(12) In this report of 632 adults who used tacrolimus twice daily for up to 12 weeks, a 90% or greater improvement from baseline in AD was observed in 37% of patients in the tacrolimus 0.1% group, 27 % in the tacrolimus 0.03% group and 7% of patients applying vehicle. To evaluate the long-term efficacy in the paediatric population, Kang et al treated 225 children with AD, age 2–15 years, with tacrolimus ointment 0.1% for up to 12 months.(13) Substantial improvement was observed during the first week, which was maintained during the course of the study. Subsequent studies conducted over several years suggest that safety and efficacy are maintained. Several studies have compared tacrolimus ointment with corticosteroid treatment.(14) Tacrolimus seems to be equivalent to moderate-to-potent topical corticosteroids. Several studies have been carried out to determine the safety of tacrolimus ointment in the short and long term.(15) These studies have shown that tacrolimus ointment is a safe drug in adults and children. The most common adverse events are the transient sensation of skin burning and pruritus at the site of application. The prevalence of these mild application-site adverse events was highest during the first few days of treatment and then declined as the skin healed. No case of skin atrophy was reported. In a recent publication, there were no significant differences between the number of bacterial, viral or fungal infections in tacrolimus-treated patients compared with vehicle-treated patients, with the exception of folliculitis, which was significantly more common in tacrolimus-treated patients.(16) In the same way as with corticosteroid treatment, percutaneous absorption of tacrolimus decreases as patients’ barrier function improves. Blood tacrolimus concentrations after topical application were measured at various times during several studies in adults and/or paediatric patients with AD. Tacrolimus concentrations were below the limit of quantification (<0.5ng/ml) in 75–90% of blood samples.(8) Systemic immunosuppression is associated with an increased risk of nonmelanoma skin cancer. Therefore, immunomodulatory agents such as tacrolimus ointment and pimecrolimus cream may in theory increase the risk of cutaneous malignancies. Clinical data available to date indicate that TCIs are not associated with skin cancer. However, further long-term postmarketing surveillance is needed to confirm these findings.

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Pimecrolimus cream
The efficacy and safety of pimecrolimus cream have been evaluated in more than 2,000 patients with AD. In total, seven phase III trials have been carried out in children and adults with AD. Pimecrolimus is a TCI developed specifically to treat AD, and it is indicated twice daily in mild-to- moderate AD in patients older than 2 years.(17) The efficacy and safety of pimecrolimus in AD was demonstrated in a small, randomised, blinded, placebo-controlled trial. In 34 adult patients, pimecrolimus proved to be superior to placebo, and no clinically significant adverse events were reported.(18) The three six-week, randomised, double-blind, vehicle-controlled studies with pimecrolimus comprised two trials with children age 1–17 years and one study with infants age 3–23 months.(19,20) At baseline, most patients had moderate disease. By week 6, treatment success was observed in 34.8% of children in the pimecrolimus group, compared with 18.4 % of children in the vehicle group, and in 54.5% of infants treated with pimecrolimus versus 23.8% of vehicle-treated infants. Pimecrolimus has been evaluated in three 12-month vehicle-controlled trials.(10) A two-year study in infants and young children has recently been published; pimecrolimus treatment significantly reduced the incidence of flares compared with vehicle (p<0.001).(21) During a 12-month paediatric trial, 56.9% of infants and 50.8% of older children treated with pimecrolimus remained flare-free, compared with 28.8% of vehicle-treated patients in each study, while 44.8% of pimecrolimus-treated adults and 18.8% of vehicle-treated adults did not require corticosteroids during six months of therapy.(22) Although pimecrolimus is an effective steroid-sparing agent, to date only one published trial has directly compared pimecrolimus treatment with corticosteroid therapy.(23) This study concluded that pimecrolimus was less effective than beta-methasone-17-valerate 0.1%. Systemic absorption of pimecrolimus is consistently low, both in children and adults, regardless of age, extent of body surface area treated or duration of therapy. Clinical data available to date indicate that pimecrolimus is not associated with skin cancer, skin atrophy or high risk of skin infections. Pimecrolimus is well tolerated when applied topically. Adverse effects have generally been limited to local irritation such as burning and pruritus. A recently published study has shown that long-term treatment with pimecrolimus cream 1% does not appear to interfere with the development of a normal response to vaccination.(24)

Tacrolimus ointment versus pimecrolimus cream
One trial evaluated tacrolimus ointment 0.1% and pimecrolimus cream 1% in 198 children with moderate-to-severe AD. Tacrolimus was significantly more effective than pimecrolimus based on multiple endpoints.(25) Another study comparing pimecrolimus cream 1% with tacrolimus ointment 0.03% in paediatric patients with moderate AD concluded that pimecrolimus had better formulation attributes and local tolerability than tacrolimus ointment 0.03%, while providing similar efficacy and overall safety.(26)

Conclusion
Topical corticosteroids and emollients have formed the basis of conventional therapy for AD for the past 50 years. Tacrolimus ointment and pimecrolimus cream provide a new, effective, well-tolerated and safe treatment for the entire spectrum of mild-to- severe AD.

Because TCIs do not cause skin atrophy, they may be safely used for months or years on all skin areas, including the face and the intertriginous areas.

References

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25. Fleischer AB Jr. Controlling atopic dermatitis with Protopic – new insights. 12th Congress of the European Academy of Dermatology and Venereology, Barcelona, Spain; 15-18 October 2003. Oral presentation.
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