Topical Immunomodulators: Novel Alternatives for the Treatment of Pediatric Atopic Dermatitis

Amy S. Paller, MD

Atopic dermatitis, or eczema, is the most prevalent inflammatory dermatosis of pediatric patients, currently affecting 7% to 17% of American children .[1] As is true for asthma, the prevalence has increased dramatically during the past 3 to 4 decades. In fact, up to 50% of patients with atopic dermatitis have asthma, and up to 80% develop allergic rhinitis. Three of four major criteria must be present to confirm the diagnosis of atopic dermatitis: a chronic, relapsing course; pruritus; typical morphology and distribution; and a personal or family history of atopic disease. Sixty percent of patients show manifestations of the disorder during the first year of life, and parents commonly first note the rash during the first weeks of life. topic dermatitis manifests in almost 90% of patients by 5 years of age.

The intense pruritus of atopic dermatitis and the obvious nature of the rash can significantly alter the lives of affected patients. Affected preschool children are excessively dependent and fearful, showing more behavioral problems. Mothers of affected preschool children with atopic dermatitis are more distressed, do not feel supported socially, and usually choose to stay home rather than work. Overall, 50% of school-age children with atopic dermatitis show psychological disturbances, as compared with 27% of control children. These disturbances are a function of the severity of the disorder. Although testing of school-age children with mild atopic dermatitis shows no difference from controls, disturbances are noted in 53% of moderately affected and 80% of severely affected children.

The most commonly reported disturbances include excessive worrying, tears on arrival at school, stomachaches, and sleeping problems. The rate of psychological disturbances in children with atopic dermatitis tends to be greater than in children with several other disorders; for example, 38% of children with leukemia and 55% of children with hemiplegia show psychological disturbances. The incessant itchiness of atopic dermatitis causes sleeplessness, irritability, and perceived hyperactivity in affected children, which compromises their social relationships with teachers and peers at school. Affected children often show embarrassment, poor self-esteem, and lack of self-confidence.

Figure 1. Erythema, scaling, and edema, most severe on the cheeks and chin, is typical of atopic dermatitis on the face of an affected infant.

The characteristic distribution of the dry, red, poorly demarcated patches of atopic dermatitis varies based on patient age. Typically during infancy, the face is most frequently affected (Figure 1), particularly the cheeks and chin, although generalized involvement may occur. Owing to the marked edema associated with the inflammation, the cheeks and less commonly other affected areas often exude a serous drainage, which can be confused with secondary staphylococcal infection. The diaper area in infants is almost always spared, often with a sharp demarcation from affected skin; this sparing is thought to result from the combination of the moist environment of the diaper, and the protection from both scratching and contact with irritants and allergic triggers. The dry, erythematous eruption of eczema shows more extensor surface localization in toddlers, but by childhood and adolescence, involvement of the antecubital, popliteal, wrist, and ankle areas is characteristic (Figure 2). Chronicity leads to lichenification, characterized by thickening of skin and, in darker-skinned patients, hyperpigmentation. In lighter-skinned patients, hypopigmentation at sites of previous inflammation is more typical, and can be quite noticeable, especially during the summer months when the noninflamed skin tans more easily than involved skin. The severity of atopic dermatitis may range from severe (>50% body surface area involvement with marked erythema) to mild (slight erythema and dryness, localization to <10%, e.g., antecubital and popliteal sites only).

Although the molecular basis of atopic dermatitis is unclear, the dermatitis represents a disorder of cutaneous immune dysfunction influenced by genetic predisposition and external triggers. Patients with atopic dermatitis demonstrate T-lymphocyte activation, an imbalance in the production of Th1/Th2 cytokines, hyperstimulated Langerhans cells, and excessive B cell production of IgE. As a result of the altered cutaneous immunity and poor skin barrier function, patients with atopic dermatitis are at increased risk for the development of widespread cutaneous Staphylococcus aureus, Herpes simplex, and molluscum contagiosum infections.

Figure 2. Erythema, dryness, excoriations, and lichenification of the fold areas at the ankle and wrist, with prominent involvement on the dorsum of the hands and feet.

CURRENT THERAPY FOR PATIENTS WITH ATOPIC DERMATITIS

Treatment of children with atopic dermatitis must be individualized. In general, patients benefit from avoidance of substances that might trigger an irritant response (such as wool or harsh soaps) or an allergic response (such as to milk), vigorous use of emollients, application of topical anti-inflammatory medications, and, particularly with flares, the use of antihistamines (which are thought to be useful primarily because of their sedating properties).

Bathing and Use of Moisturizers

Although the concept that excessive bathing of children with atopic dermatitis has merit, bathing followed by use of emollients is considered to be a critical component in the care of the affected child. Bathing provides the opportunity to hydrate the skin, and this hydration may be maintained by coating the skin with a moisturizer within 2 to 3 minutes after emerging from the bathtub, before evaporative loss and drying are able to occur. A daily bath or even twice daily bath of up to 10 minutes in duration allows a period of fun for the baby, which encourages effective paternal-infant bonding, desquamation of skin, and removal of microorganisms. In general, a thick emollient should be applied after the bath, particularly during the dry winter months.

Topical Treatment

Topical corticosteroids are the mainstay of therapy, and have been the only available topical anti-inflammatory treatment for atopic dermatitis for several decades. In general, ointment forms of topical steroids tend to be more effective, although the cosmetic elegance of cream formulations may be preferred by older children and adolescents. Topical corticosteroids are available in a wide variety of strengths, ranging from the class VII (e.g., hydrocortisones) and class V and VI steroids (e.g., nonhalogenated medium strength steroids) to the ultrapotent, class I topical corticosteroids. In general, there is no role for class I topical steroids in the treatment of atopic dermatitis in children. In contrast, the usage of class V and class VI topical steroids is generally quite safe. Application of class II to class IV steroids is usually best limited to treatment of flares or more recalcitrant sites, such as the hands and feet.

Although the efficacy of a topical corticosteroid is directly related to its potency, increased potency also raises the risk of potential side effects. Inappropriate or excessive use of medium to potent strength halogenated topical corticosteroids, and, occasionally, nonhalogenated low to medium strength topical corticosteroids, has been related to the occurrence of local adverse reactions (cutaneous atrophy, striae, telangiectasia, and perioral dermatitis). The highest risk exists when topical steroids are applied to the face, diaper, or intertriginous regions. Application of topical corticosteroids to the eyelid region, a common site of the dermatitis (Figure 3), should be limited because of the increased related risk of increased intraocular pressure or glaucoma and cataract formation).

Medium-strength to high-potency topical corticosteroids may also cause systemic side effects in pediatric patients because of percutaneous absorption, particularly if a large area is covered or the steroid is applied to an intertriginous or occluded site. This risk is greatest in infants because their ratio of body surface area to weight is significantly higher than in adults. Absorption of potent topical corticosteroids may suppress the hypothalamic-pituitary-adrenal axis, resulting in growth retardation and, rarely, Cushing syndrome. As atopic dermatitis improves, it is prudent to use less potent topical steroids or to lower the frequency of application, replacing corticosteroid application with emollient use.

Figure 3. Eyelid and periorbital involvement in an older child with atopic dermatitis.

Systemic Therapy

Moderate to severe dermatitis may become recalcitrant to topical corticosteroid therapy, particularly after chronic use. Although administration of systemic corticosteroids is remarkably effective for most patients with atopic dermatitis, the rapid recurrence and often rebound after discontinuation of therapy and the high risk of potential side effects make its use impractical. Systemic cyclosporine has been administered to children with atopic dermatitis whose dermatitis is refractory to the effects of even potent topical corticosteroids. In an open-label trial of 2- to 16-year-old children with atopic dermatitis, cyclosporine 5 mg/kg/day caused significant improvement or total clearing in 22 of the 27 patients. Similarly, we have seen excellent responses to administration of the microemulsion form of cyclosporine (3 mg/kg/d) to severely affected, recalcitrant patients, with clearance or marked improvement in most patients within a few months of initiating therapy. Withdrawal of cyclosporine usually leads to rapid flaring of the dermatitis, but the potential risks of hypertension, renal abnormalities, and systemic immunosuppression preclude its long-term use.

NEWER TOPICAL THERAPIES

In the past, patients who required the long-term use of moderate strength to potent topical corticosteroid agents, whose disease became refractory to topical corticosteroid agents, or who developed complications from the use of topical corticosteroids have had no effective topical therapeutic alternatives. However, two new noncorticosteroid topical immunomodulators have been developed to treat patients with atopic dermatitis, tacrolimus ointment and pimecrolimus cream.

Tacrolimus Ointment

Tacrolimus (also known as FK506) is a potent macrolide immunosuppressant that has been commercially available for several years. It is used primarily to prevent organ rejection after liver, kidney, and bone marrow transplantation. The mechanism of action of tacrolimus involves its binding to an immunophilin, FK binding protein, and inhibiting the formation of a complex combining calcium, calmodulin, and the protein phosphatase calcineurin. Dephosphorylation of the transcription factor nuclear factor of activated T cells (NF-AT) is prevented, thereby blocking the transport of NF-AT into the nucleus, which is necessary for cytokine production (Figure 4a, b). Similar to the action of cyclosporine, tacrolimus both directly suppresses T-cell activation and cytokine production, and inhibits the expression of the high affinity receptor for IgE on Langerhans cells. Tacrolimus also inhibits degranulation and the synthesis of proinflammatory mediators from mast cells in vitro. Sustained systemic administration of tacrolimus may cause renal function impairment, hypertension, abnormal glucose tolerance, immunosuppression, and the development of B-cell lymphoma, especially in patients who contract Epstein-Barr viral infections.

In an attempt to maintain the potent anti-inflammatory effects of cyclosporine without the systemic risks, topical formulations of cyclosporine were tested, but were found to be ineffective for treating atopic dermatitis. In contrast, tacrolimus, formulated into an ointment preparation, is effective; it is 10 to 100 times more potent than cyclosporine and has a lower molecular weight. The use of a topical preparation focuses its anti-inflammatory actions on the skin and minimizes the potential for systemic effects.

Clinical Trials With Tacrolimus Ointment

Tacrolimus ointment has now been tested in approximately 5,000 American children, more than one-half of whom are between the ages of 2 and 6 years. Several published trials have shown the efficacy and safety of the medication for the treatment of moderate to severe atopic dermatitis in children as young as 2 years of age.[2] At least moderate improvement occurs in the majority of treated patients, with a decrease in erythema and pruritus often evident by 1 week after initiation of therapy. The longest duration of use of topical tacrolimus in children in the United States has been more than 4 years.

In a double-blind, placebo-controlled, multicenter study, 180 children between the ages of 7 and 16 years were treated for 3 weeks with twice daily topical tacrolimus ointment. Marked to excellent improvement was demonstrated in approximately 70% of patients treated with active medication, in contrast to similar improvement in 38% of placebo-treated children.[3] Statistically significant differences in body surface involvement and patient assessment of pruritus were also noted among all active treatment groups and vehicle controls. No significant difference in effectiveness was noted among the 3 active treatment groups (0.03%, 0.1%, and 0.3% concentrations). Eight additional children (5�11 years of age) showed good to excellent improvement at treated sites during a study of the pharmacokinetics of topical tacrolimus. In another randomized, double-blind study, 33 children aged 3�6 years old were administered tacrolimus 0.03%, tacrolimus 0.1%, or vehicle. More than 70% of children treated with either concentration of tacrolimus showed moderate to excellent improvement, while only 12% of those using the vehicle showed at least a good response in this 3-week trial. A multicenter, double-blind, randomized trial compared tacrolimus at 0.03% and 0.1% concentrations with vehicle in 351 2- to 15-year-old patients.[4] More than 90% improvement was seen in 36% (0.03% concentration) to 41% (0.1% concentration) of patients, in comparison with >90% improvement in 8% of vehicle-treated patients by the end of the 12-week study. Similarly, at least 50% improvement was noted in 76% and 80% of patients treated with 0.03% and 0.1% tacrolimus ointment, respectively, while only 31% of vehicle-treated patients showed at least 50% improvement. Body surface area involvement and pruritus were significantly decreased in both treatment groups.

In a multicenter, open-label trial of 0.1% tacrolimus ointment applied chronically twice daily for up to 1 year to 255 patients between the ages of 2 and 15 years, the Eczema Area and Severity Index (EASI) score continued to decrease from 39% of baseline at 3 months after initiation of treatment to 29% of baseline at 12 months; the severity of pruritus, decreased by 3 months to 46% of baseline, was stable between 3 months and 12 months of treatment.[5] The quality of life for both toddlers and children with atopic dermatitis was significantly improved by the application of tacrolimus ointment.[6]

Figures 4a, b. Mechanism of immunosuppressive action of tacrolimus in blocking the generation of several cytokines. Tacrolimus binds to FK binding protein, and inhibits the calcium (Ca)-activated protein phosphatase calcineurin from cleaving the phosphate group of NF-AT (nuclear factor of activated T cells). This inhibition prevents the translocation of the transcription factor to the nucleus and thus suppresses the production of cytokines associated with T-cell activation, such as interleukin 2, interleukin 4, interleukin 5, interleukin 13, and interferon-gamma. (Reprinted with permission from J Pediatr 2001;138:163-16).

To date, the only significant side effect reported for topical tacrolimus in pediatric trials has been a burning or stinging sensation and increased pruritus, especially during the first several days of application. This adverse reaction tends to subside with continued use, usually by 7 days after initiation of therapy, concomitant with clinical improvement. Given the chronicity of atopic dermatitis and the risk of systemic problems if tacrolimus is absorbed, blood tacrolimus levels have been measured in several trials. Eighty-one to 90% of pediatric patients have had undetectable levels of circulating tacrolimus. Detectable levels are almost always below the therapeutic range (trough blood levels for systemic FK506 to prevent transplant rejection are in the range of 5 to 15 ng/mL). Blood levels high enough for detection tend to be transient, and a positive correlation has been noted with extent of body surface involvement, severity of the atopic dermatitis, and concentration of tacrolimus ointment.

Prescribing physicians have the responsibility to ensure the correct diagnosis of atopic dermatitis before treating a child with topical tacrolimus. Treatment of children with Netherton syndrome, a rare genetic disorder of red, thick, itchy skin, has resulted in high blood levels of tacrolimus, related to the deficient cutaneous barrier in these children.[7] Non-application site adverse events, such as headache or flulike symptoms, have not occurred at increased frequency in tacrolimus-treated pediatric patients, even in the trials of use up to 1 year. Although there is a theoretical risk of increased cutaneous infections owing to local cutaneous immunosuppression, no significant increase in cutaneous infection has been noted. In fact, tacrolimus ointment has been shown to decrease colonization of staphyloccocal organisms.[8]

Topical tacrolimus has not shown the atrophogenic potential of the corticosteroids, and the use of tacrolimus alone as a topical (or systemic agent) has not been associated with increased intraocular pressure or an increased risk of cataracts or glaucoma. Neither systemically administered or topical tacrolimus causes the hypertrichosis seen with systemic cyclosporine administration. As with topical steroids, topical tacrolimus suppresses the inflammation, and does not cure atopic dermatitis. Thus, discontinuation of medication will likely eventuate in a flare of the dermatitis.

Tacrolimus (Protopic�) ointment was approval by the U.S. Food and Drug Administration in December 2000, and became commerically available in February 2001 for use in children 2 years of age or older with atopic dermatitis. Because the 0.1% concentration showed no statistically significant advantage in efficacy beyond the 0.03% concentration, only the 0.03% concentration has been approved for pediatric use, although both 0.03% and 0.1% concentrations are approved for use in adults. Tacrolimus ointment application is appropriate as an alternative to topical corticosteroid use, and is recommended for intermittent use. Given the potential for cutaneous immunosuppression, the theoretical potential risk of increased ultraviolet light-induced damage, and the lack of decades of follow-up data, the vigorous use of sun protection should be encouraged concomitant with prescription of tacrolimus.

Pimecrolimus (SDZ ASM 981) cream

Pimecrolimus is a new molecule, derived from the macrolactam ascomycin, which has been developed for the treatment of inflammatory skin diseases. Similar to cyclosporine and tacrolimus, it inhibits the dephosphorylation of NF-AT by binding to the complex, and is a selective inhibitor of inflammatory cytokine release from activated T cells and mast cells. Even orally administered pimecrolimus reportedly shows a low potential for systemic immunosuppression, concentrating in the skin.

Clinical Trials With Pimecrolimus in Pediatric Patients With Atopic Dermatitis

Twice daily application of 1% pimecrolimus cream has been tested in several clinical trials in Europe and the United States in children with atopic dermatitis. The application of 1% pimecrolimus twice daily for 3 weeks in double-blind, randomized pediatric studies in Europe led to an approximately 70% mean reduction in the dermatitis in the 5�16 year-old group, and a 57% mean improvement in the 1�4 year-old patients.[9] Two trials have been conducted in the United States, and data have been pooled. These randomized, double-blind trials of children between the ages of 1 and 17 years with mild to moderate atopic dermatitis included 267 children who were actively treated with the 1% pimecrolimus (403 patients in trial). A significant difference in efficacy between vehicle and active medication groups was seen by 8 days after initiation. In the 6-week trial, 35% of patients treated with pimecrolimus showed 90% improvement; 90% improvement was seen in only 18% of vehicle treated patients. As with tacrolimus and topical corticosteroids, discontinuation of the pimecrolimus leads to recurrence of the dermatitis.

A transient perception of mild to moderate warmth or burning is the only significant local adverse effects of the 1% pimecrolimus cream. In pediatric studies, 60% of the blood levels of pimecrolimus were below the limit of detection (0.4 ng/mL), and the maximum blood level measured was 1.8 ng/mL.[9] Pimecrolimus does not lead to atrophy or other side effects that may be induced by application of topical corticosteroids.[10]

CONCLUSIONS

Topical corticosteroid medications are the most widely used therapeutic agents for patients with atopic dermatitis. Long-term treatment with these agents is complicated by the potential for side effects, particularly related to their atrophogenic potential, and the possibility of tachyphylaxis. For many children with moderate to severe atopic dermatitis, only the more potent topical corticosteroids effect improvement and, in some cases, the disease is recalcitrant to topical corticosteroids altogether. The many clinical trials of topical tacrolimus attest to its safety and efficacy for pediatric patients older than 2 years of age; trials have now been initiated in infants as young as 1 month of age. Likewise, pimecrolimus cream shows promise for the treatment of mild to moderate atopic dermatitis, and is likely to be available commercially in approximately a year. Although the risks of long-term application require further study, preliminary data have shown no significantly increased risk of infection or photocarcinogenesis after more than 3 years of use in children treated with topical tacrolimus.

Tacrolimus ointment and pimecrolimus cream have several features that distinguish them from the traditional topical corticosteroid therapies. First, they are effective on the face and intertriginous areas, without causing concern about resultant cutaneous atrophy and telangiectasia.10 Secondly, these nonsteroidal agents do not induce glaucoma or cataract formation, so use on the often affected periorbital areas does not have to be restricted. Children who have already experienced side effects from topical corticosteroids might be placed on these novel therapies to allow for the possibility of reversal of steroid-induced changes. Finally, topical tacrolimus and pimecrolimus cream may be used as an alternative to topical corticosteroids, particularly when children require moderate to potent topical steroids or are recalcitrant. The lack of corticosteroid-induced side effects of topical tacrolimus and pimecrolimus and the proven anti-inflammatory effects provide the hope that these new medications may also prove valuable for the gamut of other corticosteroid-responsive disorders in children, such as irritant diaper dermatitis, seborrheic dermatitis, contact dermatitis, thin plaque forms of psoriasis, alopecia areata, and vitiligo.

REFERENCES

1. Laughter D, Istvan JA, Tofte SJ, Hanifin JM. The prevalence of atopic dermatitis. J Am Acad Dermatol 2000;43:649–655.

2. Paller AS. Use of nonsteroidal topical immunomodulators for the treatment of atopic dermatitis in the pediatric population. J Pediatr 2001;138:163–168.

3. Boguniewicz M, Fiedler VC, Raimer S, Lawrence ID, Leung DY, Hanifin JM. A randomized, vehicle-controlled trial of tacrolimus ointment for treatment of atopic dermatitis in children. J Allergy Clin Immunol 1998;102:637–644.

4. Paller A, Eichenfield L, Leung DY, Stewart D, Appell M. A 12-week study of tacrolimus ointment for the treatment of atopic dermatitis in pediatric patients. J Am Acad Dermatol 2001;44:S47–57.

5. Kang S, Lucky A, Pariser D, Lawrence I, Hanifin J, and the Tacrolimus Ointment Study Group. Long-term safety and efficacy of tacrolimus ointment for the treatment of atopic dermatitis in children. J Am Acad Dermatol 2001;44:S58–S64.

6. Drake L Prendergast M, Maher R, Breneman D, Korman N, Satoi Y, Beusterien KM, Lawrence I. The impact of tacrolimus ointment health-related quality of life of adult and pediatric patients with atopic dermatitis. J Am Acad Dermatol 2001;44:S65–S72.

7. Remitz A, Kyllonen H, Granlund H, Reitamo S. Tacrolimus ointment reduces staphylococcal colonization of atopic dermatitis lesions. J Allergy Clin Immunol 2001;107:196–197.

8. Allen A, Siegfried E, Silverman R, Williams ML, Elias PM, Szabo SK, Korman NJ. Significant absorption of topical tacrolimus in 3 patients with Netherton syndrome. Arch Dermatol 2001;137:747–750.

9. Harper J, Green A, Scott E, Ebelin ME, Gr�ndl B. Dorobek M, Cardno P, et al. First experience of topical SDZ ASM 981 in children with atopic dermatitis. Br J Dermatol 2001;144:781–787.

10. Queille-Roussel C, Duteil PC, Lefebvre MC, Rapatz G, Zagula M, Ortonne JP. The new topical ascomycin derivative SDZ ASM 981 does not induce skin atrophy when applied to normal skin for 4 weeks: a randomized, double-blind controlled study. Br J Dermatol 2001;144:507–513.

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