**4. Occlusion in clinical practice**

Occlusive therapy, in particular WWD occlusion, can be useful as a 'stepped-up' therapy in controlling acute erythrodermic AD or as a second-line therapy for severe and/or refractory disease. There is limited convincing data that WWD occlusion is superior to conventional open application of topical corticosteroids. However, occlusive therapy represents an important alternative to currently available, but often undesirable standard treatment modalities for AD. A few drawbacks of standard therapies include dependency on superpotent topical corticosteroids, frequent and inconvenient sessions of phototherapy, and serious systemic side effects with oral medications (e.g. nephrotoxicity with cyclosporine use).

Based on the studies on occlusive therapy, it appears that the greatest benefits of topical corticosteroids under occlusion is achieved during the first week of therapy. This suggests that if used as 'rescue' therapy for acute flares or intermittently for maintenance, durations of up to 1 week might be adequate (Wolkerstorfer et al. 2000; Pei et al. 2001). Anecdotally, long-term effects are thought to be sustained when WWD occlusion are continued with emollients for 2–4 more weeks to improve skin hydration (Nicol 1987). Variations in protocol regarding duration of WWD occlusion and rewetting procedures possibly contributed to differences observed in efficacy and incidence of infection. It may, therefore, be advisable to limit occlusion to less than 8 hours duration, apply WWD no more than twice daily, and avoid rewetting procedures.

It is difficult to ascertain the extent to which occlusion may promote bacterial colonization. However, the use of anti-bacterial agents, when applied alone or under occlusion, appears to not only inhibit bacterial colonization, but also reduce disease severity. (Abeck et al. 1999; Brockow et al. 1999; Gauger 2006) Thus, it seems logical that antibacterials, whether topical or systemic, might be a beneficial adjunct to occlusive therapy helping to decrease the potential risk of clinical infection. As such, topical antibacterials in combination with topical corticosteroids under occlusion may be useful when treating small areas of skin for a limited period of time, while systemic antibacterials in combination with topical corticosteroid under occlusion may more be appropriate when treating larger areas of involvement. Yet, the use of antibacterials must be weighed against the potential risk of antimicrobial resistance and contact sensitization. (Williams 2000; Zhai and Maibach 2001)

More specifically, according to Williams (2000), there are three categories of patients with AD: 1) those with obvious clinical infection, in whom anti-staphylococcal therapy is essential, 2) those with mild disease and a lower density of S. aureus colonization, in whom no evidence supports additional benefit of anti-staphylococcal therapy, and 3) those with fissured or

serum levels had reached 12.9 μg/l after 5 days of treatment, corresponding to high-dose immunosuppression. Beyeler et al. (2006) attributed the increased systemic absorption to the combination of severely damaged skin barrier function, application of tacrolimus to a large

The wide variation in occlusive techniques and predominance of uncontrolled trials with small sample sizes make direct comparison of studies evaluating the safety and efficacy of occlusive therapy difficult. Limited numbers of studies using control groups restricts the conclusions that can be drawn regarding the benefit of occlusive therapy versus conventional therapies. However, it can be concluded that occlusive therapy has been shown, both formally and anecdotally, to be very effective in severe or exacerbated AD. It, therefore, offers an important alternative or adjunct therapy to more commonly used approaches. The randomized controlled trials described in this chapter resulted in divergent outcomes regarding infectious complications and efficacy. Differences could be related to the study populations (i.e. exacerbated versus moderate AD) or different topical

While the exact mechanism of action of occlusive therapy is still unknown, a recent pilot study demonstrated significant down-regulation of 7 serum chemokines following WWD occlusion for 1 week in 6 children with severe AD. Of these, 4 chemokines are considered to be potential serum markers for the disease activity of AD. (Ong et al. 2008) In another study evaluating WWD occlusion using diluted tacrolimus and fluticasone propionate cream in APOC1 mice with AD, WWD occlusion improved transepidermal water loss, reinforcing that this may be one of the therapeutic aspects of occlusive therapy. (Oranje et al. 2009) Future studies should evaluate the efficacy of occlusive therapy versus open topical corticosteroid application with measurements on the differences in systemic absorption. Studies should also investigate the impact of varying the durations of occlusive therapy. Given the number of protocols utilizing inpatient or specialized nurse-assisted visits, it would be useful to understand the contribution of professional supervised application. To our knowledge, no studies to date have evaluated occlusion as preventive therapy (i.e., to

WWD occlusion may be a reasonable first-line therapy for acute exacerbations of AD and second-line therapy for refractory disease. DWD occlusion appears to be efficacious having relatively low risk of infectious complications and may be particularly useful in treatment of chronic AD lesions. However, it remains unclear if occlusive therapy offers significant advantageous over conventional open therapy. The risk of infection associated with occlusive therapy, while greater than open therapies, seems to be manageable and may be mitigated by limiting the duration of occlusion, avoiding rewetting and perhaps adding antibacterial agents. Transient changes in morning cortisol levels and rare clinical HPA suppression seen with the use of topical corticosteroids under occlusion are concerning side effects, but are likely related to corticosteroid potency and the absolute amount applied. The hydrogel patch offers an innovative approach to the treatment of AD instantly correcting the barrier defect, and it may have similar efficacy as topical corticosteroids without the systemic risks. Further controlled studies are needed to better evaluate the risks and benefits

surface area, and occlusion under zinc bandages. (Beyerler et al. 2006)

corticosteroid application regimens.

**5. Conclusion** 

prevent disease flares and maintain cutaneous hydration).

of these occlusive modalities in the treatment of AD.

cracked eczema without overt signs of infection such as crusting or folliculitis. (Williams 2000) While the latter group of patients carry an intermediate to high levels of *S. aureus*, studies are contradictory regarding the clinical benefits of anti-staphylococcal therapy in these patients. Clinicians may choose to institute antimicrobial therapy, in combination with topical corticosteroids under occlusion. If poorly responsive to WWD occlusion, addition of corticosteroid with topical or oral antibiotics has been helpful anecdotally, suggesting that subclinical infection or heavy colonization may impede response to topical corticosteroids. (Nicol 1987) Despite half a century of topical corticosteroid use in eczematous skin, the clinical criteria for the addition of a topical antimicrobial agents remains to be determined.

In terms of the concern for adrenal suppression with topical corticosteroids under occlusion, the minimal available data suggests that a decrease in cortisol levels can occur, but these effects are generally transient. The use of mid- or high-potency corticosteroid, an ointment vehicle, occlusion, and a disrupted skin barrier are all contributing factors that can increase the risk of systemic side effects including this possibilty of adrenal suppression. Of note, there has been only one suggested fatal case of adrenal insuffiency from topical corticosteroid use. However, the details of this case are limited. It is known that the patient was an 11-year old girl with generalized psoriasis being treated with betamethasone cream under occlusion for a prolonged durations. However, the concentration and the exact quantity of betamethasone cream applied, as well as the duration of therapy are unknown. (Levin and Maibach 2002)

Several strategies may be used to limit the potential for such complications. Possible options include using occlusive therapy only intermittently, reducing topical corticosteroid potency gradually as inflamed skin improves, and applying occlusion only once-daily. Studies have demonstrated that twice-daily application of topical corticosteroids to be no more effective than once-daily regimens and more prone to systemic side effects. (Lagos and Maibach 1998; Green et al. 2005) In addition, diluting topical corticosteroids may be helpful in reducing the risk of serious side effects. However, such preparations may alter the physiochemical properties of the agent and may not serve to reduce disease activity. (Haigh and Smith 1991; Gao and Li Wan Po 1994; Ohtani et al. 2002; Kizu et al. 2004) Furthermore, the application of a hydrogel patch, which appeared to have similar efficacy as topical corticosteroid use, may potentially serve as an ideal method of treating AD while avoiding topical corticosteroids. (Park et al. 2011) But, additional studies on the efficacy of the hydrogel patch in the treatment of AD are needed. Ultimately, if prolonged topical corticosteroid use is required in certain patients with refractory disease, adrenal function may be monitored using morning plasma cortisol and urinary steroid levels, in combination with rapid ACTH stimulation testing, while evaluating the patient for cutaneous atrophy or Cushingoid features (Levin and Maibach 2002). But, the rare occurence of topical corticosteroid-induced Addison's disease makes this suggestion impractical for most patients.

Topical immunosuppressive agents such as pimecrolimus or tacrolimus under occlusion have not yet been studied extensively. These agents might represent a valuable nonsteroidal alternative, though systemic absorption should be measured to confirm that immunosuppressive levels have not been reached. An open-label study evaluating topical pimecrolimus cream 1% in the treatment of chronic hand dermatitis showed that twice-daily application under occlusion was safe and effective, resulting in low pimecrolimus blood levels. (Thaci et al. 2003) Beyeler et al. (2006) reported a case of a female patient treated with tacrolimus 0.1% ointment under occlusion with Unna's paste boots (zinc bandages), whose

cracked eczema without overt signs of infection such as crusting or folliculitis. (Williams 2000) While the latter group of patients carry an intermediate to high levels of *S. aureus*, studies are contradictory regarding the clinical benefits of anti-staphylococcal therapy in these patients. Clinicians may choose to institute antimicrobial therapy, in combination with topical corticosteroids under occlusion. If poorly responsive to WWD occlusion, addition of corticosteroid with topical or oral antibiotics has been helpful anecdotally, suggesting that subclinical infection or heavy colonization may impede response to topical corticosteroids. (Nicol 1987) Despite half a century of topical corticosteroid use in eczematous skin, the clinical

In terms of the concern for adrenal suppression with topical corticosteroids under occlusion, the minimal available data suggests that a decrease in cortisol levels can occur, but these effects are generally transient. The use of mid- or high-potency corticosteroid, an ointment vehicle, occlusion, and a disrupted skin barrier are all contributing factors that can increase the risk of systemic side effects including this possibilty of adrenal suppression. Of note, there has been only one suggested fatal case of adrenal insuffiency from topical corticosteroid use. However, the details of this case are limited. It is known that the patient was an 11-year old girl with generalized psoriasis being treated with betamethasone cream under occlusion for a prolonged durations. However, the concentration and the exact quantity of betamethasone cream applied, as well as the duration of therapy are unknown.

Several strategies may be used to limit the potential for such complications. Possible options include using occlusive therapy only intermittently, reducing topical corticosteroid potency gradually as inflamed skin improves, and applying occlusion only once-daily. Studies have demonstrated that twice-daily application of topical corticosteroids to be no more effective than once-daily regimens and more prone to systemic side effects. (Lagos and Maibach 1998; Green et al. 2005) In addition, diluting topical corticosteroids may be helpful in reducing the risk of serious side effects. However, such preparations may alter the physiochemical properties of the agent and may not serve to reduce disease activity. (Haigh and Smith 1991; Gao and Li Wan Po 1994; Ohtani et al. 2002; Kizu et al. 2004) Furthermore, the application of a hydrogel patch, which appeared to have similar efficacy as topical corticosteroid use, may potentially serve as an ideal method of treating AD while avoiding topical corticosteroids. (Park et al. 2011) But, additional studies on the efficacy of the hydrogel patch in the treatment of AD are needed. Ultimately, if prolonged topical corticosteroid use is required in certain patients with refractory disease, adrenal function may be monitored using morning plasma cortisol and urinary steroid levels, in combination with rapid ACTH stimulation testing, while evaluating the patient for cutaneous atrophy or Cushingoid features (Levin and Maibach 2002). But, the rare occurence of topical corticosteroid-induced

Topical immunosuppressive agents such as pimecrolimus or tacrolimus under occlusion have not yet been studied extensively. These agents might represent a valuable nonsteroidal alternative, though systemic absorption should be measured to confirm that immunosuppressive levels have not been reached. An open-label study evaluating topical pimecrolimus cream 1% in the treatment of chronic hand dermatitis showed that twice-daily application under occlusion was safe and effective, resulting in low pimecrolimus blood levels. (Thaci et al. 2003) Beyeler et al. (2006) reported a case of a female patient treated with tacrolimus 0.1% ointment under occlusion with Unna's paste boots (zinc bandages), whose

Addison's disease makes this suggestion impractical for most patients.

criteria for the addition of a topical antimicrobial agents remains to be determined.

(Levin and Maibach 2002)

serum levels had reached 12.9 μg/l after 5 days of treatment, corresponding to high-dose immunosuppression. Beyeler et al. (2006) attributed the increased systemic absorption to the combination of severely damaged skin barrier function, application of tacrolimus to a large surface area, and occlusion under zinc bandages. (Beyerler et al. 2006)

The wide variation in occlusive techniques and predominance of uncontrolled trials with small sample sizes make direct comparison of studies evaluating the safety and efficacy of occlusive therapy difficult. Limited numbers of studies using control groups restricts the conclusions that can be drawn regarding the benefit of occlusive therapy versus conventional therapies. However, it can be concluded that occlusive therapy has been shown, both formally and anecdotally, to be very effective in severe or exacerbated AD. It, therefore, offers an important alternative or adjunct therapy to more commonly used approaches. The randomized controlled trials described in this chapter resulted in divergent outcomes regarding infectious complications and efficacy. Differences could be related to the study populations (i.e. exacerbated versus moderate AD) or different topical corticosteroid application regimens.

While the exact mechanism of action of occlusive therapy is still unknown, a recent pilot study demonstrated significant down-regulation of 7 serum chemokines following WWD occlusion for 1 week in 6 children with severe AD. Of these, 4 chemokines are considered to be potential serum markers for the disease activity of AD. (Ong et al. 2008) In another study evaluating WWD occlusion using diluted tacrolimus and fluticasone propionate cream in APOC1 mice with AD, WWD occlusion improved transepidermal water loss, reinforcing that this may be one of the therapeutic aspects of occlusive therapy. (Oranje et al. 2009)

Future studies should evaluate the efficacy of occlusive therapy versus open topical corticosteroid application with measurements on the differences in systemic absorption. Studies should also investigate the impact of varying the durations of occlusive therapy. Given the number of protocols utilizing inpatient or specialized nurse-assisted visits, it would be useful to understand the contribution of professional supervised application. To our knowledge, no studies to date have evaluated occlusion as preventive therapy (i.e., to prevent disease flares and maintain cutaneous hydration).

#### **5. Conclusion**

WWD occlusion may be a reasonable first-line therapy for acute exacerbations of AD and second-line therapy for refractory disease. DWD occlusion appears to be efficacious having relatively low risk of infectious complications and may be particularly useful in treatment of chronic AD lesions. However, it remains unclear if occlusive therapy offers significant advantageous over conventional open therapy. The risk of infection associated with occlusive therapy, while greater than open therapies, seems to be manageable and may be mitigated by limiting the duration of occlusion, avoiding rewetting and perhaps adding antibacterial agents. Transient changes in morning cortisol levels and rare clinical HPA suppression seen with the use of topical corticosteroids under occlusion are concerning side effects, but are likely related to corticosteroid potency and the absolute amount applied. The hydrogel patch offers an innovative approach to the treatment of AD instantly correcting the barrier defect, and it may have similar efficacy as topical corticosteroids without the systemic risks. Further controlled studies are needed to better evaluate the risks and benefits of these occlusive modalities in the treatment of AD.

Hartmann, F. and J. J. Lahmann (1977). Effect of the external use of triamcinolone acetonide

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Kizu, J., W. Ichihara, et al. (2004). Survey of mixing commercially available corticosteroid

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Lee, J. H., S. J. Lee, et al. (2007). The effect of wet-wrap dressing on epidermal barrier in patients with atopic dermatitis. *J Eur Acad Dermatol Venereol,* 21(10): 1360-1368. Levin, C. and H. I. Maibach (2002). Topical corticosteroid-induced adrenocortical insufficiency: clinical implications. *Am J Clin Dermatol,* 3(3): 141-147. Mallon, E., S. Powell, et al. (1994). Wet wrap' dressings for the treatment of atopic ezcema in

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*Dermatolog Treat,* Accepted for publication.

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#### **6. References**


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**17** 

*Japan* 

**Suplatast Tosilate for Prophylaxis** 

S. Yoshihara, M. Ono, Y. Yamada, H. Fukuda, T. Abe and O. Arisaka

The onset of asthma may be related to Th2 cytokine dominance at the time when food allergies occur several months after birth. This study investigated the effectiveness of early intervention with a Th2 cytokine inhibitor (suplatast tosilate) for prevention of asthma in infants with food allergies and atopic dermatitis. Suplatast tosilate dry syrup (6 mg/kg daily) or a histamine H1-blocker (ketotifen fumarate dry syrup: 0.06 mg/kg daily) was administered randomly to 53 infants with atopic dermatitis caused by food allergies. The primary endpoints were the incidence of asthma and the time to the onset of wheezing. The peripheral blood Th1/Th2 ratio, total IgE level, and eosinophil count were measured before and after treatment. After 24 months of treatment, the prevalence of asthma was significantly lower in the suplatast group (20.8%) than in the ketotifen group (65.6%, p < 0.01). Additionally, the time from the start of treatment to the initial episode of wheezing for infants who developed asthma was significantly longer in the suplatast group than the ketotifen group (p < 0.01). Furthermore, the eosinophil count was significantly decreased by suplatast treatment (p < 0.05), and there was a significant difference between the suplatast and ketotifen groups with respect to both the eosinophil count (p < 0.01) and the Th1/Th2 ratio (p < 0.05). The results of the present pilot study suggest that suplatast tosilate is useful

Asthma frequently develops by the age of 3 yr (1) and recent research has demonstrated that its onset is tending to occur at a younger age (2). Various hypotheses have been suggested with respect to the etiology of asthma. According to the Tucson cohort study performed in the United States, there is a low probability of atopic asthma developing in infants with recurrent wheezing up to the age of 3 yr, and they are considered to be a separate population from the infants in whom recurrent wheezing persists until later childhood (3). In the former group, viral infection is the direct cause of wheezing, while the latter group have an atopic constitution and their asthma may persist during the school years and even into adulthood. Thus, this latter group may be a population for which early intervention is important. It is known that chronic asthma is more likely to develop in patients who are positive in tests for food or house dust allergens (4, 5). The rate of progression to adult asthma is also high among individuals who test positive for food allergens, such as those in

for the primary prevention of wheezing and asthma in children.

**2. Atopic dermatitis is associated with asthma** 

**1. Introduction** 

*Department of Pediatrics, Dokkyo University School of Medicine, Tochigi* 

 **of Pediatric Atopy** 

