Topical tacrolimus in atopic dermatitis: Effects of ... - Helda - Helsinki.fi

al. 1986, Burrows et al. 1989, Kono et al. 2001) or positive SPT (Witt et al. 1986). AD
severity is known to correlate with s-IgE (Wütrich 1978, Laske & Niggemann 2004),
and IgE-associated AD is a risk factor for allergic asthma (Sears et al. 1991). In the
present studies, BHR and airway inflammation were found to a lesser extent also in
patients with normal s-IgE levels or negative skin prick test reactions. However,
previous studies have indicated that airway eosinophilia and BHR are not completely
dependent on s-IgE but rather on T cell pathways (Mehlhop et al. 1997, Hogan et al.
1997, Gavett et al. 1994, Riffo-Vasquez et al. 2000). In Study V, improvement in AD
and respiratory parameters occurred to a similar extent in both IgE-associated and non-
IgE-associated AD, but the group of patients with non-IgE-associated AD was too small
(only ten) to make definite conclusions possible as to differences between groups.
Several studies suggest that epicutaneous antigen exposure can promote systemic
allergic responses and lead to airway hyper-responsiveness. These effects can be seen
especially in barrier-disrupted skin. Tacrolimus ointment suppresses T cell-induced
inflammation efficiently and has favorable effects on the barrier function of the skin by
normalizing TEWL and reducing staphylococcal colonization. Tacrolimus has shown
suppressive effects on the keratinocytes (Lan et al. 2004), which in part initiate the
inflammation in barrier-disrupted skin (Leung et al. 2004). In addition, tacrolimus
ointment reduces the expression of several chemokines such as CCR3 (Park et al. 2005),
which has been shown to play an important role in eosinophil recruitment to the skin
and lung as well as in development of airway hyper-responsiveness (Ma et al. 2002).
The systemic effect of tacrolimus is unlikely to explain the present results because
systemic exposure to topical tacrolimus decreases along with skin improvement. The
highest blood concentrations after topical tacrolimus treatment have been approximately
3% of those of transplant patients on systemic tacrolimus (Rubins et al. 2005).
The most likely explanation for our results is resolution of the cutaneous T cell
inflammation and inhibition of the systemic T cell responses which originate from the
skin and are capable of affecting the airways. Additionally, improvement in the skin
barrier could reduce the penetration of antigens through the skin and thus inhibit
systemic sensitization. Further support for the idea that topical tacrolimus can improve
not only the skin barrier function in AD but consequently also other functional
impairments of the skin is our finding of an improvement in the weakened or anergic
recall antigen reactions of AD patients (Mandelin et al., in press), suggesting
normalization of the T cell profile (Caproni et al. 2007). This would also explain the
decrease in s-IgE levels in those patients who showed the greatest improvement in AD.
The increase in number and sum of positive SPT results during this study may also
indicate normalization of skin reactivity, although the repeatability of the SPT is not
very good, and duplicate tests would have produced more reliable results (Dreborg
1989). However, in this study the effect was indeed systematic.
In summary, the present studies suggest that replacing topical corticosteroid
treatment with long-term intermittent topical tacrolimus treatment for AD is not
associated with the adverse events common during corticosteroid treatment, ones such
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