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Chapter 54 Antihistamines in Atopic Eczema T. Zuberbier 54.1 Introduction Atopic eczema is known as a chronically relapsing disorder where mainly activation of T cells leads to an eczematous reaction of the skin. However, there is multiple evidence that IgE mediated reactions are an aggravating factor in the majority of patients and both an increase of mast cells and an increase of dermal histamine have been observed in atopic eczema. While topical treatment in atopic eczema is the first choice, antihistamines have been used for decades, especially in children, as additional therapy to control itching. However, the level of evidence was originally poor and now only with the development of new, nonsedative antihistamines are large placebo-controlled, double-blind randomized studies available. In reviewing this topic, it is therefore important to distinguish between the first generation, more or less sedating antihistamines, and the second generation of antihistamines, which have a lower or no sedative effect and express various nonhistamine receptorrelated anti-inflammatory properties. 54.2 First-Generation Antihistamines Various groups of first-generation antihistamines have been marketed since the 1950s. Regarding the pharmacokinetics, all these substances have to be metabolized to exert their action and the half-life is rather short, within a few hours. The main disadvantages are dry mouth, sedation, and impairment of cognitive functions [6, 5, 12, 13]. Unfortunately, even when given at night, a hangover can occur quite frequently and needs to be discussed with patients. Nevertheless, the use of strongly sedating antihistamines has been favored by many doctors in the past arguing that although the antipruritic effect of antihistamines is not proven, the sedative effect reduces the impulse of the patients to scratch and thus is of value, especially since atopic dermatitis patients tend to damage their skin through uncontrolled scratching in their sleep. However, especially in small children, the long-term use of these sedating substances with an unknown effect on the development of cognitive functions, for which undisturbed sleep with REM and non-REM phases is of importance, can no longer be justified. It may be argued that at least in acute conditions, sedation is a true relief for the patient and it would not be harmful to use these drugs for a short period. However, it might also be argued that in these conditions, a combination of a modern-generation antihistamine with a true short-acting sedative with no after-effects is probably superior to the use of a sedating antihistamine. Regarding efficacy, there are no large studies comparing different sedating first-generation antihistamines in atopic eczema. Comparing efficacy to placebo, several small studies with mainly negative results are reviewed by Klein and Clark [7]. There is only one multicenter, double-blind, placebo-controlled study according to modern standards conducted in 155 children with atopic dermatitis [10], which shows that chlorpheniramine is no more effective than placebo in relieving the symptoms of atopic eczema with nocturnal itching in childhood. The latter paper could lead to the assumption that antihistamines in general are not helpful in relieving pruritus in atopic eczema, but it must be remembered that the new, second-generation antihistamines exert not only an H1-antagonizing effect. 54 504 54 Antihistamines in Atopic Eczema 54.3 Second-Generation Antihistamines The first nonsedating antihistamines marketed were terfenadine and astemizole, which later were found to have cardiac side effects. Due to hepatic metabolism through the P450 enzyme system and drug interactions, very high serum levels could be reached where these two drugs showed a concentration-dependent side effect. The newer nonsedating antihistamines are, among others, azelastine, cetirizine, desoxyloratadine, ebastine, fexofenadine levocetirizine (desoxyloratadine is the active metabolite of loratadine, levocetirizine the active metabolite of cetirizine). All of these substances are considerably less sedating or nonsedating, even in concentrations higher than the recommended dosage. Also, another frequent, and perhaps the most disturbing side effect of the older antihistamines, the development of a dry mouth, is rarely seen anymore. The reason for this is the change in chemical structure compared to the first generation. The newer agents are less lipophilic and are mainly prevented from penetrating the CNS. Also they express a higher and more specific binding to the H1-receptor, with hardly any interaction with the cholinergic receptors. Desloratadine, fexofenadine and levocetirizine are the active metabolites of their predecessors and are excreted with no further metabolism. A half-life of approximately 12 h ensures a lasting action for 24 h. Although the modes of excretion are different (Levocetirizine, mainly renal; fexofenadine and desoxyloratadine, mainly hepatic), all three of these substances are nearly devoid of any drug interactions and also have no synergistic effects with ethanol. Most important in the discussion of the value of modern nonsedating antihistamines in the treatment of atopic eczema are the nonhistamine receptor-related anti-inflammatory properties of these substances. Cetirizine inhibits eosinophil chemotaxis in vitro and in vivo and reduces LTB4 release and the expression of endothelial adhesion molecules (reviewed in [15]. Loratadine and desoxyloratadine modulate cytokine release, especially IL-6 and IL-8, from human mast cells and basophils [8] and reduce the expression of endothelial adhesion molecules [9]. It has also been shown that fexofenadine reduces the expression of cellular adhesion molecules and inhibits the eosinophilinduced release of IL-8, GMCSF, and soluble ICAM-1 from human nasal epithelial cells [1]. One of the major characteristics of atopic eczema is the high influx of inflammatory cells for which the upregulation of endothelial adhesion molecules is a prerequisite. Boone et al. [2] demonstrated that in atopic dermatitis, especially ICAM-1 and VCAM-1 were constantly upregulated. The same authors also showed that cetirizine at a dosage of 20 mg (twice the recommended dosage for allergic rhinitis) in contrast to placebo significantly reduced the expression of VCAM-1, whereas ICAM-1 was not affected. In comparison, the same authors looked at the endothelial adhesion molecules in allergic contact dermatitis. These patients showed the same levels of ICAM at baseline as patients with atopic dermatitis with low levels of VCAM-1 expression. However, VCAM-1 expression was upregulated after challenge with the relevant contact allergens. 54.4 Clinical Studies There are only a few double-blind, placebo-controlled studies available. Small studies with fewer than 40 patients included support efficacy with acrivastine, cetirizine, loratadine, and terfenadine (reviewed in [7]), but are criticized for methodology problems. The first study in a large population to investigate long-term treatment with an antihistamine in atopic dermatitis was conducted in infants in a multinational, double-blind, randomized, placebo-controlled trial (the ETAC trial). The investigators treated 817 children aged 12 – 24 months for 18 months with either cetirizine (0.25 mg/kg) or placebo twice daily. All infants suffered from moderate atopic eczema with an average SCORAD of 25. The primary endpoint of efficacy was the development of asthma, the secondary parameters were the consumption of concomitant medications for which all drugs except H1-antihistamines could be used by the patients, and the severity of atopic eczema. The severity of atopic eczema decreased significantly during the 18 months of treatment in both the placebo group and the cetirizine group, which is in line with the natural course of atopic eczema in early childhood. The number of infants who had accompanying symptoms of urticaria during the study period was significantly lower in the cetirizine group (5.8 % vs 16.2 %), and the overall use of other treatments for atopic ecze- References ma was not different in both treatment groups. The most interesting part of the study involves, however, the different subgroups. In the subgroup of infants with a SCORAD of 25, there was a statistically significant corticosteroid-sparing effect. The effect on the onset of asthma and the follow-up for another 18 months of the infants enrolled in the ETAC study has been reported in detail by Warner et al. [14]. Although there was no difference in the prevalence of asthma between active and placebo treatment in the overall population, there were highly significant changes in those children sensitized to house dust mite or grass pollen. In these groups, treatment with cetirizine for 18 months significantly reduced the likelihood of developing asthma compared to the treatment with placebo. At the end of the 18month treatment period, the overall percentage of children developing asthma was reduced by approximately 50 % in both house dust mite- and grass pollen-sensitized groups. This effect was maintained in the 18month follow-up period for those children sensitized to grass pollen. In another study comparing the effect of loratadine vs placebo in 48 children with mild atopic eczema (mean SCORAD 12) and additional treatment with mometasone furoate 0.1 % cream, Chunharas et al. [3] showed that after 14 days of external corticosteroid therapy, atopic eczema was nearly fully cleared up, independently of the comedication loratadine or placebo (SCORAD below 2 in both groups). Regarding the safety of long-term use of cetirizine in patients with atopic eczema, Stevenson et al. [11] reported tests included in the above-mentioned ETAC study. It was shown that there were no differences between cetirizine high-dose treatment (0.25 mg/kg twice daily) and placebo in terms of behavior, cognitive, and psychomotor development or learning processes. In conclusion, it can be summarized that the use of first-generation antihistamines in atopic dermatitis is usually not helpful due to the sedative effect. The application of modern, second-generation antihistamines may be useful, possibly for the expression of non-H1receptor-related activities, which are dose-dependent. The use appears to be beneficial in subgroups of patients with more severe atopic eczema. In patients with a low SCORAD, a topical therapy appears to be sufficient. Of special interest is the fact that the early use of antihistamines may prevent the development of asthma in subpopulations at high risk. The administration of antihistamines over a long period appears to be safe and should therefore be offered to those patients in whom an additional benefit can be expected. References 1. Abdelaziz MM, Devalia JL, Khair OA, Bayram H, Prior AJ, Davies RJ (1998) Effect of fexofenadine on eosinophilinduced changes in epithelial permeability and cytokine release from nasal epithelial cells of patients with seasonal allergic rhinitis. J Allergy Clin Immunol 101:410 – 420 2. Boone M, Lespagnard L, Renard N, Song M, Rihoux JP (2000) Adhesion molecule profiles in atopic dermatitis vs. allergic contact dermatitis: pharmacological modulation by cetirizine. J Eur Acad Dermatol Venereol 14:263 – 266 3. Chunharas A, Wisuthsarewong W, Wananukul S, Viravan S (2002) Therapeutic efficacy and safety of loratadine syrup in childhood atopic dermatitis treated with mometasone furoate 0.1 per cent cream. J Med Assoc Thai 85:482 – 487 4. Diepgen TL; Early Treatment of the Atopic Child Study Group (2002) Long-term treatment with cetirizine of infants with atopic dermatitis: a multi-country, doubleblind, randomized, placebo-controlled trial (the ETAC trial) over 18 months. Pediatr Allergy Immunol 13:278 – 286 5. Goetz DW, Jacobson JM, Apaliski SJ, Repperger DW, Martin ME (1991) Objective antihistamine side effects are mitigated by evening dosing of hydroxyzine. Ann Allergy 67: 448 – 454 6. Hindmarch I, Parrott AC (1978) A repeated dose comparison of the side effects of five antihistamines on objective assessments of psychomotor performance, central nervous system arousal and subjective appraisals of sleep and early morning behaviour. Arzneimittelforschung 28:483 – 486 7. Klein PA, Clark RAF (1999) An evidence-based review of the efficacy of antihistamines in relieving pruritus in atopic dermatitis. Arch Dermatol 135:1522 – 1525 8. Lippert U, Kruger-Krasagakes S, Moller A, Kiessling U, Czarnetzki BM (1995) Pharmacological modulation of IL6 and IL-8 secretion by the H1-antagonist decarboethoxyloratadine and dexamethasone by human mast and basophilic cell lines. Exp Dermatol 4:272 – 276 9. Molet S, Gosset P, Lassalle P, Czarlewski W, Tonnel AB (1997) Inhibitory activity of loratadine and descarboxyethoxyloratadine on histamine-induced activation of endothelial cells. Clin Exp Allergy 27:1167 – 1174 10. Munday J, Bloomfield R, Goldman M, Robey H, Kitowska GJ, Gwiezdziski Z, Wankiewicz A, Marks R, Protas-Drozd F, Mikaszewska M (2002) Chlorpheniramine is no more effective than placebo in relieving the symptoms of childhood atopic dermatitis with a nocturnal itching and scratching component. Dermatology 205:40 – 45 11. Stevenson J, Cornah D, Evrard P, Vanderheyden V, Billard C, Bax M, Van Hout A; ETAC Study Group (2002) Longterm evaluation of the impact of the h1-receptor antagonist cetirizine on the behavioral, cognitive, and psychomotor development of very young children with atopic dermatitis. Pediatr Res 52:251 – 257 505 506 54 Antihistamines in Atopic Eczema 12. Vuurman EF, van Veggel LM, Uiterwijk MM, Leutner D, O’Hanlon JF (1993) Seasonal allergic rhinitis and antihistamine effects on children’s learning. Ann Allergy 71: 121 – 126 13. Vuurman EF, van Veggel LM, Sanders RL, Muntjewerff ND, O’Hanlon, JF (1996) Effects of semprex-D and diphenhydramine on learning in young adults with seasonal allergic rhinitis. Ann Allergy Asthma Immunol 76:247 – 252 14. Warner JO; ETAC Study Group (2001) Early treatment of the atopic child. A double-blinded, randomized, placebocontrolled trial of cetirizine in preventing the onset of asthma in children with atopic dermatitis: 18 months’ treatment and 18 months’ posttreatment follow-up. J Allergy Clin Immunol 108:929 – 937 15. Zuberbier T, Henz BM (199) Use of cetirizine in dermatologic disorders. Ann Allergy Asthma Immunol 83:476 – 480