What's new in atopic dermatitis?
Authors: D.J. Eedy
Journal: British Journal of Dermatology (2008)

There is a widespread recognition that the prevalence of atopy in children in Western countries has increased over recent decades; it has recently been shown to have reached 30%.1 The prevalence of atopic dermatitis (AD) in children in the U.K. has been estimated at 15–20%,2, 3 with prevalences of 17·2%, 21·3% and 30·8% having been reported from Oregon, Denmark and Australia, respectively.4-6 Although hereditary factors are important for the risk of AD, the increase in prevalence and variation within and between countries suggest that non-hereditary risk factors also play a substantial part. AD has been found to be commoner in older siblings,7, 8 in less crowded households,8 with late entry into nursery care,9 with increased maternal education,8 and probably in higher social class families.8-10 The inverse relationship between the incidence of atopy and sibship size and the risk of atopy being linked to higher birth order7, 8 led Strachan7 to propose the ‘hygiene hypothesis’ which suggests that infections in early childhood may reduce the risk of AD. Unlike earlier studies, a recent study surprisingly failed to show a protective effect of breastfeeding in infancy and the subsequent development of AD.8 Interesting observations have come about through the ‘natural experiment’ that resulted from the reunification of Germany in 1990. The prevalence of atopic disease rose substantially in Leipzig in the 6 years following reunification, as a more Western lifestyle became more prevalent.11 However, in contrast to atopy in general, this relationship with respect to AD is more complex. The prevalence of AD was found to be consistently higher in East Germany, in contrast to the higher prevalence of hay fever and asthma in West Germany,12 suggesting that AD follows a risk pattern that is different from respiratory allergies and sensitization. However, when this relationship was examined in more detail, extrinsic-type AD (allergic sensitization, as assessed by positive skin prick test) was consistently and significantly higher in children in West Germany than in those in East Germany, suggesting that factors other than allergy are responsible for the higher prevalence of AD in East Germany.12 Factors which may contribute to the higher manifestation of intrinsic-type AD in East Germany may include air pollution, nutritional factors and infections. The marked variation in the prevalence of AD between countries is also observed within countries. In the U.K., in a study of 7-year-old children, there was a tendency for a higher prevalence of AD in the south and eastern parts of the country,13 even after corrections for affluence and other confounding factors. Explanations for this observation may include higher annual temperatures in southern areas acting as a direct trigger for eczema, higher humidity giving rise to increased house dust mite (HDM) populations or increased rainfall in the north and west of Britain resulting in lower pollen counts in the air.13 The role of HDMs in both the initiation and continuance of AD in children has been proposed for some time but remains controversial. Surprisingly, a recent study suggested that increased exposure to HDMs in early life appeared to offer a protective effect against AD.8 However, in another study of young children with extrinsic-type AD, HDM allergen avoidance measures led to a significant improvement in AD, especially in the autumn and winter seasons when HDMs are at their highest level.14 The latter study suggests that the use of allergen avoidance measures such as encasing mattresses and pillows, removal of soft toys and carpets and frequent vacuuming of carpets should be suggested to all families with children suffering from extrinsic AD. The introduction of HDM avoidance measures in the first months of life to children at risk may help to prevent HDM sensitization15 and particularly reduce the risk of asthma.16 While environmental factors may be important, they must be considered in conjunction with genetic predisposition to atopy. Twin studies have shown a much higher occurrence of atopy in monozygotic rather than dizygotic twins (85% vs. 21%).17 Furthermore, two recent studies have shown that a major susceptibility locus for AD maps to chromosome 3q21,18, 19 and also to loci on 1q21, 17q25 and 20p.19 These loci correspond closely to psoriasis loci and suggest that these are gene loci representing general effects for dermal inflammation and immunity. What remains to be determined is how genetic and environmental factors interact in the determination of the disease susceptibility and expression. Experimental investigation offers the prospect of improving interventions through a better understanding of basic immunological mechanisms and cytokine-mediated inflammation in AD. It is now well recognized that CD4+ and CD8+ T cells are divided into two distinct populations based on their cytokine-producing patterns. Type 1 (Th1) are associated with delayed-type hypersensitivity reactions and secrete interleukin (IL)-2 and interferon (IFN)-γ, while type 2 (Th2) cells are involved in the production of IL-4, IL-5 and IL-13 but not IFN-γ.20 In a recent study looking at circulating lymphocyte populations, an increase in the frequency of circulating skin-homing type 2 cytokine-producing cells, associated with a decreased frequency of skin-homing type 1 cytokine-producing cells, has been found in the peripheral blood of patients with AD.21 This concept was expanded further in a study which looked at the Th1 and Th2 cytokine secretion patterns of peripheral blood monocyte cells (PBMC) in patients with AD and healthy controls in the presence of HDMs.22 In this study IL-13 levels were significantly elevated in patients with AD when compared with healthy controls, while levels of IFN-γ (a Th1 cytokine) were not significantly different between these two groups. Furthermore, IL-13 levels were significantly higher in AD patients who had high levels of HDM-specific IgE when compared with AD patients who had low levels of IgE. Tacrolimus significantly inhibited the HDM-induced IL-13 production in PBMC. It was concluded that these peripheral IL-13-producing cells are probably involved in the IgE overproduction seen in AD patients. In a similar study23 on PBMC from adult patients with AD, there were higher levels of IL-4- and IL-13-positive cells when compared with non-atopic controls. In the one patient who was studied before and after 8 days of cyclosporin treatment, there was a 50% or greater reduction in T cells expressing IL-4 and IL-5 but only a 15% reduction in the IL-13-positive T cells, although it was suggested that longer periods of cyclosporin therapy may have had a greater influence on the IL-13 cytokine-producing T cells.23 These immunologically based studies further our knowledge of how the Th2 lymphocyte populations and their cytokines may influence AD and may be linked to external triggering factors such as HDMs and treatment factors such as cyclosporin. The role of Staphylococcus aureus in aggravating AD is well known to dermatologists; the mechanism of action suggested is that the bacterium acts by the secretion of superantigens (SAgs),24 minute concentrations of which can stimulate large numbers of T cells and massive inflammatory cytokine release. While much attention has been paid to this immunological mechanism for SAgs in the exacerbation of AD, other mechanisms of disease activation probably exist. In an in vitro study of PBMC, staphylococcal SAgs induced corticosteroid insensitivity through a cytokine-mediated induction of the glucocorticoid receptor-β.25 It is thus possible that SAg-producing microbes act not only to trigger the onset of and aggravate the course of AD, but also to induce corticosteroid insensitivity, thereby further reducing the anti-inflammatory effects of topical steroids in AD. Alternatively, as shown by a recent study, staphylococcal antigens may have actions other than those of SAgs. In a study examining the actions of two cationic staphylococcal proteins, NP-tase and p70, on the cytokine release from PBMC in AD patients, it was noted that there was a predominance of activation of the Th2 response in a subset of the patients.26 It was thus concluded that these staphylococcal proteins could, in 30–50% of patients with AD, further skew the balance towards increasing Th2 cytokine release. These cytokines could, in turn, increase the eczematous response in the skin in a manner independent of any SAg or corticosteroid resistance role. While it is well recognized that, in children, AD causes misery to both the patients and the parents, only recently has this been investigated using a Quality of Life Index.27 Not surprisingly, the highest scores for the children were for itching, scratching, mood change and sleep disturbance, while those for the parents were sleep disturbance, tiredness, exhaustion and emotional distress. Given the disturbance that AD induces, it is obvious that effective treatment that alleviates symptoms is of paramount importance. Given the efficacy and relative safety of topical steroids, it is often frustrating when parents express a desire not to use them through an irrational fear and anxiety about their side-effects. In a recent survey, over 70% of parents worried about using topical steroids on their child's skin and 25% admitted to low compliance because of their anxieties.28 The highest perceived risk was skin thinning (35%), and parents often confused the potency of topical steroids, particularly that of hydrocortisone. These authors coined the phrase ‘corticosteroid phobia’ and suggested that to overcome this fear, time spent with parents by healthcare professionals and in particular, dermatology nurses, may be time well spent.28 A disappointing feature of this study was that there seemed to be excessive caution from some general practitioners when prescribing topical steroids, which tended to increase parents' anxieties as they got conflicting messages about safety of the treatment. Given that dermatologists report favourably on the efficacy of wet wraps in treating children with AD, it is surprising that virtually nothing has been published on this subject until recently. In a study looking at the efficacy of the wet-wrap technique in children, Wolkerstorfer et al.29 examined the efficacy and effect on the hypothalamic-pituitary-adrenal (HPA) axis. The results of their study showed a dramatic improvement in refractory AD irrespective of the dilution of topical steroid applied under the wet wraps, and suggested that weaker dilutions of topical steroids under wet wraps may be of similar efficacy to those of stronger topical steroids. Most improvement was also found during the first week of treatment, with only minor additional improvement during the second week. While some suppression of the HPA axis was seen, the authors concluded that longer and larger studies are required to address this issue in terms of safety, but that it seems probable that the short-term use of low-potency topical steroids is quite safe. Most of the advantage from wet wraps is probably gained from the protection of the skin from scratching, and also cooling of the skin and enhanced penetration of emollients and corticosteroids. New treatments for AD are, or soon will be available, many based on our better understanding of the role of cytokines in AD. One such treatment is tacrolimus, which is based on calcineurin inhibition resulting in suppression of T-cell activation and inhibition of inflammatory cytokine release.30 Tacrolimus is felt to have an excellent safety profile, with little systemic absorption and no skin thinning, and it can be used on the face and intertriginous areas.31 Tacrolimus ointment (0·03% or 0·1%) achieved greater than 90% clinical improvement in adult32 and paediatric33 patients. However, tacrolimus induced skin burning and pruritus in around half the patients treated, with influenza-like symptoms, skin redness and headache occurring in around a quarter.31 The skin burning and itch seemed to diminish during the first week of treatment, as the dermatitis was alleviated.31 A large study of 255 children treated with tacrolimus 0·1% twice daily for up to 12 months34 reported that apart from transient skin burning and itching, there was no increased incidence of infection or significant adverse events. This suggests that tacrolimus is safe and effective in the long-term treatment of AD in childhood,34 and tacrolimus has recently been released on to the American market as Protopic® (0·03%, 0·1%). SDZ ASM 981, an ascomycin macrolactam derivative, that acts by specifically inhibiting the production and secretion of proinflammatory cytokines,35 has been shown to be an effective and safe topical agent in the treatment of AD,36 both in adults37 and children.38 Using ultrasound, Queille-Roussel et al.39 showed that SDZ ASM 981 in a 1% cream formulation, in contrast to two potent topical steroids, did not induce skin atrophy over a 4-week treatment period. While this is a relatively short treatment period, it seems likely that SDZ ASM 981 has the potential to treat AD more safely than by using potent corticosteroids,40 especially in children and for areas such as flexures or the face. With regard to emerging systemic treatments, mycophenolate mofetil (MMF)41 seems promising for adult patients with AD. MMF is currently used in the prophylaxis of organ rejection in renal transplant patients. In a pilot study of 10 patients, MMF proved very effective, was well tolerated, and improved disease severity by 68%, which was better than that observed with cyclosporin in a previous placebo-controlled study.42 In a preliminary study, MMF used for 12–29 months to treat three adults with chronic AD appeared to have achieved good disease control with an excellent safety profile.43 While MMF can give rise to nausea, vomiting and diarrhoea, it does not appear to produce the clinically significant problems of hepatotoxicity or nephrotoxicity associated with cyclosporin.42 Both psoralen plus ultraviolet (UV) A (PUVA) and narrow-band UVB phototherapy are effective phototherapeutic modalities in the treatment of resistant AD, but until recently the relative efficacy of these treatments had not been compared. This issue has been addressed in a half-side comparison study from Vienna44 comparing bath-PUVA with narrow-band (TL-01) UVB phototherapy in adults with severe chronic AD. Both regimens appeared to be equally effective when administered in equi-erythemogenic doses, but most patients favoured the narrow-band UVB phototherapy because it does not require the concomitant administration of a photosensitizer. In another less conventional systemic treatment reminiscent of the use of Chinese herbal decoctions in AD, drinking oolong (green) tea three times daily brought about a marked improvement in around 63% of patients in an open trial, with the beneficial effect being noted in the first 2 weeks. The good response was still maintained at 6 months in 54% of the patients.45 The efficacy of oolong tea may be brought about by its polyphenol content, but more definitive studies would be required before such treatments could be generally advocated. Given the high prevalence and morbidity of AD, how much does this cost the National Health Service (NHS) in the treatment of children alone? Recently, Emerson et al.46 looked at not only the cost to the NHS but also the cost to families in terms of changing the home environment, transport costs and other items. It was estimated that the total annual cost of treating children under 5 years was £30 million for the NHS and £17 million for families. Of the total cost that was borne by the NHS, 64% was attributed to costs of consultation and treatment. Of the prescribing costs, estimated at £10 million per annum in the U.K., 76% were for emollients and bath oils, with 20% being for topical steroids. It is perhaps surprising that the cost of topical steroids was relatively low, but as new topical immunosuppressive drugs come on the market the overall prescribing costs for the NHS may well increase dramatically. Family expenditure due to AD included changes to the home environment such as anti-HDM measures, vacuum cleaners, over-the-counter medicines, visits to alternative practitioners, income loss and transport costs. Interestingly, parents tended to spend more on private consultations with alternative practitioners than with private dermatologists, although the number of families seeking alternative care was small. How successful are British dermatologists in treating AD? Having originally set working standards which were felt to be achievable for the treatment of AD in secondary care,47 Shum et al.48 carried out an audit of four of these standards, on both children and adults, 6 weeks after they had attended dermatology departments. Although sleep loss had decreased significantly at 6 weeks postconsultation, only 44% of adults and 47% of children had an improvement in sleep loss, which fell short of the working standard of 70%. While Quality-of-Life Indices significantly improved, only 49% of adults and 44% of children had a > 25% relative improvement, which fell below the 60% target in both cases. Sixty-one per cent of adults and 59% of children recorded an improvement in the worst aspect of their skin condition after 6 weeks, falling short of the 80% working standard. For those patients who were away from work or school because of AD, 70% of adults and 88% of children had returned to work/school by 6 weeks: this met the working standard of 80% for children, but not for adults. One reason for these disappointing results may be that the initial audit standards were set too high, but this seems unlikely (with the possible exception of sleep loss in children) as the standards could be met by one of the 11 NHS administrative areas. This outcome for the management of AD in secondary care is disappointing and less than most dermatologists would have anticipated or liked. It suggests that an improvement in practice and/or a re-evaluation of the audit standards is needed, which should be examined in future audit cycles.