Recent advances in atopic dermatitis treatment

teaser

Wojciech Silny
MD PhD
Professor

Magdalena Czarnecka-Operacz
MD PhD
Department of Dermatology and Allergic Diseases Diagnostic Centre
University of Medical Sciences
Poznan
Poland
E:[email protected]

Management of atopic dermatitis (AD), especially in cases of exacerbated skin inflammatory processes, is a real therapeutic challenge. It requires efficient short-term control of acute signs and symptoms in addition to long-term stabilisation, flare prevention and avoidance of possible side-effects. This paper presents an overview of up-to-date therapeutic approaches that may be applied in AD. Starting from prophylactic treatment, we cover basic fields and methods currently available to treat AD.

Prophylactic treatment
Preventive therapies for AD are similar to those applied in other atopic diseases. Prophylactic management consists of primary, secondary and additional types of prevention.(1)

Primary prevention
The aim of primary prevention strategies is to reduce the risk of developing signs and symptoms of AD. It applies to children born into atopic families who have a high risk of developing atopic disorders. This type of prevention consists of prolonged breastfeeding of infants, appropriate diet for breastfeeding mothers, delayed introduction of solid foods and reduction of exposure to airborne allergens (indoor and outdoor airborne allergens). Although conflicting data on breastfeeding and development of allergy have been published during the last few years, current evidence suggests that exclusive breastfeeding for the first four to six months reduces the incidence of allergy associated with cow’s milk, as well as cow’s milk sensitisation, AD and possibly wheeze or asthma. The protective effects of breastfeeding on allergy prevention are strongest in infants with at least one first-degree relative with atopic disease. This protection is less prominent in the general population. Recent clinical studies indicate that a balanced maternal diet containing fresh fruits and vegetables (antioxidants) and fat of predominantly vegetable origin may be associated with a lower incidence of atopy in the infant. However, this has not been systematically evaluated in large studies. There is currently insufficient data to advise mothers on any changes in nutrition for primary prevention during pregnancy or breastfeeding. Dietary restrictions to the maternal diet are not recommended except for mothers with food allergy. Based on current evidence and understanding it would seem that early introduction of multiple foods before four months of age may increase the manifestation of AD. In a family at risk and where breastfeeding is not possible, a hydrolysed formula can help reduce the incidence of atopic manifestations. However, the role of such formulas in case of cow’s milk sensitisation in primary prevention warrants further investigation. It is advised to avoid smoking and exposure to all nicotine products during fetal development and during the first years of life.

Awareness that the human intestinal flora is a major factor in health and disease has led to different strategies with pre- and probiotics to promote health and avoid disease. Early studies suggest that probiotics given in early life may prevent the development of AD in infants at risk. However, further studies on the safety and efficacy of this approach are necessary.

Secondary prevention
Secondary prevention can be defined as the prevention of disease or its progression in infants with early signs or markers of disease. Avoidance of sensitising foods and airborne environmental allergens may be helpful, as well as preventive pharmacotherapy, allergological diagnostics and consideration of allergen-specific immunotherapy. To prevent infections in AD patients, it is recommended to apply proper skincare and to select a “safe” profession.

Additional prevention
These preventive strategies are needed in patients with chronic and relapsing course of the disease in order to prevent further development of skin problems as well as involvement of additional systems (eg, respiratory system) by atopic inflammation. Special educational programmes and early prophylactic strategies may be beneficial .

Topical treatment
The primary aim in the treatment of AD is the control of local factors to optimise skincare and treatment.(2) Proper primary skin management in AD seems to be one of the main elements of therapy in both the acute and the chronic phase of the disease, as it restores skin barrier function. The main targets of topical skincare are dryness and skin irritation. Prevention and treatment of skin dryness is essential and, therefore, moisturising is most effective if done at least three or more times a day, in particular immediately after bathing, to lock in the moisture absorbed during the bath. Moisturising emollients are also used in long-term intermittent therapy with topical glucocorticosteroids (GCSs) and in parallel with topical immunomodulatory formulas. Preparations containing urea (5-10%), liquid and white soft paraffin, glycerol or sorbolene, essential fatty acids and ceramides are appropriate.

It is also advised to use therapeutic bath products containing natural or mineral oils. Topical analgesics such as polidocanol 3% are sometimes added in order to reduce the chronic itching sensation. A 10-15-minute bath should be taken without any additional detergents, and the temperature of water should be equal to the body temperature. After the bath, skin should be dried gently and, immediately after bathing, it should be moistened when the skin is still slightly humid. It is important to advise pH 5.5 dermo‒cosmetics in nonirritant and low-allergy formulas that allow renovation of the impaired lipid barrier.

Topical GCSs are still used as a first-line anti-inflammatory treatment. According to clinical status, GCSs may be applied once or twice daily in continuous or intermittent regimens.(3) Intermittent is recommended in order to reduce steroid-related side-effects in cases of chronic topical GCS treatment. Consequent baseline emollient skincare combined with early anti-inflammatory intervention with topical GCSs of appropriate potency may result in satisfactory clinical effects with a good safety profile. For intermittent therapy with topical GCSs, the anti-inflammatory formulation is applied every second day while moisturising factors are used in between active treatment. Topical GCS preparations may also be used for three consecutive days with moisturising supplementary formulations afterwards for another three days. Then the whole cycle starts again. Potent and very potent steroids may be used only once a week or only at weekends (“weekend treatment”).

Calcineurin inhibitors (CNIs) are a new class of topical immunomodulators presenting anti-inflammatory and antiallergic properties.(4,5) Two steroid-free topical CNIs, tacrolimus and pimecrolimus, are used in the treatment of AD. Their mechanism of action is closely related to that of ciclosporin, a drug that was developed about a decade earlier and has found systemic application in dermatology for AD, �psoriasis, pyoderma gangrenosum and other diseases. CNIs bind tightly to a cellular protein macrophillin 12 and block calcineurin activity, resulting in blockage of numerous cytokines transcription (eg, Il-2, IFN-γ, IL-3, IL-4, TNFα). Both medications inhibit mast cell activity as well as production and release of proinflammatory cytokines and mediators. Unlike pimecrolimus, tacrolimus inhibits the activity and function of Langerhans cells. Pimecrolimus is more lipophilic than tacrolimus, and its systemic absorption is lower. Both medications are recommended for twice-daily application. The most frequently observed side-effect is a transient warmth or burning and itching sensations at the application site. These side-effects are related to the release of neuro‒peptides; they may last up to one hour, and the intensity and duration typically decrease to zero within one week.

Pimecrolimus 1% cream formulation is available for the treatment of both children and adults. It is recommended from the first signs of flaring in mild- to-moderate AD, especially on the face.

Tacrolimus is available in two concentrations: 0.03% ointment for the treatment of  children and 0.1% ointment for adults. It is advised for moderate or severe AD therapy.

CNIs present good safety profile. They do not cause skin atrophy, and other GCS-related side-effects. Langerhans’ cell inhibition has been observed with the use of tacrolimus and, therefore, more frequent viral skin infections (varicella zoster) may be expected, although further investigations are necessary. Topical CNIs should be also recommended as a maintenance treatment to reduce the use of strong GCSs in such areas as the face, skin folds and napkin areas.

Systemic treatment
Antihistamines, as well as other anti-inflammatory, antipruritic and sedating medications, are widely used in systemic treatment of AD.

As the clinical effects of antihistamines are related to the blockage of H(1)-receptors, these agents decrease pruritus and permit sleep during flares. Unfortunately, histamine is not the only mediator of the itching sensation in AD, and the clinical effect of this group of medications may be unsatisfactory. The sedating effects of the classical generation of antihistamines may be helpful, while the more recent nonsedating group of drugs presents various antipruritic effects.(6-8) Both first- and second-generation antihistamines are often used in daily practice. In cases of acute exacerbation of the skin inflammatory process, first-generation antihistamines should be administered in intravenous form. One should be obviously aware of the whole variety of side-effects (not only sedation). Second-generation antihistamines may be used in long-term treatment, depending on the course of the disease (see Box).

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The use of systemic GCSs should be limited to severe erythrodermic cases. They are rapidly effective but should be avoided as side-effects are expected in the long-term treatment. In severe cases of AD, ciclosporin A (3-5mg/kg/day) may be administered.(9) Clinical efficacy of this treatment has been well documented in various trials performed in children and adults. Ciclosporin A is rapidly effective in reducing skin inflammation and itching sensation, but it requires a close follow-up of liver and renal impairment.

In selected cases of AD patients with a well-documented IgE-mediated airborne allergy (eg, house dust mites, plant pollen allergens, moulds), specific immunotherapy (SIT) with allergy vaccinations may be considered as an alternative therapeutic approach. Conventional SIT (ie, subcutaneous injections of allergen extracts) is known to be a curative treatment for specific forms of IgE-mediated allergies. SIT is the only treatment that may affect the natural course of allergic diseases, as it may prevent the onset of new sensitisations and as it influences the natural course of the atopic disease (it reduces the development of asthma in patients with allergic rhinitis). Therefore, SIT can also be regarded as a preventive method. It seems to be extremely important in AD patients who are at high risk of allergic respiratory signs and symptoms. The use of SIT leads to noticeable clinical improvement in AD patients, although further studies are needed to understand the reason why this occurs. Although SIT is still being discussed as a controversial therapeutic option for AD patients, more studies showing satisfactory clinical effects are being published.(10-14)

Additionally, azathioprine (2.5mg/kg/day), mycophenolate mofetil (2g/day), leukotriene antagonists, high doses of intravenous immunoglobulins and interferon gamma may be used.(15,16)

Other methods
Psychotherapy, behavioural treatments, supplementation of unsaturated fatty acids and balneotherapy are also used in the treatment of AD patients. UV therapy has also been described to be effective. Both UVB and UVA or combination UVA/UVB, as well as psoralen/UVA (PUVA), have been used. The efficacy of phototherapy is not clearly understood in terms of the underlying mechanism, but it seems that UVB may affect Langerhans’ cell function, and that UVA may influence both Langerhans cells and eosinophils.(17)

In case of exacerbation of skin inflammation, UVA1 (340-400nm) is recommended. This treatment results in a decrease in eosinophil cationic protein (ECP) levels – one of the markers of AD activity. Narrow-band UVB (311nm) is generally advised at the chronic stage of the disease.

Conclusion
Treatment of AD still remains a great challenge for physicians. It requires wide experience in the field of dermatology and allergology and, until now, results have not always been satisfactory for our patients.

References

1. Aas K, et al. Prevention of atopic diseases. In: European Allergy White Paper. AVISO sprl, Van Moerbeke D, Bruxelles 1997:60-74.
2. Post Dermatol Alergol 2004;21:265-77.
3. Br J Dermatol 2003;148:3-10.
4. J Allergy Clin Immunol 2002;110:277-84.
5. J Dermatol Treat 2003;14:5-16.
6. Br J Dermatol 1989;121:635-7.
7. BMJ 1989;298:96-105.
8. Lancet 1994;343:1342-6.
9. Dermatol Ther 1996;1:24-31.
10. Ann Allergy 1974;32:321-30.
11. Clin Exp Allergy 1992;22:440-6.
12. Wiad Lek 2005;58:47-55.
13. Wiad Lek 2005;58:184-92.
14. Wiad Lek 2005;58:287-94.
15. Post Dermatol Alergol 2002;19:152-60.
16. Alerg Astma Immunol 2002;7:118-23.
17. Dermatol Ther 1996;1:24-31.