Current approaches in atopic dermatitis therapy

teaser

Maria Luisa Pacor
MD
Professor
Dipartimento di Medicina Clinica e Sperimentale
Università degli Studi di Verona
Italy

Gabriele Di Lorenzo
MD
Dipartimento di Medicina Clinica e delle Patologie Emergenti
Università degli Studi di Palermo
Italy
E:[email protected]

Atopic dermatitis (AD) is a chronic inflammatory skin disease associated with cutaneous hyperreactivity to environmental triggers that are innocuous to normal nonatopic individuals.(1) The diagnosis of AD is based on the following constellation of clinical findings: pruritus, facial and extensor eczema in infants and children, flexural eczema in adults, and chronicity of the dermatitis. AD usually presents during early infancy and childhood, but it can persist into or at the start of adulthood.(2) The lifetime prevalence of AD is 10–20% in children and 1–3% in adults.

Various studies indicate that AD has a complex aetiology, with activation of multiple immunological and inflammatory pathways.(3) At least two forms of AD have been delineated: an “extrinsic” form associated with immunoglobulin E (IgE)-mediated sensitisation and involving 70–80% of patients, and an “intrinsic” form without IgE-mediated sensitisation and involving 20–30% of patients.(4) Both forms of AD present with associated eosinophilia. In extrinsic AD, memory T-cells expressing the skin-homing receptor, cutaneous lymphocyte-associated antigen (CLA), produce increased levels of Th2 cytokines. These include interleukin (IL)-4 and IL-13, which are known to induce isotype switching to IgE synthesis, and IL-5, which plays an important role in eosinophil development and survival. These CLA+ T-cells also produce abnormally low levels of IFN-gamma, a Th1 cytokine known to inhibit Th2 cell function. Intrinsic AD is associated with less IL-4 and IL-13 production than extrinsic AD.(5)

Management of AD
Successful management of AD requires a multipronged approach. Schematically, the therapeutic approach requires:

• Identification and avoidance of the immunological trigger factors (ie, allergens, infections, irritants, psychogenic factor).
• Reduction of the inflammatory cell infiltration in the dermis.
• Blockade of the effect of the cytokines and mediators released by the inflammatory cells.(6)

Topical corticosteroids are the mainstay of anti-inflammatory treatment, showing efficacy in the control of both acute and chronic skin inflammation. Corticosteroids mediate their anti-inflammatory effects through a cytoplasmic glucocorticoid receptor (GCR) in target cells. In this process, ligand-bound GCR binds to various transcription factors, including activator protein-1 and nuclear factor kB (NFkB), via protein–protein interactions to inhibit the transcriptional activity of various proinflammatory genes encoding proinflammatory proteins such as cytokines, chemokines and adhesion molecules.(7)

Due to concerns about potential side-effects associated with chronic use, topical corticosteroids have not been used for maintenance therapy, especially on nonlesional skin, in AD. However, normal-appearing skin in AD is associated with subclinical inflammation, suggesting that maintenance anti-inflammatory therapy may be required to prevent relapse.

Topical tacrolimus vs ciclosporin
Topical tacrolimus, a macrolide lactone isolated from Streptomyces tsukubaensis, is a potent immunosuppressive agent with a spectrum of activity similar to that of ciclosporin. It has recently been approved by the US Food and Drug Administration for the treatment of AD. Tacrolimus inhibits the activation of a number of key effector cells involved in AD, including T-cells and mast cells.(8)

Short-term, multicentre, blinded, vehicle-controlled trials in both adults and children have shown topical tacrolimus to be effective. In a minority of patients, local irritation has been reported with tacrolimus. Long-term studies with tacrolimus have been performed in adults and children, with demonstrated sustained efficacy and no significant side- effects. Unlike topical glucocorticoids, tacrolimus is not atrophogenic and can be used safely for facial and eyelid eczema. It could be used in the treatment of patients who are poorly responsive to topical steroids or have steroid phobia, and for treatment of face and neck dermatitis where ineffective, low-potency topical corticosteroids are normally used due to fears of steroid-induced skin atrophy. However, although systemic absorption of tacrolimus is low, there is a need for careful surveillance to rule out the possibility of skin cancers and increased viral skin infections when such agents are used long-term.(8,9) In a recent study, our research team observed only a mild cutaneous burning and no systemic effects in patients treated with tacrolimus ointment (0.1%) for six weeks.(10)

Ciclosporin A is a potent systemic calcineurin inhibitor. A number of studies have demonstrated its efficacy in both children and adults with severe, refractory AD, although toxicity, primarily renal, limits its chronic use.(11) However, the results of our comparative study demonstrate that tacrolimus ointment twice daily and ciclosporin administered orally once daily are effective on SCORAD (SCORing Atopic Dermatitis), daily symptoms and antihistamine H(1) rescue. A comparison of tacrolimus and ciclosporin shows that there is a faster onset of action in the group treated with tacrolimus, with the two drugs presenting the same safety. Finally, our data support the preferential use of topical tacrolimus 0.1% in AD.(10)

Ultraviolet (UV) light therapy and antimetabolites, including mycophenolate mofetil (a purine biosynthesis inhibitor), methotrexate and azathioprine, can be a useful treatment modality for chronic recalcitrant AD. However, the potential for systemic toxicities restricts the use of antimetabolites and requires close monitoring.

Other treatments
Although a number of anecdotal studies and case reports suggest clinical benefit from allergen-specific desensitisation in AD, double-blind, controlled trials have failed to show consistent efficacy of immunotherapy compared with placebo in the treatment of AD.(12) Recently, omalizumab, a humanised IgG1 monoclonal antibody against IgE, has been shown to be effective in the treatment of allergic asthma and allergic rhinitis.(13) Thus, it could potentially neutralise the effects of IgE in AD. However, the high serum IgE levels seen in AD may limit the usefulness of this antibody, although it may have a role in forms of AD with low or medium serum IgE level.

Conclusion
The future will be the development of more effective and safer drugs in the treatment of AD. However, given the complexity of immune pathways that lead to AD, it is possible that more selective anti-inflammatory or immunomodulatory agents would be less effective.(14) The factors determining the chronicity, skin remodelling and natural history of this disease remain poorly characterised. In addition, the role of microbes and autoantigens in the initiation and progression of AD requires further clarification. Thus, it will be important to characterise the key immune pathways leading to the different phenotypes of AD better, as medications may vary in their effectiveness for the treatment of different forms of AD. An understanding of the genes responsible for individual variation in response to therapy will be tied to the development of pharmacogenetic drugs and the targeting of effective therapies to the different phenotypes of AD.

References

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14. Ellis C, Luger T, Abeck D, et al. Br J Dermatol 2003;148 Suppl 63:3-10.