الفهرس 
Atopic DermatitisOnly 14 pages are availabe for public view
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Abstract
The aim of this essay is to review the wide recent literature covering the different therapeutic modalities in atopic dermatitis. Treatment should be aimed at general skin care and avoidance of triggering factors in order to prevent flares, as much as possible, and thus making the patient in a controlled disease state for as long as possible. If control couldn’t be achieved and an exacerbation occurred due to whatever triggering factors, then treatment should be started by symptomatic treatment in order to control the inflammation and the pruritus which can lead to more aggrevation of the condition through the itch-scratch cycle. Upon achievement of control , maintenance therapy has to be adopted in order to elongate the flare-free period as much as possible.
This review also discusses the clinical picture of AD in the different age groups while pointing to the signs and symptoms that may be encountered clinically.
Exacerbations often start as increased itch without visible skin lesions. This is followed by erythema, papules and infilterations, thus AD is termed “an itch that rashes and not a rash that itches”. Lesions are distributed in a characteristic age-related pattern, where each stage shows specific sites of predilection in addition to difference in types of skin lesions according to whether the AD takes the acute, subacute or the chronic form. Acute skin lesions are characterized by intensely pruritic, erythematous papules over erythematous skin associated with extensive excoriations, erosions, and serous exudate. Subacute dermatitis is associated with erythematous, excoriated, scaling papules whereas, chronic dermatitis is characterized by thickened skin, accentuated skin markings (lichenification), and fibrotic papules. In chronic AD, all 3 types of skin reactions frequently coexist in the same individual.
Multiple factors incriminated in the aetiopathogenesis of the disease have been discussed , as well. AD is thought to result from an interplay of a variety of factors; the most important of which are the genetic factor, skin barrier dysfunction together with immunologic dysregulation. Besides, the host environment as well as bacterial and viral infections of the skin do have a role.
Still unraveling the genetic basis of AD is challenging, but the most important breakthrough in the past 2-3 years, by far, was the discovery of loss of function mutations in the filaggrin gene (FLG) in a large population of AD patients. That might be a turning point in the treatment in the next years to come.
Immune dysregulation is incriminated in AD in the form of disruption in both innate and acquired immunity. Acquired immune dysregulation can be summarized as: humoral factor, represented by the excessive production of IgE together with discovery of IgE autoantibodies in AD patientsin addition to cell-mediated immunity which shares in the pathogenesis, as well. A variety of immune effector cells were proved to have a role. Skin lesions evolve as a result of complex interactions between IgE-bearing APCs, T-cell activation, mast cell degranulation, keratinocytes, eosinophils and a combination of immediate and cellular immune responses. T cells do have a significant role where both Th1 and Th2 share in the pathogenesis of AD. The T-cell infiltrate of acute AD lesions is dominated by Th2 cells while that of chronic lesions is predominantly made up of Th1 cells. Thus , a biphasic profile of cytokine expression therefore occurs according to which type of Th cells is dominating.
The acute skin lesions are associated with marked infilteration of Th2 cells with predominance of IL4 and IL13. However, with the infilteration of eosinophils and macrophages in chronic AD, there is a rise in IL12 resulting in a switch to Th1 cellular responses with predominance of IL5 and IFN- γ.
This biphasic Th2/Th1 switch is paralleled clinically and histologically by acute population and spongiosis followed by development of lichenification , epidermal hyperplasia and dermal fibrosis.
Another important factor is colonization of bacteria especially Staph aureus which has been isolated from the skin of more than 90% of AD patients .This colonization is facilitated by the deficiency in antimicrobial peptides which is part of the innate immune deficiency occurring in skin diseases such as AD. Thus, treatment with antimicrobials might be essential in some cases.
Treatment options available for AD patients are the core of this essay. Treatment involves preventive management as well as curative management. Flare prevention involves a dual strategy where the regular daily use of emollients and moisturizers together with trigger avoidance and patient education have to go hand in hand in order to decrease the frequency of flares. Treatment strategy should be individualized according to the severity , life style and compliance of the patient.
Topical agents include topical corticosteroids , which have been the standard therapy for the past fifty years, but they should be restricted to only short courses especially with corticosteroids of high potency which should also be avoided in areas of highly sensitive skin example face and intertriginous areas. Therefore, the discovery of topical calcineurin inhibitors (TCIs) in the past ten years has expanded the options for the topical therapy in AD patients especially in those with face and groin involvement.A very narrow range of adverse effect has been claimed , though discovery of photocarcinogenic effect in murine models has raised some debate and led to the recommendation of inserting a blackbox warning in the brochures of Tacrolimus and Pimecrolimus .Yet, up till now, advantages of TCIs are more than their disadvantages especially if used as infrequent as possible up to only once per week in maintenance therapy. Besides , the patient should stick to the regular use of sunblocks all through the treatment course. Barrier repairing agents and ceramide rich emollients are also used in treatment of AD ; not only in prevention.
Moreover, phototherapy may be combined with topical corticosteroids in some patients. Phototherapy may help ; namely narrowband UVB (311nm) and UVA1 may be of benefit. Photochemotherapy in the form of PUVA may be used but it carries the risk of squamous cell carcinoma and melanoma which may occur even years after PUVA therapy has ceased.
Systemic therapy in AD may be needed especially in severe recalcitrant cases. In brief , options include using anti-histamines in a trial to control itching which is by far the most irritating symptom, that even anti-depressants may be used for the same purpose .Oral corticosteroids may be used , but only for short courses for recalcitrant disease. Besides, Cyclosporin , Azathioprine , Methotrexate and Mycophenolate Mofitel may be used but with caution due to grave adverse effects, in addition to the high incidence of relapse as with Cyclosporine for example. Other systemic agents include leukotriene inhibitors.
Intravenous Igs and biologic agents have shown benefit in some patients though their expense represents an obstacle to practical use on a wide scale. The idea behind biologic agents is a trial at correcting or blocking the foci of immune dysregulation in the pathogenesis. An example is Omalizumab.It is a recombinant humanized Ab against IgE which stops IgE attachment to mast cells and thus prevent IgE-mediated inflammatory changes.Other biologics include Efalizumab(CD11a blocker) which inhibits Tcell activation, Infliximab (anti TNF-α) and Retuximab (anti CD20 Ab). Likewise, leflunomide is an immunosuppressant with inhibitory effect on both Tcells and eosinophils which are important cells in AD pathogenesis. Thus, it may prove promising in the future.
Allergen specific immunotherapy may prove helpful in mild to moderate AD, but its role in the severe form may be actually limited.
Short term anti-staphylococcal therapy can be useful in heavily-colonized individuals; where a topical or a systemic antibiotic may be used according to the spread and degree of superinfection , although using antibiotics should be short term in order to avoid emergence of resistant bacteria. Anti-virals may be needed ,as well, since AD patients are highly prone to viral infections.This may be attributed to : (1) relative deficiency in Tc (2)deficiency in AMPs in atopic skin and (3) deficiency of what is called plasmacytoid dendritic cells . Antifungals may be needed in some patients due to prevalence of fungal infections in a group of patients, where anti fungals may help reduce the severity of the lesions.
Other systemic treatment that may prove some help may include the PPAR-γ ligand (Rosiglitazone). PPARs are nuclear hormone receptors that are expressed in many cells including keratinocytes. Though PPAR-γ was originally identified as a regulator of adipogenesis and glucose homeostasis , yet recent data have linked them to several genes involved in inflammation.Thus, PPAR-γ agonists may reduce certain inflammatory mediators in the skin and regulate epidermal barrier homeostasis thus helping in AD control.Yet, studies on wider scale are needed before this information can be generalized.
Probiotics in the current years and for years to come continue to be an area of active investigation as our understanding evolves of the gut microbiota’s role in the altered immune response of atopic patients. Physicians should be aware of these developments as probiotics may be an important complementary approach in the treatment and the natural long-term course of various pediatric diseases. The role of probiotics in AD treatment may be limited to eczema associated with food allergy in young children, however the role in AD prevention may be wider than this. They are likely to have an important place in the management of AD in the future, and further studies are clearly warranted to better define their role.
Vitamin D3 has been suggested to enable efficient anti-microbial defense at epithelial surfaces. Oral supplementation of 1,25D3 or vitamin D3 precursors might be beneficial in AD , as 1,25D3 increases cathelicidin expression and antimicrobial activity in keratinocytes in vitro. Thus, increasing vitamin D3 metabolism or increasing vitamin D3 serum levels could contribute to the restoration of an effective barrier in AD, however more clinical studies have to be performed to prove its safety and benefits. Overall, current data overwhelmingly support the importance of AMPs to healthy human skin, but the key steps to put this information to therapeutic use remain to be examined.
Last but not least , although multiple therapeutic modalities for AD do exist , there is no single monotherapy that has proven exceptional in ameliorating the symptoms and hence, combination therapy is the rule. Treatment depends on setting protocols or what is known as paradigms that can be fitted to every group of patients depending on the degree of severity, compliance and clinical response.