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Etiopatogenesis Penyakit ini dipengaruhi multifaktorial, seperti faktor genetik, imunologik, lingkungan, sawar kulit dan farmakologik.

Konsep dasar terjadinya DA adalah melalui reaksi imunologik. Faktor Genetik DA adalah penyakit dalam keluarga dimana pengaruh maternal sangat besar. Walaupun banyak gen yang nampaknya terkait dengan penyakit alergi, tetapi yang paling menarik adalah peran Kromosom 5 q31 33 karena mengandung gen penyandi IL3, IL4, IL13 dan GM CSF (granulocyte macrophage colony stimulating factor) yang diproduksi oleh sel Th2. Pada ekspresi DA, ekspresi gen IL-4 juga memainkan peranan penting. Predisposisi DA dipengaruhi perbedaan genetik aktifitas transkripsi gen IL-4. Dilaporkan adanya keterkaitan antara polimorfisme spesifik gen kimase sel mas dengan DA tetapi tidak dengan asma bronchial ataupun rinitif alergik. Serine protease yang diproduksi sel mas kulit mempunyai efek terhadap organ spesifik dan berkontribusi pada resiko genetik DA Respons imun pada kulit Salah satu faktor yang berperan pada DA adalah faktor imunologik. Di dalam kompartemen dermoepidermal dapat berlangsung respon imun yang melibatkan sel Langerhans (SL) epidermis, limfosit, eosinofil dan sel mas. Bila suatu antigen (bisa berupa alergen hirup, alergen makanan, autoantigen ataupun super antigen) terpajan ke kulit individu dengan kecenderungan atopi, maka antigen tersebut akan mengalami proses : ditangkap IgE yang ada pada permukaan sel mas atau IgE yang ada di membran SL epidermis. Bila antigen ditangkap IgE sel mas (melalui reseptor FcRI), IgE akan mengadakan cross linking dengan FcRI, menyebabkan degranulasi sel mas dan akan keluar histamin dan faktor kemotaktik lainnya. Reaksi ini disebut reaksi hipersensitif tipe cepat (immediate type hypersensitivity). Pada pemeriksaan histopatologi akan nampak sebukan sel eosinofil. Selanjutnya antigen juga ditangkap IgE, sel Langerhans (melalui reseptor FcRI, FcRII dan IgE-binding protein), kemudian diproses untuk selanjutnya dengan bekerjasama dengan MHC II akan dipresentasikan ke nodus limfa perifer (sel Tnaive) yang mengakibatkan reaksi berkesinambungan terhadap sel T di kulit, akan terjadi diferensiasi sel T pada tahap awal aktivasi yang menentukan perkembangan sel T ke arah TH1 atau TH2. Sel TH1 akan mengeluarkan sitokin IFN-, TNF, IL-2 dan IL-17, sedangkan sel TH2 memproduksi IL-4, IL-5 dan IL-13. Meskipun infiltrasi fase akut DA didominasi oleh sel TH2 namun kemudian sel TH1 ikut berpartisipasi. Jejas yang terjadi mirip dengan respons alergi tipe IV tetapi dengan perantara IgE sehingga respons ini disebut IgE mediated-delayed type hypersensitivity. Pada pemeriksaan histopatologi nampak sebukan sel netrofil. Selain dengan SL dan sel mas, IgE juga berafinitas tinggi dengan FcRI yang terdapat pada sel basofil dan terjadi pengeluaran histamin secara spontan oleh sel basofil. Garukan kronis dapat menginduksi terlepasnya TNF dan sitokin pro inflamasi epidermis lainnya yang akan mempercepat timbulnya peradangan kulit DA. Kadang-kadang terjadi aktivasi penyakit tanpa rangsangan dari luar sehingga timbul dugaan adanya autoimunitas pada DA. Pada lesi kronik terjadi perubahan pola sitokin. IFN- yang merupakan sitokin Th1 akan diproduksi lebih banyak sedangkan kadar IL-5 dan IL-13 masih tetap tinggi. Lesi kronik berhubungan dengan hiperplasia

epidermis. IFN dan GM-CSF mampu menginduksi sel basal untuk berproliferasi menghasilkan pertumbuhan keratinosit epidermis. Perkembangan sel T menjadi sel TH2 dipacu oleh IL-10 dan prostaglandin (P6) E2. IL-4 dan IL-13 akan menginduksi peningkatan kadar IgE yang diproduksi oleh sel B. Respons sistemik Perubahan sistemik pada DA adalah sebagai berikut : - Sintesis IgE meningkat. - IgE spesifik terhadap alergen ganda meningkat. - Ekspresi CD23 pada sel B dan monosit meningkat. - Respons hipersensitivitas lambat terganggu - Eosinofilia - Sekresi IL-4, IL-5 dan IL-13 oleh sel TH2 meningkat - Sekresi IFN- oleh sel TH1 menurun - Kadar reseptor IL-2 yang dapat larut meningkat. - Kadar CAMP-Phosphodiesterase monosit meningkat disertai peningkatan IL-13 dan PGE2 Sawar kulit Umumnya penderita DA mengalami kekeringan kulit. Hal ini diduga terjadi akibat kadar lipid epidermis yang menurun, trans epidermal water loss meningkat, skin capacitance (kemampuan stratum korneum meningkat air) menurun. Kekeringan kulit ini mengakibatkan ambang rangsang gatal menjadi relatif rendah dan menimbulkan sensasi untuk menggaruk. Garukan ini menyebabkan kerusakan sawar kulit sehingga memudahkan mikroorganisme dan bahan iritan/alergen lain untuk melalui kulit dengan segala akibat-akibatnya. Faktor lingkungan Peran lingkungan terhadap tercetusnya DA tidak dapat dianggap remeh. Alergi makanan lebih sering terjadi pada anak usia <5 tahun. Jenis makanan yang menyebabkan alergi pada bayi dan anak kecil umumnya susu dan telur, sedangkan pada dewasa sea food dan kacang-kacangan. Tungau debu rumah (TDR) serta serbuk sari merupakan alergen hirup yang berkaitan erat dengan asma bronkiale pada atopi dapat menjadi faktor pencetus DA. 95% penderita DA mempunyai IgE spesifik terhadap TDR. Derajat sensitisasi terhadap aeroalergen berhubungan langsung dengan tingkat keparahan DA. Suhu dan kelembaban udara juga merupakan faktor pencetus DA, suhu udara yang terlampau panas/dingin, keringat dan perubahan udara tiba-tiba dapat menjadi masalah bagi penderita DA. Hubungan psikis dan penyakit DA dapat timbal balik. Penyakit yang kronik residif dapat mengakibatkan gangguan emosi. Sebaliknya stres akan merangsang pengeluaran substansi tertentu melalui jalur imunoendokrinologi yang menimbulkan rasa gatal. Kerusakan sawar kulit akan mengakibatkan lebih mudahnya mikroorganisme dan bahan iritan (seperti sabun, detergen, antiseptik, pemutih, pengawet) memasuki kulit.

Eczema: An Overview and Update Vincent St Aubyn Crump February 2009

Introduction
Atopic eczema or atopic dermatitis in children, along with the other atopic diseases, asthma & hay fever (allergic rhinitis), has considerably increased in Western population over the last 30 years (almost tripled). The prevalence is about 1020% of children under the age of 14 years, and 2-10% in adults. This very common condition has a significant emotional, social and economic impact on the sufferer and his/her family, and thus it is important for all healthcare clinicians to be familiar and up-to-date with the disease and its therapeutic management based on Evidence.

Definition
Stedmans medical dictionary defines Eczema as: Generic term for inflammatory conditions of the skin, particularly with vesiculation in the acute stage, typically erythematous, edematous, papular, and crusting; followed often by lichenification and scaling and occasionally by duskiness of the erythema and, infrequently, hyperpigmentation; often accompanied by sensations of itching and burning; the vesicles form by intraepidermal spongiosis; often hereditary and associated with allergic rhinitis and asthma. This definition, like most definitions of eczema, to a large extent is defining atopic eczema, which will also be the focus of this paper, but for completeness and to assist in differentiating AD from the other types of eczema, the other types of eczema will be mentioned in the differential diagnosis of Atopic Eczema towards the end of this paper as well. Some writers use the classification of endogenous eczema to mean atopic eczema and exogenous to include irritant and allergic contact dermatitis. Others classify the patients with AD who are allergic as extrinsic and those without as intrinsic eczema. Atopy is defined as a form of allergy in which there is a hereditary or constitutional

tendency to develop hypersensitivity reactions. This tendency to produce specific IgE responses to allergens is associated with atopic eczema, but up to 40% of individuals with the disease phenotype may not be atopic. This makes continued use of the term atopic eczema somewhat problematic. A more useful nomenclature of Atopic eczema / dermatitis syndrome (AEDS), which was proposed by the European Academy of Allergology and Clinical Immunology (EAACI) Nomenclature Task Force in 2001 has been updated by the World Allergy Organization in 2004.( Ref Johansson et al, JACI, 2004). The new nomenclature is based on the mechanisms that initiate and mediate allergic reactions. The term eczema is proposed to replace the provisional term Atopic eczema / dermatitis syndrome (AEDS). The term atopy should not be used until an IgE sensitization has been documented by IgE antibodies in the blood of a person or a positive skin prick test to common environmental allergens such as dust mites, pollens , or cat. The term eczema can therefore be split into atopic eczema and non-atopic eczema. This WAO nomenclature further classifies contact eczema as follows:

Delayed hypersensitivity caused by close contact with low-molecularweight chemicals (like nickel) which provoke a predominantly TH1 lymphocytemediated allergic contact dermatitis. The non-allergic variety can also be described by terms like irritant contact dermatitis.

Intrinsic vs Extrinsic Atopic Dermatitis


Intrinsic (non-allergic) Physical exam Frequency of AD Family history Age of onset Association with other atopic disease (asthma, hay fever) Serum IgE level Skin prick tests or RAST to Foods & aeroallergens Triggers: Food Aeroallergens Irritants Cytokine profile II-4 comparable ~25% Yes Late Rare Normal Negative

Extrins

comparab ~75% Yes

Early (ch

Common High Positive

No No Yes Low

Yes Yes Yes High

Atopic hereditary is less predictive for AD than sensitization to common food and inhalant allergens in early childhood.

Case 1: Atopic Eczema secondary to egg allergy


Cade developed eczema on cheeks at 6 weeks while he was being breast-fed. Mom suspected that he was reacting to her breast milk since she thought at times he was very unsettled after feeding. At 2 months he had his first attempt at a cows milk formula and spat it out and developed peri-oral urticaria. Mother assumed a cows milk allergy and decided to breast-feed only. Despite exclusive breast-feeding the eczema progressively got worse. It required twice daily hydrocortisone creams and intermittent locoid cream to keep it moderately controlled. At 6 months when he came to see me, he had chronic eczema on his cheeks in his flexures and also few small urticarial plaques on his trunk. Skin Prick Test: Milk=4mm, Egg=12mm, wheat=0, soy=0, peanut=6mm House dust mites=0, cat=0, dog=0. Management and Progress Mother was told to eliminate eggs and peanut from her diet as well as the milk which she had been eliminating for the last 4 months. Weaning onto a hypoallergenic formula was recommended, but mom preferred to continue breast-feeding (with omission of milk and eggs from her diet) for another 3 months. In 2 weeks she was able to reduce the hydrocortisone to alternate days and the skin was free of eczema.

Case 2: Contact Dermatitis to several agents used to treat eczema, masquerading as atopic eczema
Glenys is a 51 yr-old non-atopic female who developed eczema for the first time 2 years prior to her consulting me. The rash started on her hands and then gradually spread to limbs, then trunk then involved entire body, including her face. She has seen numerous doctors and alternative practitioners and tried several topical steroids including Locoid, which she though made the rash much worse. She also tried several antihistamines and several different herbal creams and supplements. She had moderate benefit from a 2 month course of prednisone. At one stage was prescribed fluoxetine, which she took for 3 months and thought that it gave the best relief to the intense itching.

Medications: A herbal cream containing tea tree oil. Multivitamins and flaxoil which she has been on for 18 months. Of significance, she was also using a shampoo containing chamomile. On Examination: patches of chronic lichenified eczema on legs, and trunk. There was evidence of excoriations especially on legs. Skin Prick Test: were negative to 20 common environment and food allergens. Patch Test: Positive to fragrance 1, tea tree oil and compositae at 48 hrs and 72 hrs and weak positive reactions to budesonide hydrocortisone butyrate and tixocortal pivolate at 72 hrs. Extended steroid patch test showed that she was tolerant to mometasone. Diagnosis: Allergic contact dermatitis to tea tree oils, fragrances and steroids. Management: her eczema improved after stopping her herbal cream and using mometsone ointment and a fragrance-free moisturizer.

Pathogenesis of Atopic Dermatitis (AD)


The hallmarks of atopic dermatitis are a chronic, relapsing inflammation of the skin, and the current thinking is that this is due to a defect in the epidermal barrier function that leads to dry skin, and IgE-mediated sensitization to foods and aeroallergens. One of the most exciting recent developments in our understanding of atopic eczema has been new research suggesting that the primary defect in AD is with the (physical) barrier function of the epidermis, leading to the secondary immunologic and inflammatory changes instead of the primary defect being immunologic. Genetics of Atopic dermatitis Atopic dermatitis is a complex genetic disease that arises from gene-geneenvironment interactions. The concordance rate for AD is 15% for dizygotic twins, but as high as 77% among monozygotic twins.

Atopic Dermatitis: A Skin Barrier Disease


Barrier Function of the skin An intact epidermis is a prerequisite for the skin to function as a physical and chemical barrier. The barrier is the stratum corneum, which forms a brick and mortarlike structure of the upper epidermal layer. An alteration of the barrier that causes

increased transepidermal water loss is the hallmark of atopic dermatitis. For a long time efforts to understand the etiology and pathophysiology of atopic dermatitis concentrated on the immune system. Due to very important recent discoveries in the last few years increasing attention has been paid to the barrierforming epidermis.

The innate immune system in Atopic dermatitis


The epithelial cells are the first line of defense between the skin and the environment. The epithelial sensing structures for pathogens are abnormal in AD, which is one of the reasons bacterial, viral and fungal infections are more common in patients with AD.

Triggers for atopic eczema


In understanding the pathogenesis (hopefully leading to better management) of atopic eczema it is important to remember that it is a multifactorial disease with multiple triggers. The triggers also vary depending on the genetics, age, environment and even the psyche (mindset) of the individual. Therefore, not every patient will react to every trigger. The most important triggers based on evidence based medicine include:

Dry skin (almost universal due to defective barrier function): - Climate: winter, excess sweating - long frequent hot showers. Staph infection (and other microbes) Food allergy in infants* Irritants - soaps, detergents, wet work - cigarette smoke - clothing: wool, synthetic fibers - habitual scratching. Environmental allergens (house dust mites, pollens, pets) Emotional stresses (school exams, work pressures, relationship problems) Iatrogenic - Irritant or allergic contact dermatitis to topical treatment Hormonal: Pregnancy and menstrual cycle.

Atopic Dermatitis stands at the frontier between allergy and autoimmunity About 25% of adults with AD have IgE antibodies against self-proteins. It is believed that scratching damages skin cell, releasing autoantigens that induce IgE autoantibodies.

Evidence based medicine on what causes Worsening of Eczema

Food allergy in children suffering from atopic eczema There should no longer be any controversy in the fact that food is a significant trigger for eczema in infancy. Studies showing prevalence of food allergy (proven by DBPC food challenges) in children with eczema: Author Sampson & McCaskill Burks et al Sampson Burkes Niggeman et al Eigenman & Calza Year 1985 1988 1992 1998 1999 2000 n 113 46 320 165 107 74 Food Allergy (%) 56 33 63 39 51 34

Staph Aureus and Atopic Eczema


S. aureus rarely colonises normal skin. Only 2% of adolescents and adults are colonized in non-specialized skin sites, although this increases to 35% in the anterior nares and 5-15% in the axillae, perineum and toe webs. This is in contrast with almost universal colonization among atopic dermatitis patients. Super antigens in AD. Numerous studies have shown that superantigens produced by staph aureus play a central pathogenic role in AD. These enterotoxins are more potent than most antigens at stimulating the immune system.

Superantigens trigger mast cell degranulation directly and amplify IgEmediated allergic reactions. Superantigens induce dermatitis on application to skin by patch testing.

The importance of s aureus colonization in AD is supported by the observation that not only patients with impetiginised AD, but also AD patients without superinfection, show a synergistic clinical response to combined treatment with antistaphylococcal antibiotics and topical steroids.

House dust mites and aeroallergens causing eczema


Three provocation studies suggest an association between exposure and flares, and this evidence is also supported by 2 patch test studies.

Stress causing eczema


Kimata studied the impact of road traffic, video games and ringing mobile phones on wheal response and neuropeptides in eczema (not eczema severity) in 2 provocation case control studies. In all 3 groups, increased wheal responses, substance P, VIP, and nerve growth factor were increased in the eczema group but not in controls.

Effect of UV radiation on atopic eczema


Deguchi H et al felt that sun exposure is an aggravating factor responsible for the recalcitrant facial erythema in adult patients with atopic dermatitis, however the result of this study of sun exposure on an unselected group of patients with recalcitrant facial eczema is unclear.

Diagnostic approach
Atopic eczema or atopic dermatitis is a common inflammatory, chronically relapsing, extremely pruritic skin disease. It has a wide spectrum of dermatologic manifestations. There is no definitive gold standard for the diagnosis of atopic eczema. and uniformity in the use of diagnostic criteria is lacking From a systematic review looking at several sets of criteria the UK Diagnostic Criteria were found to be the most extensively validated. However, there is room for improvement in methodological design for future intervention studies, but I think it is probably the best we have at present. A carefully taken history using the UK Diagnostic criteria followed by a full examination of the patient should diagnose most cases of true atopic eczema.

The UK Diagnostic Criteria for Atopic Dermatitis


Must have an itchy skin condition over the past 12 months, PLUS 3 or more of the following:

Onset below the age of 2 History of flexural involvement (around the eyes, around the neck, front of elbows, behind knees, front of ankles) Generally dry skin Personal or (in children under 4 years) allergic disease in parents or siblings Visible flexural dermatitis (around the eyes, around the neck, front of elbows, behind the knees, front of ankles).

Clinical Features of Atopic Dermatitis (AD)

AD usually begins early in life; 45% of al cases begin within the first 6 months of life, 57% of cases begin by age 2 years, and 87% of cases by the age of 5 years

The principal feature of AD is pruritus, which is universally present (almost 100% negative predictive value), and scratching is a major factor in the pathogenesis of the acute and chronic lesions. If it does not itch its probably not eczema Early lesions of AD are erythematous and dry with small papules, mild scaling, and areas of excoriation. Lesions that are moist and oozing or those with intense erythema suggest the possibility of superficial secondary infection. Chronically affected areas show accentuated skin lines and thickening of the skin (lichenification) and post-inflammatory pigment abnormalities are common (especially in dark skin). The pattern of distribution of AD lesions changes with age. Areas affected in infants include the cheeks, trunk and extensor surfaces of the extremities. The area around the nose is never involved, and this headlight sign is characteristic of AD. During childhood and adolescence, the distribution shifts to the flexures and the neck. The severity of AD tends to decrease after childhood, although occupational eczema and increased skin sensitization is common.

Other types of eczema that is often confused with AD


Eczema in the broadest sense (inflammation of the epidermis and dermis) is a component of many skin diseases. Despite this, eczema can be very easily diagnosed visually. The real problem is usually in differentiating the different types of eczema. Some find it easy to classify eczema (dermatitis) into those diseases that are caused by external factors (exogenous dermatitis), namely irritant contact dermatitis and allergic contact dermatitis, and those that do not require external induction or endogenous eczema, the commonest examples being atopic eczema and seborrheic dermatitis.

Classification of Eczema: Differential Diagnosis of Atopic Eczema


Exogenous dermatitis

Contact Dermatitis - Irritant contact dermatitis - Allergic Contact dermatitis.

Endogenous dermatitis

Atopic Eczema Seborrheic Dishidrotic Dermatitis or Pompholyx Neurodermatitis or lichen simplex chronicus Nummular eczema

Ichthyosis Unclassified Eczema or Nonspecific Endogenous Eczema.

Contact Dermatitis
Contact dermatitis is the term for the type of eczema resulting from exposure to allergens (allergic contact dermatitis) or irritants (irritant contact dermatitis). Contact dermatitis accounts for at least 60% of occupational skin diseases. Seborrheic dermatitis Seborrheic dermatitis is a common, inflammatory skin condition that causes flaky, white to yellowish scales to form on oily (sebum rich) areas such as the scalp, inside the ear, the sides of the nose, between the eyebrows and the midsternal area. It can occur with or without erythema. Dishidrotic Dermatitis or Pompholyx

Other synonym is vesicular palmoplantar eczema. It causes small vesicles on the palms and sides of the fingers and soles of the feet. Intense burning or itching. Excessive sweating in affected areas. Risk factors: - stress, female gender - hot weather - Pre-existing atopy and contact dermatitis - Smoking, oral contraceptives, aspirin.

Neurodermatitis or Lichen simplex These are types of eczema that are thought to be self-induced by habitual scratching, and are usually localized. Common areas affected include, the lower legs, scrotum and vulvae. They are usually very difficult to treat and sometimes require intralesional injection of steroids and psychotherapeutics. Nummular eczema Nummular (meaning "coin-shaped") dermatitis is a form of eczema, characterized by round-to-oval erythematous plaques most commonly found on the arms and legs. Lesions start as papules, which then coalesce into plaques. Early lesions may be studded with vesicles containing serous exudates. They are usually very pruritic. Very little is known about the pathogenesis, except an increased amount of mast cells is usually found in these lesions, compared to non-lesional skin.

Ichthyosis Ichthyosis is the term used to describe continual and widespread scaling of the skin. The skin is very dry, thickened and scaled. It is associated with increased wrinkling of the palms and soles and increased skin infections. It comes from a Greek root Ichthy, meaning fish. It may be inherited (genetic) or acquired during life. The inherited forms are rare and are generally present from infancy and are usually lifelong conditions. Acquired Ichthyosis can develop at any age due to a number of medical problems, such as kidney disease.

Unclassified Eczema (UE) or Nonspecific Endogenous Eczema


The term nonspecific endogenous eczema (dermatitis) is preferred because a major criterion for diagnosis is the exclusion of exogenous contact factors. These are patients with eczema that does not fit any of the distinct patterns above. Unclassified eczema is a common type of eczema with a very poor prognosis. This is a diagnosis of exclusion. The diagnosis is made after atopic eczema, allergic contact dermatitis, seborrhoeic dermatitis and the other well defined forms of eczema are excluded. Differences between atopic eczema, seborrhoeic dermatitis and allergic contact dermatitis Probably the conditions that are most often confused with AD are allergic contact dermatitis and infantile seborrhoeic dermatitis. Infantil e Allergic contact Seborr dermatitis hoeic < 3 months None May involve nappy area Any +++ Localized dependng on cause +/Patch test positive Usually clears

Feature

Atopic Eczema

Age Pruritus Distribution of rash Family history of atopy Skin test or RAST Prognosis

>2-3 months ++++ Spares nappy area

Often positive Positive in about 75% Chronic

Often negative Usually negative Self-limiting

once trigger found

Iatrogenic eczema
In one study 2% patients tested were allergic to topical steroids and also equally (2%) to propylene glycol. Allergens associated with medications used to treat eczema include:

Allergy to Corticosteroids - The incidence of contact allergy to corticosteroids has increased dramatically since the late 1980s. Allergic Contact dermatitis due to: - fragrance in moisturisers - Vehicles in creams o Propylene glycol is present in Elide, cetaphil, and some topical steroids o An irritant reaction (burning, stinging, itching or redness within 20 minutes of applying the cream) occurs in >56% of children with atopic eczema when aqueous cream is used as an emollient, compared to only 17% of children using other emollients, according to an audit published in Pharmaceutical Journal.

Investigations in Eczema

Skin Prick Test (SPT) - Can be done to confirm atopy or to assist in the diagnosis of food allergy. A positive test to a food only confirm sensitivity and this needs to be followed up with an oral challenge (ideally double-blind). Atopy Patch Test (APT) - APT using common food allergens (like milk, eggs) applied to the skin of the upper back for 48 hours, and read again at 72 hrs, has become a very useful way of picking up non-IgE (delayed) reactions to these foods. APT was found to be more sensitive and specific method than skin prick test or RAST-type tests, in diagnosing delayed food allergy in children with AD. The combination of SPT and APT significantly enhances identification of food allergy in children with AD. Patch Test - Should be considered in all cases of AD that is not responding to conventional treatment with topical steroids and emollients, since this is the only way to diagnose a secondary allergic contact dermatitis to the topical steroids or one of the vehicles in the creams being used. Oral Food Challenges (Double-blind Placebo-controlled) - This is the gold standard for diagnosing food allergy as a trigger for atopic eczema. One of the drawbacks to this test is that it is very time-consuming and

the flare-up of eczema can be delayed outside of the observation period.

Evidence based management of Atopic Dermatitis


Good science demands independent replication of new ideas and results and abandonment of accepted theories in light of more reliable evidence. Failure to comply leads to damaging bad science. Progress of good science often requires serendipity, making discoveries by accident and sagacity of things not sought. Science and Serendipity Mark B Pepys, Clin Med 2007;7762-78

A multifaceted Approach to the Treatment of AD


A multipronged approach is required for treatment of AD. This should include:

Skin hydration Control of itching Look for and Remove triggers / exacerbating factors - Infection - Irritants - Allergens - Emotional stress Education.

Conventional Pharmacotherapy
Moisturizer and emollients
Emollients and moisturizers are used interchangeably, but technically speaking, moisturizer adds moisture to the skin and emollients soften the skin. An ideal preparation for dry skin should have both properties. Since we now know that defective skin barrier function is the primary or underlying cause of atopic eczema, it is easier to understand why moisturizers and emollients are so important in its management. It is important to emphasize to patients that they will need to make a habit of using moisturizers daily, for the rest of their life, regardless of whether their eczema is in remission or not. The faulty skin barrier causes an increase in transepidermal water loss. As a result, the corneocytes shrink and cracks open between them, permitting the penetration of irritants and/or allergens, and causing the development of eczematous lesions. Even in normal skin, repeated use of soaps and solvents produces eczematous reaction in the same way because they remove the epidermal lipids. Essentially emollients are lipid containing agents that provide a lipid film that sits on the surface of the skin and encourages the build up of water in the stratum corneum.

They do this mostly by preventing the evaporation of water from the skin surface. One study has shown that emollients may reduce the need for topical steroids by about 50%. In New Zealand there is a vast array of moisturizers / emollients to choose from, but they all work in one or more of the following ways:

Occlusive Moisturizers: These contain oils such as liquid paraffin (mineral oil), white soft paraffin, yellow soft paraffin, wool fat or lanoline, coconut oil, or emulsifying wax. They all work by providing a layer of oil on the surface of the skin, which prevents evaporation of water from the skin surface. These oils may be mixed with varying amounts of water to produce moisturizer with different properties, e.g. lotions, creams or ointments. Humectant moisturizers: contain ingredient such as urea, glycerin, lactic acid, glycolic acid, which penetrate into the stratum corneum, where they attract and retain water. They are particularly useful in very dry skin. Keratolytics: In chronic eczema there is a build up of a skin protein called keratin, which makes the skin hard and scaly. At higher concentrations lactic acid and glycolic acid act as keratolytics, which means they have the ability to break down the keratin in hardened and thickened skin. Some of the moisturizers will have these keratolytics added for this purpose.

Finding the most suitable emollient for an individual is a matter of trial and error, but some basic rules apply: Tips for choosing the best moisturizer / emollient:

The key to getting the best out of moisturizers /emollients is education. In theory greasier oil based products are more effective but these are rarely tolerated and are not used by people with mild to moderate eczema. Lotions are mixtures of oil in water, and are light & non-greasy, and have a cooling effect. They are good for mildly dry & weeping eczema. They are also good for hairy areas, such as scalp. Creams are also mixtures of oil in water, but slightly thicker than lotions. They are generally non-greasy, and easily absorbed. They are therefore more cosmetically acceptable than ointments. Ointments are thick, occlusive oil based moisturizers that is most suitable for very dry skin. Many patients dont like them , as they find them too greasy. It is best to let children choose their favorite emollient. Caregivers should specifically ask about skin reactions like stinging, burning, itching or redness after using emollients before, and avoid prescribing them. Urea-containing emollients are of great help to patients with atopic dermatitis.

How to use emollients

Emollients should be used directly after bath or shower.

It is important to emphasize the importance of using moisturizer at least twice daily. The application of moisturizer and topical steroids should be separated by at least 1 hour to avoid dilution of the steroid. If applied several times daily to the whole body children will require at least 250g per week and adults 500g per week.

Adverse reactions to emollients and moisturizers

Allergic contact dermatitis: Apart from paraffin and water, almost any ingredient of emollients may sensitize. Patch testing will help to identify contact allergens. The main sensitizers are: - Perfumes / fragrances - Preservatives (antimicrobials) - Lanoline - Propylene glycol Irritants.

Topical corticosteroids
Glucocoticoids are the mainstay of anti-inflammatory therapy in the management of chronic AD. Topical steroids will help majority of patients with AD, and absolute steroid insensitivity is unusual, but a spectrum of steroid responsiveness exists. From the observation that combined treatment of AD with antibiotics and steroids is more effective than steroids alone, this would suggest that s. aureus secrete products that can induce steroid insensitivity. Recently Leung et al made the discovery that when T-cells are stimulated with superantigens, as compared to other stimuli, they become insensitive to the immunosuppressive effects of steroids. The main advantages of topical steroids are their proven clinical effectiveness, low cost, and wide variety of preparations.

Topical Corticosteroids in NZ Classified by relative potencies


Brand name Group 1: Superpotent Clobetasol propionate 0.05% Group 2: High potency Betmethasone diproprionate 0.05% Group 3: Mid to high potency Betamethasone dipropionate 0.05% Group 4: Mid potency Mometasone furorate 0.1% Generic name Dermol Diprosone Diprosone Elocon Elocon Betnovate, Beta Vehicle Ointment, Cream Ointment Cream Ointment Cream Ointment, Cream

Group 5: Mid to low potency Hydrocortisone butyrate 0.1% Group 6: Low to mid potency Clobetasone butyrate 0.05% Group 7: Low potency Hydrocortisone 0.5%, 1%

Locoid Eumovate Aristocort

Cream Cream Cream Cream, Ointment

Principles of prescribing Topical Steroids


Amount of steroids prescribed Adult: 30 g for whole body once

3g for head and face 3g for an arm 6g for a leg 9-12g for the trunk.

Fingertip units for application of topical steroids


One fingertip unit is the amount of cream that is squeezed out of a standard 5mm size nozzle along an adult fingertip. Two fingertip units is about the same as 1gm of topical steroids. Choice of Steroid class by disease severity and site Potency class Low potency Mid potency Potent Disease/site Ezcema of face Flexural eczema in babies Eczema elsewhere in children and flexures Lichenified eczema Discoid Eczema Seborrhoeic dermatitis of trunk Lichen simlex Discoid eczema Eczema of palms and soles

Superpotent

Adverse effects of topical steroids


The local side effects of using potent steroids for long period of time (such as striae, skin atrophy, telangiectasia, perioral dermatitis, erythema, acne, glaucoma and cataract) are well described, and well known to all of us and will not be discussed any

further. Probably what is not so well known is the increasingly recognized side effect of allergic contact dermatitis to the steroid molecule. Contact allergy to topical corticosteroids is sufficiently common to justify their inclusion for patch testing in the standard series and tixocortol pivalate and budesonide have been recommended as contact allergy markers.

Rational approach to treating staph infection in AD


Staph colonization rates are lower in clinically uninvolved skin than in lichenified or inflamed skin, and highest in acute weeping lesions, with the density of colonization being roughly proportional to the severity of eczema.

Staph Infection & AD


Staph is found on 90% of AD skin vs 5% of non-AD skin The majority of AD staph produce superantigens, which induces inflammation T-cells activated by superantigens are steroid insensitive Combination of antibiotics/corticosteroid therapy is more effective than either therapy alone.

Oral Antibiotics in Eczema


Signs of bacterial infection in atopic eczema include:

Weeping Crusting Pustules or cellulitis A sudden worsening of the eczema.

In these cases oral antibiotics should be prescribed. In New Zealand flucloxacillin and dicloxacillin are commonly prescribed. In case of penicillin allergy erythromycin is used. Swabs for bacteriology are always a good idea, but are particularly useful if patients do not respond to treatment, in order to identify antibiotic resistant strains of S. aureus or to detect additional streptococcal infection. Dietary treatment of childhood atopic eczema (EBM) In a systematic review Fiocchi et al looked at 14 prospective studies looking at dietary intervention in the management of childhood AD. Allergenic food exclusion claimed efficacy in 13 of the 14 studies and was most useful n infants, in patients with elevated IgE levels and/or multiple food sensitization and in patients with a diagnosis of food allergy.

Topical Immunomodulators (Tacrolimus and pimecrolimus (elidel)


Tacrolimus (which is not currently available topically in NZ) is probably as strong as betamethasone valerate (potent steroid). NICE guideline recommends tacrolimus for moderate to severe eczema that has not responded to appropriate potency topical steroids. Pimecrolimus (Elidel): is less potent than tacrolimus. There is some evidence that it prevents flares of atopic eczema. It is useful for head and neck eczema. Despite the concerns expressed by the US FDA about their potential to cause malignancies, to date there are no data supporting an increased incidence of cutaneous malignancies or lymphoma in patients treated with these drugs. In New Zealand Elidel is recommended for short-term or intermittent long-term treatment of AD in patients >= 3 months when topical steroids are ineffective, intolerable or inappropriate. My personal experience is that it is not very effective for treating flare-ups, but better at preventing eczema of the face and neck (part of the maintenance regimen).

Do oral antihistamines stop the itch of AD? The Evidence


There are no good studies investigating the efficacy of oral antihistamines in AD. The evidence to date is that it does not relieve the itch, but can be useful if they have sedating properties. Infants with eczema that is being triggered by food allergy will often have superimposed urticaria with their eczema and can have dramatic improvement from oral non-sedating antihistamines.

Systemic Treatment of Severe Atopic Eczema:


Immunomodulating pharmacotherapy
Cyclosporin A Cyclosporine usually leads to prompt relief of symptoms within 2 weeks of starting treatment. However, following cessation of therapy, relapse within 6 weeks is common. Adverse effects include renal toxicity, hypertension, nausea and abdominal pain. Systemic Steroids

2 small RCT looked at systemic steroids in children. Unfortunately no data was identified for prednisone, which would be the standard systemic steroids in NZ. Anecdotally, the big problem with systemic steroids in treating atopic eczema is the frequent rebound on stopping. Azathioprine Azothiaprine can be very effective in treating severe AD, but is a slower acting medication (4 6 weeks), and has the potential to cause bone marrow suppression, hepatotoxicity, squamous cell carcinoma and lymphomas. Mycophenolate mofetile This drug can lead to improvement in AD after 8 and 12 weeks of treatment. Phototherapy Phototherapy has an anti-inflammatory effect on the cells of the immune system. Types of UV therapy that have been used successfully in treating AD include psoralen and UVA (PUVA), combination of broadband UVA/UVB, broadband UVA, broadband UVB, narrowband UVB (311nm), and UVA1 (340-400nm). Adverse effects include premature aging of the skin and increased likelihood of squamous cell carcinoma and melanoma.

Prevention of Atopic Dermatitis (AD)


In the case of primary prevention (preventing AD in high risk individuals), there is no evidence that exclusive breastfeeding, infant avoidance of allergens, mother avoidance of certain foods or aeroallergens will prevent the development of AD. There are some conflicting reports of treatment with probiotics, particularly Lactobacillus, during pregnancy or infancy may delay the onset of AD in infants and children.

Education in evidence based management of AD


Some recent studies have shown that patient education through a nurse practitioner may be able to improve patient concordance and, as a consequence, can reduce the unnecessary use of topical steroids in atopic eczema. The studies showed that the education requires time, that is often not available in a busy clinic. Basic education in management of atopic dermatitis should include:

Skin barrier function is abnormal and Importance of daily emollients for life Control vs cure Identify the individual triggers including foods Signs of infection

Provide written individual treatment plan Offer educational websites or support groups.

Advice against career choices that may exacerbate AD or lead to hand eczema:

Hairdresser Cook or cleaner Butcher Factory worker (wet work).

Identify and discuss hidden concerns (what patients / parents often arent telling you):

They are looking for a cure arents fear that the child will be permanently scarred They have steroid phobia and does not like long-term use of antihistamines and therefore compliance is an issue They are concerned about food allergy being a cause They are keen to try or are trying alternative therapies.

Consider a therapist /counseling if there is:


Significant family distress or dysfunction Excessive absence from school (especially if out of proportion to AD severity Poor coping skills (family or child) Evidence of depression, obsessive-compulsive disorder, or neurotic scratching / excoriations.

Unconventional Treatment of AD and evidence for using them (or not):


Immunotherapy for Atopic Eczema It has been shown that reduction of the house dust mite allergen load is effective as preventative and therapeutic measure in atopic Eczema. Furthermore, recent data indicate that specific immunotherapy with house dust mite allergen is effective in patients with atopic eczema. Wet wrap bandages Wet wraps can occasionally be a helpful treatment in infants and young children where limb scratching is a major problem. It involves the application of a weak topical steroid, like 1% hydrocortisone ointment or just emollients under an inner wet and an outer dry layer of cotton tubular bandage or garment. At present clear evidence

for wet wraps is very limited. There is some concern about side effects, with regards to applying steroids under occlusion in children. From my clinical experience, wet wraps with 1% hydrocortisone is particularly helpful to break the itch-scratch cycle in kids who have developed habitual scratching.

Alternative Medicines in Atopic Dermatitis


Alternative medicine has been termed as a means of therapy or examination that has no scientific basis, and no effective or diagnostic reliability validation has been demonstrated. The use of such medicine is increasing, without the benefit of controlled trials on the subject. Alternative medicines for treating eczema are very popular in New Zealand. Some of the alternative remedies used in New Zealand to treat eczema include:

Chinese Herbs Homeopathy Evening primrose oil Studies have failed to show benefit Dietary restriction without scientific testing (Alternative testing).

Chinese herbal creams Parents consider herbal remedies as natural products that are usually derived from plants, and therefore should be harmless. Some of these products are also very effective in clearing stubborn eczema. In 1999 Keane et al analyzed 11 herbal creams obtained from children attending dermatology outpatient clinics in the UK. Eight of the 11 creams contained dexamethasone at concentrations inappropriate for use on the face of children. In 2003 the Ministry of Healths Medicines Safety Authority in New Zealand, (Medsafe) recalled a herbal cream that illegally contained potent steroids (clobetasol propionate ) and ketaconazole. Again in 2005 herbal products were recalled for containing betamethasone.

Summary of Treatment options for Atopic Eczema


Mild AD Moderate AD Severe AD Access Severity and look for triggers at every visit Emollients and Education Mild Potency topical Steroids Moderate potency Topical steroids Elidel Antibiotics (?) Potent topical steroids Elidel Wet Wraps Antibiotics (?)

Antihistamines

Phototherapy (UV-B and/or UVA) Systemic therapy:

Wet Wraps

Cyclosporin Oral steroids Azathioprine Antiseptic solutions Psychotherapeutics (?)

Recommendations for referral for Specialist care


Uncertainty of the diagnosis If severe infection with herpes simplex (eczema herpeticum) is associated with systemic symptoms urgent referral is recommended If secondarily infected eczema is not responding to appropriate oral antibiotics plus adequate potency topical steroids If food allergy is suspected in infancy If eczema is causing significant social or psychological problems If contact dermatitis is suspected and confirmation is required by patch testing.

Follow-up:
Checklist for recalcitrant eczema: Why is the eczema not improving?

Lack of Compliance due to steroid phobia Food Allergy in infants Secondary infection (staph, viruses, fungi) Iatrogenic Dermatitis due to - Co-existence of a contact dermatitis related to creams being used - Irritant dermatitis. Emotional / Psychological stresses causing habitual scratching More education needed: especially on the important role of emollients.

Some Key References:


Brenninkmeijer EE et al. Diagnostic Criteria for Atopic Dermatitis: A Systematic review. Br J Dermatol. 2008;158(4): 754-765 Rance F et al Food allergy in children suffering from atopic eczema Pediatr Allergy Immunol 2008: 19: 279-284 Williams HC, Burney PG et al. The UK working Partys Diagnostic Criteria for Atopic Dermatitis I. Derivation of a minimum set of discriminators for atopic dermatitis. Br J Dermatol 1994;131:383-96

Eigenmann PA et al Prevalence of IgE-mediated food allergy among children with AD. Pediatrics 1998;101:E8 Schmitt J et al Systemic Treatment of Atopic Eczema: A Systematic review. Acta Derm Venerol 2007;87: 100-111 B Li L-f et al Prognosis of unclassified eczema: a follow-up study. Arch Dermatol. 2008;144(2): 160-164 Sichere SH et al Food hypersensitivity and AD: pathophysiology, epedimiology, diagnosis, and management. J Allergy Clin Immunol 1999;104: S114-S122 Ottens S et al More than 50% of positive challenge with foods are associated with late eczematous reactions in AD Allergy Clin Immunol Int 2006 Tupker RA et al Induction of eczema by inhalation of dust mite. J Allergy Clin Immunol 1996; 97:1064-70 Wanukul S et al Eczematous skin reaction from patch testing with aeroallergens in atopic children with and without atopic dermatitis. Pediatr Dermatol 1993; 10: 209-13 Hoare C, Li Wan Po A et al., Systematic review of treatment for atopic eczema. Southampton National Coordinating Centre for HTA, 2000 (Health Technology Assessment; Vol 4) Wolkerstorfer A, et al Efficacy and safety of wet wrap dressing in children with severe atopic dermatitis: influence of corticosteroid dilution. Br J Dermatol 2000;143: 999-1004 Novak N, Bieber T. Allergic and non-allergic forms of atopic diseases. J Allergy Clin Immunol 2003;112:252-262 Burden AD, Beck MH. Contact Hypersensitivity to topical steroids. Br J Dermatol. 1992 Nov;127(5):497-500 Wanukul S et al Eczematous skin reaction from patch testing with aeroallergens in atopic children with and without atopic dermatitis. Pediatr Dermatol 1993; 10: 209-13 Cork ML et al An audit of adverse drug reactions to aqueous cream in children with atopic dermatitis. The Pharmaceutical Journal. Nov. 2003. Vol.271

PATOGENESIS Seperti dibahas diatas anafliaksis alergi selain berdasarkan mekanisme imunologik juga dapat disebabkan oleh ketidakseimbangan sistem saraf otonom. Sistem parasimpatik (kholinergik) dan sistem simpatik (adrenergik) mempunyai efek yang berlawanan terhadap organ sasarannya, sehingga keadaan inipun akan mempengaruhi terhadap keseimbangan antara sel mediator dan sel sasarananya (otot polos). Reaksi alergi dimulai ketika alergen melewati barier epitel dan atau endotel dan kemudian berinteraksi dengan 2 molekul antibodi IgE sitotropik yang berikatan dengan sel (cell bound IgE antibodies) sehingga menimbulkan rangkaian peristiwa biokimia. Kekuatan barier alami seperti kulit atau saluran cerna harus dapat ditembus, dan alergen ini harus mencapai sel yang tersensitisasi di jaringan (sel mast) atau darah (basofil).6 Peristiwa tersebut termasuk aktivasi proesterase (E) menjadi esterse aktif () yang menyebabkan agregarsi mikrotubuli dalam sitoplasma mastosit. Mikrotubuli angat diperlukan untuk pergerakan butir-butir yang mengandung beberapa mediator tertentu ke arah tepi sel sehingga dapat dilepaskan ke luar sel, yaitu histamin, SRS-A dan ECF-A. Sebaliknya pembentukan mikrotubuli akan dihambat oleh pembentukan cAMP dari ATP oleh adenilsiklase karena mikrotubuli akan bercerai-berai. Lagi pula cAMP dalam sito plasma dalam keadaan seimbang dengan konsentrasi cGMP. Dengan demikian degranulasi tersebut tergantung dari konsentrasi cAMP dan cGMP. Maka apapun yang menyebabkan kenaikan kadar cGMP atau penurunan cAMP akan menimbulkan degranulasi. Perangsangan saraf parasimpatis (misalnya N. Vagus) akan mendorong produksi asetilkolin yang akan mengubah enzim guanilatsiklase menjadi aktif. Enzim aktif ini akan mengubah GTP menjadi cGMP. Sedangkan efek perangsangan parasimpatis ini akan dihambat oleh antagonisnya yaitu atropin. Dengan mekanisme yang sama perangsangan saraf simpatis akan mempengaruhi konsentrasi cAMP. Perangsangan saraf simpatis sendiri akan mengakibatkan 2 jenis efek karena adanya 2 jenis reseptor yang berbeda. Perangsangan melalui reseptor -adrenergik akan menghasilkan penurunan cAMP dalam sel mastosit, sedangkan perangsangan melalui -adrenergik akan meningkatkan konsentrasi cAMP yaitu melalui pengaktifan enzim adenilatsiklase sehingga ATP akan diubah menjadi cAMP. Dengan demikian jelaslah bahwa sistem saraf otonom dapat mempengaruhi degranulasi mastosit melalui pengaturan cGMP dan cAMP. Namun sebaliknya juga dapat diatur oleh adanya aktifitas enzim fosfodiesterase yang akan menghancurkan keduanya cAMP dan cGMP. Reseptor untuk adrenergik dan dapat dirangsang oleh molekul yang sama dengan efek berbeda. Norepinefrin yang dihasilkan oleh ujung saraf noradrenergik misalnya akan mempengaruhi reseptor dengan efek yang berbeda. Perangsangan reseptor akan lebih besar efeknya dari pada perangsangan reseptor . Sebaliknya epinefrin yang dihasilkan oleh kelenjar adrenal akan memberi efek lebih besar apabila merangsang reseptor . Belakangan ditemukan adanya 2 jenis reseptor adrenergik 1 dan 2 yang penyebarannya pada sel-sel jaringan tidak merata. Misalnya reseptor 2 lebih banyak terdapat pada jaringan paru-paru. Keadaan ini dimanfaatkan untuk pengobatan asma bronkhiale dengan salbutamol yang merupakan agonis untuk reseptor 2. Oleh karena keseimbangan siklik nukleotida juga mempengaruhi keadaan sel sasaran, maka dasar pengobatan alergi juga memperhatikan keadaan fisiologik sel sasarannya. Apabila sel sasarannya otot polos terjadi peningkatan kadar cAMP maka otot polos tersebut ada dalam keadaan relaksasi. Keadaan tersebut juga terjadi pada sel sasaran lainnya, misalnya sel kelenjar

sehingga akan terjadi pengecilan pembuluh darah dan pengurangan sekresi kelenjar. Keadaan tersebut dapat mengrangi gejala alergi. Mekanisme kerja obat yang sering digunakan dalam mengatasi renjatan anafilaktik diantaranya: 1. Adrenalin. Adrenalin termasuk golongan adrenergik yang akan meningkatkan konsentrasi cAMP dalam mastosit sehingga terjadi hambatan degranulasi. Selain itu adrenalin mempunyai khasiat terhadap sel sasaran, yaitu: (1). Perangsangan terhadap pembuluh darah kulit, selaput lendir dan terhadap kelenjar liur. (2). Mengendurkan otot polos usus, bronkhus dan pembuluh darah otot rangka. (3). Perangsanga jantung dengan akibat peningkatan denyut jantung, kekuatan kontraksinya dan tekanan darah. (4). Perangsangan pusat-pusat pengaturan di otak, misalnya pernafasan. Kesemuanya ini kalau disimpulkan akan mengurangi gejala-gejala renjatan anafilaktik. 2. Antihistamin. Antihistamin merupakan kelompok obat-obatn yang berkerja menghambat histamin yang dihasilkan oleh mastosit. 3. Teofilin Teofilin termasuk kelompok xantin yang mempunyai khasiat mengatasi renjatan anafilaktis. Mekanisme kerjanya melalui mastosit dan sel sasarannya seperti halnya adrenalin. Teofilin menghambat kerja enzim fosfodiesterase yang akan merusak cAMP, sehingga kadar cAMP akan meningkat akibatnya degranulasi mestosit dihambat. Selain itu teofilin akan bekerja pada pusat pernafasan dan otot-otot bronkhus, lebih-lebih otot-otot brunkhus dalam keadaan kontraksi. Kesemuanya akan mengrangi gejala-gejala renjatan anafilaktik. 4. Kortikosteroid Kortikosteroid merupakan kelompok obat-obatan yang paling banyak dipakai pada penyakit radang dan penyakit imunologik. Walaupun pada beberapa binatang, pemberiannya menimbulkan kerusakan pada jaringan limfoid, namun pada manusia hal tersebut tidak terjadi. Koretokosteroid mempunyai efek menghambat radang, disamping menghambat respons imun dan menstabilkan dinding mastosit. Dengan menghambat respons imun mungkin dapat menghambat sintesis IgE.