Atopic Dermatitis Dr F Iraji Atopic Dermatitis About

Atopic Dermatitis Dr. F. Iraji

Atopic Dermatitis About 10 percent to 20 percent of all infants have eczema; however, in nearly half of these children, the disease will improve greatly by the time they are between five and 15 years of age. Others will have some form of the disease throughout their lives. interactions between environmental, immunological, genetic and pharmacological factors.

Atopic Dermatitis A strong familial inheritance pattern seems to exist for both AD and other atopic diseases, with more than half of patients with AD reporting a family history of respiratory atopy. Researchers are continuing to examine the role that chromosomal markers (chromosomal 11), eosinophilia, cell-mediated immunity, interleukins, and other inflammatory mediators play in the pathophysiology of AD

Atopic Dermatitis Immunological abnormalities associated with AD include: elevated T-cell activation; an imbalance in the Th 1/Th 2 T-cell subsets; increased production of inflammatory cytokines; elevated Ig. E levels (in the majority of cases); increased numbers of dendritic cells and mast cells; and increased numbers of eosinophils in the peripheral circulation.

Cutaneous Immune response The Langerhans cell, as well as T-cells, and keratinocytes by production of cytokines. T-cell cytokines can be divided into Th-1 cytokines, the prototype being gamma interferon, Th-2 cytokines including Interleukins-4, 5, and 10. Cutaneous diseases primarily Th-1 mediated including psoriasis and allergic contact dermatitis whereas the prototype of the Th-2 mediated disease is atopic dermatitis.

Atopic Dermatitis the presentation of antigen by dendritic cells mediated by Ig. E molecules bound to Fce. RI receptors; intrinsic defects in keratinocyte function; delayed eosinophil apoptosis; disruption of prostaglandin metabolism and the effects of Staphylococcus aureus colonisation and superantigen production.

Atopy and atopic dermatitis (AD) Worldwide increased incidence of Atopy and AD, mainly in developed countries, could be related to environmental as well as psychosocial factors. Exposure to infections very early in life and the use of probiotics of Lactobacillus rhamnosus in mothers might protect against the development of AD.

superantigens in atopic dermatitis S. aureus exacerbates or maintains skin inflammation in AD is by secreting a group of toxins known to act as superantigens. These molecules stimulate marked activation of T cells and accessory cells expressing HLA-DR.

superantigens in atopic dermatitis over half of AD patients have S. aureus cultured from their skin that secrete superantigens such as enterotoxins A, B and toxic shock syndrome toxin-1 (TSST-1).

superantigens in atopic dermatitis most AD patients make specific Ig. E antibodies directed against the staphylococcal superantigens found on their skin. These findings raise the possibility that superantigens induce specific Ig. E in AD patients and mast cell degranulation in vivo when the superantigens penetrate their disrupted epidermal barrier.

superantigens in atopic dermatitis correlation has been found between the presence of Ig. E to superantigens and severity of AD. Patients with superantigens on their skin generally have increased Ig. E levels to specific allergens.

superantigens in atopic dermatitis the combination of topical steroids with antibiotics are much more effective than either topical steroids or antibiotic therapy alone. This suggests that S. aureus secrete products which interfere with the action of steroids.

superantigens in atopic dermatitis superantigens can induce steroid resistance. Therefore antibiotics may enhance steroid action by reducing S. aureus superantigens on the skin. These data indicate that effective therapy in AD requires a combination of therapies which reduce skin inflammation and S. aureus on the skin.

The atopic itch is considered to be a fundamental symptom of atopic dermatitis (AD) to the extent that a non itching rash excludes a diagnosis of AD. substance P have been shown to modulate the function of inflammatory cells and those of the endothelium and epithelium through effects on cell proliferation, cytokine production and adhesion molecule expression.

The chemical mediators of itch substances act on the sensory receptors that respond to itch stimuli. The result of this interaction is the perception of itch at the site of mediator release.

Substance P sensory nerve-derived neuropeptide that demonstrates a number of proinflammatory bioactivities and is thought to play a role in inflammatory skin disease

Substance P The neurotransmitter responsible for carrying sensations of pain between the brain and the skin. It also stimulates vasodilatation in the arterioles and increased permeability of capillaries in the epidermis.

Substance P Stimulate mast-cell degranulation, and thus, histamine release. When injected into the skin, substance P produces the wheal-and-flare response typical of the effects of histamine on the skin - redness, swelling, and itch.

House dust mite and the Atopy patch test identification of allergens which may be responsible for the exacerbation of skin lesions in atopic dermatitis (AD) are based on the identification of specific Ig. E in the skin (prick tests) or in the serum (RAST, etc).

patch test Patch tests based on prolonged exposure of the skin to inhalants or food, aiming at the detection of delayed reactions, represent a testing modality reproducing skin responses to allergens normally occurring in AD.

patch test Problems related to patch testing in atopics mainly concern standardization of patch test modalities (exposure times and reading) and of the allergenic materials

patch test delayed skin reactivity in healthy subjects and other control populations has been poorly investigated and this hampers the understanding and the interpretation of skin responses to Atopy patch tests in patients with AD and respiratory Atopy

Major criteria (need 3 or more) Pruritus Typical morphology and distribution Flexural lichenification in adults Facial and extensor involvement in infants and children Dermatitis - Chronically or chronically relapsing Personal or family history of atopy (asthma, allergic rhinitis, atopic dermatitis

Minor criteria need 3 or more) ( Cataracts Cheilitis Conjunctivitis - Recurrent Eczema - Perifollicular accentuation Facial pallor or erythema Food intolerance Hand dermatitis – Non allergic Ichthyosis Ig. E- Elevated Immediate (type I) skin test reactivity Infections (cutaneous)

Minor Dennie-Morgan infraorbital fold Itching when sweating Keratoconus Keratosis pilaris Nipple dermatitis Orbital darkening Palmar hyperlinearity Pityriasis Alba White dermographism Wool intolerance Xerosis

Physical Acute lesions are erosions with serous exudate or intensely itchy papules and vesicles on an erythematous base. Subacute lesions are characterized by scaling, excoriated papules, or plaques over erythematous skin. In its chronic phase, skin shows lichenification and pigmentary changes (increased or decreased) with excoriated papules and nodules.

Typical AD for Infants and Toddlers Affects the cheeks, forehead, scalp, and extensor surfaces Erythematous, illdefined plaques on the cheeks with overlying scale and crusting Erythematous, illdefined plaques on the lateral lower leg with overlying scale 33

More Examples of Atopic Dermatitis Note the distribution of face and extensor surfaces 34

Typical AD for Older Children Affects flexural areas of neck, elbows, knees, wrists, and ankles Lichenified, erythematous plaques behind the knees Erythematous, excoriated papules with overlying crust in the antecubital fossa 35

Physical The pattern of disease varies based on the age of the patient. Infants: Lesions typically develop during the third month of life. Dry, red, scaly areas appear on the cheeks but spare the perioral and perinasal areas.

Physical The lips may become affected as the child smacks and licks the lips during winter months. Usually, the diaper area is spared, although infants may develop lesions and lichenification at easy to reach crevices: directly below the diaper, extensor surface of the forearm, or back of the hand. If the scalp is involved, it may be very difficult to distinguish AD from seborrheic dermatitis

Children: – Atopic dermatitis appears in areas of repeated flexion and extension (antecubital fossae, neck wrists, and ankles). Areas of high perspiration are most often affected, especially when combined with form-fitting clothing. Lesions are red, scaly, have sharply demarcated borders, and develop lichenification over time.

Adults These patients develop generalized eruptions. These are the patients whose mood and behavior are most affected by AD, especially as the disease causes social embarrassment and sleep disruption. The disease may actually remit in many of the pubescent patients.

Adults Atopic dermatitis during adulthood most commonly manifests as hand dermatitis, because adults are exposed to irritating chemicals and they wash their hands more frequently than children. Eyelid inflammation is common in adults with AD and causes patients to rub excessively at their eyes. This may cause atopic pleats (Dennie. Morgan infraorbital fold), an extra line on the lower eyelid that, although common in patients with AD, is also seen in patients without the disease

Other associations Dry skin and xerosis: A hallmark of AD, patients have rashes and severely dry skin that itches. Even infants with AD have excessively dry skin, especially in the winter months. Continued moisturized and mild soaps help with this.

Other associations – Ichthyosis vulgaris can be observed in patients with atopic dermatitis. Characterizing features are dry, rectangular scales on the extensor surfaces of the arms and legs. This condition is treated with 1% ammonium lactate lotion and often improves with age. – Hand foot dermatitis may be the only manifestation in adults and adolescents. Fissuring of the palms, soles, and fingers often occurs.

Other associations – Keratosis pilaris is an asymptomatic condition where horny follicular papules on the extensor surfaces of the upper arms, buttocks, and anterior thighs (sparing the palms and soles). Lesions may also appear on the face and may be confused with acne, especially in the adolescent patient. Treatment may be with topical steroids or ammonium lactate cream. – Hyperlinear palmar creases may be seen in patients with AD often associated with continued itching and scratching.

Other associations – Keratoconus is an elongation and protrusion of the corneal surface, which is seen in a few patients with AD. Its appearance is not associated with cataracts. – Patients with AD do have a higher likelihood of cataracts; however, most of these are asymptomatic. The appearance of cataracts may be related to the use of systemic steroids throughout the lifetime of the patient with AD. – Pityriasis alba (asymptomatic, hypopigmented scaling plaques on the face and arms) may also be seen in patients with AD. No acute treatment is indicated.

Causes Exact etiology is unknown, but several triggers have been identified. Anything that could dry the skin may exacerbate atopic dermatitis. Potential triggers include excessive bathing, swimming, hand washing, and lip licking. Contact with solvents, detergents, deodorants, cosmetics, and soaps can exacerbate the disease. Cigarette smoke has also provoked inflammation.

Causes Patients are extremely sensitive to temperature changes. They should avoid clothing that traps heat or causes sweating. They will also see increased flare-ups during times of low humidity, as dry air exacerbates the disease. Commercial humidifiers may help with the symptoms. Although no direct correlation has ever been documented, most AD show increased sensitivity to aeroallergens like dust mites. Some researchers believe these allergens can trigger exacerbations of AD, but this has not been proven.

Other Problems to be Considered Lichen simplex chronicus Seborrheic dermatitis Nummular eczema Xerotic eczema Dyshidrotic eczema Prelymphomatous Drug reactions Hyperimmunoglobulin E syndrome Photosensitivity rashes Wiskott-Aldrich syndrome

Lab Studies The diagnosis of AD is based on history and physical examination. Laboratory tests are not helpful for diagnosing atopic dermatitis; however, they may be used to exclude other disorders. Serum immunoglobulin E (Ig. E) levels usually are elevated. This may be useful for treating refractory AD with anti-Ig. E antibodies (omalizumab). This medication is not currently approved for AD treatment.

Procedures Biopsy: Pathologic findings include spongiosis with a severely damaged stratum corneum, with hyperproliferation in advanced case

Before prescribing a treatment plan a dermatologist considers the type of eczema, extent and severity of the eczema, patient’s medical history, and a number of other factors. Medication and otherapies will be prescribed as needed to: Control itching Reduce skin inflammation Clear infection Loosen and remove scaly lesions Reduce new lesions

Atopic Dermatitis: Treatment 4 Major Components Anti-inflammatory Anti-pruritic Antibacterial Moisturizer 54

Care Many patients with AD present to a clinic during acute exacerbation. Therapy is targeted toward alleviation of pruritus and prevention of scratching. ED physicians must also look for signs and symptoms of bacterial superinfection and treat accordingly.

Skin care – In the acute setting patients should be instructed to bathe once-to-twice daily using mild soaps (eg, Dove). There is no preference over showers or baths, whichever makes the patient most comfortable. – The patient should dry quickly and immediately (within 3 min) lubricate the skin. Many creams and lotions are available, and the optimal one is the greasiest the patient can tolerate.

Skin care – Creams (eg, Eucerin, Cetaphil) are preferred over lotions, as they have lower or no water content and will not evaporate off of the skin during the day. Parents may use petroleum jelly on infants, but most children and adults will not tolerate the texture

Topical steroids Acute attacks should be treated by midhigh strength topical steroids for up to 2 weeks. Medium-to-high potency topical steroids should not be used on the face or neck area because of the potential adverse effects. These are preferred over low-mid strength medications, as they better control exacerbations. Patients should apply the ointment within 5 minutes of twice-daily bathing.

Antihistamines: Physicians have been prescribing antihistamines for years to control the pruritus associated with acute AD. Little evidence exists that antihistamines help with the itching in an awake patient; however, the use of sedating antihistamines is supported to control scratching while the patient is asleep.

Systemic steroids The use of systemic steroids in the treatment of acute exacerbation of AD is controversial. Most authors reserve oral prednisone (at least 20 mg/d for 7 d) for the most severe cases, although it seems the disease quickly relapses once the medication is discontinued. Patients also tend to discontinue topical steroid creams and other treatment as they feel better, which contributes to the relapse after oral steroids are done.

Advances in the treatment of AD Topical immunosuppressive drugs (tacrolimus and pimecrolimus) and leukotriene receptor antagonists, the preventive role of systemic antistaphylococcal antibiotics, and topical moisturizers.

Topical Immunomodulators Immunosuppressive macrolides are synthesized by fungus-like bacteria of various Streptomyces strains. Of these macrolides, tacrolimus (FK 506, Prograf®, Protopic®) and sirolimus (rapamycin, Rapamune®) are natural products, whereas pimecrolimus (ASM 981, Elidel®) is semi synthetic

Topical Immunomodulators (TIMs) represent a new class of therapeutic agents, which specifically target T-cell activation through a mode of action completely distinct from that of corticosteroids. Tacrolimus (Protopic®) is the first in this new class of topical immunomodulatory agents.

Topical Immunomodulators Topical agents that can down regulate an immune response can include Tacrolimus, which acts by inhibiting early cell cycle stages of T-cell activation by blocking nuclear factor of activated T- cells in the nucleus (NFAT). Pimecrolimus also inhibits T-cell activation and both agents have demonstrated efficacy in atopic dermatitis.

Topical Immunomodulators As a consequence, the activation of T -cells is inhibited at an early stage, including the expression of inflammatory T-cell cytokines such as interleukin (IL-2, IL-3, IL-4, IL-5), granulocyte-macrophage colonystimulating factor, interferon-g and tumor necrosis factor a.

Topical Immunomodulators The effect of TIMs has also been studied on antigen-presenting cells, as well as their impact on the release of pre-formed inflammatory mediators from mast cells and basophils and it seems that their immunomodulatory properties have a positive effect on the overall immune mechanisms underlying AD.

Topical Immunomodulators TIMs bind to the same receptor within Tlymphocytes, an immunophilin referred to as the FK-binding protein (FKBP). The TIM -FKBP complex binds calcineurin, inhibiting its dephosphorylating action and thereby the nuclear factor of activated T-cells is prevented from translocating to the nucleus.

Tacrolimus (Protopic®) The first in this new class of topical immunomodulatory agents, effective for chronic actinic dermatosis, special types of psoriasis and seborrheic dermatitis etc.

Tacrolimus ointment Highly effective treatment of AD and is known to be a potent inhibitor of T-cell activation in the skin. It has recently been demonstrated that epidermal dendritic cells (DCs) isolated from untreated lesional skin of AD patients highly stimulate autologous T-cells. This activity was greatly diminished concurrent with clinical improvement during application of tacrolimus.

Tacrolimus Ointment (0. 03%-0. 1%BID) immunomodulatory effects of topical tacrolimus extend beyond its pronounced effect on T-cells located in the skin, by also positively affecting other cellular players involved in the pathogenesis of AD.

Tacrolimus ointment Furthermore, there was a concomitant decrease in the expression of Fce. RI in LCs and inflammatory dendritic epidermal cells (IDECs). Decrease in the IDEC population within the pool of epidermal DCs suggesting a reduction in local inflammation.

Pimecrolimus Cream Pimecrolimus (Elidel, ASM 981) cream 1%, a selective inhibitor of inflammatory cytokine release, was found to be safe and effective in the management of adult patients and children with atopic dermatitis. A significant improvement of eczema and relief of pruritus was observed within the first week.

pimecrolimus 1% cream safe and effective therapy in children as well as infants being able to prevent the progression and recurrence of the disease and thus offering an excellent therapeutical approach for the long-term management of atopic dermatitis.

Pimecrolimus 1% cream effectively improve eczema even in severe cases, to prevent the occurrence of eczema and to significantly reduce the incidence of recurrences as well as the use of corticosteroids in children as well as infants.

Indications of Tacrolimus It is effective in a variety of inflammatory dermatoses, specially those responsive to cyclosporin. Its main indication, however, is atopic eczema.

Efficacy Tacrolimus in atopic eczema Long term studies performed up to 12 months showed the absence of severe systemic side effects and very low or unmeasurable serum concentrations. Thus, Tacrolimus represents the first nonsteroidal anti-inflammatory drug for the use in atopic eczema since the introduction of glucocorticosteroids in the 1950.

Tacrolimus: clinical results in Atopy The era of immunosuppressive drugs in dermatology has been heralded by the introduction of cyclosporin. This drug is useful particularly for severe inflammatory skin diseases, but is ineffective on topical application. Tacrolimus is the prototype of topically active immunosuppressive macrolides. , Tacrolimus is effective in psoriasis only under occclusion , skin ulcers.

Topical calcineurin inhibitors: are available for patients older than 2 years. These medications may be used all over skin surfaces (including face, neck, and hairline) because they do not have the side effects seen with topical steroids. Evidence supports the twice -daily use of these creams during acute exacerbation of AD, and some evidence exists to support use up to 4 years. The long-term side effects (including the possibility of increased risk for malignancy) have not fully been elucidated. Side effects of tacrolimus include burning and stinging on broken skin.

Oral immunosuppressive agents: Patients with refractory AD may benefit from oral immunosuppressive agents, such as cyclosporine A. This medication is effective in treating severe AD in the acute setting. It is not recommended for longterm use.

Light treatment (phototherapy) is another option for unresponsive and severe eczema. People with eczema often comment that sunshine improves their skin, and light treatment is sometimes offered in hospital dermatological centres. UVB light therapy can be extremely beneficial, as can PUVA, which involves a combination of a drug called psoralen taken by mouth, followed two hours later by UVA light treatment. Short-term side effects of light treatment include sunburn-like reactions, and potential long-term side effects include premature skin ageing and skin cancer.

Alternative treatments Gamolenic acid (evening primrose extract) is an alternative remedy sometimes used to treat eczema. It is thought that it might work by increasing the levels of the essential fatty acid that may be deficient in, and perhaps responsible for the symptoms of, atopic eczema. Two products containing gamolenic acid, . Evening primrose oil is still available as a dietary supplement from health food shops for those who wish to try it, but it is no longer a licensed medicine for the treatment of eczema. A three month trial should be long enough to produce benefits.

Traditional Chinese herbal medicines are another alternative treatment for eczema, though at present it is unclear whether they do more harm than good. Results from several studies have suggested that patients with atopic eczema benefit from these therapies, but there is also concern about the side effects of some of the herbs on the liver and heart. Cases of corticosteroids being illegally added to Chinese herbal creams have also been reported, and this is hard to monitor as the production of such herbal products is not standardised or regulated. For these reasons it is recommended that Chinese herbal remedies should only be used under specialist supervision.

: Further Inpatient Care Few patients with AD will require hospitalization. Patients with cellulitis or severe secondary infection may require IV antibiotics and sedation. Deterrence/Prevention: The mainstay of treatment for AD is prevention of outbreaks. Patients should continue to take short showers/baths followed by immediate hydration of skin with emollients even during rash-free times. They should also continue to avoid any triggers that my exacerbate AD.

Complications Because of frequent scratching and fissuring of the skin, secondary infection is not uncommon. Suspect infection in persons with fever, surrounding erythema, or yellow crusting of the lesions. In severe exacerbations, it may be difficult to identify signs of secondary infection; empirical treatment for infection may be warranted.

Eczema herpeticum (Kaposi varicelliform eruption) can be a life -threatening complication of atopic dermatitis. Most commonly seen during an initial infection with HSV in a child whose AD has recently healed, the vesicular eruption can progress from mild to fatal quickly.

Eczema herpeticum This disease should be suspected in any child with a remote history of AD, high fever, lymphadenopathy, and vesicular eruption, especially of the face. Affected patient should be treated with acyclovir (dose appropriate for age) and monitored closely. Atrophy or striae occur if fluorinated corticosteroids are used on the face or in skin folds. Systemic absorption of steroids may occur if large areas of skin are treated, particularly if high-potency medications and occlusion are combined.

Prognosis About 90% of patients with AD have spontaneous resolution by puberty. Adults who continue to have the disease usually have localized dermatitis (eg, chronic hand or foot dermatitis, eyelid dermatitis, lichen simplex chronicus. (

Prognosis Unfavorable prognostic factors for AD (in order of relative importance) include the following: – Persistent dry or itchy skin in adult life – Widespread dermatitis in childhood – Family history of AD – Associated bronchial asthma – Early age at onset – Female gender

Prognosis The objective when treating a patient for AD is control of exacerbations, not elimination of the disease. Using the above treatment modalities, patients and their families can hope to minimize the frequency and severity of outbreaks.

Patient Education Instruct patients about proper skin care. Patients should bathe appropriately, keep skin well lubricated, use mild soaps, and avoid known triggers. The goal is control, not cure.

Special Concerns Given the chronic nature of this disease and patients' concerns about appearance, emotional support and psychological counseling may be helpful. Physicians need to be sensitive to the needs of patients and their families

Dupilumab is a fully human monoclonal antibody that binds to the alpha subunit of the IL-4 receptor. Through blockade of this receptor, dupilumab inhibits downstream signaling of IL-4 and IL-13, cytokines of type 2 helper T lymphocytes (Th 2) that are believed to play a key role in atopic diseases, including asthma and atopic dermatitis.

Dupilumab was evaluated in four small, industry-sponsored randomized trials in adult patients with moderate to severe atopic dermatitis. In the largest study, 109 patients were randomly assigned to receive weekly subcutaneous dupilumab at a dose of 300 mg (55 patients) or placebo (54 patients). At 12 weeks, 85 percent patients in the active treatment group had a 50 percent or greater reduction in the Eczema Area and Severity Score versus 35 percent in the placebo group.

dupilumab The results of these trials indicate that dupilumab may be an alternative systemic therapy for long-standing atopic dermatitis in adults, despite the relatively low proportion of patients achieving complete or near-complete clearance after 16 weeks of treatment. The results of two ongoing maintenance and open -label extension trials are expected to provide additional information on the long-term efficacy and safety of dupilumab for the treatment of atopic dermatitis.

Crisaborole is a small-molecule, topical phosphodiesterase-4 inhibitor in clinical development for the treatment of mild to moderate atopic dermatitis. Preliminary studies in adolescents and adults indicated that crisaborole 2% ointment may improve the clinical signs of atopic dermatitis, including erythema, excoriation, exudation, lichenification, and, in particular, pruritus.

Crisaborole Adverse effects of topical crisaborole were mild and mainly limited to application site reactions (pain, paresthesia). Systemic exposure to crisaborole appears to be limited even after maximal use (3 mg/cm 2

Crisaborole crisaborole appears a promising nonsteroidal topical treatment for mild to moderate atopic dermatitis. However, studies of longer duration than four weeks are needed to evaluate its long-term efficacy and safety

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