Management of Atopic Dermatitis: Role of Immunomodulators

Atopic Dermatitis
Atopic dermatitis (AD) is a chronic, relapsing, inflammatory skin condition associated with immunological dysfunction that is characterized by an itchy red rashes. Majority of the patients having a personal or family history of atopic diathesis. The most common skin disorder seen in infants and children. 60% present in first year of life It is a chronic skin disease with frequent episodes of remissions and flare ups. Atopic March: atopic dermatitis food allergies asthma allegic rhinitis

Epidemiology
Atopic eczema is common and the prevalence is increasing.
Arising trend in AD has been observed in India also in last four decades*. AD was the commonest dermatoses in children constituting 28.46% of pediatric patients.

* Kanwar AJ, De D. Epidemiology and clinical features of atopic dermatitis in India. Indian J Dermatol 2011;56:471-5

Trigger factors
Environmental irritants and allergens
Irritants, e.g. soaps and detergents (including shampoos, bubble baths, shower gels and washing-up liquids).

Skin infections: Staphylococcus aureus.

Contact allergens Extremes of temperature and humidity. Most patients improve in summer and are worse in winter. Sweating. Abrasive fabrics, e.g. wool. Dietary factors Inhaled allergens, e.g. house dust mites, pollens, pet dander and moulds.

Endogenous factors
Stress Hormonal changes in women - e.g. premenstrual flare-ups, deterioration in pregnancy.

Pathophysiology
The pathogenesis of atopic dermatitis is multifactorial and involves a complex immunologic cascade, including
disruption of the epidermal barrier IgE dysregulation

defects in the cutaneous cell mediated immune response and

genetic factors

Two main hypotheses have been proposed:

1. 2. Immune dysfunction Defective epidermal barrier

Pathophysiology
Immune Dysfunction

Pathophysiology
Defective epidermal barrier
In an individual genetically predisposed to AD, premature breakdown of

the corneodesmosomes leads to enhanced desquamation, analogous to

having rusty iron rods all the way down through the brick wall. The brick wall starts falling apart and allows the penetration of allergens thereby causing lesions ofAD.

Normal Skin

Skin of individual predisposed to AD

Increased desquamation of cells

Entry of allergens in the skin

Reported Immunological Features of Atopic Dermatitis

Increased IgE production Specific IgE to multiple antigens Increased basophil spontaneous histamine release Decreased CD8 suppressor/cytotoxic number and function Increased expression of CD 23 on mononuclear cells
Chronic macrophage activation with increased secretion of GM-CSF, PGE2 and IL-10 Expansion of IL-4 and IL-5 secreting Th 2-like cells Decreased numbers of IFN-gamma-secreting Th 1-like cells

Clinical Manifestations
Seen in early infancy, in 50 - 75% of cases,
age of onset is 6 months or younger

Clearance rate of 60% expected by age 16, relapses occur in adulthood

Worse prognosis
severe childhood disease early onset

concomitant or family history of asthma/allergic rhinitis, biparental history of atopy

Child with severe skin lesions

Child with mild eczema

Flexural involvement

Infected eczema in an atopic child Child with severe Pruritus and skin lesions

Clinical Features
Three main age-related stages.
Infantile phase Childhood phase Adult phase

Dry skin and pruritus associated with all stages.

Skin barrier function decreased, may lead to increased absorption of topically applied treatments. Usually improves with adequate treatment

Clinical Phases
1. Infantile Phase ( 0-2 years )
Onset around 3 months of age.
Under 6 months, the face and scalp commonly involved, at an older age, limb folds and hands involved

Red, scaly, crusted weeping patches with excoriations seen on both cheeks and extensor surfaces of extremities
Course chronically relapsing and remitting

Clinical Phases (contd)

2. Childhood Phase ( 2-12 years )

Papular areas in flexural regions common. Persistent rubbing and scratching leads to lichenified plaques and excoriations
3. Adult Phase (puberty onwards)

Flexural lichenified eczema with facial involvement in periorbital regions seen. Upper trunk, shoulders, scalp affected with chronic remissions and exacerbations

Diagnosis of Atopic Dermatitis

This requires the presence of three or more major and three or more minor criteria as defined by Hanifin and Rajka

Major criteria
1.pruritus
2.typical morhology and distribution 3.chronicity 4.family history of atopy

Minor criteria
Xerosis Recurrent conjuctivitis

Icthyosis/hyperlinear palms/keratosis p.
IgE reactivity Elevated IgE level Early onset Skin infection Chelitis Nipple eczema

Keratoconus
Dennie morgan fold Anterior c. cataract

Orbital darkening
Facial erythema Pityriasis alba

Food hypersensitivity
White dermatographism

Morbidity
Impact on quality of life occurs at all ages.
Psychological problems from visible skin lesions due to stigmatization Itch-scratch cycle Sleeplessness, lack of concentration at school or work Repeated treatments, time involved, financial costs

Management
Hydrate with tub soaks and moisturizers

Control inflammation with topical corticosteroids

Reduce flare and control disease with immunomodulators Treat secondary bacterial infections with topical and systemic antibiotics Manage pruritis with antihistamines UVA and UVB phototherapy

Management of Atopic Dermatitis

No single, ideal treatment available
Each patient should have a flexible plan tailored for their need Dietary history important, dietary manipulation controversial Family education important Reduce exposure to allergens

General Treatment Guidelines

Moisturizers are the
cornerstone of therapy in AD Frequent use important because AD is often accompanied by dry skin.

Creams, ointments or lotions can be used depending on individual needs

Avoidance of drying bathing products Itch control Distressing symptom, use oral antihistamines, try to break the itch-scratch cycle

General Treatment Guidelines (contd.)

Control of infection
Patients with extensive AD are often colonized with Staph. aureus. A course of oral antibiotics topical antibiotics needed for lichenified, excoriated lesions not responding to treatment. Viral infections, eg. warts, eczema herpeticum are seen in these patients.

Selection of treatment
This depends on Disease severity Age Compliance Efficacy Safety data Treatment costs

Rx Treatment Options
1. 2. 3. Topical corticosteroids Topical immunosuppressants Systemic corticosteroids
Off-Label and other treatment options
1. Photochemotherapy

2.
3. 4. 5.

Cyclosporin
Azathioprine Thymopentin Interferon- therapy

6.
7.

Traditional Chinese medicine

-linoleic acid

Topical corticosteroids (TCS)

First introduced in the 1950s and are currently the mainstay of prescription therapy for atopic dermatitis
Safe and effective when used as recommended Weakest steroid that will keep the eczema under control should be used Potent steroids should be used in short pulses, generally 2-3 weeks

Factors to consider when prescribing topical corticosteroids

1. Type of preparation (base and potency)
Base can be ointment, cream, emulsion, gel or lotion Potency classified from group I (most potent) to VII (least potent) 2. 3. 4. 5. 6. Acute or chronic eczema Age of child Site to be treated Extent of eczema Method of application

Mechanism of action of TCS

1. Antiinflammatory effects TCS affect inflammatory cells, chemical mediators and tissue responses which are all responsible for cutaneous inflammation 2. Antiproliferative effects TCS may reduce mitotic activity in the epidermis, leading to flattening of the basal cell layer and thinning of the stratum corneum and stratum granulosum 3. Atrophogenic Effects TCS can promote atrophy of the dermis through inhibition of fibroblast proliferation, migration, chemotaxis and protein synthesis

Adverse Effect of Topical Corticosteroid

Cutaneous or local adverse effects may include:

Atrophic changes Easy bruisability Increased fragility Purpura

Topical corticosteroids may increase the risk for infections, including:

Aggravation of cutaneous infection Granuloma gluteale infantum Masked infection (tinea incognito) Secondary infections

Stellate pseudoscars
Steroid atrophy Striae Telangiectasis Ulceration

Note: It is difficult to quantify the incidence of side effects caused by topical corticosteroids as a whole, given their differences in potency

Miscellaneous adverse effects of topical corticosteroids

Contact dermatitis
Delayed wound healing Hyperpigmentation Hypertrichosis (hirsutism)

Hypopigmentation
Perioral dermatitis Photosensitization

Topically applied high and ultra-high potency corticosteroids can be absorbed well enough to cause systemic side effects such as:
Hypothalamic-pituitary-adrenal suppression Glaucoma Septic necrosis of the femoral head Hyperglycemia Hypertension

Risk factors for systemic adverse effects

Young age (infants and children)
Liver and renal disease Amount of TCS applied Extent of skin disease treated Frequency of application Length of treatment Potency of drug Use of occlusion

It is not established whether catch up growth in children will occur when TCS are discontinued.

Topical Immunosuppressants
Newest pharmacological class for AD
Introduced in this decade Direct immunosuppressive action in diseases with immunologic basis 2 FDA approved products
Tacrolimus (FK506) Pimecrolimus (SDZ ASM 981)

Background
Tacrolimus ointment approved on 12/08/2000, 0.03% ointment approved for children 2 to 15 years, 0.1% ointment approved for adults.
Indication in both age groups is short and intermittent long term therapy of patients with moderate to severe AD. Systemic tacrolimus first introduced for prevention of allograft rejection, now used in kidney, liver and heart transplantation

Background (contd)
Pimecrolimus cream 1% approved on 12/13/2001
Indicated for patients 2 years of age and older for short and intermittent long term therapy in the treatment of mild to moderate atopic dermatitis

Both drugs not approved for use in children less than 2 years of age

MECHANISM OF ACTION
Substance P: neurotransmitter which itching
Calcinurin inhibitor, therefore breaks the scratchitch cycle Release of calcinurin activates inflammatory cytokines which cause tissue irritation & IgE Lipophilic Attaches to T-cells, which sit high in the epidermis

Therefore, does not permeate into the dermis

Mechanism of Action

Calcineurin = Enzyme with phosphotase activity causes dephosphoralation Calmodulin = Intracellular protein that combines with calcium & activates variety of cellular processes

IMMUNOMODULATORS IN ATOPIC TREATMENT

Decrease atopic flare by:
Decrease pruritus Decrease use of topical steroids

Low systemic absorption

Burning and warmth most frequent adverse event

MINIMAL SYSTEMIC ABSORPTION

12 week randomized double-blind multicenter trials

 Indication
Short-term & intermittent long-term therapy in moderate to severe AD

Dosage
0.03% in children aged 2-15 years twice daily 0.03% and 0.1% in adults twice daily

Adverse Events
Most common were sensation of skin burning & pruritus at application sites, prevalence decreased after first 4 days. Flu-like symptoms, Allergic reactions, Skin erythema, Headache,

Skin infection, Folliculitis, Rash, Skin tingling, Acne &

hyperaesthesia may occur rarely.

Proven Safety Profile in 3 years of Pediatric Clinical Trials

Gentle for children, even on head neck, intertriginous areas & large body surface areas.
Studied in >6000 pediatric patients. No immunosuppression or effect on immune parameters. No skin atropy or growth retardation.

Precautions
In treatment of infected AD. Before commencing treatment with tacrolimus ointment, clinical infections at treatment sites should be cleared Treatment may be associated with an increased risk of viral infections. In presence of these infections, balance of risks & benefits associated should be evaluated.

* MF Rehaman et al. 2008

* Breuer K et al. 2005

* Hanifin et al. 2005

Salient Features
Rapid onset of action

Minimal systemic absorption

Safe & efficacious application to head/neck region Few adverse effects Safety & efficacy of tacrolimus ointment monotherapy has been demonstrated for periods of upto 2 year in adults & children.

Salient Features contd

Does not interfere with (or decrease) collagen synthesis or cause skin atrophy. Associated with a reduction in staphylococcal skin colonization in AD lesions. Demonstrated antifungal activity against strains of Malessezia furfur, a possible allergen.