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Management

of

Atopic Dermatitis:

Role of

Immunomodulators

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Atopic Dermatitis

Atopic dermatitis (AD) is a chronic, relapsing, inflammatoryskin condition associated with immunological dysfunction thatis characterized by an itchy red rashes.

Majority of the patients having a personal or family history ofatopic 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 remissionsand flare ups.

Atopic March: atopic dermatitisfood allergiesasthmaallegic rhinitis

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Epidemiology

Atopic eczema is common and the prevalence is increasing.

Arising trend in AD has been observed in India also in last fourdecades*.

AD was the commonest dermatoses in children constituting28.46% of pediatric patients.

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

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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 inpregnancy.

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Pathophysiology

Immune Dysfunction

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Pathophysiology

Defective epidermal barrier

Entry of allergens

in the skin

Normal Skin Skin of individual

predisposed to AD

Increased

desquamationof cells

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 ofallergens thereby causing lesions ofAD.

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Reported Immunological Features ofAtopic Dermatitis

Increased IgE production

Specific IgE to multiple antigens

Increased basophil spontaneous histamine release

Decreased CD8 suppressor/cytotoxic number andfunction

Increased expression of CD 23 on mononuclear cells

Chronic macrophage activation with increased secretionof 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-likecells

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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 occurin adulthood

Worse prognosis

severe childhood disease

early onset

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

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Child with severe skin lesionsChild with mild eczema

Flexural involvement

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Infected eczema in an atopic child

Child with severe Pruritus andskin lesions

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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

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Clinical Phases

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 withexcoriations seen on both cheeks and extensorsurfaces of extremities

Course chronically relapsing and remitting

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Clinical Phases (contd)

2 Childhood Phase ( 2-12 years ) Papular areas in flexural regions common.

Persistent rubbing and scratching leads tolichenified 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

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Diagnosis of Atopic Dermatitis

This requires the presence of three or more majorand three or more minor criteria as defined byHanifin and Rajka

Major criteria 1.pruritus

2.typical morhology and distribution

3.chronicity

4.family history of atopy

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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 schoolor work

Repeated treatments, time involved,financial costs

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Management

Hydrate with tub soaks and moisturizers

Control inflammation with topical corticosteroids

Reduce flare and control disease withimmunomodulators

Treat secondary bacterial infections with topical andsystemic antibiotics

Manage pruritis with antihistamines

UVA and UVB phototherapy

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Management of Atopic Dermatitis

No single, ideal treatment available

Each patient should have a flexible plan tailored fortheir need

Dietary history important, dietary manipulationcontroversial

Family education important

Reduce exposure to allergens

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General Treatment Guidelines

Moisturizers are the

cornerstone of therapy in AD

Frequent use important because AD is oftenaccompanied by dry skin.

Creams, ointments or lotions can be used dependingon individual needs

Avoidance of drying bathing products

Itch control Distressing symptom, use oralantihistamines, try to break the itch-scratch cycle

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General Treatment Guidelines(contd.)

Control of infection

Patients with extensive AD are often colonized withStaph. aureus.

A course of oral antibiotics topical antibioticsneeded for lichenified, excoriated lesions notresponding to treatment.

Viral infections, eg. warts, eczema herpeticum areseen in these patients.

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Selection of treatment

This depends on -

Disease severity

Age Compliance

Efficacy

Safety data

Treatment costs

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Rx Treatment Options

1. Topical corticosteroids

2. Topical immunosuppressants

3. Systemic corticosteroids

Off-Label and other treatment options

1. Photochemotherapy

2. Cyclosporin

3. Azathioprine

4. Thymopentin

5. Interferon-therapy6. Traditional Chinese medicine

7. -linoleic acid

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Topical corticosteroids (TCS)

First introduced in the 1950s and are currentlythe mainstay of prescription therapy for atopicdermatitis

Safe and effective when used as recommended

Weakest steroid that will keep the eczema undercontrol should be used

Potent steroids should be used in short pulses,generally 2-3 weeks

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Factors to consider when prescribingtopical 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. Acute or chronic eczema

3. Age of child

4. Site to be treated

5. Extent of eczema

6. Method of application

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Mechanism of action of TCS

1. Antiinflammatory effects

TCS affect inflammatory cells, chemical mediators and tissueresponses which are all responsible for cutaneous inflammation

2. Antiproliferative effects

TCS may reduce mitotic activity in the epidermis, leading toflattening of the basal cell layer and thinning of the stratumcorneum and stratum granulosum

3. Atrophogenic Effects

TCS can promote atrophy of the dermis through inhibition offibroblast proliferation, migration, chemotaxis and proteinsynthesis

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Cutaneousor local adverse effects

may include:

Atrophic changes

Easy bruisability

Increased fragility

Purpura

Stellate pseudoscarsSteroid atrophy

Striae

Telangiectasis

Ulceration

Topical corticosteroids may increase

therisk for infections, including:

Aggravation of cutaneous infection

Granuloma gluteale infantum

Masked infection (tinea incognito)

Secondary infections

Adverse Effect of Topical Corticosteroid

Note: It is difficult to quantify the incidence of

side effects caused by topical corticosteroids

as a whole, given their differences in potency

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Contact dermatitis

Delayed wound healing

Hyperpigmentation

Hypertrichosis (hirsutism)

Hypopigmentation

Perioral dermatitis

Photosensitization

Miscellaneous adverse effects of topical corticosteroids

Hypothalamic-pituitary-adrenal suppression

Glaucoma

Septic necrosis of the femoral head

Hyperglycemia

Hypertension

Topically applied high and ultra-high potency corticosteroids can be

absorbed well enough to cause systemic side effects such as:

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Risk factors for systemic adverseeffects

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 occlusionIt is not established whether catch up growth in children will

occur when TCS are discontinued.

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Topical Immunosuppressants

Newest pharmacological class for AD

Introduced in this decade

Direct immunosuppressive action in diseases withimmunologic basis

2 FDA approved products

Tacrolimus (FK506)

Pimecrolimus (SDZ ASM 981)

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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 andintermittent long term therapy of patients withmoderate to severe AD.

Systemic tacrolimus first introduced for preventionof allograft rejection, now used in kidney, liver andheart transplantation

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Pimecrolimus cream 1% approved on 12/13/2001

Indicated for patients 2 years of age and older forshort and intermittent long term therapy in thetreatment of mild to moderate atopic dermatitis

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

Background (contd)

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Mechanism of Action

Calcineurin = Enzyme with phosphotase activity causes dephosphoralation

Calmodulin = Intracellular protein that combines with calcium & activates variety of cellularprocesses

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IMMUNOMODULATORS INATOPIC TREATMENT

Decrease atopic flare by:

Decrease pruritus

Decrease use of topical steroids

Low systemic absorption

Burning and warmth most frequent adverseevent

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MINIMAL SYSTEMIC ABSORPTION

%

12 week randomized double-blind multicenter trials

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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

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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.

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Proven Safety Profile in 3 years ofPediatric 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.

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Precautions

In treatment of infected AD. Before commencing treatmentwith tacrolimus ointment, clinical infections at treatmentsites should be cleared

Treatment may be associated with an increased risk of viralinfections.

In presence of these infections, balance of risks & benefits

associated should be evaluated.

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* MF Rehaman et al.2008

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* Breuer K et al. 2005

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* Hanifin et al. 2005

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Salient Features

Rapid onset of action

Minimal systemic absorption

Safe & efficacious application to head/neck region

Few adverse effects

Safety & efficacy of tacrolimus ointmentmonotherapy has been demonstrated for periodsof upto 2 year in adults & children.

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Salient Features contd

Does not interfere with (or decrease) collagensynthesis or cause skin atrophy.

Associated with a reduction in staphylococcal skincolonization in AD lesions.

Demonstrated antifungal activity against strains ofMalessezia furfur, a possible allergen.

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