Atopic dermatitis: A deep Atopic dermatitis: A deep insight and therapeutic insight and therapeutic

implicationsimplications

By Dr. M. Y. Abd-ElmawlaBy Dr. M. Y. Abd-Elmawla

MD Dermatology And MD Dermatology And VenereologyVenereology

Atopic dermatitisAtopic dermatitis

(AD) is a highly pruritic, (AD) is a highly pruritic, recurring inflammatory skin recurring inflammatory skin disease. It usually develops in disease. It usually develops in early childhood and is frequently early childhood and is frequently seen in children with a personal seen in children with a personal history of respiratory allergy history of respiratory allergy and/or a family history of atopic and/or a family history of atopic disease.disease.

THEORIES IN PATHOGENESIS of A DTHEORIES IN PATHOGENESIS of A D

cAMP/ PDE abnormalities hypothesiscAMP/ PDE abnormalities hypothesis1.1. Genetically defined PDE Genetically defined PDE

isoforms lead to inadequate cellular isoforms lead to inadequate cellular cAMP levels.cAMP levels.

2.2. cAMP cAMP normallynormally causes negative causes negative modulation of immune and modulation of immune and inflammatory responses. inflammatory responses.

3.3. Inflammatory cells in Inflammatory cells in ADAD fail to shut offfail to shut off normally leading to normally leading to increased increased production of production of IL-4IL-4 and and IgEIgE, secretion of , secretion of IL-10IL-10 and and prostaglandin E2 by prostaglandin E2 by monocytemonocyte , and excessive release of , and excessive release of histaminehistamine by by mast cellsmast cells and and basophilsbasophils..

The allergy hypothesisThe allergy hypothesisEarly (perhaps even in Early (perhaps even in

utero) antigenic exposures cause utero) antigenic exposures cause the genetically the genetically susceptible susceptible personperson to proliferate to proliferate antigenically stimulated antigenically stimulated Th2-Th2-dominant T-cell clonesdominant T-cell clones, , elaborating elaborating IL-4IL-4, , IL-5IL-5, , IL-6IL-6, , IL-10IL-10, , and and IL-13IL-13 on re-exposure to the on re-exposure to the antigen , thus stimulating antigen , thus stimulating excessive excessive IgEIgE production by the production by the B cell and a tendency to B cell and a tendency to eosinophileosinophil-rich inflammation.-rich inflammation.

Immunohistology of the skinImmunohistology of the skin

Uninvolved skinUninvolved skin : hyperkeratosis and a sparse : hyperkeratosis and a sparse perivascular cellular infiltrate consisting perivascular cellular infiltrate consisting primarily of T lymphocytes. primarily of T lymphocytes.

Acute skin lesionsAcute skin lesions : : spongiosisspongiosis of the of the epidermis, a sparse epidermal infiltrate epidermis, a sparse epidermal infiltrate consisting mainly of lymphocytes.. consisting mainly of lymphocytes.. The dermisThe dermis: perivenular inflammatory cell : perivenular inflammatory cell infiltrate consisting of infiltrate consisting of T lymphocytesT lymphocytes, , monocytemonocyte--macrophagesmacrophages& & mast cellsmast cells, in , in various stages of degranulation. various stages of degranulation. Eosinophils, basophils, and neutrophilsEosinophils, basophils, and neutrophils : : rarelyrarely present in present in acuteacute lesions. lesions.

Chronic lichenified lesionsChronic lichenified lesions:: The epidermis : hyperplastic with The epidermis : hyperplastic with

elongation of the rete ridges, prominent elongation of the rete ridges, prominent hyperkeratosis, and minimal spongiosis. hyperkeratosis, and minimal spongiosis. An increased number of Langerhans cells An increased number of Langerhans cells in the epidermis, and macrophages in the epidermis, and macrophages dominate the dermal mononuclear cell dominate the dermal mononuclear cell infiltrate. Mast cells are increased in infiltrate. Mast cells are increased in number & fully granulated. number & fully granulated.

Increased numbers of eosinophilsIncreased numbers of eosinophils showing various stages of degeneration.showing various stages of degeneration.

In both acute and chronic lesionsIn both acute and chronic lesions::The endothelial cells exhibit The endothelial cells exhibit E-E-

selectinselectin, , intercellular adhesion molecule-intercellular adhesion molecule-11, and , and vascular cell adhesion molecule-1vascular cell adhesion molecule-1

Systemic Immune ResponseSystemic Immune ResponseIn ADIn AD

Elevated numbers of circulating eosinophils .Elevated numbers of circulating eosinophils . Increased serum immunoglobulin E (IgE) levels. Increased serum immunoglobulin E (IgE) levels. Increased basophil spontaneous histamine releaseIncreased basophil spontaneous histamine release Increased expression of CD23 on mononuclear cellsIncreased expression of CD23 on mononuclear cells Chronic macrophage activationChronic macrophage activation with increased with increased

secretion of granulocyte macrophage colony-secretion of granulocyte macrophage colony-stimulating factor (stimulating factor (GM-CSFGM-CSF), prostaglandin E2 (), prostaglandin E2 (PGE2PGE2 ), ), and interleukin-10 (and interleukin-10 (IL-10IL-10))

Expansion of IL-4–, IL-5–, and IL-13–secreting Expansion of IL-4–, IL-5–, and IL-13–secreting Th2-type Th2-type cellscells

Decreased numbers of interferon-γ (IFN-γ) secreting Decreased numbers of interferon-γ (IFN-γ) secreting Th1-type cellsTh1-type cells

Increased serum sIL-2 receptor levelsIncreased serum sIL-2 receptor levels Increased serum eosinophil cationic protein, Increased serum eosinophil cationic protein,

eosinophil-derived neurotoxin levels, and eosinophil eosinophil-derived neurotoxin levels, and eosinophil major basic protein levelsmajor basic protein levels

Increased urinary eosinophil proteinIncreased urinary eosinophil protein

Biphasic pattern of cytokine Biphasic pattern of cytokine expression in atopic skin lesionsexpression in atopic skin lesions

Acute skin lesions are rich in TH 2 (IL-Acute skin lesions are rich in TH 2 (IL-4 and IL-13) cytokine expression. 4 and IL-13) cytokine expression.

Chronic skin lesions : increased Chronic skin lesions : increased expression of IL-5 and IFN-gamma expression of IL-5 and IFN-gamma and IL-12, with significant decrease in and IL-12, with significant decrease in IL-4 and IL-13 as compared with acute IL-4 and IL-13 as compared with acute lesions.lesions.

IL-12 in chronic AD skin lesions plays IL-12 in chronic AD skin lesions plays a key role in TH 1 cell developmenta key role in TH 1 cell development

IL12IL12 expression in expression in eosinophileosinophils or s or macrophagesmacrophages initiates the switch to initiates the switch to TH 1 cell development in chronic AD.TH 1 cell development in chronic AD.

Factors affecting the differentiation Factors affecting the differentiation of helper T cells in ADof helper T cells in AD

1-1-Role of Cytokines Role of Cytokines environmentenvironment

2-2-GeneticsGenetics 3-3-Pharmacologic FactorsPharmacologic Factors 4-Costimulatory Signals4-Costimulatory Signals

5-5-Chemoattractant FactorsChemoattractant Factors

1-1-Role of Cytokines Role of Cytokines environmentenvironment:: TH 1TH 1 cells are induced by cells are induced by IL-12IL-12

produced by macrophages and produced by macrophages and dendritic cells. dendritic cells.

IL-4IL-4 inhibits IFN-gamma production and inhibits IFN-gamma production and down-regulates the differentiation of down-regulates the differentiation of TH 1 cells. TH 1 cells.

IL-4IL-4 promotes the development of TH 2 promotes the development of TH 2 cells. cells.

T cellsT cells in in unaffected skinunaffected skin and and acuteacute skin lesions& skin lesions& circulating T cellscirculating T cells, , express increased amounts of express increased amounts of IL-4IL-4, , IL-IL-55, and , and IL-13IL-13..

2-2-GeneticsGenetics::

The presence of a The presence of a clustered family of cytokine clustered family of cytokine genes (IL-3, IL-4, IL-5, IL-13, and genes (IL-3, IL-4, IL-5, IL-13, and GM-CSF) on chromosome 5q31-GM-CSF) on chromosome 5q31-33. 33.

linkage of AD to linkage of AD to chromosome 1q21chromosome 1q21, , the region containing the the region containing the epidermal epidermal differentiation complexdifferentiation complex ( (EDCEDC), was ), was reportedreported

@ِ@ِAtopic skinAtopic skin lesions revealed altered lesions revealed altered expression of genes located within expression of genes located within the the EDCEDC, in particular , in particular up regulation ofup regulation of S100A8S100A8 and and S100A7S100A7 and and down down regulationregulation of of loricrinloricrin and and filaggrinfilaggrin((FLGFLG)( )( loss-of-function loss-of-function mutations in the filaggrin mutations in the filaggrin FLGFLG gene gene)) , , compared with healthy control compared with healthy control samplessamples

The The epidermal differentiation complexepidermal differentiation complex ((EDCEDC) is a cluster of genes on ) is a cluster of genes on chromosome 1q21chromosome 1q21 encoding proteins encoding proteins that fulfil important functions in that fulfil important functions in terminal differentiation in the human terminal differentiation in the human epidermis, including epidermis, including filaggrinfilaggrin, , loricrinloricrin, , S100S100 proteins and others. proteins and others.

Variation within Variation within EDCEDC genes plays an genes plays an important role in the pathogenesis important role in the pathogenesis

of three common skin disorders, of three common skin disorders, ichthyosis vulgaris, ichthyosis vulgaris, atopic dermatitisatopic dermatitis ((ADAD) and psoriasis) and psoriasis. .

FLG expression and functions in the skin barrier:1

The precursor proprotein profilaggrin is strongly expressed within keratohyalin granules, tightly limited to and accounting for the typical appearance of the granular layer.

The SC stains strongly positive for filaggrin. Filaggrin has several proposed site-specific functions

under the influence of the epidermal terminal differentiation program through the outer granular layer

Cleavage of profilaggrin to filaggrin and the lipid bilayer of the inner SC (filament compaction, contribution to barrier integrity)

During desquamation of the outer SC (production of amino acid degradation products that contribute to the hydration of these outer layers and likely contribute to the ‘‘acid mantle’’).

FLG expression and functions in the skin barrier:2

Profilaggrin is dephosphorylated in conditions of increasing calcium concentration and is then proteolytically cleaved by the proteases matriptase (inhibited by the protease inhibitor LETKI).

After proteolysis, the filaggrin B domain locates to the nucleus as part of the terminal differentiation process.

Free filaggrin protein is crosslinked to keratin filaments by transglutaminases and subsequently deiminated by peptidylarginine deiminases (PADs) 1 and 3.

Further posttranslational modification is undertaken by caspase 14 to produce the free amino acid hygroscopic degradation products urocanic acid (UCA) and pyrrolidone carboxylic acid (PCA; ) which contribute to SC hydration.

3-3-Pharmacologic FactorsPharmacologic Factors:: Leukocytes from patients Leukocytes from patients

with AD have increased cyclic with AD have increased cyclic adenosine monophosphate (cAMP)-adenosine monophosphate (cAMP)-phospho-diesterase (PDE) enzyme phospho-diesterase (PDE) enzyme contributing to the increased IgE contributing to the increased IgE synthesis by B cells and IL-4 synthesis by B cells and IL-4 production by T cells production by T cells

Elevated cAMP-PDE in atopic Elevated cAMP-PDE in atopic monocytes contributes to the monocytes contributes to the secretion of increased levels of IL-10 secretion of increased levels of IL-10 and PGE2 & inhibits IFN-gamma and PGE2 & inhibits IFN-gamma production by T cells .production by T cells .

4-Costimulatory Signals4-Costimulatory Signals::

Generation of TH 2 cells Generation of TH 2 cells is dependent on the interaction is dependent on the interaction of cluster differentiation (CD) 28 of cluster differentiation (CD) 28 with B7.2 expressed on B cells of with B7.2 expressed on B cells of patients with AD. Langerhans' patients with AD. Langerhans' cells in the lesional skin of AD cells in the lesional skin of AD express B7.2 .express B7.2 .

5-5-Chemoattractant FactorsChemoattractant FactorsThe chemokines stimulating The chemokines stimulating

migration of inflammatory cells to the migration of inflammatory cells to the skin are expressed by keratinocytes , skin are expressed by keratinocytes , endothelial cells and, dendritic cells .endothelial cells and, dendritic cells .

The chemokines, monocyte chemotactic The chemokines, monocyte chemotactic protein-4, and eotaxin in AD skin protein-4, and eotaxin in AD skin lesions induce chemotaxis of lesions induce chemotaxis of eosinophils and Th2 lymphocytes into eosinophils and Th2 lymphocytes into the skin.the skin.

Leukotriene B4 is also released on Leukotriene B4 is also released on exposure of AD skin to allergens acting exposure of AD skin to allergens acting as a chemoattractant for the initial as a chemoattractant for the initial influx of inflammatory cellsinflux of inflammatory cells

Factors contributing to Skin Factors contributing to Skin Localization of Allergic DiseaseLocalization of Allergic Disease

1-Route of allergen sensitization. 1-Route of allergen sensitization.

2-Tissue chemokine expression. 2-Tissue chemokine expression.

3-Expression of homing receptors on 3-Expression of homing receptors on memory effector T cells: regulated by memory effector T cells: regulated by interaction of expressed T-cell homing interaction of expressed T-cell homing receptors with vascular endothelial-cell receptors with vascular endothelial-cell surface antigens. The cell adhesion surface antigens. The cell adhesion molecule that results in T-cell homing to molecule that results in T-cell homing to the skin is termed the skin is termed cutaneous cutaneous lymphocyte-associated antigenlymphocyte-associated antigen (CLA). (CLA).

Mechanisms of Chronic Skin Mechanisms of Chronic Skin InflammationInflammation in AD in AD

1-Epidermal keratinocytes1-Epidermal keratinocytes produce produce increased levels of chemokines increased levels of chemokines enhancing the chemotaxis of enhancing the chemotaxis of eosinophils. eosinophils.

2-Mechanical trauma2-Mechanical trauma: induces the release : induces the release of of TNF-α TNF-α and many other and many other proinflammatory cytokines from proinflammatory cytokines from epidermal epidermal kera-tinocyteskera-tinocytes. .

3-Enhanced production of GM-CSF3-Enhanced production of GM-CSF by by epidermal keratinocytesepidermal keratinocytes and infiltrating and infiltrating macrophages plays an important role in macrophages plays an important role in maintaining the survival and function of maintaining the survival and function of monocyte-macrophages, Langerhans' monocyte-macrophages, Langerhans' cells, and eosinophils.cells, and eosinophils.

4-The prolonged survival of eosinophils:due4-The prolonged survival of eosinophils:due to to Increased IL-5 expressionIncreased IL-5 expression during the during the transition from acute to chronic AD and transition from acute to chronic AD and secretion of autocrine factors secretion of autocrine factors inhibiting inhibiting cell apoptosiscell apoptosis

5-Colonization by superantigen-producing5-Colonization by superantigen-producing Staphylococcus aureusStaphylococcus aureus: :

Superantigens stimulate epidermal Superantigens stimulate epidermal macrophagesmacrophages & & LangerhanLangerhans cells to s cells to produce produce IL-1IL-1, , TNFTNF, and , and IL-12IL-12 inducing the inducing the expression of E-selectinexpression of E-selectin on vascular on vascular endothelium, allowing an initial influx of endothelium, allowing an initial influx of CLA+ memory/effector cells.CLA+ memory/effector cells.

6.6.- - The environmental triggersThe environmental triggers: : Xerosis , Contact and Xerosis , Contact and aeroallergens, Infectious aeroallergens, Infectious agents (lipophylic agents (lipophylic yeast,dermatophytes,herpes yeast,dermatophytes,herpes simplex virus,……….), simplex virus,……….), Foods( eg.egg ,wheat, Foods( eg.egg ,wheat, peanuts ),Climate and Psych.peanuts ),Climate and Psych.

The xerotic epidermis due to The xerotic epidermis due to ceramides reduction ceramides reduction && loss-of-loss-of-function mutations in the filaggrin function mutations in the filaggrin ((FLGFLG)) gene gene ( ( impaired barrier impaired barrier functionfunction), provokes and sustains ), provokes and sustains inflammation by activation of an inflammation by activation of an epidermis-initiated cytokine epidermis-initiated cytokine cascade. The impaired barrier cascade. The impaired barrier function of atopic skin allows function of atopic skin allows greater absorption of irritant greater absorption of irritant agents and contact allergens.agents and contact allergens.

FLG insufficiency and bacterial infections in atopic dermatitis

FLG insufficiency might critically modify pH-related altered commensal bacteria expression, thus manipulating host immunity.

Altered host immunity to bacterial infections is a notable feature of atopic dermatitis.

Exposure of immune system to Staph. aureus superantigens can trigger and establish a permanent TH2 immune response through activation and amplification of innate immune responses.

The neutralizing acid SC pH has also been shown to independently facilitate excessive protease activity and reduce the activity of key lipid processing enzymes, resulting in the formation of defective lamellar membranes and a disrupted permeability barrier.

Atopic dermatitis versus Atopic dermatitis versus psoriasis inflammatory reactionpsoriasis inflammatory reaction

Proposed criteria for the Proposed criteria for the diagnosis of AD.diagnosis of AD.

EssentialEssential NonessentialNonessential

Atopy (personal or family Atopy (personal or family history)history)

XerosisXerosis

PruritusPruritus Keratosis pilarisKeratosis pilaris

Eczematous lesionsEczematous lesions Pityriasis albaPityriasis alba

Vascular instabilityVascular instability Allergic shinersAllergic shiners

   Morgan-Dennie linesMorgan-Dennie lines

   Palmar hyperlinearityPalmar hyperlinearity

   Anterior capsular Anterior capsular cataractscataracts

   KeratoconusKeratoconus

Therapeutic approaches Therapeutic approaches and implicationsand implications

AVOIDANCE OF IRRITANTS(eg, AVOIDANCE OF IRRITANTS(eg, detergents, soaps, and detergents, soaps, and chemicals)chemicals)

AVOIDANCE OF ALLERGENS(food AVOIDANCE OF ALLERGENS(food and aeroallergens).and aeroallergens).

HYDRATION and MOISTURIZERSHYDRATION and MOISTURIZERS

Adequate rehydration preserves the stratum corneum Adequate rehydration preserves the stratum corneum barrier, minimizing the direct effects of irritants and barrier, minimizing the direct effects of irritants and allergens and maximizing the effect of topically allergens and maximizing the effect of topically applied therapiesapplied therapies

Very hot water : avoided to prevent both vasodilation, Very hot water : avoided to prevent both vasodilation, triggering pruritus& damage to the skin barrier triggering pruritus& damage to the skin barrier caused by scalding. caused by scalding.

Baths : followed by the immediate application of an Baths : followed by the immediate application of an occlusive emollient( occlusive emollient( ointment-basedointment-based ) over the entire ) over the entire skin surface to retain moisture .skin surface to retain moisture .

• Cream-based alternatives : weaker occlusiveCream-based alternatives : weaker occlusive effects &used only if the ointment-based effects &used only if the ointment-based emollients are not well tolerated. emollients are not well tolerated.

• Ceramide-dominant, barrier repair topical Ceramide-dominant, barrier repair topical emollient:emollient: : : a safe& useful in the treatment of A Da safe& useful in the treatment of A D

• Wet dressings :used on dry lichenified lesions : Wet dressings :used on dry lichenified lesions : improve hydration & increaseimprove hydration & increase the penetration of the penetration of topical corticosteroids.topical corticosteroids.

Reduction of bacterial (eg, Reduction of bacterial (eg, S aureusS aureus)) colonizationcolonization

With topical antibiotics or brief With topical antibiotics or brief courses of oral antibiotics is especially courses of oral antibiotics is especially useful in AD patients with crusted or useful in AD patients with crusted or exudative disease.exudative disease.

Topical corticosteroidsTopical corticosteroids- Applied only to areas of acute - Applied only to areas of acute exacerbations, emollients are used over the exacerbations, emollients are used over the remainder of the skin. remainder of the skin. -The absorption of topical steroids : better -The absorption of topical steroids : better through through hydrated skinhydrated skin:, the ideal time for :, the ideal time for application is within 3 minutes of taking a application is within 3 minutes of taking a bath. bath. - Creams generally : tolerated well but are - Creams generally : tolerated well but are less moisturizing than ointmentsless moisturizing than ointments• Ointments : the most moisturizing steroid Ointments : the most moisturizing steroid

vehicles( best on thickened lichenified plaques ).vehicles( best on thickened lichenified plaques ).

Systemic corticosteroidsSystemic corticosteroids

In patients with severe In patients with severe treatment-resistant A D. Oral treatment-resistant A D. Oral corticosteroids improve the lesions of corticosteroids improve the lesions of atopic dermatitis. Flare occurs when atopic dermatitis. Flare occurs when these medications are stopped. . The these medications are stopped. . The potential for a rebound effect can be potential for a rebound effect can be decreased by tapering the drug while decreased by tapering the drug while increasing topical corticosteroid increasing topical corticosteroid treatment and aggressively hydrating treatment and aggressively hydrating the skin.the skin.

ANTIHISTAMINES AND ANTIHISTAMINES AND ANTIDEPRESSANTSANTIDEPRESSANTS

Sedating agents (hydroxyzine (Atarax) and Sedating agents (hydroxyzine (Atarax) and diphenhydramine (Benadryl) : effective in diphenhydramine (Benadryl) : effective in controlling prurituscontrolling pruritus

Tricyclic antidepressants : doxepin Tricyclic antidepressants : doxepin (Sinequan) & amitriptyline (Elavil) have (Sinequan) & amitriptyline (Elavil) have an antihistaminic effect, inducing sleep an antihistaminic effect, inducing sleep and reducing pruritusand reducing pruritus

Topical forms of doxepin ,diphenhydramine Topical forms of doxepin ,diphenhydramine (cream, gel or spray forms) and (cream, gel or spray forms) and benzocaine are systemically absorbed. benzocaine are systemically absorbed. They can cause allergic contact They can cause allergic contact dermatitis.dermatitis.

PHOTOTHERAPYPHOTOTHERAPY

Administered as Administered as ultraviolet A (UVA), ultraviolet B ultraviolet A (UVA), ultraviolet B (UVB) or combined UVA and UVB. (UVB) or combined UVA and UVB. Psoralen plus UVA (PUVA) Psoralen plus UVA (PUVA) photochemotherapy may be a photochemotherapy may be a treatment option in patients with treatment option in patients with extensive refractory disease.extensive refractory disease.

Topical Tacrolimus &Topical Tacrolimus & PimecrolimusPimecrolimus

Tacrolimus & Pimecrolimus bind a cyclophilin-like Tacrolimus & Pimecrolimus bind a cyclophilin-like cytoplasmic protein & macrophilin 12 in order cytoplasmic protein & macrophilin 12 in order

These complexes inhibit calcineurin, interfering with These complexes inhibit calcineurin, interfering with gene transcription of multiple cytokines.gene transcription of multiple cytokines.

Both drugs inhibit degranulation and the synthesis Both drugs inhibit degranulation and the synthesis of mast cell mediators and cytokines.of mast cell mediators and cytokines.

Tacrolimus decreases the expression of activation Tacrolimus decreases the expression of activation molecules such as interleukin-2 receptor (IL-2R) molecules such as interleukin-2 receptor (IL-2R) (CD25), CD80, CD40, and MHC class I and II.(CD25), CD80, CD40, and MHC class I and II.

Tacrolimus has an inhibitory effect on proliferation Tacrolimus has an inhibitory effect on proliferation induced by staphylococcal enterotoxin B in induced by staphylococcal enterotoxin B in peripheral blood mononuclear cells (PBMCs) from peripheral blood mononuclear cells (PBMCs) from patients with AD.patients with AD.

Systemic immunomodulatorsSystemic immunomodulators

Cyclosporine (Sandimmune)(Cyclosporine (Sandimmune)(5mg per kg PO) : 5mg per kg PO) : effective in patients with refractory atopic effective in patients with refractory atopic dermatitis. It binds a cyclophilin protein, dermatitis. It binds a cyclophilin protein, inhibiting calcineurin, interfering with gene inhibiting calcineurin, interfering with gene transcription of multiple cytokines .transcription of multiple cytokines .

Mycophenolate Mofetil(Mycophenolate Mofetil(MMF)MMF)MMF): an inhibitor of de novo purine MMF): an inhibitor of de novo purine biosynthesis. Lymphocytes depend on de biosynthesis. Lymphocytes depend on de novo purine biosynthesis and are affected novo purine biosynthesis and are affected significantly by the action of MMF.significantly by the action of MMF.An initial dose of 1 g of oral MMF daily An initial dose of 1 g of oral MMF daily during the first week and 2 g daily for during the first week and 2 g daily for another 11 weeks is used in severe A D.another 11 weeks is used in severe A D.

Systemic immunomodulatorsSystemic immunomodulators(cont..)(cont..)

Interferon-γInterferon-γ Interferon gamma is a Th1 cytokine Interferon gamma is a Th1 cytokine

suppressing IL-4–mediated IgE production and is suppressing IL-4–mediated IgE production and is beneficial , effective and safe in the treatment of beneficial , effective and safe in the treatment of moderate-to-severe AD. Clinical improvement in moderate-to-severe AD. Clinical improvement in their patients correlated with reductions in white their patients correlated with reductions in white blood cell counts, eosinophil and lymphocyte counts, blood cell counts, eosinophil and lymphocyte counts, and with normalization of the CD4-to-CD8 ratio and with normalization of the CD4-to-CD8 ratio among lymphocytes.among lymphocytes.

Intravenous Immunoglobulin(IVIg)Intravenous Immunoglobulin(IVIg)Used in severe AD due to anti-inflammatory Used in severe AD due to anti-inflammatory

and immunomodulatory properties. and immunomodulatory properties. IVIg reduces IL-4 protein expression in AD and IVIg reduces IL-4 protein expression in AD and

decreases in ICAM-1, ELAM-1, and ECP levels. decreases in ICAM-1, ELAM-1, and ECP levels. IVIG's role in apoptosis, and Fc receptor IVIG's role in apoptosis, and Fc receptor

function and its influence on cytokine cascadesfunction and its influence on cytokine cascadesDose: 2 g/kg per month for seven infusionsDose: 2 g/kg per month for seven infusions

  AlogrithmAlogrithm : :Treatment of atopic Treatment of atopic dermatitisdermatitis..

Conclusion and Future Conclusion and Future directionsdirections

Corticosteroids, UV therapy including NB UVB(311 nm) Corticosteroids, UV therapy including NB UVB(311 nm) and the immunosuppressant macrolides are all and the immunosuppressant macrolides are all therapeutic agents that are likely to be effective in therapeutic agents that are likely to be effective in controlling the complex inflammatory cascades of controlling the complex inflammatory cascades of chronic AD. chronic AD.

Given the central role of TH 2 cytokines and Given the central role of TH 2 cytokines and chemokines in the development of AD, strategies chemokines in the development of AD, strategies directed at reducing TH 2 responses and blocking directed at reducing TH 2 responses and blocking the action of chemokines by antagonists of relevant the action of chemokines by antagonists of relevant receptors will be important. receptors will be important.

The potential role of IFN-γ, IL-12, and IL-18 in restoring The potential role of IFN-γ, IL-12, and IL-18 in restoring the shift toward a more balanced TH 0 response with the shift toward a more balanced TH 0 response with equal production of TH 1 and TH 2 cytokines equal production of TH 1 and TH 2 cytokines warrants studies .Further studies upon the cytokines warrants studies .Further studies upon the cytokines blocking agents may present a safe and effective blocking agents may present a safe and effective modality for AD therapymodality for AD therapy

THANK YOUTHANK YOU