Atopic dermatitis: A deep insight and therapeutic implications By Dr. M. Y. Abd-Elmawla MD Dermatology And Venereology
Atopic dermatitis (AD) is a highly pruritic, recurring inflammatory skin disease. It usually develops in early childhood and is frequently seen in children with a personal history of respiratory allergy and/or a family history of atopic disease.
THEORIES IN PATHOGENESIS of A D cAMP/ PDE abnormalities hypothesis 1. Genetically defined PDE isoforms lead to inadequate cellular cAMP levels. 2. cAMP normally causes negative modulation of immune and inflammatory responses. 3. Inflammatory cells in AD fail to shut off normally leading to increased production of IL-4 and IgE, secretion of IL-10 and prostaglandin E2 by monocyte , and excessive release of histamine by mast cells and basophils.
The allergy hypothesis Early (perhaps even in utero) antigenic exposures cause the genetically susceptible person to proliferate antigenically stimulated Th2-dominant T-cell clones, elaborating IL-4, IL-5, IL-6, IL-10, and IL-13 on re-exposure to the antigen , thus stimulating excessive IgE production by the B cell and a tendency to eosinophil-rich inflammation.
Immunohistology of the skin Uninvolved skin : hyperkeratosis and a sparse perivascular cellular infiltrate consisting primarily of T lymphocytes. Acute skin lesions : spongiosis of the epidermis, a sparse epidermal infiltrate consisting mainly of lymphocytes.. The dermis: perivenular inflammatory cell infiltrate consisting of T lymphocytes, monocyte- macrophages& mast cells, in various stages of degranulation. Eosinophils, basophils, and neutrophils : rarely present in acute lesions.
Chronic lichenified lesions: The epidermis : hyperplastic with elongation of the rete ridges, prominent hyperkeratosis, and minimal spongiosis. An increased number of Langerhans cells in the epidermis, and macrophages dominate the dermal mononuclear cell infiltrate. Mast cells are increased in number & fully granulated. Increased numbers of eosinophils showing various stages of degeneration. In both acute and chronic lesions: The endothelial cells exhibit E-selectin, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1
Systemic Immune Response In AD
Elevated numbers of circulating eosinophils .
Increased serum immunoglobulin E (IgE) levels.
Increased basophil spontaneous histamine release
Increased expression of CD23 on mononuclear cells
Chronic macrophage activation with increased secretion of granulocyte macrophage colony-stimulating factor (GM- CSF), prostaglandin E2 (PGE2 ), and interleukin-10 (IL-10)
Expansion of IL-4–, IL-5–, and IL-13–secreting Th2-type cells
Decreased numbers of interferon-γ (IFN-γ) secreting Th1- type cells
Increased serum sIL-2 receptor levels
Increased serum eosinophil cationic protein, eosinophil- derived neurotoxin levels, and eosinophil major basic protein levels
Increased urinary eosinophil protein
Biphasic pattern of cytokine expression in atopic skin lesions Acute skin lesions are rich in TH 2 (IL-4 and IL-13) cytokine expression. Chronic skin lesions : increased expression of IL-5 and IFN-gamma and IL- 12, with significant decrease in IL-4 and IL-13 as compared with acute lesions. IL-12 in chronic AD skin lesions plays a key role in TH 1 cell development IL12 expression in eosinophils or macrophages initiates the switch to TH 1 cell development in chronic AD.
Factors affecting the differentiation of helper T cells in AD 1-Role of Cytokines environment 2-Genetics 3-Pharmacologic Factors 4-Costimulatory Signals 5-Chemoattractant Factors
1-Role of Cytokines environment: TH 1 cells are induced by IL-12 produced by macrophages and dendritic cells. IL-4 inhibits IFN-gamma production and down-regulates the differentiation of TH 1 cells. IL-4 promotes the development of TH 2 cells. T cells in unaffected skin and acute skin lesions& circulating T cells, express increased amounts of IL-4, IL-5, and IL-13.
2-Genetics: The presence of a clustered family of cytokine genes (IL-3, IL-4, IL-5, IL-13, and GM-CSF) on chromosome 5q31-33.
linkage of AD to chromosome 1q21, the region containing the epidermal differentiation complex (EDC), was reported ِAtopic skin lesions revealed altered expression of genes located within the EDC, in particular up regulation of S100A8 and S100A7 and down regulation of loricrin and filaggrin(FLG)( loss-of- function mutations in the filaggrin FLG gene) , compared with healthy control samples
The epidermal differentiation complex (EDC) is a cluster of genes on chromosome 1q21 encoding proteins that fulfil important functions in terminal differentiation in the human epidermis, including filaggrin, loricrin, S100 proteins and others. Variation within EDC genes plays an important role in the pathogenesis of three common skin disorders, ichthyosis vulgaris, atopic dermatitis (AD) 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-Pharmacologic Factors: Leukocytes from patients with AD have increased cyclic adenosine monophosphate (cAMP)-phospho- diesterase (PDE) enzyme contributing to the increased IgE synthesis by B cells and IL-4 production by T cells Elevated cAMP-PDE in atopic monocytes contributes to the secretion of increased levels of IL-10 and PGE2 & inhibits IFN- gamma production by T cells .
4-Costimulatory Signals: Generation of TH 2 cells is dependent on the interaction of cluster differentiation (CD) 28 with B7.2 expressed on B cells of patients with AD. Langerhans' cells in the lesional skin of AD express B7.2 .
5-Chemoattractant Factors The chemokines stimulating migration of inflammatory cells to the skin are expressed by keratinocytes , endothelial cells and, dendritic cells . The chemokines, monocyte chemotactic protein-4, and eotaxin in AD skin lesions induce chemotaxis of eosinophils and Th2 lymphocytes into the skin. Leukotriene B4 is also released on exposure of AD skin to allergens acting as a chemoattractant for the initial influx of inflammatory cells
Factors contributing to Skin Localization of Allergic Disease 1-Route of allergen sensitization. 2-Tissue chemokine expression. 3-Expression of homing receptors on memory effector T cells: regulated by interaction of expressed T-cell homing receptors with vascular endothelial-cell surface antigens. The cell adhesion molecule that results in T- cell homing to the skin is termed cutaneous lymphocyte-associated antigen (CLA).
Mechanisms of Chronic Skin Inflammation in AD 1-Epidermal keratinocytes produce increased levels of chemokines enhancing the chemotaxis of eosinophils. 2-Mechanical trauma: induces the release of TNF-α and many other proinflammatory cytokines from epidermal kera-tinocytes. 3-Enhanced production of GM-CSF by epidermal keratinocytes and infiltrating macrophages plays an important role in maintaining the survival and function of monocyte-macrophages, Langerhans' cells, and eosinophils.
4-The prolonged survival of eosinophils:due to Increased IL-5 expression during the transition from acute to chronic AD and secretion of autocrine factors inhibiting cell apoptosis 5-Colonization by superantigen-producing Staphylococcus aureus: Superantigens stimulate epidermal macrophages & Langerhans cells to produce IL-1, TNF, and IL-12 inducing the expression of E-selectin on vascular endothelium, allowing an initial influx of CLA+ memory/effector cells.
6.- The environmental triggers: Xerosis , Contact and aeroallergens, Infectious agents (lipophylic yeast,dermatophytes,herpes simplex virus,……….), Foods( eg.egg ,wheat, peanuts ),Climate and Psych.
The xerotic epidermis due to ceramides reduction & loss-of-function mutations in the filaggrin (FLG) gene ( impaired barrier function), provokes and sustains inflammation by activation of an epidermis-initiated cytokine cascade. The impaired barrier function of atopic skin allows greater absorption of irritant 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 psoriasis inflammatory reaction
Proposed criteria for the diagnosis of AD. Essential Nonessential Atopy (personal or family history) Xerosis Pruritus Keratosis pilaris Eczematous lesions Pityriasis alba Vascular instability Allergic shiners
Anterior capsular cataracts
Therapeutic approaches and implications AVOIDANCE OF IRRITANTS(eg, detergents, soaps, and chemicals) AVOIDANCE OF ALLERGENS(food and aeroallergens).
HYDRAT A ION and MOISTURIZERS
Adequate rehydration preserves the stratum corneum barrier, minimizing the direct effects of irritants and allergens and maximizing the effect of topically applied therapies
Very hot water : avoided to prevent both vasodilation, triggering pruritus& damage to the skin barrier caused by scalding.
Baths : followed by the immediate application of an occlusive emollient( ointment-based ) over the entire skin surface to retain moisture . • Cream-based alternatives : weaker occlusive effects &used only if the ointment-based emollients are not well tolerated. • Ceramide-dominant, barrier repair topical emollient: : a safe& useful in the treatment of A D • Wet dressings :used on dry lichenified lesions : improve hydration & increase the penetration of topical corticosteroids.
Reduction of bacterial (eg, S aureus) colonization With topical antibiotics or brief courses of oral antibiotics is especially useful in AD patients with crusted or exudative disease. Topical corticosteroids - Applied only to areas of acute exacerbations, emollients are used over the remainder of the skin. -The absorption of topical steroids : better through hydrated skin:, the ideal time for application is within 3 minutes of taking a bath. - Creams generally : tolerated well but are less moisturizing than ointments • Ointments : the most moisturizing steroid vehicles( best on thickened lichenified plaques ).
Systemic corticosteroids In patients with severe treatment- resistant A D. Oral corticosteroids improve the lesions of atopic dermatitis. Flare occurs when these medications are stopped. . The potential for a rebound effect can be decreased by tapering the drug while increasing topical corticosteroid treatment and aggressively hydrating the skin.
ANTIHISTAMINES AND ANTIDEPRESSANTS Sedating agents (hydroxyzine (Atarax) and diphenhydramine (Benadryl) : effective in controlling pruritus Tricyclic antidepressants : doxepin (Sinequan) & amitriptyline (Elavil) have an antihistaminic effect, inducing sleep and reducing pruritus Topical forms of doxepin ,diphenhydramine (cream, gel or spray forms) and benzocaine are systemically absorbed. They can cause allergic contact dermatitis.
PHOTOTHERAPY Administered as ultraviolet A (UVA), ultraviolet B (UVB) or combined UVA and UVB. Psoralen plus UVA (PUVA) photochemotherapy may be a treatment option in patients with extensive refractory disease.
To T pical Ta T crolimus & Pimecrolimus
Tacrolimus & Pimecrolimus bind a cyclophilin-like cytoplasmic protein & macrophilin 12 in order
These complexes inhibit calcineurin, interfering with gene transcription of multiple cytokines.
Both drugs inhibit degranulation and the synthesis of mast cell mediators and cytokines.
Tacrolimus decreases the expression of activation molecules such as interleukin-2 receptor (IL-2R) (CD25), CD80, CD40, and MHC class I and II.
Tacrolimus has an inhibitory effect on proliferation induced by staphylococcal enterotoxin B in peripheral blood mononuclear cells (PBMCs) from patients with AD.
Systemic immunomodulators Cyclosporine (Sandimmune)(5mg per kg PO) : effective in patients with refractory atopic dermatitis. It binds a cyclophilin protein, inhibiting calcineurin, interfering with gene transcription of multiple cytokines . Mycophenolate Mofetil(MMF) MMF): an inhibitor of de novo purine biosynthesis. Lymphocytes depend on de novo purine biosynthesis and are affected significantly by the action of MMF. An initial dose of 1 g of oral MMF daily during the first week and 2 g daily for another 11 weeks is used in severe A D.
Systemic immunomodulators(cont..) Interferon-γ Interferon gamma is a Th1 cytokine suppressing IL-4–mediated IgE production and is beneficial , effective and safe in the treatment of moderate-to-severe AD. Clinical improvement in their patients correlated with reductions in white blood cell counts, eosinophil and lymphocyte counts, and with normalization of the CD4-to- CD8 ratio among lymphocytes. Intravenous Immunoglobulin(IVIg) Used in severe AD due to anti-inflammatory and immunomodulatory properties. IVIg reduces IL-4 protein expression in AD and decreases in ICAM-1, ELAM-1, and ECP levels. IVIG's role in apoptosis, and Fc receptor function and its influence on cytokine cascades Dose: 2 g/kg per month for seven infusions
Alogrithm :Tre T atment of atopic dermatitis.
Conclusion and Future directions Corticosteroids, UV therapy including NB UVB(311 nm) and the immunosuppressant macrolides are all therapeutic agents that are likely to be effective in controlling the complex inflammatory cascades of chronic AD. Given the central role of TH 2 cytokines and chemokines in the development of AD, strategies directed at reducing TH 2 responses and blocking the action of chemokines by antagonists of relevant receptors will be important. The potential role of IFN-γ, IL-12, and IL-18 in restoring the shift toward a more balanced TH 0 response with equal production of TH 1 and TH 2 cytokines warrants studies .Further studies upon the cytokines blocking agents may present a safe and effective modality for AD therapy