he skin is the body's largest organ. Fifteen percent of the average adults weight is skin, and it covers a surface area of nearly 2 square meters. The importance of this complex organ to our survival is illustrated by the high mortality rate of people who have been badly burned. Skin is a peculiar organ with regard to its microcirculation. The dermal vasculature is enriched with abundant anastomosis. It forms a single compartment where blood can be pulsed in any direction. Under various pro-inflammatory stimuli, endothelial cells express diverse adhesion molecules whose specificity leads to the intradermal collection of specific leukocyte types (T-cells). Such basic mechanism is the origin of all inflammatory dermatoses. It is possible and even probable that some antihistamines, flavonoids and antiseptics modulate in a beneficial way the expression of some adhesion molecules (1). 

SKIN FUNCTION

 

Protection against physical trauma and harmful substances and microbes.
The skin plays a vital role in regulating body temperature.
Helps maintain fluid and electrolyte balance.
It is an important sensory organ that transmits sensations such as pressure, touch, warmth, cold and pain

 

Skin Structure (fig.1)
The skin has three main layers:
 

The epidermis is the thin, protective outer layer.
The dermis is the tough, elastic second layer.
The subcutaneous tissue is the layer of fatty and connective tissue beneath the dermis.

 


 

The Epidermis
It is a layered epithelium made up of five distinct cell layers:

Stratum Corneum (Horny Cell Layer)
Stratum Lucidum (Clear Cell Layer)
Stratum Granulosum (Granular Cell Layer)
Stratum Spinosum (Prickle Cell Layer or Spinous Cell Layer)
Stratum Germinativum (Basal Cell Layer)

The skin is a continuous process of self-renewal, and each epidermal layer corresponds to a specific stage in this process, which is called keratinization.

Normal keratinization and desquamation depends on the presence of healthy stratum corneum, in which cells are manufactured and shed at normal rate.

The Dermis
The dermis is 20 to 40 times thicker than the epidermis, This skin layer provides a flexible support structure and encloses blood vessels, nerves, and skin appendages (eccrine and apocrine sweat glands, hair follicles and sebaceous glands). Blood vessels in the dermis provide nutrition to the skin, help maintain a constant body temperature, and provide circulating white blood cells that help defend against infection and foreign substances. The eccrine sweat glands help regulate body temperature by manufacturing and excreting sweat onto the skin. Apocrine sweat glands, which are responsible for body odor which is produced when bacteria decomposes the apocrine sweat, which itself is odorless.

Sebaceous glands, which produce the oily substance sebum, are located deep in the dermis. These glands are most abundant on the scalp, face, upper back, and chest. Sebaceous glands are usually associated with hair follicles, forming what is called the pilosebaceous (pilary+sebaceous) unit. The pilosebaceous unit is the site of developing acne.

The Subcutaneous Tissue
It is a layer of fat that lies beneath the dermis and acts as an insulator and shock absorber. These tissues also store energy in the form of calories as a reserve nutritional source.

Dermatitis
Skin disease is seen commonly in internal medicine since many general medical disorders have cutaneous manifestations. The most common of these is dermatitis, which suggests perhaps that the most important area for internal medicine skin curricula would be the treatment of dermatitis.

Allergic contact dermatitis (Fig 3 A , B, C &D .)
Contact allergy is an allergic skin reaction from contact with a substance that is usually harmless to others. The commonest clinical manifestation is an itchy rash that develops over a few days, after skin contact with a substance. The affected area first becomes itchy, then red and swollen with vesicles (water bubbles). 
A substance that can cause contact allergy is called a contact allergen. Common contact allergens are:
 

1. Metals e.g. nickel in watch straps, chrome in cement
2. Skin care products e.g. fragrances, lanolin
3. Medication e.g. flavine, neomycin

 


Fig (3 A, B, C&D)

Allergic contact dermatitis, also known as contact hypersensitivity, is a T-cell-dependent skin disease with the kinetics of a delayed-type hypersensitivity response. Although this disorder is rarely life threatening, the costs to society of occupation-related allergic contact dermatitis are high. If the contact-sensitizing antigen is a compound in the workplace that is impossible to avoid or that cannot be identified, the problem may lead to an inability to work in that environment (2).

ATOPIC DERMATITIS
Atopic dermatitis is a common, intensely pruritic skin disorder that is challenging and frustrating to treat (3). This disorder, primarily occurring in infants and children, is commonly seen in pediatric dermatology practice. Onset is within the 1st year of life in 60% of cases and within the first 5 years in 85%, and is thought to affect about 10-15% of the population. Atopic dermatitis clears in about 40% of children and persists in some adults as hand dermatitis. 

Atopic dermatitis is a genetic disorder influenced by environmental factors. The mode of inheritance and genes involved are not clear. The high concordance rate of 77% in monozygotyic twins (15% in dizygotic twins) and the obvious familial occurrence support the genetic theory (4). Atopic dermatitis can be viewed as an exaggerated cutaneous immune response to environmental antigens. Patients with this disorder have a humoral response characterized by IgE antibodies associated with T cells that produce type 2 cytokines.
The antigens that induce such responses are termed allergens, and the allergens frequently responsible for atopic dermatitis are derived from the house-dust mite

The function of type 2 T-cell cytokines:
 

Promote the growth and activation of eosinophils (interleukin-5).
Switch the antibody isotope from IgM to IgE (interleukin-4 and interleukin-13).
Cause reduction in cell-mediated immunity (interleukin-10) (5). There is a definite defect in cell-mediated immunity within the skin of patients with atopic dermatitis and increased susceptibility to cutaneous viral and fungal infections, yet these patients are not systemically immunosuppressed.

 

The chronically dry skin of most patients with atopic dermatitis has prompted investigators to assess epidermal lipids. There is a significant decrease in ceramide concentrations in involved and uninvolved skin (6). 

sphingomyelin acylase, an epidermal enzyme, has been identified in the stratum corneum of patients with atopic dermatitis. One of the products of this enzyme, sphingosyl-phosphorylcholine may be a potent modulator of epidermal-cell function, inducing prostaglandin-E2 synthesis and possibly contributing to inflammation in atopic dermatitis (7). 

Filaggrin, a precursor of so-called "natural moisturizing factors" has been also found to be decreased in non-lesional atopic-dermatitis skin (8). 

Atopic dermatitis occurs in three main age-related stages that may be separated by periods of remission or overlap:
 

The infantile stage up to age 2 years, is typified by highly pruritic, red, scaly, crusted, and sometimes weeping patches on both cheeks and on the extensor parts of the extremities. Eczematous changes of the scalp and wheal formation may also be seen. The napkin area is generally spared and early infantile atopic dermatitis may be difficult to distinguish from seborrheic dermatitis on clinical grounds alone.
The childhood stage from 2 years to 12 years shows papulation rather than exudation, and occurs in the flexural areas, especially the antecubital and popliteal fossae, the volar aspect of the wrists, ankles, and neck. Thickened plaques show lichenification and excoriation. In black children, follicular papular lesions are prominent and striking and hypopigmentation and hyperpigmentation may cause parents concern
In the adult stage, from puberty onwards, patients have had few or no skin problems since infancy or may have suffered a chronic relapsing course with periods of remission. Lichenification occurs in the flexural areas and facial involvement is common, especially the forehead and periorbital regions. The wrists, hands, ankles, feet, fingers, and toes are often involved.

 

Pruritis is such a cardinal feature of atopic dermatitis that its absence may suggest another diagnosis even if many of the other symptoms are strongly characteristic. Most patients with atopic dermatitis have a personal or family history of atopy (9).

Complications:
Staphylococcus aureus and beta-hemolytic streptococci commonly colonize or secondarily infect the skin of patients with atopic dermatitis. Eczema herpeticulum is a serious viral complication in which painful monomorphous vesicles suddenly develop with oozing, crusting, and erosion. Other viral complications, especially in children, are recalcitrant warts and molluscum contagiosum (10). 

Ocular complications of atopic dermatitis of long duration include periorbital pigmentary darkening, eyelid dermatitis, keratoconjunctivitis, cataracts, ocular herpes simplex, and, rarely, retinal detachment. 
Several psychological disturbances have been described in patients with atopic dermatitis that are probably reactions to the chronic disease process. Nevertheless, sleep disturbances have been shown in atopic children that have substantial effects on daytime psychological functioning (11).

ACNE VULGARIS (PIMPLES)
Acne is a common skin condition, which consists of blackheads, whiteheads, red spots, and sometimes-deeper boil-like lesions called nodules or cysts. It afflicts most people during the teenage years. However, the disease may affect women in their thirties. The exact cause is unknown. One theory is that when hormone levels increase during puberty, the skin of the acne- prone person reacts by producing excess sebum (oils). The bacteria (Propionibacterium acnes Staphylococcus aureus, and Staph. Epidermidis) found on the skin alter these oils to produce substances that cause acne. The hair follicle, the site of acne may get plugged with dead skin cells. Sebum and bacteria may accumulate and cause pimples.

SENILE PURPURA
The skin of an aged person is thinner and easily disrupted. Blood vessels, too, are easily disrupted, resulting in bruises called senile purpura. Senile purpura is commonly seen on the forearms. Its presence does not indicate vitamin deficiency or a bleeding disorder. The skin heals slowly following injury.

LICHEN PLANUS
These lesions represent another important but less common category of papulosquamous disease. Lichen planus more often involves flexural areas, particularly the flexural surface of the wrist in contrast to psoriasis, which is more typically found on extensor surfaces. The character of the scale of lichen planus also differs from that of psoriasis. The lesions of lichen planus frequently show a reticulate or lacy white pattern called Wickham's striae. Lichen planus also typically produces lesions, which are flat-topped, and polyangular (rectangular or polygonal in shape) rather than rounded papules.

XEROSIS/ASTEATOTIC ECZEMA
The skin becomes dry and flakes easily as the oil contents of skin decreases with age. Dry skin becomes itchy. Sensation of dryness is common. 

Dry skin has a rough and finely flaking or scaly surface. These are seen in the upper back and the limbs, especially the shins. Sometimes asteatotic eczema occurs in areas of dry skin. These are seen as poorly demarcated, scaly round red patches. Sometimes a distinctive appearance of red scaly fissures in an irregular netlike pattern resembling cracked porcelain is seen.

ROSACEA
Rosacea is another very common condition in primary care often mistaken for lupus. When there is prominent rhinophyma the diagnosis is relatively easy to make. However, rosacea should be considered in any patient with central facial erythema provoked by emotion, alcohol, exertion, warm meals, warm liquids, or spicy foods. 
Most patients are very fair-skinned. Some patients presents not only with erythema of rosacea, but also the papular or pastular component as well.

BLISTERING DISORDERS
Herpes Simplex: It is a viral disease. Herpetiform vesicular disease implies vesicles clustered on an Erythemetous and often indurated base. 

Herpes zoster: Is a common blistering disorder common in elderly in which reactivation of the chicken pox that an individual had when young. This presents as a band of blisters on one side of the head or body or along one limb. It can be associated with severe pain.

MONILIASIS/CANDIDIASIS
This fungal infection is common on the lip area and genitals of persons with diabetes, those taking oral steroids and on long-term antibiotics. It is itchy and the rash is red with white flakes. Females may have a genital discharge and itch.

GENERALIZED DERMATOPHYTE (TINEA CORPORIS)
Dermatophyte infection is another important category of papulosquamous disease. In the very young and in the very old or the otherwise immunocompromised, extensive tinea corporis can mimic most of the generalized papulosquamous diseases.


The pathogenesis of common skin diseases
In order to understand the pathogenesis of the common Skin disorders, one should be acquainted with the following processes that could involve the skin in various pathological disorders.

Inflammation And Immune Responses:
Inflammation and the immune response are two interrelated processes the skin manifist to defend itself and the body it encloses.

Inflammation: is a complex series of vascular and cellular changes that helps repair of damaged tissue. Dilatation of capillaries causes redness (erythema), and leakage of plasma into the skin causing swelling (edema) and heat.

Immune response: is orchestrated by the immune systems, an intricate mix of cellular (T-cells), molecular, and and antibody components (B-cells) that protects the body against invaders. An invader that the immune system recognizes as harmful is called an antigen. When the immune system recognizes a foreign antigen it responds by producing one or both of two types of defenders:
 

The B- lymphocytes that produce antibodies, which are molecules that circulates in the bloodstream and neutralizes antigens and is called immunglobulin (Ig). The most common blood circulating immunoglobulins are IgG, IgM and IgE (IgE antibodies increase in hypersensitivity reactions).
The T cell. T cells assault antigens directly by producing substances called lymphokines. Lymphocytes are able to recognize foreign antigens because they have a sort of memory, they remember an invader from a previous encounter and are programmed to destroy those cells.

 

However, sometimes, abnormal immune response due to abnormal immune system does occur and the immune system does mistake a harmless substance, such as pollen or wool, as harmful antigen. The subsequent immune response is called allergic reaction. Although inflammation and immune response interact to protect and defend the skin, these defenders also produce common skin problems, which send patients to dermatologists for medication to treat erythema, swelling, lesions, itching and other symptoms. The most common skin disease seen by the internest is Dermatitis.

The Role of the Cellular Immune System (T Cells) in Common Dermatological Disorders


(Fig.2)

Disruption of the skin is the primary stage that leads to the most damaging consequence that is invasion by pathogenic microorganisms.

The spectrum of insults that cause disruption of the skin are:
 

Chemical agents.
Thermal and electromagnetic radiation.
Mechanical trauma.

 

The need for an effective mean of protection against this challenge has been a fundamental force behind the evolution of the immune system. 

The role of Celluar immunity (T cells) in dermatological disorders: The T cells act in the following steps (Fig.2) (12). When an offending antigen is introduced epicutaneously through intact skin. The sensitizing antigens are typically unstable reactive molecules that can form complexes with host proteins. The cell-presenting antigen migrates to the local skin draining lymph nodes.
 

1. The naive T cell of the immune system encounters the antigen for which it is specific on an antigen-presenting cell in a skin- draining lymph node.
2. The naïve T cells is activated and becomes a memory T cell with the expression of cutaneous lymphocyte antigen (CLA) and a distinct although undefined set of chemokine receptors. 
3. CLA- positive T cells possess the molecular keys that allow them to migrate to skin the site where the antigen was first encountered by the host where they proliferate and express activation molecules, and undergo the transition to memory T cells (13). Thus, memory T cells in inflammatory skin diseases express CLA on their surface; in contrast, T cells in inflammatory diseases involving tissues other than skin are predominantly CLA-negative (14). These CLA positive cells, which are generated in lymph nodes draining skin and are recruited back to the skin during inflammation, mediate many common skin diseases, including allergic contact dermatitis, psoriasis, atopic dermatitis, alopecia areata, drug-related eruptions, and lichen planes. (15). The patterns of T-cell movement and migration that mediate cutaneous immune surveillance are central to an understanding of the clinical and pathological features of T-cell-mediated skin diseases. 

 

CLA-Positive T Cells and Cutaneous Inflammation:
 

CLA-positive T cells represent 10 to 15 percent of all circulating T cells in peripheral blood.
Although they have some features in common (e.g., their expression of CLA and certain chemokine receptors), their T-cell antigen-receptor specificities are quite heterogeneous.
Once activated, they may be capable of producing either type 1 T-cell cytokines (interferon- (gamma), interleukin-2, and lymphotoxin) or type 2 T-cell cytokines (interleukin-4, 5, 10, and 13). 

 

This heterogeneity of phenotype and function is likely to be important for a successful and flexible host response to the plethora of distinct pathogens encountered in skin. 

Thus, cutaneous inflammation preferentially recruits memory T cells that have been activated by skin-related antigens because circulating CLA-positive T cells have previously encountered antigens in lymph nodes draining skin (16). For T cells to perform effector functions in skin, however, they must recognize antigen through their antigen receptors. They then become activated, producing effector molecules, including type 1 or type 2 T-cell cytokines. Therefore, only CLA-positive T cells that actually encounter the antigen for which their antigen receptor is specific will be activated during a given episode of cutaneous inflammation. These cytokines (and possibly direct cell-mediated injury of keratinocytes) induce the clinical pattern of cutaneous inflammation that is characteristic of each skin disease

Colonization and infection with Staphylococcus aureus and streptococci has been reported to exacerbate Atopic Dermatitis and psoriasis. Recent studies demonstrating that bacterial toxins can act as superantigens provide mechanism(s) by which S. aureus and streptococci could mediate an inflammatory skin lesion that consists predominantly of activated T-cells and monocytes. These observations provide a new direction for the development of novel approaches for the treatment of skin inflammation (17).

The Role of The Free Radical Nitrous Oxide

The gaseous free radical nitrous oxide is an important biologic mediator with physiologic and pathophysiologic roles in nearly every organ system. Recent progress has allowed the identification of the nitrous oxide pathway in several cell types that reside in the skin, including keratinocytes, melanocytes, Langerhans cells, fibroblasts, and endothelial cells. Convincing evidence suggests that nitrous oxide synthesis in these cells can be modulated by a diverse of inflammatory and immune stimuli, and thereby contributes to the pathogenesis of several human skin diseases. Characterization of these intrinsic and extrinsic regulatory stimuli of nitrous oxide synthesis has afforded substantial insights into the role of nitrous oxide in inflammatory, hyperproliferative, and autoimmune skin diseases, as well as skin cancer, and may ultimately form the basis for therapeutic intervention (18).

Conventional treatment of atopic dermatitis

Topical Corticosteroids
Topical corticosteroids are the mainstay of conventional therapy for atopic dermatitis and may be used in conjunction with topical antibiotics. 

The potency, concentration, and the vehicle of topical corticosteroids have to be selected with regard to the localization and morphology of the lesions to be treated. Efficacy has to be weighed against potential adverse effects, which mostly manifest on the skin (such as atrophy, striae distensae, purpura, telangiectasia, cutaneous infections), and only rarely as hypercorticolism due to systemic absorption. Contact allergy to corticosteroids is not rare. Hypersensitivity occurs especially in individuals who have been suffering for years of atopic dermatitis, Oral or parenteral administration of corticosteroids to sensitive individuals causes exacerbation of pre-existing contact dermatitis or widespread allergic cutaneous drug reactions. Cross-reactions to other corticosteroids occur frequently (19). Although systemic corticosteroids are very effective for severe, acute flares of atopic dermatitis their repeated or chronic use may lead to severe adverse effects.

Oral antibiotics
It is used to treat staphylococcal colonization or infection is frequently helpful.

Oral antihistamines
It may help decreasing scratching in some patients due to its sedative effect, but their role is limited. Topical antihistamines may be used for pruritis but they may cause allergic contact dermatitis.

Phototherapy
Phototherapy is especially helpful for atopic dermatitis unresponsive to topical treatment. The combination of ultraviolet (UV) A with UVB seems to be superior to UVB therapy alone (20). 

High-dose UVA-1 therapy is especially useful in acute exacerbations of atopic dermatitis and for relief of symptoms, often with complete clearance on the face, which is very sensitive to side effects of topical steroids. The long-term effects of high-dose UVA1 are not known, and this therapy should not be used in children.

Cyclosporin
It is dramatically effective in the treatment of atopic dermatitis in children and adults, however the risk of hypertension, renal toxicity, and possible propensity for malignant disorders cannot be ignored. Therefore, the risk-benefit ratio should be carefully assessed (21). 

Azathioprine
It is also effective for the treatment of atopic dermatitis but there are no prospective controlled studies to support its use (22). One of the main drawbacks of azathioprine therapy is its slow onset of action, usually 4-6 weeks. Because of the danger of myelosuppression, strict monitoring of white blood cell and platelet counts is essential (23).

  • March 10, 2015
  • DermaMed Pharmaceutical Inc.

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