Skin Disorders - Part 1 - Pharmaceutical Care B - PDF

Skin disorders Pharmaceutical Care B Richard Summers Part 4 Acne Classifications Three main types Comedonal acne – initial phase Onset of puberty Nose progress to forehead, cheeks, chin Papulopustular acne Most common type – involves reddish pimples Mild to severe M...

Skin disorders Pharmaceutical Care B Richard Summers Part 4 Acne Classifications Three main types Comedonal acne – initial phase Onset of puberty Nose progress to forehead, cheeks, chin Papulopustular acne Most common type – involves reddish pimples Mild to severe Most common on face (also involves neck, chest, back and upper arms Nodulocystic acne More severe form Involves presence of large, deep lesions (nodules) as well as acne cysts (face, back, chest – commonly males) Most people can have a combination Acne Vulgaris Acne, most common in teenagers, can occur in adults and in the first few weeks of life (transplacental hormone influences), occasionally starts at age 8 or 9. At ages 12-14, hormone testosterone involved. In general, estrogens decrease sebaceous gland activity and androgens increase it. Males experience a peak in testosterone at age 18, female testosterone peaks at 31. Oral contraceptives (estrogenic effects) have a mild effect on acne. 15% adolescents will seek medical attention 3 – 5% acne patients develop cystic scarring acne Acne Lesions Closed comedo (whitehead) Open comedo (blackhead) Inflammatory papule Pustule Cyst Excoriation Acne Sebaceous follicle Increased production Skin less likely to shed Increased cells cause pore to become blocked => comedone Comedone grows over time (~5mths for formation of a whitehead) Either dilates (becoming a blackhead) Or ruptures (inflammation) Pathology of Acne: acne results from inflammatory reactions to keratin and sebum that have spilled into the dermis keratin and sebum breakdown products are highly irritating substances that excite both a neutrophilic and lymphocytic cell infiltrate intense inflammation in the dermis around the hair follicle eventually it may resolve with scarring an oilier face and upper trunk are found in acne significant comedones usually precede inflammatory lesions by two to three years acne is polymorphic, with several different types of lesions at any one time It can be graded as mild, moderate or severe for all types Acne Emotional: low self esteem occurs, especially in the teenage years, causing depression Factors affecting acne cosmetics: ‘oil acne’ develops due to application of potentially comedogenic substances in cosmetics premenstrual flare: present in 70% of women sweating: from working in hot humid environments stress: this is a doubtful cause in itself, but is worsened by the presence of acne Common acne myths dispelled Acne is not caused by food. It is not caused by eating chocolate, drinking soda, or eating greasy foods like french fries or pizza. The sun doesn't make acne better. When your skin is tan, pimples may seem better because the redness is harder to see. The sun will not make acne go away. Acne is not caused by dirt or sweat. Acne is not due to ‘hormonal imbalance’ Acne is not related to sexual behaviour Things that worsen Picking at pimples can leave red spots on your face. If your hands are dirty, it can also make the pimple worse. The redness usually clears up after several months. Acne can cause scarring Acne can take months to clear up. How can acne be prevented? The best way not to get acne is to prevent it. Once you have acne, you can't cure it. You just have to wait for it to heal. Gently wash face twice a day with a mild soap and warm water. Others Most people do not get acne after their teenage years. Some women have acne because of their periods. Gently wash your face twice a day with a mild soap and warm water. Don't scrub your face. It can irritate the skin and make acne worse. Hair gels and hairspray can irritate your face if they are put near the hairline. Washing your hair helps keep oil away from your face. Wash your face after exercising. Mild cleansers, can be used to wash the face. Antibacterial pads can also be used to clean the face. Exfoliating cleaners and scrubs can be used. They remove the outer layer of the skin and open pores. Drugs that can cause acne are: ACTH (adrenocorticotrophic hormone) corticosteroids dexamethasone in neurosurgical patients anabolic steroids used in bodybuilding androgens in females the oral contraceptive pill iodides and bromides isoniazid in those who inactivate the drug slowly dantrolene danazol quinidine lithium azathioprine Acne Oily seborrhea and acne often go hand in hand, and there is often a family tendency. Types of acne: comedone acne, papular acne, acne excoriee des jeunes filles, acne pustulosa, atrophic acne, indurated acne, cystic acne, acne cachecticorum, acne conglobata (tunnelling), acne keloidalis, tropical acne, acne neonatorum and chloracne (occupational –exposure to halogenated cpds). Fulminans (rare) rapid onset many tender pimples on face and chest (exclusively in boys 13-16) Chloracne Dioxin fulminans vulgaris Newborn acne Acne neonatorum Usually occurs at birth Mostly affects boys Appears as comedones (blackheads and whiteheads) some pimples on cheeks or forehead Arises from effects of mother’s hormones Resolves on its own More severe treat with topical Abs Infant acne Third to sixth month Boys> girls Involves face Presents with comedones, pimples, and even cysts May have underlying hormonal problem Treat same way as adult Acne Vulgaris Pathogenesis of Acne Vulgaris sebaceous gland hypertrophy and increased sebum production plugging of pilosebaceous follicle => a small closed papule (comedo) called a whitehead. Hyperkeratosis - mouth of the hair follicle blocks the duct. If duct opens, compacted follicular cells at tip give comedones appearance - blackhead. lipase hydrolyses triglycerides in sebum to free fatty acids Acne Anaerobic bacterium, Propionibacterium acnes, degrades triglycerides in sebum to free fatty acids and glycerol and => chemotactic factors and inflammatory mediators These & FFA => inflamed lesions of pustules, nodules or multilocular cysts if the lesions coalesce. Inflammatory lesions can scar, with permanent disfigurement. Genetic background to acne determines the rate of sebum production, in response to androgens. Androgens, at puberty, induce hypertrophy of sebaceous glands, the excess secretion rate in predisposed individuals triggers the acne. Acne Treatment How is acne treated? Many OTCs lotions and creams that treat acne, such as benzoyl peroxide. The creams work by killing bacteria. Benzoyl peroxide is a bleach. It also bleaches washcloths, towels, and clothes. For many people, washing the face twice a day with a mild soap and using benzoyl peroxide is all that is needed. retinoic acid – tretinoin (Retin-A®) antibiotics - tetracycline topical systemic isotretinoin (isotretinoin®) – for severe cystic acne Questions to ask in acne history should include age of onset, topical preparations used, family predisposition, response to any prior therapies (including side effects experienced), medications, allergies, menstrual status including whether the patient is pregnant, atopy, general health, occupation and emotional effect of the acne avoidance of all known precipitants is the first step, followed by education of the patient in appropriate skin care topical treatment alone may be indicated for mild to moderate comedonal acne with superficial inflammatory (papular or pustular) lesions that are non-scarring  systemic therapy is indicated for moderate to severe (scarring or non-scarring) acne or acne with persistent hyperpigmentation may be given alone in those who are intolerant to topicals, or in whom they have failed combination therapy is recommended Choice of topical Predominantly anticomedonal Adapalene (Differin Gel/cream) Tretinoin Azelaic acid (Acnederm Medicated Lotion) Isotretinoin Predominantly antimicrobial Benzoyl peroxide Clindamycin Erythromycin Azelaic acid Tetracycline Azelaic acid Azelaic acid is an aliphatic dicarboxylic acid that has an antibacterial action against propionibacteria effective against bacteria that have become resistant to erythromycin and tetracycline. It inhibits division of keratinocytes. Topical SE; local burning, scaling or itching, mild to moderate non-inflammatory comedonal acne, especially of the face Predominantly anti-inflammatory Adapalene Antibiotics Benzoyl peroxide Keratolytics Salicylic acids, soaps, cleansers Alpha-hydroxy acids Many topical preparations produce an irritant dermatitis, particularly in atopic patients if redness and dryness develop the agent should be discontinued temporarily until the skin settles resuming, the agent should be applied less liberally, or diluted with a non-comedogenic lotion topical treatment should be continued for a minimum of three months to adequately assess efficacy no response to treatment then compliance may be doubtful Systemic therapies 13-cis Retinoic acid (isotretinoin) Steroids (rarely in severe acne fulminans with systemic illness) Antibiotics Mainstay of treatment for pustulopapular acne initially reduce bacterial counts and have a direct anti-inflammatory effect Most effective antibiotics are tetracyclines and erythromycin tetracyclines in the form of doxycycline and minocycline are the most commonly used resistance to these antibiotics by some strains of bacteria may become a problem in the future tetracyclines are contraindicated in children under 12 and in pregnant and lactating patients erythromycin or trimethoprim are preferred alternatives in children Poor penetration into sebaceous follicles => some improvement after 2-3 months (4-6 months for max benefit). Extended Tx to avoid relapse. (tetracyclines, oxytetracycline, doxycycline). Alternatives include ciprofloxacin and cotrimoxazole. Resistance to erythromycin. Antibiotics Antibiotics should always be given for a prolonged period (three to six months or more) to achieve the best results it is often useful to combine oral and topical therapy Tetracycline, which operates by reducing the amount of lipase in the sebaceous secretion or by altering the skin flora, some of which might be instrumental in producing irritant triglycerides, wax esters and free fatty acids in the pore, can be extremely effective poor patient adherence leads to sporadic dosing Cyproterone acetate (Androcur) cyproterone acetate is an anti-androgen that can only be given to women it is given with oestrogen to prevent menorrhagia and to ensure contraceptive cover as it may feminise a male fetus if the patient is pregnant a combination preparation with ethinyloestradiol is a useful alternative in late teenage girls who want the benefit of an oral contraceptive pre-menopausal women suffering premenstrual flares may find cyproterone therapy beneficial however, its effect is slow useful in women with moderate or severe acne combined with ethinylestradiol. Reduces sebum flow by 40%. Oestrogen given with a non- androgenic progestogen. Improvement can take 2-4 months. 13-cis Retinoic acid (isotretinoin) Revolutionised Tx of severe acne over last 20yrs Expensive & highly teratogenic, use monitored & restricted to appropriate cases of severe or treatment resistant acne Tx of choice in nodulocystic and scarring acne sexually active females on isotretinoin need adequate contraception Retinoids act by reducing sebum secretion and normalising keratinisation of the follicular lining Keratolytic action, unblocks pilosebaceous follicles => allows flow of sebum to extrude the plug. Reduces sebum production by 90% by decreasing sebocyte proliferation. Topically causes erythema and scaling (start low dose). 13-cis Retinoic acid (isotretinoin) over 90% of patients have complete clearance of their acne, and in most there is no relapse patients should be informed that transient exacerbation of acne has been seen, generally during the initial period of therapy 13-cis Retinoic acid (isotretinoin) Tx course 4 - 6 months dose on weight and severity and varies from 1 mg/kg/day, to 15 mg/kg/day for truncal acne High doses => prolonged remission. predictable side effects include dryness of the lips, eyes and skin, epistaxis, mild alopecia, aches and pains it may raise lipids & occasionally LFTs patients are monitored before and during therapy can cause premature closure of the epiphyses (growth plate in bone) ; not be given readily to children who are actively growing SE; dry lips, nose and eyes, increased plasma triglycerides, and, less commonly, myalgia. Teratogenesis - major problem (avoided during and for one menstrual cycle after stopping treatment). 13-cis Retinoic acid (isotretinoin) because of the relationship of isotretinoin to Vit A, avoid Vit supplements => additive effects wax epilation should be avoided in patients on isotretinoin and for a period of five to six months after treatment because of the risk of scarring or dermatitis dermabrasion avoided & for a period of five to six months after treatment because of the risk of hypertrophic scarring in atypical areas Side effects - isotretinoin papilloedema, headache, nausea and vomiting and visual disturbances Screen patients for papilloedema and cease isotretinoin & refer to a neurologist for further diagnosis corneal opacities have occurred in patients receiving isotretinoin for acne and more frequently when higher drug dosages were used in patients with disorders of keratinisation all isotretinoin patients experiencing visual difficulties should discontinue the drug and have an ophthalmological examination Side effects - isotretinoin decreased night vision has occurred Onset often sudden, warned to be cautious when driving or operating any vehicle at night due to the possible occurrence of keratitis, patients with dry eyes should be monitored Visual difficulties refer for an expert ophthalmological examination and withdrawal of isotretinoin considered Side effects - isotretinoin LFTs - rises in alanine and aspartate aminotransferase enzymes (ALT and AST) reported. AST and lipids, should be measured before therapy and at monthly intervals during therapy and at the end of treatment – dose reduce or cease isotretinoin - elevation of serum triglycerides and cholesterol & a decrease in HDL – related to Tx duration (reversible on cessation). degree of elevation ? dose dependent doses > 1 mg/kg/day, approximately one in four patients has been found to develop elevated triglycerides while taking isotretinoin lower doses, elevated trig levels uncommon Side effects - isotretinoin acute pancreatitis, ? associated with trig levels > 8 g/l, has been reported Discontinue if hypertriglyceridaemia or symptoms of pancreatitis occur predisposing factors such as a family Hx of lipid disorders, obesity, alcohol abuse, diabetes and smoking should be assessed Lipid profile determined prior to therapy and again after about four weeks to establish if the patient has experienced any lipid response some reverse triglyceride elevations by wt reduction and restriction of dietary fat and alcohol while continuing to take isotretinoin Side effects - isotretinoin Reversible; serum lipid values usually return to normal on reduction of the dose or discontinuation of treatment high risk patients – check more often (with diabetes, obesity, alcoholism or lipid metabolism disorder) lipids and/or blood glucose Side effects - isotretinoin Hepatotoxicity Several cases of clinical hepatitis reportedly related to isotretinoin therapy 15% mild to moderate elevations of LFTs, some normalised with dose reduction or continued administration of the drug If normalisation does not readily occur or if hepatitis is suspected during treatment with isotretinoin, the drug should be discontinued and the aetiology further investigated Side effects - isotretinoin Psychiatric disorders Depression, psychosis and, rarely, suicidal ideation and attempts have been reported with isotretinoin caution in patients with a Hx of depression and all patients should be monitored for signs of depression ? mechanism of action; discontinuation of therapy may be insufficient and further evaluation by a psychiatrist may be necessary Evidence is conflicting and acne itself has been associated with psychiatric disorders Counsel and monitor for psychological symptoms Side effects - isotretinoin Inflammatory bowel disease isotretinoin has been associated with inflammatory bowel disease (including regional ileitis) in patients without a prior history of intestinal disorders patients experiencing abdominal pain, rectal bleeding or severe (haemorrhagic) diarrhoea should discontinue isotretinoin immediately Side effects - isotretinoin anaphylactic reactions Rarely reported and only after previous topical exposure to retinoids allergic cutaneous reactions are reported infrequently serious cases of allergic vasculitis, often with purpura (bruises and red patches) of the extremities and extracutaneous involvement have been reported severe allergic reactions necessitate interruption of therapy and careful monitoring Side effects - isotretinoin exercise tolerance myalgia and arthralgia may occur and may be associated with reduced tolerance to vigorous exercise isolated instances of raised CK levels have been reported in patients receiving isotretinoin, particularly those undergoing vigorous physical activity impaired renal function isotretinoin should be started at a lower dose in patients with severe renal insufficiency and afterwards adjusted according to tolerance Treatment of Acne Scars Dermabrasion and sandpapering help cure icepick scars, although less of this is being done today with the increased use of cis-retinoic acid. Carbon dioxide slush treatment is almost always helpful. Cross-hatching scarification occasionally is helpful, and chemical peeling with either 25% trichloracetic acid or phenol is effective in skilled hands. Punch and suture, or drill and Gelfoam for small deep pits occasionally are helpful. Laser resurfacing with CO2 lasers and Erbium Yag lasers are some of the more modern therapuetics for scar revision. Acne Rosacea Rosacea is a term used to describe a chronic condition (Rosaceous, rosy) characterized by diffuse inflammation of the central portion of the face with seborrhea, telangiectasia and acneiform eruptions. Result of repeated flushing, which in most instances is related to frequent intake of hot spicy foods, e.g., hot coffee, tea, soup or alcohol. Anything too hot, too cold, too sweet, too sour or too spicy aggravates the condition. Late spring, summer Lesions: Stage 1: frequent episodes of flushing Stage 2: persistent erythema and telangiectases Stage 3: papules and pustules (occasionally cysts) Stage 4: Rhynophyma – bulbous ruddy appearance of nose (occasionally oto-, mento-,or zygophyma) Anatomic distribution: Face (cheeks, forehead, chin); rarely, limbs (arms, wrists, thighs), and palms(?) Hidradenitis Suppurativa - Acne Inversa Chronic inflammatory suppurative and scarring skin disease boil-like lumps (nodules and abscesses); pus like discharge; difficult to heal open wounds (sinuses) Occurs in apocrine sweat gland-bearing skin axillae, anogenital regions, under female breast More common in females Painful “boil”, lumps hurt if pressed, can be itchy Appears usually after puberty Exact cause unknown Genetics – family members Sex hormones (Progesterone OC aggravate) Endocrine – obesity, hirsutism, polycystic ovaries Smoking Secondary bacterial infection Women x3 more than men (20-40yr age) Associated with Crohn’s disease Suspect if women complain of boils in groin! (presents small tender pustules) Hidradenitis Suppurativa - Acne Inversa Treatment; difficult, catch early, antibiotics General measures Stop smoking Wt loss, Diet, low-glycaemic, low dairy, aim for IBW Loose fitting clothing – avoid friction Hair removal (laser), antiperspirants or zeasorb powder (reduce friction) Antiseptic wash, bleach baths, acne preparations (reduce commensal bacteria) Hydrogen peroxide, (medical honey reduce malodour) Draining sinuses, simple dressing, absorbent panty-liners Medical treatment Antibiotics, topical clindamycin, Flucloxacillin Prolonged 3/12 course tetracycline or metronidazole, cotrimoxazole, fluoroquinolones Metformin ( long-term beneficial) Ocs Isotretinoin Steroids; immunomodulatory Tx (MTX, AZA, cyclosporine, biologics infliximab, anakinra) Surgical excision Analgesics Acne - Summary Plugged pores (blackheads and whiteheads), pimples, and even deeper lumps (cysts or nodules) on the face, neck, chest, back, shoulders and the upper arms. Acne affects most teenagers to some extent. However, the disease is not restricted to any age group; adults in their 20s - even into their 40s - can get acne. Whilst not a life threatening condition, acne can be upsetting and disfiguring. When severe, acne can lead to serious and permanent scarring. Even less severe cases can lead to scarring. To avoid acne scarring, treating acne early is important. Acne Treatment Choice will depend on the nature of the lesions and severity. Topical treatments do not influence the rate of production of sebum. Benzoyl peroxide has antibacterial activity against P. acnes & keratolytic action,=> reduce # of comedones. Scaling and skin irritation limits its use to short treatment periods. Topical antibacterials eg clindamycin, erythromycin and tetracycline, less effective than oral. Similar efficacy to benzoyl peroxide (use for mild to moderate acne). Treatment choice Initially non-inflammatory comedones topical treatment such as azelaic acid or retinoids. Early inflammatory lesions, a topical antibacterial or benzoyl peroxide, alone or in combination. More severe inflammatory acne usually requires topical or systemic antibacterials with topical retinoid. Systemic treatment with isotretinoin for more severe and unresponsive acne. Oestrogen and antiandrogen therapy are alternatives for women, and oral contraceptives can be of benefit. Common cause for Tx failure is non-adherence to the recommended regimen Skin disorders Pharmaceutical Care B Richard Summers Part 2 Skin part 2 Describing skin conditions Use of terms What they mean  Some terms - Primary Lesion Macule: a circumscribed change in skin colour no elevation or depression (1cm) Patch: a flat, circumscribed, discoloration of skin or mucous membrane > 1.0 cm Papule: a solid elevated lesion < 0.5 cm diameter Variations keratotic, flat-topped, follicular, umbilicated, pedunculated, necrotic and others Plaque: a raised lesion that has a greater area as compared to its elevation above the skin surface (often coalesence of papules) Wheal (hive): a rounded or flat-topped elevated lesion formed by local dermal oedema (a pale red colour in the superficial dermis, 2-3 mm to > 10 cm in diameter. Nodule: a palpable solid lesion of varying size, > 0.5 cm and less than 2 cm in diameter, which may be present in the epidermis, dermis or subcutis Vesicle: a circumscribed elevated lesion which contains free fluid Vesicles are 0.5 cm or less in diameter Bulla: a fluid-filled lesion > 1.0 cm diameter usually elevated. (blister) Tumour: sometimes used for a "nodule" > 1.0 cm in diameter. Applies to all levels of the skin, a general term for any mass, benign or malignant. Pustule: a discrete elevated vesicle or bulla of skin, usually small, containing purulent exudate composed of inflammatory leukocytes (pus), with or without cellular debris. May be superficial, deep-seated, follicular, grouped, etc. and may arise secondarily from a vesicle Macule Circumscribed change in skin colour without elevation or depression Macules are flat – They cannot be palpated Papule Solid elevated lesion usually 0.5cm or less in diameter Plaque Raised lesion that has a greater area as compared to its elevation above the skin surface Plaques are raised broad and palpable Wheal – (hive) Rounded or flat-topped elevated lesion formed by local dermal oedema Wheals are broad flares of edematous skin Nodule Vesicle Secondary Lesions Scar - a hard plaque of dense fibrotic tissue covered by a thin epidermis. A mark of injury from any sort of process (physical or pathologic). fibrous tissue replacing normal skin in areas of healing, variety of dermal and epidermal changes with wound healing, cf hypertrophic scar, keloid Atrophy - Atrophy usually refers to thinning of the epidermis leaving an easily wrinkled and/or shiny surface. Atrophy may also apply to dermal and/or subcutaneous tissue, with or without changes in the epidermis. Ulcer - loss of skin tissue or substance from the surface downward, leaving an uncovered or denuded wound that is slow to heal. Erosion - denuded skin, usually implying the loss of the epidermis. Fissure - a vertical splitting or separation of the skin. Crust - dried surface fluid, serum, purulent exudate blood, with or without tissue debris. "scab". Excoriation - a scratch mark, often with denudation of the skin to form a small ulcer. Exposure of the corium by mechanical removal of the epidermis. Scale - a thin flake of epithelium which is separated from the underlying intact skin proper. Lichenification - a thickening of the skin surface and an increase of skin markings, usually seen with chronic coalescence of papular lesions, especially atopic eczema. Vegetating - a lushly growing, proliferating, process, usually with elevated or exophytic features. More terms….. Purpura : a non-blanching erythema or violaceous colour due to extravasation of blood into the tissue Cyst: a sac containing liquid or semisolid material usually in the dermis Atrophy : a thinning of epidermis or dermis Sclerosis : a hardening or induration of skin Poikiloderma: a combination of atrophy, hyper and hypopigmentation and telangiectasis Telangiectasia: dilated superficial blood vessels, especially of the upper reticular dermal plexus => port-wine stain Atrophy  Scar After skin is injured, the healing process usually leaves a flat scar. Sometimes it is hypertrophic, or thickened, but confined to the margin of the wound. Hypertrophic scars often subside by themselves (a year or more). Tx such as injections of cortisone (steroids) can speed this process. Keloids When the scar from a cut or wound extends and spreads beyond the size of the original wound, it is known as a keloid. Keloids may vary in size, shape, and location, and are more frequent in people with skin of color. Common on the ear lobes, chest, back, or arms, keloids usually occur after an injury or infection. May occur spontaneously or as a result of a slight inflammation eg acne pimple especially on the mid- chest. Keloids frequently develop after surgery or after body piercing or burns. Depending on the location, treatment may consist of cortisone injections, pressure dressings, silicone gels, surgery, laser treatment, cryosurgery, liquid nitrogen, radiation therapy, or combination therapy. Unfortunately, keloids are difficult to treat and tend to return, sometimes larger than before. Can be itchy, tender and even painful to touch lichenification Fissure Excoriation Ulcer Scale More Terms…. acanthotic (thick) atrophy (thin) hyperkeratosis vesiculation spongiosis exocytosis erosion ulceration Acanthosis Is greek for spine or prickle and indicates a thickening of the skin through an increase in the number of prickle cells (keratinocytes that lie above the basal layer) Acanthosis of the skin may result from two mechanisms a. Increased proliferative activity of the basal cell b. Decreased exfoliation of terminally differentiated keratinocytes Clinical examples of "a" include psoriasis and chronic irritation (rubbing) Clinical examples of "b" include several hereditary dermatoses such as ichthyosis Atrophy Due to a decreased number and vertical diameter of cells and shortening or absence of the rete (network) ridges – wasting away, diminution in size of a cell, tissue, organ or part atrophy may result from a wide variety of physical, immunological and iatrogenic stimuli whatever inciting cause, the germinative cells at the basal layer respond by decreasing their proliferative activity Clinical examples of diseases that are characterized by atrophy include radiation dermatitis (physical), locally applied (iatrogenic) or increased circulating (Cushing's disease) corticosteroids, autoimmune disease (SLE, scleroderma), pressure atrophy (underlying tumors) and vascular insufficiency (stasis dermatitis) Hyperkeratosis indicates an increase in the thickness of the most superficial, fully keratinized ("cornified") layer of the skin the keratin layer is the final differentiated product of the active replicating differentiating epidermis abnormalities of the keratin layer can almost always be traced back to an underlying disturbance in the basal or prickle cell layer a wide variety of diseases, both trivial and serious, can alter the balance of the epidermal keratinocytes, hyperkeratosis is a frequent and non-specific finding in the skin clinical examples of diseases that show hyperkeratosis include psoriasis, dermatitis, and warts  Spongiosis Microscopic presence of serum within the epidermis in the extracellular space (between the keratinocytes when a small amount of fluid is present only a subtle widening of the space between keratinocytes may be seen; with larger amounts of serum, microvesicles develop since keratinocytes don't make serum, the only way for serum to make it's way into the epidermis is from the underlying dermis serum usually follows inflammatory cells into the epidermis through simple osmotic forces most common disease in which spongiosis is seen is dermatitis (eg, poison ivy) Exocytosis is the presence of inflammatory cells in the intercellular space in the epidermis presence of inflammatory cells is usually accompanied by spongiosis presence of inflammatory cells in the epidermis usually indicates an immunological response of the body's immune system to a perceived or real antigenic stimulation Langerhans cell is a bone marrow derived cell that migrates to the epidermis during foetal development and acts as the antigen presenting cell in the epidermis Dysplasia is used to describe cells that show aberrant growth and differentiation dysplastic cells lie in a continuum between benign and fully malignant represents a stop action photograph of one of the earliest and still reversible steps in the multistep process of malignancy reflected microscopically by nuclear hyperchromasia and increased cell size (disordered differentiation) and increased number (aberrant growth) may affect any epithelial cell in the body Dysplasia in the epidermis, dysplasia arises in the basal keratinocytes and is reflected by disorganization and enlargement of the cells clinically and microscopically this lesion is called an actinic keratosis if the process of malignant transformation continues, the dysplastic cells become fully malignant, invade the dermis, and are now capable of spread beyond the skin (metastasis) once the malignant cells have invaded the dermis, the lesion is termed squamous cell carcinoma (reflecting the cell of origin) Erosion is incomplete loss of the epidermis is in contrast with ulceration which is complete loss of the epidermis and frequently a portion of the superficial dermis What to look for in skin Color - melanin, carotenoids, oxy Hgb, reduced Hgb Moisture - wetness or dryness of skin Turgor - tissue hydration Hair - distribution, texture and amount Nails - pitting, thickening, colour changes, onychodystrophy, onychomaedesis, onychogryphosis, onychoschizia, subungual hyperkeratosis, pterygium, Mucous membranes - oral, ocular, genital Macular Lesions Brown Grey Slate Blue Black White Pink - Red Yellow Scale Papular Lesions With Scale Psoriasis - Pretibial lower leg - Micaceous scale Koebner Phenomenon Lichen Planus, Hypertophic Facial Papule(s) Basal Cell Carcinoma - Right Cheek - "Rodent Ulcer" with rolled border  Nodular Lesions Nodules Cutaneous Sarcoidosis - Right Cheek Nodules around Joints Skin Richard Summers Part 3 Overview ◼ Dermatitis ◼ Atopic ◼ Contact ◼ Perioral dermatitis ◼ Psoriasis  Topical applications ◼ Topical preparations - two components: a base and the active ingredient, ◼ Ointments - greases such as white or yellow soft paraffin (skin is very dry then preference is for ointment) ◼ Pastes - suspensions of powder in an ointment - to apply medications confined to one area of the skin ◼ Creams - emulsions of water with a grease - absorbed more quickly into the skin - often used as a vehicle for active ingredients ◼ Lotions - used on wet surfaces and hairy areas – Less messy ◼ Transdermal preparations Dermatitis ◼ The word "dermatitis" = inflammation of the skin. ◼ Eczema and dermatitis often used interchangeably ◼ "Atopic" refers to diseases that are hereditary, tend to run in families, and often occur together. ◼ In atopic dermatitis, the skin becomes extremely itchy and inflamed, causing redness, swelling, cracking, weeping, crusting, and scaling. ◼ Dry skin is a very common complaint and an underlying cause of some of the typical rash symptoms. Dermatitis ◼ Non-specific inflammatory response of the skin to combination of endogenous & exogenous factors. ◼ Erythematous rash ◼ Itchy ◼ Scaly ◼ Acute, weeping, crusting, blisters ◼ Spongiosis (intracellular oedema) & superficial inflammation ◼ Not a clear distinction b/w dermatitis and eczema ◼ Endogenous – atopic seborrhoeic, discoid, lichen simplex, asteatotic, varicose, hand and/or foot ◼ Exogenous irritant contact, allergic contact, photoallergic, phototoxicity  Atopic dermatitis – atopic eczema ◼ Dermatitis describes eczematous inflammation triggered by external factors. ◼ Atopic dermatitis (eczema). Often associated with asthma and hay fever and has a familial tendency. Pathogenesis determined by genetic, environmental, pharmacological and immunological factors. ◼ There are two forms of atopic dermatitis:  the extrinsic type (70-80% of cases) is associated with IgE-mediated sensitisation (a raised IgE concentration in blood)  Intrinsic type, less common, not IgE-mediated.  Atopic Dermatitis ◼ Skin reacts abnormally and easily to irritants, food, and environmental allergens becomes red, flaky and very itchy.  vulnerable to surface infections caused by bacteria. The skin on the flexural surfaces of the joints (for example inner sides of elbows and knees) are the most commonly affected regions in people. ◼ Often occurs together with other atopic diseases like hay fever, asthma. ◼ It is a familial and chronic disease and its symptoms can increase or disappear over time. ◼ Although there is no cure for atopic eczema and its causes not well understood, it can be treated very effectively in the short term through a combination of prevention (learning what triggers the allergic reactions) and drug therapy.  Atopic Dermatitis ◼ Prevalence affecting about 10-20% of children and 1-3% of adults in industrialized countries ◼ Any age, common in infants, teenager  3-7% of population at some point ◼ Although it may be familial (inherited), eczema is primarily aggravated by contact with or intake of allergens. ◼ It can also be influenced by other "hidden" factors such as stress or fatigue.  Atopic dermatitis ◼ Circulating mononuclear cells have a reduced ability to produce interferon gamma, which normally inhibits IgE production and T-helper type 2 (Th2)-cell proliferation. ◼ Production of cytokines - stimulate eosinophil activation & adhesion to vascular walls is increased => changes in the immune regulation,  Th2-cells proliferate.  Dominance of Th1 or Th2 response is partially programmed in early life, with exposure to microbial antigens promoting the normal Th1 dominance. ◼ Th1-cell responses, induced by infections, antagonise the development of Th2-cells, maybe the increasing use of antibacterials in childhood => the rise in atopic dermatitis  Atopic dermatitis ◼ Affected skin is red, scaly and extremely dry. ◼ Dryness - consequence of the inflammation - permeability barrier function of the skin is also impaired => increased transepidermal water loss. ◼ There may be vesicles and weeping and crusting over the skin surface. ◼ Scratching produces excoriation and thickening of the skin. ◼ The affected skin is infiltrated with activated T-cells, with selective recruitment of Th2-cells, and eosinophils. ◼ Increased skin carriage of Staphylococcus aureus on the affected skin may also maintain skin inflammation by activating T-cells and macrophages. Atopic Dermatitis ◼ Impetigo Ecezma – atopic dermatitis ◼ Common behind knees, elbows (flexures), wrists, face  Atopic Dermatitis - Prevention ◼ Diet: association of food allergy with atopic dermatitis has now been clearly demonstrated. Many common food allergens can trigger an allergic reaction: such as milk, nuts, cheese, tomatoes, citrus fruits (barrier before eating), wheat, yeast, soy, and corn. If avoid allergens early on, the frequency of reactions to these later in life is decreased significantly. ◼ Environment and lifestyle: Dust is a very common allergen and irritant, smoking, Animal dander (hypo-allogenic animals). Anger, stress, and lack of sleep are also factors that are known to aggravate eczema. Excessive heat (especially with humidity) and coldness are known to provoke outbreaks, as well as sudden and extreme temperature swings. ◼ Soap, shampoo, bubble bath, heavily chlorinated pools or spas, rough clothing, wool. ◼ Scratch test; allergy skin-patch, to pinpoint the triggers of allergic reactions. ◼ If the eczema is severe, it may take some time (days to weeks depending on the severity) for the body's immune system to begin to settle down after the irritants are withdrawn.  Treatment of atopic dermatitis ◼ Emollients - hydrophobic agents – soften skin. Seal skin surface & reduce water loss. Paraffin derivatives most effective (greasy poorly accepted). Aqueous creams, are more cosmetically acceptable.  ?What are available products ◼ Avoid irritants, soaps, detergents, alcohols, astringents and additives in creams such as fragrances, tea tree oil, lanolin and topical anaesthetics.  ?what are some of the soap substitutes, bath additives, shampoo substitutes ◼ Wet dressings help prevent skin fissuring and reduce scratching. ◼ Corticosteroid ointment - least potent, minimise SE. Anti- inflammatory effect - mainstay of treatment, but tachyphylaxis limits long-term value.  Treatment of atopic dermatitis ◼ Topical calcineurin inhibitors, eg tacrolimus (potent) or pimecrolimus (Elidel®) (mild to moderate), inhibit intracellular phosphatase calcineurin => reduced activation of inflammatory cells involved in pathogenesis of dermatitic lesions; T-cells, dendritic cells, mast cells and keratinocytes. Local burning is the major unwanted effect.  Caution in children increased intracellular cAMP levels.  suppresses inflammation and secretion of cytokines, eg:TNF α  Mechanism(s)not well defined ◼ Mild to moderate atopic dermatitis in 2yrs and older ◼ 28 days per treatment course (thin layer BD) ◼ ADR hypersensitivity Rn, ◼ Class adr effects: no evidence with Staquis®  ADR: dermatitis, site pain, URTI, nasopharyngitis, cough, pyrexia  Contact Dermatitis ◼ Two main types are recognised. ◼ Due to an external agent inducing direct irritation (irritant contact dermatitis). ◼ Immunological sensitisation involving a delayed hypersensitivity response (allergen – allergic contact dermatitis). ◼ Once the skin has been sensitised, the potential for further reaction persists indefinitely. ◼ Sterilisation can arise in response to topical application of drugs. ◼ Phototoxic dermatitis occurs when the allergen or irritant is activated by sunlight.  Contact Dermatitis - allergic ◼ Allergic response caused by contact with a substance ◼ Involving immunoregulatory cytokines & T lymphocytes. ◼ Induction phase - primes and sensitizes the immune system => Rn. ◼ Elicitation phase - response is triggered (termed a Type IV delayed hypersensitivity reaction involving a cell- mediated allergic response. ◼ Contact allergens are essentially soluble haptens (LMW), as such, can cross stratum corneum of the skin. Only cause response as part of a complete antigen, involving association with epidermal proteins => hapten-protein conjugates. ◼ The conjugate formed is then recognized as a foreign body by the Langerhans cells or Dendritic cells => transported via lymphatic system to the regional lymph nodes => present the antigen to T-lymphocytes.  Contact Dermatitis - allergic ◼ This process is controlled by cytokines and chemokines - with tumor necrosis factor alpha (TNF-α) and certain members of the interleukin family (1, 13 and 18) – to promote or inhibit the mobilization and migration of these LCs (langherhan cells) these transform into DCs (dendritic cells) (immunostimulatory). ◼ Once within the lymph glands the T cells divide and differentiate & if allergen is experienced again the T cells will respond more quickly and more aggressively. ◼ There are two major phenotypes of cytokine production T-helper 1 and 2 (Th1 and Th2). ◼ Th1 phenotypes are characterised by their focus on Interleukin and Interferon, while Th2 cells action is centred more around the regulation of IgE by cytokines.  Contact Dermatitis ◼ Allergic dermatitis usually confined to area where trigger actually touched the skin, whereas irritant dermatitis may be more widespread on the skin. ◼ Symptoms of both include the following:  Red rash. This is the usual reaction. The rash appears immediately in irritant contact dermatitis; in allergic contact dermatitis, the rash sometimes does not appear until 24-72 hours after exposure to the allergen.  Blisters or wheals. (welts), and urticaria (hives) often form in a pattern where skin was directly exposed to the allergen or irritant.  Itchy, burning skin. Irritant contact dermatitis tends to be more painful than itchy, while allergic contact dermatitis often itches. ◼ While either form of contact dermatitis can affect any part of the body, irritant contact dermatitis often affects the hands, which have been exposed eg dipping into container with irritant solution. Contact Dermatitis Contact Dermatitis  Contact Dermatitis-Plastics ◼ In all branches of the plastics industry, sensitization is a potent hazard and is best prevented, since it can almost never be cured except by removal from the environment ◼ Deodorants and antiperspirants may contain neomycin, zirconium, formaldehyde and antibacterial agents, such as hexachlorophene, which can sensitize, as well as aluminium salts. ◼ Deodorant soaps containing salicylanilide derivatives or hexachlorophene analogues can photosensitize  Contact Dermatitis ◼ Other causes fabric finishes, dyes, oils, tars, rubber, soap, cosmetics and perfume, insecticides, wood resins, plants, paints, plastics, glues, fibre-glass, metals, polishes, ointments (home remedies) and occupational hazards ◼ The sensitization type of allergic eczematous contact dermatitis usually occurs anywhere from 5 to 7 days and occasionally as long as 20 days after the initial or sensitizing contact, at the site of contact. ◼ Rubber, latex, Adhesive tape ◼ There are no circulatory or otherwise detectable antibodies produced, although there is a local tissue allergy. ◼ This condition is usually, though not invariably life-long. ◼ The most common sensitizers are plants, paraphenylenediamine (hair dye), nickel, rubber components and the dichromates Other products ◼ Nickel (nickel sulfate hexahydrate) - metal frequently encountered in jewellery and clasps or buttons on clothing ◼ Gold (gold sodium thiosulfate) - precious metal often found in jewelry ◼ Formaldehyde - a preservative with multiple uses, e.g., in paper products, paints, medications, household cleaners, cosmetic products and fabric finishes ◼ Cobalt chloride - metal found in medical products; hair dye; antiperspirant; metal- plated objects such as snaps, buttons or tools; and in cobalt blue pigment Contact Dermatitis-Cosmetics ◼ Dermatitis most commonly occurs from hair dyes, nail polishes, perfumes, lipsticks and sunscreen agents (PABA). The chief site of the eruption is the eyelids area, with ears and neck next. ◼ Balsam of Peru - a fragrance used in perfumes and skin lotions, derived from tree resin ◼ Perm solutions, ◼ Toothpastes, mouthwashes ◼ Adhesives to attach eye-lashes ◼ Sensitise or photosensitise  Treatment of contact dermatitis ◼ Immediately after exposure to a known allergen or irritant, wash with soap and cool water to remove or inactivate most of the offending substance. ◼ Weak acid solutions [lemon juice, vinegar] can be used to counteract the effects of dermatitis contracted by exposure to basic irritants [phenol etc.]. ◼ If blistering develops, cold moist compresses applied for 30 minutes 3 times a day can offer relief. ◼ Calamine lotion and cool baths may relieve itching. ◼ Antihistamines can also relieve itching. ◼ Avoid scratching, as this can cause secondary infections. ◼ Provision of a barrier to an irritant, eg; wearing gloves, or removing an allergen may be sufficient. ◼ Dilute topical corticosteroid ointment. ? Type hydrocortisone (OTC) or Rx, (may require oral steroid) ◼ Potassium permanganate soaks can help to dry up exudative lesions. ◼ Prevention ; identify allergen and avoid Peri-oral dermatitis Peri-oral dermatitis ◼ Inflamed areas that usually appear around the mouth and nasal folds  Can also occur on the chin and lower eyelids ◼ More common in young women  ? Incorrect use of cosmetics ◼ Red scaly patches, sometimes small papules and rarely pustules ◼ Patches can be irritated and sensitive ◼ Cause unknown, thought to be related to topical steroid use and skin care  Other theories include UV, toothpaste (flurinated), OCs, hormones  Steroids ?worsen, ? trigger Peri-oral dermatitis ◼ Often misdiagnosed and treated with topical steroids  Temporary improvement before worsens  Important to recognise and avoid use of steroids!!! ◼ Treatment involves long course of oral antibiotics  Doxycycline 100mg daily 4-12 wks  Minocycline 100mg daily 4-12 wks ◼ Topical antibiotics  Metronidazole, erythromycin, clindamycin ◼ Resolves in 2/12 then maintenance Peri-oral dermatitis ◼ Avoid inappropriate skincare  Occlusive, mineral oils, zinc cream ◼ Avoid topical steroids on face ◼ Differentiate from  Ezcema  Seborrhoeic dermatitis  Rosacea ◼ Pharmacist role  Diagnosis Important  Triggers, management Psoriasis Psoriasis ◼ Relatively common (about 3% of Australians) ◼ Main feature; red scaly area or patch  Characterised by raised, well-defined pink or red lesions (plaques) covered with silvery-white scale ◼ Particularly on the knees, elbows and scalp and sometimes on other parts of the trunk (lower back), and legs. (can affect other skin areas; genital, palms and soles of feet and nails) ◼ Psoriasis affects both sexes and all races. It can occur at any stage of life, although it starts most frequently in young adults peaks(16-22yrs) can also peak 57 to 60yrs.  2 age peaks 20-30yrs; and 50-60yrs ◼ Itching is usually only mild. (30% itchy) ◼ Psoriasis only rarely affects general health apart from arthritis (5-30% psoriatic arthritis).  A flare can impact on an individual’s feelings of wellbeing and have a major impact on their way of life and daily activities.  Once a person develops psoriasis it usually continues, although it may get better or worse over time and even seem to disappear for prolonged periods. Psoriasis ◼ Although no one single cause for psoriasis has been found, it is known that inherited factors are important  Autoimmune disorder – exact cause unknown but has strong genetic predisposition (30% positive family history ◼ T- cell immunity a key ◼ Cytokines induce neutrophils ◼ Rapid epidermal turnover ◼ Altered epidermal function ◼ Systemic effects (joints, metabolic) Psoriasis ◼ Impacts on QOL ◼ Psychosocial issues, poor self-image, anxiety, depression ◼ Can help with support; understanding condition and avoiding triggers  Psoriasis ◼ Psoriatic skin lesions produced by a very rapid proliferation of epidermal cells. ◼ Cell turnover time is decreased from about 28 days to 3-4 days, ◼ Prevents adequate maturation. Instead of producing a normal keratinous surface layer, skin thickens, forming a silvery scale with dilated upper dermal blood vessels. ◼ Rapidly-matured new cells mix with old cells in the stratum corneum to form raised, scaly red skin lesions (plaques). ◼ Typically inflamed skin; sensitive to irritation ◼ Plaques itchy, painful, they can crack => bleed ◼ Can be localised or extensive area ◼ Plaques irregular and round to oval, can coalesce => larger lesions  Psoriasis ◼ Inflammatory cells such as T- lymphocytes infiltrate into the dermis and then the epidermis. Driven by an immune reaction in the dermis initiated by an unknown antigen. ◼ In a person predisposed to get psoriasis, psoriasis can be brought out or made worse by emotional stress, scratching, rubbing, injury (trauma), certain medications, pregnancy, some infections, obesity, climate, sunburn, excessive alcohol intake (>2 std drinks/day) and smoking. Psoriasis ◼ Infectious episode – precipitating factor  Flare-ups 2-3wks after acute viral or bacterial infection  Guttate; group A beta-haemolytic strep ◼ Trauma – “Koebner phenomenon”  Injury to skin brings out particular skin disease  Lesions appear a day to several wks after localised trauma  Rubbing, scratching, acupuncture, bites, surgery or even mechanical pressure ◼ Climate  Seasonal changes => affect severity  Worse in winter  Improvement in warmer months – UV exposure (but some get worse with sun) ◼ Psoriasis exacerbated by several drugs,  lithium, chloroquine, hydroxychloroquine, β-Blockers, NSAIDs and ACE inhibitors.  Psoriasis ◼ Epidermal antigen-presenting cells in the dermis mature after contact with the antigen, migrate to regional lymph nodes and activate T-cells. ◼ T-cells proliferate and enter the circulation and extravasate into the skin at sites of inflammation. Assisted by local chemokine production. ◼ In the dermis, interaction with the initiating antigen results in Th1 responses, with secretion of cytokines such as interferon gamma, interleukin 2 and tumour necrosis factor alpha (TNFα). ◼ The cytokines stimulate proliferation and impair maturation of keratinocytes & produce vascular changes in the skin. Psoriasis ◼ This increased activity of the immune system in the skin => accumulation of white immune cells (lymphocytes) and produce TNF, interleukins, interferons and growth factors. ◼ These immune cells and the chemicals produced trigger changes => an abnormally rapid rate of skin cell multiplication or turnover, => causes skin affected by psoriasis to thicken, redden, shed an increased number of visible skin scales and contributes to sensations of skin irritation or itch.  Psoriasis ◼ Genetic component to psoriasis, interacts with the unknown environmental factors to produce the lesions. ◼ Polygenic ◼ Twins; monozygotic vs dizygotic ◼ Susceptibility genes: ◼ PSORS-1 locus = HLA Cw6 & comeodesmosin genes ◼ HLA Cw6:  90% with early onset psoriasis  50% with late onset psoriasis  7% normal population ◼ PSORS-2 – recently identified:  Caspase recruitment domain family-14 (CARD-14)  Mutant gene higher activation of NF-KB activating transcription factor (cyclosporin inhibits here) ◼ Roles of genes for  iL-12B & IL-12 receptor  IL-23A and IL-23 receptor  EARP1  And more Psoriasis ◼ Psoriatic plaques usually affect the elbows, knees, lower back, buttocks, scalp and nails. ◼ Various subtypes of the condition present with different clinical manifestations. An inflammatory arthritis occurs in up to 40% of people with psoriasis.  Psoriatic arthritis – joint pain, swelling and stiffness, esp peripheral joints of hands and feet. ◼ Increased risk of other inflammatory and autoimmune conditions;  Inflammatory bowel disease, coronary artery disease, components of metabolic syndrome (impaired glucose regulation)  Chronic inflammatory process => coronary artery calcification => CVD ◼ Increased risk of obesity ◼ Increased risk of lymphoma ◼ There are several treatments for the skin lesions, both topical and systemic, but none produce long-term remission.  Psoriasis - types Chronic plaque (psoriasis vulgaris) Most common form 85-90% Well-defined, inflamed (ham red), plaques with silvery scale (knees, elbows, low back, scalp) Flexural (inverse) psoriasis Can occur alone or accompanied by plaques Distinct reddened patches – body folds (intertriginous areas) As areas moist – minimal scaling Scalp psoriasis Seen in approx 50% Maybe discrete plaques or scale extending beyond hairline Guttate psoriasis (latin “drop”) Acute form; often triggered by URTI streptococcal (often generalised rash Chronic and recurrent and may be painful (+/- fever & tenderness) Uncommon form Erythrodermic psoriasis Painful red rash over large area and maybe accompanied with fever Peeling and blistering can occur. Rare form – can develop gradually from chronic plaque form or acutely. Clinical types ◼ Chronic plaque ◼ Plaques  Well demarcated  (ham) red  Scaly  Silvery scale ◼ Sites  Elbows & knees  Low back  scalp Clinical types ◼ Flexural inverse  Mainly skin folds (under breast, arms, thighs, buttocks)  Well demarcated thin red plaques  Lack scale (moist environment)  Often mistaken for tinea or dermatitis  Deep red patches of skin in body folds (?shiny)  Uncommon (can have other forms  Skin sensitive, challenge to Tx Clinical types ◼ Scalp psoriasis (50% with plaque with have outbreak with scalp) ◼ Overlap with dandruff (sebo-psoriasis) ◼ Thin plaque to very thick ◼ Can be some hair loss Clinical types ◼ Guttate psoriasis (tear drop) ◼ Many small plaques ◼ Concentrated around trunk upper arms and thighs (face ears and scalp – faint and disappear quickly) ◼ Rapid onset ◼ Preceding infection;  Typically 2 weeks post throat infection with Strep Pyogenes ◼ Affects children, young adults, ◼ Good chance of spontaneously clearing completely ◼ Settles better with Tx  Clinical types ◼ Psoriasis – pitting of the nails Clinical types ◼ Pustular psoriasis ◼ Fluid filled ◼ Usually more acute ◼ Can be severe ◼ Uncommon form ◼ May be febrile, sore, unwell, increase HR ◼ Not infected!! Clinical types ◼ Palmar/ plantar psoriasis ◼ Well demarcated ◼ Thicker scale ◼ May be pustular ◼ Nail change common ◼ Overlap with dermatitis ◼ Always consider tinea ◼ Harder to Tx Clinical types ◼ Erythrodermic psoriasis ◼ Most severe form  ?induced by withdrawal of topical or oral steroids  Medications (lithium)  Alcohol  Infection  Low Ca ◼ > 90% BSA ◼ May be febrile, sore, unwell ◼ Poor temperature regulation ◼ High output heart failure, dehydration, hypothermia, oedema, death PASI = psoriasis area severity index Psoriasis treatment ◼ Range of strategies  Education, lifestyle (stress management), topical, systemic Tx, phototherapy, skin care (emmollients) ◼ Majority of people (limited disease reduce risk of adverse effects and avoid disease resistance ◼ Sequential therapy  Potent agent used to induce remission, followed by longer-term Tx with better safety profile Psoriasis treatment ◼ Emollients These reduce scaling and itching and may be sufficient in mild psoriasis +/- keratolytic. ◼ Keratolytics such as salicylic acid break down keratin and soften skin => improves penetration of other treatments. Salicylic acid ointment is most frequently used. ◼ Topicals used intermittently or continuously and in combination ◼ Vehicle influences penetration and subsequent efficacy  Topical Corticosteroids ◼ Used sparingly on limited areas (FTU). ◼ Anti-inflammatory, antiproliferative, immunosuppressive and vasoconstrictive actions ◼ Range of potencies and formulations (depends on site and disease severity) ◼ Moderate to high potency (initial – esp with thick chronic plaque) ◼ Low potency on face and intrigenous areas ◼ Unwanted effects can be troublesome.  Cutaneous SE (skin atrophy)  Systemic absorption – prolonged use  Limit high potency to twice daily up to 4 weeks (occasionally for longer term) ◼ Withdrawal of a high-potency corticosteroid => a rebound phenomenon and even generalised pustular psoriasis. Topical corticosteroids ◼ Fingertip unit (FTU) ◼ To dose topical corticosteroids and calcipotrol ◼ FTU is the distance between the distal skin- crease (crease of first joint) to the tip of the finger ◼ Amount squeezed from tube should cover equivalent area of two palmar surfaces on the patient’s body ◼ One FTU (adult) approximately 0.5g and should cover two elbow or knee areas.  Psoriasis treatment ◼ Vitamin D analogues – Calcipotriol (Daivonex®) ◼ Vitamin D regulates epidermal proliferation and differentiation & has immunosuppressant properties. ◼ Calcipotriol binds to vit D receptors => inhibiting keratinocyte proliferation and increasing keratinocyte differentiation ◼ Clean and simple to apply and are particularly useful for chronic plaque psoriasis, although complete clearing of the plaques is unusual. ◼ Ointment has greater emollient effect than cream, but is more messy. ◼ Calcipotriol should not usually be used for the face, where it often causes irritation; (also flexures); this is less troublesome elsewhere. Effective but slow to work (6wks) – delay in onset. ◼ Side effects; common: burning, pruritus, oedema, peeling, dryness, erythema – they tend to resolve with continued use ◼ Excessive use (>100g/wk) or renal disease => hypercalcaemia and parathyroid hormone suppression. ◼ The ease of use makes them a popular choice if a keratolytic is insufficient. ◼ Also as combination ® therapy with betamethasone diproprionate (Daivobet )  Psoriasis treatment ◼ Topical retinoids. Tazarotene gel can be applied to plaque psoriasis and has minimal systemic absorption.  Unlike other retinoids, tazarotene is selective for retinoic acid receptor (RAR) proteins, with no affinity for retinoid X receptors (RXR).  Normalises abnormal keratinocyte differentiation, reduces hyperproliferation, decreases expression of inflammatory markers  Tx chronic plaque psoriasis  Applied once a day in evening ◼ Not often used  Slow to work,  Expensive ◼ Local irritation (& pruritis) and of unaffected skin common so may combine with steroid => reduce unwanted effects.  It should be avoided for 1 month before conception, because of potential teratogenic effects.  Dithranol ◼ An anthraquinone that is extracted from tree bark. ◼ Decreases cell division and is very effective for healing psoriatic plaques. Antiproliferative effect ◼ Effective especially in thick plaque psoriasis ◼ In hospital, it is applied in a stiff paste so that the dithranol does not come into contact with, and burn, normal skin. (avoid flexures) ◼ It is left in contact with the plaque for 24 h. ◼ Dithranol is also used as a cream (? Higher concentration 0.5% to 2% (up to 5%) with Acid Sal) that is applied to the plaque for 15-30 min and then washed off. ◼ Oxidation products stain the skin brown => discoloration of healed areas for a few days. (stain bedding, clothes etc & doesn’t wash out). ◼ Dithranol is usually very effective in treating psoriasis. The main potential problems with anthralin are irritation of the skin, temporary skin discolouration and permanent staining of fabric.  Coal Tar preparations ◼ Crude coal tar is a mixture of a large number of hydrocarbons that have a cytostatic action. ◼ Anti-inflammatory and antipruritic ◼ It enhances the healing effect of UVB radiation on psoriatic lesions. ◼ Disadvantage – messy (poor pt acceptability), color and odour.  LPC 2% to 10% cream or oint bd (?add acid sal) ◼ Modest efficacy when used alone. ◼ More refined tar preparations have greater acceptability, but are even less effective.  Phototherapy ◼ Ultraviolet light inhibits DNA synthesis and depleting intra-epidermal T-lymphocytes. ◼ Avoid in pts very fair and who burn in the sun. UVB ('sunburn' wavelength 290-320 nm), administered 3 x per week, is very useful for extensive small plaques of psoriasis.  Total of 20 to 25 treatments ◼ Greatest benefit from narrowband UVB (around 311 nm) rather than broadband UVB. ◼ Long-wavelength UVA (320-400 nm) requires more specialised equipment & prior oral photosensitising drug eg. psoralen (a process called photochemotherapy or PUVA).  Phototherapy ◼ Psoralen may locate between pyrimidine base pairs in the DNA helix and inhibits cell replication. ◼ PUVA (Psoralen + UVA) reserved for severe, resistant psoriasis and it is more effective than treatment with UVB. ◼ Psoralen => nausea, and headache acutely. Long-term PUVA => accelerated skin ageing and risk of skin cancer.  Systemic treatments ◼ Avoid topical Tx in advanced inflammatory forms; can cause skin irritation (apart from emollients and corticosteroids, (most useful for chronic plaque psoriasis) ◼ Systemic Tx - reserved for most severe forms. ◼ Methotrexate - very effective Tx at low dosages for resistant and widespread disease.  Actions are cytostatic (slows epidermal cell proliferation) and immunosuppressant.  Oral or IM dosing is commonly used once a week.  Dose with folic acid to minimise ADRs (nausea, stomatitis, blood dyscrasias)  Can take 3/12 to induce remission  Bone marrow depression & hepatotoxicity (liver fibrosis) complications check blood counts every 2-3 months & liver biopsy every 1-2 years.  Retinoids ◼ Includes vitamin A (retinol) and therapeutically useful synthetic vitamin A derivatives, such as acitretin, the active metabolite of etretinate, which is no longer used. ◼ Orally, they are anti-inflammatory and cytostatic. ◼ Vitamin A, and its metabolites all-trans-retinoic acid and 9- cis-retinoic acid, are involved in epithelial cell growth and differentiation. ◼ Retinoids enter cells by endocytosis => interact with two forms of retinoic acid nuclear receptor, RARs and RXRs (retinoid X receptor), (related to steroid/thyroid hormone receptors) ◼ The retinoid receptor complex initiates gene transcription ? affect cell growth and differentiation by modulation of growth factors and their receptors. ◼ Response delayed by up to 2 months.  Retinoids ◼ Etretinate long half-life (up to 6 months) sequestration in subcutaneous fat. ◼ Elimination - hepatic metabolism. ◼ Unwanted effects - dry lips and nasal mucosa, dryness of the skin with localised peeling over the digits, and transient thinning of hair. Dose- dependent and reversible. ◼ Longer-term problems include ossification of ligaments, increased plasma triglycerides and increased plasma cholesterol. ◼ Teratogenic - women must use adequate contraception during treatment and stop treatment for 2 years before conception.  Cyclosporin or Tacrolimus ◼ Immunosuppressants - effective in psoriasis - lower doses than prevention of allograft rejection. ◼ Cyclosporin can induce rapid remission 6-12 wks ◼ Induction therapy for resistant plaque forms ◼ Orally given twice a day ◼ Courses usually restricted 12-16wks (due to ADRs)  Hirsutism, gingival hyperplasia, neoplasia ◼ Remissions induced by these drugs are usually short ? TNFα antibodies may cause this.  Biological therapies ◼ Target specific mediators involved in immunologic/inflammatory response producing clinical manifestations. ◼ Target activity of T-lymphocytes and pro-inflammatory cytokines (eg TNF-α) ◼ Less toxic to liver, kidneys and bone marrow than other systemic Tx ◼ PBS eligibility criteria ($, severe disabling unresponsive disease) ◼ Adalimumab (Humira®), etanercept (Embrel®), golimumab (Simponi®), infliximab (Remicade®), ustekinumab 4x yr inj (Stelara®) ◼ Most see response in 4wks and significant improvement by 12wks. Biological therapies ◼ PASI > 15 needed  And past failures also must improve by 75% to stay on it ◼ Etanercept and infliximab IV - treatment-resistant psoriasis.  Blocking TNFα inhibits the production of chemokines and endothelial adhesion molecules that attract activated lymphocytes into the skin.  Infliximab produces a more rapid response than etanercept.  Infliximab best but by infusion and can => antibodies and so decrease efficacy  Other 'biological' agents undergoing trial for the management of severe psoriasis.  Rituximab ◼ Rituximab, targets the B-cell CD20 antigen and causes rapid and specific B-cell depletion, is indicated for, CD20+ B-cell, non-Hodgkin lymphoma (NHL). ◼ Case report woman experienced a partial sustained remission of her psoriasis after treatment with rituximab for NHL. ◼ Converse is also reported in management of RA and psoriasis developed. ◼ Rituximab In Psoriatic Arthritis: a multi-centre randomised placebo-controlled double blind pilot-study of rituximab in patients with active psoriatic arthritis ◼ Australian Prescriber Vol 29, No 5, October 2006  The pathogenesis of psoriasis involves a number of immune mechanisms including the activation of T lymphocytes and the release of inflammatory cytokines such as TNF.  Inhibitors of TNF can induce an improvement (mod to severe) plaque psoriasis. Infliximab infusions showed that after 50 weeks 61% of patients had a 75% improvement in their psoriasis. Response sustained following treatment cessation. ◼ Efalizumab - targets part of the lymphocyte function-associated antigen-1 (LFA-1) on T cells. This antigen has roles in both T cell activation and migration so binding to it can improve moderate to severe psoriasis.  Fumaric Acid esters ◼ Oral Tx - severe psoriasis ? works by promoting a Th2-like lymphocyte response in place of the Th1- dominated response found in psoriasis. ◼ Fumaric acid - poorly absorbed from the gut so given as an ester. ◼ Rapidly hydrolysed to monomethylfumarate & metabolised in cells to water and carbon dioxide in the citrate cycle. ◼ Monomethylfumarate - very long half-life - 36 hr. ◼ SE; GI upset in > 2/3 of pts, flushing in 1/3. Fumaric acid esters for severe psoriasis: a retrospective review of 58 cases. Harries MJ; Chalmers RJ; Griffiths CE Br J Dermatol. 2005 Sep;153(3):549-51.  Other treatments ◼ Recombinant protein; alefacept (Amevive)  CD2 binding on memory effector T Lymphocytes inhibiting activation in psoriatic plaques  CI in HIV pts (? Affecting CD4 counts) ◼ Ustekinumab – targets IL-12/23  75% improve - 12wks  Mthly sc inj then every 12 wks Treatment of chronic plaque psoriasis by selective targeting of memory effector T lymphocytes. Ellis CN; Krueger GG, N Engl J Med 2001 Jul 26;345(4):248-55. A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis. Krueger et al N Engl J Med. 2007 Feb 8;356(6):580-92.  Natural therapies and lifestyle changes ◼ Herbal remedy claims? ◼ ?Hx Sarsparilla ◼ ?Kalawalla Polypodium leucotomos 50:1 standardized extract ◼ ?Selsun Blue ◼ ?Oregan Grape questionable results from studies ◼ People who smoke have a higher risk of developing psoriasis than non-smokers. Giving up smoking after the onset of psoriasis will not, unfortunately, lead to the clearance of psoriasis. ◼ People with psoriasis often take advantage of natural sunlight’s beneficial effects. Light therapy using a special fluorescent light bulb is, however, safer and more effective. ◼ Any cream with moisturising properties can be beneficial in improving psoriasis and this is the probable basis for a number of non-prescription “miracle” treatments. ◼ Diet has not been shown to be an important factor in controlling or treating psoriasis. However, obesity leading to large folds of skin can make psoriasis in these folds difficult to manage. Excessive alcohol consumption may worsen psoriasis. ◼ Wearing light rather than dark coloured clothes can make shed skin flakes less obvious. ◼ Vitamin A and vitamin D are beneficial in psoriasis, but the high doses required to help those with psoriasis are potentially toxic or dangerous. Thus, safer, less toxic vitamin analogues have been developed (calcipotriol & acetretin) which require a prescription from your doctor. Check with your doctor before taking a specific high dose vitamin A or vitamin D supplement. ◼ Psychological distress can have profound effects on the immune system. Such distress is reported as a trigger factor by around two thirds of people with psoriasis, and the most stressed do least well in therapy. A psychologist may be able to teach you better ways of coping with the problem.  Psoriasis ◼ With appropriate treatment, psoriasis can be well controlled for the vast majority of sufferers. ◼ Unfortunately, not everyone responds to all therapies and, in some people, particularly those with more severe psoriasis, combination therapy may be required. ◼ At this stage it is not possible to cure psoriasis. Psoriasis Australia http://www.psoriasisaustralia.org.au/ Skin Richard Summers Part 1 Overview ◼ Skin function  The Skin ◼ The skin is the largest organ of the body, ◼ Different functions.  Thermoregulation, protection, metabolic functions and sensation. ◼ Two main regions,  epidermis – thin outer layer  dermis (thicker layer) attached to an underlying hypodermis (subcutaneous connective tissue) stores adipose tissue.  Sebaceous glands (lubricating substance sebum)  Sweat glands (perspiration)  Pacinian corpuscle (deep pressure, vibration)  Functions of the Skin ◼ Prevents loss of essential body fluids, ◼ Protects the body against the entry of toxic environmental chemicals. ◼ The skin part of the innate immunity (natural resistance) of the body against invasion by micro-organisms. Natural defence (dryness, constant desquamation, normal flora, fatty acids of sebum and lactic acid of sweat). ◼ Langerhans cells in the epidermis have an antigen- presenting capacity and might play an important role in delayed hypersensitivity reactions. ?role in immunosurveillance against viral infections. ◼ Melanin pigment of the skin protects the nuclear structures against damage from ultraviolet radiation.  Functions of the Skin ◼ Temperature regulation (hypothermia and hyperthermia) ◼ Important role in calcium homeostasis by contributing to the body's supply of vitamin D. ◼ Vitamin D3 (cholecalciferol) produced in the skin by the action of ultraviolet light on dehydrocholesterol. ◼ It is then hydroxylated in the liver and kidneys (needs parathyroid hormone to activate) to 1,25 dihydroxycholecalciferol, the active form of vitamin D.  This increases calcium absorption (through stimulation of synthesis of calcium-binding proteins in the mucosal cells of the intestine), and on the kidneys promoting calcium reabsorption.  Pigmentary System ◼ Melanocytes and Skin Color  epidermal melanin units. (melanocyte supplies melanin pigment to group of keratinocytes about 36).  Pigmentation is determined primarily by the amount of melanin transferred to the keratinocytes. ◼ The melanocyte is a dendritic cell (basal layer of the epidermis) ◼ Melanocytes arise from the neural crest as melanoblasts and migrate to the dermis, hair follicles, leptomeninges, uveal tract and retina. ◼ Melanosomes are responsible for melanin synthesis and pigment transfer from the melanocyte to the surrounding keratinocytes. ◼ Racial pigmentation not due to differences in the number of melanocytes, but rather to differences in melanocyte activity. In black skin, there is greater production of melanosomes, higher degree of melanization of melanosomes, and larger unaggregated melanosomes showing slow rate of degradation. ◼ Melanin is a brown-black, light-absorbing pigment, protecting the skin against UV.  (1) Eumelanin, a brown to black pigment found within the ellipsoid melanosomes;  (2) Phaeomelanin, a yellow-red pigment found within the spherical melanosomes.  Post-inflammatory hyperpigmentation ◼ Post-inflammatory hyperpigmentation (darkening of skin)  After injury such as a cut, scrape, bite, or burn, or after certain skin disorders such as acne or eczema. It is seen in all skin types but is more common and noticeable in darker skin. ◼ The inflammation causes a stimulation of pigment production. If the skin is injured into the deeper level, the pigment will appear darker and be even more resistant to treatment. ◼ Common, but difficult problem to treat. Topical bleaching agents, retinoids and some topical anti-inflammatory agents are helpful. Light chemical peels and microdermabrasion have been found to be safe and effective  Darkened areas of skin may take many months or years to fade, medication may fade pigment more rapidly.  Sunscreen may prevent postinflammatory hyperpigmentation from becoming darker  Vitiligo ◼ Vitiligo - pigment cells are destroyed and irregular white patches result. Unknown cause (? autoimmune disorder - the body makes antibodies to its own pigment). ◼ The extent of loss differs with each person. Most patients with vitiligo do not regain skin color without treatment.  Treatment - cortisone or other creams, light treatments, laser treatments, intense pulsed light (IPL), or skin grafting  PUVA therapy, combining a medication called psoralen and ultraviolet A light treatments. Dermatosis Papulosa Nigra ◼ Flesh Moles ◼ Occurs almost exclusively in African-Americans and most frequently in women. ◼ Brown or black raised, dark spots usually appear on the cheeks. ◼ Resemble moles or flat warts but they are a variant of a benign growth called seborrheic keratoses. ◼ Can be removed for cosmetic reasons.  Sensory apparatus of skin ◼ Skin is innervated with around one million afferent nerve fibres. Most terminate in the face and extremities; relatively few supply the back. ◼ The cutaneous nerves contain axons with cell bodies in the dorsal root ganglia. ◼ The main nerve trunks entering the subdermal fatty tissue each divide into smaller bundles. ◼ Groups of myelinated fibres fan out in a horizontal plane to form a branching network from which fibres ascend, usually accompanying blood vessels, to form a mesh of interlacing nerves in the superficial dermis. ◼ Throughout their course, the axons are enveloped in Schwann cells and as they run peripherally, an increasing number lack myelin sheaths. Most end in the dermis; some penetrate the basement membrane, but do not travel far into the epidermis.  Sebaceous glands ◼ Sebaceous glands all areas of the skin (except palms, soles, and dorsa of the feet). They are holocrine glands, i.e., their secretion is formed by complete destruction of the cells. ◼ Most have their ducts opening into hair follicles (pilosebaceous apparatus). ◼ Free sebaceous glands open directly to the surface of the skin, e.g., Meibomian glands of the eyelids, Tyson's glands of the prepuce, and free glands in the female genitalia and in the areola of nipples. ◼ Sebum production is under hormonal control. ◼ Sebaceous gland development – puberty stimuli - androgen.  (1) sebum production is low in children;  (2) in adults, sebum production is higher in men than in women;  (3) in men, sebum production falls only slightly with advancing age,  it decreases in women significantly after the age of 50. ◼ Estrogens opposite effect to that of androgens. Estrogen administration decreases the size of glands and the production of sebum. ◼ The sebum - triglycerides and free fatty acids, wax esters, squalene, and cholesterol. ◼ Controls moisture loss from the epidermis and protects against fungal and bacterial infections (FFA). NB. Ringworm of scalp becomes rare after puberty.  Sweat Glands ◼ Sweating response to exercise or thermal stress controls body temperature through evaporative heat loss. ◼ Several million eccrine sweat glands. (can be up to several litres per hour and 10 litres per day). ◼ Eccrine Sweat gland - secretory coil deep in the dermis, and a duct which conveys the secreted sweat to the surface.  (1) secretion in response to acetylcholine from sympathetic nerve endings,  (2) reabsorption of sodium in excess of water => a hypotonic skin surface sweat. ◼ Also an excretory organ for heavy metals, organic compounds, and macromolecules. The sweat is composed of 99% water, electrolytes, lactate (provides an acidic pH to resist infection), urea, ammonia, proteolytic enzymes, and other substances. ◼ There is a hypothalamic preoptic sweat centre to regulate temperature. Inhibited by atropine (emotional sweating can occur over the whole skin surface, but usually it is confined to palms, soles, axillae, and the forehead). ◼ Apocrine glands present in the axillae and anogenital area which are under the control of sex hormones, mainly androgens.  Sensory endings ◼ Two types: corpuscular (embrace non-nervous elements) and 'free', which do not. ◼ Corpuscular endings  encapsulated receptors, of which a range occurs in the dermis  non-encapsulated, exemplified by Merkel's 'touch spot' which is epidermal (oval cells).  Each Merkel's touch spot is composed of a battery of Merkel cells  All Merkel cells are in contact with terminals of myelinated axons ◼ The Pacinian corpuscle is one of the encapsulated receptors. It is an ovoid structure about 1mm in length, which is lamellated in cross-section like an onion, and is innervated by a myelinated sensory axon which loses its sheath as it traverses the core. The Golgi-Mazzoni corpuscle SC tissue in finger (movement and vibration detectors) Pacinian corpuscles detect gross pressure changes and vibrations. Any deformation in the corpuscle causes action potentials to be generated, by opening pressure-sensitive sodium ion channels in the axon membrane. This allows sodium ions to influx in, creating a receptor potential. ◼ The Krause end bulb is an encapsulated swelling on myelinated fibres situated in the superficial layers of the dermis. Characteristics of the papillary ridges of glabrous (hairless skin) skin; they are touch receptors; (endings are directly related to collagen fibrils; they are stretch receptors). ◼ “Free nerve endings”, derived from non-myelinated fibres occur in the superficial dermis and in the overlying epidermis; they are receptors for pain, touch, pressure and temperature. Hair follicles have fine nerve filaments running parallel to and encircling the follicles; each group of axons is surrounded by Schwann cells; they mediate touch sensation. Axon terminal Dendrite Neuron Schwann cell  Cutaneous Sensory System: Connection to CNS ◼ The brain receives two types of sensations:  (1) superficial sensations, including pain, temperature and crude touch  (2) deep sensations, sense of position, movement, vibration, muscle and fine touch. Some sensations must reach the cortex to be felt. eg tactile localization, tactile discrimination and stereognosis, mid-zones of temperature, and sense of position and movement. ◼ Pathway of pain, temperature and crude touch sensations:  (1) neuron is present in the posterior root ganglion. Acts as a pain receptor, while its axon passes towards the spinal cord. It ascends to tip of the posterior horn forming the Lissauer's tract, and then ends around the cells of the substantia gelatinosa of Rolandi which are present at the tip of the posterior horn of the grey matter.  (2) The second order neuron is present in the substantia gelatinosa of Rolandi. Its axon crosses to the opposite side in the anterior commissure & terminates in the thalamus.  (3) The third order neuron is present in the thalamus. Its axon travels in the posterior limb of the internal capsule behind the pyramidal fibres and terminates in sensory area of the cerebral cortex  Cutaneous Sensory System: Connection to CNS ◼ Pathway of deep sensations and fine touch:  (1) The first order neuron is also present in the posterior root ganglion. Its dendrite passes to the periphery, while its axon enters the spinal cord and ascends directly (without relay) in the posterior column of the spinal cord, forming the Gracile and Cuneate tracts. The two tracts end in the medulla around the Gracile and Cuneate nuclei.  (2) The second order neuron is present in the Gracile and Cuneate nuclei of the medulla. Its axon crosses to the opposite side then ascends in the brain stem (forming the medial lemniscus) to reach the thalamus where it terminates.  (3) The third order neuron is present in the thalamus. Its axon passes upwards in the internal capsule to end in the sensory area of the cerebral cortex.  Physiology of sensory receptors ◼ Adaptation: stimulus constant strength is applied to a receptor, declines over time. There are two types of receptors:  (1) tonic slowly-adapting receptors: as the nociceptors (pain receptors) CNS continuously informed about the state of the body; and  (2) phasic rapidly-adapting receptors: as Pacinian corpuscles--these receptors adapt rapidly and cannot be used to transmit a continuous signal to the CNS - they are stimulated only when the stimulus strength is changed. ◼ Touch sensation provoked by a harmless stimulus to skin distinguish between hard and soft objects; touch receptors belong to the class of mechanoreceptors and many of them can be found around hair follicles, so removal of hair decreases touch sensitivity; the tips of the fingers and lips are rich in touch receptors. ◼ Tickle and itch: Sensations experienced when mild stimulation of the pain nerve endings occurs; tickle and itch sensations transmitted by C unmyelinated nerve fibers; histamine produces itch while pain signals suppress it; (itch sensation excites the scratch reflex.) ◼ Endorphins and enkephalins are important opioid neurotransmitters in the CNS that mediate the sensation of itch. Morphine alleviates pain but aggravates itch, as itch and pain share common neurological pathways.  Naloxone, an opioid antagonist, has been found to reduce histamine-provoked itch.  Physiology of sensory receptors ◼ Mast cells - high histamine content & contain serotonin (lots in skin) role in type I immediate hypersensitivity Rn (IgE-mediated anaphylactic reaction). ◼ Temperature sensation: Receptors for warmth and cold are specialized free nerve endings; a rise in skin temperature above body temperature => sensation of warmth, a fall in skin temperature below body temperature is experienced as cold sensation; pain is felt > 45 °C or < 10 °C  NB; the mucous membrane of the mouth is less sensitive than the skin, thus tea can be drunk at a temperature which is painful to fingers. ◼ Paradoxical cold: Cold receptors stimulated by intrinsic heat (e.g., shivering that occurs with fever). ◼ Pain is evoked stimuli (chemical, mechanical, thermal, or electrical) intensity to produce tissue damage. The nociceptors (pain receptors) are free nerve endings. ◼ Cutaneous pain may be sharp and localized, or dull and diffuse. A painful stimulus causes at first sharp pain, followed by dull aching pain. Reflex withdrawal movements also occur, with an increase in HR & BP  Cutaneous vascular system ◼ Circulation through the skin serves two functions:  (1) nutrition of the skin tissue  (2) regulation of body temperature by conducting heat from the internal structures of the body to the skin, where it is lost by exchange with the external environment ◼ Anterior hypothalamus controls body temperature.  Heating this area causes vasodilatation of all the skin vessels of the body and sweating. Cooling => vasoconstriction of skin vessels and stoppage of sweat secretion. (sympathetic nerves)  Epidermopoiesis ◼ Epidermis provides first barrier of protection from invasion of foreign substances into the body. ◼ Principal cell called a keratinocyte. ◼ Epidermis is subdivided into five layers or strata,  stratum corneum (SC) (horny layer fully keratinized dead cells) in which a keratinocyte gradually migrates to the surface and is sloughed off in a process called desquamation.  stratum lucidum  stratum granulosum (SGR),  stratum spinosum (SS),  stratum germinativum (SG),  Epidermopoiesis cont. ◼ The stratum germinatum (SG) provides the germinal cells necessary for the regeneration of the layers of the epidermis. ◼ Separated from the dermis by a thin layer of basement membrane. ◼ Mitotic division - a newly formed cell will undergo a progressive maturation called keratinization as it migrates to the surface.  The total epidermal renewal time is 52-75 days.  Production rate is balanced with that of cell loss. Control consists of balancing stimulatory and inhibitory signals. Seen in wound healing - cytokines and growth factors  Epidermopoiesis cont. ◼ Maturation of a keratinocyte is characterized by the accumulation of keratin, called keratinization. ◼ The cells of the stratum granulosum (SGR) accumulate dense basophilic keratohyalin granules. These granules contain lipids & help to form a waterproof barrier that functions to prevent fluid loss from the body. ◼ The stratum lucidum is normally only well seen in thick epidermis and represents a transition from the stratum granulosum to the stratum corneum. ◼ The cells of the stratum corneum (SC) are flattened keratinized cells devoid of nuclei and cytoplasmic organelles. Adjacent cells overlap at their margins and this locking together of cells, together with intercellular lipid, forms a very effective barrier.  The stratum corneum varies in thickness depending on the region of the body, being thickest over the palms of the hands and soles of the feet.  Regulation epidermopoiesis: Stimulatory factors ◼ Growth factors stimulate the epidermal cells: epidermal growth factor (EGF), transforming-growth-factor-alpha (TGFalpha), interleukins (IL) and other immunological cytokines, and basic fibroblast growth factor (bFGF). ◼ EGF binds to specific cell-surface receptors (EGFR) present in the basal layer of epidermis. => binding carries EGF into an intracellular cycle within the cytoplasm and nucleus to mediate effects. EGF has been shown to increase the growth and persistence of epidermal keratinocytes and promotes wound healing in vitro. ◼ TGF alpha produced by keratinocytes is related to EGF & binds to and activates the EGF receptor. It stimulates keratinocyte growth. ◼ epidermis also contains large amounts of Interleukin-1.  Two forms, alpha and beta, mitogenic for keratinocytes (other effects include: fibroblast proliferation and synthesis of collagenase, stimulation of IL-2 production, stimulation of B-cell function, and fever induction).  IL-1 releases IL-6 from keratinocytes. IL-6 stimulates growth of keratinocytes. ◼ Keratinocytes also synthesize IL-3, IL-4, IL-8 (neutrophil activating protein), and granulocyte-macrophage colony stimulating factor. ◼ Keratinocytes can secrete cytokines => modulate lymphocyte activation and granulocyte function. Complex interactions ? synergistic or antagonistic. ◼ The factors controlling synthesis and secretion of these factors may be important in the pathogenesis of skin disease as well as epidermal growth control  Regulation epidermopoiesis: Stimulatory factors cont. ◼ The epidermal cell cycle is also controlled by intracellular : cAMP and cGMP.  These are formed and broken down by external signals acting on the cell membrane.  cAMP acts as a '2nd messenger' of i.e. catecholamines and polypeptides, which do not themselves penetrate the surface of cells.  Cyclic AMP inhibits epidermal cell division while cGMP stimulates it.  Epidermal mitosis exhibits a circadian rhythm, inversely related to blood adrenaline levels. ◼ Steroid hormones like testosterone enter the target cells. ◼ Epidermal keratinocytes contain 5 alpha-reductase enzyme and they can convert testosterone to 5 alpha-dihydrotestosterone (DHT) which binds to specific cytosol receptors and alters protein synthesis via messenger RNA. ◼ Androgens and vitamin A stimulate epidermal mitosis; glucocorticoid hormones inhibit it. ◼ Prostaglandins, can increase cAMP. The main one formed in the epidermis is PGE2. ◼ Polyamines, including spermidine, putrescein and spermine, stimulate mitosis. Ornithine decarboxylase is a particularly important enzyme for the generation of this group of substances.  Regulation of Epidermopoiesis: Inhibitory Factors ◼ Growth inhibitors for keratinocytes include chalones, transforming- growth-factor-beta (TGF beta), alpha and gamma interferons (IFN- gamma), and tumour necrosis factor (TNF). ◼ Chalones slow basal mitosis. ◼ TGF beta stimulates fibroblast growth and increases fibrosis but inhibits the growth of keratinocytes. But reported to stimulate wound healing. ◼ Alpha and gamma interferons have cytostatic effects on keratinocytes (in vivo & in vitro). High doses of Interferon-gamma are cytotoxic. ◼ 30% TNF localizes in epidermis suggesting the presence of many TNF- binding sites. Keratinocytes also secrete TNF. ◼ TNF can cause release of IL-1. It stimulates fibroblast proliferation and cytokine production. TNF reversibly cytostatic to keratinocytes.  Why is it important? ◼ Panitumumab (Vectibix) tx Metastatic colorectal cancer  anti-EGFr antibody ◼ Although EGF receptors normally help regulate the growth of many different cells in the body, these receptors also can stimulate cancer cells to grow. ◼ Some cancer cells actually require signals mediated by EGFr for their survival. ◼ Residing on the surfaces of these tumor cells, EGF receptors are activated when naturally occurring proteins in the body, such as epidermal growth factor (EGF) or transforming growth factor alpha (TGF-alpha), bind to them.  This binding changes the shape of the EGF receptors, which, in turn, triggers internal cellular signals that stimulate tumor cell growth. ◼ Panitumumab binds to EGF receptors, preventing the natural ligands such as EGF and TGF-alpha from binding to the receptors and interfering with the signals that might otherwise stimulate growth and survival of the cancer cell. ◼ Cetuximab (Erbitux)– another EGFr antibody, also showing promise in head and neck cancer in combo with radiation therapy.