Drugs For Psoriasis - Symptoms, Types and Treatment of Psoriasis

Psoriasis

•        Is an inflammatory chronic, controllable but not curable condition that may affect the skin and joints. It is one of the commonest immune-mediated skin diseases.

•        It is characterized by well-delineated, thickened erythematous epidermis or dermal plaques covered with a distinctive silvery scale.

•       On the skin, it manifests as a red scaly rash

Epidemiology of Psoriasis

• Psoriasis is slightly more common in women than in men.
• Although the disease can develop at any time, 10–15% of all cases are diagnosed in children under 10, the average age at the onset of symptoms is 28.

·         Psoriasis is most common in fair-skinned people and extremely rare in dark-skinned individuals

PATHOPHYSIOLOGY OF PSORIASIS

·         Normal skin cells mature and replace dead skin every 28–30 days.

·         Psoriasis causes skin cells to mature in less than a week.

·          Because the body can’t shed old skin as rapidly as new cells are rising to the surface, raised patches of dead skin develop on the arms, back, chest, elbows, legs, nails, folds between the buttocks, and scalp.

·         The main abnormality in psoriasis is increased epidermal cell turnover (about 10x the normal rate)

·         The presence of lymphocytes and Langerhans cells suggests an immunological cause of the hyperproliferation in psoriasis

·         It is postulated that mediators and cytokines  released  by the immune cells recruit more inflammatory cells to the process

·         The inflammatory cells further produce cytokines that promote their own proliferation and attract more lymphocytes

·         Changes in the blood vessels are associated with the mediator activity

·         However, the relationship between these observations and the underlying genetic defect is not yet known.

SKIN CHANGES IN PSORIASIS

·         Many skin changes occur in psoriasis which may either be cause or effect of the disease

o   The epidermis is thickened (acanthosis)

o   The granular layer is absent and epidermal cell nuclei are seen persisting in the horny layer(parakeratosis)

o   In the dermis, the dermal capillaries are dilated, tortuous and closer to the surface of the skin than normal

• Large numbers of inflammatory cells are present in all layers of the skin
• Granulocytes are predominant and form microabscesses in the epidermis
• Langerhans cells and lymphocytes are also increased

PSORIASIS BASED ON SEVERITY

•       Psoriasis is considered:

–       mild if it affects less than 5% of the surface of the body;

–      moderate, if 5–30% of the skin is involved,

–      severe, if the disease affects more than 30% of the body surface.

TYPES OF PSORIASIS

•       Dermatologists distinguish different forms of psoriasis according to:

–       what part of the body is affected,

–      How severe symptoms are,

–      how long they last,

–      the pattern formed by the scales.

PLAQUE PSORIASIS

•       Plaque psoriasis (psoriasis vulgaris) is the most common form of the disease,

•       It is characterized by small, red bumps that enlarge, become inflamed, and form scales.

•       The top scales flake off easily and often, but those beneath the surface of the skin clump together.

•       Removing these scales exposes tender skin, which bleeds and causes the plaques (inflamed patches) to grow.

•       Plaque psoriasis can develop on any part of the body, but most often occurs on the elbows, knees, scalp, and trunk.

SCALP PSORIASIS

•       This form of psoriasis is characterized by scale-capped plaques on the surface of the skull.

NAIL PSORIASIS

•       The first sign of nail psoriasis is usually pitting of the fingernails or toenails.

•       Size, shape,and depth of the marks vary, and affected nails may thicken, yellow, or crumble.

•       The skin around an affected nail is sometimes inflamed, and the nail may peel away from the nail bed.

GUTTATE PSORIASIS

•       Named from the Latin word gutta, which means “a drop,”

•       Guttate  psoriasis is characterized by small, red, drop-like dots that enlarge rapidly and may be somewhat scaly.

•       Often found on the arms, legs, and trunk and sometimes in the scalp,

•       Guttate  psoriasis can clear up without treatment or disappear and resurface in the form of plaque psoriasis.

PUSTULAR PSORIASIS

•       Pustular psoriasis usually occurs in adults.

•        It is characterized by blister-like lesions filled with non-infectious pus and surrounded by reddened skin.

•       Pustular psoriasis,  can be limited to one part of the body (localized) or can be widespread,

•       It may be the first symptom of psoriasis or develop in a patient with chronic plaque psoriasis.

•       Generalized pustular psoriasis is also known as Von Zumbusch pustular psoriasis.

•       Widespread, acutely painful patches of inflamed skin develop suddenly.

•       Pustules appear within a few hours, then dry and peel within two days.

•       Generalized pustular psoriasis can make life-threatening

•       demands on the heart and kidneys.

•       Palmar-plantar pustulosis (PPP) generally appears between the ages of 20 and 60.

•       PPP causes large pustules to form at the base of the thumb or on the sides of the heel.

•       In time, the pustules turn brown and peel.

•       The disease usually becomes much less active for a while after peeling.

•       Acrodermatitis continua of Hallopeau is a form of PPP characterized by painful, often disabling, lesions on the fingertips or the tips of the toes.

•       The nails may become deformed, and the disease can damage bone in the affected area.

INVERSE PSORIASIS

•       Inverse psoriasis occurs in the armpits and groin, under the breasts, and in other areas where skin flexes or folds.

•       This disease is characterized by smooth, inflamed lesions and can be debilitating.

•        

ERYTHRODERMICS PSORIASIS

•       It is characterized by severe scaling, itching, and pain that affects most of the body,

•       Erythrodermic  psoriasis disrupts the body’s chemical balance and can cause severe illness.

This particularly inflammatory form of psoriasis can be the first sign of the disease, but often develops in patients with a history of plaque psoriasis

PSORIATIC ARTHRITIS

•       About 10% of partients with psoriasis develop a complication called psoriatic arthritis.

•       This type of arthritis can be slow to develop and mild, or it can develop rapidly.

•       Symptoms of psoriatic arthritis include:

–       joint discomfort, swelling, stiffness, or throbbing

–       swelling in the toes and ankles

–       pain in the digits, lower back, wrists, knees, and ankles

–       eye inflammation or pink eye (conjunctivitis).

PRECIPITATING FACTORS FOR PSORIASIS

•       Genetics-Over 70% of the patients have a family history

•       Infection

–      streptococcal infections in the the upper respiratory tract may be followed 10-14 days later by an attack of psoriasis.

–      This is very common in children and may be the first presentation of the disease, in a typical guttate pattern

•       Koebner phenomenon

–      An injury to the skin e.g. a cut, burn, scratch or operation scar may subsequently cause psoriasis to develop at that site which may later spread to other areas.

•       Drugs - Lithium, chloroquine and beta blockers may provoke a flare of psoriasis in susceptible patients.

•       Stress – Emotional or physical stress  have been associated with psoriatic attacks

•       Alcohol and smoking - Excess alcohol consumption may aggravate psoriasis. - Smoking has been associated with pustular psoriasis of skin and hands

CLINICAL FEATURES OF PSORIASIS

•       The typical psoriatic lesion is a red, scaly, sharply demarcated plaque

•       The plaque may be of any size and may affect any part of the body

–      The most common sites are the extensor surfaces of the elbows and knees, the sacrum and the scalp

–      Hands and feet are frequently involved

•       The scale is silvery and easily scrapped off, revealing tiny bleeding points

•       Psoriasis is not characteristically itchy but may be when inflammed, rapidly spreading or involving the palms and soles.

•       Psoriasis tends to appear for the first time in young adults

–      However, it may start at any time from infancy to old age

–      It runs a chronic, relapsing course

TREATMENT OF PSORIASIS

•       Treatment is aimed at controlling the current attack and not curing the psoriasis

•       Treatment does not influence the future disease progress.

•       Emollients are used to prevent drying and fissuring of elbows and knees

•       Other treatments are aimed at reducing epidermal cell turnover

•       Different types of psoriasis may respond best to different treatments

TOPICAL THERAPY FOR PSORIOSIS

•       EMOLLIENTS These may be the only drugs required in mild cases

•       Soothing applications are essential for management of erythroderma although the patient may need systemic therapy.

TOPICAL STEROIDS MECHANISM OF ACTION

•       These are essential in acutely inflammed plaques. Their effectiveness in psoriasis  is based primarily on their anti-inflammatory activity. The antimitotic effects of corticosteroids on human epidermis may account for an additional mechanism of action in psoriasis and other dermatologic diseases associated with increased cell turnover.

CHEMISTRY AND PHARMACOKINETICS

•       The original topical glucocorticosteroid was hydrocortisone, the natural glucocorticosteroid of the adrenal cortex.

–      The 9 -fluoro derivative of hydrocortisone was active topically, but its salt-retaining properties made it undesirable even for topical use.

–      Prednisolone and methylprednisolone are as active topically as hydrocortisone.

•       However, triamcinolone and fluocinolone, the acetonide derivatives of the fluorinated steroids, do have a distinct efficacy advantage in topical therapy.

•       Betamethasone  is not very active topically,

–      However, attaching a 5-carbon valerate chain to the 17-hydroxyl position results in a compound over 300 times as active as hydrocortisone for topical use.

•       Fluocinonide is the 21-acetate derivative of fluocinolone acetonide;

–      The  addition of the 21-acetate enhances the topical activity about fivefold.

–      Fluorination of the steroid is not required for high potency.

Topical corticosteroids: Intralesional injections

•       The limited penetration of topical corticosteroids can be overcome in certain clinical circumstances by the intralesional injection of relatively insoluble corticosteroids,

–      These include  triamcinolone acetonide, triamcinolone diacetate, triamcinolone hexacetonide, and betamethasone acetate-phosphate.

•        When these agents are injected into the lesion, measurable amounts remain in place and are gradually released for 3–4 weeks.

•       Intralesional injection of corticosteroids  is often effective for  lesions that are generally unresponsive to topical corticosteroids.

–      Examples: keloids, hypertrophic scars, acne cysts

•       The dosage of the triamcinolone salts should be limited to 1 mg per treatment site, to decrease the incidence of local atrophy

–       i.e. 0.1 mL of 10 mg/mL suspension.

–       

TOPICAL CORTICOSTEROIDS: ADVERSE EFFECTS

•       All absorbable topical corticosteroids possess the potential to suppress the pituitary-adrenal axis

–      Therefore cases of severely impaired stress response can occur

•       Iatrogenic Cushing's syndrome may occur as a result of protracted use of topical corticosteroids in large quantities.

•       Applying potent corticosteroids to extensive areas of the body for prolonged periods, with or without occlusion, increases the likelihood of systemic effects.

•       NOTE:

–      Fewer of these factors are required to produce adverse systemic effects in children,

–      Growth retardation is of particular concern in the pediatric age group.

–       

TOPICAL CORTICOSTEROIDS: LOCAL ADVERSE EFFECTS

•       Adverse local effects of topical corticosteroids include the following:

–      Atrophy,  which may present as depressed, shiny, often wrinkled "cigarette paper"-appearing skin with prominent telangiectases and a tendency to develop purpura and ecchymosis;

–      Steroid  rosacea, with persistent erythema, telangiectatic vessels, pustules, and papules in central facial distribution;

–      Perioral  dermatitis, steroid acne, alterations of cutaneous infections, hypopigmentation, hypertrichosis;

–      Increased  intraocular pressure; and allergic contact dermatitis.

–       

•       TAR COMPUNDS

•       Tar preparations are used mainly in the treatment of psoriasis and  dermatitis.

•       The phenolic constituents endow these compounds with antipruritic properties,

–      This makes  them particularly valuable in the treatment of chronic lichenified dermatitis.

–      Coal tar is used in combination with emollients, salicylic acid and topical steroids

–      However its use has become less popular with the advent of cleaner and less smelly compounds

–      Attempts to purify coal tar to make it more cosmetically acceptable has resulted in loss of potency

–      Coal tar compounds are mostly used on:

–      Guttate  and scalp psoriasis

–      Local  pustular psoriasis of the palms and soles.

•        

–      TAR COMPOUNDS: ADVERSE EFFECTS

•       The most common adverse reaction to coal tar compounds is an irritant folliculitis,

•       Phototoxicity and allergic contact dermatitis may also occur.

•       Tar preparations should be avoided in patients who have previously exhibited sensitivity to them.

SALICYLIC ACID

•       It is used to reduce scale, in preparation for other treatments.

•       It can be mixed with emollients , coal tar and steroids.

VITAMIN D ANALOGS

•       Calcipotriol is a synthetic vitamin D3 derivative

•       It is effective in the treatment of plaque-type psoriasis vulgaris of moderate severity

•       It is colourless, odourless and does not stain

•       It has similar efficacy to 0.1% betamethasone ointment

–      It causes more irritation but no long term skin atrophy

SYSTEMIC THERAPY FOR PSORIASIS

INDICATIONS FOR SYATEMIC THERAPY

•       Systemic therapy is used in treatment of:

–      Severe  and widespread psoriasis

–      Failure or intolerance of topical treatment

–      Rapid relapse of psoriasis after clearance

–       

PSOLARENS AND UVA (PUVA)

•       Psolarens are drugs that are activated by long wave UV light (UVA, wavelength 320-400nm)

•       Psolarens include:

–      Methoxsalen

–      Trioxsalen

–       

PUVA: MECHANISM OF ACTION

•       Psolarens form covalent linkages with pyrimidine bases in DNA when exposed to light of an appropriate wavelength.

•       Additional mechanisms that contribute to beneficial effects of PUVA therapy in hyperproliferative disorders include:

–      PUVA evokes immunological changes by affecting T lymphocytes and epidermal Langerhans cells.

–      It increases melanin in the skin and is therefore useful in treatment of vitiligo

–      It also inhibits mast cell release of inflammatory mediators

•       The psolaren is either  taken by mouth  2 hours before exposure to UVA or applied topically immediately before exposure.

•       This allows the drug to reach its maximum concentration in the skin

PUVA: Other therapeutic uses

•       PUVA  is used to repigment the leukoderma of vitiligo.

–      Success rates are highest in young individuals with recent onset of disease involving nonacral areas.

–      Localized vitiligo can be treated with topical PUVA and more extensive disease with systemic administration. PUVA is employed in the treatment of:

–      cutaneous T-cell lymphoma, atopic dermatitis and urticaria pigmentosa,

–      It is also employed as a preventive modality in some forms of photosensitivity.

–       

–      PUVA: TOXICITY

–      The major acute side effects of PUVA include nausea, blistering, and painful erythema.

–      PUVA-induced redness and blistering generally peak within 48–72 hours.

–      Chronic PUVA therapy accelerates photoaging and the development of  nonmelanoma skin cancer and melanoma.

–      Squamous cell carcinomas occur at 10 times the expected frequency.

–      In patients receiving >250  treatments, there is an increased risk of melanoma.

–      Careful monitoring of patients for cutaneous carcinoma therefore is essential.

ACITRETIN

•       This is a 2^nd generation retinoid used in the treatment of severe resistant psoriasis, acute pustular psoriasis  and palmoplantar psoriasis.

•       It is given orally at a dosage of 25–50 mg/d.

•       Adverse effects attributable to acitretin therapy are similar to those seen with isotretinoin and resemble hypervitaminosis A.

•       Elevations in cholesterol and triglycerides may be noted with acitretin, and hepatotoxicity with liver enzyme elevations has been reported.

•       Acitretin is more teratogenic than isotretinoin in the animal species studied to date, which is of special concern in view of the drug's prolonged elimination time (more than 3 months) after chronic administration.

•       ACITREN USE IN PREGNANCY AND CAUTIONS

•       Acitretin must not be used by:

•       Women  who are pregnant

•       Women who may become pregnant while undergoing treatment or at any time for at least 3 years after treatment is discontinued.

•       Ethanol must be strictly avoided during treatment with acitretin and for 2 months after discontinuing therapy.

•       Patients must not donate blood during treatment and for 3 years after acitretin is stopped.

Tazarotene

•       Tazarotene (Tazorac) is a topical acetylenic retinoid prodrug that is hydrolyzed to its active form by an esterase.

•       The active metabolite, tazarotenic acid, binds to retinoic acid receptors, resulting in modified gene expression.

•       The  mechanism of action in psoriasis may be due  to both anti-inflammatory and antiproliferative actions.

•       TAZAROTENE PKINETICS

•       Tazarotene is absorbed percutaneously, and teratogenic systemic concentrations may be achieved if applied to more than 20% of total body surface area.

•       Women of childbearing potential must therefore be advised of the risk prior to initiating therapy, and adequate birth control measures must be utilized while on therapy.

•       ADVERSE EFFECTS TAZAROTENE

•       Adverse local effects include a burning or stinging sensation (sensory irritation) and peeling, erythema, and localized edema of the skin (irritant dermatitis).

•       Potentiation of photosensitizing medication may occur, and patients should be cautioned to minimize sunlight exposure and to use sunscreens and protective clothing.

•       CYTOTOXIC DRUGS

•       The folic acid antagonist methotrexate is the most common cytotoxic drug in use for psoriasis

•       It is the most effective treatment for psoriatic arthritis

BIOLOGIC AGENTS FOR PSORIASIS

•       Alefacept (Amevive) is an immunosuppressive dimeric fusion protein that consists of the extracellular CD2-binding portion of the human leukocyte function antigen-3 linked to the Fc portion of human IgG1.

–      Alefacept interferes with lymphocyte activation, which plays a role in the pathophysiology of psoriasis, resulting in a reduction in subsets of CD2 T lymphocytes and circulating total CD4 and CD8 T-lymphocyte counts.

–      The recommended dosage is 7.5 mg given once weekly as an intravenous bolus or 15 mg once weekly as an intramuscular injection for a 12-week course of treatment.

–      Alefacept

•       Patients should have CD4 lymphocyte counts monitored weekly while taking alefacept,

–       dosing should be withheld if CD4 counts are below 250 cells/ L.

–      The drug should be discontinued if the counts remain below 250 cells/ L for 1 month.

•       Alefacept is an immunosuppressive agent and should not be administered to patients with clinically significant infection.

•       Because of the possibility of an increased risk of malignancy, it should not be administered to patients with a history of systemic malignancy.

EFALIZUMAB

•       Efalizumab (Raptiva) is an immunosuppressive recombinant humanized IgG1 kappa isotype monoclonal antibody that binds to CD11a subunit of leukocyte function antigen-1.

•       This binding affects the activation, adhesion, and migration of T lymphocytes.

•       The recommended dosage is a single 0.7 mg/kg subcutaneous injection conditioning dose followed by weekly subcutaneous injections of 1 mg/kg not to exceed a maximum single dose of 200 mg.

•       Monitoring of monthly platelet counts is indicated to detect possible severe immune-mediated thrombocytopenia.

•       Efalizumab is an immunosuppressive agent and should not be given concurrently with other immunosuppressive medication.

ETANERCEPT

•       Etanercept (Enbrel) is a dimeric fusion protein consisting of the extracellular ligand-binding portion of the human TNF receptor linked to the Fc portion of human IgG1.

•       Etanercept binds specifically to TNF-α and – β and blocks interaction with cell surface TNF receptors that play a role in the inflammatory process of plaque psoriasis.

•       The recommended dosage of etanercept is a 50 mg subcutaneous injection given twice weekly for 3 months followed by a maintenance dose of 50 mg weekly.

•       Serious life-threatening infections and sepsis have been reported with the use of etanercept,

•       Concurrent use with other immunosuppressive therapy should be avoided.