2. Psoriasis

3.  Clinical manifestations. There are two major types: 1.Eruptive, inflammatory type with multiple small guttate lesions and a greater tendency toward spontaneous resolution. It is relatively rare. It appears rapidly and in young adults, often following streptococcal pharyngitis 2.Chronic stable (plaque) psoriasis with chronic indolent lesions present for months and years, changing only slowly  It affects about 90% of the psoriatic patient population  Psoriasis is a non-infective, usually chronic inflammatory skin disease that is characterized mainly by well defined, red plaques covered by silvery scales. psora = "itch"  Plaque is an elevated, solid, superficial lesion more than 0.5 cm in diameter, which tends to be flat over the whole surface Chronic Plaque Psoriasis Guttate (eruptive) psoriasis

4. Psoriasis  Clinical presentation varies among individuals, from those with only a few localized plaques to those with generalized skin involvement (erythroderma)  Although psoriasis may affect any part of the body, it has a tendency for the knees, elbows, scalp, palms and soles. Nail involvement occurs in up to 50% of patients  Psoriasis of the scalp does not lead to hair loss, even after years of thick plaque-type involvement  It usually gets distributed symmetrically  It can eventually progress to the joints (psoriatic arthritis)

5. Psoriasis, Etiology  Psoriasis etiological and triggering factors include:  Genetic background and heredity The tendency to develop psoriasis is genetically determined When one parent has psoriasis, 8% of offspring develop psoriasis; when both parents have psoriasis, 41% of children develop psoriasis  Physical trauma (Koebner phenomenon) It is a major factor in eliciting lesions Rubbing, scratching tattoo applications, and surgical incisions stimulate the psoriatic proliferative process and elicit psoriatic lesions  Psychosocial stress A factor in flares of psoriasis is said to be as high as 40% in adults and higher in children Psychosocial trauma can play a part in initiating the disease and causing relapse  Drugs Oral lithium, antimalarial drugs, interferon, NSAIDs and  -adrenergic blockers can cause flares in existing psoriasis The use of systemic corticosteroids, although helpful initially, may result in a dramatic flare, or the development of a pustular variant of psoriasis when the dose is reduced rapidly  Other nongenetic factors include obesity, smoking, alcohol ingestion, ultraviolet and chemical injury

6. Psoriasis, Etiology, pathophysiology  Infections Acute streptococcal infection precipitates guttate psoriasis Psoriasis is strongly associated with streptococcal throat infection  Psoriasis now is known to be an autoimmune inflammatory disease mediated by group A streptococcal antigen–specific T lymphocytes that migrate to the dermis and react with epidermal keratinocytes  Then, T cells increase in number and secrete inflammatory mediators such as tumor necrosis factor-alpha (TNF  ) and interferon gamma (IFN  ), which in turn cause inflammation and induce keratinocyte proliferation  psoriasis The normal physiological role of T-lymphocyte is to help protect the body against infection Maintenance of psoriatic lesions is considered an ongoing autoreactive immune response Infiltration of T-cells occurs before obvious epidermal changes are seen Although psoriasis may vary widely in its clinical appearance, the tendency of the epidermis to hyperproliferate is common to all patients. Keratinocyte turnover is ten times more rapid than usual Keratinocyte maturation is abnormal (immature cells) Vascular changes (angiogenesis) also can occur

7. 6 DERMIS STRATUM BASALE STRATUM SPINOSUM STRATUM GRANULOSUM STRATUM CORNEUM Proliferation Immaturity Leukocyte accumulation Disorganized NORMALNORMAL PSORIASISPSORIASIS

8. Psoriasis, Epidemiology, Course and Prognosis  Age of onset Early: Peak incidence occurs at 22.5 years of age Early onset predicts a more severe and long-lasting disease, and there is usually a positive family history of psoriasis Psoriasis in children younger than age 15 is rare Late: Presents about age 55  Incidence, race and sex Psoriasis affects 1% to 2% of the world's population. It may be more common among Scandinavians and less common among Native Americans and black Africans. Both sexes are affected equally  Course and Prognosis  Acute guttate psoriasis appears rapidly Sometimes this type of psoriasis disappears spontaneously in a few weeks without any treatment  More often, guttate psoriasis evolves into chronic plaque psoriasis. This is stable and may undergo remission after months or years, recur, and be a lifelong companion Remission and relapse occur unpredictably Spontaneous remissions of up to 5 years have been reported in approximately 5% of patients  Chronic generalized psoriasis is one of the "miseries that trouble mankind," causing shame and embarrassment and a compromised lifestyle

9.  Itching  Pain  Excessive heat loss  Patient complaints  Unsightliness of the lesions  Feelings of being socially outcast  Excessive scale Psoriasis, Symptoms of chronic plaque psoriasis

10. Management of Psoriasis  Although there are no curative therapies for psoriasis, there are treatment options that adequately suppress the disease process and sometimes afford short periods of remission  The spectrum of treatment options depends on the extent and severity as well as the emotional response to the disease  Management includes use of topical agents and systemic agents (orally or percutaneously administered agents)  All of these treatments may be used alone or in combination with one another  Goal of treatment:  Lubrication  Removal of scales  To slow down lesion proliferation  Pruritus management  To prevent complications  Lessening patient stress

11. Treatment of Psoriasis  Topical and systemic treatments  Wide range of therapies for the treatment of moderate to severe psoriasis  None induce a permanent remission  Many have side effects that can place limits on their use I.Topical preparations: They are first-line therapies for localized psoriasis. This consists of a limited number of chronic stable psoriasis plaques. They include: 1.Corticosteroids 2.Pimecrolimus 3.Vitamin D3 analogues 4.Retinoids 5.Tar preparations 6.Keratolytics (salicylic acid) 7.Emollients 8.Photochemotherapy 9.Excimer laser-derived 308-nm ultraviolet (UV) B therapy

12. Topical corticosteroids are available in numerous vehicles including powders, sprays, lotions, gels, foams, creams, emollient creams and ointments Ointments: They help hydrate the lesion. They are good for dry, hyperkeratotic, scaly lesions Cream: For use on all areas. They are useful for infected lesions Solutions: For scalp psoriasis. They often contain alcohols which can be painful with open lesions 1.Corticosteroids: They are the most commonly prescribed therapy for psoriasis in North America MOA includes anti-inflammatory effect, reducing itching & scaling, anti-proliferative and immunosuppressive effects Generally, corticosteroids range in strength from weak hydrocortisone to potent corticosteroids, such as, betamethasone and clobetasol Abrupt discontinuation of systemic corticosteroids should be avoided, otherwise a rebound exacerbation of the condition may occur Use of strong corticosteroids for long periods should be avoided Management of Psoriasis, Topical preparations, contd.

13.  Side Effects The major concerns with all corticosteroid preparations are dermal atrophy, skin fragility, fast relapse times and tachyphylaxis Systemic absorption  Suppression of the hypothalamic-pituitary-adrenal axis Skin atrophy Burning sensation Poor wound healing Pyogenic infections Tachyphylaxis (medications that are highly effective initially, lose efficacy with prolonged use)  To avoid tachyphylaxis and the other side effects of topical corticosteroids, they are applied twice daily for 2 weeks, after which they are applied on weekends Topical fluorinated glucocorticoids (e.g., fluocinolone acetonide, clobetasol propionate) in ointment base are applied after the scales are removed by soaking in water. Ointment is applied to wet skin, covered with plastic wrap and left on overnight Only weak preparations, such as hydrocortisone, should be used on the face, perineum and flexural areas Management of Psoriasis, Topical preparations, contd.

14. 2.Pimecrolimus and tacrolimus They are potent immunosuppressants They are calcineurin inhibitors which work mainly by inhibiting early activation of T-lymphocytes Pimecrolimus and tacrolimus ointments, compared with topical glucocorticoids, do not cause skin atrophy, and therefore can be used safely in locations such as the face Burning, while occurring in some patients, appears to be less common with pimecrolimus than with tacrolimus. In addition, pimecrolimus has less systemic absorption It is recommended that patients using pimecrolimus use sunscreen and avoid excessive UV exposure; this may increase the incidence of lymphoma Management of Psoriasis, Topical preparations, contd.

15. 3.Vitamin D derivatives: Vitamin D3 analogues are good nonsteroidal antipsoriatic topical agents and are not associated with cutaneous atrophy  The second most commonly used group of psoriasis medications  Calcipotriene (calcipotriol; 0.005%, ointment and cream) is a synthetic vitamin D3 derivative that has been shown to be effective in the treatment of plaque type psoriasis of moderate severity Trials with this formulation have shown efficacy rates equal to a medium- potency steroid ointment, and it can be combined with the corticosteroids It is available as cream, ointment and scalp lotion inhibition of cell proliferation and induction of cell differentiation in psoriatic skin It activates the vitamin D receptor, which belongs to the steroid/thyroid hormone receptor superfamily (nuclear receptors). The receptor-vitamin D complex binds to DNA and modulates the transcription of genes related to cell proliferation and differentiation  This results in inhibition of cell proliferation and induction of cell differentiation in psoriatic skin Management of Psoriasis, Topical preparations, contd.

16. 3.Vitamin D derivatives (contd.):  Side effects and interactions Burning, pruritus, skin irritation, tingling of the skin Potential risks include mild irritation and hypercalcemia, although this has not been observed with the recommended doses Phototherapy may inactivate vitamin D analogues and, conversely, vitamin D analogues may block the therapeutic component of ultraviolet light; thus these topical agents should be applied after phototherapy, not before Topical salicylic acid inactivates calcipotriene. Thus, creams or ointments containing salicylic acid should not be used with calcipotriene Management of Psoriasis, Topical preparations, contd.

17. 4.Topical Retinoids (Vitamin A derivatives)  An important example is tazarotene: It is a third-generation retinoid approved for the treatment of psoriasis  It is the first topical retinoid approved by the FDA for the treatment of psoriasis  MOA: It is a retinoid prodrug that is hydrolyzed by an esterase to its active form, tazarotenic acid, which binds to retinoic acid receptors, resulting in modified gene expression, thereby leading to: Normalization of abnormal keratinocyte differentiation Reduction in keratinocyte proliferation A decrease in the expression of inflammatory markers  Tazarotene gel, applied once daily to dry skin, may be used as monotherapy or in combination with other medications e.g., topical corticosteroids for the treatment of localized plaque psoriasis  Side effects, contraindications and precautions: Burning, itching, and skin irritation are relatively common It is recommended that tazarotene should not be used by pregnant women. It is prescribed with caution to women of childbearing age Patients should avoid sun exposure  Potentiation of photosensitizing medication may occur, and patients should be cautioned to minimize sunlight exposure and to use sunscreens & protective clothing Management of Psoriasis, Topical preparations, contd.

18. 5.Coal Tar (قطران الفحم): This old topical medication is a complex mixture of substances produced during carbonization and distillation of coal  The exact MOA of tar in psoriasis is not well characterized, but it includes: Antiproliferative and antipruritic effects Antibacterial effects Anti-scaling effects : It decreases epidermal cell mitosis and scale development Anti-inflammatory effects  In the chronic stages of psoriasis, tar preparations are quite useful and offer an alternative to the use of topical corticosteroids 5% coal tar concentration is most effective (range is 1%-6%) It is used only on lesions that are well separated, not too big It is used together with salicylic acid (keratolytic) for psoriasis of the scalp Tar baths and shampoos are helpful  Problems with coal tar: Smell Sting; irritation Stain skin and fabrics Sensitize, contact dermatitis

19. Management of Psoriasis, Topical preparations, contd. 5.Coal Tar (contd.)  Goeckerman regimen: Tar is usually used in combination with UVB phototherapy (the application of 1% crude coal tar in a hydrophilic ointment before daily irradiation with UVB) This is the oldest and used to be the most frequently used treatment for patients with moderate-to-severe disease. It is effective within 2 to 3 weeks. This treatment leads to remission of psoriasis in at least 80% of patients The difficulties with this treatment are the time required for exposure to coal tar and UVB, patients' dislike of the smelly, irritant coal-tar preparations and the expense of the treatment. In rare cases, skin cancer has been induced by this treatment This treatment is no longer popular because of its poorly tolerated side effects, and it is not more effective than calcipotriene 6.Tree Bark Extracts  Anthralin: It is a synthetic form of a tree bark extract that is considered to be one of the most effective anti-psoriatic agents available It slows the production of excess skin cells Anthralin is combined with salicylic acid for psoriasis treatment it can cause skin irritation and staining of clothing and skin

20. Management of Psoriasis, Topical preparations, contd. 7.Ultraviolet (UV) irradiation  It is used for the control of psoriatic skin lesions  Patients often notice improvement in skin lesions during the summer months  UV radiation may act by slowing keratinization and anti-inflammatory effects (inducing apoptosis of pathogenic T-cells)  It has a potential to accelerate photo-damage and increase the risk of cutaneous malignancy 8.Emollients and Moisturizers  They soothe, smooth and hydrate the skin  They are used for dry and scaly skin  In case of scalp psoriasis, the scales may be thick and adherent  Emollients are useful with other more specific treatment  White soft paraffin ointment is an example 9.Topical salicylic acid  Advantages of salicylic acid Emollients containing keratolytic agents such as salicylic acid helps remove scales and reduce hyperkeratosis Ointments containing 2-10% salicylic acid are used with topical medications to enhance absorption of other drugs

21. Management of Psoriasis, Topical preparations, Conclusions  Some preparations should never be mixed together because they interfere with each other. For example, salicylic acid inactivates calcipotriene cream or ointment  On the other hand, drugs such as anthralin (tree bark extract) may require the addition of salicylic acid to work effectively  There is not one topical drug that is best for all people with psoriasis. Because each drug has adverse effects or becomes less effective over time, it is common to rotate them  Keratolytics are often added to these preparations to enhance their penetration into the skin

22. Management of Psoriasis, Phototherapy

23. Management of Psoriasis, Systemic Treatments II.Systemic Treatments: Although the majority of patients with limited chronic plaque psoriasis may be treated successfully with one or more topical agents, approximately 20% require more aggressive treatment Systemic treatment should be limited to patients with physically, socially, or economically disabling psoriasis that has not responded to topical treatment (severe, resistant, complicated forms of psoriasis) They include:  Psoralen and UVA  Oral retinoids; acitretin  Immunosuppressant therapy Patients undergoing systemic treatment are required to have regular blood and liver function tests because of the toxicity of the drugs Pregnancy must be avoided for the majority of these treatments

24. Management of Psoriasis, Systemic Treatments 1.PUVA (Psoralen + Ultraviolet A): See before (2 nd Lecture) PUVA involves topical treatment with psoralen followed by UVA. Psoralen makes the body more sensitive to UVA light. Psoralen is given 2 h before UVA irradiation This treatment leads to symptomatic control of severe, disabling psoriasis, not responsive to other therapy Theories of MOA:  Psoralen intercalates into DNA, inhibiting DNA replication and thus, inhibiting epidermal cell hyper-proliferation  Increased apoptosis of activated T-cells PUVA is a highly effective treatment with a significant duration of remission. In over 85% of patients, skin lesions disappear after 20 to 30 treatments. Therapy is usually given 2-3 times per week for several months. Maintenance therapy involves as little as once every 2-4 weeks, with eventual discontinuation of treatment Most patients accept PUVA therapy because of the high likelihood of response and the absence of need for topical medication between treatments

25. Management of Psoriasis, Systemic Treatments The therapeutic index of this treatment is high if the cumulative exposure to UVA radiation is less than that likely to cause cancer or severe photodamage To minimize the cumulative dose of radiation, PUVA can be combined with the oral retinoid etretinate (see later) Oral and topical retinoids are synergistic with oral PUVA, while their dose and the number of phototherapy treatments can be reduced, with the added benefit of a potential reduction in skin carcinogenesis 1.PUVA (contd.) Side effects  The short-term side effects of PUVA are  Nausea, burning, and pruritus  increased risks of sensitivity to the sun, sunburn  The long-term problems are:  An increased risk of photodamage to the skin (premature aging) and of skin cancer related to the cumulative exposure to UVA radiation  Cataract: Protective glasses must be worn during and after treatment

26. Management of Psoriasis, Systemic Treatments The original third generation retinoid used for psoriasis, etretinate, was superseded by its natural metabolite, acitretin, which was shown to have similar efficacy with a better pharmacokinetic profile Since they are not immunosuppressive, retinoids might have a role in the treatment of psoriasis in children, patients with HIV infection and those who are prone to cancer 2.Oral retinoids: They are vitamin A derivatives, and they have been used in the treatment of psoriasis for the past two decades Oral retinoids are approved for the treatment of severe psoriasis in adults resistant to other form of therapies Oral retinoids are especially effective in the treatment of erythrodermic and pustular variants of psoriasis Significant improvement can be achieved within 8 weeks of therapy These synthetic hormones bind to nuclear retinoid receptors, thereby altering gene transcription and returning keratinocyte proliferation and differentiation to normal

27. Management of Psoriasis, Systemic Treatments Contraindications  Patients with severely impaired liver or kidney function  Hyperlipidemia  Pregnant females or those who intend to become pregnant  Birth control must be continued for at least three years after the woman stops taking acitretin because the drug stays in the body for a very long time and will affect unborn babies 2.Oral retinoids (contd.): Retinoids are considered excellent for use in combination with other treatments and when used with UVB or PUVA, their dose and the number of phototherapy treatments can be reduced, with the added benefit of a potential reduction in skin carcinogenesis  This also will minimize the dose-related side effects of retinoids, such as dryness of skin and conjunctiva, and pruritus Systemic retinoid toxicity is similar to hypervitaminosis A; hence, mucocutaneous side- effects (e.g., skin dryness, conjunctivitis, and hair loss) are common. Other side-effects include hyperlipidaemia, osteoporosis and ligamentous calcifications

28. Management of Psoriasis, Systemic Treatments 3.Drugs affecting the immune response: Systemic drugs acting on the immune system are generally used by specialists in a hospital setting  Examples: a)Methotrexate b)Cyclosporine c)Mycophenolate mofetil

29.  The uptake of MTX into the cell is mediated by the reduced folate carrier (green) (1) and by an endocytotic pathway activated by a folate receptor (blue) (2)  Once inside the cell, MTX is polyglutamylated by the enzyme folylpolyglutamate synthase (3)  Both MTX and its polyglutamates (Glu) are potent inhibitors of dihydrofolate reductase, an enzyme that converts dihydrofolate (FH2) to FH4 (4)  The depletion of FH4, leads to an impairment of both purine and thymidine synthesis, an inhibition of DNA replication and cell death in rapidly dividing tissues, including the hyperproliferative psoriatic epidermis. MTX also stimulate apoptosis and death of activated T lymphocytes (immunosuppressive effect) Management of Psoriasis, Systemic Treatments, contd. 3.a) Methotrexate (MTX): It is an antimetabolite. It is a folic acid analog and the main folate antagonist Folic acid Methotrexate

30. Management of Psoriasis, Systemic Treatments, MTX Despite the advent of new therapies, MTX continues to play a central role as an affordable, gold standard treatment for recalcitrant psoriasis and psoriatic arthritis MTX is widely used for the treatment of rheumatoid arthritis and autoimmune diseases, and it is one of the most widely used antimetabolites in cancer chemotherapy Dose: The cell cycle in psoriatic keratinocytes is rapid. Oral administration of MTX in 3 doses (usually 2.5 to 5 mg each) at 12-hour intervals, with the three doses given once weekly, can inhibit the replication of these cells with minimal side effects When stability or adequate clearance is achieved, the lowest effective dose of MTX should be sought by tapering the dose slowly by about 2·5 mg per month Administration can be by oral, intravenous, intramuscular, or subcutaneous routes Contraindication & Side effects: The patient's hematologic status and renal and liver function should be normal if methotrexate is to be given Adequate renal function is necessary because 85% of the drug is excreted through the kidneys, and patients with poor renal function have sustained increases in plasma drug concentrations, leading to acute side effects, including leukopenia and acute GI erosions The chief long-term side effect of MTX therapy is cirrhosis; patients with a history of liver disease or excessive alcohol intake and those with abnormal liver function should not receive the drug

31. Management of Psoriasis, Systemic Treatments, MTX, Contraindication & Side effects, contd. Because of its teratogenicity, MTX is absolutely contraindicated during pregnancy, and pregnancy should be avoided for at least 3 months after discontinuing treatment with MTX. It is also contraindicated in lactating mothers Bone marrow suppression is the most common cause of MTX-related death; hence, appropriate screening every 1–3 months is essential MTX is contraindicated in pre-existing severe anemia, leukopenia, thrombocytopenia A number of drugs, including sulphonamides and their derivatives, may potentiate the risk of bone marrow suppression Like pregnancy, alcohol abuse is an absolute contraindication It should not be also used in patients with immunodeficiency or active infectious disease Side effects include BM suppression, nausea, vomiting, stomatitis and development of megaloblastic anemia (folate supplementation!)  MTX-induced DHFR inhibition makes cells megaloblastic, as a consequence of the impairment of DNA synthesis, whereas RNA and protein synthesis are less affected  Folic Acid is effective in the treatment of megaloblastic anemias due to a deficiency of folic acid resulting from MTX treatment & other causes MTX antagonizes both mammalian and microbial DHFR, whereas diaminopyrimidines such as trimethoprim bind to the bacterial DHFR but not mammalian DHFR

32. Management of Psoriasis, Systemic Treatments 3.b) Cyclosporine: Cyclosporine is a potent immunosuppressant It is a calcineurin Inhibitor (as discussed before) and results in inhibition of T- cell activation Hypertension and renal dysfunction are the major adverse effects 3.c) Mycophenolate mofetil: It is an antiproliferative immunosuppressant approved for prophylaxis of organ rejection in patients with renal, cardiac and hepatic transplants It inhibits the enzyme inosine monophosphatase dehydrogenase, thereby depleting guanosine nucleotides essential for DNA and RNA synthesis  Inosine monophosphate dehydrogenase is the rate-limiting enzyme in de novo synthesis of guanosine nucleotides  T- and B-lymphocytes are more dependent on this pathway than other cell types are. This is the principal mechanism by which mycophenolate mofetil exerts immunosuppressive effects

33. Management of Psoriasis, Systemic Treatments 4.Monoclonal antibodies: Infliximab is a monoclonal antibody administered intravenously for treating several chronic inflammatory diseases Infliximab works by blocking the effects of tumor necrosis factor alpha (TNF- alpha) It is used for treating the inflammation due to psoriasis and psoriatic arthritis Adalimumab is another TNF-alpha inhibitor 5.Phosphodiesterase (PDE) 4 inhibitors: Apremilast is a new oral agent for the treatment of moderate severe plaque psoriasis MOA: It is a PDE4 inhibitor with TNF-α inhibitory activity. It reduces production of multiple cytokines involved in the pathogenesis of psoriasis  PDE4 is a key enzyme involved in modulating production of inflammatory mediators by immune cells