PSORIASIS PRESENTATION FOR EDUCATION.pptx

PSORIASIS PRESENTATION WITH DIFFERENT TYPES, ETIOLOGY ETC

1. PSORIASIS

2. A common chronic inflammatory skin disorder characterized by recurrent exacerbations and remissions of thickened, erythematous , and scaling plaques . Occurs in all racial groups but is most prevalent in whites. Equally common in males and females. Of patients, 75% present with symptoms of psoriasis before the age of 46 years

3. ETIOLOGY A complex and multifactorial disease due to the interaction between environmental factors (exogenous or endogenous antigens) and a specific genetic background. ENVIRONMENTAL FACTORS Factors such as climate, stress, alcohol, smoking, infection, trauma, and drugs may aggravate psoriasis. Warm seasons and sunlight reportedly improve psoriasis in 80% of patients, whereas 90% report worsening in cold weather. Alcohol seems to have a greater influence on the progression of psoriasis in men.

4. Infection has been identified retrospectively as a common precipitating factor in psoriasis. A variant known as guttate (small drop-like plaques) psoriasis is often associated with infections of group A β-hemolytic streptococci. Psoriatic lesions may develop at the site of injury on normal appearing skin ( Koebner response). This response may be induced by a variety of trauma that includes rubbing, venipuncture , bites, surgery, and mechanical pressure.

5. Lithium carbonate, β-adrenergic blocking agents, some antimalarial agents, nonsteroidal anti-inflammatory drugs, ACE inhibitors, tetracyclines , and interferons are among the most commonly reported drugs to exacerbate psoriasis or to trigger psoriasiform lesions

6. GENETIC FACTORS A number of genetic loci have been identified by genome-wide linkage scans and two loci have been replicated: PSORS1 on chromosome 6 , within the major histocompatibility complex, and PSORS2 on chromosome 17q PSORS1 accounts for an estimated 30% to 50% of the genetic contribution to psoriasis.

7. TYPES OF PSORIASIS Plaque psoriasis Most common form, plaque psoriasis causes dry, raised, red skin lesions (plaques) covered with silvery scales. The plaques itch or may be painful and can occur anywhere on the body, including genitals and the soft tissue inside the mouth. In severe cases of plaques , the skin around the joints may crack and bleed .

8. PLAQUE PSORIASIS

9. Nail psoriasis: Psoriasis can affect fingernails and toenails , causing pitting, abnormal nail growth and discoloration . Psoriatic nails may become loose and separate from the nail bed ( onycholysis ). Severe cases may cause the nail to crumble.

10. Scalp psoriasis: Psoriasis on the scalp appears as red, itchy areas with silvery-white scales Flakes of dead skin may be seen in the hair or on the shoulders, especially after scratching the scalp.

11. SCALP PSORIASIS

12. Guttate psoriasis: Primarily affects people younger than 30 and is usually triggered by a bacterial infection It's marked by small, water-drop-shaped sores on the trunk, arms, legs and scalp The sores are covered by a fine scale and are not as thick as typical plaques.

13. GUTTATE PSORIASIS

14. Inverse psoriasis : Mainly affecting the skin in the armpits, in the groin, under the breasts and around the genitals. Inverse psoriasis causes smooth patches of red, inflamed skin. More common in overweight people and is worsened by friction and sweating.

15. Pustular psoriasis Uncommon form of psoriasis can occur in smaller areas on the hands, feet or fingertips . It generally develops quickly , with pus-filled blisters appearing just hours after skin becomes red and tender. The blisters dry within a day or two, but may reappear every few days or weeks. Generalized pustular psoriasis can also cause fever, chills, severe itching and fatigue.

16. PUSTULAR PSORIASIS

17. Erythrodermic psoriasis Least common type of psoriasis. Erythrodermic psoriasis can cover the entire body with a red, peeling rash that can itch or burn intensely. It may be triggered by severe sunburn , by corticosteroids and other medications, or by another type of psoriasis that's poorly controlled.

18. ERYTHRODERMIC PSORIASIS

19. Psoriatic arthritis: In addition to inflamed, scaly skin, psoriatic arthritis causes pitted, discolored nails and the swollen, painful joints that are typical of arthritis. Symptoms range from mild to severe, and psoriatic arthritis can affect any joint. It can cause stiffness and progressive joint damage that in the most serious cases may lead to permanent deformity.

20. PATHOPHYSIOLOGY IMMUNOLOGIC MECHANISMS A central role for activated T cells has been demonstrated by response to drugs that block T-cell activation, migration, or cytokine secretion in psoriasis. Cutaneous inflammatory T-cell–mediated immune activation requires two T-cell signals that are mediated via cell-cell interactions by surface proteins and by antigen - presenting cells (APC) such as dendritic cells or macrophages.

21. The “first signal” is the interaction of the T-cell receptor with antigen presented by the APC (antigen presenting . The “second signal,” also called costimulation , is mediated through various surface interactions. Both signals are essential for initial activation of T cells in psoriasis.

22. Once T cells are activated, they migrate from lymph nodes and the circulation into skin. Specific cell surface proteins on T cells and vascular endothelium including selectins , integrins , and other adhesion molecules mediate this movement. Once in the skin, activated T cells secrete various cytokines that induce the pathologic changes of psoriasis. Cytokines are proteins secreted by immune cells that bind to very specific receptors on the cell surface, influencing keratinocytes and other cells to produce pathologic changes characteristic of psoriasis.

23. The cytokine profile in psoriasis is known as aT -helper cell type 1 (Th1) response; this subset of T cells produces primarily interferon-γ (IFN-γ ) and interleukin (IL)-2. Other local cells, including keratinocytes and local neutrophils , are induced to produce other cytokines, including tumor necrosis factor-α (TNF-α)17 and interleukin (IL)-8,18 which are believed to be important in the pathophysiology of psoriasis. All of these cytokines are important in the development of psoriasis and represent possible targets of biologic therapies.

24. Cytokines and chemokines with a currently recognized potential role in psoriasis include: Granulocyte-macrophage colony-stimulating factor Regulated on activation, normal T-cell expressed and secreted (RANTES; causes keratinocyte proliferation) Epidermal growth factor Monokine induced by interferon-γ (MIG; increases neutrophil migration) IL-8 Inducible protein-10 (increases differentiation of type 1 T cells)

25. IL-12 Macrophage inflammatory protein-3α (MIP-3α; produces angiogenesis) IL-1 Thymus- and activationregulated chemokine (TARC; produces epidermal hyperplasia) IL-6 (increases other chemokine release) INF-γ (increases upregulation of adhesion molecules on endothelial cells) TNF-α Endothelial growth factor (VEGF )

26. DEFECTS IN THE EPIDERMAL CELL CYCLE As a result of pathogenic T-cell production and activation, psoriatic epidermal cells proliferate at a rate sevenfold faster than normal epidermal cells. The germinative cell population increases in psoriatic skin, and duration of the epidermal cell cycle is calculated at 37.5 hours (versus 300 hours in normal skin).

27. CLINICAL PRESENTATION OF PSORIASIS GENERAL Although psoriasis is a nonmalignant, hyperproliferative epidermal cell disorder, it results in accumulated, immature, excessively thickened skin that is manifested as plaques. SYMPTOMS Pruritus is a complaint in about 25% of patients. Severe widespread psoriasis may involve symptomatology similar to that of exfoliative dermatitis, which may include fever and chills.

28. Psoriatic arthritis is a distinct clinical entity in which both psoriatic lesions and inflammatory arthritis-like symptoms occur. Classically, distal interphalangeal joints and adjacent nails are involved, but knees, elbows, wrists and ankles also may be involved.

29. SIGNS In general, psoriatic lesions are characterized by erythematous papules and plaques often covered with silver-white scales. Initial lesions are usually small papules that enlarge over time and coalesce into plaques. If the covering scale is removed, a salmon-pink to erythematous lesion is exposed, perhaps with punctate bleeding from prominent dermal capillaries ( Auspitz sign). Psoriatic lesions vary in appearance depending on the anatomic site and the variant of psoriasis.

30. Scalp involvement may vary from diffuse scaling on an erythematous scalp to thickened plaques with exudation, microabscesses and fissures. Trunk, back, arm, and leg lesions may appear as generalized, scattered, discrete, guttate (resembling drops or spots), or large plaques. Palms, soles, face, and genitalia may be commonly involved. Yellowing under the nail plate also may be seen. LABORATORY TESTS Skin biopsy of lesional skin

31. TREATMENT Goals of treatment of psoriasis are directed at skin normalization: reduction or clearing of erythema , papules, and plaques, as well as scales. The Psoriasis Area and Severity Index (PASI) serves as a uniform method to determine the amount of body surface area affected, along with the degree of erythema , induration , and scaling.

32. Mild psoriasis is considered to have a PASI score of less than 12 Moderate involvement is PASI 12 to 18 Severe psoriasis is PASI greater than 18.

33. NON PHARMACOLOGIC THERAPY EMOLLIENTS Frequently used during therapy-free periods to minimize skin dryness that may lead to early recurrence. These agents hydrate stratum corneum and minimize cutaneous transepidermal water loss (evaporation). Have antipruritic activity, and possess mild vasoconstrictor activity.

34. As lotions, creams, or ointments, emollients often need to be applied several times per day (about four times per day) to achieve a beneficial response. Adverse effects of emollients include folliculitis(hair follicles inflammation) and allergic or irritant contact dermatitis.

35. BALNEOTHERAPY Balneotherapy (and climatotherapy ) is a therapeutic approach that consists of bathing in waters containing certain salts, often combined with natural exposure to the sun. The mixture of salts in the water reduce activated T cells in skin and are remittive for psoriasis. Reduction in serum manganese and lithium levels is significant after bathing with Dead Sea salt, an effect believed to be related to effectiveness of the salts.

36. ULTRAVIOLET B PHOTOTHERAPY Ultraviolet B (UVB) light (290 to 320 nm) continues to be an important phototherapeutic intervention for psoriasis. Exposure to UV light by natural sunlight has been used to treat psoriasis for centuries. The most effective wavelength of UVB for treatment of psoriasis is 310 to 315 nm, and this has led to the development of a UVB “narrow-band” (NB) light source, in which 83% of the UVB emission is at 310 to 313 nm.

37. Numerous topical and systemic psoriatic therapies are used adjunctively to hasten and improve the response to UVB phototherapy. Several studies showed an advantage to combining short-contact anthralin with UVB. The addition of calcipotriene also improved results compared to UVB alone.

38. Emollients enhance efficacy of UVB and may be applied to the skin just before treatments for this purpose. UVB phototherapy has also produced more effective results when added to systemic psoriatic treatments, such as methotrexate and retinoids

39. EXCIMER LASER PHOTOTHERAPY Most laser therapy has been ineffective, while excimer lasers, which generate a 308-nm UVB wavelength , have some efficacy at clearing psoriasis and inducing moderately prolonged remissions. The excimer laser has some advantages over traditional NB-UVB phototherapy, including the capability to successfully treat psoriatic plaques with fewer treatments and with a smaller UV radiation dose. Moreover, it may have a lower risk of carcinogenicity and photoaging .

40. DRUG TREATMENTS FOR PSORIASIS Topical therapy: Keratolytics Coal tar Corticosteroids Anthralin Vitamin D analogues ( calcipotriene and calcitriol ) Tazarotene Immunomodulators ( tacrolimus and pimecrolimus )

41. Systemic therapy: Acitretin Cyclosporine Tacrolimus Methotrexate Mycophenolate mofetil Sulfasalazine 6-Thioguanine Hydroxyurea

42. Biologic therapy: Infliximab Etanercept Alefacept Efalizumab Photochemotherapy : PUVA

43. Topical Therapy: First-Line Agents Keratolytics Used to remove scale, smooth the skin, and decrease hyperkeratosis. When applied to large, inflamed areas of skin, salicylic acid may induce salicylism , with symptoms of nausea, vomiting, tinnitus, and hyperventilation.

44. Salicylate poisoning in small children is potentially more serious than in older people because they are at higher risk of developing metabolic acidosis . The keratolytic effect of salicylic acid enhances penetration and efficacy of some other topical agents such as corticosteroids. Salicylic acid, as a gel or lotion, is usually applied two to three times a day in concentrations of 2% to 10%.

45. Corticosteroids Most widely used agents for the treatment of psoriasis in the United States. They are often used to decrease erythema , scaling, and pruritus . Topical vasoconstricting potencies of corticosteroids are ranked by the Stoughton-Cornell classification in seven classes. Class I corticosteroids , very high-potency, include products such as clobetasol propionate, halobetasol propionate, and betamethasone dipropionate (optimized vehicle).

46. High-potency agents are used primarily as alternatives to systemic adrenocorticoid therapy when local therapy is feasible. Examples of conditions for which very-high-potency products are used include thick, chronic psoriatic plaques.

47. They should be used for finite periods of time (as short as possible) and on relatively small body surface areas. Class VII corticosteroids are agents with the lowest level of vasoconstricting potency (e.g., hydrocortisone 1%). They have a weak antiinflammatory effect and are safest for long-term application. These products are also the safest products for use on the face and intertriginous areas, in infants and young children, and with occlusion when necessary and appropriate.

48. Intermediate classes include products with a medium-potency ranking and are used in moderate inflammatory dermatoses . Medium-potency preparations can be used on the face and intertriginous areas for limited periods of time. Topical corticosteroids appear to inhibit phospholipase A, and to thus reduce levels of arachidonic acid, prostaglandins, and leukotrienes in skin. Moreover, steroid receptors have been identified in skin, with synthesis and mitosis of DNA in epidermal cells being inhibited by topical corticosteroids as demonstrated by decreased epidermal proliferation.

49. Topical corticosteroids are available in ointments, creams, lotions, gels, sprays, shampoos, and mouses An ointment is considered the most clinically effective dosage form in psoriasis treatment because it consists of an oily phase that is occlusive and conveys a hydrating effect. Because of the lipophilicity of ointments, penetration of corticosteroid into dermis is enhanced, resulting in increased vasoconstriction.

50. Ointments are not suitable for use in areas such as the axilla , groin, or other intertriginous areas where maceration and folliculitis can develop secondary to the occlusive effect. Creams—typically emulsified products with an aqueous phase—are preferred by some patients as more cosmetically desirable. They can be used in intertriginous areas even though their lower oil content makes them more drying than ointments. Topical corticosteroids are usually applied 2 to 4 times daily during long-term therapy.

51. Vitamin D Analogues Vitamin D, important in cellular and systemic calcium metabolism, also inhibits keratinocyte differentiation and proliferation, suggesting a role in the treatment of hyperkeratotic skin disease. Vitamin D and its analogues provide antiinflammatory benefits by inducing a shift toward TH2 cytokine expression, with a decrease in IL-2, IL-6, IL-8, INF- γ, and granulocyte-macrophage colony-stimulating factor. Use of vitamin D has been limited by its propensity to cause hypercalcemia .

52. Calcipotriene binds to vitamin D receptors as does vitamin D, but it is 100 times less active on systemic calcium metabolism because of its rapid local metabolism. On average, improvement is seen within 2 weeks of treatment with calcipotriene , with approximately 70% of patients demonstrating marked improvement after 8 weeks of therapy. Adverse effects of calcipotriene include lesional and perilesional irritation, occurring in approximately 10% of treated patients and consisting of mild burning and wound.

53. Irritant contact dermatitis is reported to occur more commonly on the face. Calcipotriene , available in a 0.005% concentration as a cream, ointment, and solution , is generally applied one to two times per day (no more than 100 g/wk). Although calcitriol (1,25-dihydroxyvitamin D3) is not yet available in the United States, it is used in the treatment of mild to moderate plaque psoriasis. Calcitriol is effective in improving or clearing psoriatic plaques.

54. Tacalcitol (1α, 24-dihydroxyvitamin D3) is a biologically active hormone derived from vitamin D. In a study of 157 patients with chronic plaque psoriasis, tacalcitol ointment applied once daily during a 6-month treatment period decreased mean PASI score by 67% and body area affected from 13.3% to 8.8%. Reported adverse effects of tacalcitol are limited to local, transient, mild irritation.

55. Tazarotene A synthetic retinoid, is a prodrug that exerts its pharmacologic activity when hydrolyzed to its active metabolite, tazarotenic acid. Like other topical retinoids , it modulates keratinocyte proliferation and differentiation. Effective for the treatment of mild to moderate plaque psoriasis. Predominant treatment-related adverse effects are mild to moderate pruritus , burning, stinging, or erythema .

56. Tazarotene is often used in combination with topical corticosteroids to decrease the incidence of local adverse events and to increase efficacy. Application of the gel to eczematous skin or to more than 20% of body surface area is not recommended because this can lead to extensive systemic absorption. Available as a 0.05 or 0.1% gel and cream , and is applied once a day, usually in the evening.

57. Topical Therapy: Second-Line Agents Coal Tar Coal tar contains numerous hydrocarbon compounds formed from distillation of bituminous coal. Although the mechanism of action is not fully understood, coal tar, when applied to normal skin, stimulates transient epidermal hyperplasia followed by a cytostatic effect with epidermal thinning.

58. There is evidence that ultraviolet B (UVB) light–activated topical coal tar forms photo adducts with epidermal DNA, thereby inhibiting DNA synthesis. This downregulated epidermal proliferation rate approaches a normal rate of proliferation and leads to reduction in plaque elevation. Coal tar treatment is a burdensome, time-consuming treatment with disadvantages that include local irritation, unpleasant odor, staining of skin and clothing, and increased sensitivity to ultraviolet (UV) light, including the sun.

59. The risk of carcinogenicity is low; however, there are cases indicating a higher rate of nonmelanoma skin cancers in patients chronically exposed to tar and UV light. Coal tar preparations of 2% to 5% tar are available in lotions, creams, shampoos, ointments, gels, and solutions. It also can be used in bath water. It is generally applied in the evening and allowed to remain in skin contact through the night.

60. Anthralin An anthrone derivative of chrysarobin , was introduced under the name dithranol in Great Britain decades ago. Chronic plaque-type and guttate psoriasis respond better than other variants to anthralin treatment. Topical anthralin , particularly with UV light, is long established as an effective approach to the treatment of psoriasis.

61. Anthralin possesses antiproliferative activity on human keratinocytes , inhibiting DNA synthesis by intercalation between DNA strands. It induces NF- κB (nuclear factor kappa light chain enhancer of activated b cells) in murine keratinocytes . Because NF κB is involved in the transcription of proinflammatory cytokines such as IL-6, IL-8, and TNF-α, these findings can be helpful in explaining the irritant properties of anthralin .

62. The patient must apply anthralin products only to affected areas of skin because contact with uninvolved skin can result in excessive and unwanted irritation and staining . Skin staining usually disappears within 1 to 2 weeks of discontinuation. Staining of affected plaques is a positive response sign Usually it is applied in the evening and allowed to remain overnight.

63. Inflammation, irritation, and staining of skin and clothing (via oxidation and binding to keratins) are often therapy-limiting effects. Fortunately, anthralin exerts its clinical effects at low cellular concentrations ; classic anthralin therapy starts with low concentrations (0.1% to 0.25%) and gradually proceeds to higher concentrations (0.5% to 1%). Short-contact anthralin therapy regimens are alternative modes of application with decreased local adverse effects. Liposomal-based anthralin 0.5% gel can also be used for short contact therapy (10–20 minutes) and can noticeably reduce staining of skin and irritation.

64. Topical Calcineurin Inhibitors (TCIs) Pimecrolimus and tacrolimus are calcineurin inhibitors capable of exerting a local immunomodulating effect that can serve to normalize hyperproliferation of epidermis. The benefit in using these agents, as opposed to topical corticosteroids, is that these immunomodulators do not cause skin atrophy.

65. Although not commercially available in the United States, sirolimus is an immunosuppressive drug similar in structure to tacrolimus , however it does not inhibit calcineurin . Sirolimus inhibits a central kinase that transduces signals from the IL-2 receptor. By blocking this receptor, sirolimus inhibits T-cell stimulation by IL- 2. Clinical studies have demonstrated that topical sirolimus sufficiently crosses the stratum corneum /epidermis and is therefore effective in psoriasis.

66. SELECTED TOPICAL PSORIASIS TREATMENT REGIMENS AND ADVERSE EFFECTS

67. SYSTEMIC THERAPY:FIRST LINE AGENTS Acitretin An oral retinoid, is the active metabolite of etretinate . Indicated for the treatment of severe psoriasis, including erythrodermic and generalized pustular types , but is more useful as an adjunct in the treatment of plaque psoriasis. In contrast to the fast-acting cyclosporine and methotrexate , acitretin resolves psoriatic lesions more slowly. Acitretin has a shorter half-life than etretinate .

68. Its mechanism of action is not completely understood; it may achieve benefits by acting on retinoid receptors in the keratinocyte nucleus to correct abnormal cell differentiation. Acitretin has shown good results when combined with other psoriatic therapies, including PUVA(psoralen and ultraviolet A ) and UVB, cyclosporine, and methotrexate . The combination of acitretin and PUVA is highly effective and provides faster and more complete clearance, as well as allowing a decrease in the doses of both agents, thereby limiting the risk of adverse effects.

69. Adverse effects are dose dependent. They include hypervitaminosis A (i.e., dry lips/ cheilitis , dry mouth, dry nose, dry eyes/ conjunctivitis, dry skin, pruritus , scaling, and hair loss), hepatotoxicity,skeletal changes, hypercholesterolemia, and hypertriglyceridemia . Acitretin is a known teratogen and thus is contraindicated in females who are pregnant or who plan pregnancy within the 3 years following drug discontinuation. Absorption is enhanced when taken with food. Concurrent ingestion of alcohol converts acitretin to etretinate , which has a longer half-life.

70. An initial recommended dose of acitretin is 25 to 50 mg once daily , with therapy continued until lesions have resolved. A dosage of 50 mg/day is typically required for plaque psoriasis, and even at this relatively high dose, acitretin is only moderately effective. It is better tolerated when taken in conjunction with a meal.

71. SYSTEMIC THERAPY: SECOND-LINE AGENTS Cyclosporine An effective immunosuppressive agent that inhibits the first phase of T-cell activation, cyclosporine is used in the treatment of both cutaneous and arthritic manifestations of severe psoriasis . Inhibits the release of inflammatory mediators from mast cells, basophils , and polymorphonuclear cells. An oral microemulsion formulation of cyclosporine has shown a better pharmacokinetic profile, resulting in a more consistent and predictable rate of absorption than the original formulation

72. Cyclosporine is nc with prolonged use. To decrease the risk nephrotoxicity , the dose of cyclosporine should be kept below 5 mg/kg per day. In addition, use for more than 2 years of cumulative treatment may increase the risk of malignancy, including skin cancers and lymphoproliferative disorders.

73. Other complications include hypertension, hypomagnesemia , hyperkalemia , decreased liver function, elevation of serum lipids, gastrointestinal intolerance, paresthesias , hypertrichosis , and gingival hyperplasia The typical dose of cyclosporine is usually between 2.5 and 5 mg/kg per day.

74. Tacrolimus A macrolide immunosuppressive agent indicated for the prevention of organ transplant rejection and useful as an alternative treatment in severe recalcitrant psoriasis. Like cyclosporine, inhibits T-cell activation. Adverse effects include diarrhea, nausea, paresthesias , hypertension, tremor, and insomnia. Other toxicities with topical tacrolimus — including renal insufficiency and immunosuppression —rarely reported. In recalcitrant plaque-type psoriasis, patients receive tacrolimus at oral doses of 0.05 mg/kg per day (increased up to 0.15 mg/kg per day as needed).

75. Methotrexate Methotrexate , a common antimetabolite , was introduced several decades ago for the treatment of psoriasis and remains an effective therapeutic approach. It is a synthetic analogue of folic acid that acts as a competitive inhibitor of the enzyme dihydrofolate reductase , that is responsible for the conversion of dihydrofolate to tetrahydrofolate . Tetrahydrofolate is an essential cofactor for the synthesis of thymidylate and purine nucleotides required for DNA and RNA synthesis.

76. Methotrexate inhibits replication and function of T and B cells and suppresses secretion of various cytokines such as IL-1, IFN-γ , and TNF-α. It also suppresses epidermal cell division. Indicated in patients with moderate to severe psoriasis. Particularly beneficial for patients with psoriatic arthritis. It is also indicated for patients that are refractory to topical or ultraviolet therapy. Methotrexate should be avoided in patients with active infections because of its immunosuppressive Activity.

77. Methotrexate is associated with nausea and vomiting as well as mucosal ulceration, stomatitis , malaise, headaches, macrocytic anemia, and pulmonary toxicity. Nausea and macrocytic anemia can be ameliorated by administering oral folic acid in doses of 1 to 5 mg/day. Bone marrow toxicity that leads to leukopenia , anemia, and thrombocytopenia has been shown to be induced by methotrexate .

78. A serious long-term adverse effect is hepatotoxicity . Consequently, methotrexate should typically be avoided in patients with liver disease. Risk factors for hepatotoxicity include a history of excessive alcohol consumption, hepatitis, persistent elevated liver function tests, and family history of inheritable liver disease. Malignant lymphomas have been reported in several patients treated with methotrexate .

79. Contraindicated in pregnant women because it is teratogenic . Drug interactions may potentiate methotrexate toxicity. For ex: nonsteroidal anti-inflammatory drugs can reduce renal clearance of methotrexate , resulting in toxic levels.

80. DRUGS THAT INCREASE TOXICITY OF METHOTREXATE

81. The starting methotrexate dose is 7.5 to 15 mg per week, and this is increased incrementally by 2.5 mg every 2 to 4 weeks until a response is evident. Maximal doses are typically about 25 mg per week. It can be administered orally, subcutaneously, or intramuscularly. It is renally excreted and should therefore not be administered to patients with impairment of kidney function.

82. Mycophenolate Mofetil Mycophenolate mofetil , a semisynthetic morpholinoester of mycophenolic acid, initially was used to prevent acute rejection after renal and cardiac transplantation , but it is now used as part of combination therapy in moderate to severe psoriasis and other autoimmune dermatoses . It reversibly blocks de novo synthesis of guanine nucleotides required for DNA and RNA synthesis. The drug has been shown to have a specific lymphocyte antiproliferative effect.

83. Commonly reported adverse effects of mycophenolate mofetil include gastrointestinal toxicity (diarrhea, nausea, and vomiting), hematologic effects (anemia, neutropenia , and thrombocytopenia), and an increased incidence of viral and bacterial infections. Mycophenolate mofetil is usually administered in 500-mg doses four times a day; the dosage can be increased up to 4 g/day.

84. Sulfasalazine Sulfasalazine , commonly used in the treatment of inflammatory bowel disease and rheumatoid arthritis, is selectively used as an alternative treatment, particularly in patients with concurrent psoriatic arthritis. An anti-inflammatory agent that inhibits 5-lipoxygenase. When used as a single agent in the treatment of psoriasis, it is not as effective as is therapy with methotrexate , PUVA, or acitretin .

85. One possible advantage of sulfasalazine therapy compared with other systemic treatments is its relatively high margin of safety. The usual dose of oral sulfasalazine is 3 to 4 g/day for 8 weeks.

86. 6-Thioguanine A purine analog that acts as an antimetabolite in the S-phase of cell division, 6-thioguanine is approved for treatment of leukemia, but has been used as an alternative treatment for psoriasis for decades when conventional therapies have failed. It appears to be less hepatotoxic than methotrexate and therefore may be more useful in treating hepatically -compromised patients with severe psoriasis.

87. Adverse effects of 6-thioguanine include bone marrow suppression, gastrointestinal complications including nausea and diarrhea, and elevation of liver function tests. The typical dose of 6-thioguanine is 80 mg twice weekly, increased by 20 mg every 2 to 4 weeks. Its maximum dose is considered to be 160 mg three times a week.

88. Hydroxyurea Hydroxyurea inactivates the enzyme ribonucleotide reductase , inhibiting cell synthesis in the S-phase of the DNA cycle. An antimetabolite that is primarily used to treat hematologic malignancies, it has been used for the treatment of psoriasis for more than 3 decades. It is selectively used, particularly in those with liver disease who would be at risk of adverse effects with other antipsoriatic agents. Hydroxyurea is less effective than methotrexate .

89. Adverse effects are bone marrow toxicity with leukopenia or thrombocytopenia, cutaneous reactions, leg ulcers, and megaloblastic anemia. The typical dose of hydroxyurea is 1 g/day, with gradual increase to 2 g/day as needed as tolerated. Improvement is gradual, usually seen after 4 weeks of therapy.

90. BIOLOGIC THERAPY The biologic agents currently used in moderate to severe psoriasis treatment are infliximab , etanercept , alefacept , and efalizumab . In psoriasis, biologic agents typically act through one or more of the following mechanisms: (1) elimination of activated T cells (2) inhibition of T-cell activation (3) interference with T-cell trafficking to the skin (4) neutralization of the effects of Th1-type cytokines (5) induction of immune deviation by introducing Th2- type cytokines

91. Infliximab Infliximab is a chimeric monoclonal antibody (immunoglobulin G1; IgG1) directed against TNF-α. It binds with high affinity to the soluble and transmembranous forms of TNF-α and inhibits binding of TNF- α with its receptors. TNF-α is believed to play an important role in the pathogenesis of psoriasis. Increased amounts of TNF-α have been found in psoriatic lesions.

92. The proposed mechanism of action of TNF-α includes stimulation of synthesis of numerous cytokines and induction of the expression of intracellular adhesion molecules on endothelial cells and keratinocytes . The most common adverse effects of infliximab are headaches, fever, chills, fatigue, diarrhea, pharyngitis , upper respiratory and urinary tract infections, and hypersensitivity reactions ( urticaria , dyspnea , and hypotension).

93. Infliximab has been also associated with infections and lymphoproliferative disorders. It is not associated with end-organ toxicity, and blood counts, liver enzyme levels, kidney function, and complement values can be expected to remain normal during treatment. This gives it a major advantage over other systemic psoriasis treatments. Infliximab is administered in three doses at weeks 0, 2, and 6, of 5 mg/kg or 10 mg/kg by slow intravenous infusion.

94. Etanercept Etanercept , another TNF-α blocker, is a genetically engineered fusion protein that combines the extracellular domain of the TNF-α receptor with the Fc region of human IgG1. Etanercept binds free and membrane-bound TNF-α, competitively interfering with the interaction of TNF-α with cell-bound receptors, and inhibits the effects of this cytokine on target cells. Unlike the chimeric infliximab , etanercept is fully humanized, thereby minimizing the risk of immunogenicity.

95. Etanercept has been approved in several countries for subcutaneous treatment of rheumatoid arthritis and psoriatic arthritis. Adverse effects of etanercept include a local reaction at the injection site (20% of patients), respiratory tract and gastrointestinal infections, abdominal pain, nausea and vomiting, headaches, and rash. Serious infections (including tuberculosis) and malignancies have rarely been observed. Etanercept is usually given in doses up to 50 mg subcutaneously twice a week.

96. Alefacept Alefacept is a dimeric fusion protein that combines the first extracellular domain of human LFA-3 with the Fc portion of human IgG1. The LFA-3 segment of alefacept binds specifically to CD2 on T cells to prevent costimulatory signals delivered by LFA-3 and thereby inhibit cutaneous T-cell activation and proliferation. Alefacept is approved for treatment of moderate to severe plaque psoriasis in patients and is also effective for the treatment of psoriatic arthritis.

97. Significant clinical response is achieved after about 3 months of therapy, and improvements are relatively long lasting. The most common adverse events are mild and include pharyngitis , influenza-like symptoms, chills, dizziness, nausea, headache, injection site pain and inflammation, and nonspecific infection; the frequency of these effects is low. Also, the drug produces no increase in the rate of opportunistic infections or malignancies. Alefacept is administered by intramuscular injection in once weekly doses of 15 mg for 12 weeks.

98. Efalizumab Efalizumab is a humanized monoclonal antibody (IgG1) against CD11-α integrin . The most frequent adverse effects of efalizumab are mild to moderate influenza-like complaints such as headache, nausea, chills, nonspecific infection, pain, fever, and asthenia; however, organ toxicity, serious infections, and malignancies have not been reported. The usual dose is 1 mg/kg subcutaneously once weekly.

99. PHOTOCHEMOTHERAPY UVA combined with oral methoxsalen is a photochemotherapeutic approach to treatment of psoriasis. Photochemotherapy is an important treatment consideration for patients with moderate to severe psoriasis, when time needed to treat and risk factors are balanced with potential benefit. The mechanism of action of both UVB and PUVA in treating psoriasis is thought to be immunomodulatory . Phototherapy apparently modulates expression of cellular adhesion molecules and induces T-cell apoptosis.

100. Candidates for PUVA therapy usually have moderate to severe, incapacitating psoriasis unresponsive to conventional topical and systemic therapies. Adverse effects from oral methoxsalen include nausea, dizziness, and headache. Long-term adverse effects from combined psoralen ( methoxsalen ) and UV light include actinic skin damage, solar elastosis(accumulation of abnormal elastin in dermisof skin) , dry and wrinkled skin, and hyperpigmentation or hypopigmentation .

101. An increased risk of skin cancers, both squamous cell carcinoma and melanoma, exists after PUVA therapy, and is correlated with the cumulative UVA exposure. Oral methoxsalen is usually dosed with milk or food to minimize risk of nausea and gastrointestinal upset. Systemic PUVA is approved for the treatment of psoriasis.

102. It consists of oral ingestion of a potent photosensitizer such as methoxsalen (8-methoxypsoralen) at a constant dose (0.6 to 0.8 mg/kg) and variable doses of UVA, depending on patient skin type and history of previous response to ultraviolet radiation . Approximately 2 hours after ingesting psoralen , the patient is exposed to UVA light. Photochemotherapy is performed two or three times a week. In most patients, control and partial clearing occurs by the twenty-fifth treatment.

103. Another method—one that may have less carcinogenic potential—is to topically deliver the photosensitizer ( methoxsalen ) to the skin by addition to the bath water (bath PUVA) instead of through systemic administration. Major advantages of this therapy are minimal risk of systemic effects and the overall reduction of UVA dose to one-fourth that required with conventional PUVA. A reduction in the risk of nonmelanoma skin cancer has also been demonstrated.

104. PSORIASIS TREATMENT SPECTRUM