1. PSORIASIS Etymology: Gk, psoriasis, itch

2. Etiology Prevalence in is 1-3% and in America and western Lower prevalence rates are found in Japanese and psoriasis is rare in West Africans Psoriasis first appears during 2 peak age ranges:The first peak occurs in persons aged 16-22 years, and the second occurs in persons aged 57-60 years

3. Pathogenesis The initiation and maintenance of lesions requires activated T Lymphocytes Drugs suppressing T-cell activity contribute to the improvement of psoriasis

4. An unknown antigen may cause Antigen- presenting cells (APCs) to be activated in the epidermis The APCs internalize and process the antigen, which is then presented on the APC surface Activated APCs then travel to the lymph nodes and activate naive T cells by binding to it

5. Binding leads to the recognition of intracellular adhesion molecule-1 (ICAM-1) on the surface of the APC by lymphocyte function-associated antigen-1 (LFA-1) on the surface of the T cell. This interaction sends a necessary but insufficient activation signal to the T cell Additional costimulatory signals are sent to the T cell as a result of several other interactions The net effect of all of these signals is an activated T cell with enhanced affinity for endothelial cells

6. The activated T cell travels along the microvasculature into the dermis and then into the epidermis In the skin, activated T cells undergo a second activation similar to the previous encounter with APCs in the lymph node Reactivated T cells then produce cytokines (soluble proteins that can exert both direct and indirect effects on other cells). These cytokines include interleukin-2 (IL-2) and interferon-gamma (IFN-g) These cytokines induce other cells to produce TNF-a, IL-8, and granulocyte-macrophage colony-stimulating factor (GM-CSF)

7. Activated T cells and the cytokines cause aborted maturation and excessive proliferation of the keratinocytes. The turnover in the epidermal cells is reduced from 2 weeks to 1 day. These histopathological alterations are clinically evident as plaques

8. Genetics Psoriasis was present in 73% of monozygotic twins compared with 20% in dizygotic twins Psoriasis susceptibility 1 (PSOR1) locus on chromosome 6 is associated with up to 50% of cases The relative risk of persons bearing the HLA- Cw6 phenotype to develop psoriasis is about 10-fold higher than other persons but only about 10 % of HLA-Cw6 carriers develop psoriasis

9. When both parents are affected by psoriasis, the rate in siblings is as high as 50%. When one parent is affected, the rate is 16.4% When neither parent has psoriasis, only 7.8% of siblings of probands are affected Other studies have shown that 36-71% of patients with psoriasis have one relative who is also affected by psoriasis

10. Excerbating Factors Can be divided into local and systemic factors. Local factors 1-Trauma: e g, physical, chemical, electrical, surgical, infective, and inflammatory types of injury or even excessive scratching can aggravate or precipitate localized psoriasis (Koebner reaction)

11. 2-Sunlight: Most patients generally consider sunlight to be beneficial for their psoriasis. Most report a decrease in illness severity during the summer months or periods of increased sun exposure; however, a small minority find that their symptoms are aggravated by strong sunlight

12. Systemic factors 1-Infection: Pharyngeal streptococcal infections have been shown to produce guttate psoriasis. Some evidence suggests that subclinical streptococcal colonization or overgrowth could be responsible for refractory plaque psoriasis. An increase in psoriasis activity was observed in HIV infected patients. 2-Drugs: Some drugs cause an exacerbation of psoriasis. Lithium and withdrawal from systemic corticosteroids are well known to cause flares of disease. Beta-blockers, antimalarials, and nonsteroidal anti-inflammatory drugs (NSAIDs) have also been implicated.

13. 3-Psychogenic/emotional factors: Many patients report an increase in psoriasis severity with psychological stress. A clear cause-and-effect relationship between disease exacerbation and stress unfortunately has not been proven but, pruritus associated with increased anxiety or depression may promote scratching and a Koebner reaction.

14. 4-Smoking: An increased risk of chronic plaque psoriasis exists in smokers 5-Alcohol: Alcohol is considered a risk factor for psoriasis 6-Endocrine: Psoriasis severity has been noted to fluctuate with hormonal changes. Disease incidence peaks at puberty and during menopause. Pregnant patients' symptoms are more likely to improve than worsenl. In contrast, the disease is more likely to flare in the postpartum period

15. Clinically Symptoms: Over 65% of patients complain of itching Patients may report that their disease worsens in the winter and improves in the summer The isomorphic phenomenon (Koebner reaction): 38-76% of patients recognize that new lesions appear at sites of injury 7-14 days after the skin has been injured In some patients, so-called reverse-Koebner reactions have also been noted in which preexisting psoriatic plaques actually clear after injury or trauma to the skin.

16. Elevated, symmetrical plaques that vary in size from one to several centimeters. They have -Irregular to oval -Sharply demarcated boundaries -Dry, thin, silvery-white scales variable in amount and thickness

17. -Auspitz sign(Grattage test): Removing the scale reveals a smooth, red, glossy membrane with tiny punctate bleeding points. These points represent bleeding from enlarged dermal capillaries after removal of the overlying epithelium

18. -Rich red color:often referred to as 'salmon pink‘. This quality of color is of special diagnostic value to differentiate psoriasis from eczema in lesions on the palms, soles and scalp. In the fair-skinned individual, the color is less rich and almost magenta pink. In dark-skinned races, the quality of the color is lost

20. Clinical patterns 1-Psoriasis Vulgaris(Plaque-type) Seen in approximately 90 % of patients Single small papules become confluent, forming plaques Lesions may extend laterally and become circinate because of the confluence of several plaques (psoriasis gyrata)

21. The borders may resemble a land map (psoriasis geographica) Annular psoriasis:Ring-like lesions

22. Elephantine psoriasis is an uncommon form characterized by thickly scaling, large plaques, usually on the lower extremities

23. Distribution: The extensor aspects of the extremities, particularly the elbows and knees, along with scalp, lower lumbosacral, buttocks, and genitalia. Other sites of predilection include the umbilicus and the intergluteal cleft

24. 2-Guttate Psoriasis (Latin Gutta=drop) Characterized by eruption of small (0.5 to 1.5 cm in diameter) papules over the upper trunk and proximal extremities Manifests at an early age Streptococcal throat infection frequently precedes or is concomitant with the onset or flare

25. 3-Inverse Psoriasis Localized in the major skin folds, such as the axillae, the inguinal and inframammary areas Scaling is usually minimal or absent, and the lesions appear glossy Sweating is impaired in affected areas

26. 4-Psoriatic erythroderma The disease affects all body sites Erythema is the most prominent feature with superficial scaling

27. Patients with erythrodermic psoriasis lose excessive heat because of generalized vasodilatation, and this may cause hypothermia Psoriatic skin is often hypohidrotic due to occlusion of the sweat ducts There is an attendant risk of hyperthermia in warm climates Lower extremity edema is common secondary to vasodilatation and loss of protein from the blood vessels into the tissues

28. High-output cardiac failure and impaired hepatic and renal function may also occur Erythrodermic psoriasis may start from worsening of plaque psoriasis to involve most body areas or it may be a response to treatment as a generalized Koebner reaction

29. 5-Pustular Psoriasis Several clinical variants of pustular psoriasis exist: ِ A-generalized Pustular Psoriasis (Von Zumbusch Type) B-annular Pustular Psoriasis C-impetigo Herpetiformis D-acrodermatitis Continua Of Hallopeau

30. A-Generalized pustular psoriasis (von Zumbusch type) It is usually preceded by other forms of the disease The disease occurs as attacks characterized by fever that lasts several days and a sudden generalized eruption of sterile pustules 2 to 3 mm in diameter

31. The pustules are disseminated over the trunk and extremities, including the nail beds, palms, and soles The pustules usually arise on highly erythematous skin, first as patches and then becoming confluent as the disease becomes more severe

32. The erythema that surrounds the pustules often spreads and becomes confluent, leading to erythroderma Various provoking factors are known including withdrawal of oral corticosteroids, infections, and irritating topical treatment

33. B-Annular Pustular Psoriasis It is a rare variant of pustular psoriasis Lesions may appear at the onset of pustular psoriasis, with a tendency to spread and form enlarged rings, or they may develop during the course of generalized pustular psoriasis The characteristic features are pustules on a ring-like erythema

34. C-Impetigo Herpetiformis lesions are identical to annular pustular psoriasis but occur during pregnancy Onset is usually early in the third trimester and persists until delivery It tends to develop earlier in subsequent pregnancies It is often associated with hypocalcemia There is usually no personal or family history of psoriasis

35. D-Acrodermatitis Continua of Hallopeau It is rare sterile, pustular eruption of the fingers or toes slowly extends proximally Continuous pustulation leads to nail destruction and atrophy of the distal phalanx It may be associated with generalized pustular psoriasis of the Zumbusch type

36. 6-Sebopsoriasis It is a common clinical entity It presents with erythematous plaques with greasy scales localized to seborrheic areas (scalp, glabella, nasolabial folds, perioral and presternal areas, and intertriginous areas)

37. In the absence of typical findings of psoriasis elsewhere, distinction from seborrheic dermatitis is difficult It may represent a modification of seborrheic dermatitis by the genetic background of psoriasis

38. 7- Napkin psoriasis Usually begins between the ages of 3 and 6 months First appears in the napkin areas as a confluent red area with appearance a few days later of small red papules on the trunk that may also involve the limbs These papules have the typical white scales of psoriasis

39. Related Physical Findings 1- NAIL CHANGES IN PSORIASIS Found in up to 40 percent of patients Nail pitting is the commonest feature

40. Onycholysis:white areas of the nail plate due to separation of the nail plate from its underlying attachment to the nail bed Subungual hyper- keratosis is due to hyperkeratosis of the nail bed

41. Nail plate crumbling Beau’s lines:horizontal, lines going across the nail

42. 2-Geographic tongue Presents as asymptomatic erythematous patches with serpiginous borders, resembling a map The lesions have a migratory character It has been postulated to be an oral variant of psoriasis, as these lesions show several histologic features of psoriasis. However, geographic tongue is a relatively common condition and is seen in many nonpsoriatic individuals

43. 3-Psoriatic Arthritis Develops in approximately 10-15 % of those with psoriasis In approximately 50% of those affected arthritis appears one decade after the onset of psoriasis, whereas in the remainder the onset occurs with the disease or precedes it

44. The most distinctive features of psoriatic arthritis are Distal interphalangeal joint arthritis Dactylitis

45. Enthesitis(inflammation of the insertion points of tendons and joints into bone) Periosteal new bone formation Asymmetric oligoarthritis& spondylitis The blue arrow = a normal joint space Red arrow = “cup and saucer” effect of the fourth metatarsal bone being jammed into the base of the fourth toe The yellow circle = “Pencil appearance”destruction characteristic of the disease

46. Modifying Factors Obesity :Obese individuals are more likely to present with severe psoriasis Smoking:(<20 cig./day) associated with more than a twofold increased risk of severe psoriasis Infection: Streptococcal throat infection and guttate psoriasis have been linked Drugs: Antimalarials, β blockers, lithium, NSAID, imiquimod, angiotensin-converting enzyme inhibitors: Exacerbate psoriasis

47. Prognosis Chronic plaque psoriasis is in most cases a lifelong disease, manifesting at unpredictable intervals. Spontaneous remissions, lasting for variable periods of time, may occur in the course of psoriasis in up to 50 % of patients. The duration of remission ranges from 1 year to several decades

48. Guttate psoriasis is often a self-limited disease, lasting from 12 to 16 weeks without treatment. It has been estimated that one-third to two-thirds of these patients later develop the chronic plaque type Erythrodermic and generalized pustular psoriasis have a poorer prognosis, with the disease tending to be severe and persistent

49. PASI Score (Psoriasis Area and Severity Index) It is a method to estimate severity of psoriasis in order to evaluate the clinical efficacy of new treatments Psoriatic plaques are graded based on three criteria: redness (R), thickness (T), and scaliness (S) Severity is rated on a 0-4 scale (0 for no involvement up to 4 for severe involvement) The highest PASI score is 72; the lowest is 0

50. Histopathology

51. Dilated vessels in dermal papillae, perivascular cuffing with lymphocytes

52. Parakeratosis Orthokeratosis of normal basket- weave type Loss of granular layer

53. Munro micro- abscesses i.e. collections of neutrophils in the horny layer

54. Spongiform pustule of Kogoj: An infiltration of neutrophils into necrotic Malpighian layer in which the cell walls persist as a spongelike network Commonly seen in pustular psoriasis

55. Test tube-like elongation of rete ridges Relatively thin suprapapillary plates

56. Treatment Topical Phototherapy Systemic

57. I-TOPICAL THERAPY

58. 1-Topical corticosteroids They are commonly first-line therapy in mild to moderate psoriasis and in sites such as the flexures and genitalia, where other topical treatments can induce irritation Improvement is usually achieved within 2 to 4 weeks, then maintenance is achieved by use in the weekends only Topical steroids can be classiefied as:

59. GENERIC NAMEBRAND NAME CLASS 1 - Superpotent Clobetasol propionateDermovate Clobetasol butyrateEumovate CLASS 2 - Potent Betamethasone valerateBetnovate, Betaval, Betaderm Betamethasone dipropionateDiprosone Mometasone furoateElocon Fluticasone propionateCutivate FluocinonideTopsyn Diflucortalone valerateNericid Triamcinolone acetonideTopicort Fluocinolone acetonideSynalar CLASS 3 - Mid-Strength PrednicarbateDermatop Hydrocortisone Alclometasone dipropionatePerderm

60. Topical steroids under occlusion do have a limited place in the management of recalcitrant psoriasis of the scalp, hands, feet and other areas Potent preparations are likely to be needed on the scalp and knuckles particularly Conversely, the flexures and inner thighs need much weaker products to avoid striae

61. Tachyphylaxis (decrease in efficacy with time) of topical steroids in psoriasis is well- established Long-term topical corticosteroids may cause striae and adrenal suppression Intensive treatment with the most potent preparations can induce generalized pustular psoriasis Because of these side effects potent topical steroids e.g. clobetasol may be used on alternate day basis

62. To avoid systemic effects of class I glucocorticoid, a maximum of 50 g ointment may be used per week For small plaques (< 4cm), triamcinolone acetonide aqueous suspension 10 mg/mL diluted with normal saline is injected into the lesion

63. 2- Vitamin D Analogues Calcipotriene (calcipotriol)”Betdaivonex” Potent topical corticosteroids are superior to calcipotriene. But calcipotriene was more effective than coal tar or anthralin The efficacy of calcipotriene is not reduced with long-term treatment Calcipotriene is applied twice daily Salicylic acid inactivates calcipotriene

64. Hypercalcemia is the only major concern When the amount used does not exceed the recommended 100 g/week, calcipotriene can be used with a great margin of safety It is often used in combination with or in rotation with topical corticosteroids in an effort to maximize therapeutic effectiveness while minimizing steroid- related skin atrophy

65. Other vitamin D analogues are tacalcitol and maxacalcitol In view of their efficacy, cosmetic acceptability and relative safety, they may accepted as first-choice therapies in the topical treatment of mild to moderate psoriasis, although cost may be a problem

66. 3-Coal Tar The use of tar to treat skin diseases dates back nearly 2000 years Tar is the dry distillation product of organic matter heated in the absence of oxygen In 1925, Goeckerman introduced “The Goekerman technique” which uses crude coal tar and UV light for the treatment of psoriasis

67. Coal tar, in concentrations 5- 20% can be compounded in creams, ointments, shampoos and and pastes It is often combined with salicylic acid (2-5% ), which by its keratolytic action leads to better absorption of the coal tar Disadvantages include: allergic reactions, folliculitis, it has an unwelcome smell and appearance and can stain clothing and other items. Coal tar is carcinogenic

68. 4- Tazarotene(zar, Zarotex) It is a third-generation retinoid It reduces mainly scaling and plaque thickness, with limited effectiveness on erythema It is available in 0.05 percent and 0.1 % gels, and a cream When used as a monotherapy, a significant proportion of patients develop local irritation(especially with the 1% formulations)

69. Efficacy can be enhanced by combination with mid- to high-potency steroids or UVB phototherapy but it has been recommended that UV doses be reduced by at least one-third if tazarotene is added in the middle of a course of phototherapy

70. 5-Topical Calcineurin Inhibitors (Tacrolimus”Tarolimus” & Pimecrolimus ”Elidel” ) They inhibit calcineurin, thus blocking both T-lymphocyte signal transduction and IL-2 transcription They are not effective in plaque psoriasis. However, for treatment of inverse and facial psoriasis, these agents appear to provide effective treatment

71. The main side effect of these medications is a burning sensation at application site Anecdotal reports of lymph node or skin malignancy require further evaluation in controlled studies, and these drugs have a U.S. Food and Drug Administration (FDA) “black box warning”

72. 6-Dithranol(Dithranol) It is a naturally occurring substance found in the bark of the araroba tree in South America It is made up in a cream, ointment, or paste It is mainly used on plaques resistant to other therapies It can be combined with UVB phototherapy with good results using the Ingram regimen

73. Classic anthralin therapy starts with low concentrations (0.05 to 0.1 percent) incorporated in petrolatum or zinc paste combined with salicylic acid 1% and given once daily. The concentration is increased weekly in individually adjusted increments up to 4 percent until the lesions resolve Most common side effects are irritant contact dermatitis and staining of clothing, skin, hair, and nails

74. 7-Emollients Between treatment periods, skin care with emollients should be performed to avoid dryness Emollients reduce scaling, may limit painful fissuring, and can help control pruritus They are best applied immediately after bathing or showering The use emollients in combination with topical treatments improves hydration while minimizing treatment costs

75. II-PHOTOTHERAPY

76. Determination of the minimal erythema dose (MED) 1-The patient wears a thick cotton shirt which has 10 small, vertical holes on its back 2-The patient is exposed to 50 mj of UV on the back while all the holes are opened

77. 3-The first hole is closed and another exposure is given By that time the skin under the first hole was exposed to 50 mj of UV while the skin under the second hole was exposed to 100 mj 4-The second hole is closed and the procedure is repeated in the same way (closing an hole and giving a dose) for all the holes 5-After 24-72 hours the skin of the back is examined and the first skin area showing well-defined erythema is determined and the amount of UV causing it is called "the minimal erythema dose"

78. Dosing Excimer laserPUVANB-UVB 2-6 MED twice weekly Initial dose 0.5-2.0 J/cm 2, depending on skin type followed by twice weekly Increase dose by 40% per week until erythema, then maximum 20% per week until a maximum of 15 J/cm 2 Initial dose at 50% of MED followed by 3 treatments /w Lubricate before ttt Increase dose by at least 10-20% of the MED NB-UVB=Narrow-band Ultraviolet B (Wave length 310-331 nm) PUVA=Psoralen +ultraviolet A (Wave length 315–380 nm) Excimer laser (Wave length 308 nm)

79. Efficacy Excimer laserPUVANB-UVB 75% improvement in 72% of patients in an average of 6.2 treatments Induces remission in 70%-90% of patients > 70% improvement study after 4 wk of treatment

80. Side Effects Excimer laserPUVANB-UVB Erythema, blisters, hyperpigmentati on, and erosions Similar to NB- UVB but the risk is higher Photodamage Polymorphic light eruption Increased risk of skin aging and skin cancer

81. Excimer laserPUVANB-UVB As NB-UVBAbsolute: Light-sensitizing disorder, lactation, melanoma Relative: Age < 10 yr, pregnancy, photosensitizing drugs, non- melanoma skin cancers Absolute: Photosensitivity disorders Relative: Photosensitizing drugs, melanoma, and nonmelanoma skin cancers Contraindications

82. Devices used

83. III-SYSTEMIC THERAPY

84. CYCLOSPORIN A: Neoral 100mg/ml Suspension & 100 mg capsules METHOTREXATE: Methotrexate 2.5 mg tab & 50 mg/lm vial ACITRETIN: Acitretin 25 mg cap

85. Mechanism of action AcitretinMethotrexateCyclosporin A Binds to retinoic acid receptors. May contribute to improvement by normalizing keratinization and proliferation of the epidermis Blocks dihydro- folate reductase leading to inhi- bition of purine and pyrimidine synthesis. Also blocks AICAR transformylase, leading to accu- mulation of anti- inflammatory adenosine Binds cyclo- philin producing a complex that blocks calci- neurin, reducing the effect of the NF-AT in T cells, resulting in inhibition of interleukin 2

86. Dosing AcitretinMethotrexateCyclosporin A Initiate at 25- 50 mg daily and escalate and titrate to response Start with a test dose of 2.5 mg and then gradually increase dose until a therapeutic level is achieved (average range, 10-15 mg weekly; maximum, 25-30 mg weekly High-dose method: 5 mg/kg daily, then tapered Low-dose method: 2.5 mg/kg daily, increased every 2- 4 wk up to 5 mg/kg daily, then tapered

87. Efficacy AcitretinMethotrexateCyclosporin A Modestly effective as monotherapy May reduce the severity of psoriasis by at least 50% in more than 75% of patients Up to 90% of patients achieve clearance or marked improvement

88. Side effects AcitretinMethotrexateCyclosporin A Hepatotoxicity Lipid abnormalities Fetal abnorma- lities or death Alopecia, mucocutaneous toxicity Hyperostosis Chronic use may lead to hepatic fibrosis Fetal abnorma- lities or death Myelosupp- ression Pulmonary fibrosis Nephrotoxicity Hypertension Immuno- suppression Neurotoxicity Increased risk of malignancy

89. Monitoring AcitretinMethotrexateCyclosporin A Baseline CBC and CMP Repeat laboratory tests weekly × 6 wk, then every 2 wk × 2 mo, and then monthly. Monitor BP Baseline CBC, CMP, LFTs Repeat baseline tests weekly during dose escalation, then every 2 wk. Hold if WBC ≤ 4.0 ×10 9 /L, platelet count is < 125 × 10 9 /L, or Hg < 110 g/L BP Baseline CBC CMP, Mg, uric acid, lipids, urinalysis Repeat tests every 2-4 wk, then every month along with BP AcitretinMethotrexateCyclosporin A Baseline CBC and CMP Repeat laboratory tests weekly × 6 wk, then every 2 wk × 2 mo, and then monthly. Monitor BP Baseline CBC, CMP, LFTs Repeat baseline tests weekly during dose escalation, then every 2 wk. Hold if WBC ≤ 4.0 ×10 9 /L, platelet count is < 125 × 10 9 /L, or Hg < 110 g/L BP Baseline CBC CMP, Mg, uric acid, lipids, urinalysis Repeat tests every 2-4 wk, then every month along with BP

90. Contraindications AcitretinMethotrexateCyclosporin A Absolute: Severe infections Malignancy Absolute: Inherited deficiency of thiopurine methyltransferase enzyme due to increased risk of myelosuppression Liver toxicity Pregnancy Absolute: Prior bone marrow depression Pregnancy Lactation Relative: Renal abnormalities

91. Use in Pregnancy AcitretinMethotrexateCyclosporin A X category The drug is contraindicated in women who are or may become pregnant D category There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life- threatening situation) C category Studies on animals revealed teratogenic or embryocidal effects and there are no controlled studies in women It should be given only if the potential benefit justifies the potential risk to the fetus

92. REMARKS

93. CYCLOSPORIN A Because the nephrotoxic effects of CsA are largely irreversible, CsA treatment should be discontinued if kidney dysfunction and/or hypertension occur. CsA-induced hypertension may be treated with calcium antagonists such as nifedipine The most common adverse effects noted in patients using CsA for short periods of time are neurologic, including tremors, headache, paresthesia, and/or hyperesthesia Long-term treatment of psoriasis with low-dose CsA was found to increase risk of non- melanoma skin cancers

94. concomitant administration of folic acid (1 to 5 mg/day) reduces certain side effects, such as nausea and megaloblastic anemia, without diminishing the efficacy of antipsoriatic treatment The very long half-life of MTX may account for its efficacy after weekly administration and may also help to explain why its onset of action is rather slow (therapeutic effects usually require 4 to 8 weeks to become evident) METHOTREXATE

95. In the most recent guidelines, patients with normal liver function tests and without a history of liver disease or alcoholism are not asked to undergo liver biopsy until they have been treated with a cumulative MTX dose of 1.0 to 1.5 g. Repeat biopsies are done approximately 1.0 to 1.5 g thereafter if liver function test and biopsy findings are normal

96. Some groups have recommended the use of amino terminal type III procollagen peptide (PIIINP) assay for screening of liver fibrosis But the FDA has not yet approved the use of this assay for diagnostic use within the United States

97. Another well-known side effect of MTX is myelosuppression, especially pancytopenia, which usually occurs in the setting of folate deficiency. Leucovorin calcium (folinic acid) is the only antidote for the hematologic toxicity of MTX. When an overdose is suspected, an immediate leucovorin dose of 20 mg should be given parenterally or orally, and subsequent doses should be given every 6 hours.

98. Several classes of drugs, including nonsteroidal anti-inflammatory drugs and sulfonamides, may interact with MTX to increase toxicity MTX is renally excreted and should therefore not be administered to patients with impairment in renal function, as MTX side effects are generally dose-related

99. ACITRETIN The clinical forms most responsive to acitretin as monotherapy include generalized pustular and erythrodermic psoriasis Acitretin induces clearance of psoriasis in a dose-dependent fashion. Overall, higher starting doses (i.e., ≥50 mg/day) appeared to clear psoriasis faster but adverse effects occur more frequently

100. Most patients relapse within 2 months after discontinuing acitretin Acitretin should be discontinued if liver dysfunction, hyperlipidemia, or diffuse idiopathic hyperostosis develops

101. Uncommonly used Systemic drugs

102. 1- Sulfasalazine After 8 weeks of treatment 41 % of the patients had marked improvement, 41 % had moderate, and 18 % had minimal improvement Dose:1 gm 4 times/day orally

103. 2-Mycophenolate mofetil It inhibits T and B lymphocytes proliferation, thereby suppressing cell- mediated immune responses and antibody formation The drug is usually well tolerated with few side effects In a dose between 2 to 3 g daily, a 47 % improvement was achieved in 12 weeks

104. IV-BIOLOGIC THERAPY (Biologics)

105. They are proteins produced by living organisms to block specific molecular steps important in the pathogenesis of psoriasis Currently available biologics for psoriasis target either the T cells or block the inflammatory action of TNF-α.

106. When to use biologics? I. Severe disease is defined as PASI score of 10 or more or a BSA of 10% or greater or life threatening disease such as erythrodermic or pustular psoriasis II. Disease should have been severe for 6 months; resistant to treatment

107. III.Patients fulfill at least one of following clinical categories: 1. Have developed or are at higher than average risk of developing clinically important drug related toxicity 2. Are unresponsive, to or cannot receive standard systemic therapy 3. Have disease that requires repeated inpatient management for control. 4. Have psoriatic arthritis

108. some tests that should be done before starting treatment with biologics: Liver function tests CBC including platelet count A hepatitis panel TB testing

109. Mechanism of action AdalimumabInfliximabEtanerceptEfalizumabAlefacept Fully human recombinant monoclonal antibody that specifically targets TNF- α Chimeric monoclonal antibody that has high specificity, affinity, and avidity for TNF-α Human recombinant, soluble TNF- α receptor. Binds TNF-α and neutralizes its activity Blocks the interaction of LFA-1 with intercellular adhesion molecule-1. Inhibits T-cell activation, trafficking, and adhesion to keratino- cytes Binds CD2 on T cells, blocking the CD2-LFA3 interaction, thus interfering with T-cell activation and causing T-cell apoptosis

110. Dosing AdalimumabInfliximabEtanerceptEfalizumabAlefacept 40-mg injections subcutane- ously every other week Intravenous infusions over 2 h. 5- 10 mg/kg at weeks 0, 2, and 6 25- to 50-mg injections subcutane- ously twice weekly Subcut. injections. Conditioning: 0.7 mg/kg. Maintenance: 1 mg/kg weekly 15 mg IM once weekly for 12 weeks

111. Efficacy AdalimumabInfliximabEtanerceptEfalizumabAlefacept 80% of patients achieve PASI-75 at 12 wk. 80% of patients achieved a PASI-75 at wk 10 49% of patients given 50 mg twice/wk achieved a PASI-75 at 12 wk 27% of patients achieve a PASI-75 at 12 wk 21% of patients achieved a PASI-75 at wk 14. PASI-75=75% reduction in PASI scores over treatment period

112. Remission duration AdalimumabInfliximabEtanerceptEfalizumabAlefacept Unknownhighly variable between individuals and may depend on the initial dose given Variable and dose-related ranging from 70-90 days about 2 months Average 8 months

113. Side effects AdalimumabInfliximabEtanerceptEfalizumabAlefacept 1.Cytopenias 2.Injection site reactions 3.Infections 4,5,6,7 as Etanercept 1.Infusion- related reactions 2.Exacerba- tion of MS 3.Infections 4,5,6,7 as Etanercept 1.Pancyto- penia 2.Exacerba- tion of MS 3.Serious infections 4.Malignancy 5.Worsening of congestive heart failure 6.Lupus-like symptoms 7. Live vacc- ines should not be given 1.Thrombo- cytopenia 2.Exacerb- ation of psoriasis 3.Serious infections 1.Lympho- penia 2.Malignancy 3.Serious infections 4.Not recomme- nded for HIV patients

114. Monitoring&Long-term use AdalimumabInfliximabEtanerceptEfalizumabAlefacept Baseline PPD Regular platelet counts CD4+ T-cell counts every 2 wk during treatment Expected to be similar to other TNF-α inhibitors Large databases in patients with other immunologic diseases indicate relative safety PASI respo- nse continues to increase to wk 24. Large databases in patients with other immunologic diseases indicate safety PASI respo- nses continue to increase to wk 24 and maintained in patients receiving long-term continuous therapy (up to 24 mo). Up to nine courses have been administered over 4-5 yr in small number of patients with incremental benefits

115. Use in Pregnancy AdalimumabInfliximabEtanerceptEfalizumabAlefacept Ctegory B Ctegory C Studies on animals revealed teratogenic or embryocidal effects and there are no controlled studies in women Ctegory B Animal- reproduction studies have not demo- nstrated a fetal risk but there are no controlled studies in pregnant

116. How Supplied AdalimumabInfliximabEtanerceptEfalizumabAlefacept HUMIRA ® prefilled syringe that delivers 40 mg of Adalimumab REMICADE ® vial contains 100 mg lyophilized powder infliximab ENBREL ® prefilled syringes available in 25 & 50 mg strengths RAPTIVA ® vial contains lyophilized powder that yields 100 mg/mL of efalizumab of reconstituted solution AMEVIVE ® vial contains 15 mg lyophilized powder alefacept that yields 0.5 mL of reconsti- tuted solution Cost/year $20,186 Cost/year $26,320 Cost/year $17,160 Cost/year $21,385 Cost/year $18,735

117. REMARKS

118. Alefacept was the first biological agent approved by the FDA in January 2003 for the treatment of patients with moderate to severe chronic plaque psoriasis Efalizumab currently, is the only biological agent approved for continuous administration and can be self- administered as weekly subcutaneous injections

119. Etanercept:The current license recommends intermittent courses no longer than 24 week Infliximab: once significant disease relapse has occurred, repeat infusions do not achieve the same rate of disease clearance as that seen on the initial three dose induction treatment

120. Choice of agent to use Etanercept should be considered the first choice for patients with significant uncontrolled psoriatic arthritis Infliximab is useful in clinical circumstances requiring rapid disease control e.g. in unstable erythrodermic orpustular psoriasis due to it very rapid onset of action and high response rate Efalizumab should be considered the first choice for patients with a high risk of latent TB or with evidence of demyelinating disease

121. Treatment of certain sites

122. Scalp Mild (no thick plaques) Tar or ketoconazole shampoos followed by betamethasone valerate, 1% lotion; if refractory, clobetasol propionate, 0.05% scalp application Severe (Thick, adherent plaques): Removal of scales from plaques before active treatment by 10% salicylic acid in mineral oil, covered with a plastic cap and left on overnight.

123. After shedding of scales, fluocinolone cream or lotion with the scalp covered with plastic or a shower cap, left on overnight or for 6 h. When the thickness of the plaques is reduced, clobetasol propionate, 0.05% lotion, can be used for maintenance. If unsuccessful or rapid recurrence or if associated with generalized psoriasis, consider systemic treatment

124. Nails Injection of the nail fold with intradermal triamcinolone acetonide (3 mg/mL) is effective but painful and impractical when all nails are involved PUVA is somewhat effective when administered in special hand-and-foot lighting units providing high-intensity UVA Long-term systemic retinoids (acitretin, 0.5 mg/kg) are also effective, as are systemic MTX

125. Inverse psoriasis Initiate therapy with topical steroids but as these are atrophy-prone regions, steroids should be applied for only limited periods of time;then switch to topical vitamin D derivatives or tazarotene or topical tacrolimus or pimecrolimus. If resistant or recurrent, consider systemic therapy

126. Guttate Psoriasis Treat streptococcal infection with antibiotics. Narrow-band UVB irradiation is the most effective. If it fails, try PUVA

127. Generalized Pustular Psoriasis Patients should be hospitalized and treated in the same manner as patients with extensive burns Rapid suppression and resolution of lesions is achieved by oral retinoids (acitretin, 50 mg/d). Supportive measures should include fluid intake, IV antibiotics to prevent septicemia, cardiac support, temperature control, topical lubricants, and antiseptic baths Systemic steroids to be used only as rescue intervention as rapid tachyphylaxis occurs

128. Psoriatic Arthritis MTX, once-a-week schedule as outlined above Infliximab or etanercept are highly effective