PSORIASIS

PSORIASIS

Etymology: Gk, psoriasis, itch

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

Pathogenesis

• The initiation and maintenance of lesions requires activated T Lymphocytes

• Drugs suppressing T-cell activity contribute to the improvement of psoriasis

• 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

• 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

• 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)

• 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

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

• 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

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)

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

• 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.

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.

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

ClinicallySymptoms:• 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.

• 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

-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

-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

Clinical patterns1-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)

• The borders may resemble a land map (psoriasis geographica)

•Annular psoriasis:Ring-like lesions

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

• 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

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

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

4-Psoriatic erythroderma

• The disease affects all body sites

• Erythema is the most prominent feature with superficial scaling

• 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

• 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

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

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

• 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

• 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

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

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

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

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)

• 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

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

Related Physical Findings

1- NAIL CHANGES IN PSORIASIS

• Found in up to 40 percent of patients

• Nail pitting is the commonest feature

• 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

• Nail plate crumbling

• Beau’s lines:horizontal, lines going across the nail

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

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

The most distinctive features of psoriatic arthritis are

• Distal interphalangeal joint arthritis

• Dactylitis

• 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

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

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

• 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

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

Histopathology

• Dilated vessels in dermal papillae, perivascular cuffing with lymphocytes

• Parakeratosis

• Orthokeratosis of normal basket-weave type

• Loss of granular layer

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

• 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

• Test tube-like elongation of rete ridges

• Relatively thin suprapapillary plates

Treatment

• Topical

• Phototherapy

• Systemic

I-TOPICAL THERAPY

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:

BRAND NAMEGENERIC NAME

CLASS 1 - Superpotent

Dermovate Clobetasol propionate

EumovateClobetasol butyrate

CLASS 2 - Potent

Betnovate, Betaval, BetadermBetamethasone valerate

DiprosoneBetamethasone dipropionate

Elocon Mometasone furoate

Cutivate Fluticasone propionate

Topsyn Fluocinonide

NericidDiflucortalone valerate

TopicortTriamcinolone acetonide

Synalar Fluocinolone acetonide

CLASS 3 - Mid-Strength

Dermatop Prednicarbate

HydrocortisoneHydrocortisone

PerdermAlclometasone dipropionate

• 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

• 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

• 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

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

• 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

• 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

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

• 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

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)

• 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

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

• 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”

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

• 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

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

II-PHOTOTHERAPY

Determination of the minimal erythema dose (MED)

1-The patient wears a thick cotton shirt which has 10 small, vertical holes on its back2-The patient is exposed to 50 mj of UV on the back while all the holes are opened

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"

DosingNB-UVBPUVAExcimer laser

•Initial dose at 50% of MED followed by 3 treatments /w •Lubricate before ttt•Increase dose by at least 10-20% of the MED

•Initial dose 0.5-2.0 J/cm2, 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/cm2

•2-6 MED twice weekly

•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)

Efficacy

NB-UVBPUVAExcimer laser

> 70% improvement study after 4 wk of treatment

Induces remission in 70%-90% of patients

75%

improvement in 72% of patients in an average of 6.2 treatments

Side Effects


•Photodamage•Polymorphic light eruption•Increased risk of skin aging and skin cancer

Similar to NB-UVB but the risk is higher

Erythema, blisters, hyperpigmentation, and erosions


Absolute:Photosensitivity disordersRelative:Photosensitizing drugs, melanoma, and nonmelanoma skin cancers

Absolute:Light-sensitizing disorder, lactation, melanoma

Relative:Age < 10 yr, pregnancy, photosensitizing drugs, non-melanoma skin cancers

As NB-UVB

Contraindications

Devices used

III-SYSTEMIC THERAPY

• CYCLOSPORIN A: Neoral 100mg/ml Suspension & 100 mg capsules

• METHOTREXATE: Methotrexate 2.5 mg tab & 50 mg/lm vial

• ACITRETIN: Acitretin 25 mg cap

Mechanism of action Cyclosporin A Methotrexate Acitretin

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

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 to retinoic acid receptors. May contribute to improvement by normalizing keratinization and proliferation of the epidermis

Dosing Cyclosporin A Methotrexate Acitretin

High-dose method: 5 mg/kg daily, then taperedLow-dose method: 2.5 mg/kg daily, increased every 2-4 wk up to 5 mg/kg daily, then tapered

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

Initiate at 25-50 mg daily and escalate and titrate to response

Efficacy

Cyclosporin A Methotrexate Acitretin

Up to 90% of patients achieve clearance or marked improvement

May reduce the severity of psoriasis by at least 50% in more than 75% of patients

Modestly effective as monotherapy

Side effects


•Nephrotoxicity•Hypertension•Immuno-suppression•Neurotoxicity•Increased risk of malignancy

•Chronic use may lead to hepatic fibrosis •Fetal abnorma-lities or death•Myelosupp-ression•Pulmonary fibrosis

•Hepatotoxicity•Lipid abnormalities•Fetal abnorma-lities or death•Alopecia, mucocutaneous toxicity•Hyperostosis

Monitoring Cyclosporin A Methotrexate Acitretin

•BP•Baseline CBC•CMP, Mg, uric acid, lipids, urinalysis Repeat tests every 2-4 wk, then every month along with BP

•Baseline CBC, CMP, LFTs

Repeat baseline tests weekly during dose escalation, then every 2 wk. Hold if WBC ≤ 4.0 ×109/L, platelet count is < 125 × 109/L, or Hg < 110 g/L

•Baseline CBC and CMP

Repeat laboratory tests weekly × 6 wk, then every 2 wk × 2 mo, and then monthly. Monitor BP


•BP•Baseline CBC•CMP, Mg, uric acid, lipids, urinalysis Repeat tests every 2-4 wk, then every month along with BP

•Baseline CBC, CMP, LFTs

Repeat baseline tests weekly during dose escalation, then every 2 wk. Hold if WBC ≤ 4.0 ×109/L, platelet count is < 125 × 109/L, or Hg < 110 g/L

•Baseline CBC and CMP

Repeat laboratory tests weekly × 6 wk, then every 2 wk × 2 mo, and then monthly. Monitor BP

Contraindications Cyclosporin A Methotrexate Acitretin

Absolute:•Prior bone marrow depression •Pregnancy•LactationRelative:Renal abnormalities

Absolute:•Inherited deficiency of thiopurine methyltransferase enzyme due to increased risk of myelosuppression• Liver toxicity• Pregnancy

Absolute:•Severe infections•Malignancy

Use in PregnancyCyclosporin A Methotrexate Acitretin

C categoryStudies 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

D categoryThere 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)

X categoryThe drug is contraindicated in women who are or may become pregnant

REMARKS

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

• 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

• 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

• 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

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.

• 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

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

• Most patients relapse within 2 months after discontinuing acitretin

• Acitretin should be discontinued if liver dysfunction, hyperlipidemia, or diffuse idiopathic hyperostosis develops

Uncommonly used

Systemic drugs

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

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

IV-BIOLOGIC THERAPY

(Biologics)

• 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.

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

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

• some tests that should be done before starting treatment with biologics:

• Liver function tests

• CBC including platelet count

• A hepatitis panel

• TB testing

Mechanism of action

Alefacept Efalizumab Etanercept Infliximab Adalimumab

Binds CD2 on T cells, blocking the CD2-LFA3 interaction, thus interfering with T-cell activation and causing T-cell

apoptosis

Blocks the interaction of LFA-1 with intercellular adhesion molecule-1. Inhibits T-cell activation, trafficking, and adhesion to keratino-cytes

Human recombinant, soluble TNF-α receptor. Binds TNF-α and neutralizes its activity

Chimeric monoclonal antibody that has high specificity, affinity, and avidity for TNF-α

Fully human recombinant monoclonal antibody that specifically targets TNF-α

Dosing


15 mg IM once weekly for 12 weeks

Subcut. injections. Conditioning: 0.7 mg/kg. Maintenance: 1 mg/kg weekly

25- to 50-mg injections subcutane-ously twice weekly

Intravenous infusions over 2 h. 5-10 mg/kg at weeks 0, 2, and 6

40-mg injections subcutane-ously every other week

Efficacy


21% of patients achieved a PASI-75 at wk 14.

27% of patients achieve a PASI-75 at 12 wk

49% of patients given 50 mg twice/wk achieved a PASI-75 at 12 wk

80% of patients achieved a PASI-75 at wk 10

80% of patients achieve PASI-75 at 12 wk.

PASI-75=75% reduction in PASI scores over treatment period

Remission duration


Average

8 months

about 2 months

Variable and dose-related ranging from 70-90 days

highly variable

between individuals and may depend on the

initial dose given

Unknown

Side effectsAlefacept Efalizumab Etanercept Infliximab Adalimumab

1.Lympho-penia

2.Malignancy

3.Serious infections

4.Not recomme-nded for HIV patients

1.Thrombo-cytopenia

2.Exacerb-ation of psoriasis


1.Pancyto-penia

2.Exacerba-tion of MS


4.Malignancy

5.Worsening of congestive heart failure

6.Lupus-like symptoms

7. Live vacc-ines should not be given

1.Infusion-related reactions

2.Exacerba-tion of MS

3.Infections

4,5,6,7 as Etanercept

1.Cytopenias

2.Injection site reactions

3.Infections

4,5,6,7 as Etanercept

Monitoring&Long-term useAlefacept Efalizumab Etanercept Infliximab Adalimumab

CD4+ T-cell counts every 2 wk during treatment

Regular platelet counts

Baseline PPDBaseline PPD

Baseline PPD

Up to nine courses have been administered over 4-5 yr in small number of patients with incremental benefits

PASI respo-nses continue to increase to wk 24 and maintained in patients receiving long-term continuous therapy (up to 24 mo).

PASI respo-nse continues to increase to wk 24. Large databases in patients with other immunologic diseases indicate safety

Large databases in patients with other immunologic diseases indicate relative safety

Expected to be similar to other TNF-α inhibitors

Use in Pregnancy


Ctegory B

Animal-reproduction studies have not demo-nstrated a fetal risk but there are no controlled studies in pregnant

Ctegory C

Studies on animals revealed teratogenic or embryocidal effects and there are no controlled studies in women

Ctegory BCtegory BCtegory B

How SuppliedAlefacept Efalizumab Etanercept Infliximab Adalimumab

AMEVIVE® vial contains 15 mg lyophilized powder alefacept that yields 0.5 mL of reconsti-tuted solution

RAPTIVA®

vial contains lyophilized powder that yields 100 mg/mL of efalizumab of reconstituted solution

ENBREL®

prefilled syringes available in 25 & 50 mg strengths

REMICADE ®

vial contains 100 mg lyophilized powder infliximab

HUMIRA ® prefilled syringe that delivers 40 mg of

Adalimumab

Cost/year

$18,735

Cost/year

$21,385

Cost/year

$17,160

Cost/year

$26,320

Cost/year

$20,186

REMARKS

• 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

• 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

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

Treatment of certain sites

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.

• 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

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

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

Guttate Psoriasis

• Treat streptococcal infection with antibiotics.

• Narrow-band UVB irradiation is the most effective. If it fails, try PUVA

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

Psoriatic Arthritis

• MTX, once-a-week schedule as outlined above

• Infliximab or etanercept are highly effective

Documents

PSORIASIS