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ONCOTREX

PSORIASIS

Dr. Harish Lalan

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Functions of the Skin

barrier to physical agents protects against mechanical injury prevents dehydration of body through fluid loss reduces the penetration of UV Radiation helps regulate body temperature provides a surface for grip acts as a sensory organ acts as an outpost for immune surveillance plays a role in Vitamin D production has a cosmetic association

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Histology --Skin

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Histology of Skin… contd

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EPIDERMIS

STRATUM BASALE Deepest layer of the epidermis Single layer of columnar or cuboidal cellsstem

cells with mitotic activity Renewal of epidermis takes about 3 to 4 weeks Melanin is produced by melanocyte cells

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EPIDERMIS

STRATUM SPINOSUM

Irregularly polygonal cells Spine-like cytoplasmatic extensions of the

cells which interconnect the cells of this layer

Lamellar granules in the cytoplasm of the spinous cells

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EPIDERMIS

STRATUM GRANULOSUM

One to few layers of flattened cells Cytoplasm contains keratohyalin granules Lamellar granules release lipids to fill

entire interstitial space Nuclei begin to degenerate in the outer part

of stratum granulosum

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EPIDERMIS

STRATUM LUCIDUM

Several layers of flattened dead cells Faint nuclear outlines are visible in only

few cells Stratum lucidum difficult to identify in

thin skin 

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EPIDERMIS

STRATUM CORNEUM

Cells are completely filled with keratin filaments (horny cells)

Nuclei can no longer be identified Cells are very flat Horny cells are constantly shed off

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DERMIS

PAPILLARY REGION  Outer (superficial) region of dermis has bumps

called dermal papillae protrusions of dermal connective tissue which

indent the base of the epidermis

   

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DERMIS

RETICULAR REGION  Lies beneath the papillary layer and consists of

larger, more coarsely textured collagen fibers Plus nerves and nerve endings, blood vessels,

sweat glands, and more

Reticular = network

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PATHOLOGY

NORMAL SKIN From St. Basale to St.

Corneum 4 weeks Basal layers divide

every 13-14 days Mature differentiate

and shed off healthy skin

PSORIATIC SKIN Basal layer to

Corneum 4 days Basal layer cells

divide every 1.5 days Do not differentiate

thus forming a scaly inflamed red skin

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PATHOLOGY

• The T cells in the epidermis induce the changes seen in psoriatic skin and are also necessary for maintaining lesions. After T cells have been activated, which happens when they attach to antigen-presenting cells, they migrate to the skin and cause the secretion of cytokines and the exaggeration of the immunologic process.

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PATHOLOGY… contd

• The T cells and secretions of other inflammatory cells induce changes in the keratinocytes. These keratinocytes contain a variety of immunomodulating cytokines, such as interleukin-1 (IL-1), IL-6, IL-8, and tumor necrosis factor (TNF), which are each expressed differently in psoriasis. For example, expression of IL-8 and TNF is increased in psoriasis, while the administration of IL-10 may alleviate symptoms of the disease.

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Initiation

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TREGTpAPC

Monocyte

Eosinophil

Mast/Basophil

Neutrophil

Macrophage

TH2

TH1

BTC

Ag

SensitizationPathogenic T Cell Development

Effector/Suppressor Imbalance

Local Tissue

Inflammation

Tissue damage

Fibrosis

I.M.I.D.

Psoriasis

Immubiology of IMIDImmubiology of IMID

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T Cell Driven Pathology

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Psoriasis Pathogenesis

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T-Cell Activation in the Lympnodes

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T-Cell Binding & Trafficking….

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Psoriatic Cascade

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Imbalance of cytokines in IMID

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Common Areas

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PSORIASIS

Psoriasis is a chronic, inflammatory genetic, noncontagious skin disorder

appears in many different forms and can affect any part of the body.

Commonly affected areas include scalp, elbows, knees, arms, stomach and back

Waxing –waning & autoimmune in origin

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Waxing & Waning

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Types of Psoriasis

Plaque Psoriasis Pustular Psoriasis Erythrodermic Psoriasis Guttate Psoriasis Psoriatic Arthritis Inverse Psoriasis Nail Psoriasis

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Plaque Psoriasis

Most common form Occurs commonly in young adults Characterized by sharply, demarcated,

erythematous papules and plaques covered with silver white scales

Symmetrical distribution Starts small and will enlarge over time Raised papules Scalp, extensor elbows, knees, back

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Pustular Psoriasis

Rare, but severe and potentially life threatening Acute onset Characterized by lesions with a mixture of brown

and white non-infected pustules associated with erythema and scaling.

Affects palms and soles symmetrically Systemic symptoms include fever and malaise

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Guttate Psoriasis

“Drop like”Characterized by small, scaly, erythematous

spots of psoriasisOccurs abruptly in patients with no prior

history of psoriasisLocated on trunk and extremitiesClassically follows beta-hemolytic

streptococcal pharyngitis

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Psoriatic Arthritis

1-5% of psoriasis patientsCharacterized by inflammation, swelling

and destruction of peripheral interphalangeal joints, knees and ankles

Elevated rheumatoid factor is NOT seen in psoriatic arthritis patients

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Inverse Psoriasis

Involves interiginous areas: inguinal, perineal, genital, intergluteal, and axillary regions

May be misdiagnosed as fungal or bacterial infection due to lack of scaling

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Erythrodermic Psoriasis Characterized by widespread exfoliation of fine

scales and erythema (> 90% of BSA) Symptoms include fever, chills, malaise,

hypothermia, and hypoalbuminemia may be present

Pneumonia and renal failure may occur High output heart failure may develop in people

with heart disease Massive protein loss, dysregulation of core body

temperature, and excessive fluid loss Other complications include pustulosis,

arthropathy, and staphylococcal infections

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Nail Psoriasis

Characterized by pitting of nails and localized change in color to tan or brown

Usually diagnostic of psoriasisUnresponsive to most treatments

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Impact on Physical Health

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Impact on Mental Health

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General Measures

SunshineBaths Emollients Occlusive dressingsRest

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Emollients

Emollients reduce desquamation, may limit painful fissuring and can act as an antipruritic

emollients used are white soft paraffin or vaseline

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Keratolytics

helpful for descaling plaques for treatment with more active topical agents

Keratolytics [salicylic acid usually 5% ] combined with an emmolient base.

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Coal tar

Stand by therapy since over a century cosmetically less acceptable[crude Prep] Refined prep [cosmetically good] less active 0.5–5% in white or yellow soft paraffin Irritation common start with 0.5% frequently combined with 1% hydrocortisone

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Dithranol (Anthralin)

Is one of the oldest treatments available for psoriasis used in conjunction with ultraviolet B (UVB) phototherapy in indoor patients

Irritation/burning of un involved skin coupled with purple–brown discolouration of skin, clothes etc.

Newer microcrystalline formulations of dithranol less irritant and more cosmetically acceptable

Direct anti-proliferative effect on epidermal keratinocytes

Usage limited for cosmetic unattractiveness

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Topical corticosteroids

High rate of patient compliance due to cosmetic elegance

Have potential side-effects, if used without supervision

Mild potency --flexures, face, genitalia High potency—recalcitrant psoriasis esp on

the hands or feet

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Topical corticosteroids……

Preferable usage for small areas of Plaque and not in large area involvement

Limited time duration & under supervision skin thinning, striae, telangiectasia , tachyphylaxis , rapid relapse

combination or rotation-- coal tar, dithranol, vitamin D3 analogues or retinoids

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Vitamin D3 analogues

Normalise abnormal epidermal keratinocyte proliferation and differentiation +anti-inflammatory effect

Effective [6-8wks], clean, safe First line therapy for psoriasis irritation of

uninvolved, perilesional skin. Hypercalcaemia Can be combined with sys. /topical therapy

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ROLSICAL

Therapy of choice for mild to moderate plaque psoriasis

Best efficacy & tolerability amongst all topical agents inc. vitamin D analogues

Specially useful for sensitive body areas e.g. face, hairline and body folds

Can be co-prescribed with other topical and systemic therapy

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Rolsical--MOA

Regulates keratinocyte growth, differentiation & maturationinhibits epidermal cell proliferation

Regulates immune stimulationInhibits lymphocyte proliferation Inhibits-IL-1& IL-2 production

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Topical retinoid

Normalise epidermal keratinocyte proliferation and differentiation

Tazarotene is applied once daily Significant irritation of uninvolved skin Combined usage with D3 analogues and

steroids [to enhance efficacy and reduce irritancy]

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Phototherapy

Used for 70 years as therapyUVB monotherapy thrice/weekBurning and potential carcinogenicityUVB often combined with topical Tar

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Photochemotherapy (PUVA)

Photosensitising medication (psoralen) with (320–400 nm) ultraviolet A (UVA)

Cataracts, photoageing & nonmelanoma skin cancers

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Methotrexate

Is used to treat severe and/or disabling psoriasis since 1960s.

Approved by USFDA in 1971 for treatment of Psoriasis.

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Methotrexate - Effectiveness

Extensive psoriasis, erythrodermic and acute pustular psoriasis, physically disabling psoriasis of the palms and soles, psoriasis in the elderly, & severe psoriatic arthritis.

Clearance or remission can last for a few weeks to a year or more after stopping therapy.

In people with at least 30 percent skin covered with psoriasis who are not responsive to, or eligible for, conventional topical or ultraviolet light treatments (UVB and PUVA).

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Methotrexate

Improvement begins within four to six weeks.

Its substantially clears within two or three months of starting therapy.

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Methotrexate Short Term Side Effects

Anemia Nausea Insomnia Loss of appetite Tiredness Temporary hair loss in some patients

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Methotrexate Contraindications

women who are pregnant men or women who are trying to conceive a child

(conception should be avoided during and for at least 12 weeks after discontinuing MTX therapy)

people with severe anemia people with cirrhosis of the liver people with active hepatitis people with significant liver or kidney

abnormalities

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Methotrexate – MOA

• anti-inflammatory action of MTX is not mediated by lymphocyte apoptosis, but by the suppression of T cell activation and adhesion molecules.

• suppression of intercellular adhesion molecule (ICAM)-1 was adenosine and folate-dependent

• MTX suppression of the skin-homing cutaneous lymphocyte-associated antigen (CLA) was adenosine-independent.

• MTX Inhibits Keratinocyte proliferation.• MTX inhibits dihydrofolate reductase --- inhibits

folate ---• Inhibits DNA/RNA synthesis.

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Methotrexate – Dosage

orally or by intramuscular or subcutaneous injection

once (day) in a week7.5 mg/25mg in single or divided dosage

(on a single day)

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Systemic retinoids

Acitretin [metabolite of etretinate] is in use Acitretin is often combined with PUVA Severe psoriasis, Generalised pustular and

palmoplantar pustular psoriasis cheilitis and xerosis, alopecia sticky, fragile

skin. safety in terms of carcinogenicity or organ

toxicity

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Cyclosporine

Selective immunosuppressive agent To be used not > 3-4months at a time Effective for recalcitrant severe psoriasis

plaque,erythrodermic&pustular Paraesthesiae, hypertrichosis, malaise and gingival

hypertrophy Hypertension and nephrotoxicity Lymphomas, internal malignancies, skin cancers, and

serious infections Not to combine with photo or photochemotherapy Cost and toxicity prevent wide usage

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Clinical improvement was associated with decreased synthesis of IL-1 beta,TNF-alpha and IL-8 induced by bacterial lipopolysaccharide, IL-1 alpha and IL-1beta in PBMC in vitro. These findings suggest that MTX therapy reverses the inflammatory type of rheumatoid arthritis (RA) blood mononuclear cells by stimulating cytokine inhibitor production while inhibiting inflammatory cytokine release at the same time.

Methotrexate action in rheumatoid arthritis

Br J Rheumatol. 1995 Jul;34(7):602-9.

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The changes in expression of ICAM-3, Ki-67, PCNA, and CD31 in psoriatic lesionsbefore and

after methotrexate treatment.

In post treatment biopsies a decrease in the degree of epidermal hyperplasia and a significant reduction in the severity of the inflammatory infiltrate (P<0.05) were observed. In addition, CD31 and ICAM-3 expression was significantly decreased on dermal cellular infiltrate, (respectively; P<0.05, P<0.01). Ki67and PCNA expression were suppressed concurrently in about 90% of cases (P<0.01).

Arch Dermatol Res. 2005 Dec;297(6):249-55. Epub 2005 Oct 8.

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Folate supplementation during methotrexate therapy for patients with

psoriasis

According to studies reviewed, the use of folate supplements in patients treated with methotrexate reduces the incidence of hepatotoxicity and gastrointestinal intolerance without impairing the efficacy of methotrexate..

: J Am Acad Dermatol. 2005 Oct;53(4):652-9.

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T Cell Targeting

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T Cell Targeters……

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T cell targeting agents:

Alefacept, Efalizumab approved for severe plaque psoriasis only. contraindicated in the presence of infection

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TNF-α Targeting…

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Biologics That Target Tumor Necrosis Factor-alpha

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Tumor Necrosis Factor (TNF) Blockers

Etanercept, Infliximab and Adalimumab Injectables and quite costly Reserved for severe psoriasis e.g. pustular

psoriasis Congestive heart failure, unmasking of

demyelinating disease (e.g. optic neuritis and multiple sclerosis), precipitation of diabetes mellitus, and hyperthyroidism

Contraindicated in the presence of infection

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Fulfilling an unmet need in psoriasis : do biologicals hold the key to

improved tolerability? An increased incidence of lymphomas has been

postulated to be associated with etanercept, infliximab and adalimumab; serious infections, such as tuberculosis, have also been reported with these three biologicals, all of which target TNF-alpha. Demyelinating disorders, such as multiple sclerosis, have been reported with some biologicals as has congestive heart failure.

Drug Saf. 2006;29(1):49-66.

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PSORIASIS

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TREATMENT OPTIONS…..

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Strategise Rx

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ALGORITHM

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Treatment Approach

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Evaluate Objectively

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PASI –a Preffered Measure

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PASI –a Preffered Measure

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Clin Research & PASI

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THANK YOU !