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11/19/2012

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Head to Toe Psoriasis, How to Treat ?

Charoen Choonhakarn, MDDivision of Dermatology, Faculty of Medicine

Khon Kaen University

Psoriasis• Chronic inflammatory skin disease, 1-2% of populati on

• Male = female, age at onset 22.5 and 55 yrs

• Trigger: genetic and environment

• HLA association; Cw 6, B13, B17, PSORS 1 and 2

• Mother or father 8-15%, mother and father 40-50%

• Early onset ; clinical more severe, genetic influen ce

• Degree of disability and negative impact on QoL= IH D, DM, cancer

• Severe psoriasis / arthritis : increased risk of CV S disease, DM (metabolic syndrome) , depression

Elder JT, et al. Arch Dermatol 1994. Christophers E. Clin Dermatol 2007. Burden AD, et al. BMJ 2010.

Etiology• Unknown (genetic and environment)

1. Abnormal proliferation and differentiation of keratinocytes

(36 hr. VS 311 hr. of epidermal cell cycle)

2. Immune system

cell - mediated (T helper cell), cytokines, chemokines (TNF , interleukin)

3. Gene (PSORS 1-7)

Bowcock AM and Krueger JG. Nat Rev Immunol ,2005.

Precipitating factor

1. Skin trauma “Koebner phenomenon”

2. Infection

Streptoccous (URI) : guttate type (childhood),

HIV : extensive and sudden onset

3. Stress 30-40%

4. Alcohol drinking, smoking (food?)

5. Drug

chloroquine, beta-blocker, lithium, NSAIDs,

steroid withdrawal : pustular psoriasis

Clinical feature• Skin (head to toe)

Well-demarcated, silvery scale, erythematous on extensor surface

• NailsOil spot, pits, onycholysis, subungual hyperkeratosis

• Joints and enthesopathy Axial or peripheral (small or large joints)

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Variation1. Chronic plaque “psoriasis vulgaris”

2. Guttate ; papule

3. Erythrodermic ; diffuse

4. Pustular ; localized or generalized

5. Inverse ; flexural area

Chronic plaque type

Guttate type

Erythrodermic psoriasisPustular type, generalized

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Palmoplantar pustular psoriasis

Inverse psoriasis

Psoriasis treatment

• Encourage a healthy lifestyle with regular exercise, weight management, cessation of smoking, and moderation of alcohol consumption

• Encourage patients to be actively involved in their care management

• Discuss treatment options, risk, and benefit with the patients, to be involved in decision making

Psoriasis treatment

1. Mild : BSA ≤ 10%, PASI ≤ 10

Rx- topical therapy or phototherapy

2. Moderate to severe : BSA > 10 %,

PASI > 10, DLQI>10 Rx- phototherapy or systemic therapy

Foulkes AC, et al. Clin Exp Dermatol, 2011, Burden AD, et al. BMJ,2010.

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Treatment of psoriasis

• Topical therapyTopical corticosteroid* Calcipotriol*Tazarotene Tars Anthralin Salicylic acid

Immunomodulators

• Systemic therapy• Conventional:

Methotrexate Cyclosporine Acitretin

• Biologics:Etanercept Infliximab Ustekinumab

• PhototherapyNarrow-band UVB PUVA (psoralen-UVA)Excimer laser

*First-line topical therapy

Topical treatment1. Topical glucocorticoids First-line for mild to moderate psoriasis

Improvement within 2-4 wks, maintenance with interm ittent application (weekends)

Good for intertrigenous, genitalia, and pustular ty pe Long-term use increases S/E Tachyphylaxis

2. Vitamin D 3 analogue

Calcipotriol, tacalcitol, maxacalcitol: First-line for mild to moderate psoriasis

Short term: efficacy< potent topical steroids, > an thralin Efficacy not reduced with long term treatment, appl y BID>ODIncreased efficacy by combination with topical ster oidsMinimal S/E in long-term use, hypercalcemia, not ex ceed 100g/wk

Lebwohl and Ali. J Am Acad Dermatol,2001.

Topical treatment3. Tars or liquor carbonis detergents (LCD)

5-20% in cream, ointment, pasteEffective, irritation and bleach cloth and hair, u npleasant odor

4. Anthralin Effective “short contact treatment”

5. Keratolytics salicylic acid, lactic acid, ureaSynergistic effect, enhances absorption of other ag ents

6. Retinoids Tazarotene (0.05, 0.1% gel, cream): Efficacy = moderate potency topical steroids Reduce skin atrophy from topical steroidsS/E irritation, + mid to high-potency topical stero ids

7. Calcineurin inhibitors Tacrolimus (0.03, 0.1% ) Chronic plaque: not effectiveEffective for facial and inverse types psoriasis (black-box warning) Lebwohl and Ali. J Am Acad Dermatol,2001.

Plaque type treatment• Regular application of emollient to reduce scaling

and itch• Short term

- Intermittent potent TC for rapid improvement, avoid regular use of TC for prolonged periods- Combination of calcipotriol and betamethasone dipropionate OD (higher efficacy and more rapid onset of action, QoL>calcipotriol bid)

• Long term- Vitamin D analogue, calcipotriol first, but if this causes troublesome local irritation, switch to an alternative vitamin D analogue - If ineffective or not tolerated consider-coal tar, tazarotene gel, short contact dithranol

Burden AD, et al. BMJ,2010. van de Kerkhof PCM. BJD 2004. Saraceno R, et al. J Dermatol Treat 2007.

van de Kerkhof PCM. BJD 2004.

-828 patients with psoriasis vulgaris :Psoriasis Disability Index, EuroQoL 5D questionnaire and visual analogue scale (VAS)-The TCP used once or twice daily and calcipotriol used twice daily (4 wks)were found to have statistically significant beneficial effects on patients’ QoL over vehicle. -The TCP, applied once daily, was superior to calcipotriol twice daily in terms of reductions on the EuroQoL questionnaire and VAS

Combination of calcipotriol and betamethasone

Sequential therapy

Phase Vitamin D3 analogue

Topical steroids class I

Clearance

2-4 weeks

bid od or bid

Transition1-6 months

bid weekday

bid weekend

Maintenanceuntil remission and prevent relapse

bid none

Burden AD, et al. BMJ,2010.

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Scalp treatment• Mild case :

Tar or keratolytic shampoo • Moderate to severe case :

Intermittent potent TC ( lotion, solution, foam, g el ) Combination of calcipotriol and betamethasone dipropionate OD ( improvement QoL, quick onset of improvement )

Overnight application of salicylic acid or oil preparation (olive or coconut oil) to remove thick scale

• Recalcitrant case :Phototherapy: ultraviolet comb, excimer laser (UVB 308 nm)Systemic therapy

Burden AD, et al. BMJ,2010. Ortonne JP, et al. JEADV 2009. Mrowietz U, et al. J Dtsch Dermatol Ges.2011.

Combination of calcipotriol and betamethasone, scalp preparation

• 721 patients with scalp psoriasis received calcipotriol 50 µg/g, betamethasone 0,5 mg/g topically for 4 weeks

• Severity was assessed by physician’s global assessment (PGA) and QoL by using a scalp-specific questionnaire

Results• Mean PGA improved from 4.26 to 2.49 (–41.8 %,

p < 0.0001)• QoL improved from 10.57 to 3.22 (–69.5 %,p < 0.0001)• Among patients with pretreatment 89.5 % of patients and

87.9 % of dermatologists judged treatment response to this combination as better/much better compared to previous therapy

Mrowietz U, et al. J Dtsch Dermatol Ges.2011.

Mrowietz U, et al. J Dtsch Dermatol Ges.2011.

Ortonne JP, et al. JEADV 2009.

Facial / flexural psoriasis treatment

• Moderate potency TC (1st line short term use)

• Vitamin D analogue• Tacrolimus ointment• Avoid dithranol, topical retinoids


Nail signs /anatomic site / treatment

Nail bed psoriasis Nail matrix psoriasisOnycholysis Splinter hemorrhagesOil drop (salmon patch)Nail bed hyperkeratosis

PittingLeukonychiaRed spots in the lunulaNail plate thickening / crumbling

Cacipotriol ointmentTopical corticosteroids (+keratolytics)Systemic therapy

Topical corticosteroidsCalcipotriol TarzaroteneSteroid injectionSystemic therapy

Burden AD, et al. BMJ,2010. Lebwohl and Ali. J Am Acad Dermatol,2001.

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Secondary care

Not respond to topical treatment1. Narrow band UVB phototherapy

2. Psoralen plus UVA photochemotherapy

Severe or refractory psoriasis1. MTX for long term use + psoriatic arthritis

2. Cyclosporine for short term intermittent use

3. Acitretin as an alternative except in women of ch ildbearing potential

Not suitable for above systemic Rx :fumaric acid esters as an alternative maintenance

Offer biologic drugs( fail to respond, intolerant, contraindication)


Physical therapy• For patient with BSA >25-30%

• Should be first considered in, chronic plaque type, young age, pregnant patient, guttate lesions, HIV-infected patient, HBV-or HCV-infected patient

1. Narrow band UVB

(object to oral medication, thin lesion, young age, pregnancy,

lactation)

2. Psoralen + UVA (PUVA) + tar bath (Goeckerman)(thick lesion, palms and soles, nail disease, failu re to UVB)

3. Retinoids + PUVA (RePUVA)

4. Laser (excimer) (recalcitrant localized plaque)

Menter A, et al. J Am Acad Dermatol 2010., Pathirana D, et al. JEADV 2009.

Systemic agents

1. Severity of the disease (>10% BSA or PASI)

2. Type of the disease (pustular or erythrodermic)

3. Underlying diseases (liver, kidney, infection, HIV)

4. Contraindication (CHF, Neurological disease)

5. Age

6. Associated symptoms (arthritis)

7. Previous treatment

Systemic agents

Conventional

1. Methotrexate plaque type, arthritis

2. Retinoids pustular psoriasis or chronic plaque type

3. Cyclosporine erythrodermic psoriasis, arthritis

Non-conventional

fumaric acid esters, hydroxyurea, sulfasalazine, mycophenolate, azathioprine, dapsone, tetracycline

Biologics plaque type, arthritis

eg. etanercept, infliximab, ustekinumab

Methotrexate

• Start with a test dose 2.5 mg, average range 10-15 mg/wk, maximum 25-30 mg/wk

• May reduce the severity at least 50% in >75% of patients

• Side effects: hepatoxicity, hepatic fibrosis, myelosuppression, infection, fetal abnormalities

• Monitoring: baseline CBC, LFTs weekly until target dose, then every 4-8 wks, liver biopsy every 1.5 g or 3-4.5 g in selected cases (procollagen type III N-terminal peptide, PIIINP)

• Absolute C/I: pregnancy, lactation• Pregnancy category X


Menter A, et al. J Am Acad Dermatol 2009.

Acitretin

• Dosage: 0.5-1 mg/kg/day• Modestly effective as monotherapy• Side effects: hepatotoxicity, lipid abnormalities,

fetal abnormalities or death, alopecia, sticky skin , mucocutaneous toxicity, hyperostosis

• Monitoring: baseline CBC, LFTs, lipid, pregnancy test every 4 wks, spinal x-rays if symptoms

• Combined with PUVA or NUVB to minimize S/I and to improve therapeutic response

• Absolute C/I: pregnancy during or within 3 yrs afte r termination, lactation

• Pregnancy category X



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Cyclosporin A

• High-dose approach : 5 mg/kg/day then tapered• Low-dose approach : 2.5 mg/kg/day, increase every 2-4

wk up to 5 mg/kg/day• Very effective, up to 90% of patients achieve

clearance or marked improvement• Side effects: nephrotoxicity, HT, immunosuppression ,

increase risk of malignancy if before PUVA• Monitoring: BP, CBC, BUN/Cr, Mg, uric acid, every 4 -8

wks• Absolute C/I: uncontrolled HT, abn. renal function,

history/current malignancy• Intermittent short-course safer than chronic long-t erm

use• Pregnancy category C



Fumaric acid esters

• Initiate at low dose and escalate dose weekly, maximum 1.2 g/day

• 80% mean reduction in PASI• Side effects: GI symptoms, diarrhea, flushing,

headache, lymphopenia, acute renal failure• Absolute C/I: chronic disease of GI and kidney,

pregnancy, lactation• Not US FDA approved, widely use in Europe• Pregnancy category C


Hydroxyurea

• 500 mg daily, 1.0-1.5 g daily based on response• 85 patients with chronic plaque, 61% of patients

had satisfactory remission• Side effects: BM suppression, teratogenicity,

mutagenicity, skin rash• Monitoring: CBC, Blood chemistry, LFTs, every 2-

4 wks, hold dosage if severe anemia, WBC<2,500 or platelet< 100,000

• Absolute C/I: prior BM depression, pregnancy, lactation

• Pregnancy category D


Mycophenolate mofetil

• Initiated at 500-750 mg bid, then 1.0-1.5 g bid

• Appears to be only moderately effective• Side effects: GI (constipation, diarrhea,

N/V), myelosuppression, HT, edema• Monitoring: BP, CBC, blood chemistry,

weekly x 6 wk, every 2 wk x 2mo, then monthly

• Absolute C/I: severe infection, malignancy• Pregnancy category C


Sulfasalazine

• Starting dose 500 mg tid, if tolerated after 3 d, 1 g tid, if tolerated after 6 wk, 1 g qid

• Appears to be moderately effective• Side effects: headache, N/V, rash, pruritus,

hemolytic anemia• Monitoring: CBC, blood chemistry, G6PD, CBC +

blood chemistry weekly x 1 mo, every 2 wk x 1 mo, monthly x 3 mo, then every 3 mo

• Absolute C/I: hypersensitivity to sulfasalazine, sulfa drugs, salicylates, porphyria, intestinal urinar obstruction, G-6-PD def.

• Pregnancy category C


Biologics

• Induction of clearance (short-term efficacy):infliximab is the most effective (80% of pts achieving a PASI-75 at wk 10, adalimumab (71-79% at wk16), etanercept (34% 25 mg twice a wk, 49% 50 mg twice a wk at wk 12)

• After wk 12 : initial response rates are maintained by infliximab and adalimumab but tend to increase moderately with etanercept

• Long-term efficacy : etanercept (50 mg twice a wk) peaked at wk 48 with PASI-75 in 63%, decrease to 52% by wk 96, infliximab (every 8 wk) 80% with PASI-75 at wk 24, decrease to 60.5% at wk 50


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Biologics

• Intermittent therapy: rebound phenomenon• Approved for chronic plaque type and

arthritis• Combination with oral systemic agents:

methotrexate (FDA-approved for arthritis)• Reactivation of latent infection, induction or

exacerbation of demyelinating disease, worsening cardiac failure, anaphylaxis (infliximab) 10%

• Pregnancy category B (efalizumab C)


New biologics

• Ustekinumab : human IgG monoclonal Ab to p40 subunit of IL-12 and IL-23

• PHOENIX 1 and 2 : 45 and 90 mg SC at wk 0, 4 and every 12 wks

• PASI-75: 67.1% vs 66.4% at wk 12, 76.1% vs 85% at wk 24

• ACCEPT study : ustekinumab and etanercept 50 mg SC 2 times/wk

• PASI-75 : 67.5% (45 mg), 73.8% (90 mg), 56.8% (etanercept)


Biologics

Infliximab Etanercept Ustekinumab

Mechanism Chimeric monoclonal Ab for TNF-alpha

Human recombinant for TNF-alpha receptor

Human monoclonal Ab to IL-12, Il-23

Dosing 5 mg/kg IV infusions at wk 0,2,6, every 8 wk

25-50 mg SC twice weekly

45 and 90 mg SC at wk 0, 4 and every 12 wks

Efficacy PASI-75 wk 10, 82%, wk 26, 50%

PASI-75 wk 12, 34%, wk 24, 44%

PASI-75 wk 12, 67%, wk 24, 76%

Safety Serious infection, TB, MS, malignancy, heart failure

Serious infection, TB, MS, malignancy, heart failure

Serious infection, TB, malignancy

Pregnancy B B -

Pathirana D, et al. JEADV 2009. Week 0 Week 10

Infliximab significantly improves psoriasis

Infliximab significantly improves psoriasis

“Rotational therapy”

“ Combination therapy”

Response

Non response

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Combination systemic therapy

Combination Recommendation Comments

Phototherapy + retinoids ++ Increased efficacy

Phototherapy + MTX + Increased phototoxicity

Biologics + MTX + Depending on biologics

Biologics + Cyclosporin + Depending on biologics

Biologics + retinoids + Depending on biologics

Phototherapy + cyclosporin - Increased risk of SCC

Cyclosporin + MTX - Increased immunosuppression but possible

Retinoids + MTX - Increased hepatotoxicity

Retinoids + cyclosporin - No evidence of increased efficacy

Pathirana D, et al. JEADV 2009.

Women of child-bearing potential and during pregnancy

• Avoid MTX (fetotoxic, abortifactant) and retinoids (teratotoxins)

• In selected cases: isotretinoin may be preferred, s hort half-life• Improvement or remission during pregnancy• If needed: emollients or topical treatments• Topical steroids and calcipotriol: pregnancy catego ry C,

caution should be exercised• Several biologics (category B) can be used in pregnancy• Cyclosporin (category C) and nonteratogenic• PUVA and UVB appear to be safe


Children

• First-line: Topical treatments, UVB• PUVA is generally contraindicated

(carcinogenic risk)• Systemic agents: MTX or cyclosporin

or biologics


Patients with HIV infection

• More severe and refractory to traditional treatment s• Many have significant psoriatic arthritis• Many effective drugs for psoriasis are immuno

suppressive • First-line for mild to moderate: Topical treatments• First-line for moderate to severe: phototherapy and

antiretrovirals, second-line : oral retinoids• More refractory, severe: cautious use of

cyclosporin, MTX, hydroxyurea and anti-TNF• Regular monitoring of CD4 counts and HIV viral

loads

Menon K, et al. J Am Acad Dermatol 2009.

Patients with hepatitis C • Exacerbated by interferon therapy• Psoriasis therapies are potentially hepatotoxic,

immunosuppressive• Mild to moderate:

first-line: topical treatments second-line : ultraviolet B phototherapy

• Moderate to severe:first-line: ultraviolet B phototherapy + topical therapies, second-line : oral retinoids, etanercept, infliximab,

adalimumab, PUVAthird-line : cyclosporin, alefacept, efalizumab,

azathioprine• Contraindicated: MTX, MMF

Frankel AJ, et al. J Am Acad Dermatol 2009.


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Males Females


THANK YOU

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