1. health and fitness
2. therapy

11/19/2012
Psoriasis
• Chronic inflammatory skin disease, 1-2% of population
Head to Toe Psoriasis,
How to Treat ?
• Male = female, age at onset 22.5 and 55 yrs
• Trigger: genetic and environment
• HLA association; Cw6, B13, B17, PSORS 1 and 2
• Mother or father 8-15%, mother and father 40-50%
• Early onset ; clinical more severe, genetic influence
Charoen Choonhakarn, MD
Division of Dermatology, Faculty of Medicine
Khon Kaen University
• Degree of disability and negative impact on QoL= IHD,
DM, cancer
• Severe psoriasis / arthritis : increased risk of CVS
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
Clinical feature
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
• Skin (head to toe)
Well-demarcated, silvery scale, erythematous on
extensor surface
• Nails
Oil spot, pits, onycholysis, subungual hyperkeratosis
• Joints and enthesopathy
Axial or peripheral (small or large joints)
chloroquine, beta-blocker, lithium, NSAIDs,
steroid withdrawal : pustular psoriasis
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Variation
1. Chronic plaque “psoriasis vulgaris”
2. Guttate; papule
3. Erythrodermic; diffuse
4. Pustular; localized or generalized
5. Inverse; flexural area
Chronic plaque type
Guttate type
Pustular type, generalized
Erythrodermic psoriasis
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Inverse psoriasis
Palmoplantar pustular 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 therapy
Topical corticosteroid*
Calcipotriol*
Tazarotene
Tars
Anthralin
Salicylic acid
Immunomodulators
Topical treatment
1. Topical glucocorticoids
First-line for mild to moderate psoriasis
• Systemic therapy
• Conventional:
Methotrexate
Cyclosporine
Acitretin
• Biologics:
Etanercept
Infliximab
Ustekinumab
Improvement within 2-4 wks, maintenance with intermittent
application (weekends)
Good for intertrigenous, genitalia, and pustular type
Long-term use increases S/E
Tachyphylaxis
2. Vitamin D3 analogue
Calcipotriol, tacalcitol, maxacalcitol:
First-line for mild to moderate psoriasis
• Phototherapy
*First-line topical therapy
Short term: efficacy< potent topical steroids, > anthralin
Efficacy not reduced with long term treatment, apply BID>OD
Increased efficacy by combination with topical steroids
Minimal S/E in long-term use, hypercalcemia, not exceed
100g/wk
Narrow-band UVB
PUVA (psoralen-UVA)
Excimer laser
Lebwohl and Ali. J Am Acad Dermatol,2001.
Topical treatment
3. Tars or liquor carbonis detergents (LCD)
5-20% in cream, ointment, paste
Effective, irritation and bleach cloth and hair, unpleasant odor
Plaque type treatment
•
•
4. Anthralin
Effective “short contact treatment”
5. Keratolytics salicylic acid, lactic acid, urea
Synergistic effect, enhances absorption of other agents
6. Retinoids Tazarotene (0.05, 0.1% gel, cream):
Efficacy = moderate potency topical steroids
Reduce skin atrophy from topical steroids
S/E irritation, + mid to high-potency topical steroids
7. Calcineurin inhibitors Tacrolimus (0.03, 0.1% )
Chronic plaque: not effective
Effective for facial and inverse types
psoriasis (black-box warning)
Lebwohl and Ali. J Am Acad Dermatol,2001.
•
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.
Combination of calcipotriol and betamethasone
-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
Sequential therapy
Phase
Clearance
Vitamin D3
analogue
Topical steroids
class I
bid
od or bid
bid weekday
bid weekend
bid
none
2-4 weeks
Transition
1-6 months
Maintenance
until remission and
prevent relapse
van de Kerkhof PCM. BJD 2004.
Burden AD, et al. BMJ,2010.
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Combination of calcipotriol and betamethasone,
scalp preparation
Scalp treatment
•
Mild case :
•
Tar or keratolytic shampoo
•
•
Moderate to severe case :
Intermittent potent TC ( lotion, solution, foam, gel )
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
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
Burden AD, et al. BMJ,2010. Ortonne JP, et al. JEADV 2009. Mrowietz U, et al. J Dtsch Dermatol Ges.2011.
Mrowietz U, et al. J Dtsch Dermatol Ges.2011.
Ortonne JP, et al. JEADV 2009.
Mrowietz U, et al. J Dtsch Dermatol Ges.2011.
Facial / flexural psoriasis treatment
Nail signs /anatomic site / treatment
Nail bed psoriasis
• Moderate potency TC
(1st line short term use)
• Vitamin D analogue
• Tacrolimus ointment
• Avoid dithranol, topical retinoids
Nail matrix psoriasis
Onycholysis
Splinter hemorrhages
Oil drop (salmon patch)
Nail bed hyperkeratosis
Pitting
Leukonychia
Red spots in the lunula
Nail plate thickening / crumbling
Cacipotriol ointment
Topical corticosteroids
(+keratolytics)
Systemic therapy
Topical corticosteroids
Calcipotriol
Tarzarotene
Steroid injection
Systemic therapy
Burden AD, et al. BMJ,2010.
Burden AD, et al. BMJ,2010. Lebwohl and Ali. J Am Acad Dermatol,2001.
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Secondary care
Physical therapy
• For patient with BSA >25-30%
Not respond to topical treatment
• Should be first considered in, chronic plaque type,
young age, pregnant patient, guttate lesions, HIVinfected patient, HBV-or HCV-infected patient
1. Narrow band UVB phototherapy
2. Psoralen plus UVA photochemotherapy
Severe or refractory psoriasis
1. Narrow band UVB
1.
MTX for long term use + psoriatic arthritis
2.
Cyclosporine for short term intermittent use
3.
Acitretin as an alternative except in women of childbearing
potential
(object to oral medication, thin lesion, young age, pregnancy,
lactation)
2. Psoralen + UVA (PUVA) + tar bath (Goeckerman)
(thick lesion, palms and soles, nail disease, failure to UVB)
Not suitable for above systemic Rx :
fumaric acid esters as an alternative maintenance
Offer biologic drugs
3. Retinoids + PUVA (RePUVA)
4. Laser (excimer) (recalcitrant localized plaque)
( fail to respond, intolerant, contraindication)
Menter A, et al. J Am Acad Dermatol 2010., Pathirana D, et al. JEADV 2009.
Burden AD, et al. BMJ,2010.
Systemic agents
1. Severity of the disease
2. Type of the disease
(liver, kidney, infection, HIV)
(CHF, Neurological disease)
5. Age
6. Associated symptoms
Conventional
1. Methotrexate plaque type, arthritis
(pustular or erythrodermic)
3. Underlying diseases
4. Contraindication
(>10% BSA or PASI)
Systemic agents
2. Retinoids pustular psoriasis or chronic plaque type
3. Cyclosporine erythrodermic psoriasis, arthritis
Non-conventional
fumaric acid esters, hydroxyurea, sulfasalazine,
mycophenolate, azathioprine, dapsone, tetracycline
(arthritis)
7. Previous treatment
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 Nterminal peptide, PIIINP)
• Absolute C/I: pregnancy, lactation
• Pregnancy category X
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 after
termination, lactation
• Pregnancy category X
Lebwohl and Ali. J Am Acad Dermatol,2001.
Lebwohl and Ali. J Am Acad Dermatol,2001.
Menter A, et al. J Am Acad Dermatol 2009.
Menter A, et al. J Am Acad Dermatol 2009.
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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-term
use
Lebwohl and Ali. J Am Acad Dermatol,2001.
• Pregnancy category C
Menter A, et al. J Am Acad Dermatol 2009.
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
Lebwohl and Ali. J Am Acad Dermatol,2001.
Hydroxyurea
Mycophenolate mofetil
• 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 24 wks, hold dosage if severe anemia, WBC<2,500
or platelet< 100,000
• Absolute C/I: prior BM depression, pregnancy,
lactation
• Pregnancy category D
• 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
Lebwohl and Ali. J Am Acad Dermatol,2001.
Lebwohl and Ali. J Am Acad Dermatol,2001.
Sulfasalazine
Biologics
• 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
• 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
Lebwohl and Ali. J Am Acad Dermatol,2001.
Menter A, et al. J Am Acad Dermatol 2009., Pathirana D, et al. JEADV 2009.
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Biologics
New 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)
• 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)
Menter A, et al. J Am Acad Dermatol 2009., Pathirana D, et al. JEADV 2009.
Menter A, et al. J Am Acad Dermatol 2009., Pathirana D, et al. JEADV 2009.
Infliximab significantly improves psoriasis
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.
Infliximab significantly improves psoriasis
Week 0
Week 10
Response
“Rotational therapy”
Non response
“ Combination therapy”
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Combination systemic therapy
Combination
Phototherapy + retinoids
Recommendation
++
Women of child-bearing potential and
during pregnancy
Comments
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
•
•
•
Avoid MTX (fetotoxic, abortifactant) and retinoids
(teratotoxins)
In selected cases: isotretinoin may be preferred, short half-life
Improvement or remission during pregnancy
If needed: emollients or topical treatments
Topical steroids and calcipotriol: pregnancy category 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
Menter A, et al. J Am Acad Dermatol 2009.
Pathirana D, et al. JEADV 2009.
Children
• First-line: Topical treatments, UVB
• PUVA is generally contraindicated
(carcinogenic risk)
• Systemic agents: MTX or cyclosporin
or biologics
Menter A, et al. J Am Acad Dermatol 2009., Pathirana D, et al. JEADV 2009.
Patients with HIV infection
• More severe and refractory to traditional treatments
• 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, PUVA
third-line: cyclosporin, alefacept, efalizumab,
azathioprine
• Contraindicated: MTX, MMF
Menter A, et al. J Am Acad Dermatol 2011.
Frankel AJ, et al. J Am Acad Dermatol 2009.
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Males
Females
Menter A, et al. J Am Acad Dermatol 2011.
Menter A, et al. J Am Acad Dermatol 2011.
THANK YOU
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