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Conven&onal systemic treatments: how to use, what to choose? Manuelle Viguier, MD, PhD
Saint-Louis Hospital, Paris, France
Factors influencing the decision to use and the
choice of systemic treatments in psoriasis Patient history1
§ Location of lesions
§ Associated symptoms
(severe itching)
§ Body surface area, PASI
§ Quality of life impact
§ Psychosocial
considerations
§ Comorbid diseases
§ Association with psoriatic
arthritis
•  Pregnancy wish
Treatment
considerations2
§ History of therapy
§ Concomitant therapy/
drug interactions
§ Efficacy profile
§ Safety profile
§ Route of
administration
§ Accessibility to special
treatment facilities/
hospital/dermatologist
§ Costs
1. Ortonne JP. J Eur Acad Dermatol Venereol. 2006;20(Suppl 2):77–79.
2. Callen JP, et al. J Am Acad Dermatol. 2003;49:897–899.
Treatment options2
Systemics:
§ Methotrexate
§ Cyclosporine
§ Acitretin
§ Fumaric acid esters
§ Phototherapy
§  Narrow UVB
§  Psoralen plus UVA
(PUVA)
Biologics:
§ Adalimumab (Humira®)
§ Etanercept (Enbrel®)
§ Infliximab (Remicade®)
§ Ustekinumab (Stelara®)
German S3 Guidelines
Treatment algorithm for chronic plaque psoriasis according to
disease severity
Chronic Plaque Psoriasis
Calcineurin inhibitors
Base Therapy
Dithranol
Mild
BSA <10%
PASI <10
Corticoids
Topical
Therapy
Systemics are
recommended for the
treatment of moderate to
severe psoriasis
Laser
Tazarotene
Tar
Vitamin D3
Moderate
BSA >10%
PASI >10
Attending: climate therapy
Attending: psychosocial
therapy
Ciclosporin
Severe
Systemic
therapy
+ Topical Therapy
Fumaric acid ester
Adalimumab
Methotrexate
Etanercept
Photo: UV-B Balneophoto PUVA
Infliximab
Ustekinumab
Retinoids
This tool may contain scientific/medical information on unapproved
products or product uses. This information is for educational purposes only.
Please consult the applicable prescribing information for details on
approved uses of products.
Nast A et al. J Dtsch Dermatol Ges. 2011;9(Suppl. 2):S1-S104
Assessment of response under systemic
treatment: a European consensus proposal
Poor clearance
Moderate clearance
Good clearance
∆ PASI <50
∆ PASI ≥50 <75
∆ PASI ≥75
CHANGE
TREATMENT REGIMEN
• Increase dose
• Decrease dose interval
• Add systemic
medication
• Add topical medication
• Switch to another drug/
class
Poor QoL Good QoL
DLQI >5
Mrowietz U, et al. Arch Dermatol Res. 2011;303:1-10.
DLQI ≤5
CONTINUE
TREATMENT REGIMEN
Comparison of selected therapies
(8-16 weeks) for moderate-to-severe psoriasis
Infliximab 5mg/kg
Adalimumab* 40mgeow
Ustekinumab 45mg
PUVA
70
CSA 5 mg/kg
70
77-82
63-77
Etanercept 50mg x 2/wk
49
MTX 15 mg/w
35.5-40
CSA 2.5mg/kg/d
28
Efalizumab* 1mg/kg/wk
26
Alefacept** 15mg/wk
17
0
10
20
30
40
50
60
70
80
90
100
% Patients achieving ≥ PASI 75
* No longer approved
** Not approved in Europe
Adapted from Stern RS. JAMA 2003
Phototherapy For Psoriasis: US Guidelines
(American Academy of Dermatology)
n  Suitable for plaque-type psoriasis with ≥10% BSA involvement
– Also for those with debilitating limited disease (palms and soles)
- Also for psoriasis resistant to topical treatment.
n  NB UVB can also be combined with a synergistic effect with:
– Topical therapies
– Systemic therapies (including biologics)
PUVA can also be combined with:
-  Topical therapies
-  Acitretine
n  Topical PUVA recommended for psoriasis of palms and soles and
plaque-type psoriasis
Menter A, et al. J Am Acad Dermatol. 2010;62:114–135 (EPub 2009 Oct 7).
Phototherapy for Psoriasis: General considera4ons • 
Response:
–  Expected after 1-2 weeks
–  PASI 75 after 4–6 weeks in >75% of patients
• 
Safety:
-  Contraindications:
-  photodermatoses/photosensitive disease,
-  prior history of cutaneous malignancies,
-  pregnancy or breastfeeding (PUVA),
-  combination with ciclosporin (PUVA)
–  Adverse effects:
• 
• 
• 
• 
• 
actinic erythema,
itching,
blistering,
increased risk of cutaneous malignancies,
nausea (PUVA),
•  hepatitis (PUVA).
–  Drug Interactions: drugs causing phototoxicity or photoallergy.
Pathirana D, et al. J Eur Acad Dermatol Venereol. 2009;23(Suppl 2):5–70.
Systemic Psoralen Plus Ultraviolet Light A (PUVA) in psoriasis Indication
•  Adults with psoriasis resistant to topical therapy or BSA >10%
Dosing
•  8-methoxypsoralen, 5-methoxypsoralen or trimethylpsoralen taken
1–2 hours before exposure to UVA
•  2–3 times per week
•  Once clearance achieved, maintenance may be used
Efficacy
•  ~90% clearance with 20–25 treatments
•  Remission times: 3–12 months
Safety
•  Acute toxicities: nausea/vomiting, actinic erythema, pruritis, blisters
•  Long-term: photocarcinogenesis in Caucasians with skin types I–III,
photoaging and lentigines
Clinical
issues
•  Contraindicated in lupus, porphyria or xeroderma pigmentosum
•  Caution in skin types I and II, previous skin cancer, severe liver
disease, previous use of cyclosporine/methotrexate
•  Cautious use with other photosensitizing agents/systemic retinoids
•  Pregnancy category C
Menter A, et al. J Am Acad Dermatol. 2010;62:114–135 (EPub 2009 Oct 7).
PUVA in psoriasis: Advantages and Disadvantages Major advantages Major disadvantages
•  High efficacy and good dura4on of remission. •  Limited number of treatment sessions (<200) •  Requires a high degree of effort. •  Care required when selec4ng pa4ents for treatment •  Poten4al skin ageing/burning •  Increased incidence of squamous cell cancer, basal cell carcinomas, melanomas •  Cannot be used during pregnancy. •  Low acute risk of adverse event with appropriate dosing . •  Can be combined with re4noids. 1.  Menter A, et al. Lancet. 2007;370:272–284.
2.  Menter A, et al. J Am Acad Dermatol. 2010;62:114–135 (Epub 2009 Oct 7).
Narrowband Ultraviolet Light B (UVB): Efficacy •  15–20 treatments are generally required to achieve more than 50% improvement in psoriasis. •  Approximately 63–80% of pa4ents achieve clearance. 1. Naldi L, Griffiths CEM. Br J Dermatol. 2005;152:597–615.
2. Kleinpenning MM, et al. Br J Dermatol. 2009;161:1352–1356.
10
Narrowband UVB: Advantages and Disadvantages Major advantages
•  High efficacy1
•  Effective in combination therapy
(MTX, acitretine)1,2
•  Low acute risk of adverse events
with appropriate dosing2
•  Can be used in children and
during pregnancy.
1.  Menter11 A, et al. Lancet. 2007;370:272–284.
2.  Menter A, et al. J Am Acad Dermatol. 2010;62:114–135 (EPub 2009 Oct 7).
Major disadvantages
•  Potential skin aging
•  Acute side effects include
erythema, itching, burning and
stinging
•  Might increased risk of skin
cancers
•  Does not result in long-term
remission and may take time to
achieve remission
•  Limited number of sessions
Phototherapy For Psoriasis: Summary •  Phototherapy op4ons for trea4ng psoriasis include narrowband UVB and oral and topical psoralen plus UVA (PUVA). •  Phototherapies carry a risk of skin ageing and skin cancers (especially PUVA). •  Narrowband UVB may be slightly less effec4ve than PUVA, but it has a more favourable safety profile regarding skin cancers. •  Phototherapy has no effect on psoria4c arthri4s. Acitre4n overview (1) •  Oral re4noid used to treat psoriasis since 1984. •  Reduces prolifera4ve ac4vity in skin and favours differen4a4on of epidermal kera4nocytes. Pathirana D, et al. J Eur Acad Dermatol Venereol. 2009;23(Suppl 2):5–70.
13
Acitre4n Overview (2) Indication
•  Severe plaque-type psoriasis in adults (FDA indication)
Dosing*
•  10–50 mg/day as a single dose
•  When added to UV light, dose should be reduced by 30–50%
Efficacy
•  Not well defined, widely variable but dose-dependent
•  Response expected after 4–8 weeks
•  3–6 month period is needed to achieve maximum response
•  Considered less effective than other systemic therapies
•  Only 23% of patients treated with 50 mg/day for 8 weeks achieved
PASI 75
Safety
•  Major toxicities: teratogenicity
•  Common toxicities: mucocutaneous side effects, hyperlipidaemia,
elevated transaminases, joint pain
Clinical issues
•  Pregnancy category X (risk can remain for years after use).
•  Treatment of women of child-bearing age strongly discouraged.
•  Most acceptable use in combination with UVB or PUVA therapy,
which is highly effective
•  Lipid and liver monitoring required
•  No efficacy on PsA.
Menter A, et al. J Am Acad Dermatol. 2009;61:451–485.
Pathirana D, et al. J Eur Acad Dermatol Venereol. 2009;23(Suppl 2):5–70.
Acitre4n: Drug Interac4ons Drug
Type of interaction
Tetracycline
Induction of idiopathic intracranial hypertension
Phenytoin
Plasma protein displacement
Vitamin A
Augmentation of retinoid effect
Methotrexate
Liver toxicity
Low-dose progesterone pills
Insufficient contraceptive effect
Lipid-lowering drugs
Increased risk of myotoxicity
Antifungal imidazoles
Liver toxicity
Pathirana D, et al. J Eur Acad Dermatol Venereol. 2009;23(Suppl 2):5–70.
15
Acitre4n: Contra-­‐indica4ons Absolute contraindications
•  Severe renal or hepatic dysfunction
•  Women of child-bearing age
•  Excessive alcohol abuse
•  Contraindicated co-medication
Relative contraindications
•  Diabetes mellitus
•  Wearing contact lenses
•  Childhood
•  History of pancreatitis
•  Hyperlipidemia (especially
hypertriglyceridemia), including drugcontrolled
•  Arteriosclerosis
Pathirana D, et al. J Eur Acad Dermatol Venereol. 2009;23(Suppl 2):5–70.
16
Methotrexate: Efficacy in Psoriasis
Trial
Design
Oucome under
MTX
CHAMPION1
RCT Adalimumab vs MTX 15-25 mg/w
•  24.5% PASI75 at wk12
•  35.5% PASI75 at wk16
RESTORE2
RCT Infliximab vs MTX 15-20mg/wk
•  41.9% PASI75 at wk16
•  30.7% PASI75 at wk26
Briakinumab vs MTX3
52 wk double blind RCT Briakinumab vs MTX
up to 25mg/wk
•  22,1% PASI75 at wk12
•  39,9% PASI75 at wk24
•  23,9% PASI75 at wk52
Saurat JH, et al. Br J Dermatol 2008; 158:558-566
Barker J, et al. Br J Dermatol DOI 10.1111/j.1365-2133.2011.10615.x
Reich K, et al. N Engl J Med 2011;365:1586-96.
What about a MTX cumulative dose?
Is there a real danger for liver fibrosis?
• 
Few data available on the incidence of liver fibrosis in psoriasis patients: « in 5
studies eligible for assessment the frequency of liver fibrosis varied from 5,7% to
71,8% ! »
• 
• 
• 
• 
• 
• 
The duration of MTX treatment in studies varied from 1 to 11 years
Few data on other risk factors exposure
Significant associated risk factors: Type II diabetes, obesity.
Viral B and C hepatitis: close to significant increase of risk
Alcohol intoxication: non significant increase of risk
A sytematic review of rhumatology litterature (88 studies) estimates the incidence of
liver fibrosis at 2,7% after 4 years of MTX.
Montaudié H, et al. J Eur Acad Dermatol Venereol. 2011;25 Suppl 2:12-8.
Salliot C, et al. Ann Rheum Dis 2009;68:1100–1104.
Prospec4ve Case-­‐control Study of Liver fibrosis in pa4ents receiving MTX using non Invasive methods (Fibroscan/Fibrotest) Overweight and alcohol intake are associated with an increased risk of liver fibrosis
in patients receiving methotrexate.
No influence of cumulative dose or of duration of treatment.
Laharie D et al. J Hepatol 2010;53:1035-40.
Kalb RE, et al. J Am Acad Dermatol. 2009 ; 60:824-37
•  The liver biopsy is no more recommended even after 1,5 g of
cumulative dose (the conference of consensus of 2009):
• The european guidelines of 2011 insist on liver test survey and
especcially on the elevation of PIIINP:
Pathirana D, et al. J Eur Acad Dermatol Venereol 2009; 23(Suppl. 2): 1–70
•  French Psoriasis group recommends: « the liver biopsy is an invasive
act with possible complications and should not be performed for the evaluation
of tolerance during MTX treatment. The survey should be oriented by biologial
tests (PIIINP, fibrotest®) combined if needed with fibroscan® test.
Beylot-Barry M, et al . Ann Dermatol Venereol. 2011;138:833-5.
How could we reduce the risk of liver fibrosis? •  All guidelines recommend a particular vigilance in
patients with risk factors:
– 
– 
– 
– 
– 
– 
– 
– 
Excessive alcohol consumtion
History of hepatitis
Familial and personal liver disease
Diabetes
Obesity
Steatosis
Hepatotoxic medications
Hyperlipidemia
Kalb RE, et al. J Am Acad Dermatol. 2009 ;60: 824-37
Barker J et al . JEADV 2011; 25: 758-764
Profile of a “ideal” methotrexate pa4ent according to EU guidelines Male or female adult pa&ent, collabora&ve and trustworthy With moderate to severe psoriasis Without immune deficiency, ac&ve infec&on Without chronic liver disease (hepatosteatosis) Without concomitant use of drugs with poten&al interac&ons with MTX metabolism With liver and kidney func&on tests within the normal range Without axial PsA resistant to NSAID Pathirana D, et al. J Eur Acad Dermatol Venereol. 2009 Oct;23 Suppl 2:1-70
.
Ciclosporin in psoriasis: overview
Ciclosporin
Approval for psoriasis
●  1993
Indication
●  Patients with moderate-to-severe psoriasis in whom conventional
therapy is ineffective or inappropriate
Recommended initial dosage
●  2.5–3 (max. 5) mg/kg daily (4–6 weeks)
Recommended maintenance dosage
●  Short term therapy
●  Over 8–16 weeks, with dose reduction at the end of induction
therapy (e.g. 0.5 mg/kg every 14 days)
●  Or continuous long-term therapy
●  With dose reduction every 2 weeks to a maintenance dosage of 0.5–
3 mg/kg/day. In case of relapse, increase dosage
●  Maximum total duration of therapy: 2 years
Clinically significant response
expected after
●  4 weeks
Response rate
●  Dose-dependent, after 8–16 weeks with 3 mg/kg daily: PASI 75 in
approximately 50% after 8 weeks (70% with 5 mg/kg daily)
This tool may contain scientific/medical information on unapproved products or
product uses. This information is for educational purposes only. Please consult the
applicable prescribing information for details on approved uses of products.
Pathirana D, et al. JEADV. 2009;23(Suppl 2):1–69.
Efficacy of ciclosporin in psoriasis Numerous clinical trials confirm the efficacy of ciclosporin
in the treatment of psoriasis
PASI 75 response rates after 10–16 weeks of treatment with ciclosporin according
to dosage
Author
Year
N
Meffert
1997
44
Thaçi
2002
60
Christopers
1992
108
Laburte
1994
119
Mahrle
1995
137
Koo
1998
152
Ellis
1991
25
Bigby
2003
44
Ellis
1991
20
IMGSP
1993
36
Laburte
1994
132
Dose
●  There is a tendency for
higher doses to produce a
higher percentage of
remission
2.5 mg/kg/d
3 mg/kg/d
5 mg/kg/d
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
Proportion of patients with response ≥ PASI 75 after 10–16 weeks
Proportion of patients (black square) in the study group and its 95% confidence interval (black lines)
This tool may contain scientific/medical information on unapproved products or
product uses. This information is for educational purposes only. Please consult the
applicable prescribing information for details on approved uses of products.
Maza A et al. JEADV 2011;25(suppl. 2):19-27
Profile of the “ideal” ciclosporin pa4ent according to EU guidelines Male or female adult pa&ent, collabora&ve and trustworthy With moderate to severe psoriasis resistant to conven&onal therapies1,2 Without immune deficiency, ac&ve infec&on and/or history of neoplas&c disorders1,2 With blood pressure values within the normal limit1,2 Without concomitant use of nephrotoxic and/or immunosuppressive drugs, as well as drugs with poten&al interac&ons with ciclosporin metabolism1,2 With liver and kidney func&on tests within the normal range1,2 Without history of excessive photo(chemo)therapy, and/or recent use of radiotherapy1,2 Without ac&ve PsA 1. Pathirana
This tool may contain scientific/medical information on unapproved products or
product uses. This information is for educational purposes only. Please consult the
applicable prescribing information for details on approved uses of products.
D, et al. J Eur Acad Dermatol Venereol. 2009 Oct;23 Suppl 2:1-70
2. Sandimmun Neoral Core Data Sheet.
Combina4on of conven4onal systemic treatments with biologics: Is it worth doing it in prac4ce? Methotrexate in Combined Regimen with Biologics: RCT with Etanercept in Psoriasis This tool may contain scientific/medical information on unapproved products or
product uses. This information is for educational purposes only. Please consult the
applicable prescribing information for details on approved uses of products.
Gottlieb A, et al. Br J Dermatol. 2012.
Methotrexate in Combined Regimen with Etanercept in Psoriasis : Efficacy This tool may contain scientific/medical information on unapproved products or
product uses. This information is for educational purposes only. Please consult the
applicable prescribing information for details on approved uses of products.
Gottlieb A, et al. Br J Dermatol. 2012.
Etanercept -­‐Methotrexate Combina4on Study (Nordic) Screening*
(N=60)
Randomize
d
(N=59)
ETN
50 mg
BIW
ETN
25 mg BIW
ETN 50 mg BIW + MTX
(n=31)
ETN 25 mg
BIW + MTX
ETN 50 mg
BIW + MTX†
(n=28)
Week 0
Week 4
Week 12
Week 24
*Patients treated with methotrexate ≥7.5 mg weekly for 3 months before study and had an
inadequate response
†Methotrexate tapered and discontinued up to week 4
Zachariae C, et al. Acta Derm Venereol. 2008;88(5):495-501.
29 Etanercept -­‐Methotrexate Combina4on Study (Nordic): PASI Response Rates (n=28)
Patients achieving PASI (%)
(n=31)
†
*
Week 12
Week 24
*P=0.034 vs. etanercept 50 mg BIW + MTX tapered; adjusted for gender, P=0.035
†P=0.013 vs. etanercept 50 mg BIW + MTX tapered; adjusted for gender, P=0.031
Zachariae C, et al. Acta Derm Venereol. 2008;88(5):495-501.
30 Etanercept and acitre4n: a 24-­‐week RCT •  44% PASI 75 at week 24 for combined treatment •  Similar to that obtained with etanercept 25 mg twice weekly •  Combined treatment not associated with significant altera4ons in serum parameters •  Including AST, ALT, cholesterol and triglycerides Etanercept 25 mg twice weekly
Acitretin daily (0,4 mg/kg/d) plus etanercept 25 mg once weekly
Acitretin daily (0,4 mg/kg/d) as a single oral dose.
*P = 0.001 for both etanercept groups
compared with acitretin alone.
Gisondi. Br J Dermatol 2008:158;1345–1349.
Etanercept and narrow UVB: a 12-­‐week single arm open-­‐label study •  ETN 50 mg twice weekly plus NB-­‐UVB twice-­‐weekly. •  85% PASI75 at 12 weeks. •  More than 20% of pa&ents achieved PASI100 aTer 12 weeks Kircik L, et al. Journal of Drugs in Dermatology 2008.
Comparison of selected therapies
(8-16 weeks) for moderate-to-severe psoriasis
Infliximab 5mg/kg
Adalimumab* 40mgeow
Ustekinumab 45mg
PUVA
70
CSA 5 mg/kg
70
77-82
63-77
Etanercept 50mg x 2/wk
49
MTX 15 mg/w
35.5-40
CSA 2.5mg/kg/d
28
Efalizumab* 1mg/kg/wk
26
Alefacept** 15mg/wk
17
0
10
20
30
40
50
60
70
80
90
100
% Patients achieving ≥ PASI 75
* No longer approved
** Not approved in Europe
Adapted from Stern RS. JAMA 2003
Take-­‐home final points regarding systemic conven4onal treatments in Pso •  Acitre&n: –  Modest efficacy in plaque-­‐type psoriasis. –  Interes4ng to combine with phototherapy. –  Usage limited by childbearing age, by dyslipidemia, by hepa44s, by lack of effect on PsA. •  Methotrexate: –  Good efficacy/safety profile. « Gold standard conven4onal systemic treatment ». –  Efficient in peripheral PsA (not axial). –  Usage limited by the risk of liver fibrosis and by pregnancy. •  Ciclosporin: –  As effec4ve as biotherapy, depending on the dosage. –  Can be used during pregnancy. –  Usage limited by renal func4on (no use longer than 2 years), comedica4ons, past phototherapy and poor efficiency on PsA.