Non-biologic therapies for plaque psoriasis

1
Non-biologic therapies for plaque psoriasis
2
Topical therapies

• Topical therapies for psoriasis include
• Coal tar dithranol calcipotriol, calcitriol and
  tacalcitol (vitamin D analogues)
  tazarotene(vitamin A analogues)
  corticosteroids1
• Choice of treatment depends on the extent and
  pattern of psoriasis, and patient preference1
• Effective in short term (68 weeks) with a 2
  point improvement on a 12 point severity scale2
• Poor adherence to topical therapy in psoriasis
  may be common3

1. Psoriasis - General Management. Available
from http//www.bad.org.uk/site/769/Default.aspx.
Accessed 17 Feb 2010. 2. Mason J, et al. Br J
Dermatol 2002146351-64. 3. Richards HL, et al.
J Am Acad Dermatol. 199941(4)581-3.
3
Non-biologic systemic therapies for
moderate-to-severe psoriasis
PASI 75 responses at primary endpoints
100
71
70
75
63
60
52
Patients achieving PASI 75 ()
50
25
12weeks
16weeks
Up to24 weeks
12weeks
16weeks
0
PUVA33 times weekly (n30)
Ciclosporin2 3-5 mg/kg/d (n42)
NB-UVB4 (n20)
Acitretin1 Mean dose0.54 mg/kg/day (n127)
Methotrexate2 15-22.5 mg/wk (n43)
Note Not head-to head comparisons.

1. Geiger JM. Skin Therapy Lett. 200381-3,7. 2.
   Heydendael VM, et al. N Engl J Med.
   2003349658-65. 3. Sivanesan SP, et al. J Am
   Acad Dermatol. 200961(5)793-8. 4. Mahajan R,
   et al. J Eur Acad Dermatol Venereol. 2010
   May24595-600.

4
Broadband and narrowband UVB phototherapy

• Effective treatments for guttate or plaque
  psoriasis resistant to topical therapy
• Requirement to visit clinic may limit use for
  some patients
• Combination with other anti-psoriasis treatments
  (tars, topical calcipotriol, oral retinoids) have
  proved effective
• Phototherapy requires good metering, equipment
  monitoring and maintenance of patient records to
  track UV exposure

Psoriasis - General Management. Available from
http//www.bad.org.uk/site/769/Default.aspx.
Accessed 9 Mar 2009.
5
Photochemotherapy (PUVA)

• Combination with other anti-psoriasis treatments
  (vitamin D analogue preparations, retinoids) have
  proved effective1
• Potential adverse effects include itch, burning,
  risk of cataracts(eye protection required for 24
  hours post therapy) and risk of skin cancer with
  chronic UV exposure1
• There does not appear to be an increased risk of
  nonmelanoma skin cancer with long-term PUVA
  therapy in Asian and Arabian-African populations2
• Phototherapy requires good metering, equipment
  monitoring and maintenance of patient records to
  track UV exposure1

1. Psoriasis - General Management. Available
from http//www.bad.org.uk/site/769/Default.aspx.
Accessed 9 Mar 2009.. 2. Murase JE, et al. Int J
Dermatol. 200544(12)1016-21.
6
Photochemotherapy (PUVA)
ITT LOCF analysis
UVA methoxsalen (n30)
UVA placebo (n10)
Sivanesan SP, et al. J Am Acad Dermatol.
200961(5)793-8.
7
Indications for systemic therapy

• Failure of adequate trial of topical therapy
• Repeated hospital admissions for topical therapy
• Extensive chronic plaque psoriasis in the elderly
  or infirm
• Generalised pustular or erythrodermic psoriasis
• Severe psoriatic arthropathy
• Rule of tens
• Body surface area affected (BSA) gt10, or
• PASI score gt10, or
• DLQI gt10

Psoriasis - General Management. Available from
http//www.bad.org.uk/site/769/Default.aspx.
Accessed 17 Feb 2010.
8
Oral systemic therapies

• Methotrexate a folic acid antagonist that
  interferes with purine synthesis and thus
  inhibits DNA synthesis and cell replication it
  also has specific T-cell suppressive activities
• Ciclosporin an immunosuppressant that inhibits
  the activation of T cells and may also exert a
  direct effect on epidermal keratinocytes
• Oral retinoids vitamin A analogues (acitretin
  is the principal licensed product in this class)
  which reduce epidermal proliferation and
  differentiation

Menter A, Griffiths CEM. Lancet. 2007 370272-84.
9
MethotrexateProposed mechanisms of action

• Immunomodulatory effects1
• Inhibition of proliferating lymphoid tissue
• Inhibition of IL-1 activity and IL-6 production
• Anti-inflammatory effects1
• Reduced neutrophil and monocyte chemotaxis
• Inhibition of leucocyte accumulation at sites of
  inflammation
• Inhibition of epidermal proliferation1
• Interference with cell kinetics via temporary
  reduction on DNA synthesis

1. Zachariae H. Methotrexate. In van de Kerkhof
P, editor. Textbook of Psoriasis, 2ed. Oxford
Blackwell Publishing 2003. 2. Methotrexate -
Compound Summary. Available at
http//pubchem.ncbi.nlm.nih.gov. Accessed 17 Feb
2010.
10
CiclosporinProposed mechanism of action
Cyclosporine - Compound Summary. Available at
http//pubchem.ncbi.nlm.nih.gov. Accessed 17 Feb
2010. de Rie MA, Bos JD. Cyclic Immunosupressive
Drugs. In van de Kerkhof P, editor. Textbook of
Psoriasis, 2ed. Oxford Blackwell Publishing
2003.
11
Methotrexate and ciclosporinPASI 75 responses at
Week 12
100
p0.0094
80
58
60
Patients ()
40
24
20
0
Methotrexate7.5-15 mg/week (n37)
Ciclosporin3-5 mg/kg/day (n31)
Flytström I, et al. Br J Dermatol 200815811621
12
Methotrexate and ciclosporinPASI 75 responses at
Week 16
100
p0.29
80
71
60
58
60
Patients ()
40
24
20
0
Methotrexate7.5-15 mg/week (n43)
Ciclosporin3-5 mg/kg/day (n42)
Heydendael VM, et al. N Engl J Med. 2003
349658-65.
13
MethotrexateLong-term treatment up to 26 years

• Majority of patients respondedwell to treatment
• No obvious relation between cumulative dose or
  duration of methotrexate therapy and frequency or
  severity of side effects
• One or more side-effects were observed in 61 of
  patients
• Therapy was discontinued in 20of patients
• Patients should be regularly monitoredin
  particular for liver and bone marrow toxicity.

100
n157
76
80
60
Patients ()
40
18
20
6
0
Good
Poor
Moderate
Treatment response
MTX dose regimen 15-20 mg/wkMean cumulative
dose 3394 mgMean treatment duration 237 weeks
Haustein UF, Rytter M. J Eur Acad Dermatol
Venereol. 200014(5)382-8.
14
MethotrexateSafety considerations
Absolute contraindications Severe infections, severe liver or kidney disorders, bone marrow dysfunction, pregnancy or breastfeeding, impaired lung function or pulmonary fibrosis, alcohol abuse, immunodeficiency, acute peptic ulcer
Important side effects Bone marrow depression, liver toxicity, pneumonia, and alveolitis
Important drug interactions Trimethoprim, probenecid, retinoids, NSAIDs
Special considerations Dosage only once weekly overdose may lead to leucopenia/pancytopenia and thus be life-threatening

• "Its clinical application is restricted by severe
  adverse drug reactions .... However, with
  precise patient selection, thorough patient
  information, strict monitoring, use of the lowest
  effective dose, and the additional administration
  of folic acid, an acceptable safety profile can
  also be attained for methotrexate therapy."

Pathirana D, et al. J Eur Acad Dermatol Venereol.
200923 Suppl 21-70.
15
CiclosporinIntermittent therapy in patients
non-responsive to topicals
Cumulative remission ratesfor each treatment
period
Ciclosporin courses required during the study
1.0
400
400
0.8
300
259
0.6
Patients
Cumulative remission rate
200
0.4
117
100
0.2
26
0
0
2
1
3
4
0
14
28
42
56
70
84
98
112
126
140
Patients ()
Time (days)
Ho VC, et al. The PISCES Study Group. Br J
Dermatol. 1999141(2)283-91.
16
CiclosporinIntermittent therapy in patients
non-responsiveto topicals time to relapse
Abrupt
Taper
Proportion of patients who have not relapsed.
Ho VC, et al. The PISCES Study Group. Br J
Dermatol. 1999141(2)283-91.
17
CiclosporinSafety considerations
Absolute contraindications Impaired renal function uncontrolled hypertension uncontrolled infections malignant disease (current or previous, in particular haematologic diseasesor cutaneous malignancies, with the exception of basal cell carcinoma)
Important side effects Renal failure, hypertension, liver failure, nausea, anorexia, vomiting, diarrhoea, hypertrichosis, gingival hyperplasia, tremor, malaise, paresthesias
Important drug interactions Many different interactions the metabolism of ciclosporin is dependenton the hepatic enzyme cytochrome P450-3A4
Special issues Increased risk of lymphoproliferative disease in transplant patients.Increased risk of squamous cell carcinoma in psoriasis patients following excessive photochemotherapy

• "Ciclosporin can be considered for long-term
  therapy (up to 2 years) in individual cases, but
  patients should be monitored closely for signs of
  increasing toxicity, especially for decreases in
  renal function or the efficacy of treatment."

Pathirana D, et al. J Eur Acad Dermatol Venereol.
200923 Suppl 21-70.
18
AcitretinLong-term efficacy and safety

• Open-label study optimal dosesof acitretin
  (10-70 mg) administeredto patients with severe
  psoriasis (n63) for 12 months
• PASI reduced by 76 in patients reaching Week 52
• Side-effects were common, including cheilitis
  (78), hair loss (52) and pruritis (51)
• 14 patients withdrew due to adverse reactions

PASI scores for patientswho completed the study
30
20
15
Absolute PASI score
10
5
0
52
43
35
26
12
8
4
0
Time (weeks)
Murray HE, et al. J Am Acad Dermatol.
199124(4)598-602.