Locally acting therapies & usage patterns Dr Oriol Yélamos

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1 Department of Dermatology Hospital de la Santa Creu i Sant Pau op yr ig ht I P C N O V A R T I S P S O R I A S I S P R E C E P T O R S H I P C Locally acting therapies & usage patterns Dr Oriol Yélamos Barcelona, July 9th-10th, 2013

2 Therapeutic approach in psoriasis Topical therapies Glucocorticosteroids Vitamin D analogues Topical calcineurin inhibitors Others Phototherapy PUVA UVBnb Systemic therapies Cyclosporin Methotrexate Acitretin Biological agents LOCALLY ACTING THERAPIES AntiTNF: infliximab, etanercept, adalimumab Anti-p40: ustekinumab 18 7

3 When to use locally acting therapies? In mild to moderate psoriasis In localised psoriasis Pregnancy? Comorbidities? Patient preference FUNDAMENTAL TO DETERMINE PSORIASIS SEVERITY FUNDAMENTAL TO DISCUSS PATIENT S EXPECTATIONS 18 8

4 Definition of severity PASI 36.5 DLQI 5 How do you define mild, moderate, severe psoriasis? ig ht Rule of tens? Spanish consensus: C op yr 1. Mild psoriasis (grade I): amenable to topical treatment. 2. Moderate to severe psoriasis (grade II): requires (or has previously required) systemic treatment > Based on extension,course, arthritis, visibility, physical or psychological handicap, non-suitability to topical treatment, etc. Puig L, et al. Actas Dermosifiliogr. 2009;100:

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6 Scalp psoriasis is very troublesome 19 1

7 Ortonne JP, et al. J European Acad Dermatol Venereol 2009, 23,

8 Impact of mild psoriasis on QoL Yélamos O, Ros S, Pirla MJ, Puig L. Poster in AEDV Spanish National Congress, 2013 Skindex-29: emotional > symptomatic and functional High scores in social dysfunction Anxious +- depressive symptoms in 75% (n=15) Low self-esteem in 90% (n=18) 19 3

9 Topical therapies: overview Psoriasis prevalence in Spain: 1,4% Most of patients suffer from limited psoriasis (mild to moderate) 70% of patients treated with topical treatments only (despite its severity) Topical treatments remain a mainstay in the management of psoriasis Little attention has been paid in recent years Topical treatments considered one of the worst aspects of psoriasis Low adherence as a major concern of topical therapies Puig L, et al. Actas Dermosifiliogr. 2009;100: Schaarschmidt ML et al. J Eur Acad Dermatol Venereol. 2013;27:

10 Topical therapies Pros > Safe in mild or localised psoriasis > Widely available > No or minimal systemic effects Cons > Limited efficacy > Inconvenience of application > Time consuming BAD ADHERENCE 19 5

11 Topical therapies Corticosteroids Vitamin D3 and analogues (calcipotriol, calcitriol, tacalcitol) Calcineurin inhibitors (tacrolimus, pimecrolimus) Retinoids (tazarotene) Dithranol Keratolytics (salicylic acid, urea) Combinations + VEHICLE > Major role of the vehicle and galenics of topical treatments (can determine adherence to topical treatment!) 19 6

12 Mechanisms of action of topical steroids Uva L et al. Int J Endocrinol. 2012;2012:

13 Potency classification of corticosteroids Schoepe S, et al. Exp Dermatol ;15: According to vasoconstrictive properties 19 8

14 Topical corticosteroids (TCS) Efficacy First stage treatment using high potency or superpotent TCS 75% clearance of plaques in 4 weeks using clobetasol bid Maximal efficacy: 2-4 weeks Safety Safe if used during short periods (4w average) Long-term use induces local adverse effects Exceptionally systemic adverse events (Cushing) Carrascosa JM et al Actas Dermosifiliogr. 2009;100: Mason J et al. Br J Dermatol. 2002;146:

15 ig ht yr C op Local adverse effects of topical corticosteroids 20 0

16 Vitamin D analogues Calcipotriol, calcitriol and tacalcitol Efficacy Mechanism not completely well-understood > Normalisation of keratinocyte growth Calcipotriol > calcitriol and tacalcitol Similar efficacy as TCS after 8 weeks of application Safety Lesional and perilesional irritation (especially face and folds) Possible hypercalcemia and hypercalciuria > Avoid using calcipotriol >100g weekly Ashcroft DM et al BMJ. 2000;320: Carrascosa JM et al Actas Dermosifiliogr. 2009;100:

17 TCS + vitamin D analogue Betamethasone + calcipotriol Efficacy Betamethasone 0.5 mg/g + calcipotriol 50 ug/g: Dovobet/Daivobet 2 preparations: ointment and gel Once daily application Better results than vitamin D analogues PASI50 after 1 week à enhances adherence! Safety Few adverse events Safe when used in a long-term basis Mason J et al. Br J Dermatol. 2002;146: McCormack PL, Drugs Apr 16;71(6): Kragballe K et al. Br J Dermatol. 2006;154:

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19 ADRs associated with long-term TCS use: 10 patients (4.8%) Skin atrophy: 4 patients (1.9%) In 3 patients the atrophy resolved In 1 patient it persisted (he had been applying TCS for >10 y!) Folliculitis: 3 patients (1.4%) Concomitant use of corticosteroid reduces calcipotriol irritation Vitamin D analogues reduce skin atrophy derived from TCS Calcipotriol+betamethasone is safe and well tolerated at 52w 20 4

20 Topical calcineurin inhibitors Tacrolimus and pimecrolimus Efficacy Off-label indication in psoriasis Poor effect in plaque psoriasis due to little skin penetration Restricted to facial psoriasis and inverse psoriasis Safety Local adverse events: pruritus, itching, erythema FDA warning concerning elevated risk of lymphomas Lebwohl M et al. J Am Acad Dermatol. 2004;51: Yamamoto T et al. Eur J Dermatol ;13:

21 Retinoids Tazarotene Efficacy Two formulations: 0.05% and 0.1% gel Slower response compared with TCS Good responses in nail psoriasis No differences between tazarotene and placebo Efficacy and tolerability can be enhanced by the addition of TCS Safety Up to 40% of patients experience local irritation > Pruritus, itching, erythema 10% of patients have to withdraw the treatment due to AE Fischer-Levancini C. Actas Dermosifiliogr Oct;103(8):725-8 NICE guidelines: Assessment and management of psoriasis Oct Mason AR et al. Topical treatments for chronic plaque psoriasis. Cochrane Database Syst Rev

22 NICE Cochrane review 20 7

23 Dithranol and coal tars Efficacy Antiproliferative and anti-inflammatory effects Used as thick plaques and in scalp psoriasis Can be combined with phototherapy Low evidence 83% improvement of scalp psoriasis with coal tar 50% reduction of scalp psoriasis at week 18 with dithranol Worse results than corticosteroids Safety Irritation, bad smell, stains clothes, skin and nails Carcinogenic (coal tar) Puig L et al. Actas Dermosifiliogr. 2010;101(10): Carrascosa JM et al. Actas Dermosifiliogr. 2009;100:

24 Salicylic acid Efficacy Keratolytic à increases x 2-3 penetration of TCS > mometasone, betamethasone Useful combination in body thick plaques and in scalp psoriasis Safety Avoid using >20% BSA (possible absorption) May produce local irritation Not suitable if allergy to salycilates Do not combine with UV nor vitamine D analogues Lebwohl M. Int J Dermatol. 1999;38: Endzweig-Gribetz CH et al. J Cutan Med Surg. 2002;6:

25 Uva L et al. Int J Endocrinol. 2012;2012:

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28 Coal tar shampoos, which are widely prescribed in primary care for scalp psoriasis, are no better than placebo Ranking 1. superpotent corticosteroids 2. calcipotriol combined with a highly potent corticosteroid 3. highly potent corticosteroids No significant difference in efficacy between once-daily two-compound formulation (Dovobet /Daivobet ), or as the twice daily TCS/calcipotriol formulation was found to produce the most QALYs Cost-benefit analysis twice-daily application of a potent topical corticosteroid was found to be most cost-effective 21 3

29 NICE guidelines on topical treatment of psoriasis 21 4

30 NICE guidelines on topical treatment of psoriasis 21 5

31 Colombo GL et al. Clinicoecon Outcomes Res. 2012;4:

32 Scalp psoriasis: European consensus on grading and treatment algorithm Ortonne JP, et al. J European Acad Dermatol Venereol 2009, 23,

33 Scalp psoriasis: European consensus on grading and treatment algorithm Ortonne JP, et al. J European Acad Dermatol Venereol 2009, 23,

34 Spanish Delphi Consensus on topical treatment of scalp psoriasis The galenics and vehicle of topical treatment are factors of outmost importance as regards treatment efficacy and patients adherence Lotions, shampoos and gels are preferred by dermatologists and provide better adherence There is a requirement for specific QoL evaluation instruments Topical corticosteroids are first line treatment for acute bouts of scalp psoriasis Vitamin D analogues are second line treatments with a good safety profile. Puig L et al. Actas Dermosifiliogr 2010;101:

35 Properties required by topical treatments of scalp psoriasis Adherence C Therapeutic success op yr Positive evaluation Acceptable cosmesis ig ht Efficacious Quick Safe 22 0

36 Suggested usage patterns Topical corticosteroids Application of superpotent or highly potent TCS Once daily better if superpotent If potent/highly potent TCS are used, better a twice daily pattern The most cost-effective topical treatment Use for short term initial treatment (4w) Associate with salicylic acid in hyperkeratotic/scalp lesions Betamethasone/calcipotriol Good maintenance therapy Gel formulation better tolerated and effective for all lesions One daily aplication (better adherence) 22 1

37 Spanish Delphi consensus on topical therapy Consensus was reached on the following statements: a) adherence increases the effectiveness of topical treatments in psoriasis b) to improve adherence a) to improve communication b) provide written instructions c) simplify treatment with easy-touse, pleasant products that are preferably applied only once daily c) treatment satisfaction increases adherence and tends to improve the health-related quality of life of the patient Puig L, et al. Actas Dermosifiiogr

38 Factors determining lack of adherence in topical treatment of psoriasis Lack of satisfaction with efficacy Development of (or concern about) adverse effects Complexity and inconvenience of posology Once daily is better Patient s preference for vehicle Non-greasy, clean, non-smelling, non-staining (warm climates) Lack of adequate education, written instructions, frequency of visits, time 22 3

39 Ideal topical therapy in psoriasis Feasible to apply in patients with extensive involvement Efficacy similar to that of systemics (PASI75 at least around 50% at week 12) Convenient, non-messy Infrequent application (weekly, monthly?) No adverse effects (irritation, atrophy..) NO (minimal) systemic absorption 22 4

40 Ideal topical therapy in psoriasis Convenience Cost Compliance (Adherence) 22 5

41 Phototherapy Use of light (especially UV) to treat medical conditions Commonly given twice or three times weekly Courses last several weeks: treatments Equipment required only available in certain hospitals Involves significant time and travel commitments for patients Indications No response to topical treatments Patients with extensive psoriasis Guttate psoriasis Pregnant women (UVBnb) Localised areas > palmoplantar psoriasis à topical PUVA NICE guidelines: Assessment and management of psoriasis Oct 22 6

42 22 7 op C ig ht yr

43 Phototherapy Modalities used in psoriasis Psoralen + UVA (PUVA) UVBnb Penetration in the skin depends on wavelength UVB PUVA 22 8

44 ig ht op > Keratinocytes yr Timidine dimers formation Decreases viability of > Lymphocytes C > Antigen-presenting cells chemokines and cytokines > TNFα adhesion molecules Anti-inflammatory effect 22 9

45 Photochemotherapy - PUVA Efficacy Oral PUVA: 8-methoxypsoralen 0.6mg/kg Topical PUVA: 8-MOP 0.1% cream à palmar/plantar psoriasis Had never been evaluated using PASI in a randomized, double-blind, placebo (UVA)-controlled trial PASI75 in 63% to 70% Clearance frequent % PASI improvement UVA + oxsoralen UVA + placebo Week Sivanesan et al. J Am Acad Dermatol. 2009;61: Stern RS et al. N Engl J Med Aug 16;357(7):

46 op C ig ht yr Wk

47 Photochemotherapy - PUVA Safety Acute > Sunburn, nausea, pruritus, dry skin, irregular pigmentation Cataracts à ocular photo-protection (during and 8-24h after ttx) Photo-aging Increased skin cancer risk (BCC, SCC) No increased risk of lymphoma Stern RS et al. N Engl J Med Aug 16;357(7):

48 UVB narrow band Efficacy 311nm: similar effects as PUVA but less toxicity Currently considered the photherapy option of choice in psoriasis PASI75 in 40-80% at 8w Safety Less risk of skin aging and NMSC No psoralen toxicity Safe in pregnant/breastfeeding/children Carrascosa JM et al. Actas Dermosifiliogr. 2013;104(5):

49 Summary Skin directed therapies always preferable if possible Topical treatments are the mainstay of psoriasis treatment Best topical treatments: TCS and TCS+vit D The galenics and application scheme are of outmost importance Improving adherence to ttx is fundamental to improve efficacy Phototherapy is safe and effective for moderate-to-severe psoriasis UVBnb is preferred as it has good risk-to-benefit ratio 23 4

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