Current treatment options in the management of psoriasis

Drug review Current treatment options in the management of psoriasis Eleanor Higgins MB BCh, BAO, MRCPI and Trevor Markham MD, BAO, MRCPI SPL is a common chronic condition and treatment choice primarily centres on disease severity. Our Drug review considers the therapeutic options, their properties and safety profiles, followed by sources of further information and an analysis of prescription data. is a chronic inflammatory condition that can cause significant discomfort, disfigurement and psychological distress for patients. Fewer than half of those affected by psoriasis find their treatment highly satisfactory. Although there is no cure for psoriasis, numerous topical and systemic therapies are available with comprehensive guidelines for these available on the British Association of Dermatologists (BAD) website at www.bad.org.uk. Therapeutic modalities are often selected on the basis of disease severity, patient preference, relevant co-morbidities and efficacy. For most patients, the initial treatment plan centres on disease severity and it may be useful to consider patients as having either mild-to-moderate or moderate-to-severe disease. Mildto-moderate psoriasis may often be managed by topical therapy, while more severe disease may require systemic therapy. involving the hands, feet and face may result in more functional debilitation and greater impact on quality of life and warrant more aggressive therapeutic approaches. CPD questions available for this article. See page 44 www.prescriber.co.uk Prescriber 5 June 2010 31

Treatment regimens may clear the skin but recurrences are frequent and many patients require repeat treatment. This emphasises the importance of considering the risk-benefit profiles of proposed therapies. SPL Topical therapy Topical corticosteroid therapy can be of benefit in the treatment of psoriasis in certain sites such as the scalp, palms and soles. Corticosteroids range in potency from very mild 1 per cent hydrocortisone to very potent clobetasol propionate. Their use has been limited by adverse effects, which include skin atrophy, striae, purpura, skin fragility, telangiectasia and tachyphylaxis. Nevertheless topical corticosteroids are very useful for the treatment of psoriasis of the scalp, palms and soles (see Figure 1) where the thicker skin is more resistant to these adverse effects. Tar has been used in the treatment of psoriasis for many years, usually combined with UV phototherapy. In 1925, Goeckerman introduced daily crude coal tar with UVB phototherapy for generalised psoriasis and this treatment was widely used. 1 Bed shortages and lack of cosmetic appeal have limited patients use of tar-containing agents. Dithranol is another topical therapy with a long history in psoriasis. The standard dithranol regimen is to apply increasing concentrations (0.05-2 per cent) on a daily basis. This therapy is particularly useful for chronic plaque psoriasis (see Figure 2) but is not recommended for acute forms of the disease. 2 Dithranol is also used in combination with UV photo therapy to improve efficacy and limit side-effects. Topical vitamin D analogues are effective in psoriasis. In a six-week multicentre trial, calcipotriol was more effective than the topical corticosteroid fluocinonide (Metosyn) in plaque psoriasis. 3 Calcitriol (Silkis) 4 and tacalcitol (Curatoderm) 5 have also been shown to be effective in psoriasis, with calcitriol thought to be less irritant on the face and intertriginous sites. These agents can cause local irritation and excessive use can lead to hypercalcaemia. 6 This has led to the use of combinations of vitamin D analogues with other topical therapies, UV phototherapy and systemic therapies. Topical retinoids are another treatment option for mild-to-moderate psoriasis. 7 Figure 1. The use of topical steroids is limited by adverse effects; however, they are useful in treating areas of the body where the skin is thicker, such as the palms Phototherapy Broadband UVB has been used since the early 20th century, but the spectrum of light that is most effective for clearing psoriasis is in the narrow range around 311nm (see Figure 3). Bulbs that have an output in this range have been developed and are used in narrowband UVB (nuvb) therapy. nuvb therapy (311-313nm) is more effective than conventional broadband UVB with respect to clearing times and remission. 8 Treatment schedules are similar for both, with nuvb administered three times per week. This form of phototherapy is less erythemogenic than broadband UVB and has mainly replaced it as firstline phototherapy for psoriasis. The efficacy of nuvb compared to photochemotherapy (PUVA) has also been demonstrated. 9 In comparison to PUVA, nuvb-treated patients do not have to take tablets or wear protective eyewear. It can also be used during pregnancy and in children. Long-term safety data are awaited but nuvb is thought to be less carcinogenic than PUVA. 10 Remission is variable and patients may require repeat courses. This becomes particularly relevant when one considers the risk of nonmelanoma skin cancers associated with prolonged PUVA therapy. 11 As a result of this concern PUVA therapy is often combined with other treatments such as retinoids and vitamin D analogues to reduce the number of exposures required for clearance. A laser that emits at a wavelength of 308nm is a new therapeutic modality that has been found to be safe and effective in psoriasis in a multicentre study. 12 Compared to conventional phototherapy it has the advantage of targeting only affected skin and thus reduces the risks to uninvolved skin. www.prescriber.co.uk Prescriber 5 June 2010 33

SPL Systemic therapy Antimetabolites Methotrexate is an antimetabolite agent that has been used for many years in psoriasis treatment and remains one of the most effective therapies. 13 Methotrexate is indicated for recalcitrant disease unresponsive to topical or phototherapy and is particularly useful if the patient has an associated arthropathy. It is usually given orally once a week and folic acid supplements can be given to reduce nausea associated with this agent. Contraindications include liver abnormalities, poor renal function, anaemia, thrombocytopenia, gastritis, active infection and high alcohol intake. 14 Long-term use of methotrexate is associated with liver toxicity so regular liver function tests are required and also regular full blood counts to monitor marrow toxicity. Oral retinoids Oral retinoids are potent antipsoriatic drugs for pustular and erythrodermic psoriasis but are less effective in chronic plaque psoriasis. 16 Acitretin is given in a dose of 0.3-0.6mg per kg per day, once or twice daily with meals, for 6-12 weeks. Combination therapy with PUVA and UVB allows dose reduction and decreases the incidence of adverse effects. These may include mucocutaneous dryness, alopecia, elevated serum lipids and liver function tests, hyperostosis and teratogenicity. As a result the package insert recommends that acitretin should not be given Figure 2. Dithranol is particularly useful in the treatment of chronic plaque psoriasis and can be used in combination with UV phototherapy to improve outcomes and limit side-effects to women of child-bearing potential who may become pregnant within three years. Despite these adverse effects acitretin is a safe treatment for psoriasis. Immunosuppressors Ciclosporin was developed as an immunosuppressive transplantation drug in the early 1970s. Its efficacy in psoriasis was first described in 1979. 17 The longterm risks of therapy include nephrotoxicity 18 and hypertension. However, ciclosporin is excellent for short-term use due to its weak myelosuppressive effect in comparison to methotrexate. Hypertension can be treated with calcium-channel blockers and this has been shown to prevent loss of renal function. 19 Other immunosuppressive agents have been tried in psoriasis with mixed results, either due to lack of efficacy or the development of adverse effects. Hydroxycarbamide is an effective therapy for chronic plaque psoriasis whose main adverse effect is bone marrow toxicity (unlicensed indication). 20 Mycophenolate mofetil is a immunosuppressive transplantation agent that is safe and effective for severe psoriasis using a dose of 2g per day (unlicensed indication). 21 Fumaric acid derivatives (unlicensed indication) are widely used for psoriasis in some European countries. Four months treatment with fumaric acid derivatives in one trial resulted in efficacy in 80 per cent of patients, although adverse effects such as GI upset, flushing and lymphocytopenia occurred in 67 per cent of patients. 22 Biologics The failure of patients to respond to or to tolerate the above treatment modalities has led to the search for better therapies and recently so-called biological therapies have been developed. Biologic therapies are immunomodulators that target specific molecular steps in the pathogenesis of psoriasis, interfering with T-cell function and cytokine activity. Tumour necrosis factor (TNF) is a proinflammatory cytokine that plays a central role in the pathogenesis of psoriasis, psoriatic arthritis and other inflammatory diseases. There are three approved agents that target TNF: anti-tnf alpha monoclonal antibodies adalimumab (Humira) and infliximab (Remicade) and a soluble TNF-alpha receptor fusion protein, etanercept (Enbrel). To be considered eligible to receive a biologic agent under BAD guidelines, patients should have severe psoriasis, defined by a PASI (psoriasis area and severity index score) of 10 or more, have severe, 34 Prescriber 5 June 2010 www.prescriber.co.uk

SPL Figure 3. Narrowband UVB is first-line phototherapy for the treatment of psoriasis and is more effective than broadband UVB and comparable to PUVA with respect to clearance times and remission unstable or life-threatening disease and be ineligible for phototherapy or standard systemic therapy because of contraindications, intolerance or unresponsiveness to treatment. 23 Adalimumab is a fully humanised IgG1 monoclonal antibody for used in moderate-to-severe psoriasis. It has shown to be highly effective in three large randomised controlled trials (RCTs). 24 Onset is rapid after 12 weeks in one trial, 53 per cent of patients on adalimumab 40mg every two weeks and 80 per cent on 40mg weekly achieved a 75 per cent reduction in PASI (PASI 75) score. 25 The National Institute for Health and Clinical Excellence (NICE) has approved the use of adalimumab (40mg every two weeks) in severe plaque psoriasis, with continued therapy subject to adequate response at 16 weeks. 26 Infliximab is a chimeric monoclonal anti-tnf antibody and is also highly effective in the treatment of chronic plaque psoriasis. 24 Infliximab has a rapid onset of action, with 79 per cent of patients achieving a PASI 75 by week 10, with a sustained response in a high percentage of patients at one year. Loss of efficacy correlates with development of antibodies, which occurs in 19 per cent of patients treated with infliximab. 27 NICE recommends infliximab to be commenced at initially 5mg per kg² at weeks 0, 2 and 6 and then every eight weeks. Treatment beyond 10 weeks is only recommended in patients who achieve certain response criteria. Etanercept, a TNF-alpha receptor fusion protein, has been shown to be effective in the treatment of chronic plaque psoriasis in three large RCTs. 28 Onset of action appears to be slower than with the monoclonal antibodies. Action appears dose related and overall 34 per cent of patients receiving 25mg etanercept twice weekly achieved PASI 75 after 12 weeks, compared with 49 per cent of patients on 50mg twice weekly. 29 Recent BAD guidelines recommend that etanercept be commenced at 50mg weekly or 25mg twice weekly with disease response to be assessed at three to four months. In patients who respond, therapy may be continued according to clinical need, but longterm data on efficacy are limited to two years. 29 Some smaller studies suggest that its efficacy may be improved by the addition of methotrexate 30 or acitretin. Ustekinumab (Stelara) is a fully human IgG1 K mono clonal antibody that targets the p40 subunit of interleukins IL-12 and IL-23. These cytokines play a role in regulation of immune response and T-cell activation in psoriasis. Ustekinumab is licensed for use in patients with moderate-to-severe psoriasis at 45mg (or 90mg if >100kg) at weeks 0 and 4 and then 12 weekly thereafter. It has shown to be highly effective in the treatment of chronic plaque psoriasis, both at 45mg and 90mg, and its onset of action is evident within two weeks. By 12 weeks, 67 per cent of patients receiving a dose of 45mg and 72 per cent of those receiving 90mg achieved PASI 75. Maximal efficacy is evident between weeks 20 and 24. Factors predictive of a poorer response include higher body weight, previous poor response to at least one biologic agent, longer duration of psoriasis and a history of psoriatic arthritis. 31 NICE has approved the use of ustekinumab in patients with severe plaque psoriasis, with treatment to be continued beyond 16 weeks only in those who respond. 32 In the light of limited patient exposure, 36 Prescriber 5 June 2010 www.prescriber.co.uk

ustekinumab should be reserved for use in patients with severe psoriasis and where TNF antagonist therapy has failed or is contraindicated. 30 Potential adverse effects of TNF antagonist therapy include infections, reactivation of tuberculosis, development of demyelinating disease and worsening of cardiac failure. The BAD Biologic Interventions Registry (BAD-BIR) has been established in the UK to collect long-term safety data. This registry aims to follow up all patients on biologic therapy for five years, together with 4000 control subjects on conventional second-line drugs for psoriasis. 23 Etanercept or adalimumab are appropriate for patients with stable chronic plaque psoriasis, based on favourable risk/benefit profile and ease of administration. Where rapid disease control is required, adalimumab or infliximab may be more suitable due to early onset of action and a high chance of achieving a significant improvement in PASI 75 by three months. 33 Treatment decisions around biologics are complex and patients who have failed treatment with one or more biologic may respond to another. 34 Conclusion is a common chronic condition and has been shown to significantly influence a patient s quality of life. Topical treatments remain the mainstay of therapy in psoriasis, with 70-80 per cent of all patients with psoriasis responding adequately to topical treatments. Vitamin D 3 analogues such calcipotriol and in combination with a corticosteroid are increasingly preferred as first-line topical therapy by patients for convenience and ease of use. Newer systemic agents such as fumaric ester derivatives with less adverse effects and improved patient tolerability are being used successfully. Recent advances in our understanding of its pathophysiology have led to the emergence of biologic agents that specifically target key mechanisms in the pathogenesis of psoriasis. These biologics have led to dramatic clinical responses in patients with psoriasis, and some appear to be more efficacious than older systemic therapies. However, their exact role in the management of psoriasis remains to be fully established, especially as long-term safety data are awaited on the newer biologic agents. References 1. Thami GP, et al. Clin Exp Dermatol 2002;27(2):99-103. 2. Mahrle G. Clin Dermatol 1997;15(5):723-37. 3. Bruce S, et al. J Am Acad Dermatol 1994;31:755-9. 4. Langner A, et al. Br J Dermatol 1996;135:385-9. 38 Prescriber 5 June 2010 www.prescriber.co.uk

possible psoriasis exclude other disorders eczema, lichen planus, pityriasis rosea, tinea corporis, mycosis fungoides, cutaneous lupus erythematosus and assess degree of psychosocial disability due to psoriasis localised or mild-to-moderate psoriasis (10-15% BSA) trunk and limbs face, flexures and genitalia scalp emollients vitamin D analogue retinoid coal-tar preparation corticosteroid ointment/ cream dithranol incremental strength, short contact emollients mild-to-moderate potency topical corticosteroid vitamin D cream may be used with caution to the hairline and in flexures mild: tar shampoo moderate: corticosteroid or calcipotriol scalp lotion or gel severe: coal tar/salicylic acid/coconut oil ointment if above measures fail, refer for dermatological opinion widespread or moderate-tosevere psoriasis (15-20% BSA) 1st line topical treatment as above +/- dermatological referral 2nd line nuvb/puva methotrexate ciclosporin acitretin hydroxycarbamide mycophenolate mofetil fumaric acid esters 3rd line etanercept infliximab ustekinumab adalimumab Figure 4. Recommended management of psoriasis (BSA = body surface area) 40 Prescriber 5 June 2010 www.prescriber.co.uk

Key points topical treatments (emollients, tar, dithranol, steroids, vitamin D analogues) remain the mainstay of treatment preparations combining various topical agents are now available narrowband UVB is the first-line phototherapy for psoriasis first-line systemic agents for psoriasis include methotrexate and most recently fumaric acid esters, which are being increasingly used; ciclosporin remains an excellent therapeutic option for short-term control of psoriasis where rapid disease response is required newer biologic agents have been shown to be effective in psoriasis but long-term safety data are awaited 5. Lambert J, et al. Dermatology 2002;204:321-4. 6. Georgiou S, et al. Acta Derm Venereol 1999;79:86. 7. Lebwohl MG, et al. J Am Acad Dermatol 1998;39:590-6. 8. Green C, et al. Br J Dermatol 1988;119:691-6. 9. Markham T, et al. Arch Dermatol 2003;139:325-8. 10. Ferguson J. Arch Dermatol 1999;135:589-90. 11. Stern RS, et al. J Invest Dermatol 1988;91:120-4. 12. Feldman SR, et al. J Am Acad Dermatol 2002;46(6):900-6. Resources Further reading. Griffiths CEM, et al. In: Burns T, et al, eds. Rook s textbook of dermatology, 8th ed. Oxford: Wiley- Blackwell, 2010;1589-649. Guidelines Adalimumab for the treatment of adults with psoriasis. TA146. NICE, June 2008. Etanercept and efalizumab for the treatment of adults with psoriasis. TA103. NICE, July 2006. Infliximab for the treatment of adults with psoriasis. TA134. NICE, January 2008. general management. British Association of Dermatologists, 2008. www.bad.org.uk/site/769/ Default.aspx. management. NHS Clinical Knowledge Summaries. www.cks.nhs.uk/psoriasis. Ustekinumab for the treatment of adults with moderate to severe psoriasis. TA180. NICE, September 2009. 13. Roenigk HH Jr, et al. J Am Acad Dermatol 1998;38(3):478-85. 14. Zachariae H, et al. Dermatologica 1987;175(4):178-82. 16. Roenigk HH Jr. J Am Acad Dermatol 1999;41:S18-21. 17. Muller W, et al. Dtsch Med Wochenschr 1979;104(29):1047. 18. Lowe NJ, et al. J Am Acad Dermatol 1996;35:710-9. 19. Raman GV, et al. J Hypertens Suppl 1998;16:S39-41. 20. Smith CH. Clin Exp Dermatol 1999;24:2-6. 21. Geilen CC, et al. Br J Dermatol 2001;144:583-6. 22. Altmeyer PJ, et al. J Am Acad Dermatol 1994;30(6):977-81. 23. Smith CH, et al. Br J Dermatol 2009;161:987-1019. 24. Gorden KB, et al. J Am Acad Dermatol 2006;55:598-606. 25. Menter A, et al. J Am Acad Dermatol 2008;38:106-15. 26. Saurat JH, et al. Br J Dermatol 2008:158:556-66. 27. NICE. Infliximab for the treatment of adults with psoriasis. TA134. January 2008. 28. Gottlieb AB, et al. J Am Acad Dermatol 2004:534-42. 29. Reich K, et al. Lancet 2005;366:1367-74 30. Leonardi CL, et al. N Engl J Med 2003;349:2014-22. 31. Papp KA, et al. Br J Dermatol 2005;152:1304-12. 32. Tyring S, et al. Lancet 2006;367:29-35. 33. Zachariae C, et al. Acta Derm Venereol 2008;88:495-501. 34. Krueger GG. N Engl J Med 2997;35:580-92. Dr Higgins is a dermatology registrar and Dr Markham is consultant dermatologist at University Hospital, Galway, Ireland Groups and organisations British Association of Dermatologists. Tel: 0207 383 0266; e-mail: admin@bad.org.uk; website: www. bad.org.uk. Association. Tel: 0845 676 0076; e-mail: mail@psoriasis-association.org.uk; website: www. psoriasis-association.org.uk. and Psoriatic Arthritis Alliance (PAPAA). Tel: 0870 770 3212; e-mail: info@papaa.org; website: www.paalliance.org. Websites www.psoriasis.org. This site is provided by the National Foundation and gives information about psoriasis in general and also current research into psoriasis and treatments. www.psoriasis-help.org.uk. The Help Organisation site contains information about treatments, and also provides a discussion forum for psoriasis sufferers to exchange views and advice on living with psoriasis. www.prescriber.co.uk Prescriber 5 June 2010 41

Prescription review GPs in England wrote 1.2 million prescriptions for psoriasis treatments in 2009 at a total cost of approximately 39 million. Calcipotriol products accounted for 74 per cent of volume and 89 per cent of spending ( 35 million). Prescribing of calcipotriol has been increasing steadily over the past 10 years: in 2009 it was 69 per cent greater than in 2000 whereas costs increased by a factor of 2.7 over the same period, with a slight increase in the rate of cost growth after 2006. By contrast, prescribing and spending on other agents has changed little. Coal tar products are the most frequently prescribed in this group but their use has declined by about 13 per cent in the last five years. Trends for Cocois have been similar. Only 83 000 scrips were dispensed in 2009 for other preparations for psoriasis, such as retinoids, salicylic acid and other vitamin D derivatives, at a total cost of 1.8 million. Items (thousands) 250 calcipotriol coal tar Cocois others 200 150 100 50 0 2004 2005 2006 2007 2008 2009 Year, by quarter Figure 5. Number of prescriptions for psoriasis treatments in England by quarter, 2004-2009 NIC ( millions) 10 calcipotriol coal tar Cocois others 8 6 4 2 0 2004 2005 2006 2007 2008 2009 Year, by quarter Figure 6. Cost of prescriptions for psoriasis treatments in England by quarter, 2004-2009 www.prescriber.co.uk Prescriber 5 June 2010 43

CPD: management Answer these questions online at Prescriber.co.uk and receive a certificate of completion for your CPD portfolio. Utilise the Learning into Practice form to record how your learning has contributed to your professional development. 1. One of these statements about the treatment of psoriasis is false which is it? a. Treatment is often selected on the basis of disease severity, patient preference, relevant co-morbidities and efficacy b. Mild-to-moderate psoriasis is often managed by topical therapy c. More than half of patients find their treatment highly satisfactory d. affecting the hands, feet and face warrants more aggressive treatment 2. Which of these statements about topical therapy is false? a. The adverse effects of topical steroids on skin thickness are less of a concern on areas such as the scalp, palms and soles b. The standard dithranol regimen is to apply progressively reducing concentrations, from 2 per cent to 0.5 per cent, on a daily basis c. Topical steroids may be associated with tachyphylaxis d. Dithranol is not recommended for the treatment of acute psoriasis 3. Which of these statements about topical vitamin D analogues is false? a. They may cause hypercalcaemia b. Calcipotriol has been shown to be more effective than topical fluocinonide in the treatment of plaque psoriasis c. Calcitriol is thought to be less irritant than tacalcitol when applied to the face d. Vitamin D analogues should not be combined with photo - therapy 4. One of these statements about narrowband UVB (nuvb) is false which is it? a. It is the phototherapy of choice for psoriasis b. The spectrum of nuvb is 350nm c. Patients do not have to wear eye protection during treatment d. It can be used during pregnancy 6. Regarding the treatment of psoriasis with methotrexate, which one of these statements is false? a. It must be given by iv infusion b. It is indicated for recalcitrant disease unresponsive to topical or phototherapy c. Folic acid supplementation reduces nausea d. Regular liver function tests are required during treatment 7. Regarding the treatment of psoriasis with oral retinoids, which one of these statements is false? a. They are more effective for chronic plaque psoriasis than pustular or erythrodermic psoriasis b. Combination with PUVA or UVB allows dose reduction to reduce the incidence of adverse effects c. They are teratogenic d. They may cause mucocutaneous dryness and alopecia 8. Regarding the treatment of psoriasis with immuno - suppressants, which one of these statements is false? a. Loss of renal function associated with ciclosporin can be prevented by treatment with a calcium-channel blocker b. Ciclosporin is an inappropriate choice for short-term control because its onset of action is too slow c. Mycophenolate mofetil is not licensed for the treatment of severe psoriasis d. Fumaric acid derivatives may cause flushing 9. Which one of these statements about treating psoriasis with biological agents is false? a. Adalimumab, infliximab and etanercept target tumour necrosis factor b. Ustekinumab is a monoclonal antibody that targets IL-12 and IL-23 c. Etanercept acts more quickly than infliximab and adalimumab d. Treatment with biological agents should be continued only when an adequate response has been demonstrated after a period of 10-16 weeks (depending on the agent) 5. One of these statements about phototherapy is false which is it? a. Prolonged PUVA therapy is associated with an increased risk of nonmelanoma skin cancer b. nuvb is administered three times a week c. Laser with a wavelength of 308nm can be targeted at affected skin, reducing the risk to uninvolved skin d. Most patients achieve remission after treatment with nuvb so one course of treatment is usually sufficient 10. One of these statements about biological agents in the treatment of psoriasis is false which is it? a. A history of psoriatic arthritis predicts a poorer response to ustekinumab b. Anti-TNF agents may reactivate latent tuberculosis c. Patients who do not respond to one biological agent will rarely benefit from a second d. 19 per cent of patients develop antibodies to infliximab during treatment and this impairs its efficacy 44 Prescriber 5 June 2010 www.prescriber.co.uk