: a new option in paediatric plaque psoriasis Steve Chaplin MSc, MRPharmS, Medical Writer, Dr David Atherton MA, MB, BChir, FRCP, Honorary Consultant in Paediatric Dermatology, Great Ormond Street Hospital for Children SCIENCE PHOTO LIBRARY Psoriasis in children and adolescents can be disfiguring and adversely affect quality of life. A range of treatments are available that can control the condition, but not all patients respond or are able to tolerate the treatments. The anti-tnf alpha inhibitors are used effectively in adult psoriasis but are not currently licensed for use in children. The anti-tnf etanercept (Enbrel) has been studied in childhood psoriasis and is likely to gain a licence in the near future. In this article, the authors discuss current treatment approaches in childhood psoriasis and describe the efficacy, tolerability and potential place of etanercept in practice. The age of onset of psoriasis is below 16 years in one-third of cases in females and one-quarter of cases in males (Figure 1). 1 Case series of children with psoriasis from different ethnic groups report mean or median ages of onset of 7 years. 2 4 Based on a 5% sample of the primary care population in the UK, the prevalence of psoriasis in children was.55% in the under-s and 1.37% in 19-year-olds in 1987 2. 5 Although this is well below the levels reported in adults, these figures suggest that children under years old in the UK have psoriasis. 5 Coloured scanning electron micrograph of psoriasis skin cells (x magnification) Psoriasis in children has a marked effect on quality of life, comparable in magnitude with asthma or epilepsy. 6 Assessing quality of life by the Children s Dermatology Life Quality Index, the impact of psoriasis is greater than that of any other chronic skin disorder and similar to that of generalised eczema. 6 Children can suffer more from the psychosocial than the physical consequences of psoriasis. 7 Clinical experience shows that the impact of psoriasis on quality of life is less in younger children than in adolescents, who may be severely affected by the responses of their peers to lesions in highly visible areas such as the scalp and face. Further, participation in sports and social activities may be limited by arthropathy and, when areas of the body are exposed as in swimming, the appearance of lesions. There is little scientific evidence of the impact of childhood psoriasis on parents and carers. The safe administration of treatment for younger children requires adult involvement: topical therapies may be time-consuming to apply and hospital visits for UVB therapy may require time off school and work. The family should therefore be well informed about the nature of psoriasis and its management, and supported when making treatment choices. 6 FUTURE PRESCRIBER VOL 9(3) www.futureprescriber.co.uk
CURRENT MANAGEMENT Treatment options for children with psoriasis are the same as for adults (Table 1), though the range of licensed therapies is smaller. Management should include supportive care and address quality of life issues such as psychosocial ostracism. 7,8 Treatment should be tailored to reflect the patient s age and the extent, severity and location of the condition. Choice of treatment must take into account the needs and preferences of children and their parents/carers, bearing in mind the practicality of administration and the risk of toxicity. 7 Moisturisers and emollients are useful for inflammatory lesions and stable plaque psoriasis. 9 In general, topical treatment is appropriate for psoriasis of limited extent, whereas widespread disease requires referral for systemic treatment. For older children and adolescents, the cosmetic impact of topical treatments is an important consideration. 8 Topical treatments that are odourless and do not stain, such as calcipotriol, are easier and quicker to apply and likely to be associated with better compliance than coal tar and its derivatives. Some formulations are not licensed for all ages and doses vary with age. In the case of calcipotriol, the scalp solution is not licensed for children of any age whereas the ointment and cream are licensed for children over six years old. There are also differences in dosage: the maximum dose of the cream or ointment is limited to g/week in children aged 6 12 and 75g/week in the over 12s. Calcipotriol may cause irritation; this can be treated by concurrent use of a topical steroid, which also enhances effectiveness. 7 No. of patients Cumulative female Cumulative male 11 15 16 21 31 41 Age Figure 1. Cumulative age at onset of psoriasis in a sample of 7 patients attending a USA psoriasis research clinic 1 Topical steroids alone are appropriate for psoriasis affecting specific sites; a mild preparation is indicated for the face and flexures, and a potent preparation for the scalp, palms and soles. 9 Topical steroids suppress the disease but rebound may occur when treatment is stopped. Coal tar and dithranol stain skin and clothing. Coal tar products have a stronger odour but are less irritant to healthy skin; they are indicated for multiple small lesions and for use on the face or genitals. Dithranol is irritant to healthy skin and is best used to treat large, thick plaques; it is not appropriate for application to flexures or the face. Proprietary preparations are preferred for use at home and parents/carers may benefit from a demonstration of application technique. 7,9 Topical tacrolimus is not licensed for the treatment of psoriasis, but some evidence suggests it is useful for lesions on areas of thin skin such as the face and intertriginous zones. 11 Patients with more severe psoriasis or disease unresponsive to 51 61 71 81 91 topical preparations should be referred to a specialist for treatment with systemic therapies. Psoriatic arthropathy is not uncommon in children but may go unrecognised unless the child with psoriasis is appropriately questioned and examined. When mild, its treatment requires orally administered nonsteroidal antiinflammatory agents such as naproxen, and when more severe, more powerful systemic agents including methotrexate and/or biologics, under rheumatological supervision. UVB phototherapy is indicated for severe widespread plaque or guttate psoriasis, but its role is limited by the concern that repeated use may be associated with carcinogenicity and premature ageing of the skin in the long term. 7,9 PUVA is rarely used in children. 7 There is little formal evidence of the use of oral systemic treatments in children. 8 The retinoid acitretin is moderately effective, and worthy of a trial in children with extensive psoriasis. It is however highly teratogenic, and www.futureprescriber.co.uk FUTURE PRESCRIBER VOL 9(3) 7
Treatments Indication Common adverse effects Topical Calcipotriol Limited plaque psoriasis Local irritation Topical corticosteroids Limited plaque psoriasis Cutaneous atrophy Adrenal axis suppression (rare) Combination topical Limited plaque psoriasis Irritation, cutaneous atrophy calcipotriol/steroid Guttate psoriasis Tar Plaque psoriasis Cosmetically unattractive Guttate psoriasis Dithranol Large plaque psoriasis Staining of skin and clothes Phototherapy Ultraviolet B Guttate psoriasis Carcinogenicity Widespread plaque psoriasis Systemic Acitretin Severe psoriasis: plaque, Dry lips, hyperlipidaemia, erythrodermic, pustular skeletal changes, teratogenicity Methotrexate Severe psoriasis Myelosuppression, hepatic fibrosis Psoriatic arthritis Ciclosporin Severe psoriasis Renal impairment, hypertension Biologic Severe plaque psoriasis Injection-site reactions, infections (currently unlicensed in children) Table 1. Summary of treatment options for psoriasis in children 8 this needs to be addressed in girls of reproductive age. 9 Concern about the risk of hypertension and nephrotoxicity limit the value of ciclosporin in children, 8 and in practice it is very rarely used. Methotrexate can be of value in the treatment of severe and widespread psoriasis in children, particularly when arthropathy is present. It is most often given as a once weekly oral dose of.2.4mg/kg (up to mg). In the event of this causing nausea or vomiting, arrangements can be made to give the same dose by subcutaneous injection each week, locally. It is considered wise to give a lower initial dose, say.2mg/kg, and then to increase this in steps to the higher dose levels if necessary. Dosage can be a little awkward because no liquid preparation is readily available, and the smallest available tablet is 2.5mg. Precautions for safe prescribing of methotrexate include education for the patient and parent/carer, including warning of symptoms that might indicate myelosuppression, hepatotoxicity and respiratory disorders. 9 Recently, there has been growing interest in the therapeutic potential of biologics for psoriasis in adults and, more recently, in children. These are selective immunomodulatory drugs that comprise biologically generated fusion proteins and chimeric, humanised and fully humanised monoclonal antibodies which target pro-inflammatory cytokines. While a number of these agents have been used in the treatment of individual paediatric patients with psoriasis on an open-label basis, etanercept, which inhibits binding of tumour necrosis factor (TNF) to its receptor, will be the first biological agent to be approved for such use. There are many new biologics in current development and these may offer even greater efficacy in the longer term. ETANERCEPT The activity of TNF is increased in psoriatic plaques and it activates T-lymphocytes, enhances T-cell infiltration and augments keratinocyte proliferation. 12 is effective in the treatment of moderate to severe plaque psoriasis in adults 13 15 and it is recommended by NICE for the treatment of severe refractory plaque psoriasis in adults. 16 KEY EFFICACY DATA The efficacy and safety of etanercept has now been evaluated in 211 children and adolescents (age 4 17, median 13) with moderate-to-severe plaque psoriasis following or during phototherapy or systemic treatment (methotrexate, ciclosporin, retinoids) or poorly controlled by topical therapy. 17 The trial involved three 8 FUTURE PRESCRIBER VOL 9(3) www.futureprescriber.co.uk
phases: a 12-week double-blinded treatment period followed by a 24-week non-blinded phase in which all patients were treated, then a 12-week randomised double-blind treatment withdrawal phase. was administered at a dose of.8mg/kg up to a maximum of mg once weekly by subcutaneous injection. Low-tomoderate potency topical steroids were permitted for treating the scalp, axillae and groin. The minimum severity of psoriasis was defined by a Psoriasis Area and Severity Index (PASI) score of at least 12 (baseline median 16 17), physician s global ratings and involvement of at least % of the body surface area (baseline median %). The median duration of psoriasis was approximately six years, and approximately % of children had previously received phototherapy or systemic therapy. The primary endpoint was the proportion of patients in whom the PASI score improved by 75% (PASI 75) at week 12. was significantly more effective than placebo (PASI 75, 57 versus 11%), with a significant difference emerging after four weeks (Figure 2). There were corresponding improvements in secondary endpoints including PASI and ; physician s global assessments of the proportion of patients clear or almost clear of plaques (Figure 3) showed substantial improvement by week 12 (53 versus 13% of children). At the end of the non-blinded phase (week 36), PASI 75 rates were 65% in children who initially received placebo and 68% in those originally assigned to etanercept. The proportions of children Patients (%) Figure 2. PASI responses after 12 weeks treatment with etanercept in children and adolescents with moderate-to-severe plaque psoriasis. Copyright 8 Massachusetts Medical Society. All rights reserved. 17 Patients (%) Placebo PASI PASI 75 PASI PASI PASI 75 PASI Figure 3. Physician s global assessments after 12 weeks' treatment with etanercept in children and adolescents with moderate-to-severe plaque psoriasis: proportion of patients with scores of clear or almost clear. Copyright 8 Massachusetts Medical Society. All rights reserved. 17 assessed as clear or almost clear of lesions were 59 and 63%, respectively. Of the 138 children who entered the withdrawal phase, 94% had a PASI 75 response. Of those who then took placebo, 42% lost their response and were retreated. By week 48, the overall PASI 75 response in children currently treated with etanercept was %. improved quality of life scores significantly more than placebo (52 versus 18%, respectively). p<.1 71 2 4 1 6 8 2 12 Week Placebo 2 4 47 p<.1 11 p<.5 3 9 16 p<.5 4 2 4 6 Week p<.1 5 44 19 p<.1 39 8 13 p<.5 p<.1 75 p<.1 57 p<.1 27 23 11 7 p<.1 53 KEY SAFETY DATA The rates of injection-site reactions were 38 per patient-years with etanercept and 27 per patientyears with placebo. There were no significant differences in the incidence of infections (229 per patient-years with etanercept versus 8 per patient-years with placebo) or non-infectious (288 versus 431 per patient-years) adverse events. There were serious adverse events (seven in patients treated with etanercept and three with placebo). All adverse 13 8 12 www.futureprescriber.co.uk FUTURE PRESCRIBER VOL 9(3) 9
events resolved without complications and there were no opportunistic infections, cancers or deaths. There were no cases of rebound or morphological change of psoriasis after withdrawal of etanercept; one patient discontinued treatment during the nonblinded phase after psoriasis worsened. IMPLICATIONS FOR PRACTICE This trial showed that treatment with etanercept improves plaque psoriasis in most children and, over 48 weeks at least, is well tolerated. These children had moderate-to-severe disease of several years duration but children with guttate, erythrodermic or pustular psoriasis were excluded. Plaque psoriasis is the most common form of psoriasis in childhood, with reported rates of 34 % in different studies. 8 Although erythrodermic and pustular psoriasis are rare in children, reported rates of guttate psoriasis range from 6 44%. 8 Further studies are therefore needed to evaluate etanercept in these types of childhood psoriasis. is likely to offer a further treatment option for plaque psoriasis when topical and systemic therapies have failed or are unsuitable. In adults with psoriasis, biological agents are recommended only when other systemic therapies (including methotrexate, ciclosporin and phototherapy) have failed or the patient is intolerant of or has contraindications to these treatments. Treatment with these agents should be initiated and supervised only by a suitably experienced specialist. 16 A similar requirement for failure of systemic therapy will probably apply to the treatment of children. As is also the case with adults, vaccination schedules will need to be updated before beginning treatment and children will need to be screened before and during treatment to identify infection. Given the lack of long-term experience, regular monitoring for adverse effects will be essential. The cost implications of treatment with etanercept have not yet been determined but will include the acquisition cost of the drug, attendance at specialist clinics and the cost of monitoring for adverse effects. While savings will accrue from a reduction in the use and monitoring of other therapies, etanercept remains expensive, in common with other biological agents, and the needs of patients in terms of repeated courses in the longer term remain unknown. Treatment with etanercept improved quality of life scores and most patients in the trial derived some benefit (the PASI response rate at 36 weeks was 86 87%), but the balance of long-term benefits and risks with etanercept compared with systemic treatments is yet to be clarified. SUMMARY Psoriasis affects many children and adolescents and has profound effects on their quality of life, with implications for lost schooling and time off work for parents and carers. Topical and systemic therapies should be tailored to individual need, bearing in mind the importance of ease of use and acceptability. is effective in children and adolescents with moderate-to-severe plaque psoriasis after topical and systemic therapies have failed, approximately doubling the odds of achieving near or total clearance of lesions compared with placebo in 12 weeks. On current evidence, etanercept is likely to be indicated when systemic therapies have failed or are unsuitable, but further studies will be helpful to establish its long-term efficacy and safety. REFERENCES 1. Chaudhuri SP, Gross J. A comparative study of pediatric onset psoriasis with adult onset psoriasis. Pediatric Dermatol ;17:174 8. 2. Fan X, Xiao FL, Yang S, et al. Childhood psoriasis: a study of 277 patients from China. J Eur Acad Dermatol Venereol 7;21:762 5. 3. Seyhan M, Coflkun BK, Sa lam H, et al. Psoriasis in childhood and adolescence: evaluation of demographic and clinical features. Pediatr Int 6;48:525. 4. Kumar B, Jain R, Sandhu K, et al. Epidemiology of childhood psoriasis: a study of 419 patients from northern India. Int J Dermatol 4;43:654 8. 5. Gelfand JM, Weinstein R, Porter SB, et al. Prevalence and treatment of psoriasis in the United Kingdom: a populationbased study. Arch Dermatol 5;141:1537 41. 6. Beattie PE, Lewis-Jones MS. A comparative study of impairment of quality of life in children with skin disease and children with other chronic childhood diseases. Br J Dermatol 6;155:145 51. 7. Siddha SK, Burden D. Recognition and treatment of psoriasis in children. Pediatr Child Health 7;17:3 4. 8.Benoit S, Hamm H. Childhood psoriasis. Clin Dermatol 7;25:555 62. 9. British Medical Association, Royal Pharmaceutical Society. Preparations for psoriasis. BNF for Children 8 (http://bnfc.org/bnfc/bnfc/current/5974.htm; accessed 11.9.8).. Leo Laboratories Ltd. Dovonex ointment, Dovonex cream. Summaries of Product Characteristics. May 7. 11. Brune A, Miller DW, Lin P, et al. Tacrolimus ointment is effective for psoriasis on the face and intertriginous areas in pediatric patients. Pediatr Dermatol 7; 24:76. 12.Veale DJ, Ritchlin C, Fitzgerald O. Immunopathology of psoriasis and psoriatic arthritis. Ann Rheum Dis 5;64 (Suppl II):ii26 9. 13. Gottlieb AB, Matheson RT, Lowe N, et al.a randomized trial of etanercept as monotherapy for psoriasis. Arch Dermatol 3;139:1627 32. 14. Leonardi CL, Powers JL, Matheson RT, et al. as monotherapy in patients with psoriasis. N Engl J Med 3;349:14 22. 15. Papp KA,Tyring S, Lahfa M, et al.a global phase III randomized controlled trial of etanercept in psoriasis: safety, efficacy, and effect of dose reduction. Br J Dermatol 5;152:14 12. 16. National Institute for Health and Clinical Excellence. and efalizumab for the treatment of adults with psoriasis. Technology Appraisal Guidance No. 3. July 6. 17. Paller AS, Siegfried EC, Langley RG, et al. treatment for children and adolescents with plaque psoriasis. N Engl J Med 8;358:241 51. FUTURE PRESCRIBER VOL 9(3) www.futureprescriber.co.uk