Management of Childhood Psoriasis with Acitretin

Abstract
Psoriasis is a chronic inflammatory disease of the skin which can occur at any age-group. Psoriasis in childhood is not uncommon and has genetic susceptibility but usually an environmental trigger such as infection is thought to initiate the disease process. Childhood psoriasis has profound effects on both physical and psychosocial health of the patient. Treatment of mild psoriasis can be done with topical therapies but those which do not respond to topical therapies can be treated with phototherapy and systemic therapies. The use of systemic therapies in childhood is mainly based on the published data, case series, expert opinion and the experience as there is lack of controlled trials in the age group. Based on the experience retinoid are probably the second line drugs for the treatment of childhood psoriasis which do not respond to topical therapies and phototherapy. Using acitretin in a low dose and with proper physical examinations and laboratory investigations will reduce the hazard of potential serious adverse events. This article gives the review of use of acitretin in the childhood psoriasis.

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INTRODUCTION
Psoriasis is the chronic inflammatory disease of the skin having the world wide prevalence of 1-3% and is clinically characterized by erythematous papules and plaques covered with silvery scales(1, 2). Psoriasis can occur at any age. Psoriasis in pediatric population is not uncommon and exerts a major impact on physical and psycho-social health of a child. In about one-third of the psoriatic population, the onset of disease is seen during the pediatric age(3). In a study of 419 patients from Northern India, the age of onset of psoriasis ranged from 4 days to 14 years(4). The presence of positive family history was found to be 23% and 34.3% in two different studies(5, 6). Pediatric psoriasis has the genetic susceptibility but the environmental factors often trigger the initiation of the disease process. The most common triggering factors include respiratory infection, sore throat, stress and trauma. There are different variants of psoriasis in children like plaque, guttate, napkin, erythrodermic, pustular and nail psoriasis(2). Plaque psoriasis is the most common subtype and the pustular psoriasis is the least common subtype(7). Psoriasis in childhood and adolescence require proper management. Both the patient and the parents must be given the knowledge about the disease and its nature. Psoriasis in childhood affects the health-related quality of life. It is found that, the risk of mental illness like depression and anxiety is increased in children with psoriasis than those without psoriasis(8). Due to the presence of visible skin lesions the children with psoriasis suffer from the low self-esteem(9).
Fortunately, childhood psoriasis is usually mild and can be treated with topical therapies. Systemic treatment is required only if the disease do-not respond to topical therapies, phototherapy and if the disease is significantly impairing the psychosocial aspect of the child health. Systemic therapies for psoriasis in children are not approved by FDA. Due to the lack of controlled trials use of systemic therapies are based on case reports, published data and expert opinion. On the basis of published data and experience retinoids appear to be the second-line drug of choice for children(10).
ACITRETIN
Retinoids encompasses all the compounds either natural or synthetic, which possess the biological activity like vitamin A(11). Synthetic Retinoids are classified into three generations. Acitretin and etretinate are the second generation synthetic retinoids and are also known as aromatic retinoids(12, 13). Acitretin is the free and active metabolite of etretinate. Etretinate is strongly lipophilic and tends to accumulate more in the adipose tissue and thus has a longer elimination half-life, in contrast acitretin is less lipophilic and thus clears rapidly from the body and has the shorter elimination half-life(14).Intake with food increases the absorption of acitretin so, the bioavailability of acitretin is more when taken with food than on the empty stomach(15). Due to the longer elimination half-life of etretinate it has been largely replaced by acitretin. However, it is found that re-esterification of acitretin to etretinate can take place with the concomitant intake of alcohol. So, the female patient especially of childbearing age should be strictly instructed to not take alcohol during the period of treatment with and 2 months after the completion of treatment (16).
USE IN PEDIATRIC PSORIASIS
Pediatric psoriasis is usually mild and topical therapies are the first choice of treatment. Systemic therapy is not the first choice in childhood psoriasis. It is used in the treatment of recalcitrant psoriasis which do not respond to topical therapy, phototherapy and if it is significantly impairing the psychosocial aspects of the child health. Due to the lack of controlled trials, the use of acitretin is based on the published data, case reports and the expert opinion. However, the significant risk benefit of the treatment should always be weighed with the risk of disease without treatment. Long term use of acitretin in children with inherited disorder of keratinization supports the safety of acitretin in children, but the monitoring is always required(17). Acitretin is used effectively in the treatment of generalized pustular psoriasis, erythrodermic psoriasis, palmoplantar psoriasis and severe recalcitrant plaque psoriasis but acitretin is not effective in psoriatic arthropathy(12, 18). Acitretin is used as either monotherapy or in combination with topical agents and narrowband ultraviolet phototherapy.
In a multicenter cohort study by Ergun et al. 61 patients among 289 patients were treated with acitretin at a dose of 0.3-0.5 mg/kg/day with the mean duration of treatment being 9.16+-9.06 months. 47.5% of the patient achieved at least PASI- 75 response. 70.7% of the patient well tolerated the treatment with no side effects. 25.9% experienced the mucocutaneous side-effects, 1.7% had hyperlipidemia and 1.7% had nausea(19).
In a multicenter retrospective analysis by Lernia et al. including 18 children with plaque psoriasis ,8(44.4%) patient achieved a PASI-response 75 at 16 weeks. The starting dose of acitretin was 0.2-0.5mg/kg/day but the dose was increased to 0.6mg/kg/day in two patients after 8 weeks. Three out of eight patients achieving PASI-75 response stopped therapy for the interval of 2-6 months but had to restart the treatment after relapse and the treatment was effective even after re-introduction. 9 patient discontinued treatment due to lack of efficacy and 1 patient discontinued treatment due to arthralgia. All patients had the mucocutaneous side-effects like chelitis, dry lips, dry mouth and pruritus. The laboratory values of the patients were within the baseline during the treatment(20).
Ergin et al. reported a case of infantile pustular psoriasis treated with acitretin with the initial dose of 0.5mg/kg/day which was later increased to 0.7mg/kg/day. The skin lesion was cleared in the end of 4 months and then the acitretin was tapered to 0.3mg/kg/day for three months and then discontinued. Oral prednisolone was used initially then it was tapered and discontinued. Slight increase in serum triglyceride was observed but it returned to normal after the dose was tapered. No other adverse events were observed(21).
Salleras et al. reported a case of 4-year-old girl with congenital erythrodermic psoriasis treated with acitretin at a dose of 0.5mg/kg/day and the complete remission achieved in three months. The discontinuation of the drug led to relapse so the patient was maintained in 0.5-0.75mg/kg/day of acitretin during the aggravation of the disease. The patient was followed till 7 years of age and no other secondary effects were observed(22).
A case of annular pustular psoriasis in a 14-month old girl reported by Haug et al. was treated with acitretin in the dose of 0.9mg/kg/day and the patient achieved complete remission after 4 months. The dose of acitretin was reduced and tapered at 0.1mg/kg/day and discontinued after 10 months with no relapse in the following three years. The patient experienced mild side effects like chelitis, reversible hypercholesterinemia and elevation of alkaline phosphatase(23).
Acitretin is aa excellent option in a child with palmo-plantar psoriasis. A 14-year-old boy with palmo-plantar psoriasis treated with acitretin at a dose of 10mg/day had a good response with improvement within 6 weeks. At 3-month follow-up the patient had almost lesion free. The patient had experienced adverse events like mild chelitis and xerosis but the laboratory values remain unchanged. Later the patient was maintained on acitretin 10mg every other day together with the topical combination of 15% liquor carbonis detergens compounded in triamcinolone 0.1% ointment applied every night(24).
Combination with other therapies
Acitretin has been used in combination with NB-UVB phototherapy, methotrexate and cyclosporine A(24, 25). The effect of acitretin together with NB-UVB is found to be synergistic.
A case of 3.5-year-old boy with severe pustular psoriasis (von Zumbusch type) reported by kopp et al. was started on acitretin 1mg/kg/day with the short-term use of systemic methylprednisolone for controlling the acute stage. However, any attempt to reduce or discontinue the steroid led to exacerbation of the disease. Then the patient was given NB-UVB phototherapy three times per week. Later, after five exposures the corticosteroid was tapered and discontinued. The patient was then maintained on NB-UVB phototherapy two times weekly together with acitretin 0.3mg/kg/day. Disease was well controlled with this combination regimen. The laboratory values remained unchanged during the acitretin treatment(26).
A 9-year-old boy with generalized pustular psoriasis was treated with acitretin 10mg/day and was maintained at 10mg three times week for a year. Later he developed skin pain and localized area of pustules which led to increase in the dose of acitretin 20mg/day during the flare but later tapered to 10mg/day for the next year. But the patient eventually required the addition of NB-UVB phototherapy to maintain the remission. The patient is well maintained by this combination(24).
Adverse events of acitretin
Acitretin in known to exert a number of adverse events. Most of the adverse events are dose dependent and reverse back to normal after decreasing the dose or after discontinuation of therapy. However, it is usual to have the minor side-effects on the long term treatment with acitretin.
The most common adverse events of acitretin is the muco-cutaneous adverse events. Dry lips being the most common one and be treated with the use of emollients. Others include dry dry mouth, cheilitis, stomatitis and gingivitis and taste disturbances. Acitretin causes dryness with inflammation of mucous membrane and transitional epithelia which occasionally leads to epistaxis, rhinitis, photophobia, conjunctivitis and xeropthalmia. Alopecia, nail-fragility and paronychia have also been observed(27). Rarely patients may have the photosensitivity reactions. Retinoid dermatitis which resembles unstable psoriasis can develop 25% of the patients receiving high dose of acitretin therapy(28). Muco cutaneous side effects can be treated symptomatically, and if severe effects occur the dose reduction can be tried before the discontinuation of the drug.
Acitretin causes transient elevation of liver enzymes. The elevation is dose dependent and usually reverse back to normal after reducing the dose or after discontinuation of the therapy. Severe hepatotoxic reactions resulting from retinoids are rare. In a data of 1877 patients receiving oral acitretin only 0.26% of the patients showed overt chemical hepatitis(29). However, the hepato-toxic reactions in children are rare because the cofactors like diabetes, alcoholism, and obesity are less likely in children(12).
Acitretin also exerts the effects on lipid profile which is reverse back to normal within 8 weeks after the discontinuation of the drug(30). Retinoids are seen to cause the elevation of triglyceride and cholesterol and decrease in the high density lipoprotein. In a study it is seen that 35% of the patients had the elevation in serum triglyceride above 300mg/dl and about 15% of the patients had the elevation of cholesterol level(31). The decrease in the high density lipoprotein is also observed(29).
Retinoids have been known to cause the skeletal abnormalities especially in children. The long term treatment with etretinate is also associated with the extraspinal tendon and the calcification of ligament. However, the study including 19 children and young adults, treated with etretinate for continuous 5 years do not show any skeletal abnormality(32). No cases of diffuse idiopathic skeletal hyperostosis was seen in a retrospective study on long term use of acitretin in a low dose(33). No significant radiologic abnormalities associated with retinoids was detected in a patient of severe pustular psoriasis treated with low dose of acitretin for 9 years(34). It is usually not recommended to use oral retinoids for the treatment of psoriasis in children due to the report of occasional bone changes like premature epiphyseal closure, skeletal hyperostosis and extra-osseous calcification observed in the children on the long term treatment with etretinate(35, 36). If acitretin is to be used in a child, the child should be observed carefully for any abnormalities of growth and bone development. Routine radiography is not recommended because of the radiation hazards, but the atypical musculoskeletal pain must be investigated with x-rays. Growth chart of the child on acitretin should be maintained (27). Arthralgia, arthritis, myalgia may also occur during the treatment with acitretin. A few case of vasculitis, Wegener granulomatosis and erythema nodosum are also observed.
Retinoids are teratogenic drugs. The defect due to retinoids is termed as “retinoic acid embryopathy”. The malformations seen in the fetus include microtia/anotia, micrognathia, cleft-palate, conotruncal heart disease and aortic arch abnormalities, thymic defects, retinal or optic nerve abnormalities and central nervous system malformations(37). Even though only one report of human teratogenicity due to acitretin has been published(27), acitretin should be cautiously used as acitretin is converted to etretinate which has a longer elimination half-life. The female patient of child-bearing should strictly be instructed for the use of two effective contraceptive method stating 1-month prior of treatment, during the period of treatment and 3 years after the discontinuation of treatment(38). However, the risk of teratogenicity by use of acitretin in children is less because of the least chance of a child to get pregnant.
The concomitant use of retinoid with tetracycline and minocycline has led to pseudo-tumour cerebri(29). Pseudo-tumor cerebri was reported in a case of 14-year-old boy treated with isotretinoin and tetracycline(39). Retinoids also causes blurring of vision, headache and reduced night vision. Patient with severe headache, vomiting and visual disturbances should stop acitretin immediately and consult the doctor(27).
The concomitant use of vitamin A with acitretin must be restricted.
MONITORING GUDELINES
Before starting the treatment with acitretin, proper history taking and careful physical examination should be performed. Laboratory investigations including complete blood count, lipid profile, liver enzymes and blood sugar in diabetics should be done. Monitoring of the liver enzymes and fasting serum cholesterol and triglyceride must be done every 2-4 weeks of therapy for the first two months and then every three months(27). Children on acitretin therapy must have their growth charted. Female of child bearing age and their parents should be counselled about the teratogenic effect of the drug and use of contraception during and after the treatment. The pregnancy should be ruled out before the initiation of acitretin therapy with two negative pregnancy tests.
CONCLUSION
Acitretin is a non-immunosuppressive drug that can be effective in the treatment of childhood psoriasis. It is seen that acitretin is more effective in pustular and erythrodermic psoriasis and moderately effective in the plaque type psoriasis in children. Acitretin is used both as monotherapy and as combination therapy. As the use of acitretin in children lack sufficient data and evidence, its use in children should always be weighed with risk benefit of treatment and risk if the disease is left untreated. The side effects are mostly dose dependent so it can be minimized by using the lowest possible dose. The dose of 0.5-1mg/kg/day was seen to be effective. It should be used cautiously in the female patient. Long term treatment with acitretin require proper clinical and laboratory evaluation.
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