On-line version ISSN 1806-4841
An. Bras. Dermatol. vol.79 no.3 Rio de Janeiro May/June 2004
CLINICAL, LABORATORY AND THERAPEUTIC INVESTIGATION
Evaluation of the side effects of acitretin on children with ichthyosis - a one-year study*
Maria de Fátima de Medeiros BritoI; Iara Pessoa Sant'AnnaII; Fábia FigueiroaIII
ISubstitute Professor, UFPE and M.D.
IIM. D. Dermatologist, UPE/ Cisam
IIIMasters course student, Dermatology, UFPE
BACKGROUND: Systemic retinoids are one
of the most important dermatological therapeutics recently discovered for treating
disorders of keratinization, such as psoriasis, ichthyosis and acne
OBJECTIVES: The objective of this study was to evaluate the impact of the use of these drugs on lipid metabolism, hepatic system and on bone.
METHODS: Prospective study. Ten children with ichthyosis were evaluated during one year. Each was treated with a dose of 10 mg.day or approximately 0.5 mg.kg-1.day. This dosage was adjusted on the basis of clinical efficacy or tolerance and maintained for one year.
RESULTS: All ten children presented improvement by the end of one year. There were no alterations in transaminases, serum lipids and only one child out of six evaluated for bone age presented alterations.
CONCLUSION: The use of acitretin when administered at a correct dosage for a one-year period is secure and effective. The beneficial effect of the drug and its minimal toxicity shown in this study justify its use in children
Keywords: acitretin; child; Ichthyosis, Lamellar
Retinoids are natural or synthetic derivatives of vitamin A and have lead to important advances in the therapeutics for various dermatological diseases. They have been classified into three generations, with acitretin an active metabolite of etretinate, considered to be second generation,2 and represents the first-line therapeutics for the treatment of genetic disturbances of keratinization in children.1 However, due to the need for prolonged use, this drug is reserved for only the most serious cases.
Lamellar ichthyosis (LI) is an autosomal recessive genodermatosis with cutaneous manifestations that presents at birth and is characterized by generalized desquamation, with thick and dark scales, and erythroderma that does not spare the flexural surfaces. Also found are markedly pronounced ectropion, eclabium, flattened ears, and sparse, dry, curly and brittle hair as well as palmoplantar keratoderma.3 Thus, these children present a deformed appearance that is barely improved by current topical therapeutics, leading to profound psychological alterations not only in the patients, but also their relatives, hindering social and affective relationships and causing loss of self-esteem.
The management of IL has changed drastically since the introduction of synthetic oral retinoids, due to their action in the mechanisms of cellular proliferation and differentiation. The first sign of relief is the disappearance of ectropion,4 improvement of the eclabium and detachment of the ears, together with unclasping of the hands and a general improvement in the skin's aspect.
In children, the dose of acitretin varies from 0.5 to 1 mg/kg-1.day. In practice, the maintenance dose is around 10 mg/day, and the maximum dose should not exceed 35 mg/day.
Regarding side effects, the retinoids present acute and chronic toxicity. The most frequent acute reactions are cheilitis, conjunctivitis and hair loss, all of which are dose-dependent in incidence and gravity, and reversible after discontinuing the therapy.5 Laboratorial evaluation may show hepatic toxicity with elevation of the transaminases and hyperlipidemia.6 In children, the tolerability to acitretin is in general good and the risks are minimized if appropriate care is taken.7,8 Undesirable effects in the bones can occur during short-term therapies and especially protracted therapies that are usually permanent.5
This study demonstrated the safety of prolonged use (one year) of acitretin in children with lamellar ichthyosis.
MATERIAL AND METHODS
A prospective open study was performed on a series of cases, comprising 10 children with ages from zero to 12 years and clinical and histological diagnosis of lamellar ichthyosis, that used acitretin for a period of one year, at the Dermatology Ambulatory - Exceptional Medicines - CISAM/UPE. All children were included that used the medication for one year, selecting only those that had been submitted to clinical and laboratorial attendance before the treatment and every three months for hematological exams, for 12 months, and with compatible bone age before treatment and after one-year of follow-up. The exclusion criteria were obesity (20% above ideal weight), renal, hepatic and lipid metabolism disturbances and previous or concomitant use of another systemic medication, besides those children that did not complete the one year of clinical and laboratorial follow-up. All of the children presented universal involvement of the skin with varying degrees of desquamation, eclabium and ectropion. The mean dose of acitretin was 10 mg/dia which was adjusted according to the weight and clinical course, with a range of 0.5 to 1.0 mg/kg/day. The patients were examined periodically, and the clinical and laboratorial attendance was done before treatment, then after one month and every three months until completing the 12 months of treatment. The patients were counseled to maintain the topical treatment with moisturizers and emollients. The laboratorial management consisted of dosing serum rates of hepatic function, GOT (normal 8 - 40 I.U./L); GPT (normal 5 - 35 I.U./L); Cholesterol (normal 150 - 250 mg/dl), triglycerides (normal 50 - 150 mg.dl-1) and radiologic exams of hands and wrists for evaluating bone age [method of Greulich - pyle (normal ± 06 months of chronological age)] before and after 12 months of treatment.
Comparison of means was done using the Mann-Whitney test, at the 5% level of probability, due to the fact that the groups were independent with a small sample size.
The age of the patients varied from 18 months to 12 years, with a mean of 6.33 years and standard deviation of 4.03 (Table 1); seven (70%) were male and three (30%) female. Cholesterol, triglycerides and the transaminases were evaluated in eight children (80%) and there were no significant alterations (calculated U > critical U) at the end of the first year of the study (Table 2). The bone age was evaluated in six children (60%) and only one (16.6%) presented alteration in relation to the chronological age and was counseled to discontinue the treatment after evaluation by endocrinology (Table 3). The favorable clinical response, with varied aspects, occurred on average after the third month of treatment. An improvement was observed in the general aspect of the skin, with a decrease in the desquamation, reduction of the ectropion and improvement of the eclabium.
The age of the patients in the studied sample varied from 18 months to 12 years, with a greater concentration in the age group of zero to three years. The beginning of the treatment varies according to the severity of the picture, with reports of having been initiated within the first days of life.9
There was a prevalence among the male sex (70%) in this sample. Data in the literature does not point to a sex bias in LI; however, due to the known teratogenic effects of retinoids, and in particular etretinate and its metabolites, its indication is limited even for young females since the restriction against pregnancy after suspension of the drug is very long, lasting approximately two to three years.
There were no significant statistical alterations in the tests of hepatic function and in the lipid metabolism. Data in the literature describes rises in the transaminases of around 5 to 8% and rare acute hepatotoxic reactions. Hyperlipidemia can occur with variable frequency,6 although there appears to be a greater tolerability in children, perhaps due to lower exposure to the predisposing factors for this condition, such as alimentary habits, ingestion of alcoholic beverages, smoking and sedentary life style, thereby reducing the potentiation of these effects, in comparison with adults.
Regarding bone age, alteration was observed in one (16.6%) of the cases studied. In children, one of the fundamental aspects of long-term therapy with acitretin is the impact that this drug can have on physical growth and development. Radiologic alterations suggestive of precocious closing of the growth epiphyses have been reported and these are not uncommon. They occur in prolonged treatments and take at least one year for manifestation of the symptoms,13 which are inconstant, variable and multiple, particularly in children after several years of treatment and with high doses, that began the treatment within two to three years of life.7,8
The most frequent bone abnormalities are hyperostosis, shortening of the intervertebral spaces, osteoporosis, calcification of the ligaments and tendons, thinning of the long bones, bone reabsorption, premature closing of the epiphyses and retarded growth.7,8,10,11,12
The child in the present study that presented alteration in the bone age at the end of the first year of treatment began treatment with acitretin at two years and three months of age, with a dose of 10 mg/day and did not present other laboratorial alterations neither before, nor after one year of follow-up. However, in view of the findings, the authors suggest that this alteration should be attributed to the acitretin. The use of intermittent therapeutics is recommended or the lowest effective dose, in order to minimize the negative effects, mainly on the osteoarticular system, and the patients should be monitored on an annual basis with radiologic exams of the cervicolumbar column, the long bones and the hands and wrists for bone age.
The use of acitretin, when administered at appropriate doses and for a period of one year together with monitoring mainly of the osteoarticular system, is safe, effective and warranted by the benefits of this medication, and bearing in mind the insignificance of the laboratorial alterations presented in the current study.
1. Ruiz-Maldonado R, Tamayo L, Orozco C. The use of retinoids in pediatric patients. Dermatol Clin 1998;553:569. [ Links ]
2. Ceovic R, Pasic A, Lipozencic J. The use of retinoids in pediatric patients. Acta Dermatovenereol 2001;115:119. [ Links ]
3. Gony LP, Digiovanna JJ. Fitzpatrick's Dermatology in general medicine. 5ª ed vol II. New York: McGrow Hill, 1999: 2810 -2820. [ Links ]
4. Lopes CF. O uso dos retinóides em algumas dermatoses com exceção de psoríase e acne. An bras Dermatol 1988;63(3):309-312. [ Links ]
5. Lacour M, Mehta-Nikhar B, Atherton DJ, Harper JI. Na appraisal of acitretin therapy in children with inherited disorders of keratinization. Br J Dermatol 1996;134(6):1023-1029. [ Links ]
6. Berbis Ph. Acitretine. Ann Dermatovenereol 2001;737:745. [ Links ]
7. Prendiville J, Binngham EA, Burrows D. Premature epiphyseal closure: A complication of etretinato therapy in children. J Am Acad Dermatol 1986;15:1259. [ Links ]
8. Tamayo L, Ruiz-Maldonado R. Oral retinoid (Ro 10-9359) in children with lamellar ichthyosis, epidermolytic hyperkeratosis and symmetrical progressive erythrokeratodermia. Dermatologica 1980;161:305. [ Links ]
9. Burge S, Ryan T. Diffuse hyperostosis associated with etretinate. Lancet 1985;2:397. [ Links ]
10. David M, Hodak E, Lowe NJ. Adverse efrfects of retinoids. Med Toxicol Adverse Drugs Exp 1988;3:273. [ Links ]
11. Di Giovanna JJ, Helfgott RK, Gerber LH et al. Extraspinal tendon and ligament calcification associated with long term therapy with etretinate. N Engl J Med 1986;315:1177. [ Links ]
12. Halkier-Sorensen L, Andresen J, Etretinate and slender long bones in children. Acta Dermatovenereol 1988;68:275. [ Links ]
13. Anders V, Linköping MB. Long-term Safety of retinoid therapy. J Am Acad Dermatol 1992;27:529-533. [ Links ]
Maria de Fátima de Medeiros Brito
Rua João Ramos, 211/2601 - Graças
52011-080 Recife PE
Tel./Fax: (81) 3423 - 2185
Received in Juy, 18th of 2003.
Approved by the Consultive Council and accepted for publication in March, 12th of 2004.
* Work done at Dermatology Ambulatory / Exceptional Medications- Cisam/University of Pernambuco - Recife/PE