|Year : 2016 | Volume
| Issue : 2 | Page : 87-94
Acitretin in pediatric dermatoses
Manjyot Gautam, Harsh Tahiliani, Nitin Nadkarni, Sharmila Patil, Kiran Godse
Department of Dermatology, Dr. D Y Patil Hospital, D Y Patil University, School of Medicine, Nerul, Navi Mumbai, Maharashtra, India
|Date of Web Publication||30-Mar-2016|
Department of Dermatology, School of Medicine, Dr. D.Y. Patil Hospital, Nerul, Navi Mumbai - 400 706, Maharashtra
Source of Support: None, Conflict of Interest: None
Acitretin, a synthetic retinoid and the active metabolite of etretinate has been increasingly used over the past two decades. It has proved effective in the treatment of many conditions associated with hyperkeratosis and dyskeratosis. A Google scholar search for the use of acitretin in pediatric dermatoses was done using the words “pediatric dermatoses,” “acitretin,” “etretinate,” “systemic retinoids,” “psoriasis,” “pityriasis rubra pilaris,” “ichthyoses,” “disorders of keratinization,” “Darier's disease,” “palmoplantar keratoderma,” “verrucae,” “lichen planus,” “lupus erythematosus,” and “lichen sclerosus.” All the articles were retrieved and classified into review articles, studies, double-blinded trials, and case reports. The final data were then analyzed and presented in a narrative fashion. It has been found that acitretin is useful in a number of pediatric dermatoses. It is preferred over other drugs in pustular psoriasis. Good results can be obtained in various disorders of keratinization, and it may even prove life-saving in conditions like harlequin ichthyosis. However, long-term maintenance therapy is required and exacerbations are known on discontinuing the drug. It can also be used as alternative therapy for many other pediatric dermatoses where the primary treatment has failed. Acitretin should be used even in children for the proper indications. However, proper clinical and laboratory surveillance has to be maintained in patients on long-term acitretin.
Keywords: Acitretin, disorders of keratinization, oral retinoids, pediatric dermatoses
|How to cite this article:|
Gautam M, Tahiliani H, Nadkarni N, Patil S, Godse K. Acitretin in pediatric dermatoses. Indian J Paediatr Dermatol 2016;17:87-94
|How to cite this URL:|
Gautam M, Tahiliani H, Nadkarni N, Patil S, Godse K. Acitretin in pediatric dermatoses. Indian J Paediatr Dermatol [serial online] 2016 [cited 2018 Nov 17];17:87-94. Available from: http://www.ijpd.in/text.asp?2016/17/2/87/179415
| Introduction|| |
The term retinoids include all compounds that have a biological activity like Vitamin A.
Synthetic retinoids are classified into three generations based on their structure.
- First generation: Tretinoin, isotretinoin, alitretinoin
- Second generation: Acitretin, etretinate
- Third generation: Bexarotene, tazarotene.
First generation retinoids are nonaromatic, second generation is mono-aromatic, and third generation is polyaromatic compounds.
Acitretin is a second generation retinoid with a mono-aromatic ring structure. It was first discovered along with etretinate by Bollag in 1972. Etretinate was later phased out in 1998 because of its perceived teratogenic effects. Acitretin is the acid metabolite of etretinate with a shorter half-life. It was Food and Drug Administration approved for the treatment of psoriasis in June 1997.
The absorption of acitretin is poor when taken on an empty stomach and increases on the intake with fatty food. The bioavailability on the oral intake of acitretin is 60%. Acitretin is metabolized in the liver by cytochrome P450, where isomerization of acitretin to isoacitretin takes place. It is excreted through bile as well as kidneys. It reaches maximum plasma levels in 2 h.
Acitretin is less lipophilic than etretinate and hence, it has a short elimination half-life of 50 h. This was the main reason why it replaced etretinate. However, in the presence of alcohol, there is a reverse esterification of acitretin to etretinate which has a much longer half-life of 80–160 days. Complete avoidance of alcohol while on acitretin therapy is recommended.
Acitretin is commercially available as 10 and 25 mg capsules. For neonates and infants requiring <10 mg dose, it is advised that the capsule should be frozen and cut in the required fraction and dispensed in a liquid (honey, milk, or infant formula). Since acitretin is sensitive to light, the remaining fraction should be discarded.
Mechanism of action
Acitretin is transported to its target cells by albumin in the serum. Certain proteins in the cell membrane called cytosolic retinoic acid binding protein transport acitretin intracellularly. Acitretin activates the nuclear retinoic acid receptor (RAR) without binding to it. Certain genes containing a retinoid acid response element are upregulated by these activated RARs. These result in an expression of various proteins associated with cellular differentiation, inflammation, and apoptosis.,,
| Materials and Methods|| |
A Google scholar search for the use of acitretin in pediatric dermatoses was done using the words “pediatric dermatoses,” “acitretin,” “etretinate,” “systemic retinoids,” “psoriasis,” “pityriasis rubra pilaris (PRP),” “ichthyoses,” “disorders of keratinization,” “Darier's disease,” “palmoplantar keratoderma,” “verrucae,” “lichen planus,” “lupus erythematosus,” and “lichen sclerosus.” All the articles were retrieved and classified into review articles, studies, double-blinded trials, and case reports. The final data were then analyzed and presented in a narrative fashion.
| Results|| |
Acitretin is not the drug of choice for the majority of the children with psoriasis who have localized disease. These can be managed with topical preparations alone.
Only 1% children with psoriasis  have severe variants, some of which respond well to acitretin. These are:
- Extensive plaque psoriasis with psoriasis area severity index more than 10
- Generalized pustular psoriasis (GPP) also called as von Zumbusch disease
- Erythrodermic psoriasis
- Severe disabling palmoplantar psoriasis
- Palmoplantar pustulosis.
Acitretin is more effective for the management of GPP, erythrodermic psoriasis, palmoplantar pustulosis, and recalcitrant plaque type psoriasis but not effective in psoriatic arthropathy. Guttate psoriasis in children is usually self-limited. However, for recalcitrant and extensive guttate lesions, acitretin has often been used even in children as young as 6 months. Most of the studies of acitretin in pediatric psoriasis are based on case reports and recommend a dose of 0.5–1 mg/kg/day. The response usually starts in 3 weeks, and remission is achieved by 3 months. It can also be used in the maintenance phase and in combination with narrowband ultraviolet B (NBUVB).
- Salleras et al. have reported the use of acitretin 10 mg/day (0.5 mg/kg/day) in a 4-year-old girl suffering from congenital erythrodermic psoriasis. Complete remission was achieved in 3 months. The maintenance dose was tapered to 30 mg/week. The patient was followed up until the age of 7 years, and no adverse effect of retinoid therapy was observed in this patient
- Ergin et al. treated a 2.5-month-old girl child suffering from infantile pustular psoriasis with acitretin 0.7 mg/kg/day which led to remission of the skin lesions in 4 months. She was maintained on a dose of 0.3 mg/kg/day for another 3 months. A short course of steroids was given during the initial phase 
- In a retrospective study of GPP in childhood, de Oliveira et al. analyzed the patient records of 7 children with GPP, who had received acitretin at 1 time of the follow-up period with variable response. The average follow-up period was 4.6 years. It was effective in 5 patients 
- Chao et al. had used acitretin in a 6-week-old infant with GPP at a dose of 1 mg/kg/day that caused resolution of lesions in 6 weeks after which acitretin was tapered to 0.4 mg/kg/day as maintenance therapy for another 6 months.
- Kopp et al. reported a 3.5-year-old boy with GPP, who was treated with methylprednisolone and acitretin who got repeated flares on tapering the steroids. The patient was started on NBUVB therapy thrice per week which allowed tapering of steroids after 10 irradiations. NBUVB was then reduced to twice per week and acitretin dose reduced to 0.3 mg/kg/day 
- Acitretin has been used for the treatment of severe or recalcitrant childhood psoriasis in combination with NBUVB, cyclosporine A, methotrexate, and oral corticosteroids.
Although acitretin has been used a combination with psoralen ultraviolet A (PUVA) therapy, infliximab and etanercept in adults, such studies are lacking in children. PUVA therapy is best avoided in children below 12 years of age, and a combination of methotrexate and acitretin has a potentially cumulative hepatotoxic effect and should ideally be avoided.
Disorders of Keratinization
Currently, we do not have a curative treatment for ichthyoses. However, the advent of systemic retinoids brought a revolution in the treatment of congenital ichthyoses, especially the more severe ones.
The most important step in the management of ichthyoses is to remove the scales and take care of the xerosis without irritating the skin. In the majority of the patients, this can be achieved by judicious use of topical emollients and moisturizers with or without keratolytic agents. Most of the patients with ichthyosis vulgaris and X-linked recessive ichthyoses can be treated with topical therapies alone and the need for acitretin does not arise.
However, patients with the more severe variants of ichthyoses like nonbullous congenital ichthyosiform erythroderma (NBIE), bullous congenital ichthyosiform erythroderma (BIE), and lamellar ichthyosis (LI) generally require systemic therapy with synthetic retinoids, where they may be even lifesaving.
Retinoids do not correct the keratinization defect though they reduce the hyperkeratosis. The lesions do relapse on discontinuing acitretin, and indefinite therapy is hence required.
There is adequate data to demonstrate the efficacy of etretinate in LI. Later acitretin replaced etretinate in the treatment of LI with similar efficacy.,,, It is used in the dose of 0.5–1 mg/kg/day. The effect is generally seen after about 4 weeks of treatment in the form of a reduction in scales, improvement of ectropion/eclabium, and improvement of palmoplantar hyperkeratosis.
Acitretin needs to be continued indefinitely to keep the disease under control. Fortunately, it is well-tolerated by most children.
Nonbullous Ichthyosiform Erythroderma
The majority of patients with NBIE require indefinite treatment with acitretin.,, The dose recommended does not differ from that used in LI.
Bullous Ichthyosiform Erythroderma
The treatment of this condition with acitretin is rather challenging but a good clinical response should be expected., Since acitretin increases the fragility of the skin, increased dosage can actually worsen the blisters of BIE. Hence, the dose has to be properly titrated starting with a low dose and maintaining at the lowest effective dose  with frequent monitoring.
The use of acitretin in harlequin ichthyosis is lifesaving. The hyperkeratosis and fissuring reduce within days. Ectropion and eclabium resolve completely., Side effects encountered are very minor.
Acitretin is found to be effective in Sjogren–Larsson syndrome but ineffective in Netherton's syndrome. Actually, it is contraindicated in the later because it can cause skin irritation and precipitate a flare of atopic eczema.
Palmoplantar keratodermas (PPK) can be a severely disabling condition adversely affecting the quality of life. It is in such types of PPK that acitretin is indicated. The dose and tolerance of acitretin vary in different types of PPK. Though it is not effective in the Unna-Thost type of PPK, it has been found to be useful in Papillon–Lefevre syndrome, Vohwinkel's disease, Conradi–Hunermann syndrome, and KID syndrome. Most cases of erythrokeratoderma variabilis can be treated symptomatically with topical preparations. Only severe disease requires treatment with systemic retinoids which reduces scaling, but the erythema may persist.,, While there should be an initial loading dose of 0.5–1 mg/kg/day, satisfactory improvement can be maintained with a lower dose of 0.2 mg/kg/day.
Pityriasis Rubra Pilaris
The use of acitretin should be restricted for generalized, recalcitrant variants of juvenile PRP. Acitretin in a dose of 05–1 mg/kg/day causes marked improvement in most cases of PRP. Relapses do not occur for long periods of time after stopping therapy. Retinoids are now considered as first-line therapy for severe variants of PRP.,,
- Lacour et al. have retrospectively analyzed the use of acitretin and etretinate in 29 children with disorders of keratinization. Marked to moderate improvement was noted in most patients. No significant change in the clinical response, as well as adverse effects, was noted in 22 patients who were switched from etretinate to acitretin 
- Zhang et al. investigated the efficacy of acitretin in children with severe disorders of keratinization and observed a clinical cure rate of 82.1% and the effective rate was 17.9%. Two recalcitrant cases of Darier's disease also responded to acitretin in 6 months 
- Saracoglu et al. have reported one infant with LI and another with nonbullous congenital ichthyosiform erythroderma. Both infants presented with a collodion baby appearance and were initiated on acitretin 1 mg/kg/day. There was a satisfactory improvement in both cases 
- Chao et al. retrospectively studied 28 cases of juvenile PRP. Five of these patients received acitretin and a moderate to excellent response was obtained in them. They also noticed that acitretin at low doses was not effective in PRP and Griffith's type IV responded better as compared with Griffith's type III 
- Blanchet-Bardon et al. studied the effect of acitretin in 12 children with disorders of keratinization. The acitretin dose range was from 0.42 to 1.16 mg/kg/day. The response differed in different disorders. PPK - Papillon–Lefevre syndrome and congenital ichthyosiform erythroderma responded remarkably well. No change was observed in PPK – Unna-Thost type. They also recommend a careful tailoring of the dose for individual patients
- Steijlen et al. have studied the effect of acitretin in 7 patients with LI since birth. All patients were treated with 35 mg acitretin daily initially for 1 month. Two patients required dosage increment and the other 5 had remission, and the maintenance dose was reduced to 10–25 mg/day.
Only severe cases of Darier's disease require treatment with systemic retinoids. A good clinical response is obtained with lower doses of acitretin as compared to other diseases., The patient should be started on a low dose (0.2 mg/kg/day) and the dose should be increased in 4 weeks if the clinical response is not satisfactory. The diseases exacerbate within 3–4 weeks of stopping acitretin. Hence, long-term maintenance therapy is needed.
Prevention of Malignancies
Vitamin A and retinoids have a protective role in the development of skin cancers. Acitretin (1 mg/kg/day) has been used in genodermatoses with a high risk of malignancies. Xeroderma pigmentosum patients have a very high risk of developing skin cancers. Treatment with acitretin in such patients significantly reduces the risk of developing malignancies., Acitretin also plays a very important role in chemoprophylaxis of skin cancers in nevoid basal cell carcinoma syndrome.
Good therapeutic response in patients with epidermodysplasia verruciformis has also been achieved with retinoids in a dose-dependent manner in combination with interferon alpha-2a. Acitretin monotherapy was ineffective. However, the lesions are known to recur on stopping treatment.
Acitretin has been used off-label for various indications. However, only isolated case reports exist, and no controlled trials have been done.
Solitary case reports have claimed good resolution with acitretin in patients with multiple recalcitrant warts at doses as low as 0.5 mg/kg/day.
- Krupashankar et al. have reported the use of acitretin in a patient who had multiple warts since adolescence. Resolution of warts was observed after 3 months of therapy with 0.5 mg/kg/day 
- Proietti et al. have reported the use of acitretin in a patient with numerous warts. Resolution of lesions was obtained after 8 weeks of therapy, and it was discontinued in another 4 weeks.
Although acitretin is the drug of choice for the treatment of acute generalized lichen planus as well as unresponsive oral lichen planus in adults, there are no data supporting its use in the pediatric population.
Brockow et al. successfully treated a 9-year-old boy with acute extensive eruptive lichen planus with oral acitretin (0.5 mg/kg/day). The extent and severity of lichen planus reduced markedly after 4 weeks of therapy and remission was obtained after 8 weeks. The therapy was discontinued after 12 weeks.
Although acitretin (1 mg/kg/day) has been reported to be effective in cutaneous lupus erythematosus including the hypertrophic variant in adults,, such studies are lacking in the pediatric age group.
Bousema et al. in their randomized controlled trial observed that severe vulvar lichen sclerosus et atrophicus responded well to acitretin; however, there was a huge dropout rate in that study.
There exist anecdotal case reports about the use of acitretin in extensive and palmoplantar lichen nitidus, porokeratosis, granuloma annulare, keratosis lichenoides chronic, hyperkeratotic hand eczema, and pemphigus.
The absolute contraindication to oral retinoids viz., pregnancy is unlikely to be applicable in children. However, this contraindication should be kept in mind while prescribing acitretin to adolescent females.
The relative contraindications include patients with hepatic, renal, or lipid derangements. Oral retinoids are also relatively contraindicated in neonates and children; however, they should be considered when the benefits outweigh the risks, and regular monitoring of treatment should be done.
Minor side effects are common in most patients receiving long-term acitretin therapy. All adverse effects except teratogenicity are dose dependent and disappear on stopping therapy [Table 2].
Acitretin causes retinoid embryopathy  if taken during pregnancy and, therefore, it has to be used with caution in teenage girls who have achieved menarche. Retinoid embryopathy leads to craniofacial dysmorphias, appendageal abnormalities, hip malformations, meningoencephalocele, and multiple synostoses. There have been a few case reports of embryopathy with acitretin since it has been commercially marketed, but etretinate has been associated multiple times with severe embryopathy. Therefore, strict contraception should be advised 1 month prior to starting therapy and should be followed for 3 years after stopping treatment. Abstinence from alcohol is also important in women of childbearing age on acitretin therapy. It is advisable to use two simultaneous methods of contraception. Acitretin reduces the efficacy of progesterone only mini pill; hence, this method of contraception is best avoided. There are no reproductive risks due to semen of men taking acitretin according to the available data.
Mucocutaneous side effects are the most frequently encountered side effects. These include dryness of lips, cheilitis, and dryness with inflammation of mucous membranes and transitional epithelia., Epistaxis, rhinitis, photophobia, xerophthalmia, conjunctivitis, and taste disturbances have also been reported occasionally. Thinning, redness, and scaling of the skin particularly over the palms and soles can also occur. Retinoid dermatitis is associated with high dose acitretin therapy. Acitretin therapy can also cause increased hair loss, nail fragility, and paronychia. Long-term retinoid therapy may cause periungual pyogenic granuloma. Photosensitivity may also occur rarely, but it is advisable to counsel children about photoprotection since they are likely to indulge in outdoor activities. A higher incidence of mucocutaneous side effects is seen at higher doses.
The most common hepatic side effect of acitretin therapy is the transient elevation of liver enzymes which returns to normal on discontinuing the drug. This is less common in children since cofactors like alcoholism, diabetes, and obesity are less likely to exist in them. Patients on simultaneous treatment with other hepatotoxic drugs have a higher risk of developing hepatic side effects while on acitretin therapy. There are a few case reports  of severe hepatic reactions like cholestatic hepatitis and cirrhosis, but their incidence is very low (0.26%).
Acitretin also interferes with the lipid metabolism and alters the serum lipid profile. Hyperlipidemia is dose-dependent and returns to normal within 8 weeks of stopping therapy. Increased triglyceride is the most commonly encountered lipid profile disorder. A case of pancreatitis developing due to increased triglycerides has also been reported. Hypercholesterolemia due to increased very low-density lipoproteins and low-density lipoproteins is also encountered frequently. High-density lipoproteins can also be decreased in patients on acitretin therapy. Therefore, dietary restrictions like avoidance of alcohol and a high fish oil diet play an important role in patients on acitretin therapy.
There are occasional reports of bone changes in children in the form of premature epiphyseal closure, skeletal hyperostosis, and extraosseous calcification.,, Periosteal thickening and decreased cortical bone thickness have been associated with long-term etretinate therapy. Long-term retinoid therapy is also associated with extraspinal tendon and ligament calcification. Diffuse idiopathic skeletal hyperostosis like features have also been reported with use of retinoids; such involvement is, however, independent of dose and duration of therapy. Recent studies on the effect of acitretin in adults have failed to demonstrate any skeletal side effects, but the drug should be used with caution in children. Very few case reports of other rheumatological manifestations like arthralgias, myalgias, arthritis, osteopenia, and vasculitis have been reported.
Other Side Effects
Pseudotumor cerebri when retinoids are used concomitantly with tetracyclines and minocyclince. There are occasional reports of blurring of vision with reduced night vision. Oral retinoids also increase the insulin sensitivity which may lead to hypoglycemia and should be used with caution in diabetic children. Capillary glucose levels should be monitored more frequently than usual in such patients.
Overdose Side Effects
These side effects are similar to Vitamin A toxicity and include headache, nausea, vomiting, drowsiness, vertigo, and visual disturbances.. Acitretin should be immediately stopped when patients experience any of these symptoms.
Refer [Table 3].
After a careful history and physical examination, a baseline complete blood count, liver enzymes, fasting cholesterol with triglycerides, and blood sugars in diabetics should be done. These investigations should be repeated every month for the first 2 months and every 3 monthly thereafter. Weekly tests should be performed if the liver function tests are abnormal, and treatment with acitretin should be terminated if transaminases are 3 times the normal value. Values lower than 3 times should be managed with the help of a gastroenterologist and acitretin dose should be adjusted accordingly. The British Association of Dermatology guidelines  does not recommend routine radiographic assessments for long-term acitretin therapy because it exposes the children to unnecessary radiation. They recommend targeted X-rays for atypical musculoskeletal pains. Other authors  believe that annual X-rays and bone scans should be considered. Adolescent females and their parents should be counseled about the teratogenic implications of oral retinoids. Pretreatment pregnancy tests and advice about contraception from 1 month prior to and 1 month after treatment should be given.
| Conclusion|| |
Acitretin can be life saving in severe variants of many disorders of keratinization and can be used even in children for the proper indications. However, proper clinical and laboratory surveillance has to be maintained in patients on long-term acitretin.
Financial Support and Sponsorship
Conflicts of Interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]
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