Alitretinoin as a Treatment Modality for Ichthyosis in Women of Childbearing Age: A Case Series and Review of the Literature

Background: Acitretin, a synthetic vitamin A derivative, is the most studied and widely used oral retinoid for ichthyoses. Its major disadvantage is the need for contraceptive measures during 3 years after discontinuation. An alternative is needed for women of childbearing age. With alitretinoin, another retinoid, pregnancy is considered safe 1 month after discontinuation. Objectives: The aim of this study was to provide evidence for alitretinoin as an alternative for acitretin for ichthyosis in women of childbearing age. Our experience is shared in a case series combined with an overview of the current literature. Methods: Nine women of childbearing age (19–31 years, median 21) with different subtypes of ichthyosis (autosomal recessive congenital ichthyosis, (superficial) epidermolytic ichthyosis, erythrokeratoderma variabilis, and epidermolytic epidermal nevi, a mosaic form of epidermolytic ichthyosis) were included and treated with 30 mg alitretinoin during 2–28 months. Severity was measured by Ichthyosis Area Severity Index (IASI) and Investigator Global Assessment (IGA). A literature search in Pubmed using the Mesh terms “alitretinoin,” “skin diseases, genetic” and “ichthyosis” was performed. Results: Significant reduction in the mean scores of IGA, IASI-erythema, IASI-scaling, and IASI-total was seen. Seven patients are still being treated, 1 patient stopped to become pregnant, 1 patient discontinued due to financial reasons. Observed side effects were reversible headache (n = 6), asteatotic eczema (n = 1), “not feeling well” temporarily (n = 1), and easier blistering of the feet (n = 1). The literature search resulted in six case reports and case series about alitretinoin in ichthyosis and ichthyosis syndromes with in total 29 patients. The vast majority of articles (21/29) reported significant improvement or even complete remission of skin symptoms. However, validated outcome measures to support these results were lacking. Side effects (n = 16) were relatively mild, except for benign intracranial hypertension (n = 1) and autoimmune hypothyroidism (n = 1). Conclusion: Our study shows, with validated outcome measures, that alitretinoin is effective to mitigate the symptoms of ichthyosis in women of childbearing age and a suitable alternative to acitretin.

(IASI) and Investigator Global Assessment (IGA).A literature search in Pubmed using the Mesh terms "alitretinoin," "skin diseases, genetic" and "ichthyosis" was performed.Results: Significant reduction in the mean scores of IGA, IASIerythema, IASI-scaling, and IASI-total was seen.Seven patients are still being treated, 1 patient stopped to become pregnant, 1 patient discontinued due to financial reasons.Observed side effects were reversible headache (n = 6), asteatotic eczema (n = 1), "not feeling well" temporarily (n = 1), and easier blistering of the feet (n = 1).The literature search resulted in six case reports and case series about alitretinoin in ichthyosis and ichthyosis syndromes with in total 29 patients.The vast majority of articles (21/29) reported significant improvement or even complete remission of skin symptoms.However, validated outcome measures to support these results were lacking.Side effects (n = 16) were relatively mild, except for benign intracranial hypertension (n = 1) and autoimmune hypothyroidism (n = 1).Conclusion: Our study shows, with validated outcome measures, that alitretinoin is effective to mitigate the symptoms of ichthyosis in women of childbearing age and a suitable alternative to acitretin.

Introduction
Oral retinoids are the first-line systemic treatment in ichthyosis and lead to improvement of scaling and hyperkeratosis [1].The exact mechanism is not yet fully understood.The major disadvantage of oral retinoids is their teratogenic effect [2,3].Acitretin, which activates retinoic acid receptors, is the only oral retinoid registered for treatment of inherited disorders of keratinization.Contraceptive measures are indicated during treatment and until 3 years after the discontinuation of acitretin.In women of childbearing age, a treatment without longstanding teratogenic effect is generally preferred [1].Alitretinoin and isotretinoin are oral retinoids with a more rapid clearance, in which pregnancy is considered safe 1 month after the end of treatment.Alitretinoin and the metabolites of isotretinoin bind to retinoic acid receptors and also to retinoid X receptors [4,5].The significance of binding to these retinoid X receptors is still unclear [4].Although isotretinoin is financially more attractive, often high doses are necessary in ichthyosis, and the safety profile of this retinoid is poorer [1].Based on its relatively rapid clearance and generally more favorable safety profile, alitretinoin seems a good choice of oral retinoid in women of childbearing age.Oral use of alitretinoin is approved for the treatment of severe chronic hand eczema [1,6].The aim of this case series and literature review was to investigate the effect of off-label use of alitretinoin for ichthyosis.

Methods
The patient database of the Maastricht University Medical Center +, a center of expertise for genodermatoses, was searched for cases currently or previously using alitretinoin for congenital ichthyosis.In total, 9 patients were included.Treatment effectiveness was retrospectively measured by the Investigator Global Assessment (IGA) and Ichthyosis Area Severity Index (IASI) scores by three independent physicians based on clinical photographs before (T0) and during treatment (T1) with alitretinoin.Statistical analysis was done with a paired samples t test.This study was done under the approval of the Medical Ethics Committee of the Maastricht University Medical Centre + (METC 2020-2268A2).To review the current literature concerning usage of alitretinoin for ichthyosis, a Pubmed search was conducted with the Mesh terms "alitretinoin," "skin diseases, genetic," and "ichthyosis."This resulted in a total of 11 articles.After reading titles and abstracts, six articles were selected as relevant for the topic.

Case Series
Nine women of childbearing age, treated with alitretinoin for different subtypes of ichthyosis, were included (Table 1).Five of the included patients were known with autosomal recessive congenital ichthyosis, the other 4 patients with epidermolytic ichthyosis (EI), superficial EI, erythrokeratoderma variabilis, and linear epidermolytic epidermal nevi (a mosaic variant of EI in Blaschkoid pattern).In all patients, a possible future child wish was the main reason to choose off-label therapy with alitretinoin instead of acitretin.All patients initially received a dose of 30 mg/day, in patient 2 the dose was decreased to 10 mg/day after 22 months.The duration of therapy varied from 2 to 28 months with a median of 6 months.All patients responded well to treatment (Fig. 1; Table 2).Statistical analysis, performed in 7/9 patients, showed that mean IGA was significantly reduced by 0.95 points on a scale of 0-4 (p < 0.01) (Fig. 2).Improvement in IASI-total was at least 30% in 6/7 patients and at least 50% in 4/7 patients, with reduction of a mean score of 14.6 at T0 (baseline) to 8.5 at T1 (during treatment) on a scale of 48 (p < 0.01).IASI-erythema showed at least 30% improvement in 3/7 patients and at least 50% in 2/7 patients, with reduction of a mean score of 4.8 at T0 (baseline) to 3.0 at T1 (during treatment) on a scale of 24 (p < 0.05), while reduction in IASI-scaling of at least 30% was achieved in 6/7 patients and of at least 50% in 5/7 patients, with a mean score of 9.9 at T0 (baseline) and 5.5 at T1 (during treatment) on a scale of 24 (p < 0.01).Two patients were excluded from this analysis because clinical photographs before treatment were not available, and therefore IGA and IASI scores could not be calculated.Patients 1 and 2 discontinued alitretinoin during short periods of time, but both experienced worsening of skin symptoms within a few weeks and therefore returned to treatment.Patient 6 switched from acitretin to alitretinoin without a washout period, and experienced even a small improvement of the phenotype on alitretinoin compared to acitretin.7/9 patients are currently still under treatment with alitretinoin.Alitretinoin was discontinued in patient 1 after 15 months due to an active pregnancy wish, which was followed by a healthy pregnancy.She wished to restart treatment directly after breastfeeding was completed.Patient 5 discontinued treatment due to financial reasons.Side effects in this case series consisted of mild reversible headache (n = 6), asteatotic eczema (n = 1), "not feeling well" temporarily (n = 1), and easier blistering of the feet (n = 1).No serious adverse events occurred.All patients used contraceptive measures during the treatment with alitretinoin.

Literature Review
Six relevant articles, case reports and case series, were retrieved about ichthyosis and ichthyosis syndromes with total of 29 cases (Table 3).The treatment  Even though the clinical difference is not pronounced, the patient experiences softening of the hyperkeratosis and a reduction of irritation and pruritus, which motivated her to continue treatment for 28 months so far (currently 10 mg alitretinoin).e, f Patient 4, diagnosed with autosomal recessive congenital ichthyosis (lamellar ichthyosis, ALOX12B), had marked brown large polygonal hyperkeratotic scaling disseminated on the legs, with sparing of the knee flexures (e).After 4 months of therapy with 30 mg alitretinoin, there was significant improvement on the amount and thickness of scales (f).

Alitretinoin for Treatment of Ichthyosis
Dermatology 2024;240:170-177 DOI: 10.1159/000533934 experienced an effect on scaling that was equal to former treatment with acitretin (0.2 mg/kg/day), and erythema was improved even more effectively.The duration of treatment in this patient was not mentioned [11].In 2012, the first pilot study regarding treatment with alitretinoin in congenital ichthyosis appeared.Four patients treated with alitretinoin 30-50 mg/day for 3 months were included.All patients experienced improvement, 2 patients considering alitretinoin "at least equally effective" as acitretin 25-50 mg/day [8].Subsequently, a case series was published about 9 patients with EI treated with oral retinoids, including alitretinoin.3/9 patients improved on oral retinoids, but unfortunately details about the type of retinoid, dosage, and period of treatment in responders and nonresponders are missing [10].The largest cohort of ichthyosis patients receiving therapy with alitretinoin is described in a retrospective study of 13 patients between 12 and 36 years old [12].The subjects were diagnosed with lamellar ichthyosis (n = 7), congenital ichthyosiform erythroderma (n = 3), erythrokeratoderma (n = 1), Netherton syndrome (n = 1), and KLICK syndrome (n = 1).Eleven patients received treatment with acitretin before starting therapy with alitretinoin, and acitretin was discontinued either because of pregnancy wish (all female subjects, n = 10), ineffectiveness (n = 3), and/or side effects (n = 2).The efficacy of alitretinoin was moderate or high in 11/13 patients.Skin erythema significantly improved (median improvement on visual analog scale of 2 points on a scale of 10, range 2-5).The effect on skin scaling was inconsistent.2/13 patients discontinued therapy because of insufficient response to alitretinoin 10 mg and inability to increase the dose due to persisting headache [12].Side effects of alitretinoin reported in the abovementioned literature were mucocutaneous dryness (n = 6), headache (n = 4), myalgia (n = 2), low TSH (reversible n = 1, autoimmune hypothyroidism leading to withdrawal n = 1), skin erosions (n = 1), and benign intracranial hypertension (n = 1, leading to discontinuation).

Discussion
Our case series of 9 female patients with ichthyosis successfully treated with off-label alitretinoin, was assessed by retrospective measurement of IGA and IASI in 7/9 patients.2/9 patients had to be excluded from this analysis because clinical photographs before treatment were not available.There are no studies directly comparing effectiveness of acitretin and alitretinoin.In our case series, no serious adverse events occurred.In the current literature, evidence was found for the use of alitretinoin in ichthyosis and ichthyosis syndromes, with 14/29 cases consisting of women of childbearing age.In 11 of these patients, the long need of contraceptive measures with acitretin was specifically mentioned as the reason to choose for alitretinoin as an alternative [11][12][13][14][15][16][17].In our cohort, this was the motive for all of the cases.The vast majority of articles (21/29 cases) reported significant improvement or even complete remission of symptoms by alitretinoin.Unfortunately, validated outcome measures to support these results were not mentioned.It is therefore hard to quantify the effect measured by alitretinoin based on the current reports.Side effects were reported in 16/29 cases, mostly mild and reversible, Table 2. Mean IGA (scale 0-4), IASI-total (scale 0-48), IASI-erythema (scale 0-24), and IASI-scaling (scale 0-24) scores of patients from our case series before (T0) and during treatment (T1) with alitretinoin 30 mg except for benign intracranial hypertension (n = 1) and autoimmune hypothyroidism (n = 1).Unfortunately, there are no follow-up studies about long-term side effects of alitretinoin (longest follow-up in hand eczema is 24 weeks) [18], which is relevant in chronic diseases like ichthyosis.The longest follow-up found for ichthyosis was 36 months [12].Long-term use of oral retinoids is associated with skeletal complications, such as premature closure of the epiphyses in children and hyperostotic changes of the spine and joints.This toxicity seems to be related to the dose and duration of exposure to retinoids.Hyperostotic changes are, however, also very common in the general population without retinoid treatment, and increase with age [1,2].A retrospective study analyzed the occurrence of hyperostosis in 127 patients with disorders of keratinization treated with oral retinoids (acitretin n = 107, isotretinoin n = 40, alitretinoin n = 6).Three cases were observed after treatment with acitretin and isotretinoin.No hyperostosis was observed with alitretinoin; however, this might be due to the small group size [19].In our case series and literature review, no skeletal complications were found.Concluding, currently acitretin remains the only oral retinoid registered for treatment of ichthyosis in Europe and therefore should be seen as first choice.However, based on our data and literature review, we are convinced that alitretinoin is effective, safe and has a shorter period of teratogenic risk after discontinuation and therefore should be the first choice for women of childbearing age.Alitretinoin could also be considered as a good off-label alternative if acitretin is not effective or causes many side effects, as alitretinoin has a more favorable safety profile.To be able to compare the effectiveness of alitretinoin versus acitretin for ichthyosis, a randomized clinical trial with validated outcome measures would be necessary.?, unknown; CIE, congenital ichthyosiform erythroderma; CRIE, congenital reticular ichthyosiform erythroderma; EI, epidermolytic ichthyosis; EK, erythrokeratoderma; KID, keratitis-ichthyosis-deafness syndrome; KLICK, keratosis linearis with ichthyosis congenita and sclerosing keratoderma syndrome; LI, lamellar ichthyosis; n.a., not applicable; NS, Netherton syndrome.

Fig. 1 .
Fig. 1.Clinical improvement of patients with several ichthyosis subtypes on alitretinoin.a, b Patient 1 with erythrokeratoderma variabilis before treatment (a) and after 4 weeks of treatment with 30 mg alitretinoin (b).c, d Patient 2 with an epidermolytic epidermal nevus, presenting as symmetrically located linear distributed hyperkeratotic papules and plaques in a Blaschkoid pattern, without treatment (c) and after 4 months 30 mg alitretinoin (d).Even though the clinical difference is not pronounced, the patient experiences softening of the hyperkeratosis and a reduction of irritation and pruritus, which motivated her to continue treatment for 28 months so far (currently 10 mg alitretinoin).e, f Patient 4, diagnosed with autosomal recessive congenital ichthyosis (lamellar ichthyosis, ALOX12B), had marked brown large polygonal hyperkeratotic scaling disseminated on the legs, with sparing of the knee flexures (e).After 4 months of therapy with 30 mg alitretinoin, there was significant improvement on the amount and thickness of scales (f).

Table 1 .
Summary of the 9 female patients included in our case series *Patients 3 and 4 are siblings from consanguineous parents.
T1, during alitretinoin treatment.Patients 7 and 8 could not be included in this table because clinical photographs at T0 were not available.

Table 3 .
Studies describing alitretinoin in ichthyosis found during literature search