Despite New Ichthyosis Treatment Recommendations, 'Many Questions Still Exist'

Doug Brunk

April 13, 2021

For as many disorders of cornification and types of ichthyosis that have been shown to benefit from retinoids, a seemingly equal number have no data or show no improvement.

According to a consensus statement published in the February issue of Pediatric Dermatology, adequate data exist in the medical literature to demonstrate an improvement in use of systemic retinoids for select genotypes of congenital ichthyosiform erythroderma, epidermolytic ichthyosis, erythrokeratodermia variabilis, harlequin ichthyosis, IFAP syndrome (ichthyosis with confetti, ichthyosis follicularis, atrichia, and photophobia), KID syndrome (keratitis-ichthyosis-deafness), KLICK syndrome (keratosis linearis with ichthyosis congenita and sclerosing keratoderma), lamellar ichthyosis, loricrin keratoderma, neutral lipid storage disease with ichthyosis, recessive X-linked ichthyosis, and Sjögren-Larsson syndrome.

At the same time, limited or no data exist to support the use of systemic retinoids for CHILD syndrome (congenital hemidysplasia with ichthyosiform erythroderma and limb defects), CHIME syndrome (colobomas, heart defects, ichthyosiform dermatosis, intellectual disability, and either ear defects or epilepsy), Conradi-Hunermann-Happle syndrome, ichthyosis-hypotrichosis, ichthyosis-hypotrichosis-sclerosis cholangitis, ichthyosis prematurity syndrome, MEDNIK syndrome (mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratoderma), peeling skin disease, Refsum syndrome, and trichothiodystrophy, according to the statement.

Dr Andrea Zaenglein

"In particular, we did note that, with any disorder that was associated with atopy, the retinoids were often counterproductive," one of the consensus statement cochairs, Andrea L. Zaenglein, MD, said during the Society for Pediatric Dermatology pre-AAD meeting. "In Netherton syndrome, for example, retinoids seemed to make the skin fragility a lot worse, so typically, they would be avoided in those patients."

The statement, which she assembled with cochair pediatric dermatologist Moise L. Levy, MD, professor of pediatrics, University of Texas at Austin, and 21 other multidisciplinary experts, recommends considering use of topical retinoids to help decrease scaling of the skin, "but [they] are particularly helpful for more localized complications of ichthyosis, such as digital contractures and ectropion," said Zaenglein, professor of dermatology and pediatrics at Penn State University, Hershey. "A lot of it has to do with the size and the volume of the tubes and getting enough [product] to be able to apply it over larger areas. We do tend to use them more focally."

While systemic absorption can occur with widespread use, no specific lab monitoring is required. Zaenglein and her colleagues also recommend avoiding the use of tazarotene during pregnancy, since it is contraindicated in pregnancy (category X), but monthly pregnancy tests are not recommended.

During an overview of the document at the meeting, she noted that the recommended dosing for both isotretinoin and acitretin is 0.5-1.0 mg/kg per day and the side effects tend to be dose dependent, "except teratogenicity, which can occur with even low doses of systemic retinoid exposure and early on in pregnancy." The authors also advise patients to consider drug holidays or lower doses "especially during warmer, more humid months, where you might not need the higher doses to achieve cutaneous effects," she said.

They emphasized the importance of avoiding pregnancy for 3 years after completion of treatment with acitretin. "While the half-life of acitretin is 49 hours, it's easily converted with any alcohol exposure to etretinate," Zaenglein noted. "Then, the half-life is 120 days."

The statement, which was sponsored by the Pediatric Dermatology Research Alliance (PEDRA), also addresses the clinical considerations and consequences of long-term systemic retinoid use on bone health, such as premature epiphyseal closure in preadolescent children. "In general, this risk is greater with higher doses of therapies — above 1 mg/kg per day — and over prolonged periods of time, typically 4-6 years," she said. Other potential effects on bone health include calcifications of tendons and ligaments, osteophytes or "bone spurs," DISH (diffuse idiopathic skeletal hyperostosis), and potential alterations in bone density and growth.

"We also have to worry about concomitant effects of contraception, particularly if you're using progestin-only formulations that carry a black box warning for osteoporosis," Zaenglein said. "It is recommended that you limit their use to 3 years." Other factors to consider include genetic risk and modifiable factors that affect bone health, such as diet and physical activity, which may impact susceptibility to systemic retinoid bone toxicity and should be discussed with the patient.

Recommended bone monitoring in children starts with a comprehensive family and personal medical history for skeletal toxicity risk factors, followed by an annual growth assessment (height, weight, body mass index, and growth curve), asking regularly about musculoskeletal symptoms, and following up with appropriate imaging. "Inquiring about their diet is recommended as well, so making sure they're getting sufficient amounts of calcium and vitamin D, and no additional vitamin A sources that may compound the side effects from systemic retinoids," Zaenglein said.

The document also advises that a baseline skeletal radiographic survey be performed in patients aged 16-18 years. This may include imaging of the lateral cervical and thoracic spine, lateral view of the calcanei to include Achilles tendon, hips and symptomatic areas, and bone density evaluation.

The statement addressed the psychiatric considerations and consequences of long-term systemic retinoid use. One cross-sectional study of children with ichthyosis found that 30% screened positive for depression and 38% screened positive for anxiety, "but the role of retinoids is unclear," Zaenglein said. "It's a complicated matter, but patients with a personal history of depression, anxiety, and other affective disorders prior to initiation of systemic retinoid treatment should be monitored carefully for exacerbation of symptoms. Comanagement with a mental health provider should be considered."

As for contraception considerations with long-term systemic retinoid therapy use, the authors recommend that two forms of contraception be used. "Consider long-acting reversible contraception, especially in sexually active adolescents who have a history of noncompliance, or to remove the risk of teratogenicity for them," she said. "We're not sure what additive effects progestin/lower estrogen have on long-term cardiovascular health, including lipids and bone density."

The authors noted that iPLEDGE is not designed for long-term use. "It's really designed for the on-label use of systemic retinoids in severe acne, where you're using it for 5-6 months, not for 5-6 years," Zaenglein said. "iPLEDGE does impose significant and financial barriers for our patients. More advocacy is needed to adapt that program for our patients."

She and her coauthors acknowledged practice gaps and unmet needs in patients with disorders of cornification/types of ichthyosis, including the optimal formulation of retinoids based on ichthyosis subtype, whether there is a benefit to intermittent therapy with respect to risk of toxicity and maintenance of efficacy, and how to minimize the bone-related changes that can occur with treatment.

"These are some of the things that we can look further into," she said. "For now, though, retinoids can improve function and quality of life in patients with ichthyosis and disorders of cornification. Many questions still exist, and more data and research are needed."

Sun Pharmaceuticals and the Foundation for Ichthyosis and Related Skin Types (FIRST) provided an unrestricted grant for development of the recommendations.

Zaenglein disclosed that she is a consultant for Pfizer. She is also an advisory board member for Dermata, Sol-Gel, Regeneron, Verrica, and Cassiopea, and has conducted contracted research for AbbVie, Incyte, Arcutis, and Pfizer. The other authors disclosed serving as investigators, advisers, consultants, and/or had other relationships with various pharmaceutical companies.

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