Some studies on gene expression, disease associations, and molecular interactions have already been done for EI. Paller et al, 2017 found similarities in IL-17 and IL-23 expression between EI and Atopic dermatitis and Psoriasis. Later, Malik et al, 2019 performed molecular fingerprinting studies and found profound TH-17 skewing, which could indicate that IL-17/IL-36 targetted therapeutics designed for psoriasis may work well for the ichthyosis, with particular emphasis on EI sharing many similarities with the inflammatory markers demonstrated in psoriasis. Has et al, 2020 reclassified EI alongside Pachyonychia Congenita (PC) and Epidermolysis Bullosa Simplex (EBS), these are all keratinisation disorders caused by mutations on the Keratin genes and are associated with skin fragility and/or hyperkeratosis. Much more recently, Frommherz et al, 2024 conducted the largest population study of the German EI population study, documenting genotypes and phenotypes for 45 patients with EI alongside clinical severity scores and economic evaluation data.

These important studies have helped scientists to understand EI better, and were used to justify a clinical trial, which included adult patients with EI, for the use of a biologic therapeutic agent called Secukinumab. The findings published by Lefferdink et al, 2023 indicated that Secukinumab was a safe therapeutic option for those with EI because patients did not suffer any significant adverse reactions. However, it was found that Secukinumab did not achieve a statistically significant improvement in symptoms and therefore could not be recommended as a new therapeutic option for EI. The investigators did also state however, that whilst there was no statistical significance, some EI patients reported good improvements in their symptoms, but perhaps the tools used to measure some outcomes did not demonstrate the benefits that the participants described.

Clinical trials continue to test biologic agents for other types of Ichthyosis, but at present, there are no further studies available to patients with EI. EI is often excluded from congenital ichthyosis trials because the measurement of outcomes is more complex when the condition includes both non-uniform hyperkeratosis alongside skin fragility and blistering.

The inconclusive findings of the Secukinumab trial and the fact that EI is often excluded from clinical trials for congenital ichthyosis confirms that there is a need to better document the natural history of EI. If we are to prove without any doubt that there is or isn’t a therapeutic benefit from a new treatment, we need to know exactly what EI looks and feels like over time, and how it affects both quality of life and the cost of care during childhood and adulthood. If we cannot prove therapeutic benefit, we will never be able to justify the cost of new treatments, nor will we ever gain approval for new treatments.

This type of prospective, longitudinal study of the natural history of EB, which includes economic evaluation of the cost of care, has been active of over 10 years now. Known by the acronym ‘PEBLES’, and led by EI Cure Project Research Alliance Member, Professor Jemima Mellerio, this study has provided a mass of data which has already been used to inform clinical care, but has also been used to justify the continued need to fund research to find new treatments.