Abstract
The ichthyoses are a group of lifelong genetic disorders that share characteristics of
generalized skin thickening, scaling and underlying cutaneous inflammation. The vast majority
are orphan disorders and are associated with extremely poor quality of life related to social
ostracism from altered appearance, associated itchiness and discomfort, and functional
limitations from the skin disease. Among the more common "orphan" forms of ichthyosis are
autosomal recessive congenital ichthyosis (ARCI; includes lamellar ichthyosis/LI and
congenital ichthyosiform erythroderma/CIE), Netherton syndrome (NS) and epidermolytic
ichthyosis (EI). However, there are dozens of other syndromic and non-syndromic ichthyotic
disorders as well. Therapy is time-consuming for patients or parents and is supportive,
focusing on clearance of the scaling. There are no therapies based on our growing
understanding of what causes the disease. We have recently found marked elevations in
Th17/IL-23 pathway cytokines and chemokines in the skin of individuals with ichthyosis, most
similar to the inflammatory pattern of psoriasis. While the significance of the high
expression of Th17/IL-23 pathway genes across all forms of ichthyosis studied to date is
unknown, the high expression of genes of the Th17/IL-23 pathway in psoriasis is thought to be
causative for the disease manifestations. We propose that IL-12/IL-23 -targeting therapeutics
will safely suppress the inflammation and possibly the other features of ichthyosis,
improving quality of life. As a proof-of-concept study, we propose to treat children (6 years
of age and higher) and adults with ichthyotic disorders with ustekinumab in an open-label
trial to serially assess clinical response to and safety of ustekinumab for this group of
disorders.
