Presenting Author:

Principal Investigator:

Department:

Dermatology

Keywords:

Epidermis, ichthyosis, inflammation, autosomal recessive congenital ichthyosis, congenital ichthyosiform erythroderma, ... [Read full text] Epidermis, ichthyosis, inflammation, autosomal recessive congenital ichthyosis, congenital ichthyosiform erythroderma, lamellar ichthyosis, Netherton syndrome, epidermolytic ichthyosis, skin, IL-17, TNF-α [Shorten text]

Location:

Ryan Family Atrium, Robert H. Lurie Medical Research Center

C18 - Clinical

A shared Th17-dominant immune profile across the ichthyosis spectrum

Orphan forms of ichthyosis are genetically and clinically heterogeneous disorders, in which the epidermal barrier is abnormal resulting in increased transepidermal water loss (TEWL). Patients characteristically have generalized skin scaling, thickening, and redness. Even though affected subjects have an extremely compromised quality of life, current treatment for ichthyosis is largely supportive and unsatisfactory. Although the genetic basis for most forms is clear, how this translates into the clinical inflammation and scaling is unknown. Discovery of a shared mechanism for inflammation across the various forms of ichthyosis could lead to targeted therapy. To elucidate the basis for the immune alterations of ichthyosis and their correlation with clinical characteristics, analysis was done on skin from 21 patients with the most prevalent of the orphan forms of ichthyosis: ARCI-lamellar ichthyosis (LI), ARCI-congenital ichthyosiform erythroderma (CIE), epidermolytic ichthyosis (EI), and Netherton syndrome (NS). Ichthyotic skin was compared with skin from healthy control subjects, as well as patients with atopic dermatitis (AD) and psoriasis. The Ichthyosis Area and Severity Index (IASI) was used to capture the severity of skin redness/ erythema (IASI-E) and scaling (IASI-S) by body region and extent. Immunohistochemical analysis of markers of epidermal proliferation (keratin 16 expression) and T-cells and dendritic cells revealed that ichthyotic skin has increased hyperplasia and cellular infiltration, similar to AD and psoriasis. RT-PCR studies of immune markers revealed that IL-17/TNFα-synergistic/additive genes were highly expressed in patients with ichthyosis subtypes compared to healthy controls and were similar to levels seen in psoriasis, considered a TH17-dominant inflammatory disease. Expression of these markers was highly correlated with overall ichthyosis severity (total IASI), erythema (IASI-E), and TEWL, suggesting a link between the barrier defect and inflammation in patients with ichthyosis. Overall, the data shows that all ichthyoses share impressive TH17/IL-23 skewing in skin with strong expression of IL-17/TNF-synergistic/additive markers similar to that seen in psoriasis. These new findings suggest that the highly effective IL-17 antagonist medications used in psoriasis might be applicable to patients with ichthyosis, leading to a new treatment paradigm for ichthyosis. At Northwestern, we have recently initiated a funded clinical trial of injected secukinumab (IL-17 antagonist human monoclonal antibody) for adults with ichthyosis (clinicaltrials.gov #NCT03041038). We anticipate that this trial (4 month double-blind/8 month open-label) will determine whether the Th17 skewing is merely an antimicrobial response to the barrier deficit or is a critical factor in driving inflammation and scaling.