Can Pathogenesis-Based Therapies Transform the Treatment Landscape for Congenital Ichthyosis?

🔍 Key Finding Congenital ichthyosis subtypes harbor elevated JAK/STAT signaling, making them potential targets for JAK inhibitors, and topical isotretinoin ointment (TMB-001) shows promise as an effective, on-label treatment option for generalized hyperkeratosis, scaling, and dryness. These breakthroughs offer new therapeutic options for congenital ichthyosis patients.

🔬 Methodology Overview

• Design: Clinical review of current and future treatments for congenital ichthyosis.
• Data Sources: Published literature including clinical trials and case reports.
• Scope: Practical guidance for the longitudinal care of patients with congenital ichthyosis, encompassing general management strategies and disease-specific recommendations.
• Analysis Approach: Qualitative synthesis of evidence and expert opinion to formulate treatment recommendations.
• Focus: Topical and systemic therapies, including retinoids, biologics, and anti-inflammatory small molecules, as well as emerging targeted treatments and gene therapy.

📊 Results

• Prevalence of Vitamin D deficiency: Higher in individuals with congenital ichthyosis compared to the general population.
• Topical N-acetylcysteine: Can be used for scale removal, particularly in pediatric populations, but may cause irritation, odor, and be costly.
• Systemic retinoids: Effective for moderate to severe hyperkeratosis, but require careful dosing and monitoring due to potential side effects. Low doses (e.g., 0.25 mg/kg/day) are recommended for epidermolytic ichthyosis, while higher doses (at least 1 mg/kg/day) may be needed for severe lamellar ichthyosis.
• Secukinumab: Showed clinical improvement in some patients with Netherton syndrome and other ichthyosis subtypes with moderate to severe erythroderma and IL-17A immune skewing.
• TMB-001 (topical isotretinoin): In Phase 2 trials, 100% of per-protocol patients with recessive X-linked and autosomal recessive lamellar congenital ichthyosis achieved a ≥50% reduction in scaling (VIIS) and a ≥2-grade improvement (IGA) with the 0.05% ointment.
• JAK inhibitors: Show promise for treating congenital ichthyosis subtypes, particularly harlequin ichthyosis, due to their effects on JAK/STAT signaling. Tofacitinib showed improvement in an in vitro 3D model of harlequin ichthyosis.
• Gene therapy: While early clinical trials have been disappointing, they provide a framework for future potential gene therapy approaches.

💡 Clinical Impact This review provides practical guidance for the longitudinal care of patients with congenital ichthyosis, encompassing general management strategies and disease-specific modifications, and highlights promising pathogenesis-based therapies, including topical and systemic retinoids, biologics, and JAK inhibitors, that may transform the treatment landscape for these challenging genodermatoses. Specifically, the development of TMB-001, a novel topical isotretinoin formulation, offers a potential on-label topical retinoid option for congenital ichthyosis, addressing a significant unmet need.

🤔 Limitations

• Off-label topical retinoid use can limit access to affordable medication in appropriate quantities.
• Systemic retinoid use carries a risk of systemic and dose-limiting toxicities.
• High doses of oral retinoids for epidermolytic ichthyosis can worsen erosions.
• Long-term, high-dose systemic retinoid use in lamellar ichthyosis can lead to diffuse skeletal hyperostosis.
• Topical N-acetylcysteine can cause skin irritation, has an unpleasant odor, and can be expensive to compound.
• Few gene therapy trials have shown success, though they provide a framework for future research.
• Each subtype of ichthyosis may require a different pathogenesis-based treatment, limiting broader applicability.

✨ What It Means For You This review provides a practical roadmap for the longitudinal care of patients with congenital ichthyosis, offering disease-specific and age-based treatment recommendations. It highlights emerging pathogenesis-based therapies, such as JAK inhibitors and gene therapy, while emphasizing the current off-label use of retinoids and the potential of topical isotretinoin (TMB-001) as a promising on-label therapeutic option. This information equips clinicians with a comprehensive overview of current and future treatment strategies for this challenging group of disorders.

Reference Lilly E, Bunick CG. Congenital Ichthyosis: A Practical Clinical Guide on Current Treatments and Future Perspectives. Clinical, Cosmetic and Investigational Dermatology. 2023;16:2473–2479. https://doi.org/10.2147/CCID.S388608