What is the treatment for syndromic multisystem autoimmune disease due to ITCH (Immunoglobulin Receptor Tyrosine-based Inhibition Motif Containing Protein, E3 ubiquitin protein ligase) deficiency?

Treatment for Syndromic Multisystem Autoimmune Disease due to ITCH E3 Ubiquitin Protein Ligase Deficiency

Hematopoietic cell transplantation (HCT) is the only potentially curative treatment for syndromic multisystem autoimmune disease due to ITCH deficiency and should be pursued early in the disease course. 1

Disease Overview

ITCH deficiency is a rare genetic disorder characterized by multisystem autoimmune manifestations resulting from mutations in the ITCH gene, which encodes an E3 ubiquitin-protein ligase essential for immune regulation. This condition is classified as a primary immunodeficiency disorder with immune dysregulation 2.

Clinical Presentation

Patients with ITCH deficiency typically present with:

• Growth failure and short stature
• Dysmorphic facial features
• Chronic lung disease resembling asthma
• Very early-onset inflammatory bowel disease
• Arthritis and camptodactyly (finger contractures)
• Autoimmune manifestations including:
  • Autoimmune hepatitis (potentially progressing to acute liver failure)
  • Type 1 diabetes mellitus
  • Autoimmune thyroiditis
  • Enteropathy
  • Uveitis
  • Psoriasis
  • Immune cytopenias

Diagnostic Approach

Diagnosis is based on:

• Clinical presentation with multisystem autoimmune disease and dysmorphic features
• Genetic testing showing biallelic mutations in the ITCH gene
• Functional validation demonstrating reduced ITCH mRNA and/or absent ITCH protein
• Immunological evaluation showing abnormalities in both lymphoid and myeloid lineages

Treatment Algorithm

First-Line Therapy

1. Hematopoietic Cell Transplantation (HCT)
   • HCT has demonstrated excellent immune reconstitution and resolution of systemic disease manifestations 1
   • Early referral for HCT evaluation is recommended before end-organ damage becomes irreversible
   • HCT should be considered potentially curative rather than a last resort

Bridging Therapies (while awaiting HCT)

For management of specific organ manifestations while preparing for definitive treatment:

1. Corticosteroids

   • May reduce acute inflammation but not effective as monotherapy 2
   • Use the lowest effective dose for the shortest possible duration to minimize side effects 2

2. Immunosuppressive Agents

   • Consider conventional synthetic DMARDs based on organ involvement:
     • Mycophenolate mofetil, azathioprine, or calcineurin inhibitors for autoimmune hepatitis or enteropathy 2
     • Avoid methotrexate if lung disease is present 2

3. Targeted Biologic Therapies (based on specific manifestations)

   • Anti-TNF agents (infliximab, adalimumab) for inflammatory bowel disease, arthritis 2
   • Anti-IL-6 receptor antibodies (tocilizumab) for systemic inflammation 2
   • Rituximab (anti-CD20) for antibody-mediated manifestations 2
   • IVIG for immune cytopenias or as adjunctive therapy 2

Monitoring and Supportive Care

• Regular monitoring of organ function (liver, pancreas, thyroid)
• Aggressive management of infections due to underlying immune dysregulation
• Nutritional support for growth failure
• Hormone replacement for endocrine manifestations
• Pulmonary support for chronic lung disease

Important Considerations and Pitfalls

1. Disease Progression

   • Without definitive treatment, ITCH deficiency can progress to fatal multiorgan failure 3
   • Cases of acute liver failure requiring liver transplantation have been reported 3
   • Post-transplant recurrence of autoimmunity can occur if underlying immune dysregulation is not addressed

2. Treatment Challenges

   • Immunosuppressive medications may provide temporary relief but do not address the underlying genetic defect
   • Liver transplantation alone is insufficient, as demonstrated by recurrence of autoimmune hepatitis in transplanted liver 3
   • Increased risk of infections with immunosuppressive therapy

3. Prognosis

   • Early HCT offers the best chance for long-term survival and quality of life
   • Delayed diagnosis and treatment are associated with poor outcomes and increased mortality
   • Patients may develop post-transplant complications requiring close monitoring

ITCH deficiency represents a severe form of immune dysregulation where the absence of this critical E3 ubiquitin ligase leads to unchecked T-cell activity and loss of immune tolerance. The molecular understanding of this condition has led to the recognition of HCT as the definitive treatment option, targeting the underlying immune dysregulation rather than merely suppressing its manifestations.