Name: Infantile-Onset Multisystem Autoimmune Disease 1 | Acronym: IMAD1
Alt. names: STAT3-GOF | STAT3-related early-onset multisystem autoimmune disease | autoimmune disease, multisystem, infantile-onset, 1

Gene: STAT3 | MOI: Autosomal dominant | Mechanism of action: Gain of Function

No. of cases in DB: 61 | First reported in: 2014

Last updated on: 2023-04-01 06:10:25 by Xiao P. Peng

OMIM: 615952

Orphanet: 438159

MONDO: 0014414

DOID: -

ClinGen: Definitive (2022-02-16)

Thus far, over 200 patients have been identified with STAT3 gain-of-function (GOF) variants leading to a complex multi-system syndrome of immunodeficiency, immune dysregulation and inflammation (PMID: 25038750, 25359994, 30825606, 34390440, 34975878, 36228738). STAT3 GOF patients show a broad spectrum of phenotypes, often with infantile or childhood onset, but the majority show lymphoproliferation, short stature, growth failure, recurrent infections, and many autoimmune phenotypes, such as autoimmune cytopenias, enteropathy, endocrinopathies, and autoimmune hepatitis. Additionally, patients often have skin, lung, renal and/or neurologic involvement, as well as arthritis, vasculopathy, and increased malignancy risk. Laboratory studies may show evidence of cellular and/or humoral immunodeficiency including T, B, and NK cell lymphopenia, reduced Treg and increased Th17 proportions, hypogammaglobulinemia and expansion of double negative T cells (PMID: 36228738). Four of 27 patients tested in the largest cohort to date showed abnormal Fas-mediated apoptosis.

Increasing evidence suggests that combined use of tocilizumab (an anti-IL-6 agent) and JAK inhibitors such as ruxolitinib and tofacitinib may be effective for controlling disease activity in STAT3 GOF patients (PMID: 30092289, 33731004, 30825606, 36228738). Compared to other immunomodulatory treatment modalities, multi-organ disease appears to dramatically improve upon treatment with JAK inhibitors and the currently preferred approach is to use these with addition of an IL-6 blocking agent to achieve synergistic control not achieved with JAK inhibition alone. However, it is unclear how long such therapies can be used for in the long term, so there is the consideration of using these immunomodulators as a bridge to HSCT for patients at risk of severe disease progression. Thus far, at least 23 patients have undergone HSCT with ~62% survival rate (PMID: 36228738).