STAT3 Gain of Function Disease

STAT3 gain-of-function disease is an immune dysregulation disorder from activating variants in STAT3, often de novo and sometimes inherited as autosomal dominant. It causes early onset multi-organ autoimmunity, lymphoproliferation and growth failure.

Pathophysiology. Constitutive STAT3 activity drives IL-6 and related signalling, expands double negative T cells and lowers regulatory T cells. The immune system attacks tissues, and antibody production falls.

Onset is usually in infancy or early childhood. It is rare, and the severity ranges from mild to fatal.

The disorder is the opposite of STAT3 loss-of-function (hyper IgE) syndrome, so eczema, high IgE and skeletal findings are not typical.

• Lymphadenopathy and splenomegaly from early childhood
• Autoimmune cytopenias: haemolytic anaemia, thrombocytopenia, neutropenia
• Enteropathy with diarrhoea and failure to thrive
• Type 1 diabetes, including neonatal diabetes, and thyroid disease
• Lymphocytic interstitial lung disease
• Short stature and growth failure
• Recurrent infection and hypogammaglobulinaemia
• Arthritis, hepatitis, eczema, and rarely lymphoma

• Genetic testing of STAT3 (gain-of-function variant), with functional testing for raised STAT3 phosphorylation or transcriptional activity.
• Lymphocyte subsets: raised double negative T cells (similar to autoimmune lymphoproliferative syndrome), low regulatory T cells and low B cells.
• Immunoglobulins and specific antibody responses.
• Autoimmune workup: full blood count, reticulocytes, direct antiglobulin test, glucose and HbA1c, thyroid function and antibodies, liver enzymes.
• Imaging: high resolution CT of the chest, abdominal imaging, bone age with growth failure.
• Endoscopy with biopsy for enteropathy.

Differential diagnosis.

• Autoimmune lymphoproliferative syndrome
• CTLA-4 haploinsufficiency and LRBA deficiency
• Activated PI3K delta syndrome
• STAT1 gain-of-function disease
• IPEX syndrome and other regulatory T cell disorders
• Systemic lupus erythematosus
• Common variable immunodeficiency

• IL-6 receptor blockade: tocilizumab 8 mg/kg intravenously (maximum 800 mg) every 4 weeks, or 162 mg subcutaneously every 2 weeks if weight is under 100 kg and weekly if 100 kg or more. Check neutrophils, platelets, liver enzymes and lipids before the first dose, at 4 to 8 weeks, then every 3 months. Hold for neutrophils under 1.0 x 109/L, platelets under 100 x 109/L or ALT over 5 times the upper limit. Screen for tuberculosis and hepatitis B. Watch for bowel perforation with abdominal pain.
• JAK inhibitor: ruxolitinib 5 mg orally twice daily in adults, titrated to response up to 20 mg twice daily, with blood count every 2 weeks at first and monthly after. Taper rather than stopping suddenly.
• Other immunosuppression: prednisolone 1 mg/kg orally daily (maximum 60 mg) with taper over 4 to 8 weeks for flares; sirolimus 1 to 2 mg once daily in adults adjusted to a trough of 5 to 10 microgram/L; rituximab 375 mg/m2 intravenously weekly for 4 doses for refractory cytopenia, after hepatitis B screening.
• Immunoglobulin replacement: intravenous immunoglobulin 400 to 600 mg/kg every 3 to 4 weeks, or subcutaneous immunoglobulin 100 to 150 mg/kg weekly, with trough IgG of at least 6 g/L, usually 7 to 9 g/L.
• Prophylaxis during immunosuppression: co-trimoxazole 960 mg orally three times weekly in adults (children trimethoprim 150 mg/m2 daily in two divided doses on 3 days each week).
• Endocrine care: insulin for diabetes, levothyroxine for hypothyroidism, and growth hormone for proven deficiency after immune control.
• Enteropathy: nutritional support, infection excluded first.
• Haematopoietic stem cell transplantation for refractory disease.
• Vaccines: inactivated only; avoid live vaccines during immunosuppression.

Special groups.

• Children: growth, puberty and bone health need monitoring, because inflammation and corticosteroids slow growth.

Monitoring. Full blood count, liver enzymes and creatinine every 3 months. Trough IgG every 3 months. Glucose, HbA1c and thyroid function every 6 months. Lung function with gas transfer and CT chest yearly. Height, weight and pubertal staging at every visit.

Referral and escalation. Refer to immunology. Urgent for severe cytopenia, respiratory failure, abdominal pain on tocilizumab, or sepsis.