Efficacy of tocilizumab therapy in a patient with severe pancytopenia associated with a STAT3 gain-of-function mutation

Abstract

Background We aimed to report the clinical characteristics, immunological features, and treatment of one patient with a de novo STAT3 gain-of-function mutation identified by next generation sequencing. We investigated the efficacy of tocilizumab therapy in immune dysregulation diseases caused by STAT3 mutation. Results The patient was a 16-year-old girl. She presented with recurrent respiratory infections and chronic diarrhea after birth. She had life-threatening autoimmune pancytopenia at 14 years old. After receiving glucocorticoid therapy, she developed diabetes. However, her pancytopenia relapsed when the glucocorticoid was tapered. Next-generation sequencing showed a de novo heterozygous mutation in the STAT3 gene, c.1261G > A (p. G421R), which was previously described as a gain-of-function mutation. After tocilizumab therapy, her pancytopenia fully resolved, and insulin and glucocorticoid therapies were gradually discontinued within 12 months. She had lymphopenia and an inverted CD4/CD8 ratio before therapy. Lymphocyte subpopulation analysis indicated an expansion of effector memory CD4+, effector memory CD8+ and central memory CD4+ T cells. The proportions of memory B cells and naive CD4+ T cells were decreased, and the proportion of naïve B cells was increased. None of the abnormal lymphocytic changes improved significantly. STAT3 GOF mutations were identified by next gene sequencing in those with early-onset multi-organ autoimmunity. Including our patient, 13 patients with STAT3 GOF mutations received targeted treatment. Twelve of them were treated with tocilizumab alone or combination tocilizumab with JAK inhibitor, and ten patients improved. Conclusions Gene sequencing should be performed for patients with early-onset refractory or multiorgan immune dysregulation diseases. Targeted drugs can effectively improve the clinical problems associated with STAT3 gain-of-function mutations, while nontargeted immunosuppressive therapy is usually insufficient.

JAK/STAT defects and immune dysregulation, and guiding therapeutic choices

“…Therefore, jakinibs were employed with good results in more broadly controlling end organ disease. 86,103,104 Jakinib therapy alone or in combination with IL-6 blockade are effective, targeted therapies and should be considered for the management of STAT3 GOF.…”

“…It quickly became apparent that IL‐6 inhibition alone was not sufficient to control disease, because STAT3 is downstream of many other cytokines and this signaling was not altered in its entirety by tocilizumab therapy alone. Therefore, jakinibs were employed with good results in more broadly controlling end organ disease 86,103,104 . Jakinib therapy alone or in combination with IL‐6 blockade are effective, targeted therapies and should be considered for the management of STAT3 GOF.…”

Precision medicine: The use of tailored therapy in primary immunodeficiencies

“…This drug was initially studied for rheumatoid arthritis at a dosage of 4-8 mg/kg with infusions every 4 weeks ( 170 ). Currently is used in patients with STAT-3 GOF ( 171 ). STAT-3 is part of a pathway that stimulates the production of IL-6 and GOF mutations, has previously described, are associated to auto-inflammatory manifestations, hypogammaglobulinemia and other conditions like type I diabetes.…”

“…STAT-3 is part of a pathway that stimulates the production of IL-6 and GOF mutations, has previously described, are associated to auto-inflammatory manifestations, hypogammaglobulinemia and other conditions like type I diabetes. At a dosage of 8 mg/kg every two weeks, after 2 months treatment with toculizumab, a remission of the pancytopenia was documented, as well as the need for insulinotherapy ( 171 ). Tocilizumab has also been administrated in patients with RAG deficiency, although the full associated mechanism and long-term effects are not known ( 172 ).…”

A human STAT3 gain-of-function variant confers T cell dysregulation without predominant Treg dysfunction in mice

“…To further investigate the role of STAT3 GOF in immune dysregulation and Tregs, we developed a mouse model of STAT3 GOF with a DNA-binding domain variant identified in patients, p.G421R, on the C57BL/6 background. Patients with this variant have presented with multiorgan involvement, including autoimmune cytopenias, lymphadenopathy, hepatosplenomegaly, autoimmune hepatitis, scleroderma, polyarthritis, respiratory infections, enteropathy, and short stature ( 14 , 18 – 20 ). Using this mouse model, we performed a series of phenotypic and functional studies, focusing on Tregs, given the previously noted Treg deficiency in patients.…”