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 caus...
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2021-03-01
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| Series: | BMC Immunology |
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| Online Access: | https://doi.org/10.1186/s12865-021-00411-1 |
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doaj-61c440be3029403faa4a07ceae0b4e4f2021-03-21T12:52:59ZengBMCBMC Immunology1471-21722021-03-012211910.1186/s12865-021-00411-1Efficacy of tocilizumab therapy in a patient with severe pancytopenia associated with a STAT3 gain-of-function mutationWenjie Wang0Luyao Liu1Xiaoying Hui2Ying Wang3Wenjing Ying4Qinhua Zhou5Jia Hou6Mi Yang7Bijun Sun8Jinqiao Sun9Xiaochuan Wang10Department of Clinical Immunology, Children’s Hospital of Fudan University, National Children’s Medical CenterDepartment of Clinical Immunology, Children’s Hospital of Fudan University, National Children’s Medical CenterDepartment of Clinical Immunology, Children’s Hospital of Fudan University, National Children’s Medical CenterDepartment of Clinical Immunology, Children’s Hospital of Fudan University, National Children’s Medical CenterDepartment of Clinical Immunology, Children’s Hospital of Fudan University, National Children’s Medical CenterDepartment of Clinical Immunology, Children’s Hospital of Fudan University, National Children’s Medical CenterDepartment of Clinical Immunology, Children’s Hospital of Fudan University, National Children’s Medical CenterDepartment of Clinical Immunology, Children’s Hospital of Fudan University, National Children’s Medical CenterDepartment of Clinical Immunology, Children’s Hospital of Fudan University, National Children’s Medical CenterDepartment of Clinical Immunology, Children’s Hospital of Fudan University, National Children’s Medical CenterDepartment of Clinical Immunology, Children’s Hospital of Fudan University, National Children’s Medical CenterAbstract 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.https://doi.org/10.1186/s12865-021-00411-1STAT3 transcription factorTocilizumabImmune DysregulationGain-of-function mutations |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Wenjie Wang Luyao Liu Xiaoying Hui Ying Wang Wenjing Ying Qinhua Zhou Jia Hou Mi Yang Bijun Sun Jinqiao Sun Xiaochuan Wang |
| spellingShingle |
Wenjie Wang Luyao Liu Xiaoying Hui Ying Wang Wenjing Ying Qinhua Zhou Jia Hou Mi Yang Bijun Sun Jinqiao Sun Xiaochuan Wang Efficacy of tocilizumab therapy in a patient with severe pancytopenia associated with a STAT3 gain-of-function mutation BMC Immunology STAT3 transcription factor Tocilizumab Immune Dysregulation Gain-of-function mutations |
| author_facet |
Wenjie Wang Luyao Liu Xiaoying Hui Ying Wang Wenjing Ying Qinhua Zhou Jia Hou Mi Yang Bijun Sun Jinqiao Sun Xiaochuan Wang |
| author_sort |
Wenjie Wang |
| title |
Efficacy of tocilizumab therapy in a patient with severe pancytopenia associated with a STAT3 gain-of-function mutation |
| title_short |
Efficacy of tocilizumab therapy in a patient with severe pancytopenia associated with a STAT3 gain-of-function mutation |
| title_full |
Efficacy of tocilizumab therapy in a patient with severe pancytopenia associated with a STAT3 gain-of-function mutation |
| title_fullStr |
Efficacy of tocilizumab therapy in a patient with severe pancytopenia associated with a STAT3 gain-of-function mutation |
| title_full_unstemmed |
Efficacy of tocilizumab therapy in a patient with severe pancytopenia associated with a STAT3 gain-of-function mutation |
| title_sort |
efficacy of tocilizumab therapy in a patient with severe pancytopenia associated with a stat3 gain-of-function mutation |
| publisher |
BMC |
| series |
BMC Immunology |
| issn |
1471-2172 |
| publishDate |
2021-03-01 |
| description |
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. |
| topic |
STAT3 transcription factor Tocilizumab Immune Dysregulation Gain-of-function mutations |
| url |
https://doi.org/10.1186/s12865-021-00411-1 |
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