The Importance of Genomic Testing in Children With Complex Autoimmune Cytopenias: Precision Medicine Is Not Just for Cancer

Evans syndrome (ES) is defined as the idiopathic autoimmune destruction of at least two hematologic cells types, including destruction of erythrocytes (autoimmune hemolytic anemia), platelets (immune thrombocytopenia), and neutrophils (autoimmune neutropenia).¹  ES is a diagnosis of exclusion, and when a patient is diagnosed with ES, it is important to exclude rheumatologic disease, infection, malignancy, and immune deficiency. Historically, these diagnoses that mimic ES were often made clinically or with functional testing, and they only represented a small proportion of patients presenting with multilineage autoimmune cytopenias. Based on the heterogeneous nature of the disease, patients with ES are typically treated with nonspecific medications that are commonly used to treat other idiopathic autoimmune cytopenia syndromes including corticosteroids, intravenous immunoglobulin, and rituximab.

Multiple reports demonstrate that a large fraction of patients with ES have comorbid benign lymphoproliferation (lymphadenopathy or hepatosplenomegaly), and a small fraction develop secondary malignancies.²  Based on these comorbid features, it was hypothesized and established that a fraction of patients with ES have a genetic syndrome termed autoimmune lymphoproliferative syndrome (ALPS).³  Distinguishing ES from ALPS is important because rituximab and splenectomy are relatively contraindicated in ALPS, but are commonly used to treat ES. Additionally, multiple studies have demonstrated that mycophenolate mofetil (cellcept) or sirolimus (rapamycin) are highly effective in ALPS.^4-6  Recent work has established dysregulated mTOR signaling drives the autoimmune disease and lymphoproliferation in ALPS, suggesting mTOR inhibitors are a targeted therapy for ALPS.^4,5 

Recently, Dr. Caroline Besnard and colleagues hypothesized that a large percentage of children diagnosed with ES may have other underlying genetic disorders.⁷  They evaluated 48 children with ES throughout an 18-year period. Thirty children had ALPS, and the authors performed sequencing on the remaining 18 children. Subjects who did not have mutations in ALPS-causative genes (FAS, FASL, or CASP10) or CTLA4 had whole-exome sequencing. Seven of 18 of the children were found to have genetic defects with mutations in CTLA4 (n=3), LRBA (n=1), STAT3 (n=1), and KRAS (n=1). These important results have significant implications, as many of these conditions have targeted therapies. CTLA4 haploinsufficiency with autoimmune infiltration (CHAI) and LRBA deficiency with autoantibodies, regulatory T cell defects, autoimmune infiltration, and enteropathy (LATAIE) are recently described disorders characterized by autoimmunity, lymphoproliferation, and infection. These patients can also develop severe autoimmune neurologic disease and inflammatory bowel disease. As LRBA regulates CTLA4, patients with CHAI and LATAIE have been shown to benefit from the CTLA4 agonist, abatacept.⁸  Ras-associated leukoproliferative disorder (RALD) is a recently described condition caused by somatic mutations in KRAS or NRAS in lymphocytes, leading to autoimmune disease and lymphoproliferation.⁹  Based on dysregulation of the MAPK signaling pathway, these patients may benefit from inhibitors of that pathway, including MEK-inhibitors. STAT3 gain-of-function mutations also lead to autoimmune disease and lymphoproliferation with hyperactive cytokine signaling through activation of JAK/STAT. Anecdotal reports suggest these patients may benefit from the IL6R inhibitor tocilizumab.¹⁰  In theory, these patients may benefit from JAK/STAT inhibitors, including ruxolitinib. In another recent report, Dr. Masatoshi Takagi and colleagues performed whole-exome sequencing in 15 children with autoimmune disease and lymphoproliferation, finding mutations in five causative genes — CTLA4 (n=2), STAT3 (n=1), TNFAIP3 (n=1), IKZF1 (n=1), and PSTPIP1 (n=1).¹¹  Finally, other groups have recently demonstrated that patients with mutations in PI3KCD or PI3KR1 can present with an ES phenotype and may benefit from PI3K-specific inhibitors such as leniolisib.¹²