Refractory autoimmune cytopenias in pediatric Evans syndrome with underlying systemic immune dysregulation

Grimes, Amanda; Kim, Taylor O; Kirk, Susan E.; Flanagan, Jonathan M.; Lambert, Michele P.; Grace, Rachael F.; Despotovic, Jenny M.

doi:10.1111/ejh.13600

Cited by 12 publications

(14 citation statements)

References 23 publications

(38 reference statements)

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“…The first found seven pathogenic variants on CTLA4 , LRBA , STAT3 , and KRAS genes in a cohort of 18 children with ES ( 14 ), whereas the second identified an underlying genetic defect in 65% of cases and showed that patients carrying variants displayed a more severe disease and required more lines of treatment versus the ones without ( 15 ). Similar findings came from another multicentre study on 60 children where underlying immune dysregulation was detected in 42% of cases ( 6 ). This is relevant because the detection of specific monogenic defects may not only address a correct diagnosis, but also enable the use of targeted therapies ( 4 , 16 – 18 ).…”

Section: Introductionsupporting

confidence: 86%

“…Evans syndrome (ES) is a rare disorder classically defined by the concomitant or sequential presence of autoimmune haemolytic anaemia (AIHA) and immune thrombocytopenia (ITP) ( 1 – 3 ), but it is also described as cytopenia due to the immune-mediated destruction of at least two blood cells lineages ( 4 – 6 ). It can be either idiopathic or secondary to other conditions, such as infections, inborn errors of immunity (IEI), autoimmune and rheumatologic diseases, malignancies, and drugs.…”

Section: Introductionmentioning

confidence: 99%

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Underlying Inborn Errors of Immunity in Patients With Evans Syndrome and Multilineage Cytopenias: A Single-Centre Analysis

et al. 2022

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BackgroundEvans syndrome (ES) is a rare disorder classically defined as the simultaneous or sequential presence of autoimmune haemolytic anaemia and immune thrombocytopenia, but it has also been described as the presence of at least two autoimmune cytopenias. Recent reports have shown that ES is often a manifestation of an underlying inborn error of immunity (IEI) that can benefit from specific treatments.AimsThe aim of this study is to investigate the clinical and immunological characteristics and the underlying genetic background of a single-centre cohort of patients with ES.MethodsData were obtained from a retrospective chart review of patients with a diagnosis of ES followed in our centre. Genetic studies were performed with NGS analysis of 315 genes related to both haematological and immunological disorders, in particular IEI.ResultsBetween 1985 and 2020, 40 patients (23 men, 17 women) with a median age at onset of 6 years (range 0–16) were studied. ES was concomitant and sequential in 18 (45%) and 22 (55%) patients, respectively. Nine of the 40 (8%) patients had a positive family history of autoimmunity. Other abnormal immunological features and signs of lymphoproliferation were present in 24/40 (60%) and 27/40 (67%) of cases, respectively. Seventeen out of 40 (42%) children fit the ALPS diagnostic criteria. The remaining 21 (42%) and 2 (5%) were classified as having an ALPS-like and an idiopathic disease, respectively. Eighteen patients (45%) were found to have an underlying genetic defect on genes FAS, CASP10, TNFSF13B, LRBA, CTLA4, STAT3, IKBGK, CARD11, ADA2, and LIG4. No significant differences were noted between patients with or without variant and between subjects with classical ES and the ones with other forms of multilineage cytopenias.ConclusionsThis study shows that nearly half of patients with ES have a genetic background being in most cases secondary to IEI, and therefore, a molecular evaluation should be offered to all patients.

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Section: Introductionsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Underlying Inborn Errors of Immunity in Patients With Evans Syndrome and Multilineage Cytopenias: A Single-Centre Analysis

et al. 2022

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“…Indeed, some specific immunological alterations, if accompanied with AIHA, ITP, autoimmune neutropenia (AIN), or their combinations (Evans syndrome, ES) could be significant red flags for an associated IEI ( 13 ). These include both humoral and cell-mediated immune defects, like reduced serum immunoglobulin levels and low T cell counts ( 3 , 12 , 14 , 15 ), while only scant evidence regarding deeper immunological studies in AICs is available ( 16 ).…”

Section: Introductionmentioning

confidence: 99%

Autoimmune Cytopenias and Dysregulated Immunophenotype Act as Warning Signs of Inborn Errors of Immunity: Results From a Prospective Study

et al. 2022

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Inborn errors of immunity (IEI) are genetic disorders characterized by a wide spectrum of clinical manifestations, ranging from increased susceptibility to infections to significant immune dysregulation. Among these, primary immune regulatory disorders (PIRDs) are mainly presenting with autoimmune manifestations, and autoimmune cytopenias (AICs) can be the first clinical sign. Significantly, AICs in patients with IEI often fail to respond to first-line therapy. In pediatric patients, autoimmune cytopenias can be red flags for IEI. However, for these cases precise indicators or parameters useful to suspect and screen for a hidden congenital immune defect are lacking. Therefore, we focused on chronic/refractory AIC patients to perform an extensive clinical evaluation and multiparametric flow cytometry analysis to select patients in whom PIRD was strongly suspected as candidates for genetic analysis. Key IEI-associated alterations causative of STAT3 GOF disease, IKAROS haploinsufficiency, activated PI3Kδ syndrome (APDS), Kabuki syndrome and autoimmune lymphoproliferative syndrome (ALPS) were identified. In this scenario, a dysregulated immunophenotype acted as a potential screening tool for an early IEI diagnosis, pivotal for appropriate clinical management and for the identification of new therapeutic targets.

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“…Patients with an underlying IEI may often required more second-and third-line immunomodulating therapies and may benefit from a specific target therapy ( 36 ) ( 35 ).…”

Section: Management Of Patients With Autoimmune Cytopeniasmentioning

confidence: 99%

Pathogenesis of Autoimmune Cytopenias in Inborn Errors of Immunity Revealing Novel Therapeutic Targets

et al. 2022

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Autoimmune diseases are usually associated with environmental triggers and genetic predisposition. However, a few number of autoimmune diseases has a monogenic cause, mostly in children. These diseases may be the expression, isolated or associated with other symptoms, of an underlying inborn error of immunity (IEI). Autoimmune cytopenias (AICs), including immune thrombocytopenic purpura (ITP), autoimmune hemolytic anemia (AIHA), autoimmune neutropenia (AN), and Evans’ syndrome (ES) are common presentations of immunological diseases in the pediatric age, with at least 65% of cases of ES genetically determined. Autoimmune cytopenias in IEI have often a more severe, chronic, and relapsing course. Treatment refractoriness also characterizes autoimmune cytopenia with a monogenic cause, such as IEI. The mechanisms underlying autoimmune cytopenias in IEI include cellular or humoral autoimmunity, immune dysregulation in cases of hemophagocytosis or lymphoproliferation with or without splenic sequestration, bone marrow failure, myelodysplasia, or secondary myelosuppression. Genetic characterization of autoimmune cytopenias is of fundamental importance as an early diagnosis improves the outcome and allows the setting up of a targeted therapy, such as CTLA-4 IgG fusion protein (Abatacept), small molecule inhibitors (JAK-inhibitors), or gene therapy. Currently, gene therapy represents one of the most attractive targeted therapeutic approaches to treat selected inborn errors of immunity. Even in the absence of specific targeted therapies, however, whole exome genetic testing (WES) for children with chronic multilineage cytopenias should be considered as an early diagnostic tool for disease diagnosis and genetic counseling.

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Refractory autoimmune cytopenias in pediatric Evans syndrome with underlying systemic immune dysregulation

Cited by 12 publications

References 23 publications

Underlying Inborn Errors of Immunity in Patients With Evans Syndrome and Multilineage Cytopenias: A Single-Centre Analysis

Underlying Inborn Errors of Immunity in Patients With Evans Syndrome and Multilineage Cytopenias: A Single-Centre Analysis

Autoimmune Cytopenias and Dysregulated Immunophenotype Act as Warning Signs of Inborn Errors of Immunity: Results From a Prospective Study

Pathogenesis of Autoimmune Cytopenias in Inborn Errors of Immunity Revealing Novel Therapeutic Targets

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