Background Patients with systemic lupus erythematosus may develop secondary warm autoimmune hemolytic anemia (wAIHA). wAIHA is a rare condition characterized by the premature destruction of red blood ...cells (RBCs) mainly in the presence of pathogenic immunoglobulin G (IgG) autoantibodies that preferentially bind to RBCs at 37°C, resulting in extravascular hemolysis of these RBCs in the spleen (or liver). Nipocalimab is a high affinity, fully human, aglycosylated, effectorless monoclonal antibody that targets the neonatal Fc receptor (FcRn) to lower circulating IgG levels, including pathogenic autoantibodies. Here we describe the rationale and study design of ENERGY, an ongoing, adaptive, phase 2/3 multicenter, randomized, double-blind, placebo-controlled study that will evaluate the efficacy, safety, tolerability, pharmacokinetics, and pharmacodynamics of nipocalimab compared with placebo in patients with wAIHA (NCT04119050). Methods Subjects ≥18 years of age who have been diagnosed with primary idiopathic or secondary wAIHA and are currently receiving treatment for wAIHA or have previously received treatment for wAIHA will be included in the study. Stable doses of corticosteroids or immunosuppressants will be allowed. Approximately 111 patients will be randomized 1:1:1 to receive nipocalimab at two different dose schedules or placebo. Following completion of 24 weeks of double-blind treatment, patients may enter an open-label extension period to receive nipocalimab for 144 weeks with a follow-up period of 6 weeks after last assessment. Results ENERGY will include over 170 sites across nearly 20 countries. The primary endpoint is percentage of participants achieving durable response of improvement in hemoglobin (Hgb). The secondary endpoints include change from baseline in the total score from the Functional Assessment of Chronic Illness Therapy-Fatigue Scale, corticosteroid dose reduction from baseline, and normalization of hemolytic markers. Conclusions The results of ENERGY have the potential to identify a novel treatment option to address the significant unmet needs of patients with wAIHA. Enrollment is ongoing in this clinical trial.
Di‐monoubiquitination of the FANCI‐FANCD2 (ID2) complex is a central and crucial step for the repair of DNA interstrand crosslinks via the Fanconi anaemia pathway. While FANCD2 ubiquitination ...precedes FANCI ubiquitination, FANCD2 is also deubiquitinated at a faster rate than FANCI, which can result in a FANCI‐ubiquitinated ID2 complex (IUbD2). Here, we present a 4.1 Å cryo‐EM structure of IUbD2 complex bound to double‐stranded DNA. We show that this complex, like ID2Ub and IUbD2Ub, is also in the closed ID2 conformation and clamps on DNA. The target lysine of FANCD2 (K561) becomes fully exposed in the IUbD2‐DNA structure and is thus primed for ubiquitination. Similarly, FANCI's target lysine (K523) is also primed for ubiquitination in the ID2Ub‐DNA complex. The IUbD2‐DNA complex exhibits deubiquitination resistance, conferred by the presence of DNA and FANCD2. ID2Ub‐DNA, on the other hand, can be efficiently deubiquitinated by USP1‐UAF1, unless further ubiquitination on FANCI occurs. Therefore, FANCI ubiquitination effectively maintains FANCD2 ubiquitination in two ways: it prevents excessive FANCD2 deubiquitination within an IUbD2Ub‐DNA complex, and it enables re‐ubiquitination of FANCD2 within a transient, closed‐on‐DNA, IUbD2 complex.
Synopsis
Monoubiquitination of each subunit of the DNA‐clamping FANCI‐FANCD2 (ID2) complex is a central step in DNA interstrand crosslink repair via the Fanconi Anemia pathway. Here, structural and biochemical studies elucidate the interdependence of these two ubiquitination events.
Ubiquitination on any of the two subunits of the FANCI‐FANCD2 complex transforms the complex into a DNA clamp and promotes ubiquitination of the other subunit.
When ubiquitinated FANCI associates with DNA, both FANCI and FANCD2 are protected against deubiquitination by USP1‐UAF1.
Ubiquitin conjugated to FANCI forms extensive interactions with FANCD2, which further protect the FANCI‐ubiquitinated FANCI‐FANCD2‐DNA complex from deubiquitination.
A transient complex ubiquitinated only on FANCI, resulting from faster FANCD2 deubiquitination kinetics, remains clamped on DNA and favors FANCD2 re‐ubiquitination.
Summary
The inherited bone marrow failure syndromes (IBMFS) typically present with significant cytopenias in at least one haematopoietic cell lineage that may progress to pancytopenia, and are ...associated with increased risk of cancer. Although the clinical features of the IBMFS are often diagnostic, variable disease penetrance and expressivity may result in diagnostic dilemmas. The discovery of the genetic aetiology of the IBMFS has been greatly facilitated by next‐generation sequencing methods. This has advanced understanding of the underlying biology of the IBMFS and been essential in improving clinical management and genetic counselling for affected patients. Herein we review the clinical features, underlying biology, and new genomic discoveries in the IBMFS, including Fanconi anaemia, dyskeratosis congenita, Diamond Blackfan anaemia, Shwachman Diamond syndrome and some disorders of the myeloid and megakaryocytic lineages.
La Anemia de Fanconi (FA) es una condición genética que se caracteriza por falla de médula ósea y anomalías congénitas. El defecto se origina por mutaciones en la vía FA/BCRA. El diagnóstico ...citogenético se hace sometiendo la sangre del paciente a un clastogéno (diepoxibutano -DEB- o mitomicina C -MMC-) y se observa la presencia o ausencia de distintos efectos sobre los cromosomas tales como roturas en las cromátides o típicas figuras de intercambio cromosómico. El "gold standard" es el diagnóstico con el DEB. Sin embargo, se reconoce a la MMC como un agente de utilidad para este diagnóstico. El objetivo del trabajo fue evaluar si una concentración de MMC en pacientes pediátricos con sospecha de FA resulta útil como alternativa al DEB. Entre mayo 2019 y diciembre 2021, 100 niños sospechosos de FA y 22 controles (mediana de edad: 6 años) concurrieron al laboratorio de Citogenética para evaluación de Inestabilidad Cromosómica (IC) aplicando paralelamente los clastógenos DEB a 0,1 μg/ml y MMC a 50 ng/ml. Los pacientes se separaron en tres grupos: NO FA, FA y CONTROL. Se compararon los resultados de la prueba de IC (% de células aberrantes y roturas por células) para cada clastógeno respectivamente. Se obtuvieron metafases en el 81% de los test, en el 19% restante no había células en división, la mayoría correspondían a cultivos tratados con MMC. Los siete pacientes MMC (+) fueron además DEB (+) y pertenecían al grupo FA. Ningún cultivo DEB (-), resulto ser MMC (+). Este estudio concluye que MMC puede ser una buena alternativa al test de DEB en el diagnóstico de FA
Case Presentation: 76 year old female with past medical history(PMH) of hypertension, diabetes, non valvular atrial fibrillation presented with weakness and dyspnea on exertion for 2 weeks, she ...denied orthopnea, cough and sputum. Additional work up for AIHA showed positive direct coombs test, Warm Ab, ANA and anti-smith Ab, indeterminate dsDNA, low C3, C4, CH50 and negative cold aglutinins but no other features of Connective tissue disease on exam or in PMH.
Anemia remains a widespread public health problem. Although iron deficiency is considered the leading cause of anemia globally, the cause of anemia varies considerably by country. To achieve global ...targets to reduce anemia, reliable estimates of the contribution of nutritional and non-nutritional causes of anemia are needed to guide interventions. Inflammation is known to affect many biomarkers used to assess micronutrient status and can thus lead to incorrect diagnosis of individuals and to overestimation or underestimation of the prevalence of deficiency in a population. Reliable assessment of iron status is particularly needed in settings with high infectious disease burden, given the call to screen for iron deficiency to mitigate potential adverse effects of iron supplementation. To address these information gaps, in 2012 the CDC, National Institute for Child Health and Human Development, and Global Alliance for Improved Nutrition formed a collaborative research group called Biomarkers Reflecting Inflammation and Nutrition Determinants of Anemia (BRINDA). Data from nationally and regionally representative nutrition surveys conducted in the past 10 y that included preschool children and/or women of childbearing age were pooled. Of 25 data sets considered for inclusion, 17 were included, representing ∼30,000 preschool children, 26,000 women of reproductive age, and 21,000 school-aged children from all 6 WHO geographic regions. This article provides an overview of the BRINDA project and describes key research questions and programmatic and research implications. Findings from this project will inform global guidelines on the assessment of anemia and micronutrient status and will guide the development of a research agenda for future longitudinal studies.
Sutimlimab in Cold Agglutinin Disease Röth, Alexander; Barcellini, Wilma; D’Sa, Shirley ...
New England journal of medicine/The New England journal of medicine,
04/2021, Letnik:
384, Številka:
14
Journal Article
Recenzirano
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Cold agglutinin disease is a type of autoimmune hemolytic anemia. A total of 17 of 24 patients (71%) with cold agglutinin disease who received sutimlimab (a monoclonal antibody that targets the C1s ...protein, which activates the classic complement pathway) were transfusion-free at the end of the study.
Anemia is a common extraintestinal manifestation of inflammatory bowel disease (IBD), with a 6% to 74% prevalence and a negative impact on patient survival and quality of life, although the ...prevalence is apparently declining due to improved disease treatment. We aimed to investigate the prevalence, pathogenesis, and clinical correlates of anemia in Italian patients with IBD.
A multicenter, prospective, observational study, involving 28 Italian gastroenterology centers, was conducted to investigate the epidemiology and consequences of IBD-associated anemia. Clinical and laboratory data of anemic patients were obtained at study enrolment.
Anemia was diagnosed in 737 of 5416 adult IBD outpatients (prevalence 13.6%); females were more commonly affected than males (odds ratio, 1.5; 95% confidence interval CI, 1.2-1.7) and had more severe anemia. In the majority of cases, anemia was due to iron deficiency (62.5% of cases; 95% CI, 58.3%-66.6%), either isolated or in association with inflammation and/or vitamin deficiencies; anemia of inflammation accounted for only 8.3% of cases. More severe anemia was associated with increasing fatigue and worse quality of life. Only 68.9% of anemic patients with iron deficiency (95% CI, 63.4%-73.8%) and 34.6% of those with vitamin deficiencies (95% CI, 26.2%-44.2%) were properly treated with supplementation therapy.
In Italy, the prevalence of IBD-associated anemia is lower than previously reported. Anemia of IBD is most commonly due to iron deficiency and contributes to fatigue and poor quality of life, but remains untreated in a large proportion of patients with iron and/or vitamin deficiencies. This study is registered at clinicaltrials.gov as NCT02872376.
Anemia is a major public health concern. Young children, menstruating adolescent girls and women, and pregnant women are among the most vulnerable. Anemia is the consequence of a wide range of ...causes, including biological, socioeconomic, and ecological risk factors. Primary causes include: iron deficiency; inherited red blood cell disorders; infections, such as soil‐transmitted helminthiasis, schistosomiasis, and malaria; gynecological and obstetric conditions; and other chronic diseases that lead to blood loss, decreased erythropoiesis, or destruction of erythrocytes. The most vulnerable population groups in low‐ and middle‐income countries are often at the greatest risk to suffer from several of these causes simultaneously as low socioeconomic status is linked with an increased risk of anemia through multiple pathways. Targeted and effective action is needed to prevent anemia. Understanding the causes and risk factors of anemia for different population subgroups within a country guides the design and implementation of effective strategies to prevent and treat anemia. A coordinated approach across various expert groups and programs could make the best use of existing data or could help to determine when newer and more relevant data may need to be collected, especially in countries with a high anemia burden and limited information on the etiology of anemia.
Anemia is the consequence of a wide range of biological, socio‐economic, and ecological risk factors. Understanding causes and risk factors for different population groups is essential to target effective strategies to prevent and treat anemia. A coordinated approach could make the best use of existing data or determine when newer data should be collected, especially in countries with a high anemia burden, to design and implement the best strategies.
Aplastic Anemia Young, Neal S
New England journal of medicine/The New England journal of medicine,
10/2018, Letnik:
379, Številka:
17
Journal Article
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Once a uniformly fatal disease, aplastic anemia is now curable with allogeneic transplantation in 80% of children and 40% of adults, and immunosuppression with or without eltrombopag can induce long ...remissions in most adults.
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