Autoimmune hemolytic anemia and thrombocytopenia in a Chinese patient with heterozygous NBAS mutations: Case report.

RATIONALE: Neuroblastoma amplified sequence (NBAS)-associated disease is an autosomal recessive disorder and a broad spectrum of clinical symptoms has been reported. However, autoimmune mediated hemolytic anemia (AIHA) is rarely reported in NBAS disease. PATIENT CONCERNS: A now 21-year-old male harbors heterozygous variants of c.6840G>A and c.335 + 1G>A and was found had retarded growth, hypogammaglobulinemia, B lymphopenia, optic atrophy, horizontal nystagmus, slight splenomegaly and hepatomegaly since childhood. This case had normal hemoglobin level and platelet count in his childhood. He developed AIHA first in his adulthood and then thrombocytopenia during the treatment of AIHA. The mechanism underlying a case with pronounced hypogammaglobulinemia and B lymphopenia is elusive. In addition to biallelic NBAS mutations, a germline mutation in the ANKRD26 (c.2356C>T) gene was also detected. So either autoimmune or ANKRD26 mutation-mediated thrombocytopenia is possible in this case. INTERVENTION AND OUTCOME: He was initially managed with steroid and intermittent intravenous immunoglobulin supplement. After treatment, he responded well with a normalization of hemoglobin and serum bilirubin. But the patient subsequently experienced severe thrombocytopenia in addition to AIHA. He was then given daily avatrombopag in addition to steroid escalation. He responded again to new treatment, with the hemoglobin levels and platelet counts went back to the normal ranges. Now he was on de-escalated weekly avatrombopag and low-dose steroids maintenance. CONCLUSION: The phenotype of this case indicates that c.335 + 1G>A NBAS variant is probably a pathogenic one and c.2356C>T ANKRD26 variant is improbably a pathogenic one. AIHA may respond well to steroid even when happened in patients with NBAS disease.

Autoimmune cytopenias in children: When to think of primary immunodeficiency?

Autoimmune cytopenias are defined by autoantibodies' immune destruction of one or more blood elements. Most often it is autoimmune hemolytic anemia or immune thrombocytopenia or both that define Evans syndrome. It may be secondary to infection or to underlying pathology such as systemic autoimmune disease or primary immunodeficiency, especially when it becomes chronic over several years. Primary Immunodeficiencies or inborn errors of immunity (IEI) are no longer defined solely by infections: autoimmunity is part of the clinical features of several of these diseases. It is dominated by autoimmune cytopenias, in particular, immune thrombocytopenia (ITP) and autoimmune hemolytic anaemia (AIHA). The challenges for the clinician are the situations where autoimmune cytopenias are chronic, recurrent and/or refractory to the various long-term therapeutic options. Most of these therapies are similar in action and generally consist of non-mediated immune suppression or modulation. In these situations, primary Immunodeficiencies must be diagnosed as soon as possible to allow the initiation of a targeted treatment and to avoid several ineffective therapeutic lines.

Healthcare resource utilization of patients with warm autoimmune hemolytic anemia initiating first line therapy of oral corticosteroids with or without rituximab.

This retrospective cohort study described real-world treatment patterns and healthcare resource utilization (HCRU) of patients with warm autoimmune hemolytic anemia (wAIHA) initiating treatment with first-line (1L) oral corticosteroids (OCS) + rituximab (R) compared to 1L OCS. Patients with a wAIHA diagnosis code (D59.11) between 8/2020-3/2022 were identified using US pharmacy and medical claims databases. Patients initiating 1L OCS ± R were identified (date of initiation = 'index date') with a 1-year pre-index period and a variable (minimum 1-year) follow-up period. The final sample comprised 77 1L OCS + R patients and 400 1L OCS patients (~ 60% female, mean age > 64 years). Over the 1-year follow-up, HCRU was higher in the OCS + R cohort with higher mean number of physician office visits (22.9 and 14.4; p < 0.01), including hematology/oncology office visits, and higher utilization of rescue therapy (59.7% and 33.3%; p < 0.01), driven by higher use of injectable corticosteroids. Patients in OCS + R and OCS groups completed 1L therapy after a similar mean duration of 103.5 and 134.6 days, respectively (p = 0.24). In the majority of patients, second-line (2L) therapy was initiated at a similar timepoint: 66.2% OCS + R and 72.0% OCS cohorts (p = 0.31) initiated 2L in a mean of 218.3 and 203.2 days (p = 0.76) after the end of 1L treatment, respectively. The addition of rituximab in 1L did not extend the remission period, with most patients in both cohorts initiating 2L therapy within less than 1 year of completing 1L treatment. 1L OCS + R patients also had substantial HCRU burden. More effective novel therapies are needed to address the high unmet need in wAIHA.

Autoimmune Hemolytic Anemia in Children: Clinical Profile and Outcome.

OBJECTIVE: To discover the common triggers for AIHA in children, their clinical profile, treatment response, and outcome. METHODS: This was an ambispective descriptive study conducted between 2013 and 2020. Children aged 1 mo to 14 y with hemolytic anemia and a positive direct antiglobulin test (DAT) were included. Children with a positive DAT but without any clinicolaboratory evidence of hemolysis were excluded. Data were collected from a structured pro forma with particulars comprising clinicolaboratory profile, treatment administered, and disease outcome. RESULTS: A total of 46 children (aged between 1 mo and 14 y) were enrolled in the study. The mean age of onset was 8.7 (± 4.34) y, and 24 (52.8%) were males. Secondary causes were observed in 29 (63%) cases, while the primary cause was found in 17 (37%). Systemic lupus erythematosus (SLE) was the common trigger in 13 (45%) cases, followed by malignancy in 4 (14%) cases. Pallor (98%), hepatomegaly (72%), and splenomegaly (48%) were the most commonly observed clinical signs. The mixed immunophenotype was observed in 27 (59%) cases, followed by warm type in 12 (26%) and cold agglutinin type in 7 (15%) cases. All children received glucocorticoid therapy, and mycophenolate mofetil was commonly used as second-line therapy in 15 (33%) cases. 13 cases (71%) of primary AIHA and only 4 (14%) cases of secondary anemia achieved complete remission. Overall, 7 children (15%) died, all belonging to secondary AIHA. CONCLUSION: Secondary AIHA was more common than primary in the present study, and SLE was the standard trigger. Primary AIHA carries a better prognosis than secondary.

Prevention of Rhesus-D Alloimmunization in the First Trimester of Pregnancy: Economic Analysis of Three Management Strategies.

Anti-D alloimmunization in the first trimester of pregnancy has long been the subject of prevention with anti-D immunoglobulins during events at risk of fetomaternal hemorrhage. Although the efficacy of preventing anti-D alloimmunization by an injection of immunoglobulin at 28 weeks of gestation (WG) is obvious, the literature provides little evidence of the effectiveness before 12+6 WG and several countries have modified their recommendations. In the presumed absence of a difference in alloimmunization risk between early and late prevention, our objective was to evaluate and compare the cost of treatment for 3 alloimmunization prevention strategies in France, the United Kingdom, and the Netherlands. This was a single-center retrospective study. Our target population included all women who received anti-D immunoglobulins (Rhophylac) in the first trimester of pregnancy before 12+6 WG at Nantes University Hospital in 2018 (N = 356). Within the target population, 2 other populations were constituted based on British (N = 145) and Dutch (N = 142) clinical practice guidelines (CPG). These 3 populations were analyzed for the comparative cost of treatment for prevention from a health system perspective. The average cost of Rhophylac alloimmunization prevention for 1 episode was €117.8 from a health system perspective. The total cost attributed to prevention in 2018 at Nantes University Hospital (N = 356) was €41,931.4 according to this perspective. If the UK CPG or Dutch CPG had been applied to the Nantes target population, a saving of around 60% would have been achieved. At the national level, the cost according to the health system perspective specifically attributable to induced abortion (N estimated = 26,916) could represent a total cost of €3,170,704. This study highlighted the high cost of the French prevention strategy in the first trimester of pregnancy compared with British or Dutch strategies. The modification of our practices would allow substantial financial savings to the French health system but would also avoid the nonrecommended exposure to a blood product at this term, would allow a faster medical management and a relief of the care system.

Fostamatinib for warm antibody autoimmune hemolytic anemia: Phase 3, randomized, double-blind, placebo-controlled, global study (FORWARD).

Warm antibody autoimmune hemolytic anemia (wAIHA) is characterized by hemolysis and symptomatic anemia with no approved treatment options. Fostamatinib is an oral spleen tyrosine kinase inhibitor approved in the US and Europe for treatment of adults with chronic immune thrombocytopenia. In this phase 3 study, patients with an insufficient response to ≥1 prior wAIHA treatment were randomized to fostamatinib or placebo. The primary endpoint was the proportion of patients to achieve a durable hemoglobin (Hgb) response (Hgb ≥10 g/dL and increase from baseline of ≥2 g/dL on 3 consecutive visits) during the 24-week treatment period. Ninety patients were randomized, 45 to each arm. Of the fostamatinib-treated patients, 35.6% achieved a durable Hgb response versus 26.7% on placebo (p = .398). A post hoc analysis revealed a large placebo response in Eastern European patients. Significantly more patients on fostamatinib from North America, Australia and Western Europe exhibited a durable Hgb response compared to placebo (36% vs. 10.7%, p = .030). After censoring for Hgb values impacted by steroid rescue received during screening and excluding 2 placebo patients found to likely not have wAIHA, a reanalysis demonstrated a difference in durable Hgb response between fostamatinib and placebo (15/45 [33.3%] vs. 6/43 [14.0%], p = .0395). At least 1 AE was reported in 42 (93.3%) and 40 (88.9%) patients receiving fostamatinib and placebo, respectively. The most common AEs in the fostamatinib group were diarrhea (26.7%), hypertension (24.4%), and fatigue (15.6%). In this study, fostamatinib demonstrated a clinically meaningful benefit for patients in Western regions, and no new safety signals were identified.

Safety, tolerability, and activity of the active C1s antibody riliprubart in cold agglutinin disease: a phase 1b study.

ABSTRACT: Cold agglutinin disease is a rare autoimmune hemolytic anemia characterized by complement pathway-mediated hemolysis. Riliprubart (SAR445088, BIVV020), a second-generation classical complement inhibitor, is a humanized monoclonal antibody that selectively inhibits only the activated form of C1s. This Phase 1b study evaluated the safety, tolerability, and effect on hemolysis of riliprubart in adult patients with cold agglutinin disease. On day 1, 12 patients received a single IV dose of either 30 mg/kg (n = 6) or 15 mg/kg (n = 6) of riliprubart and were subsequently followed for 15 weeks. Riliprubart was generally well tolerated; there were no treatment-emergent serious adverse events, or treatment-emergent adverse events leading to death or permanent study discontinuation. There were no reports of serious infections, encapsulated bacterial infections including meningococcal infections, hypersensitivity, or thromboembolic events. Rapid improvements in hemoglobin (day 5) and bilirubin (day 1) were observed in both treatment cohorts. Mean hemoglobin levels were maintained at >11.0 g/dL from day 29 and mean levels of bilirubin were normalized by day 29; both responses were maintained throughout the study. Improvements in clinical markers closely correlated with a sustained reduction in the 50% hemolytic complement (CH50) throughout the study. Mean C4 levels, an in vivo marker of treatment activity, increased 1 week after treatment with either dose of riliprubart and were sustained throughout the study. In conclusion, a single IV dose of riliprubart was well tolerated, and led to rapid classical complement inhibition, control of hemolysis, and improvement in anemia, all of which were sustained over 15 weeks. This trial was registered at www.ClinicalTrials.gov as #NCT04269551.

Autoimmune Cytopenias Are Highly Associated with Inborn Errors of Immunity and They May Be the Initial Presentations in Cases without Severe Infections.

INTRODUCTION: Inborn errors of immunity (IEIs) are inherited disorders that present with increased susceptibility to infections as well as noninfectious complications. Due to the aberrant immune functions of patients with IEI, autoimmune cytopenia (AIC) may be the initial finding, which makes diagnosis a challenge. We aimed to evaluate the clinical course, laboratory findings, and treatment response of AIC in children with IEI. METHODS: Data of children with autoimmune hemolytic anemia (AIHA) and/or immune thrombocytopenic purpura (ITP) were obtained from a retrospective chart review of IEI patients diagnosed and followed in our center. Demographic and clinical features and therapeutic outcomes were evaluated. Immunologic findings were compared between patients with AIHA, ITP, and Evans syndrome (ES). The patients were also divided into two subgroups based on the presence or absence of immune dysregulation diseases (IDDs), and all data were compared between these two groups. RESULTS: Out of 562 patients with IEI, 6% (n: 34) had AIC which were ITP (23.5%), AIHA (35.5%), and ES (41.2%). AIC was the initial finding in 50% of these 34 patients. Patients with ES had a higher mean percentage of CD8+ T lymphocytes than ITP patients (40.77 ± 20.21% vs. 22.33 ± 12.48%, p = 0.011). Patients with IDDs were more likely to develop ES (p = 0.004), lymphoproliferation (p = 0.005), and resistance to first-line therapy (p = 0.021) than other IEI groups. CONCLUSION: This study shows that AIC may be the initial finding of IEI, particularly when lymphoproliferation and resistance to first-line therapy co-occur. Therefore, detailed investigation should be offered to all patients to avoid diagnostic delay.

Sirolimus is effective for primary refractory/relapsed warm autoimmune haemolytic anaemia/Evans syndrome: a retrospective single-center study.

BACKGROUND: Some patients with warm autoimmune haemolytic anaemia (wAIHA) or Evans syndrome (ES) have no response to glucocorticoid or relapse. Recent studies found that sirolimus was effective in autoimmune cytopenia with a low relapse rate. METHODS: Data from patients with refractory/relapsed wAIHA and ES in Peking Union Medical College Hospital from July 2016 to May 2022 who had been treated with sirolimus for at least 6 months and followed up for at least 12 months were collected retrospectively. Baseline and follow-up clinical data were recorded and the rate of complete response (CR), partial response (PR) at different time points, adverse events, relapse, outcomes, and factors that may affect the efficacy and relapse were analyzed. RESULTS: There were 44 patients enrolled, with 9 (20.5%) males and a median age of 44 (range: 18-86) years. 37 (84.1%) patients were diagnosed as wAIHA, and 7 (15.9%) as ES. Patients were treated with sirolimus for a median of 23 (range: 6-80) months and followed up for a median of 25 (range: 12-80) months. 35 (79.5%) patients responded to sirolimus, and 25 (56.8%) patients achieved an optimal response of CR. Mucositis (11.4%), infection (9.1%), and alanine aminotransferase elevation (9.1%) were the most common adverse events. 5/35 patients (14.3%) relapsed at a median of 19 (range: 15-50) months. Patients with a higher sirolimus plasma trough concentration had a higher overall response (OR) and CR rate (p = 0.009, 0.011, respectively). At the time of enrolment, patients were divided into two subgroups that relapsed or refractory to glucocorticoid, and the former had poorer relapse-free survival (p = 0.032) than the other group. CONCLUSION: Sirolimus is effective for patients with primary refractory/relapsed wAIHA and ES, with a low relapse rate and mild side effects. Patients with a higher sirolimus plasma trough concentration had a higher OR and CR rate, and patients who relapsed to glucocorticoid treatment had poorer relapse-free survival than those who were refractory.

Rare case of refractory mixed autoimmune hemolytic anemia in a 6-year-old child: a case report.

BACKGROUND: Mixed autoimmune hemolytic anemia (AIHA) shows combined clinical and laboratory characteristics of warm and cold AIHA. It is relatively uncommon in children. Consequently, knowledge about mixed AIHA prevalence, clinical presentation, treatment options, and prognosis in children is limited to very few case reports. CASE PRESENTATION: We describe a six-year-old Asian girl presenting with profound anemia, blood group typing discrepancy and crossmatch incompatibility, post upper respiratory tract infection. Detection of red cell warm and cold reactive autoantibodies, led to the diagnosis of mixed AIHA. Autoantibodies with laboratory evidence of hemolysis persisted despite high dose steroid therapy. Due to the inability to wean further, the patient was subsequently commenced on mycophenolate mofetil to which she seems to be responding. CONCLUSIONS: Mixed AIHA may be notoriously difficult to diagnose and treat. Detailed clinical and laboratory work-up is essential to establish the diagnosis. To the best of our knowledge, this is the first case report of mixed AIHA following upper respiratory tract infection. Awareness of this occurrence is important, as similar to warm AIHA, mixed AIHA should be treated immediately by early initiation of steroid therapy. In addition, prompt supportive care as well as long-term clinical follow-up are required to improve outcomes of these cases.

Hemoglobin cast nephropathy: a rare but serious complication of hemolysis in a pediatric patient.

BACKGROUND: Intravascular hemolysis is a serious and rare condition in children and causes the release of hemoglobin and heme into circulation, which have proinflammatory properties. These substances lead to inflammation, oxidative stress, apoptosis, and organelle dysfunction that lead to acute kidney injury (AKI). We report a pediatric case diagnosed with hemolysis-associated hemoglobin cast nephropathy due to autoimmune hemolytic anemia. CASE: A 4-year-old boy, who was admitted to another hospital with complaints of fever and dark urine for one day, developed anemia and kidney failure in the follow-up, was referred to our hospital. In physical examination, pallor and icterus on the sclera were noted. The patient had low hemoglobin and haptoglobin levels concomitant with high levels of serum lactate dehydrogenase, urea and creatinine. A peripheral blood smear showed marked spherocytes without schistocytes. A kidney biopsy was performed due to ongoing overt hemolysis and dialysis requirement, which showed findings consistent with hemoglobin cast nephropathy. Although the initial polyspecific direct antiglobulin test (DAT) was negative, due to persistent intravascular hemolysis DAT was studied monospecifically and showed IgM antibody positivity. Therefore, a diagnosis of autoimmune hemolytic anemia was made, and corticosteroid treatment was started. Hemolysis immediately ceased and the need for erythrocyte transfusion and dialysis disappeared. CONCLUSIONS: Acute kidney injury associated with hemoglobin cast nephropathy is an extremely rare condition in childhood. Although the initial course is severe and potentially life-threatening, the prognosis is favorable with the treatment of the underlying cause and management of AKI. Therefore, pediatricians should be aware of this rare clinical entity during clinical practice.

Antibody based therapeutics for autoimmune hemolytic anemia.

INTRODUCTION: Autoimmune hemolytic anemia (AIHA) treatment has been revolutionized by the introduction of target therapies, mainly monoclonal antibodies (MoAbs). AREAS COVERED: The anti-CD20 rituximab, which targets Ab production by B-cells, induces 80% of response in warm-type AIHA (wAIHA) and 50-60% in cold agglutinin disease (CAD). Other B-cell targeting MoAbs including ianalumab, povetacicept, and obexelimab are under active study. The anti-CD38 MoAb daratumumab has been used in several reports to target long-lived plasma-cells responsible for AIHA relapse, being effective even in multi-refractory cases. Anti-complement MoAbs will soon change the treatment paradigm in CAD; the anti-C1s sutimlimab rapidly increased Hb in more than 80% of the cases. Finally, MoAbs inhibiting the neonatal Fc receptor (FcRn), such as nipocalimab, can reduce the half-life of the pathogenic autoAbs, representing a promising treatment for wAIHA. EXPERT OPINION: MoAbs offer the potential to improve efficacy by reducing toxicity. However, there is a huge need for clinical trials exploring response duration rather than short-term efficacy. Complement inhibitors and anti-FcRns do not abrogate autoAb production and are being developed as long-term therapies. Thus, the combination of B-cell/plasma cell targeting drugs deserves to be explored. On the other hand, their rapid efficacy should be exploited for the acute AIHA phase.

A case of cold agglutinin disease in a bottlenose dolphin (Tursiops truncatus).

Cold agglutinin disease, one of the serological classifications of immune-mediated hemolytic anemia, is caused by the production of autoantibodies that react with erythrocytes at low temperatures. A captive bottlenose dolphin presented with regenerative and hemolytic anemia. Anticoagulated whole blood was agglutinated at room temperature (approximately 18°C), with reversal of agglutination on warming to 37°C, indicating the presence of cold agglutinin. Based on these findings, this animal was diagnosed with cold agglutinin disease. Clindamycin, doxycycline, and prednisolone were administered orally to treat the infection and immune-mediated hemolytic anemia. Anemia gradually improved after initiation of pharmacotherapy, and erythrogenesis slowed as erythroblasts disappeared and reticulocyte count decreased in peripheral blood. This represents the first report of cold agglutinin disease in a cetacean.

[Novel therapeutic agents for hemolytic anemia].

In recent years, it has become clear that various diseases are caused by complement (related molecule) abnormalities (complementopathies) or are exacerbated by complement (complement-related diseases), and novel therapeutic agents targeting complement (anti-complement agents) are now being developed. Paroxysmal nocturnal hemoglobinuria (PNH) is a hematopoietic stem cell disorder characterized by complement-mediated intravascular hemolysis due to a deficiency of complement regulatory factors, making it a perfect candidate for anti-complement agents. In 2007, the anti-C5 monoclonal antibody eculizumab was approved for PNH, as the first anti-complement agent. The indications for eculizumab are expanding, and aggressive development is underway for new anti-complement agents, not only for PNH but also a variety of other diseases. In addition, the anti-C1s antibody sutimlimab was approved last year for the treatment of cold agglutinin disease, a form of autoimmune hemolytic anemia. This presentation overviews novel anti-complement agents for these hemolytic anemias.