Primary Autoimmune Hemolytic Anemia Research Articles

Risk of hospitalization with infection in adults with primary AIHA treated with rituximab: a French nationwide study

AbstractAutoimmune hemolytic anemia (AIHA) is a rare and sometimes life-threatening disease. Infections are frequent and often severe during the course of AIHA. Rituximab is commonly used to treat patients with AIHA. This study aimed to assess the risk of hospitalization with infection after rituximab in patients with primary AIHA. We selected all adult patients newly diagnosed for primary AIHA and treated with rituximab between 2012 and 2018 in the French national health database. Patients were considered exposed to rituximab within 6 months after the first infusion. The main outcome was hospitalization with infection, identified by a discharge diagnosis of infection during the rituximab exposure. The cohort consisted of 959 patients (mean age of 67 years, standard deviation of 17.8 years; 60.5% of women). The 6-month cumulative incidence of hospitalization with infection was 17.6% (95% confidence interval [CI], 15.2-20.0). The most frequently characterized infections were pulmonary (40.2%). Opportunistic infections were observed in 28 (16.6%) patients, including 11 cases of pneumocystosis. All cases of pneumocystosis occurred in patients concomitantly exposed to corticosteroids, none of them had prophylaxis and all but 2 were aged ≥70 years. Overall, the main factors associated with hospitalization with infection were an age ≥70 years and the exposure to corticosteroids. The 30-day overall mortality after hospitalization with infection was 12.5% (95% CI, 8.0-18.0). In conclusion, the incidence of hospitalizations with infection, including opportunistic infections, as well as the subsequent mortality, are high in adult patients with primary AIHA treated with rituximab. Pneumocystosis prophylaxis should be encouraged in elderly patients exposed to corticosteroids.

Evaluation of hepatic toxicity in autoimmune hemolytic anemia (AIHA) and Evans syndrome patients: a single-center Egyptian study

IntroductionBenign auto-immune illnesses include Evans syndrome (ES) and auto-immune hemolytic anemia (AIHA). Despite being benign in nature, the patients’ livers are burdened by the disease’s chronicity and the accompanying problems beyond the course of treatment. An additional burden stems from HCV infection, of which a significant proportion of Egyptians are positive. The purpose of this study was to identify the hepatotoxicity risks and the variables that influence the prognosis and survival of patients with AIHA/ES. There are 126 AIHA patients in this observational study, which is retrospective. From June 2009 to March 2021, patients visited the Haematology Unit of the Oncology Centre in Egypt. One hundred and sixteen patients have available data.ResultsThere was no significant difference between primary and secondary AIHA groups as regards baseline hemoglobin (Hb), bilirubin, LDH, or reticulocyte count. Thirty-four patients (29.31%) had HCV-positive tests and 1 patient (0.9%) had HBV. There was no difference between HCV-positive and negative cases as regards mean Hb concentration, mean platelet, or immune markers (P > 0.05). AIHA patients with HCV-positive showed a significantly higher relapse rate (56%) than HCV-negative patients (32%) (P = 0.034). HCV positivity and low platelet counts at diagnosis were poor predictors for overall survival (OS) (P 0.022 and 0.04, respectively). Median OS was significantly better in patients with no viral hepatitis infection (1101 days, 95% CI 592–2068) than in patients with positive HCV infection (521, 95% CI 326–1325) (P = 0.019).ConclusionsAzathioprine is the least hepatotoxic in AIHA patients under treatment. Viral hepatitis represents a superadded damage to the liver besides AIHA concerning clinical characteristics and outcomes.

Primary autoimmune haemolytic anaemia is associated with increased risk of ischaemic stroke: A binational cohort study from Denmark and France.

Primary autoimmune haemolytic anaemia (AIHA) causes the destruction of red blood cells and a subsequent pro-thrombotic state, potentially increasing the risk of ischaemic stroke. We investigated the risk of ischaemic stroke in patients with AIHA in a binational study. We used prospectively collected data from nationwide registers in Denmark and France to identify cohorts of patients with primary AIHA and age- and sex-matched general population comparators. We followed the patient and comparison cohorts for up to 5 years, with the first hospitalization of a stroke during follow-up as the main outcome. We estimated cumulative incidence, cause-specific hazard ratios (csHR) and adjusted for comorbidity and exposure to selected medications. The combined AIHA cohorts from both countries comprised 5994 patients and the 81 525 comparators. There were 130 ischaemic strokes in the AIHA cohort and 1821 among the comparators. Country-specific estimates were comparable, and the overall adjusted csHR was 1.36 [95% CI: 1.13-1.65], p = 0.001; the higher rate was limited to the first year after AIHA diagnosis (csHR 2.29 [95% CI: 1.77-2.97], p < 10-9 ) and decreased thereafter (csHR 0.89 [95% CI: 0.66-1.20], p = 0.45) (p-interaction < 10-5 ). The findings indicate that patients diagnosed with primary AIHA are at higher risk of ischaemic stroke in the first year after diagnosis.

Exploration of B and T Cell Receptor Repertoires Reveals Distinct Mechanisms in Pure Red Cell Aplasia, Autoimmune Hemolytic Anemia, and Aplastic Anemia

Background: Pure red cell aplasia (PRCA), autoimmune hemolytic anemia (AIHA) and aplastic anemia (AA) are immune-mediated diseases that mainly attack erythrocyte or erythroid progenitor cells. This study aimed to investigate changes related to autoimmunity in the B cell receptor (BCR) and T cell receptor (TCR) repertoires in these diseases. Methods: Patients with newly diagnosed primary PRCA, AIHA, and AA and healthy individuals with matched age and sex (normal controls, NC) were recruited. Peripheral blood was collected, and BCR and TCR repertoires were sequenced by next-generation immunosequencing. The diversity and clonal expansion of the repertoires, gene and gene combination usage, somatic hypermutation (SHM) of BCR, and the sequence length, hydrophobicity, motifs of the most diverse epitope encoded (complementary-determining region 3, CDR3), T cell clustering, and BCR light chain and TCRα chain were analyzed. Results: 10 PRCA, 10 AIHA, 10 AA, and 7 NC were finally enrolled. For the broad repertoire metrics analysis, only the TCR repertoire of the AA group was more diverse compared with NC (p＜0.05). For BCR and TCR repertoires, PRCA, AIHA, and AA showed uniform characteristics in gene usage. The preferential gene usage of PRCA immunoglobulin heavy (IGH) chains such as IGHV3-23, IGHV3-74 were correlated with memory cells and red blood cell antigen recognition; the higher usage of IGHV4-31 in the AIHA group was associated with secretion of auto-antibodies; whereas AA patients had more gene usage of neutralizing antibodies (p＜0.05). In the gene usage in T cell receptor β (TRB) chains, PRCA patients had skewed usage of genes associated with T cell dysregulation and hyperinflammation such as TRBV1 and TRBV11-2; the increased gene usage in AIHA and AA were also found in other autoimmune diseases, which correlated with abnormal antigen recognition. PRCA and AA also had specific TRBV-J gene combination usage. Only PRCA had higher BCR SHM compared with NC (p＜0.05). The length of CDR3 was similar but the hydrophobicity was different among different disease groups. 12, 28, and 22 motifs were found respectively in BCR of PRCA, AIHA, and AA; and 13, 6, and 6 motifs were found in TCR. Compared with NC, PRCA, AIHA, and AA showed a considerable lack of physiology T cell clusters, and 147, 98, and 141 disease-specific T cell clusters in each disease was found, respectively. For light chain of BCR, PRCA and AIHA had the tendency of more usage of κ chains, whereas AA had more usage of λ chains. For TCRα chains, the three diseases used more genes related to hypersensitivity reactions (p＜0.05). Conclusion: PRCA, AIHA, and AA had different BCR and TCR repertoire characteristics in gene and gene combination usage, hydrophobicity and motifs of CDR3, and T cell clustering, which might contribute to autoimmune antigen recognition. The abnormalities were mainly T cell-related for PRCA, B cell-related for AIHA and both for AA. Keywords: pure red cell aplasia; autoimmune hemolytic anemia; aplastic anemia; BCR; TCR

Prevalence and Incidence of Primary Autoimmune Hemolytic Anemia and Cold Agglutinin Disease in the United States, 2016-2022: A Retrospective Study in Administrative Claims

Background Autoimmune hemolytic anemia (AIHA) is a decompensated acquired hemolysis caused by autoantibodies that act against red blood cells leading to anemia. Cold agglutinin disease (CAD) is a rare subtype of AIHA mediated by classical complement pathway activation, characterized by chronic hemolysis, severe anemia, fatigue, weakness, dizziness, and circulatory problems. The aim of this study was to update the epidemiology of AIHA and CAD in the United States using administrative claims data that includes commercially insured patients, as well as those with Medicare Advantage, Medicare Fee for Service (FFS) and Managed Medicaid plans. Methods Administrative closed claims from Optum CDM database (commercially insured single-payer and Medicare Advantage), Inovalon MORE 2 Registry (commercially insured multi-payer, Medicare Advantage, and Managed Medicaid), and 100% Medicare FFS (Part A/B services) data were used for this analysis. AIHA cases were defined as patients with at least 2 claims with ICD-9/10 diagnosis codes for AIHA (283.0, D59.1, D59.10, D59.11, D59.12, D59.13, D59.19) at least 30 days apart. CAD cases were defined as patients with at least 2 claims with ICD-10 diagnosis codes for CAD (D59.12) or at least 1 claim with diagnosis code for AIHA followed by 1 claim with diagnosis code for CAD (D59.12) at least 30 days apart. Index date was assigned to the first observed claims with the AIHA/CAD diagnosis. Analyses included patients 18 years of age and above with at least 180 days of continuous enrollment in their health plan prior to index for the assessment of the exclusion criteria. Patients with secondary causes of AIHA/CAD (e.g., lymphoma, leukemia, myeloma, cytomegalovirus, or Epstein-Barr virus) were excluded. US census data from years 2016-2021 was used to standardize the incidence and prevalence estimates by age and sex. Point prevalence was calculated as of January 1 st of each year using an all-data lookback. Period prevalence was calculated using a one calendar year assessment period. Incidence estimated new cases in a given year among patients with no prior evidence of AIHA in all data lookback. For CAD, estimates were presented for years 2022/23 due to the recency of the ICD-10 code specific to CAD (active as of 1 October 2020). Results Age and sex standardized point prevalence of AIHA per 1,000,000 persons was approximately 210 in the Medicare FFS across years 2016-2021, 160 in the Optum claims across years 2016-2022, and 50 in the MORE 2 database across years 2016-2022. One-year prevalence per 1,000,000 persons was approximately 190 in the Medicare FFS, 70 in the Optum claims, and 50 in the MORE 2 database across study years. Incidence per 1,000,000 was 50-60 in the Medicare FFS, 20-30 in the Optum claims, and 15 in the MORE 2 database. While overall standardized estimates differed across databases, incidence and prevalence estimates were similar when stratified by age group, indicating that standardization did not fully account for the underlying differences in the composition and representativeness of the overall US population in the three databases. Incidence and prevalence were higher among females than males and increased with age as expected. Incidence per 1,000,000 for year 2021 ranged from roughly 10-80 among those under the age of 45 years to 30-80 among those over the age of 65 years across the three databases. Point prevalence per 1,000,000 for year 2021 had a broader range from 30 to 220 among those under the age of 45 years and from 120 to 360 among those over the age of 65 years. The standardized point prevalence per 1,000,000 for CAD was 31 in Optum claims (year 2023), 33 in Medicare FFS (year 2021), and 14 in MORE 2 (year 2021). Prevalence of CAD was higher among females and increased with age. Conclusion This multi-database analysis provides updated epidemiology estimates for AIHA and CAD in the US. Age and sex standardized point prevalence for AIHA ranged from 60 to 210 per 1,000,000 across the 3 databases, with higher prevalence in the Medicare FFS database which primarily captures population over the age of 65 and was lower in the two databases that capture younger age groups, such as Managed Medicaid and commercially insured populations. Similarly, incidence of AIHA ranged from 15 to 60 per 1,000,000. Point prevalence of CAD ranged from 14 to 33 per 1,000,000. These estimates are in line with those previously reported for North America and Western Europe.

Hospitalization for Infection in Patients with Primary Autoimmune Hemolytic Anemia Treated with Rituximab. a Prospective, Nationwide Cohort Study in France

Introduction Autoimmune hemolytic anemia (AIHA) is a rare disease caused by the production of autoantibodies directed against red blood cells. Infections are frequent and severe in patients with primary AIHA. Rituximab is the reference second-line treatment for warm AIHA and the basis of the treatment of symptomatic cold agglutinin disease. However, the risk of infection after rituximab is not known in these patients with primary AIHA the real-world. Opportunistic infections had been described and the use of specific prophylaxis is debated. Consequently, this cohort study aimed to: (i) measure the incidence of hospitalization for infection after the exposure to rituximab in adult patients with primary AIHA; (ii) describe the types of these infections; (iii) measure the 30-day overall mortality after the first hospitalization for infection; (iv) determine the factors associated with hospitalization for infection; and (v) assess the effectiveness of pneumocystis prophylaxis. Methods Patients were selected from the AHEAD cohort (Autoimmune HEmolytic Anemia: a population-baseD study) between January 2012 and July 2018. This cohort consists in all adult patients with incident AIHA, selected in the French National Health Database. This database covers virtually the entire French population (67 million individuals). It links socio-demographic, outpatient, and hospitalization data. Patients with AIHA were identified using the International Classification of Diseases, tenth version (ICD-10) D59.1 code as hospital discharge or long-term disease diagnosis (the latter being coded by general practitioners). Incident cases were selected using a prior observation period of at least 2 years without the D59.1 diagnosis code. This code yielded a positive predictive value of 90.0% (95% CI: 79.5 to 96.2) in a previous validation study. We restricted the study population to adult patients exposed to rituximab. The first infusion of rituximab defined the index date. Patients with causes of secondary AIHA before the index date were excluded. We assessed the cumulative incidence of hospitalizations with a discharge diagnosis of infection during the six months after the index date (median duration of B-cell depletion). The overall mortality was measured during the 30 days after hospitalization for infection. We assessed the association of age, sex, comorbidities, red blood cell transfusions before the index date (as indicator of AIHA severity), exposure to corticosteroids, to other immunosuppressive drugs, splenectomy (time-varying exposures) as well as pneumococcal and influenza vaccinations before the index date on the occurrence of hospitalization for infection using Cox regression models. A sensitivity analysis was performed using Fine and Gray's models with death as competitive risk. Pneumocystis pneumonia was identified using the B48.5 and B59 discharge diagnosis codes. The association with specific prophylaxis was assessed. Results Between 2012 and 2018, we identified 959 adult patients with incident primary AIHA who received rituximab. The mean age was 67 years and 61% of the patients were women. The 6-month cumulative incidence of hospitalization with a discharge diagnosis of infection was 18.3% (95% CI: 15.9 to 20.9). The most frequently characterized infections were pulmonary, urogenital, and gastrointestinal. Opportunistic infections were observed in 28 (16.6%) patients. The 30-day overall mortality after the first hospitalization for infection was 12.5% (95% CI: 8.0 to 18.0). The risk factors associated with hospitalization for infection in multivariable analysis were an age ≥70 years (HR: 2.7; 95% CI: 1.6-4.6) and current exposure to corticosteroids (HR: 1.6; IC 95%: 1.2-2.2). The results of the sensitivity analysis were concordant. In total, 189 (19.7%) patients were exposed to pneumocystis prophylaxis and 14 pneumocystis pneumonia occurred. All cases occurred during the exposure to corticosteroids and in patients with no specific prophylaxis. All but 2 were aged ≥70 years. Conclusion The incidence of hospitalizations for infection and mortality after hospitalization for infection were high in adult patients with primary AIHA treated with rituximab. Opportunistic infections were not uncommon. Concomitant exposure to corticosteroids and an older age are the main risk factors for infection. Pneumocystis prophylaxis should be discussed for these patients.

Cytokine polymorphisms in patients with autoimmune hemolytic anemia.

Autoimmune hemolytic anemia (AIHA) is due to autoantibodies with or without complement activation and involves cellular and cytokine dysregulation. Here, we investigated cytokine single-nucleotide polymorphisms (SNPs) of TNF-α, TGF-β1, IL-10, IL-6, and IFN-γ, along with their serum levels. The former were related to hematological parameters, therapy, and clinical outcome. The study included 123 consecutive patients with primary AIHA [77 warm AIHA and 46 cold agglutinin disease (CAD)], followed up for a median of 49 months. Results show that the allelic frequency of TNF-α -308 G/A polymorphisms was significantly lower in patients versus controls. Moreover, the genotypic frequency of TNF-α -308G/A and TGF-β gene codon 25 G/C genotypes was significantly lower in patients versus controls. Considering cytokine SNP genotypes associated with different gene expression levels, TNF-α high gene expression was significantly more frequent in patients, TGF-β and IL-10 high gene expression was higher in patients with more severe anemia, and TGF-β high gene expression was higher in patients with active disease. Considering treatment, TNF-α and TGF-β high gene expression was more frequent in multitreated patients and particularly in CAD. It may be speculated that this genetic predisposition to a stronger inflammatory response may result in a greater immune dysregulation and in a relapsed/refractory disease. Regarding cytokine serum levels, TNF-α and TGF-β were significantly lower, and IL-10 and IL-6 were significantly higher in patients versus controls, underlying the complex interplay between genetic background and disease features.

Second-Line Therapy Sequencing in Primary Warm Autoimmune Hemolytic Anemia: Splenectomy-Rituximab Versus Rituximab-Splenectomy

Introduction: Primary warm autoimmune hemolytic anemia (wAIHA) is a hematologic condition that affects approximately 1 in 8000 people and occurs when IgG antibodies directed against self-erythrocytes cause hemolysis and exceed the bone marrow's ability to compensate. First-line treatment with glucocorticoids yields sustained remission in less than 30% of individuals. For patients requiring second-line treatment, splenectomy was the preferred treatment for over 50 years, being recommended over rituximab by leading experts as recently as 2010. In the last decade this practice shifted due to concerns of tripartite risk of splenectomy with rates of infection, thrombosis, and perioperative mortality, juxtaposed against the increased experience with rituximab. These risks are outdated as they predate the modern-day vaccination, thromboprophylaxis, and laparoscopic splenectomy era, respectively. Summarily, the 2017 British guidelines dropped splenectomy from second- to third-line for patients with primary wAIHA, consistent with expert opinion in the United States in 2023. Over these same twenty years, the mortality and morbidity of splenectomy has greatly decreased, owing to updated preoperative vaccination standards, prevention of thrombosis, and widespread use of the laparoscopic (i.e., rather than open) technique. Despite these advancements, splenectomy is now used in fewer than 10% of patients with wAIHA. In the absence of a clinical trial randomizing patients to splenectomy versus rituximab, we conducted the first simulation of second-line therapeutic sequencing for adult patients with primary wAIHA with a focus on short-run and long-run effectiveness results. Methods: We constructed a Markov simulation of adult patients with primary wAIHA and requiring second-line therapy to compare the effectiveness of strategy #1: splenectomy followed by rituximab, if necessary, versus strategy #2: rituximab followed by splenectomy, if necessary. Transition probabilities for initial response and time-variant relapse risk with rituximab and with splenectomy were drawn from retrospective primary-wAIHA-specific literature. For rituximab, we assumed that 1) patients maintained in remission for three years following treatment with a rituximab cycle would remain in remission and 2) all patients who relapse more than a year after receiving rituximab, would be retreated with rituximab. Costs were sourced from the Centers for Medicare &amp; Medicaid Services and the Centers for Disease Control and Prevention. Utility values for patients with wAIHA were specific to the reported patient disease status, whether in relapse, partial remission (defined as hemoglobin &amp;gt;10g/dL) or complete remission (defined as hemoglobin &amp;gt;12g/dL). These were sourced from the Global Burden of Disease Study and weighted for the degree of anemia corresponding with each status. Effectiveness was calculated in quality-adjusted life-years (QALYs). The primary outcomes were lifetime discounted costs, QALYs, and net monetary benefits across accepted willingness-to-pay thresholds over short- and long-runs at 5 years and lifetime, respectively. Probabilistic sensitivity analysis was employed to vary all parameters across their uncertainty intervals simultaneously over 10,000 Monte Carlo iterations. Results: In the short-run, strategies #1 and #2 cost $39,700 and $47,100 and accrued 5.21 and 5.26 QALYs (Table 1). In the long run, costs were $909,000 and $912,000 while accruing 22.0 and 22.1 QALYs. Net monetary benefit point estimates were similar across the accepted range of WTP thresholds in both the short- and long-runs. Conclusion: The balance of costs and quality-adjusted life expectancy appears to be comparatively tightly balanced in the sequencing of second-line therapies in primary wAIHA with splenectomy-rituximab versus rituximab-splenectomy. The absence of a clear rituximab-early advantage on a population level may be driven by advancements in vaccination, thromboprophylaxis, and laparoscopic surgical techniques for splenectomy over the last 20 years. Value-of-information analysis would help identify parameters whose uncertainty reduction with future study in the real world would yield a treatment strategy with a definitive advantage. In the meantime, patients whose values and preferences align with splenectomy should not be dissuaded from pursuing it due to perceived risk.

Genome-wide DNA methylation profiles analysis in primary warm autoimmune hemolytic anemia patients

ABSTRACTBackgroundAutoimmune hemolytic anemia (AIHA) is caused by auto-antibodies, secreted by overactivated B cells, directed against self-red blood cells, resulting in hemolysis. It found that aberrant DNA methylation in B cells can induce the production of autoantibodies. Therefore, we attempted to explore if similar aberrant DNA methylation occur in AIHA patients.MethodsA 49-year-old female wAIHA patient and a 47-year-old female healthy control (HC) were enrolled. Peripheral blood (PB) B cells DNA was extracted. After constructing genomic libraries, bisulfite genomic sequencing (BSP) and DNA methylation profiles were analyzed. BSP was verified using PB B cells from 10 patients with hemolysis, 10 patients with hemolytic remission, and 10 healthy controls (HCs) by Methylation-specific PCR.ResultsTotal DNA methylation of whole-genome C bases (4.8%) and CG type bases (76.8%) in wAIHA patient were lower than those in the HC (5.3 and 82.5%, respectively) (p = 0.022 and p < 0.001). DNA methylation of C bases and CG type bases in whole-genome regulatory elements, such as coding sequence, up2Kb and down2Kb in the patient were also lower than those in the HC (p = 0.041, p = 0.038, and p = 0.029). 30,180 DNA-methylated regions (DMRs) on all 23 chromosomes were identified. DMR-related genes were mainly involved in the Rap1, phospholipase D, HIF-1, calcium, vascular endothelial growth factor (VEGF) and Ras signaling pathways.ConclusionThe DNA methylation spectrum of B cells in AIHA patients is different from that of HC, and the proportion of hypo-methylation regions is higher than that of HC. DMR-related genes are mainly related to some signaling pathways.

A rare autoimmune association: Primary biliary cirrhosis and autoimmune haemolytic anaemia

There are many autoimmune diseases associated with primary biliary cholangitis (PBC), known as primary biliary cirrhosis. The association between PBC and autoimmune hemolytic anemia (AIHA) has rarely been reported. Among the 23 concomitant cases reported since 1970, PBC was diagnosed first in 10 cases and both diseases were almost simultaneously diagnosed in the remaining 13 cases. This suggests that there were few concomitant cases in which AIHA developed first before PBC. We report in this paper a 74 years old woman with concomitant autoimmune haemolytic anaemia and primary biliary cholangitis. This case suggests an association between AIHA and PBC.

Autoimmune Hemolytic Anemia in the Pediatric Age Group: The Egyptian Experience

Autoimmune hemolytic anemia (AIHA) is a common disease entity among adults; however, it is rare among the pediatric age group. Evidence is scarce regarding pediatric AIHA in the literature. The objective of this study is to assess the frequency of AIHA and describe the clinical and laboratory characteristics and treatment outcomes of a cohort of children with AIHA in Egypt. A retrospective study was conducted on 50 children with AIHA who were registered and followed up at the New Children’s Hospital in Cairo, Egypt, between January 2010 and January 2021. The study group comprised 60% females and 40% males. Their median age was 8.25 years. All patients showed low hemoglobin levels with a mean of 5.40 ± 1.34 g/dl and a median reticulocyte count of 10 (IQR: 8–15). Twelve (24%) patients were diagnosed with Evans syndrome, and a positive Coombs test was detected in 46 patients (92%). The frequency of primary AIHA was 40%, whereas it was 60% for secondary AIHA. The first line of therapy for acute attacks was high-dose IV steroids which responded well in 38 (76%) patients. Secondary AIHA was more common among our children (60%). AIHA is more prevalent in females (60%). The clinical and laboratory characteristics matched previous reports.

The potential of metabolomics as a predictive guide for clinical management in autoimmunity against red blood cells.

Autoimmune-responses leading to increased destruction of red blood cells occur in autoimmune haemolytic anaemia (AIHA). The pathophysiology of AIHA is multifactorial and not fully understood, and clinically it remains challenging to manage relapsed and treatment-refractory cases. Rabelo and colleagues conduct metabolomic profiling in plasma of 26 patients with primary warm AIHA, with consideration of haemolytic activity and relapse occurrence. They identify distinct metabolites to be increased in primary warm AIHA patients, thereby providing an encouraging basis for further validation and exploration of metabolomic profiling as a predictive tool for the management of AIHA. Commentary on: Rabelo et al. Metabolomic profile in patients with primary warm autoimmune haemolytic anaemia. Br J Haematol 2023;200:140-149.

Metabolomic profile in patients with primary warm autoimmune haemolytic anaemia.

Autoimmune haemolytic anaemia (AIHA) is a rare clinical condition with immunoglobulin fixation on the surface of erythrocytes, with or without complement activation. The pathophysiology of AIHA is complex and multifactorial, presenting functional abnormalities of T and B lymphocytes that generate an imbalance between lymphocyte activation, immunotolerance and cytokine production that culminates in autoimmune haemolysis. In AIHA, further laboratory data are needed to predict relapse and refractoriness of therapy, and thus, prevent adverse side-effects and treatment-induced toxicity. The metabolomic profile of AIHA has not yet been described. Our group developed a cross-sectional study with follow-up to assess the metabolomic profile in these patients, as well as to compare the metabolites found depending on the activity and intensity of haemolysis. We analysed the plasma of 26 patients with primary warm AIHA compared to 150 healthy individuals by mass spectrometry. Of the 95 metabolites found in the patients with AIHA, four acylcarnitines, two phosphatidylcholines (PC), asymmetric dimethylarginine (ADMA) and three sphingomyelins were significantly increased. There was an increase in PC, spermine and spermidine in the AIHA group with haemolytic activity. The PC ae 34:3/PC ae 40:2 ratio, seen only in the 12-month relapse group, was a predictor of relapse with 81% specificity and 100% sensitivity. Increased sphingomyelin, ADMA, PC and polyamines in patients with warm AIHA can interfere in autoantigen and autoimmune recognition mechanisms in a number of ways (deficient action of regulatory T lymphocytes on erythrocyte recognition as self, negative regulation of macrophage nuclear factor kappa beta activity, perpetuation of effector T lymphocyte and antibody production against erythrocyte antigens). The presence of PC ae 34:3/PC ae 40:2 ratio as a relapse predictor can help in identifying cases that require more frequent follow-up or early second-line therapies.

Type O blood, the MCHC, and the reticulocyte count impact the early recurrence of primary warm-antibody autoimmune hemolytic anemia in children: A retrospective cohort analysis.

ObjectivePrimary warm-antibody autoimmune hemolytic anemia (w-AIHA) is prone to recurrence in children. In this study, we aimed to identify risk indicators for the early recurrence of primary w-AIHA and construct an effective recurrence risk assessment model.MethodsThis was a retrospective cohort study. The clinical data of patients hospitalized with primary w-AIHA in the Department of Hematology and Oncology, Children's Hospital of Chongqing Medical University, between 1 January 2018 and 30 September 2021, were collected at the initial diagnosis. Univariate and multivariate logistic regression analyses were used to determine risk indicators for the early recurrence of primary w-AIHA in children, and ROC curve and Kaplan–Meier survival analyses were used for verification. Finally, a risk assessment model for early recurrence in children with primary w-AIHA was constructed using Cox regression and visualized using a nomogram. The model was also verified internally and externally.ResultsThis study included 62 children with primary w-AIHA. Of which, 18 experienced recurrence 1 year after the initial diagnosis. The univariate and multivariate logistic regression analyses showed that type O blood and the reticulocyte count (Ret) were risk indicators for the early recurrence of pediatric primary w-AIHA (P = 0.009, 0.047, respectively). The mean corpuscular hemoglobin concentration (MCHC) is a protective factor (P = 0.040). According to the ROC curve and Kaplan–Meier survival analyses, children with primary w-AIHA whose blood type was O or had an MCHC of <313.5 pg/fL or a Ret of ≥0.161×1012/L had a higher risk of early recurrence (HR = 2.640, 4.430 and 4.450, respectively, and P = 0.040, 0.015 and 0.018, respectively). The blood types (O), MCHCs, and Rets of 56 patients were incorporated into the Cox regression model, and the recurrence risk assessment model for children with primary w-AIHA was successfully constructed and visualized using a nomogram. The calibration curves and decision-curve analysis (DCA) suggested that the risk model has clinical applicability and effectiveness.ConclusionChildren with type O blood and an MCHC value of <313.5 pg/fL or a Ret value of ≥0.161×1012/L have a higher risk of early recurrence. The risk assessment model for the early recurrence of pediatric primary w-AIHA constructed in this study has good clinical applicability and effectiveness.

Clinical and Laboratory Characteristics of Primary Autoimmune Hemolytic Anemia Patients with Negative Results of DAT by Tube Test But Positive Results by Microcolumn Gel Assay

To investigate the clinical features and laboratory characteristics of primary autoimmune hemolytic anemia (AIHA) patients with negative results of direct antiglobulin test (DAT) by tube test but positive results by microcolumn gel assay, in order to provide references for the diagnosis of these patients. 59 patients diagnosed with primary AIHA in our hospital from January 2015 to December 2020 were retrospectively analyzed. According to the results of tube test and microcolumn gel assay, the cases were divided into 3 groups, and the clinical and laboratory characteristics of each group were compared. The cases were grouped as follows: Group I, cases with negative results by both methods of DAT (n=5); Group II, cases with negative results by tube test but positive results by microcolumn gel assay (n=26); Group III, cases with positive results by both methods of DAT (n=28). There was no significant difference in age and sex between Group II and other groups, whereas the positive rate of anti-IgG + anti-C3d of Group II was lower than that in Group III (P=0.015). The main clinical manifestations of Group II were chest tightness, shortness of breath, fatigue, as well as yellow skin and sclera or dark urine, but the incidence rate of these symptoms was not significantly different from other groups. Anemia related indexes in Group II such as red blood cell (RBC) count and hemoglobin (Hb) were lower than the reference intervals, but there was no significant difference compared with other groups. Hemolysis related indexes in Group II such as reticulocyte (Ret) ratio, indirect bilirubin (IBIL), lactate dehydrogenase (LDH) and free-hemoglobin (F-Hb) were higher than the reference intervals, and the latter two items were signficantly higher than those in Group I (P=0.031 and P=0.036). Serum complement C3 and C4 in Group II were higher than those in Group III (P=0.010 and P=0.037). Anemia severity of primary AIHA patients who were negative of DAT by tube test but positive by microcolumn gel assay was similar to those with negative or positive results by both DAT methods, but the mechanism and degree of complement system involved in hemolysis might be different. Results above may be helpful for laboratory diagnosis of this kind of patients.

Practical therapy for primary autoimmune hemolytic anemia in adults.

Autoimmune hemolytic anemias (AIHA) constitute a rare and heterogeneous group of diseases whose therapy differs according to the type of antibody involved in the genesis of the disease and the existence or not of an identified cause. With the aim of providing a practical guide for the therapy of AIHA, we summarize the emergency therapy and general measures habitually used in all forms of AIHA, as well as the specific treatment of the most frequent primary forms of AIHA: primary warm AIHA and AIHA from cold agglutinin disease (AIHA from CAD). We discuss the dependence of the treatment of the secondary forms on their underlying causes and the changes in the treatment of the primary forms in recent years. We examined the options available for the treatment of primary warm AIHA and AIHA from CAD. We found many differences and only one similarity in their treatment. The differences, particularly due to the non-responsiveness of AIHA from CAD to many treatments useful for primary warm AIHA, such as steroids, splenectomy and immunosuppressive agents, must be considered in the face of each, single case of AIHA. Preliminary identification of the type of antibody involved in the genesis of the disease and careful exclusion of a secondary form are particularly important. Rituximab plays a central role in the treatment of primary warm AIHA and AIHA from CAD.

Transfusion Challenges and Use of Best Match Blood Transfusion in Autoimmune Hemolytic Anemia Patients

Background and Objectives: In autoimmune hemolytic anemia (AIHA) patients, there is decreased survival of red blood cells (RBCs) because of increased destruction by patients' autoantibodies. Due to decreased survival of RBCs, there is an increase in erythropoiesis and other biochemical parameters of hemolysis. One of the vital tests in AIHA is direct Coombs test (DCT). In this study, we share our experience on the difficulties faced by us during the compatibility testing and providing transfusion support to these patients. Methods: This is a retrospective study done in the department of transfusion medicine in a tertiary care hospital of South India. Patients from January 2020 to March 2021 with the diagnosis of AIHA requiring transfusion were included in this study. A total of 136 patients with positive DCT with AIHA diagnosis requiring transfusion support were included in our study. Results: Out of 136 cases, 58% (n=79) of patients had incompatibility during cross matching while in 42% (n=57) had cross matched compatible unit. In all incompatible cases best match blood was transfused. Most transfusions were done for patients with DCT Grade 4+. Out of 45 patients with mixed AIHA, 40 (88.8%) patients required a transfusion (P &lt; 0.05). Of that 104 patients with transfusion support, 66 (63%) were with primary AIHA and 38 (36.04%) with secondary AIHA. Conclusion: It is tough and challenging to get compatible units in AIHA patients. Best-matched blood is useful when transfusion becomes essential during life-threatening anemia.

Survival in autoimmune hemolytic anemia remains poor, results from a nationwide cohort with 37 years of follow‐up

IntroductionAutoimmune hemolytic anemia (AIHA) is considered a chronic disease, with an overall good prognosis. However, recent reports indicate pre‐mature mortality. Causes of death have not been evaluated previously.MethodsIn a nationwide setting, we identified all patients with warm type AIHA or cold agglutinin disease (CAD), and age–sex‐matched comparators from Denmark, 1980–2016. We estimated overall survival and cause‐specific mortality from anemia, infection, cardiovascular causes, hematological or solid cancer, bleeding, or other causes, using cumulative incidence proportions.ResultsWe identified 1460 patients with primary AIHA, 1078 with secondary AIHA, 112 with CAD, and 130 801 comparators. One‐year survival and median survival were, 82.7% and 9.8 years for primary AIHA, 69.1% and 3.3 years for secondary AIHA, and 85.5% and 8.8 years for CAD. Prognosis was comparable to the general population only in patients with primary AIHA below 30 years. In all other age and subgroups, the difference was considerable. Cumulated cause‐specific mortality at 1 year was increased among patients versus comparators.DiscussionAll groups of autoimmune hemolytic anemia are associated with increased overall and cause‐specific mortality compared to the general population. This probably reflects unmet needs in both treatment and follow‐up programs.

Impact of baseline fluorescent antinuclear antibody positivity on the clinical outcome of patients with primary autoimmune hemolytic anemia

IntroductionAutoimmune haemolytic anaemia (AIHA) is an autoimmune disorder that can present in primary or secondary forms. The literature looking at impact of baseline fluorescent antinuclear antibody (FANA) positivity on outcomes of AIHA patients is infrequent. ObjectiveTo study the impact of baseline FANA positivity in patients with primary AIHA. MethodA prospective cohort study involving 29 consecutive primary AIHA patients presenting to the Haematology department from 2013 to 2015 was analysed. After recording baseline investigations including fluorescent ANA, all patients were treated as per the standard therapeutic protocols. Clinical remission, disease free survival, relapse, mortality were compared between the FANA positive and FANA Negative AIHA groups. ResultsBaseline FANA positivity was found in 17 patients (58.62%). Both the groups were comparable in terms of age, sex, Hemoglobin, LDH at presentation, number of lines of treatment needed and duration of follow up. Evan's syndrome was seen in six of FANA positive patients which was statistically significant (0 v/s 6, p = 0.023). FANA positive patients had significantly higher rates of relapse per patient month follow up (1.22 v/s 3.57, p = 0.023) and lower rates of complete response (83.33% v/s 35.29%, p = 0.0118) and relapse free survival at five years. Morbidity and mortality were numerically higher in FANA positive patients. ConclusionBaseline FANA positivity among AIHA patients was found to be associated with lower complete response rates and higher relapse rates with possible higher rates of morbidity. Presence of FANA will give us prognostic value and help us in deciding the treatment options.

Clinical and surgical outcomes of splenectomy for autoimmune hemolytic anemia.

We investigated short and long-term remission rates after splenectomy in patients with primary and secondary autoimmune hemolytic anemia (AIHA). All adults who underwent splenectomy for primary or secondary AIHA at a single center (2004-2018) were retrospectively reviewed. Short-term response was determined at 30-day postoperatively and long-term at one year. Complete response was defined as hemoglobin > 10g/dL without hemolysis, transfusions, or need for additional medical therapy for > 6months. Short-term complete response was attained in 22 of 36 patients (61%), partial response in 3 (8%), no response in 11 (31%). The response rate at 1year was complete in 14/36 (39%), partial in 14 (39%), and 8 non-response (22%). At last available follow-up (median 33.1months (IQR 19-59), 16/37 patients had experienced a complete response (43%), 14 partial response (38%), 7 non-response (19%). 80% of partial responders with primary AIHA required maintenance therapy compared to 100% with secondary AIHA. Splenectomy is associated with short- and long-term improvement in anemia and hemolysis in the majority of patients with AIHA. Immunosuppressants remain important supplemental therapy.