Type Autoimmune Hemolytic Anemia Research Articles

Sutimlimab for Cold Agglutinin Disease.

Cold agglutinin disease (CAD) is a rare type of autoimmune hemolytic anemia (AIHA) distinct from warm antibody AIHA. One of the ways it is distinct is that CAD is usually not responsive to corticosteroids compared with warm antibody AIHA. Historically, CAD therapy has been limited to immunotherapy or chemoimmunotherapy with varying responses. Cold agglutinin disease also poses a risk for thrombosis and mortality. For patients, fatigue tends to be a common symptom of CAD. The hallmark of CAD is complement-mediated hemolysis, which makes complement inhibitors a critical therapeutic option for patients. Previously, eculizumab, a C5 inhibitor, had limited therapeutic effect for CAD. More recently, sutimlimab, a C1s inhibitor, was shown in two phase III studies to be an efficacious treatment for CAD, improving hemoglobin, hemolysis, and fatigue. However, there is a paucity of medical literature on CAD and on sutimlimab in particular that is geared toward advanced practice providers (APPs). This article aims to provide APPs with a background in CAD and a focus on sutimlimab, assisting these providers in caring for patients with CAD receiving this therapy.

Red cell serological characterization of autoimmune hemolytic anemia in systemic lupus erythematosus patients

Abstract: INTRODUCTION: Autoimmune hemolytic anemia (AIHA) is a clinical condition with increased red cell destruction or decreased red cell survival due to autoantibodies against self-antigens on red blood cells. AIHA may be primary or secondary to other underlying illness. Systemic lupus erythematosus (SLE) is the most common secondary cause of AIHA. Although the incidence of AIHA in SLE patients is low (5%–10%), sometimes, it causes severe anemia which requires blood transfusion. Characterization of these autoantibodies in AIHA is very important, because the clinical condition and treatment of the patient depend on the optimal temperature reactivity, class, and subclass of immunoglobulin responsible. AIM AND OBJECTIVES: The aim and objective of this study are to perform detailed characterization of red cell autoantibodies for accurate diagnosis of AIHA in SLE patients, to find out specific class (immunoglobulin G [IgG]/IgM/IgA) of immunoglobulin and/or complement (C3c/C3d) responsible for AIHA, and their association with severity of hemolysis. MATERIALS AND METHODS: This was a prospective analytical study, done at a tertiary care hospital in Hyderabad, conducted between February 2021 and May 2022. SLE patients with AIHA were included in the study. Monospecific direct antiglobulin test (DAT) was performed to identify the specificity of autoantibody or complement. Based on hematological laboratory values, the study population was divided into three groups, i.e., mild, moderate, and severe hemolysis. DAT strength, hemolytic parameters, and severity of hemolysis were compared between different types of AIHA in SLE patients. Correlation statistics were used to know the association of severe hemolysis with DAT strength and different combinations of autoantibodies. RESULTS: Among 150 patients enrolled, 16 (10.6%) patients had severe hemolysis, 51 (34%) patients had moderate hemolysis, and 83 (55.3%) patients had mild hemolysis. Only IgG was positive in 109 (72.6%) patients, both IgG and C3d were positive in 37 (24.6%) patients, C3d was positive in 4 patients, and IgM was positive in 19 patients. High DAT reaction strength (3+–4+) and presence of C3d or IgM along with IgG were moderately correlated with severe hemolysis. CONCLUSION: Warm AIHA is the most common type of AIHA in SLE patients mediated by IgG. Mild and moderate hemolysis was seen in most cases. Severe hemolysis was moderately correlated with the presence of C3d or IgM. Further studies are warranted to find the predisposing factors leading to severe hemolysis.

Is Splenectomy still the best treatment for Autoimmune hemolytic anemia

Introduction:
 Autoimmune hemolytic anemia (AIHA) is an acquired, heterogeneous group of diseases that includes AIHA with warm type antibodies, cold agglutinin disease (CAD), mixed type AIHA, paroxysmal cold hemoglobinuria, and atypical AIHA.
 Currently CAD is defined as chronic, clonal lymphoproliferative disease, while presence of cold agglutinin in gastrointestinal tract is known as cold agglutinin syndrome. AIHA is mediated by autoantibodies against red blood cells (RBCs), these antibodies cause premature destruction of erythrocytes. The pathogenesis of AIHA is complex and still not yet fully understood.
 Aim of study:
 The purpose of the study was to review the literature on the treatment options for Autoimmune Hemolytic Anemia
 Materials and methods: A systemic review was conducted using PubMed, ScienceDirect, Google Scholar databases. The search strategy was based on following terms: Aiha, splenectomy autoimmune anemia, aiha treatment,
 Results and Conclusions:
 Based on the review of the medical literature, we believe that Splenectomy is no longer the most effective method of treating any type of AIHA and the Rituximab treatment presented by us seems to be safer and definitely less burdensome for the patient.
 Of course, splenectomy is still used in AIHA - but nowadays it is more limited due to the very high effectiveness of the described non-surgical treatment

Autoimmune haemolytic anaemia secondary to COVID-19 infection presenting as anaemia-induced unstable angina

Autoimmune haemolytic anaemia (AIHA) is a condition characterised by antibody mediated haemolysis. COVID-19 infection has been associated with multiple extra pulmonary complications of autoimmune origin, including AIHA. We report a case of a 72-year-old man who presented with unstable angina induced by severe anaemia secondary to autoimmune haemolysis. His direct antiglobulin test was positive with lgG, C3d and lgM positivity denoting a mixed type AIHA. After exclusion of other known associations of AIHA, a possible diagnosis of COVID-19 infection presenting as mixed Al HA with severe symptomatic anaemia, was made. He was managed successfully with oral prednisolone and cautious blood transfusions.

Molecular pharmacology in complement-mediated hemolytic disorders.

In the last decade, a deeper understanding of the pathogenesis of complement mediated hemolytic disorders, such as paroxysmal nocturnal hemoglobinuria (PNH), cold agglutinin disease (CAD), warm type autoimmune hemolytic anemia (AIHA) with complement activation (wAIHA), and atypical hemolytic uremic syndrome (aHUS), paved the way to the therapeutic shift from purely supportive approaches to complement-targeted therapies. This resulted in a significant improvement in disease management, survival, and quality of life. In this review, we will provide a snapshot of novel therapies for complement-mediated hemolytic anemias with a focus on those ready to use in clinical practice. C5 inhibitors eculizumab and the long-acting ravulizumab, are the established gold standard for untreated PNH patients, whilst the C3 inhibitor pegcetacoplan should be considered for suboptimal responders to anti-C5 drugs. Several additional compounds targeting the complement cascade at different levels (other C5 inhibitors, factor B and D inhibitors) are under active investigation with promising results. In CAD, immunosuppression with rituximab remains the first-line. However, recently FDA and EMA approved the anti-C1s monoclonal antibody, sutimlimab, that showed dramatic responses and whose regulatory approval is soon awaited in many countries. Other drugs under investigation in AIHA include the C3 inhibitor pegcetacoplan, and the anti-C1q ANX005 for warm AIHA with complement activation. Finally, aHUS is an indication for complement inhibitors. Eculizumab and ravulizumab have been approved, whilst other C5 inhibitors, and novel lectin pathway inhibitors are under active investigation in this disease.

Novel anti-complement therapeutics for hemolytic anemia

The anti-C5 antibody eculizumab was approved in 2007 as the first anti-complement agent for the treatment of paroxysmal nocturnal hemoglobinuria (PNH). While eculizumab's indication has been expanded to include other diseases, the development of new anti-complement agents has been aggressively pursued for various diseases. In PNH, the anti-C5 recycling antibody ravulizumab, which is an improved version of eculizumab, has been developed, with an extended dosing interval of 2 to 8 weeks, vastly improving convenience. The treatment of PNH with terminal complement inhibitors such as eculizumab and ravulizumab presents a new challenge-extravascular hemolysis. To address this issue, the proximal complement inhibitor, a C3 inhibitor called pegcetacoplan, was approved in the United States of America. Furthermore, the amplification loop inhibitors-a factor B inhibitor iptacopan, and a factor D inhibitor danicopan-are being developed. Recently, the anti-C1s antibody sutimlimab was approved for the treatment of cold agglutinin disease, a type of autoimmune hemolytic anemia. This article discusses novel anti-complement therapies for hemolytic anemia.

Evaluating patients with autoimmune hemolytic anemia in the transfusion service and immunohematology reference laboratory: pretransfusion testing challenges and best transfusion-management strategies

The serologic evaluation of autoimmune hemolytic anemia (AIHA) confirms the clinical diagnosis, helps distinguish the type of AIHA, and identifies whether any underlying alloantibodies are present that might complicate the selection of the safest blood for any needed transfusion. The spectrum of testing is generally dependent on the amount and class (immunoglobulin G or M) of autoantibody as well as the resources and methodologies where testing is performed. The approach may range from routine pretransfusion testing, including the direct antiglobulin test, to advanced techniques such as adsorptions, elution, and red cell genotyping. When transfusion is needed, the selection of the optimal unit of red blood cells is based on urgency and whether time allows for the completion of sophisticated serologic and molecular testing methods. From the start of when AIHA is suspected until the completion of testing, communication among the clinical team and medical laboratory scientists in the transfusion service and immunohematology reference laboratory is critical as testing can take several hours and the need for transfusion may be urgent. The frequent exchange of information including the patient's transfusion history and clinical status, the progress of testing, and any available results is invaluable for timely diagnosis, ongoing management of the patient, and the safety of transfusion if required before testing is complete.

Primary Epithelioid Pulmonary Angiosarcoma with WAIHA and Thrombocytopenia: A Rare Association

Abstract Introduction/Objective Angiosarcomas accounts for approximately 1%-2% of sarcomas, particularly involving the deep soft tissue. As a subtype, primary epithelioid angiosarcoma is an extremely rare neoplasm. Herein, we present an unusual primary epithelioid angiosarcoma of the right upper lung lobe with multiple nodal and bony metastases and associated severe form of autoimmune hemolytic anemia (WAIHA) and thrombocytopenia. Methods/Case Report Our case is a 79-year-old female with a recent onset of warm type autoimmune hemolytic anemia with positive coombs test and thrombocytopenia. The patient serum was also positive for EBV (IgG and IgM). On chest CT scan, a right upper lobe, metabolically active lung mass with mediastinal lymphadenopathy was found. Metabolically active bilateral osseous lesions identified within thoracic spine, ribs, bilateral humeri and femurs. A transbronchial core biopsy of the lung mass revealed poorly differentiated epithelioid hemorrhagic neoplasm with extensive necrosis and vascular background. The tumor cells are positive for AE1/AE3, CK7, FLI-1, BRG1 (SMARCA4, retained), and vimentin; and faint weak focal membranous staining for CD31, Factor VIII, and ERG. They are negative for CK20, TTF-1, Napsin-A, p63, p40, SMA, Melan-A, HMB45, GATA3, PAX-8, CDX-2, HepPar, synaptophysin, calretinin, CAMTA1, EBER (EBV) and S100 (Figure-1-A-D, H&E, 10X, CK AE2/AE3, FLI-1, CD31). This immunoprofile and histologic features favor epithelioid angiosarcoma. Results (if a Case Study enter NA) NA. Conclusion Comprehensive morphological and immunohistochemical findings supported the diagnosis of epithelioid angiosarcoma. The importance of reporting this case was the unusual pulmonary primary presentation, associated nodal and osseous secondary involvement, together with the unique systemic presentation with warm autoimmune hemolytic anemia and thrombocytopenia in a patient with active EBV infection.

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.

Dissection of Bone Marrow Microenvironment By Single Cell RNA Sequencing in Warm AIHA Patients: A Proof-of-Concept Analysis

Warm type autoimmune hemolytic anemia (wAIHA) is a rare disease characterized by variable severity and bone marrow (BM) compensation, unpredictable relapses and several complications (i.e. infections and thrombosis). Most therapies are aimed at restoring immune tolerance by targeting various immunologic mechanisms (autoantibody production, reticuloendothelial phagocytosis, and complement activation). BM composition during acute and chronic/relapsing disease phases is still under investigated, and preliminary studies showed that it may predict anemia severity and treatment response.We aimed at dissecting BM environment by single cell RNA sequencing (scRNA-seq) in patients with wAIHA. We selected 2 patients experiencing mild hemolytic reactivations handled with low dose steroids (M-AIHA) and 2 with severe relapses requiring high steroid doses and rituximab (S-AIHA). We focused on lymphoid/myeloid subpopulations and their gene expression and evaluated the association of output data with clinical features.We performed scRNA-seq for 17,989 single cells, detecting over 23,446 expressed genes per cell on average. Uniform manifold approximation and projection (UMAP), a method for nonlinear dimensionality reduction, showed the microenvironmental cell composition, including T-, B- and NK- lymphocytes and their subpopulations, plasma cells, CD14+ and CD16+ monocytes, hematopoietic stem cells, and myeloid precursors (Figure 1A). On the whole, BM microenvironment showed a high frequency of innate immunity effectors such as NK cells and monocytes (11% and 15% of total cells), likely reflecting the inflammatory state typical of autoimmune/autoinflammatory response. T-cell subpopulations were also highly represented. Specifically, more CD4+ memory than CD4+ naïve T-cells (58% vs 38%) were found, and T-regs represented a small fraction (4%). Also, CD8+ memory cells were more frequent than CD8+ naïve and CD8+ effectors (55% vs 24% vs 21%). Both CD8+ memory and effectors type 2 cells were higher than type 1 cells, indicating a likely participation of T cell compartment in disease phenotype. Finally, B cells were particularly underrepresented, probably due to recent therapy (steroids/rituximab). Figure 1B displays % of BM immune cells divided into M-AIHA and S-AIHA. S-AIHA patients showed higher CD14+ monocytes (57% vs 43%) and decreased NK cells (19% vs 81%) as compared to M-AIHA. Interestingly, within the latter compartment, the CD56 bright NKs were over-represented in S-AIHA (83% vs 17%), suggesting an attempt to negatively regulate activated lymphocytes. Moreover, S-AIHA showed a severe decrease of B cells as compared to M-AIHA, consistently with more recent rituximab treatment. Furthermore, we performed differential expression and gene set enrichment (GSEA) analysis within the different cell subset comparing M-AIHA and S-AIHA. Concerning T cells, we found differential expression of genes related to T-cell receptor, immunoglobulins and interferon alpha/gamma response. Regarding CD14+ monocytes, we observed a downregulation of pathways related to immunomodulatory/inflammatory cytokines, complement activation and apoptosis in S-AIHA versus M-AIHA. Finally, using the CopyKat tool, we found aneuploidies in myeloid cells, including stem cells, suggesting that the selective pressure from the immune environment may lead to accumulation of genetic lesions in chronic S-AIHA. This clonal evolution can possibly explain the clinical overlap with myeloid neoplasms.Overall, these preliminary data show for the first time that scRNA-seq technology is feasible in wAIHA patients and gives insights in the pathogenic role of bone marrow immunologic microenvironment. Additionally, BM composition appears to dynamically modify according to disease severity and treatment, potentially enabling tailored therapies. [Display omitted] DisclosuresFattizzo: Kira: Speakers Bureau; Alexion: Speakers Bureau; Novartis: Speakers Bureau; Momenta: Honoraria, Speakers Bureau; Annexon: Consultancy; Apellis: Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Bianchi: Agios pharmaceutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Bolli: Celgene/BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Honoraria; Amgen: Honoraria. Barcellini: Alexion Pharmaceuticals: Honoraria; Incyte: Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria, Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria.

Primary Autoimmune Hemolytic Anemia Due To Warm Reactive Autoantibodies: A Rare Case Report

Autoimmune hemolytic anemia (AIHA) is an acquired form of hemolytic anemia in which autoantibodies target red blood cell (RBC) membrane antigens, inducing cell rupture (lysis). It affects both pediatric and adult populations, although its presentation in childhood is relatively rare, with the annual incidence estimated to be approximately 0.8 per 100,000 individuals under 18 years old [3]. Here we report one such a rare case of autoimmune hemolytic anemia due to primary warm reactive autoantibodies in a 3 year old female child. As there was presence of hemolysis in peripheral blood smear & other investigations also, Direct coomb’s test was done & it came out to be positive which was suggestive of autoimmune hemolytic anemia, as following lab reports are suggestive of continuous destruction of RBC & after introduction of steroids parameters of hemolysis came out to be normal suggestive of warm reactive autoantibodies type of AIHA. Clinically also patient improved & her urine colour also became normal after when prednisolone started. Patient also did not have any features of secondary causes of warm autoantibody like Systemic lupus erythematous, immunodeficiency disorders, ulcerative colitis & lymphoproliferative disorders so it was considered primary or idiopathic. W-AIHA tends to have a chronic course and is not expected to subside without treatment. It can be a fatal disease, with a mortality rate of up to 4% in children, either because of the acuity of the presentation or because of being refractory to treatment and requiring multiple lines of therapy with frequently associated toxicity [14]. Fortunately our patient responded to steroid therapy.

SARS‐CoV‐2 vaccination in patients with autoimmune cytopenias: The experience of a reference center

<scp>SARS‐CoV</scp>‐2 vaccination in patients with autoimmune cytopenias: The experience of a reference center

Severe haemolytic anaemia in COVID 19- A rare manifestation.

Sir, The novel severe acute respiratory syndrome-corona virus 2 (SARS-CoV-2) affects various organ systems including the cardiovascular, gastrointestinal and neurological systems.[1] Autoimmune haemolytic anaemia (AIHA) is a rare immune disorder in which antibodies are produced against body's own red cells. Association of AIHA with coronavirus disease (COVID)-19 has been rarely reported. A 42-year-old female patient presented with fatigue, headache and bleeding per rectum since 3 days; she had no history of fever or upper respiratory tract infection and normal oxygen saturation. On clinical examination, she was pale and icteric and had healing fissure in ano with no active bleeding. On day two, patient complained of severe breathlessness, peripheral oxygen saturation (SpO2) 85% with hypotension and patient was shifted to intensive care unit (ICU) for further management. The oxygen was administered with facemask at 10 l/min and norepinephrine infusion started at 0.5-1 μg/kg/min. The chest radiogram and echocardiogram did not show any abnormality. Computed tomography (CT) chest [Figure 1] revealed a CORADS score of 6 and the reverse transcription polymerase chain reaction (RT PCR) assay detected the presence of SARS-CoV-2 on day three of admission. On investigation, her haemoglobin level was 3 g% and peripheral blood smear showed predominantly macrocytic hypochromic cells with a few microcytes, anisocytosis, reticulocytosis and neutrophilia. Malignant diseases, such as leukaemia and lymphoma, were ruled out as the peripheral smear did not show abnormal cells of haematological origin. Autoimmune diseases, such as systemic lupus erythematosus, were also ruled out. There was no history of medication intake (non-steroidal anti-inflammatory drugs or cephalosporins) or blood transfusion in the past known to cause drug-induced AIHA. Arterial blood gas analysis was not required as hypoxaemia was anticipated due to severe anaemia. Considering the severe anaemia and increasing breathlessness, a decision to transfuse packed red cells was taken. Her cell grouping was AB Rh D positive, whereas her serum grouping was of O group with autocontrol positive drawing attention to the pathology (O Rh D positive per previous records). Cross-matching with both AB Rh D positive and O Rh D positive packed cells were incompatible, concomitantly direct antiglobulin and indirect antiglobulin tests were also positive. Her blood also showed autoagglutination (titres <1:64), which was reactive at 37°C and with antihuman globulin phase; hence a provisional diagnosis of mixed AIHA was established secondary to infection. Intravenous methylprednisolone 30 mg/kg for 3 days, 20 mg/kg for next 3 days, and 5 mg/kg for next 4 days was started till irradiated or compatible blood was arranged as per British Society of Haematology guidelines.[2] Oral prednisolone 1 mg/kg was continued for 2 weeks and gradually tapered. The patient showed marked improvement in the next 24 h [Table 1], could be managed without any blood transfusion and ionotropic supports could be discontinued. A diagnosis of secondary AIHA triggered by COVID-19 was ascertained by exclusion as the patient had no other suggestive history.Figure 1: (a) Opacification in the right peripheral lung fields and (b) Opacifications in the bilateral posterior aspect of the lung fields due to COVID-19Table 1: Serial measurement of complete blood picture taken before and after initiation of methylprednisolone therapy for a period of 12 days‡Autoimmune haemolytic anaemia in COVID-19 has been reported in nine cases among which five had malignancy and one had congenital thrombocytopenia.[3] ANK-1 shares an immunogenic antigenic epitope (amino acids LLLQY), present on red cells with 100% identity with the SARS-CoV-2 surface glycoprotein named spike protein, which creates a potential immunological cross-reactivity between ANK-1 and spike protein, contributing to AIHA in patients with COVID-19.[4] Corticosteroids represent the first line of treatment for warm antibody type AIHA and reduce haemolysis and cytokine storm.[5] This case presents a unique scenario of acute anaemia with COVID-19, which was managed conservatively with steroids and no immunosuppressants or plasma therapy or blood transfusion was required. We wish to highlight that the novel SARS-CoV-2 can present with covert symptoms affecting the haematological system. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the legal guardian has given his consent for images and other clinical information to be reported in the journal. The guardian understands that names and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed. Financial Support and Sponsorship Nil. Conflicts of interest There are no conflicts of interest.

Inflammation and Fatigue in Patients with Cold Agglutinin Disease (CAD): Analysis from the Phase 3 Cardinal Study

Introduction CAD is a rare, chronic type of autoimmune hemolytic anemia, where hemolysis is driven by classical complement pathway (CP) activation. Complement activation assures rapid initiation of the complement cascade as part of an early immune response and inflammation. A proinflammatory state secondary to complement activation has been demonstrated in other hemolytic disease such as paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome (Weitz et al. Thromb Res. 2012; Cofiell et al. Blood. 2015). Complement activation stimulates cytokine production (tumor necrosis factor, interleukin 6 [IL-6], IL-8, IL-17) via anaphylatoxins C3a and C5a and increases vascular inflammatory markers, consistent with complement-mediated inflammation (Landsem et al. Clin Exp Immunol. 2017; Cofiell et al. Blood. 2015). In patients with chronic fatigue syndrome, complement activation is associated with higher levels of fatigue (Sorensen et al. J Allergy Clin Immunol. 2003) and inflammatory cytokine activity correlates with the severity of fatigue symptoms (Montoya et al. PNAS. 2017). In addition, IL-6 plays a more dominant role in immune stimulation, particularly during chronic inflammation stress such as rheumatoid arthritis (Choy et al. Rheumatology. 2018). In CAD, CP activation and chronic inflammation may contribute to patient fatigue, apart from anemia. CP activation resulting in a proinflammatory state has not been formally studied in CAD. The interplay between complement-mediated inflammation and fatigue also has not been previously explored in patients with CAD. In the Cardinal study (NCT03347396), efficacy and safety of the humanized monoclonal anti-C1s antibody, sutimlimab (formerly BIVV009), was evaluated in patients with CAD and recent history of blood transfusion. Here we summarize the results of inflammatory cytokine expression for IL-6 and IL-10 and their relation to fatigue over the Part A 26-week treatment period of Cardinal. Methods In Cardinal Part A, patients with CAD received intravenous doses of sutimlimab on Days 0 and 7, and biweekly infusions thereafter. Patients weighing &amp;lt;75 kg and ≥75 kg received a 6.5 g and 7.5 g dose, respectively. Cytokine levels for IL-6 and IL-10 were assessed in patients with available serum samples. Cytokine profiles and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scores were evaluated from baseline to follow-up time points at Weeks 1, 3, 5, and 25, as represented by the treatment assessment time point (TAT) after initiating sutimlimab treatment. Summary statistics describing IL-6, IL-10, and FACIT-F changes at each week were reported. Results Mean IL-6 level (mean pg/mL [standard error of the mean (SEM)]) steadily decreased from baseline (3.21 [0.958]; normal values IL-6 &amp;lt;3.2 pg/mL) to follow up at all time points after initiating sutimlimab treatment (Figure 1), showing rapid onset and durable pattern of decline as early as Week 1 (2.70 [0.839]). Mean IL-6 level was reduced by more than half by Week 3 (1.56 [0.297]), slightly rose at Week 5 (1.88 [0.383]), and was lowest at TAT (1.31 [0.201]). Mean IL-10 level (pg/mL [SEM]) also decreased in a time-dependent manner from baseline (1.36 [0.310]) initially at Week 1 (0.99 [0.250]). Mean IL-10 slightly increased at Week 3 (1.07 [0.306]), but dropped at Week 5 (0.83 [0.142]) and was lowest by TAT (0.82 [0.129]) with sutimlimab treatment (Figure 2). At baseline, mean (SEM) FACIT-F score was 32.5 (2.266) (Figures 1-2). Patient FACIT-F scores showed early and late improvements with mean score increases at Week 1 (39.67 [1.741]), Week 3 (40.70 [1.543]), Week 5 (43.75 [1.192]), and at TAT (41.86 [1.958]). Decreased inflammation, as demonstrated by IL-6 and IL-10 activity, occurred concurrently with FACIT-F score improvements over time. Conclusions In Cardinal Part A, decrease from baseline to TAT in mean proinflammatory cytokine IL-6 and regulatory cytokine IL-10 levels were observed during sutimlimab treatment, highlighting the influence of complement inhibition on inflammation in CAD. Improved FACIT-F scores are concurrent with sutimlimab treatment and inhibition of the CP. Concurrent inverse changes were noted between select inflammatory cytokines and improvements in patients' fatigue, suggesting complement-mediated inflammation may additionally contribute to manifestation of fatigue in patients with CAD. Disclosures Weitz: Apellis: Consultancy, Honoraria; Alexion: Consultancy, Honoraria, Speakers Bureau. Ueda:Novartis: Honoraria; Alexion Pharmaceuticals: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria. Shafer:Sanofi: Current Employment. Su:Sanofi: Current Employment. Foster:Sanofi Genzyme: Current Employment. Storek:Sanofi: Current Employment. Patel:Sanofi: Current Employment.

Rosai-Dorfman disease with renal involvement and associated autoimmune haemolytic anaemia in a 12-year-old girl: A case report

BackgroundRosai- Dorfman Disease (RDD) is a benign condition of unknown aetiology which is characterized by non-neoplastic proliferation of histiocytes. Pathophysiology and natural history remain obscure due to the low prevalence of disease. It is known to present with nodal or extranodal involvement and occurrence in the genitourinary system could lead to dreadful complications. RDD is diagnosed by demonstrating emperipolesis on histology and supported by S100 positivity in immunohistochemistry. Treatment is tailored individually and includes expectant monitoring, steroids, surgery, chemotherapy and radiotherapy. Prognosis will be poor if there is involvement of vital organs. We report a rare case of renal Rosai-Dorfman Disease in a 12-year-old girl which also associated with cold type autoimmune haemolytic anaemia (AIHA).Case presentationA previously healthy, 12-year-old girl presented with low grade fever and cough over one month. On examination, she was pale, mildly icteric and had a firm mass in the left hypochondrial region.Her blood count revealed significant eosinophilia, normocytic normochromic anaemia and thrombocytosis. Further laboratory investigations revealed reticulocytosis, positive urine urobilinogen, positive direct antiglobulin test and red blood cell agglutination on blood picture suggestive of autoimmune haemolytic anaemia.Ultrasound scan of abdomen revealed paraaortic and left side retroperitoneal lymphadenopathy with left renal mass. It was further evaluated by Contrast Enhanced Computed Tomography (CECT). Biopsy was done and that concluded sinus histiocytosis with massive lymphadenopathy (SHML) with positive S100 and CD1a in immunohistochemistry. Child was treated with steroids however there was no significant response as assessed by repeat CT and has been commenced on chemotherapy.ConclusionRDD is believed to be due to host immune dysregulation and precise diagnosis is imperative. It should be considered as differential diagnosis in a child presenting with massive lymphadenopathy and AIHA. Association between RDD and AIHA may possibly be explained by abnormal immune response of the host.

Cold type autoimmune hemolytic anemia- a rare manifestation of infectious mononucleosis; serum ferritin as an important biomarker

BackgroundInfectious mononucleosis is one of the main manifestations of Epstein – Barr virus, which is characterized by fever, tonsillar-pharyngitis, lymphadenopathy and atypical lymphocytes. Although 60% of patients with IMN develop cold type antibodies, clinically significant hemolytic anemia with a high ferritin level is very rare and validity of serum ferritin as an important biomarker has not been used frequently.Case presentation18-year-old girl presented with fever, malaise and sore throat with asymptomatic anemia, generalized lymphadenopathy, splenomegaly and mild hepatitis. Investigations revealed that she had cold type autoimmune hemolysis, significantly elevated serum ferritin, elevated serum lactate dehydrogenase level with serological evidence of recent Epstein Barr infection. She was managed conservatively and her hemoglobin and serum ferritin levels normalized without any intervention following two weeks of the acute infection.ConclusionCold type autoimmune hemolytic anemia is a rare manifestation of infectious mononucleosis and serum ferritin is used very rarely as an important biomarker. Management of cold type anemia is mainly supportive and elevated serum ferritin indicates severe viral disease.

Variability of findings due to seasonal alterations and number of attacks in warm-type autoimmune hemolytic anemia

Background: In this study, an examination of the variability of findings due to seasonal alterations and variability of the number of attacks in warm-type autoimmune hemolytic anemia (AIHA) was aimed. Method: Patients over 18 years of age who were admitted to Ankara Numune Training and Research Hospital between 2009 and 2017 and were diagnosed with warm-type AIHA were included in this retrospective study. For statistical evaluation, SPSS 20 for Windows was used. For comparison of categorical data, chi-square and Fisher exact chi-square tests were used. Results: The study population comprised of 52 patients. The age range of the patients was 19-89 years, with a median of 45.5 years. Among the patients, the number of attacks was 1 in 63.5% (n=33), 2 in 15.4% (n=8), and 3 in 21.2% (n=11). The type of AIHA was the warm type in all of the patients. In regard to the season during which attacks were experienced, it was determined to be winter in 26.9% (n=14), autumn in 17.3% (n=9), summer in 38.5% (n=20), and spring in 17.3% (n=9) of the patients. The rate of attacks was determined to be higher during winter in the patient group with a number of attacks of 2 or more and during summer and autumn in the patient group with the number of attacks of 1 (p=0.030). Conclusion: It was determined that, while the rate of patients who experienced only 1 AIHA attack increased during the summer and autumn seasons, attacks occurred most commonly during winter in patients with more than 1 attack.

Autoimmune hemolytic anemia.

The diagnosis of autoimmune hemolytic anemia (AIHA) can be made with a stepwise approach that aims to identify laboratory and clinical evidence of hemolysis and then determine the immune nature of hemolysis with the direct anti-globulin test. Once alternative causes for these findings have been excluded, AIHA is established, and the clinician must search for secondary causes, as well as identify the type of AIHA. Rituximab is now the preferred second-line treatment for primary warm AIHA and first-line treatment for primary cold agglutinin disease (CAD), either as monotherapy or combined with bendamustine. Complement inhibitors have shown utility in stabilizing AIHA patients with acute severe hemolysis. Future prospects are discussed and include the C1s inhibitor BIVV009 (sutimlimab) that is now entering phase 3 studies for CAD.

Plasmapheresis in a child with cold antibody autoimmune hemolytic anemia: case report

Autoimmune hemolytic anemia is a picture of hemolysis which is caused by autoantibodies against red blood cell surface antigens. It is classified as primary, secondary or warm and cold autoimmune hemolytic anemia according to the temperature at which antibodies react. It is usually an acute and self-limiting condition. Here, we present a three-year-old male patient who presented with malaise, paleness, and dark-colored urine. His hemoglobin level was 5.8 g/dL, and increased indirect bilirubin and lactate dehydrogenase levels and decreased haptoglobulin and reticulocyte levels were noted. A direct Coombs test was positive using anti-C3. Four erythrocyte suspension transfusions were given because the anemia was life-threatening. High-dose steroids (30 mg/kg/ day, methylprednisolone) and intravenous immunoglobulin (1 g/kg/day, two days) treatments were unresponsive. Plasmapheresis was performed and no further transfusions were needed after plasmapheresis. Plasmapheresis treatment can be effective in children with cold type autoimmune hemolytic anemia.

Cold Agglutinin Disease

Cold Agglutinin Disease (CAD) is a rare type of autoimmune hemolytic anemia (AIHA) characterized by the unique property of IgM autoantibodies binding to red blood cells (RBCs) at low temperatures. Agglutination of RBCs and activation of complement are precursors to expression of clinical features manifested as ischemic changes and hemolysis. Avoidance of cold exposure is necessary for all patients. Some patients require immunosuppressive agents, anti-CD20 therapy, plasma exchange and, if present, treatment of underlying disease. Overall prognosis in primary CAD is favorable but variable in the presence of B-cell neoplasms. This case report is a reminder of Cold Agglutinin Disease and the importance of recognizing it in clinical practice.