Sutimlimab in Cold Agglutinin Disease.

BACKGROUND: Cold agglutinin disease is a rare autoimmune hemolytic anemia characterized by hemolysis that is caused by activation of the classic complement pathway. Sutimlimab, a humanized monoclonal antibody, selectively targets the C1s protein, a C1 complex serine protease responsible for activating this pathway. METHODS: We conducted a 26-week multicenter, open-label, single-group study to assess the efficacy and safety of intravenous sutimlimab in patients with cold agglutinin disease and a recent history of transfusion. The composite primary end point was a normalization of the hemoglobin level to 12 g or more per deciliter or an increase in the hemoglobin level of 2 g or more per deciliter from baseline, without red-cell transfusion or medications prohibited by the protocol. RESULTS: A total of 24 patients were enrolled and received at least one dose of sutimlimab; 13 patients (54%) met the criteria for the composite primary end point. The least-squares mean increase in hemoglobin level was 2.6 g per deciliter at the time of treatment assessment (weeks 23, 25, and 26). A mean hemoglobin level of more than 11 g per deciliter was maintained in patients from week 3 through the end of the study period. The mean bilirubin levels normalized by week 3. A total of 17 patients (71%) did not receive a transfusion from week 5 through week 26. Clinically meaningful reductions in fatigue were observed by week 1 and were maintained throughout the study. Activity in the classic complement pathway was rapidly inhibited, as assessed by a functional assay. Increased hemoglobin levels, reduced bilirubin levels, and reduced fatigue coincided with inhibition of the classic complement pathway. At least one adverse event occurred during the treatment period in 22 patients (92%). Seven patients (29%) had at least one serious adverse event, none of which were determined by the investigators to be related to sutimlimab. No meningococcal infections occurred. CONCLUSIONS: In patients with cold agglutinin disease who received sutimlimab, selective upstream inhibition of activity in the classic complement pathway rapidly halted hemolysis, increased hemoglobin levels, and reduced fatigue. (Funded by Sanofi; CARDINAL ClinicalTrials.gov number, NCT03347396.).

Sutimlimab in patients with cold agglutinin disease: results of the randomized placebo-controlled phase 3 CADENZA trial.

Sutimlimab, a first-in-class humanized immunoglobulin G4 (IgG4) monoclonal antibody that selectively inhibits the classical complement pathway at C1s, rapidly halted hemolysis in the single-arm CARDINAL study in recently transfused patients with cold agglutinin disease (CAD). CADENZA was a 26-week randomized, placebo-controlled phase 3 study to assess safety and efficacy of sutimlimab in patients with CAD without recent (within 6 months prior to enrollment) transfusion history. Forty-two patients with screening hemoglobin ≤10 g/dL, elevated bilirubin, and ≥1 CAD symptom received sutimlimab (n = 22) or placebo (n = 20) on days 0 and 7 and then biweekly. Composite primary endpoint criteria (hemoglobin increase ≥1.5 g/dL at treatment assessment timepoint [mean of weeks 23, 25, 26], avoidance of transfusion, and study-prohibited CAD therapy [weeks 5-26]) were met by 16 patients (73%) on sutimlimab, and 3 patients (15%) on placebo (odds ratio, 15.9 [95% confidence interval, 2.9, 88.0; P < .001]). Sutimlimab, but not placebo, significantly increased mean hemoglobin and FACIT-Fatigue scores at treatment assessment timepoint. Sutimlimab normalized mean bilirubin by week 1. Improvements correlated with near-complete inhibition of the classical complement pathway (2.3% mean activity at week 1) and C4 normalization. Twenty-one (96%) sutimlimab patients and 20 (100%) placebo patients experienced ≥1 treatment-emergent adverse event. Headache, hypertension, rhinitis, Raynaud phenomenon, and acrocyanosis were more frequent with sutimlimab vs placebo, with a difference of ≥3 patients between groups. Three sutimlimab patients discontinued owing to adverse events; no placebo patients discontinued. These data demonstrate that sutimlimab has potential to be an important advancement in the treatment of CAD. This trial was registered at www.clinicaltrials.gov as #NCT03347422.

A Rare Case of Autoimmune Hemolytic Anemia Caused by Autoantibody with Mimicking Anti-D and Anti-C Specificity.

BACKGROUND: Most of the autoantibodies that cause autoimmune hemolytic anemia (AIHA) are non-specific. Autoantibodies expressing alloantibody specificity are rare. METHODS: We present the case of a 4-year-old boy with no history of blood transfusion or underlying medical conditions who developed AIHA caused by autoantibody with mimicking anti-D and anti-C specificity. RESULTS: Following treatment with methylprednisolone sodium succinate and transfusion of red blood cells with negative antigens for D and C, along with administration of human immunoglobulin, the patient's condition gradually improved. He was ultimately discharged with a good prognosis. CONCLUSIONS: This report highlights a rare case of AIHA characterized by autoantibody with mimicking anti-D and anti-C specificity. Treatments of these patients could be antigen-negative red blood cells, glucocorticoid and immunoglobulin.

The Variation of RhD Blood Group in Different Periods in a Patient with Systemic Lupus Erythematosus.

BACKGROUND: Autoimmune hemolytic anemia disease often produces a large number of various autoantibodies, and some autoantibodies may be related to Rh blood group. In rare cases, autoantibodies can specifically target Rh antigen, thus interfering with the identification of Rh blood group. METHODS: A case of systemic lupus erythematosus (SLE) with inconsistent RhD blood group identification results in different periods was reported and the reasons were analyzed. RESULTS: Some autoantibodies can completely block D antigen on red blood cells, resulting in no redundant D sites on red blood cells binding to reagent anti D. In addition, the immunity of the body is extremely low, and the expression of red blood cell blood group antigens in part of the body is inhibited, which will cause the weakening of the expression of Rh antigen in red blood cells. Therefore, when testing the RhD blood type of the patient, the reagent anti D does not agglutinate with the patient's red blood cells, and a false negative result of the initial screening appears. Through the RhD negative confirmation test, the patient's blood type is a serologically weak D phenotype. CONCLUSIONS: If the result of serological preliminary screening test is RhD negative or RhD variant, the recipient should be treated as RhD negative, and RhD negative red blood cells should be transfused during blood transfusion. Conditional laboratories can implement RHD genotyping, which is conducive to improving the precise blood transfusion management level of RhD negative blood recipients, saving rare blood resources and improving the treatment efficiency of patients.

A national survey of current immunohematologic testing practices for the diagnosis of autoimmune hemolytic anemia in India.

Autoimmune hemolytic anemia (AIHA) is a common term for several disorders that differ from one another in terms of etiology, pathogenesis, clinical features, and treatment. Management of patients with AIHA has become increasingly evidence-based in recent years. While this development has resulted in therapeutic improvements, it also carries increased requirements for optimal diagnosis using more advanced laboratory tests. Unfortunately, limited data are available from developing countries regarding the testing and transfusion management of patients with AIHA. The main objective of this survey was to explore the current immunohematologic testing practices for the diagnosis of AIHA in India. This online survey consisted of 30 questions, covering the place of work, the number of AIHA cases encountered in the 3 preceding years, testing method(s), transfusion management, and so forth. Individuals representing 89 laboratories completed the survey; only 78 of which responded that AIHA testing was performed in their facility's laboratory. The majority of respondents agreed that the most commonly affected age-group comprised individuals of older than 20 years, with a female preponderance. Regarding transfusion management, respondents indicated that transfusion with "best-match" red blood cell units remains the most common practice. Column-agglutination technology is used by 92 percent of respondents as the primary testing method. Although a monospecific direct antiglobulin test is available at 73 percent of the sites, most of them have limited access to other resources that could diagnose cold or mixed AIHA. Merely 49 percent of responding laboratories have the resources to perform adsorption studies for the detection of alloantibodies. Furthermore, three-cell antibody screening reagents are unavailable at 32 percent of laboratories. In 72 percent of centers, clinical hematologists would prefer to consult a transfusion medicine specialist before administering treatment to AIHA patients. There is unanimous agreement regarding the need for a national registry. The survey data indicate wide variability in testing practices for patients with AIHA in India. Future studies are needed to focus on the feasibility and cost-effectiveness of different testing strategies for developing countries.

Serologic characteristics of oxaliplatin antibodies in 15 patients with drug-induced immune hemolytic anemia.

BACKGROUND: Oxaliplatin, a third-generation platinum derivative is commonly used in combination treatment of metastatic colorectal cancer. Since 2008, it is the second most common cause of drug-induced immune hemolytic anemia (DIIHA) investigated in our laboratory. STUDY DESIGN AND METHODS: Samples from fifteen patients including nine (60%) with intravascular hemolysis, suspected of having DIIHA were studied for the presence of anti-oxaliplatin. Direct antiglobulin tests (DATs) and tests with oxaliplatin-treated red blood cells (RBCs) or untreated and enzyme-treated RBCs in the presence of oxaliplatin were performed. A pool of normal AB sera with no unexpected antibodies was used as a control for nonimmunologic protein adsorption (NIPA). RESULTS: Eleven (73%) of the fifteen patients had antibodies to oxaliplatin that reacted with drug-treated RBCs and untreated RBCs in the presence of drug by tube and/or gel method. Lower-titer reactivity (<20) obtained with four patients' sera and the corresponding pooled normal sera was most likely due to NIPA. Eighty seven percent (13/15) of the patients had positive DAT either with anti-IgG only (33%), IgG + C3d (40%), or C3d only (13%). Two patients had a negative DAT. No directly agglutinating antibody was observed with the pools of normal donor's sera in the presence of oxaliplatin. CONCLUSION: Anti-oxaliplatin can cause severe intravascular hemolysis. Complement can usually be detected on the patient's RBCs and anti-oxaliplatin can be detected in the patient's serum. RBC-bound albumin detection with anti-human albumin needs to be performed to confirm NIPA which could have contributed to the patient's hemolytic anemia.

Severe autoimmune hemolytic anemia following receipt of SARS-CoV-2 mRNA vaccine.

BACKGROUND: Large clinical trials have demonstrated the overall safety of vaccines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, reports have emerged of autoimmune phenomena, including vaccine-associated myocarditis, immune thrombocytopenia, and immune thrombotic thrombocytopenia. CASE PRESENTATION: Here we present a novel case of a young woman who developed life-threatening autoimmune hemolytic anemia (AIHA) after her first dose of a SARS-CoV-2 mRNA vaccine. Notably, initial direct antiglobulin testing was negative using standard anti-IgG reagents, which are "blind" to certain immunoglobulin (IgG) isotypes. Further testing using an antiglobulin reagent that detects all IgG isotypes was strongly positive and confirmed the diagnosis of AIHA. The patient required transfusion with 13 units of red blood cells, as well as treatment with corticosteroids, rituximab, mycophenolate mofetil, and immune globulin. CONCLUSION: As efforts to administer SARS-CoV-2 vaccines continue globally, clinicians must be aware of potential autoimmune sequelae of these therapies.

Prognostic significance of hemoglobin level and autoimmune hemolytic anemia in SARS-CoV-2 infection.

Higher levels of D-dimer, LDH, and ferritin, all have been associated with the poor prognosis of COVID-19. In a disease where there are acute inflammation and compromised oxygenation, we investigated the impact of initial hemoglobin (Hgb) levels at Emergency Department (ED) triage on the severity and the clinical course of COVID-19. We conducted a cross-sectional study on 601 COVID-19 patients in a COVID-19 national referral center between 13 and 27 June 2020. All adult patients presented at our hospital that required admission or hotel isolation were included in this study. Patients admitted to the intensive care unit (ICU) had a lower initial Hgb than those admitted outside the ICU (12.84 g/dL vs. 13.31 g/dL, p = 0.026) and over the course of admission; the prevalence of anemia (Hgb < 12.5 g/dL) was 65% in patients admitted to ICU, whereas it was only 43% in non-ICU patients (odds ratio of 2.464, 95% CI 1.71-3.52). Anemic ICU patients had a higher mortality compared with non-anemic ICU patients (hazard ratio = 1.88, log-rank p = 0.0104). A direct agglutination test (DAT) for all anemic patients showed that 14.7% of ICU patients and 9% of non-ICU patients had autoimmune hemolytic anemia (AIHA). AIHA patients had significantly longer length of hospital stay compared with anemic patients without AIHA (17.1 days vs. 14.08 days, p = 0.034). Lower Hgb level at hospital presentation could be a potential surrogate for COVID-19 severity.

Analysis of multiple organ damage and clinical immunological characteristics in systemic lupus erythematosus patients with hematologic involvement.

Objective: To investigate clinical immunological characteristics and imaging findings of multiple organ damage of systemic lupus erythematosus (SLE) patients with hematologic involvement. Methods: SLE patients diagnosed in the Second Affiliated Hospital of Nanchang University from June 2015 to March 2019 were selected, including 93 SLE patients with hematologic involvement and 68 SLE patients without hematologic involvement. Immunological indicators such as autoantibodies, immunoglobulin G (IgG), complement 4 (C4) and imaging data of several organs were measured respectively. The results were statistically analyzed. Results: SLE patients with hematologic involvement were more likely to have autoimmune hemolytic anemia (AIHA) (20.43%, P<0.05). The erythrocyte sedimentation rate (ESR) of SLE patients with hematologic involvement was 75.82 (±35.33) mm/h, IgG was 28.84 (±6.00) g/L and C4 was 0.073 (±0.031) g/L (P< 0.05). The area under the curve (AUC) of IgG was the highest among the above indicators (P<0.01). The positive anti-RO-52 antibody (OR=15.926, P<0.05) was an independent risk factor for pulmonary inflammatory lesions in SLE patients with hematologic involvement. Conclusion: Compared with the control group, abnormal immunological indicators and multiple organs damage are more obvious. Positive anti-RO-52 antibody may play an important role in the pathogenesis of pulmonary inflammation in SLE patients.

Prospective validation of an automatic reflex test for identifying spurious elevations of mean corpuscular haemoglobin concentration due to the presence of cold agglutinins.

Cold agglutinins (CA) in blood may cause false reduction in red blood cell (RBC) count and false increases of RBC indices, such as mean corpuscular haemoglobin concentration (MCHC). Preheating at 37 °C for 2 h is used to overcome this problem. We previously proposed the integration in a total laboratory automation (TLA) setting of a customized reflex test in the presence of MCHC >385 g/L for identifying spurious elevations due to CA. Here, we prospectively evaluate this approach after its introduction in our clinical practice. We evaluated 73 consecutive blood samples from 34 adult patients. Short heating (<1 min) at 41 °C using the reticulocyte channel of Sysmex XN-9000 platform was followed by calculation of optical parameters by the instrument software to ensure quick solution of the CA-dependent problems. After the reflex test in the reticulocyte channel, MCHC dropped below 385 g/L in 50 samples. The reflex markedly corrected the RBC number in eight samples obtained from three patients with CA condition. Two samples from markedly anaemic patients had low blood haemoglobin and RBC count before and after reflex. The remaining 13 samples were obtained from 12 patients, most of whom were on antiretroviral therapy or suffered severe electrolyte disorders, known conditions associated to increased MCHC. The implementation of the proposed automatic reflex by reticulocyte channel on the Sysmex XN-9000 platform in a TLA setting may solve the problem of spuriously high MCHC due to RBC agglutination for CA in a few minutes instead of waiting hours for sample preheating.

Resolution of serologic problems due to cold agglutinin mediated autoimmune hemolytic anemia and its transfusion decision.

BACKGROUND: Autoimmune hemolytic anemia (AIHA) is a rare disease characterized by hemolysis caused by autoantibodies against erythrocyte surface antigen. These antibodies can be classified as warm, cold, or mixed types. METHODS: We report two cases of cold agglutinin disease (CAD), which were eventually diagnosed owing to blood group discrepancy. Resolution was achieved after washing the red blood cells (RBCs) with warm saline and absorbing the autoantibodies at 4°C with the washed RBCs. We also assessed the patient's condition and discussed the strategy of blood transfusion. RESULTS: The first case occurred after postoperative chemotherapy for rectal cancer, and the other manifested with anemia from the outset. Direct antiglobulin tests were positive and revealed autoantibodies against C3d only. Cold agglutinin titration was performed, and the titers of both were 1:1024. Eventually, the patient's condition stabilized without blood transfusion. CONCLUSION: The serological discrepancies observed in the blood transfusion department can successfully guide blood transfusion decisions in cases of CAD.

Tolerization of recent thymic emigrants is required to prevent RBC-specific autoimmunity.

Autoimmune hemolytic anemia (AIHA) leads to accelerated destruction of autologous red blood cells (RBCs) by autoantibodies. AIHA is a severe and sometimes fatal disease. While there are several therapeutic strategies available, there are currently no licensed treatments for AIHA and few therapeutics result in treatment-free durable remission. The etiology of primary AIHA is unknown; however, secondary AIHA occurs concurrently with lymphoproliferative disorders and infections. Additionally, AIHA is the second most common manifestation of primary immunodeficiency disorders and has been described as a side effect of checkpoint inhibitor therapy. Given the severity of AIHA and the lack of treatment options, understanding the initiation of autoimmunity is imperative. Herein, we utilized a well-described model of RBC biology to dissect how RBC-specific autoreactive T cells become educated against RBC autoantigens. We show that, unlike most autoantigens, T cells do not encounter RBC autoantigens in the thymus. Instead, when they leave the thymus as recent thymic emigrants (RTEs), they retain the ability to positively respond to RBC autoantigens; only after several weeks in circulation do RTEs become nonresponsive. Together, these data suggest that any disruption in this process would lead to breakdown of tolerance and initiation of autoimmunity. Thus, RTEs and this developmental process are potential targets to prevent and treat AIHA.

Role of therapeutic plasma exchanges in refractory severe warm autoimmune hemolytic anemia: Presentation of two case reports.

BACKGROUND: Warm autoimmune hemolytic anemia (WAIHA) is a disorder with a usually good response to corticosteroid treatment, whereas in some cases first-line treatment's response is poor and other therapies such as intravenous immunoglobulins (IVIGs), rituximab, or splenectomy must be applied. STUDY DESIGN AND METHODS: Herein, we describe two patients with severe WAIHA treated at our center, who obtained a response after therapeutic plasma exchanges (TPEs) combined with low doses of IVIG. RESULTS: The first patient was an 18-year-old man with no relevant past medical history who was diagnosed with WAIHA. The patient presented a progressive clinical worsening despite treatment with prednisone, IVIG, and rituximab. After starting TPEs, signs of hemolysis rapidly improved and hemoglobin started to recover. The second patient was a 38-year-old man with a past history of immune thrombocytopenia and WAIHA. The patient presented a new flare of WAIHA, with no response after 2 weeks of treatment with corticosteroids, IVIG, and rituximab. After initiation of TPEs, the patient had an improvement in hemolysis biomarkers and recovery of hemoglobin concentration. CONCLUSION: Combination of TPEs with rituximab and IVIG might be considered as a therapeutic option in patients with severe WAIHA without response to corticosteroid and IVIG treatment.

Differential red blood cell age fractionation and Band 3 phosphorylation distinguish two different subtypes of warm autoimmune hemolytic anemia.

Warm autoimmune hemolytic anemia (wAIHA) is a blood disorder characterized by the increased destruction of autologous red blood cells (RBCs) due to the presence of opsonizing pathogenic autoantibodies. Preliminary reports published more than three decades ago proposed the presence of two wAIHA subtypes: Type I, in which autoantibodies preferentially recognize the oldest, most dense RBCs; and Type II, characterized by autoantibodies that show no preference. STUDY DESIGN AND METHODS: We evaluated patients having wAIHA for Type I and II subtype using discontinuous Percoll gradient age fractionation and direct antiglobulin test (DAT). We performed Western immunoblotting and mass spectrometry to show autoantibody specificity for Band 3. We investigated Band 3 tyrosine phosphorylation in different Percoll fractions to determine aging associated with oxidative stress. RESULTS: We confirm the existence of two subtypes of wAIHA, Type I and Type II, and that autoantibodies recognize Band 3. Type I patients were characterized by five Percoll fractions, with a DAT showing IgG opsonization F1 < F5 and elevated Band 3 phosphorylation compared to healthy controls (HCs). In contrast, Type II wAIHA patients were characterized by three to four Percoll fractions, where the DAT IgG opsonization shows F1 ≥ F3/4 and Band 3 phosphorylation was absent or significantly decreased compared to HC. CONCLUSIONS: Type I patients have increased Band 3 tyrosine phosphorylation that may represent accelerated aging of their RBCs resulting in exacerbation of a pathologic form of RBC senescence. Type II patients show decreased Band 3 tyrosine phosphorylation and lack the oldest, most dense RBCs suggesting premature RBC clearance and a more severe wAIHA.

Rhesus D alloimmunization in pregnancy from 1996 to 2015 in Iceland: a nation-wide population study prior to routine antenatal anti-D prophylaxis.

BACKGROUND: Rhesus D (RhD) incompatibility is still the most important cause of hemolytic disease of the fetus and newborn (HDFN) worldwide. The aim of this study was to investigate the incidence, causes, and consequences of anti-D alloimmunizations in pregnancy in Iceland, prior to implementation of targeted routine antenatal anti-D prophylaxis (RAADP) in 2018. STUDY DESIGN AND METHODS: This was a nation-wide cohort study of 130 pregnancies affected by RhD alloimmunization in Iceland in the period from 1996 through 2015. Data were collected from transfusion medicine databases, medical records, and the Icelandic Medical Birth Register. RESULTS: Of 130 RhD alloimmunizations, 80 cases (61.5%) represented new RhD immunization in the current pregnancy. Sensitization was discovered in the third trimester in 41 (51.3%) and occurred in the first pregnancy in 14 cases (17.5%). The most likely causative immunization event was the index pregnancy for 45 (56.25%), a previous pregnancy/birth for 26 (32.5%), abortion for 3 (3.75%), and unknown for 6 women (7.5%). Higher anti-D titers were associated with shorter gestational length, cesarean sections, positive direct antiglobulin test (DAT), and severe HDFN. Intrauterine transfusion (IUT) was performed in five pregnancies (3.8%), and 35 of 132 (26.5%) live-born neonates received treatment for HDFN; 32 received phototherapy (24.2%), 13 exchange transfusion (9.8%), and seven simple blood transfusion (5.3%). CONCLUSION: In about half of cases, RhD alloimmunization was caused by the index pregnancy and discovered in the third trimester. Thus, the newly implemented RAADP protocol should be effective in reducing the incidence of RhD immunization in Iceland in the future.

Classical complement activation on human erythrocytes in subjects with systemic lupus erythematosus and a history of autoimmune hemolytic anemia.

INTRODUCTION: Autoimmune hemolytic anemia (AIHA) is a serious manifestation of systemic lupus erythematosus (SLE) associated with significant morbidity and mortality. In order to more fully understand the causative pathways, we utilized sera from subjects with SLE and active AIHA, or a history of AIHA, to evaluate the classical complement pathway, anti-erythrocyte antibodies, and immune complexes. METHODS: To evaluate antibody-mediated complement activation on the surface of erythrocytes, as occurs in AIHA, blood type O erythrocytes were incubated with sera from 19 subjects with SLE and a history of AIHA. Circulating anti-erythrocyte antibodies and immune complexes were measured with ELISA-based assays. RESULTS: In total, 90% of subjects with SLE and a history of AIHA, but not active clinical hemolysis, had measurable anti-erythrocyte antibodies. Of those with anti-erythrocyte antibody, 53% demonstrated complement opsonization on the erythrocyte surface >twofold above negative control and 29% generated the anaphylatoxin C5a. CONCLUSIONS: For subjects with SLE and a history of AIHA, the persistence of circulating anti-erythrocyte antibodies and resultant erythrocyte complement opsonization and anaphylatoxin generation suggests the possibility that these complement effectors contribute to chronic morbidity and risk of AIHA relapse.

A Retrospective Study of the Combination of Rituximab, Cyclophosphamide and Dexamethasone for the Treatment of Relapsed/Refractory Warm Antibody Autoimmune Hemolytic Anemia.

The combination of rituximab, cyclophosphamide, and dexamethasone (RCD) is highly effective in the treatment of warm autoimmune hemolytic anemia (WAIHA) associated with chronic lymphocytic leukemia (CLL). We treated a cohort of patients with relapsed/refractory WAIHA, without CLL, with RCD. The primary objective was to evaluate the overall response (OR) of RCD therapy. Complete response (CR) was defined as a hemoglobin (Hgb) ≥12 g/dL. Partial response (PR) was defined as Hgb 10-11.9 g/dL or ≥2 g/dL increase in Hgb. Sustained response was defined as Hgb ≥10 g/dL with no treatment changes. A total of 16 patients with relapsed/refractory WAIHA received RCD (7 primary WAIHA, 9 secondary WAIHA) for a median of 4 cycles (range: 2-6). The median pretreatment Hgb was 10.0 g/dL (range: 4.3-12.2). The median best Hgb achieved was 12.5 g/dL (range: 10.6-15.1) with a median of 2 cycles until best Hgb response. The OR was 94% (11 CR, 4 PR). Two immunocompromised patients were admitted for infections during RCD treatment. There were no deaths during the treatment or follow-up period. Following a response to RCD, 4 patients received noncorticosteroid immune modulation therapy and 4 patients continued on corticosteroid therapy. Seven patients received no additional treatment.

Systemic Lupus Erythematosus, Evans Syndrome, and Neurofibromatosis: An Unusual Combination in Pediatric Patient.

Systemic lupus erythematosus (SLE) is an autoimmune disease that affects multiple organ systems. Patients can have hematologic manifestations, including Evans syndrome (ES), which is characterized by immune-mediated thrombocytopenia and anemia. The association of neurofibromatosis 1 (NF1) with autoimmune disorders is rarely reported. We will review the literature for this combination of disorders and describe a case of a 16-year-old girl who presents with immune-mediated cytopenias and is diagnosed with SLE, ES, and NF1. There are 7 reported cases of SLE and NF1 and only 2 are pediatric cases. There are no reports of the combination of SLE, ES, and NF1.

Bortezomib and dexamethasone, an original approach for treating multi-refractory warm autoimmune haemolytic anaemia.

We report the off-label use of bortezomib combined with dexamethasone in eight adults with severe and multi-refractory warm auto-immune haemolytic anaemia (wAIHA). After six cycles of induction therapy, 6 of the 8 patients achieved response (3 complete response, 3 response). Response was obtained after a median of 2 (1-4) cycles. After a median follow-up of 14 (6-36) months, six patients maintained a response (bortezomib/dexamethasone maintenance, n = 4); five patients experienced at least one moderate adverse event, including peripheral neuropathy (n = 2). These results suggest that bortezomib/dexamethasone combination is a promising approach with acceptable toxicity for treating severe refractory wAIHA in adults.

Sublytic Terminal Complement Components Induce Eryptosis in Autoimmune Haemolytic Anaemia Related to IgM Autoantibodies.

BACKGROUND/AIMS: Eryptosis, the suicidal death of red blood cells (RBCs), is characterized by phosphatidylserine (PS) exposure at the cell surface. It can be catalysed by a variety of abnormal conditions and diseases. Until now, the many questions surrounding the physiology and pathophysiology of eryptosis have not been sufficiently answered. Recently, we demonstrated IgM and IgA autoantibodies (aab) to induce PS exposure on circulating RBCs of patients with autoimmune haemolytic anaemia (AIHA). However, it remained unclear how these aab lead to eryptosis. METHODS: Serum and plasma samples from patients with clinically relevant AIHA of cold type were used to induce eryptosis in O RBCs. Serum containing fresh complement from healthy donors, antibodies to complement component, and complement factor depleted sera were added to examine the influence of the complement on PS-exposure. RBC bound annexin V PE were analysed by flow cytometry. RESULTS: Eryptosis related to IgM aab was found to be dependent on complement activation and could be effectively inhibited by EDTA, serum heat inactivation and anti-C5. PS exposure increased with sequential activation of the sublytic terminal complement components C5b6, C5b-7 and was most significant at the C5b-8 stage. A decrease was observed following the formation of the lytic membrane attack complex C5b-9, either because of lysis of eryptotic RBCs or because of inhibition of eryptosis by C9. CONCLUSION: Our findings reflect new aspects on RBC destruction in AIHA as well the impact of the terminal complement complexes on the RBC membrane. The striking differences to nucleated cell apoptosis may even have physiological meaning of RBC acting as a buffer of the complement system.