small molecules

2026-08-10 | Autoimmune hemolytic anemia in the era of immunotherapy: from pathogenesis to therapeutic strategies

Abstract Autoimmune hemolytic anemia (AIHA) is a rare hematologic disorder characterized by the accelerated destruction of red blood cells mediated by autoantibodies and is classified into warm antibody type and cold antibody type. Corticosteroids remain the first-line treatment, whereas rituximab has replaced splenectomy as the standard second-line therapy. However, a considerable proportion of patients still experience relapse or refractory disease. In recent years, with an improved understanding of its pathogenesis, significant advances have been achieved in targeted therapies for AIHA, including complement inhibitors, spleen tyrosine kinase inhibitors, Bruton tyrosine kinase inhibitors, phosphoinositide 3-kinase delta inhibitors, other novel agents, and chimeric antigen receptor T-cell therapy. Future AIHA management will focus on individualized treatment guided by precise stratification, combination strategies, and biomarkers, ultimately achieving a transition from empirical immunosuppression to mechanism-targeted precision medicine.

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2026-08-04 | Early-Onset Direct Antiglobulin Test-Negative Autoimmune Hemolytic Anemia Induced by Pembrolizumab in Perioperative Triple-Negative Breast Cancer: A Case Report.

Hematological immune-related adverse events associated with immune checkpoint inhibitors (ICIs) are rare, and autoimmune hemolytic anemia (AIHA) is particularly uncommon. A 71-year-old woman with stage IIA triple-negative breast cancer received perioperative pembrolizumab with carboplatin and paclitaxel. During the first treatment cycle, she developed acute severe anemia with laboratory findings consistent with hemolysis. Despite a negative direct antiglobulin test (DAT), major alternative causes of hemolysis were considered unlikely, leading to a clinical diagnosis of suspected ICI-associated AIHA. Oral prednisolone (1 mg/kg) promptly resolved hemolysis without recurrence. Pembrolizumab was discontinued; however, imaging demonstrated a clinical complete response, and subsequent surgery confirmed a pathological complete response (pCR). This case demonstrates that AIHA during ICI therapy may occur despite a negative DAT and underscores the importance of prompt recognition and corticosteroid therapy. Favorable oncologic outcomes, including pCR, may still be achieved despite early discontinuation of ICI therapy.

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2026-07-31 | Resolution of severe autoimmune hemolytic anemia and thrombocytopenia associated with Plasmodium vivax malaria without corticosteroid therapy: A case report.

Autoimmune hemolytic anemia is a rare but potentially life-threatening complication of Plasmodium vivax malaria. Most reported cases required corticosteroid therapy in addition to antimalarial treatment. We report the case of a 28-year-old Ethiopian man who presented with fever, pallor, and fatigue. Laboratory evaluation revealed severe anemia (hemoglobin 6 g/dL), thrombocytopenia (88,000/µL), hyperbilirubinemia, and a positive direct antiglobulin test. Peripheral smear confirmed P vivax infection with 2% parasitemia. Comprehensive immunohematological testing, including direct antiglobulin test, elution, adsorption, and extended antigen typing, confirmed immune-mediated hemolysis and excluded alloantibody-related incompatibility. The patient received 3 compatible blood transfusions and was treated with intravenous artesunate followed by primaquine, without corticosteroids or platelet transfusion. By day 5, hemoglobin improved to 10.2 g/dL, platelets normalized, and malaria smears were negative. He was discharged in stable condition. This report highlights an unusual presentation of P vivax malaria complicated by severe autoimmune hemolytic anemia and thrombocytopenia, which resolved with antimalarial therapy alone, without immunosuppressive therapy, including corticosteroids. This finding suggests that corticosteroids may not always be necessary in certain cases and underscores the importance of early recognition and comprehensive immunohematological evaluation in malaria-related cytopenias.

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2026-07-30 | Clinical Response to Thalidomide in Non-Transfusion-Dependent Thalassemia Complicated by Autoimmune Hemolytic Anemia: A Case Report and Literature Review.

Thalidomide is a well-known immunomodulator that has been recently studied for its effects in increasing HbF levels and decreasing the clinical severity of non-transfusion-dependent thalassemia (NTDT) and transfusion-dependent thalassemia (TDT) with promising results regarding the reduction of transfusion requirements. Recent studies demonstrated the effectiveness of thalidomide in reducing transfusion requirements in TDT and increasing hemoglobin levels in NTDT. This manuscript presents a case of NTDT pediatric patient with concomitant autoimmune hemolytic anemia (AIHA) having significant clinical response to thalidomide. The manuscript also provides a focused literature review on thalidomide use in this population.

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2026-07-24 | Severe Warm Autoimmune Hemolytic Anemia With Profound Anemia Requiring Multimodal Immunosuppressive Therapy

Warm autoimmune hemolytic anemia (wAIHA) is an uncommon but potentially life-threatening autoimmune disorder characterized by immunoglobulin G (IgG)-mediated destruction of erythrocytes. Secondary wAIHA frequently occurs in association with systemic autoimmune diseases, particularly systemic lupus erythematosus (SLE), while Sjögren syndrome represents a less common but recognized association. Fulminant presentations with profound anemia remain rare and require prompt diagnosis, aggressive immunosuppressive therapy, and multidisciplinary management. We present the case of a 25-year-old woman with a history of reported Sjögren syndrome, Hashimoto thyroiditis, and clinical and serologic features concerning for evolving SLE who developed rapidly progressive direct antiglobulin test (DAT)-positive wAIHA. Despite receiving five units of packed red blood cells (PRBCs) at an outside hospital, her hemoglobin continued to decline after transfer, reaching a nadir of 3.2 g/dL. Laboratory evaluation demonstrated marked hemolysis with reticulocytosis, elevated lactate dehydrogenase, indirect hyperbilirubinemia, undetectable haptoglobin, spherocytes on peripheral smear, and a DAT positive for both IgG and complement (C3). The hospital course was further complicated by thrombocytopenia and severe splenomegaly, raising concern for autoimmune overlap syndrome and possible Evans syndrome. She was successfully treated with pulse-dose intravenous methylprednisolone, intravenous immunoglobulin (IVIG), folic acid supplementation, and transfusion support. Rheumatologic evaluation revealed positive antinuclear antibody (ANA), anti-SSA, antiphospholipid, and anti-thyroid peroxidase antibodies, prompting initiation of hydroxychloroquine. Hemolysis resolved rapidly with normalization of bilirubin, recovery of platelet count, and sustained improvement in hemoglobin, allowing transition to an oral prednisone taper without requiring rituximab or splenectomy. This case highlights that wAIHA may represent the initial manifestation of evolving systemic autoimmune disease and should be considered in young patients presenting with profound hemolytic anemia. Early recognition, aggressive first-line immunosuppressive therapy, timely transfusion support, and multidisciplinary collaboration can be lifesaving and may achieve complete hematologic recovery without the need for second-line biologic therapy.

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cell therapies

2026-07-17 | Long-Term Survival, Illness Severity, and Time-to-Treatment Analysis in Dogs with Immune-Mediated Hemolytic Anemia Following Intravenous Allogeneic Mesenchymal Stem Cell Therapy: A Multicohort Follow-Up Study.

Steroid-refractory immune-mediated hemolytic anemia (IMHA) in dogs carries high early mortality, and the 15%-30% of cases that fail corticosteroid-based therapy represent a population with few effective options and a narrowing treatment window. In a prior retrospective study, intravenous allogeneic mesenchymal stem cell (MSC) therapy achieved a 76.7% hematological success rate in 43 dogs with steroid-refractory IMHA. The present multicohort follow-up study extends that work by characterizing illness severity, time-to-treatment, and long-term survival across 137 eligible patients from the same database. In Kaplan-Meier analysis of all 137 eligible patients, comprising both the nonsurvivor cohort (n = 57) and the lifespan registry (n = 80), median survival was 1,695 days (4.6 years) in the primary cohort and was not reached in the protocol-assessable cohort (n = 120). Estimated 1-year survival was 56.9% (95% CI: 48.2%-64.7%) and 65.0% (95% CI: 55.7%-72.8%), respectively, and the survival probability stabilized at approximately 52% through 8.1 years of follow-up. Among the 57 nonsurvivors, 51 had sufficient diagnostic data to calculate a Canine Hemolytic Anemia Objective Score (CHAOS) score; two-thirds (66.7%) met the high-risk threshold (CHAOS ≥ 3) at diagnosis. This exceeds the approximately 50% estimated from a published multicenter reference population, indicating that the Safari nonsurvivor cohort was enriched for severely ill dogs at presentation. Median post-treatment survival in nonsurvivors was 8 days (IQR: 3-38), and dogs receiving only one MSC dose had markedly shorter survival than those receiving two or more (median 4 vs. 19 days, P < 0.01), consistent with fulminant disease limiting completion of therapy rather than treatment failure. Diagnosis-to-treatment delay was shorter in survivors than in nonsurvivors (median 13 vs. 25 days), an exploratory finding warranting prospective evaluation. Taken together, these findings suggest that nonsurvival reflects the severity of the underlying disease and that dogs who respond to MSC therapy have potential for durable multiyear remission.

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2026-07-06 | Immune cell-derived membrane nanovesicles: A promethean fire for autoimmune disease therapy through immune cell mimicry.

Autoimmune diseases (AIDs) constitute a heterogeneous group of disorders characterized by immune dysregulation, loss of self-tolerance, and chronic inflammation, which leads to tissue damage and organ dysfunction. Current therapies for AIDs are often limited by their lack of specificity, systemic side effects, and insufficient restoration of immune tolerance. Recent advances in nanotechnology and bioengineering have introduced immune and associated cell-derived membrane vesicles (IACMVs) as a promising therapeutic platform. Derived from macrophages, dendritic cells, neutrophils, platelets, or red blood cells, IACMVs inherit key surface proteins and receptors from their parent cells, conferring endogenous biocompatibility, inflammation-specific targeting, and intrinsic immunomodulatory capabilities. These vesicles can be engineered to carry therapeutic cargoes (e.g., peptide inhibitors, nucleic acids) or modified with surface ligands to enhance disease-site specificity, making them versatile tools for specific immunomodulation. This review provides a comprehensive overview of IACMVs, focusing on their preparation techniques, functional mechanisms, and therapeutic applications in prototypical AIDs such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), autoimmune hemolytic anemia (AIHA), type 1 diabetes (T1D), multiple sclerosis (MS), and autoimmune myocarditis (AM). We highlight translational challenges, including production scalability, membrane integrity, immunogenicity, and cargo-loading efficiency, that must be addressed to advance clinical translation. Finally, we discuss future directions for optimizing IACMVs as next-generation, safe, and targeted immunotherapeutic platforms for AIDs.

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2026-06-03 | Stealth red blood cells with broad-spectrum antigenic shielding for transfusion therapy in antibody-mediated hemolytic anemia.

Red blood cell (RBC) transfusion is a cornerstone of life-sustaining therapy, yet it is profoundly challenged in autoimmune hemolytic anemia (AIHA). In this disorder, a diverse array of autoantibodies targets both the autologous and transfused RBCs, leading to their rapid clearance. This limitation is especially severe during hemolytic crises, rendering conventional transfusion ineffective and eliminating a critical therapeutic option. To overcome this, we developed a biocompatible strategy by utilizing a microbial transglutaminase that first anchors to the RBC membrane and then crosslinks a polysialic acid (PSA) network onto the cell surface. This created an immunologically inert shield that broadly masks surface antigens from pathogenic antibodies. Crucially, this "stealth" modification preserved the RBCs' native biological functions, including essential gas exchange, while conferring robust resistance to antibody-mediated hemolysis. In vitro, the engineered RBCs were protected from antibody binding and macrophage phagocytosis. This protection translated to a significantly prolonged circulation time in AIHA murine models and demonstrated excellent biocompatibility in an allogeneic transfusion setting. Our findings underscore the significant potential of this platform to enable effective, life-saving transfusion therapies for AIHA and other antibody-mediated disorders.

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2026-05-02 | A case of autoimmune hemolytic anemia with acquired functional mutation of the TLR7.

This article presents a case of recurrent autoimmune hemolytic anemia in a child with a gain-of-function (GOF) mutation of the TLR7. This patient's condition contrasts with the six previously documented cases of GOF mutations in the TLR7, thereby expanding the phenotypic spectrum of such mutations and enhancing clinical comprehension of childhood systemic lupus erythematosus (cSLE). The article discusses the mechanisms by which TLR7 GOF mutations can result in autoimmune hemolytic anemia, explores the influence of cytomegalovirus (CMV) infection on the disease's development and progression, and emphasizes the therapeutic potential of hematopoietic stem cell transplantation for cases of TLR7 GOF mutations.

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2026-04-21 | The Efficacy of Whole Blood Exchange- Lymphoplasmapheresis Combined Transfusion in Sepsis with Anemia.

Sepsis progression is driven by a dysregulated immune response and persistent leukocyte activation. Inflammation-induced hemolysis also places septic patients at high risk for anemia. Whole blood exchange has shown efficacy in severe autoimmune hemolytic anemia. Consequently, whole blood exchange-lymphoplasmapheresis combined transfusion (WLCT) is hypothesized as a potential adjunctive therapy for sepsis complicated by anemia. This retrospective study analyzed data from 219 anemic septic patients (49 WLCT vs. 156 conventional therapy) treated between January 1, 2020 and September 30, 2023. After 1:2 propensity score matching (PSM), 38 WLCT patients were compared to 76 conventional patients. Associations between WLCT and clinical outcomes were assessed using regression analyses, with robustness verified by sensitivity analyses. A generalized additive mixed model was employed to evaluate the trends in sequential organ failure assessment (SOFA) scores, vital signs, and laboratory indexes in two groups. Post-matching, WLCT was significantly associated with decreased risks of in-hospital mortality (26.32% vs. 48.68%, odds ratio [OR]: 0.38, 95% confidence interval [CI]: 0.16-0.88, P = 0.024) and incidence of liver failure (16.13% vs. 41.27%, OR: 0.27, 95%CI: 0.09-0.81, P = 0.019). Sensitivity analysis consistently supported these findings. Compared with conventional group, WLCT group demonstrated significant decreases over time in SOFA scores, activated partial thromboplastin time, bilirubin levels, alongside increased in mean arterial pressure, oxygen partial pressure, hemoglobin, red blood cell count, and plasminogen levels. Compared to pre-WLCT, levels of Interleukin-6 (18.81±22.63 vs. 116.86±277.53 pg/ml, P = 0.041), C-reactive protein (37.90±41.30 vs. 72.77±65.59 mg/L, P = 0.020) and erythrocyte sedimentation rate (18.46±22.97 vs. 50.44±45.79 mm/h, P = 0.048) were significantly lower post-WLCT. After treatment, the WLCT group demonstrated significantly lower CD3+ T lymphocytes % (53.63 ± 16.31 vs. 66.14 ± 14.94, P = 0.041) and CD3+CD4+ T lymphocytes % (28.08 ± 8.90 vs. 39.18 ± 10.70, P = 0.004), but higher CD19+ B lymphocytes % (36.09 ± 18.06 vs. 19.23 ± 12.30, P = 0.007) compared to the conventional group. This study evaluated the impact of WLCT therapy on mortality and other clinical outcomes in sepsis with anemia. WLCT might be an effective adjunctive treatment for managing sepsis with anemia, which was significantly associated with reduced mortality. Furthermore, WLCT might exhibit the potential to ameliorate outcomes by improving organ function, coagulation, anemia, and inflammatory status. Our study provides a potential treatment option for sepsis.

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proteins

2026-05-18 | Case Report: Different faces of LRBA deficiency in five Moroccan families.

LPS-responsive beige-like anchor protein (LRBA) deficiency is a primary immunodeficiency belonging to the spectrum of common variable immunodeficiency disorders, frequently associated with immune dysregulation, autoimmunity, and lymphoproliferation. Its clinical presentation is highly heterogeneous, ranging from isolated autoimmune cytopenias to severe multisystem involvement. Here, we report five cases of LRBA deficiency from five Moroccan families, highlighting the broad clinical variability of this condition. The first patient presented with chronic immune thrombocytopenic purpura (ITP) as the initial and predominant manifestation, associated with hypogammaglobulinemia. The second patient developed ITP complicated by a hemorrhagic syndrome and significant lymphoproliferation, including splenomegaly and hepatomegaly. The third patient initially presented with autoimmune hemolytic anemia (AIHA), followed by splenomegaly. The fourth patient exhibited a complex clinical course, beginning with bicytopenia and progressing to enteropathy, arthritis, pneumopathy, and type 1 diabetes mellitus, associated with splenomegaly, hepatomegaly, and lymphadenopathy. Finally, the fifth patient initially presented with ITP and subsequently developed bilateral panuveitis, arthritis, and recurrent respiratory infections. Targeted next-generation sequencing identified homozygous pathogenic variants in the LRBA gene in all five patients, consistent with a loss-of-function mechanism. These included the nonsense variants c.3811C>T (p.Arg1271*) and c.5692G>T (p.Glu1898*), a large deletion encompassing exons 30 to 34, the frameshift variant c.5060_5067delACATACCA (p.Asn1687Serfs*21), and an extended deletion involving part of exon 4 (c.476_549 + 580del). All patients required immunosuppressive therapy and/or immunoglobulin replacement. LRBA deficiency should be considered in children presenting with autoimmune cytopenias, lymphoproliferation, and multisystem autoimmunity. The marked heterogeneity of clinical manifestations underscores the importance of early molecular diagnosis to guide therapeutic decision-making. In our experience, prompt recognition and the initiation of targeted therapies, such as abatacept or early hematopoietic stem cell transplantation, may improve patient outcomes.

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2025-11-03 | Mixed autoimmune hemolytic anemia as a rare initial presentation of systemic lupus erythematosus

Abstract Introduction: Autoimmune hemolytic anemia (AIHA) is a rare disorder in which autoantibodies produced by the immune system attach to red blood cells, leading to their premature destruction. It is primarily divided into warm IgG antibodies (65% prevalence), cold C3 antibodies (15-20% prevalence), and mixed IgG and C3 antibodies (10% prevalence) based on antibody agglutination temperature. Mixed autoimmune hemolytic anemia (MAIHA) is an exceedingly rare disorder that usually presents as severe anemia with a median hemoglobin of 6. We report a rare case of a patient who presented with MAIHA as an initial presentation of SLE. Case Description:A 22-year-old Hispanic female, with no past medical history, presented to the emergency department with complaints of RUQ abdominal pain, fatigue, and dark discoloration of urine for 2 weeks. Initial labs showed a hemoglobin of 5.3 g/dL, an RBC count of 1.28 million/mcL, MCV of 126 fL, an elevated total bilirubin of 2.7 mg/dL (with an indirect bilirubin of 2.1 mg/dL), a high LDH of 278 U/L, and a significantly low haptoglobin of less than 30 mg/dL. The Direct Coombs Test (DAT) was positive with both polyspecific and C3 reagents, and the Antibody Screen was positive on both the Immediate Spin and Prewarm Indirect Coombs tests. Furthermore, a positive antibody screen was noted, and both warm and cold autoantibodies were identified. Iron studies, folate, and B-12 levels were within normal limits. The patient was started on immunosuppressive therapy for mixed autoimmune hemolytic anemia with prednisone 1 mg per kilogram divided into twice daily dosing and IVIG 1g/kg for two doses. She did not receive any blood transfusion because of no overt signs of bleeding and lack of availability of cross-matched blood. Her hemoglobin improved to 5.8 after the first dose of steroids and IVIG. On further testing, infectious workup was negative for influenza virus, RSV, SARS-CoV-2, HIV, hepatitis panel, EBV, and CMV. C4 levels were low at 9, and C3 levels were normal. Her ANA screen was positive, and the double-stranded DNA antibody level was 18 UL/ml. The patient met SLICC criteria for SLE, manifested with positive ANA by IFA 1:1280, positive dsDNA, low complement level, and hemolytic anemia. The patient continued to improve on prednisone. She was discharged on the eighth day of her hospitalization on oral prednisone at 45 mg twice daily. Her hemoglobin on the day of discharge was 7.6 g/dL, hematocrit 21.7%, and the RDW was 24.5% Discussion: MAIHA is associated with autoimmune diseases, lymphoproliferative disorders, and infections. SLE is the most common autoimmune disorder associated with mixed AIHA. Autoimmune hemolysis occurs in about 10% of patients with SLE; however, MAIHA is rarely the presenting feature. The primary treatment of MAIHA is corticosteroid therapy and avoiding exposure to cold. Our patient achieved remission with steroids and IVIG. We preferred IVIG as it is faster acting than rituximab and has fewer side effects. IVIG inhibits extravascular hemolysis by saturating the reticuloendothelial system. Most patients require more than one therapeutic intervention for AIHA.Conclusion: This case highlights that although rare, SLE can present with MAIHA. SLE should be considered as one of the causes of MAIHA, and clinicians should have a high clinical suspicion for it.

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2025-06-12 | Evans Syndrome and COVID-19 Infection or Vaccination: A Systematic Review of Case Reports.

Evans syndrome (ES) is an autoimmune disorder of unknown etiology characterized by autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP). In this systematic review, we analyzed the reported cases of ES secondary to coronavirus disease 2019 (COVID-19) infection or COVID-19 vaccination. We examined their clinical presentation, temporality between events, diagnostics tests, and treatment regimens. Our search in four databases from December 2019 to September 2023 yielded 16 case reports that met eligibility criteria for inclusion. COVID-19 and ES symptoms were defined to assess the timeline between infection/vaccination and ES onset. Finally, treatment efficacy was categorized as complete, partial, or no response based on standard hematological criteria. Eleven cases of ES were associated with COVID-19 infection, and five cases of ES were associated with COVID-19 vaccination. All 16 cases presented with anemia, thrombocytopenia, and a positive Coombs test. Four of the five patients from the vaccination subset were found to have an additional autoimmune disease as a comorbidity on presentation. For cases of ES secondary to COVID-19 infection, six patients had concomitant symptoms of COVID-19 and ES on presentation, and four patients had ES symptoms occurring from 5 days to 3 weeks following COVID-19 infection. The remaining case presented a patient with a 3-week history of ES symptoms before a positive COVID-19 test and further ES workup on admission. For the five cases of ES post-COVID-19 vaccination, all five patients presented with ES with a mean presentation time of 9 days following vaccination. Regarding treatment, intravenous immunoglobulin (IVIG) emerged as the primary regimen, administered in 13 out of the 16 cases. Among the infection-related cases, the most frequent treatment outcome was a partial response in both AIHA and ITP, observed in five of the 11 patients. In the vaccination-related cases, a partial response for AIHA and a complete response for ITP were noted in three of the five patients. Overall, while the evidence points to a temporal association especially between COVID-19 vaccination and the onset of ES, larger studies are necessary to strengthen these findings. In terms of management, early initiation of corticosteroids and IVIG appears effective as first-line therapies; however, standardized treatment protocols are needed to help reduce complications associated with COVID-19-related ES.

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2025-04-18 | Epstein-Barr virus-associated autoimmune hemolytic anemia: a clinical report and review of literature.

Epstein-Barr virus (EBV) infection is a common disease both in children and adults, but can lead to several complications; involvement of the blood system is often described, particularly neutropenia and thrombocytopenia, but autoimmune hemolytic anemia is rarely seen. A 12-year-old female was admitted to the "G. Di Cristina" Children's Hospital of Palermo for jaundice and dark urine. Laboratory investigations revealed anemia, increased levels of total and undirect bilirubin, and elevated transaminases, serum lactate dehydrogenase, and reticulocyte count; a peripheral blood smear showed anisocytosis, and the direct antiglobulin test (DAT) for cold agglutinins was positive. The laboratory evaluation of infectious disease showed the presence of EBV VCA IgM and IgG. A diagnosis of acute autoimmune hemolytic anemia EBV related was made: the patient was initially treated with intravenous methylprednisolone and then with intravenous immunoglobulin, which led to a progressive clinical improvement until complete remission. Autoimmune hemolytic anemia is rarely associated with EBV infection; a review of the English literature revealed only 16 cases. Patients with autoimmune hemolytic anemia should always be evaluated for EBV serology, even in the absence of the typical clinical and hematological features of infectious mononucleosis. For these patients, good prognosis is generally expected.

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2024-10-23 | Potent efficacy of an IgG-specific endoglycosidase against IgG-mediated pathologies.

Endo-β-N-acetylglucosaminidases (ENGases) that specifically hydrolyze the Asn297-linked glycan on immunoglobulin G (IgG) antibodies, the major molecular determinant of fragment crystallizable (Fc) γ receptor (FcγR) binding, are exceedingly rare. All previously characterized IgG-specific ENGases are multi-domain proteins secreted as an immune evasion strategy by Streptococcus pyogenes strains. Here, using in silico analysis and mass spectrometry techniques, we identified a family of single-domain ENGases secreted by pathogenic corynebacterial species that exhibit strict specificity for IgG antibodies. By X-ray crystallographic and surface plasmon resonance analyses, we found that the most catalytically efficient IgG-specific ENGase family member recognizes both protein and glycan components of IgG. Employing in vivo models, we demonstrated the remarkable efficacy of this IgG-specific ENGase in mitigating numerous pathologies that rely on FcγR-mediated effector functions, including T and B lymphocyte depletion, autoimmune hemolytic anemia, and antibody-dependent enhancement of dengue disease, revealing its potential for treating and/or preventing a wide range of IgG-mediated diseases in humans.

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antibodies

2026-08-08 | Treatment of Cold Agglutinin Syndrome Secondary to Chronic Lymphocytic Leukemia With Sutimlimab and Obinutuzumab-Venetoclax.

Cold agglutinin-mediated autoimmune hemolytic anemia (AIHA) is a rare disorder in which IgM autoantibodies lead to complement-dependent hemolysis and cold-induced circulatory symptoms. It is categorized as either cold agglutinin disease (CAD), a primary lymphoproliferative disorder (LPD), or cold agglutinin syndrome (CAS), which occurs secondary to other conditions most commonly infections or lymphoid malignancies. Although the treatment for CAS should be directed toward the underlying condition, the often slower response rates of these treatments, especially in the setting of LPD, could necessitate other strategies for patients with severe hemolytic anemia requiring more rapid control of hemolysis. For patients with CAD, inhibition of the classical complement pathway with the C1s inhibitor sutimlimab has demonstrated significant control of hemolysis, resolution of anemia, and improvement in quality of life. However, little has been published regarding the use of sutimlimab for the treatment of CAS. Here, we describe a patient with CAS secondary to chronic lymphocytic leukemia (CLL) with severe IgM-driven complement-mediated hemolysis who was successfully treated with a combination of sutimlimab and CLL-directed therapy with obinutuzumab-venetoclax. Sutimlimab provided rapid cessation of hemolysis, acting as a bridge while the obinutuzumab-venetoclax addressed the underlying CLL that was presumably responsible for the autoantibody production. This case demonstrates that combining sutimlimab with obinutuzumab-venetoclax is an effective and safe treatment for patients with CAS in the setting of CLL, supporting the use of short-term sutimlimab for CAS as a bridge to more durable treatment for underlying LPD such as CLL.

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2026-08-06 | A Case Study of PSTPIP1-Associated Myeloid-Related Proteinemia Inflammatory Syndrome Masquerading as Inflammatory Bowel Disease.

PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome is a rare autoinflammatory disorder. Systemic inflammation, cytopenia, and skin lesions are classic features, accompanied by hypercalprotectinemia and hyperzincemia. Gastrointestinal manifestations such as colitis are infrequent. We present the first case in Thailand of PAMI syndrome presenting as refractory colitis. A 23-year-old male presenting with adult-onset refractory colitis and a history of a teenage perianal abscess. Despite the relatively late onset of intestinal symptoms, the patient exhibited a complex clinical picture across multiple domains of inborn errors of immunity, including autoimmune hemolytic anemia, chronic neutropenia, hepatosplenomegaly, and severe cystic acne. Genetic testing revealed a PSTPIP1 mutation (E250K variant), and laboratory results showed pathognomonic hyperzincemia, confirming PAMI syndrome. Treatment with adalimumab led to significant clinical and endoscopic remission. PAMI syndrome should be considered a differential diagnosis in patients with atypical or refractory colitis, particularly when accompanied by systemic clues such as cytopenia, severe acne, or organomegaly. Serum zinc levels serve as a simple, cost-effective screening tool to facilitate prompt diagnosis and can function as a practical biomarker for monitoring the response to therapy.

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2026-07-28 | Targeting type I interferon in lupus autoimmune haemolytic anaemia: first report with anifrolumab.

Autoimmune haemolytic anaemia (AIHA) occurs in approximately 5-10% of patients with SLE and it is traditionally associated with higher disease activity, increased damage accrual and reduced survival. SLE management recommendations partially address disease-related haematological manifestations without specific indication for AIHA treatment. Indeed, therapeutic approaches are prevalently extrapolated from the haematology field. In the present report, we aimed at describing a case series of patients with SLE and AIHA successfully treated with anifrolumab (ANF). We described patients with SLE treated by ANF with active AIHA at the drug initiation. Clinical and laboratory data were reported in a standardised electronic form, including laboratory evidence of haemolysis. Overall disease activity was assessed by using the SLE Disease Activity Index 2000 (SLEDAI-2k). We collected patients data at baseline (T0), after 1 month (T1) and every 3 months thereafter. We included seven patients (6F/1M, median age 61 years (IQR 33), median disease duration 48 months (IQR 72)). All the patients had a positive direct Coombs test and laboratory evidence of active haemolysis at ANF starting. During treatment, we observed a progressive increase in haemoglobin (Hb) levels, with a statistically significant difference compared with baseline after 3 months of treatment (p=0.02). In parallel we registered the increase in RBC count, without the need to perform RBC transfusions after ANF starting. Overall disease activity significantly improved during the follow-up, with significant reduction of mean SLEDAI-2k values after 6 months of treatment (p=0.01). In the present case-series study, we provide the first report about the benefit of ANF in the treatment of SLE-related AIHA, a rare but potentially severe manifestation associated with increased morbidity and mortality. In our cohort, ANF treatment was associated with a rapid and sustained increase in Hb levels, evident already at 1 month and progressively improving up to 6 months.

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2026-07-17 | When hemolysis overwhelms the liver: warm autoimmune hemolytic anemia complicated by secondary cholestasis and pigment choledocholithiasis.

Hemolysis is a physiologic condition that results from the lysis of red blood cells and the release of their contents into the plasma. This condition may occur in the setting of a genetic, infectious, mechanical, or immune-mediated process. Classically, hemolysis results in a primarily indirect hyperbilirubinemia as free hemoglobin is metabolized to bilirubin, which is then conjugated and excreted; however, in rare instances, severe and chronic hemolysis may saturate the biliary excretion system and result in a direct hyperbilirubinemia. In this report, we present a 73-year-old man who presented with severe jaundice and was found to have warm autoimmune hemolytic anemia. The patient's total bilirubin level was 72.4 mg/dL, with a direct bilirubin level of 43.6 mg/dL and elevated liver enzymes. Imaging was consistent with an obstructive process, and hilar thickening on magnetic resonance cholangiopancreatography raised concern for a superimposed cholangiocarcinoma. Endoscopic retrograde cholangiopancreatography, however, removed several black pigment stones, known to be associated with chronic hemolysis, and cytology brushings were negative for malignancy. This case is an excellent illustration of how sustained extravascular hemolysis can overwhelm hepatic excretory capacity and produce secondary cholestasis that mimics malignancy.

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2026-06-16 | Warm Autoimmune Hemolytic Anemia Presenting 21 Years After Liver Transplantation: A Case Report.

BACKGROUND Autoimmune hemolytic anemia (AIHA) is characterized by immune-mediated premature red blood cell destruction. Although AIHA has been reported after solid organ transplantation, it remains uncommon, and very late-onset presentations occurring decades after transplantation are rare. Both warm and cold AIHA have been reported after transplant. Reported etiologies include immune dysregulation, infections, post-transplant lymphoproliferative disorders, and medication-associated immune hemolysis, including calcineurin inhibitor-related effects. CASE REPORT A 30-year-old woman with orthotopic liver transplantation at age 9 for biliary atresia, on long-term tacrolimus, presented 21 years after transplant with exertional dyspnea and symptomatic anemia. Laboratory evaluation revealed severe anemia with biochemical evidence of hemolysis, including undetectable haptoglobin and reticulocytosis. A direct antiglobulin test was positive for IgG, confirming warm autoimmune hemolytic anemia. Antibody identification revealed a warm autoantibody, and crossmatch-compatible red blood cells were transfused without reaction. Extensive evaluation excluded gastrointestinal bleeding, infection including Epstein-Barr virus, post-transplant lymphoproliferative disorder, and thrombotic microangiopathy. She was treated with high-dose corticosteroids with partial response, followed by early rituximab due to persistent hemoglobin instability. The tacrolimus dose was modestly reduced but not discontinued. Bone marrow biopsy excluded hematolymphoid malignancy. The patient achieved complete remission with normalization of hemoglobin and hemolysis markers after 4 rituximab doses and steroid tapering. CONCLUSIONS Warm autoimmune hemolytic anemia can present decades after solid organ transplantation and should be considered in transplant recipients with unexplained anemia. Remission can be achieved with corticosteroids and early rituximab without discontinuation of tacrolimus. Further studies are needed to clarify optimal treatment strategies for late-onset post-transplant AIHA, including the role of early rituximab.

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other

2024-08-19 | Association of paediatric autoimmune cytopenia and inflammatory bowel disease suggests a common genetic origin.

The association of autoimmune cytopenia (AIC) and inflammatory bowel disease (IBD) has been reported in small series, but the incidence of and risk factors for IBD in children with AIC are not known. One thousand six hundred nine children with chronic immune thrombocytopenic purpura, autoimmune haemolytic anaemia or Evans syndrome from the prospective OBS'CEREVANCE cohort are included in this study. Overall, 15 children were diagnosed with IBD, including 14 who developed IBD after AIC diagnosis (median delay: 21 months). The only risk factor for IBD development is age at AIC over 10 years. Out of 10 children genetically tested, germline variants associated with autoimmune disorders were identified in three (CTLA4: two, DOCK11: one). In children and adolescents monitored for AIC or past history of AIC, especially children over 10 years, gastro-intestinal (GI) symptoms (recurrent abdominal pains, GI bleeding, chronic diarrhoea, weight loss) should suggest IBD and deserve specific work-up and genetic studies. Identification of a causal germline variant will allow targeted therapy.

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2022-04-26 | Pathogenesis of Autoimmune Cytopenias in Inborn Errors of Immunity Revealing Novel Therapeutic Targets.

Autoimmune diseases are usually associated with environmental triggers and genetic predisposition. However, a few number of autoimmune diseases has a monogenic cause, mostly in children. These diseases may be the expression, isolated or associated with other symptoms, of an underlying inborn error of immunity (IEI). Autoimmune cytopenias (AICs), including immune thrombocytopenic purpura (ITP), autoimmune hemolytic anemia (AIHA), autoimmune neutropenia (AN), and Evans' syndrome (ES) are common presentations of immunological diseases in the pediatric age, with at least 65% of cases of ES genetically determined. Autoimmune cytopenias in IEI have often a more severe, chronic, and relapsing course. Treatment refractoriness also characterizes autoimmune cytopenia with a monogenic cause, such as IEI. The mechanisms underlying autoimmune cytopenias in IEI include cellular or humoral autoimmunity, immune dysregulation in cases of hemophagocytosis or lymphoproliferation with or without splenic sequestration, bone marrow failure, myelodysplasia, or secondary myelosuppression. Genetic characterization of autoimmune cytopenias is of fundamental importance as an early diagnosis improves the outcome and allows the setting up of a targeted therapy, such as CTLA-4 IgG fusion protein (Abatacept), small molecule inhibitors (JAK-inhibitors), or gene therapy. Currently, gene therapy represents one of the most attractive targeted therapeutic approaches to treat selected inborn errors of immunity. Even in the absence of specific targeted therapies, however, whole exome genetic testing (WES) for children with chronic multilineage cytopenias should be considered as an early diagnostic tool for disease diagnosis and genetic counseling.

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2020-01-09 | Pediatric Evans syndrome is associated with a high frequency of potentially damaging variants in immune genes.

Evans syndrome (ES) is a rare severe autoimmune disorder characterized by the combination of autoimmune hemolytic anemia and immune thrombocytopenia. In most cases, the underlying cause is unknown. We sought to identify genetic defects in pediatric ES (pES), based on a hypothesis of strong genetic determinism. In a national, prospective cohort of 203 patients with early-onset ES (median [range] age at last follow-up: 16.3 years ([1.2-41.0 years]) initiated in 2004, 80 nonselected consecutive individuals underwent genetic testing. The clinical data were analyzed as a function of the genetic findings. Fifty-two patients (65%) received a genetic diagnosis (the M+ group): 49 carried germline mutations and 3 carried somatic variants. Thirty-two (40%) had pathogenic mutations in 1 of 9 genes known to be involved in primary immunodeficiencies (TNFRSF6, CTLA4, STAT3, PIK3CD, CBL, ADAR1, LRBA, RAG1, and KRAS), whereas 20 patients (25%) carried probable pathogenic variants in 16 genes that had not previously been reported in the context of autoimmune disease. Lastly, no genetic abnormalities were found in the remaining 28 patients (35%, the M- group). The M+ group displayed more severe disease than the M- group, with a greater frequency of additional immunopathologic manifestations and a greater median number of lines of treatment. Six patients (all from the M+ group) died during the study. In conclusion, pES was potentially genetically determined in at least 65% of cases. Systematic, wide-ranging genetic screening should be offered in pES; the genetic findings have prognostic significance and may guide the choice of a targeted treatment.

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2013-07-31 | An innovative method to identify autoantigens expressed on the endothelial cell surface: serological identification system for autoantigens using a retroviral vector and flow cytometry (SARF).

Autoantibodies against integral membrane proteins are usually pathogenic. Although anti-endothelial cell antibodies (AECAs) are considered to be critical, especially for vascular lesions in collagen diseases, most molecules identified as autoantigens for AECAs are localized within the cell and not expressed on the cell surface. For identification of autoantigens, proteomics and expression library analyses have been performed for many years with some success. To specifically target cell-surface molecules in identification of autoantigens, we constructed a serological identification system for autoantigens using a retroviral vector and flow cytometry (SARF). Here, we present an overview of recent research in AECAs and their target molecules and discuss the principle and the application of SARF. Using SARF, we successfully identified three different membrane proteins: fibronectin leucine-rich transmembrane protein 2 (FLRT2) from patients with systemic lupus erythematosus (SLE), intercellular adhesion molecule 1 (ICAM-1) from a patient with rheumatoid arthritis, and Pk (Gb3/CD77) from an SLE patient with hemolytic anemia, as targets for AECAs. SARF is useful for specific identification of autoantigens expressed on the cell surface, and identification of such interactions of the cell-surface autoantigens and pathogenic autoantibodies may enable the development of more specific intervention strategies in autoimmune diseases.

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2004-11-01 | Transgenic Expression of CTLA-4 Controls Lymphoproliferation in IL-2-Deficient Mice

Abstract IL-2-deficient mice develop a lymphoproliferative and autoimmune disease characterized by autoimmune hemolytic anemia (AHA) and inflammatory bowel disease. We have previously reported that IL-2 is necessary for optimal up-regulation of CTLA-4, an inducible negative regulator of T cell activation. In this study, we have tested the hypothesis that reduced expression of CTLA-4 in IL-2-deficient T cells contributes to the pathogenesis of disease in IL-2-deficient mice. Expression of CTLA-4 as a transgene completely prevented lymphoaccumulation and AHA in IL-2-deficient mice. The normalization of T cell numbers was due to inhibition of expansion of conventional CD4+CD25− T cells rather than to rescue of the numbers or function of CD4+CD25+ regulatory T cells, suggesting that CTLA-4 expression on conventional T cells plays a role in maintaining normal T cell homeostasis. In addition, the inhibitory effect of the CTLA-4 transgene on T cell expansion was at least in part independent of CD28 expression. Our results suggest that deficient CTLA-4 expression on conventional T cells contributes to the pathophysiology of the lymphoproliferative disease and AHA in IL-2-deficient mice. Thus, restoring CTLA-4 expression in T cells may be an attractive strategy to control clinical autoimmune diseases in which CTLA-4 expression is reduced.

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