RARE DISEASE
Cold agglutinin disease
Cold agglutinin disease
Cold agglutinin disease
Synonyms: CAD, CAS, Chronic cold agglutinin disease, Cold agglutinin syndrome
Synonyms: CAD, CAS, Chronic cold agglutinin disease, Cold agglutinin syndrome
Synonyms: CAD, CAS, Chronic cold agglutinin disease, Cold agglutinin syndrome
Drug discovery
410
papers
On emerging therapies
Overview
Cold Agglutinin Disease (CAD) is a rare autoimmune hemolytic anemia driven by IgM autoantibodies that trigger complement-mediated destruction of red blood cells at low temperatures (32–50°F). Primarily idiopathic or linked to infections/lymphoproliferative disorders, it manifests with chronic anemia, fatigue, acrocyanosis, and cold-induced circulatory symptoms. Diagnosis hinges on C3d-positive direct antiglobulin testing and elevated cold agglutinin titers (>1:64).
Population
Prevalence: ~16 per million; annual incidence ~1–2 per million [1][6][14].
Median age at diagnosis: 65–76 years; slight female predominance (female:male ratio ~1.5:1) [6][10].
~70% of cases are primary (clonal B-cell disorder); 30% secondary to infections (e.g., Mycoplasma pneumoniae) or cancers (e.g., lymphoma) [9][10].
Burden
Therapies
First-line: Avoid cold exposure; rituximab ± bendamustine (response rates: 71%–80%) [3][11].
Complement inhibition: Sutimlimab (C1s inhibitor), FDA-approved for hemolysis reduction, achieves hemoglobin stabilization in ~54% within 1–2 weeks [3][9].
Avoid corticosteroids/splenectomy; consider plasma exchange for acute crises [3][9].
Categories: rare hematological diseases
Research Papers
410 drug discovery papers about Cold agglutinin disease, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
410 drug discovery papers about Cold agglutinin disease, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-07-21 | Concurrent Cold Autoimmune Hemolytic Anemia, Painless Thyroiditis, and Deep Vein Thrombosis Following Mycoplasma pneumoniae Pneumonia: A Rare Case of Multi-Organ Immune Complications.
A 22-year-old woman developed palpitations, fatigue, and right leg pain 18 days after suffering from Mycoplasma pneumoniae (MP) pneumonia. Laboratory tests revealed severe hemolytic anemia with elevated lactate dehydrogenase levels, a C3b/C3d-positive direct antiglobulin test, and high cold agglutinin titers, confirming cold autoimmune hemolytic anemia. Thyroid studies showed asymptomatic thyrotoxicosis without tenderness, which was consistent with painless thyroiditis. Venous ultrasonography revealed deep vein thrombosis in the right popliteal and soleal veins. She improved with cold avoidance and apixaban treatment. This case underscores that multi-organ immune complications can emerge during the subacute phase of an MP infection.
2026-06-11 | 20 | Atypical presentation of anaemia in an older woman on direct oral anticoagulants: the importance of differential diagnosis
Introduction. Anaemia in older adults on direct oral anticoagulants is attributed to occult bleeding; however, such diagnostic anchoring may impede the timely recognition of rarer aetiologies. Objectives. To report a case of severe haemolytic anaemia masquerading as gastrointestinal bleeding, underscoring the importance of differential diagnosis in older adults. Materials and Methods. An 88-year-old female on anticoagulants for atrial fibrillation presented with severe anaemia (haemoglobin 7.0 g/dL). In the context of suspected haemorrhage, such drugs were discontinued, and four red blood cell units were transfused. Subsequently, new-onset jaundice and laboratory findings (markedly elevated indirect bilirubin and lactate dehydrogenase, undetectable haptoglobin, and hyperferritinaemia) revealed overt haemolysis. Computed tomography and endoscopy excluded neoplasms or active bleeding. Reassessment confirmed haemolytic anaemia with a negative direct antiglobulin test (Coombs) and a minimal monoclonal immunoglobulin M (IgM) kappa component. Infectious/autoimmune screenings and targeted quantification of cold agglutinin titres were performed. Results. Tests for Epstein-Barr virus, Cytomegalovirus, and Mycoplasma pneumoniae yielded negative results. Notably, the cold agglutinin titre was markedly elevated (1:2048). Following the diagnosis of cold agglutinin disease (CAD) and primary hypothyroidism, steroid therapy (methylprednisolone) and erythropoietin were initiated. Anticoagulation was safely resumed with low-molecular-weight heparin. Haemoglobin stabilised at 9.7 g/dL with remission of haemolysis. The patient was discharged asymptomatic and strictly advised to avoid cold exposure. Conclusions. In older anticoagulated patients with severe anaemia, the prompt evaluation of haemolysis indices and cold agglutinins (even with a negative Coombs test) is of paramount clinical importance to avoid inappropriate transfusions and ensure correct therapeutic management.
2025-12-29 | Autoimmune Hemolytic Anemia in Non-Hodgkin's Lymphoma: Pathogenesis, Diagnosis, and Management.
Autoimmune hemolytic anemia (AIHA) is an acquired hemolytic disorder caused by autoantibodies and/or complement-mediated destruction of red blood cells (RBCs), often driven by dysregulated B lymphocyte activity. A notable clinical association exists between AIHA and lymphoproliferative disorders (LPD), particularly chronic lymphocytic leukemia, and non-Hodgkin's lymphoma (NHL). To summarize the clinicopathological link, prevalence, pathogenesis, and management strategies of AIHA associated with NHL. This narrative review synthesizes evidence from 20 peer-reviewed studies published between 2011 and 2024, identified through PubMed, Google Scholar, and manual citation tracking. Eligible studies were restricted to English-language articles addressing the prevalence, pathogenesis, clinical features, diagnosis, or treatment of AIHA in NHL. Approximately 7%-10% of NHL patients develop coexisting AIHA, while up to 20% of AIHA patients are eventually diagnosed with lymphoma. The reported incidence of AIHA among NHL patients varies widely (0.23%-15.7%), reflecting methodological and population differences. Proposed mechanisms include chronic antigen stimulation and dysregulated antibody production. The coexistence of both conditions complicates management: Treatment generally prioritizes NHL-directed therapy, while glucocorticoids and rituximab are commonly used for AIHA control. AIHA and NHL share overlapping immunopathological pathways with important clinical implications. Early recognition of AIHA in NHL is essential to optimize patient outcomes. Future priorities include developing biomarkers to identify high-risk patients and conducting large-scale randomized trials to validate complement inhibitors for cold agglutinin disease (CAD).
2025-12-05 | Management of autoimmune hemolytic anemia.
Autoimmune hemolytic anemia (AIHA) is caused by premature erythrocyte destruction mediated by autoantibodies (auto-Ab) with or without complement activation. The most frequent form (60%-70% of cases) is warm AIHA (wAIHA), driven by immunoglobulin G auto-Ab that react at body temperature. Cold agglutinin disease (CAD, 20%-25%) is the second most common form and is caused by immunoglobulin M auto-Ab that usually react at temperatures <20°C and strongly activate complement. Rarer forms (5%-10%) include mixed AIHAs (wAIHA plus CAD), and paroxysmal cold hemoglobinuria. Here, we present the management of wAIHA, as CAD is discussed separately. Approximately 50% of wAIHA are primary, whereas the remainder are secondary to various conditions (infections, lymphoproliferative disorders, systemic or organ-specific autoimmune diseases, congenital immunodeficiencies, hematopoietic stem-cell transplantation, and several drugs, including immune checkpoint inhibitors). The disease is highly heterogeneous, ranging from fully compensated to life-threatening, and frequently has a relapsing course. Standard first-line therapy includes steroids with or without intravenous immunoglobulin, transfusions when anemia is clinically significant, prophylactic anticoagulation for severe hemolysis, and recombinant erythropoietin when reticulocytopenia/inadequate bone marrow compensation is present. For severe cases, high-dose steroids and plasma-exchange may be considered. Rituximab is now the preferred second-line option for relapsed/refractory patients, comparing favorably with the traditional splenectomy. The latter is increasingly reserved for later lines together with classic immunosuppressants. Several novel treatments are in development for refractory wAIHA, encompassing drugs targeting B-cells (parsaclisib, ibrutinib, rilzabrutinib, zanubrutinib, obexelimab, ianalumab, povetacicept), plasma cells (bortezomib, daratumumab), spleen tyrosine kinase (fostamatinib, sovleplenib), and the neonatal Fc receptor (nipocalimab).
2025-12-01 | COLD AGGLUTININ DISEASE ASSOCIATED WITH COVID-19 INFECTION IN A PEDIATRIC PATIENT: A RARE CASE PRESENTING WITH SEVERE HEMOLYTIC ANEMIA AND LOBAR PNEUMONIA
Cold agglutinin disease (CAD) is a form of autoimmune hemolytic anemia caused by antibodies—typically immunoglobulin M (IgM), and less frequently IgA or IgG—that target antigens on the surface of erythrocytes. Although the etiology may involve infections or immunologic disorders, most cases are idiopathic. The clinical picture results from hemolysis triggered by antibodies that become active at cold temperatures, leading to degenerative changes in the erythrocyte membrane and autoagglutination. This causes a drop in erythrocyte count and hematocrit, while MCV, MCH, and MCHC values appear markedly elevated. Peripheral blood smears often reveal erythrocyte agglutination. Here in, we present a case of cold agglutinin disease secondary to COVID-19 infection. A 14-year-old previously healthy girl was initially treated with amoxicillin-clavulanate for upper respiratory tract infection symptoms, including fever and cough. Her symptoms worsened, and she tested positive for COVID-19 at an outside hospital. She was diagnosed with lobar pneumonia, and significant anemia noted during follow-up prompted her referral to our institution, Türkiye. Upon admission to our pediatric intensive care unit, three consecutive hemogram samples were clotted and could not be analyzed. Venous blood gas revealed hemoglobin (Hb) of 4.2 g/dL. Biochemical analyses showed LDH: 724 U/L (range 110-295 U/L), total bilirubin: 1.85 mg/dL (range 0.3-1.2 mg/dL), direct bilirubin: 0.29 mg/dL (range 0-0.2 mg/dL), and haptoglobin: 0.38 g/L (range 0.35-2.5 g/L). Direct Coombs test was negative. Peripheral smear demonstrated erythrocyte agglutination clusters. Blood samples were delivered to the laboratory in warm water immediately after collection to prevent in vitro agglutination. Repeat tests showed Hb: 8.2 g/dL, MCV: 100 fL, and a markedly elevated MCHC of 683 g/dL. Quantitative cold agglutinin testing could not be performed due to technical limitations at our center. In addition to pneumonia treatment, the patient was started on methylprednisolone at 2 mg/kg/day for presumed cold agglutinin disease. She was discharged on day 10 of treatment and her steroid therapy was tapered and discontinued by day 21. At follow-up on day 21, the patient’s hemoglobin had increased to 13.9 g/dL, and no erythrocyte agglutination was observed on peripheral smear. This case highlights a rare pediatric presentation of cold agglutinin disease associated with COVID-19 infection, complicated by severe hemolysis and lobar pneumonia. Early recognition and a multidisciplinary approach including corticosteroids and supportive care played a critical role in the patient's favorable outcome.
cell therapies
2026-06-11 | Therapeutic plasma exchange for refractory Mycoplasma pneumoniae-associated cold agglutinin syndrome: A case report.
Cold agglutinin syndrome (CAS) secondary to Mycoplasma pneumoniae typically self-resolves with antimicrobial therapy and supportive care. Therapeutic plasma exchange (TPE) has been described as an adjunct therapy in refractory CAS, but there is limited data on its use in M. pneumoniae-associated CAS. A 26-year-old male developed severe hemolytic anemia 3 weeks after initial M. pneumoniae diagnosis. Initial hemoglobin was 8.2 g/dL with marked hemolysis (lactate dehydrogenase 1398 U/L, total bilirubin 4.0 mg/dL, haptoglobin <10 mg/dL). Antibody screen was positive for cold antibody. Direct antiglobulin test was C3-positive. Despite appropriate antimicrobial therapy, he required 17 units of packed red blood cells over 20 days of admission. TPE was initiated on day 11 for refractory hemolysis. Four sessions were performed (on days 11, 14, 17, 18). Antibody screens became negative post-TPE and markers of hemolysis improved. Following the final 1.5 plasma volume exchange, the patient achieved his longest transfusion-free interval (5 days). Research flow cytometry demonstrated elevated surface IgG and C3 on red cells pre-exchange that decreased over the course of TPEs but remained above baseline at discharge. The patient required three additional units of red cell transfusions post-discharge but achieved transfusion independence by day 30. Total transfusion requirement was 20 units. This case of M. pneumoniae-associated CAS highlights atypical features including failure of antimicrobial therapy and supportive care alone, exceptional transfusion needs, and ongoing hemolysis despite TPE. TPE may serve as adjunctive therapy in transfusion-dependent refractory CAS in the setting of M. pneumoniae infection.
2026-04-11 | CD19 CAR-T therapy induces remission in refractory autoimmune hemolytic anemia with ITP and antiphospholipid syndrome.
Autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP), and antiphospholipid antibody syndrome (APLAS) are B cell-driven autoimmune diseases defined by pathogenic autoantibodies. CD19-directed chimeric antigen receptor (CAR)-T cells have recently demonstrated the ability to reset dysregulated B cells and induce long-lasting remission in refractory systemic autoimmune diseases. Evidence for efficacy in severe, treatment-refractory AIHA, however, is limited. We report the clinical course of a 47-year-old woman with life-threatening cold- and warm-agglutinin AIHA refractory to nine prior treatment lines, accompanied by ITP and APLAS. In an uncontrolled flare, she received a fludarabine/cyclophosphamide-containing lymphodepletion followed by autologous CD19-directed, 4-1BB-costimulated CAR-T cells (zorpocabtagene-autoleucel [Zorpo-cel], 1 × 106/kg) on the basis of compassionate use. Treatment efficacy and safety were assessed over an 11-month follow-up period. Zorpo-cel showed a rapid and sustained B cell depletion. Transfusion independence was achieved by day 7, with hemoglobin normalization by day 25, including resolution of hemolysis markers. Cold-agglutinin titers decreased, and previously elevated antiphospholipid antibodies normalized without recurrence throughout 11 months of follow-up. ITP stabilized. No cytokine release syndrome or neurotoxicity occurred. Mild transaminase elevation and thrombocytopenia were observed, most likely correlating with pre-existing severe iron overload due to erythrocyte transfusions. This case demonstrates that CD19-directed CAR-T cell therapy can induce rapid, durable remission of severe, refractory cold-agglutinin AIHA and simultaneously improve coexisting APLAS and ITP on a favorable toxicity profile. However, more data from controlled clinical trials are needed for final conclusions. This work was funded by Deutsche Forschungsgemeinschaft and Deutsche Krebshilfe.
2026-03-12 | Mixed Autoimmune Hemolytic Anemia With Refractory Cold Agglutinin Syndrome in a Child Successfully Treated With Serial Whole Blood Exchange Transfusions and Immunosuppression.
Mixed autoimmune hemolytic anemia can manifest with severe intra- and extravascular hemolysis, with autoagglutination contributing to vaso-occlusive microangiopathic phenomena. We present a case of mixed autoimmune haemolytic anemia with unusually severe cold agglutinin syndrome causing cutaneous, cerebral, ocular, and aural manifestations of microvasculopathy and massive intravascular haemolysis, requiring 6 double-volume whole-blood exchanges over 8 days to temporise severe hemolysis and autoagglutination while immunosuppression with high-dose steroids, rituximab, and bortezomib took effect. Whole-blood exchange permitted fluid-neutral clearance of preformed antibodies and antibody-coated red cells, with dramatic resolution of microvasculopathy and hemolysis, before discharge home on oral steroid therapy.
2025-11-24 | Precision targeting of autoreactive B cells in systemic lupus erythematosus using anti-9G4 idiotope synthetic immune receptor T cells.
Chimeric antigen receptor (CAR)-T cell therapies that broadly target B cells can achieve complete remission in severe systemic lupus erythematosus (SLE) but carry an increased risk of infection and cytokine-related toxicities that limit their use. Alternative strategies that combine the potency of immune effector cell therapies with more precise targeting approaches have the potential to control disease without the challenges of broad immunosuppression. B cells expressing immunoglobulin heavy variable gene 4-34 (IGHV4-34)-derived B cell receptors (BCRs) are a major source of disease-relevant autoantibodies in lupus and other autoimmune diseases. Here, we exploit a common feature of IGHV4-34 BCRs, namely the 9G4 idiotope (9G4id), to develop precision cellular immunotherapies that target autoreactive B cells. Anti-9G4 CAR-T cells and anti-9G4 chimeric T cell receptor (cTCR) T cells, integrating anti-9G4 antibody fragments into a re-engineered TCR scaffold, eliminated autoreactive Ramos B cells expressing SLE patient-derived 9G4id BCRs with equal potency, while sparing non-9G4 Ramos B cells. Using SLE patient PBMCs, autologous anti-9G4 cTCR-T cells and anti-9G4 CAR-T cells selectively depleted primary human 9G4id B cells, while maintaining total B cell numbers. Similarly, anti-9G4 T cells eliminated B cells expressing 9G4id BCRs from patients with cold agglutinin disease and Burkitt lymphoma. Compared to broad targeting with CD19 CAR-T cells, anti-9G4 T cell therapies showed lower cytokine release (~6-8-fold for interferon [IFN]-γ). In addition, anti-9G4 cTCR-T cells showed ~17-fold lower IFN-γ secretion compared to anti-9G4 CAR-T cells, despite achieving similar cytotoxicity. Together, our findings suggest that anti-9G4 precision cellular therapies provide a strategy to selectively target pathogenic B cells in SLE, while minimizing risks of infection and cytokine-related toxicities.
2025-10-26 | CD19 CAR-T induces complete and durable remission in cold agglutinin syndrome associated relapse and refractory diffuse large B cell lymphoma
Primary cold agglutinin disease (CAD), a well-characterized indolent B cell clonal disorder, and secondary cold agglutinin syndrome (CAS), which frequently brings on by underlying conditions like i...
proteins
2026-07-28 | Discovery and engineering of novel IgM proteases for the treatment of autoimmune and inflammatory diseases 2253144
Abstract Introduction IgM is a multifunctional immunoglobin that acts as the first line of defense against systemic pathogens. IgM’s multimeric structure, together with its complement binding ability, makes IgM a highly potent inflammation driver. The presence of autoreactive IgM antibodies causing complement dependent damage has been described in inflammatory and autoimmune conditions such as Cold Agglutinin Disease (CAD) and Multifocal Motor Neuropathy (MMN) . For this reason, the development of IgM autoantibodies degrading therapy represents an attractive approach. Methods Employing Seismic’s IMPACT platform and evolutionary screening, we identified several novel and selective IgM proteases. Discovered proteases cleave soluble IgM in plasma and the IgM BCR in B cells from healthy individuals. Results CAD is an autoimmune hemolytic anemia, caused by IgM autoantibodies that bind to red blood cells (RBC), causing agglutination and activate complement cascade resulting in RBC death. Seismic’s IgM protease cleaves RBC bound IgM, preventing agglutination in whole blood from CAD donors, an unmet need not targeted by current approved treatment. In addition, IgM cleavage reduced cold-induced complement deposition on RBC from CAD patients. Conclusion Further engineering and optimization with our IMPACT Platform for the novel proteases is currently under way. Funding Source n/a Topic Categories Therapeutic Approaches to Autoimmunity (THER)
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.
2024-09-04 | When you think you should transfuse…don't!
A 48-year-old female presented to the emergency department with severe fatigue. Admission laboratory test results were hemoglobin 6.6 g/dL, platelet count 287,000/μL, and white blood cell count 25,200/μL. Lactate dehydrogenase was elevated at 898 U/L, haptoglobin was markedly decreased (< 31 mg/dL), indirect bilirubin was elevated (5.3 mg/dL), and the absolute reticulocyte count was low at 0.0050/μL. A sample was sent to the immunohematology reference laboratory. The direct antiglobulin test immunoglobulin G was negative; C3 was 1+. All cells were reactive at immediate spin phase, indirect antiglobulin testing (IAT) with polyethylene glycol, with low ionic strength saline, neat, prewarm, and in the solid phase. All cells were nonreactive at IAT-ficin. Additional testing included a cold antibody titer that was 1:4096 and thermal amplitude studies demonstrating reactivity of 2+ at 37°C. These results were consistent with a clinically significant anti-Pr and cold agglutinin disease (CAD). Although rituximab is effective in autoimmune hemolytic anemia, this may take weeks. The patient was treated with pegcetacoplan, a pegylated peptide that targets C3 inhibiting hemolysis. The patient was discharged on day 29 with a hemoglobin of 8 g/dL. This is a report of one of the first patients successfully treated with pegcetacoplan for CAD.
2014-08-22 | Peptide Inhibitor of Complement C1, a Novel Suppressor of Classical Pathway Activation: Mechanistic Studies and Clinical Potential
The classical pathway of complement plays multiple physiological roles including modulating immunological effectors initiated by adaptive immune responses as well as an essential homeostatic role in the clearance of damaged self-antigens. However, dysregulated classical pathway activation is associated with antibody-initiated, inflammatory diseases processes like cold agglutinin disease (CAD), acute intravascular hemolytic transfusion reaction (AIHTR) and acute/hyperacute transplantation rejection. To date, only one putative classical pathway inhibitor, C1 esterase inhibitor (C1-INH), is currently commercially available and its only approved indication is for replacement treatment in hereditary angioedema (HAE), which is predominantly a kinin pathway disease. Given the variety of disease conditions in which the classical pathway is implicated, development of therapeutics that specifically inhibit complement initiation represents a major unmet medical need. Our laboratory has identified a peptide that specifically inhibits the classical and lectin pathways of complement. In vitro studies have demonstrated that these Peptide Inhibitors of Complement C1 (PIC1) bind to the collagen-like region of the initiator molecule of the classical pathway, C1q. PIC1 binding to C1q blocks activation of the associated serine proteases (C1s-C1r-C1r-C1s) and subsequent downstream complement activation. Rational design optimization of PIC1 has resulted in the generation of a highly potent derivative of fifteen amino acids. PIC1 inhibits classical pathway mediated complement activation in ABO incompatibility in vitro as well as inhibiting classical pathway activation in vivo in rats. This review will focus on the pre-clinical development of PIC1 and discuss its potential as a therapeutic in antibody-mediated classical pathway disease, specifically AIHTR.
2005-07-01 | Treatment of Autoimmune Hemolytic Anemia
The appropriate therapy of autoimmune hemolytic anemia (AIHA) is dependent on the correct diagnosis and classification of this family of hemolytic disorders. Although the majority of cases are warm AIHA, there are several distinct types of cold AIHA and a number of drug-induced etiologies of AIHA, which must be investigated to determine if stopping a drug will induce a remission. In warm AIHA, corticosteroids are standard, followed by consideration of splenectomy in recalcitrant cases. If steroids and splenectomy are insufficient, other forms of immunosuppressive therapy are typically initiated. In cold AIHA, keeping the patient warm in often sufficient, but therapy directed at an underlying lympholiferative disorder may be helpful. Brisk hemolysis, inadequate responses to therapy, and worsening anemia require transfusion therapy. Although the pretransfusion workup is made difficult by the presence of the autoantibody, transfusion services can usually provide blood safe for transfusion by excluding underlying alloantibodies. When transfusion is urgently required and compatible blood cannot be located, incompatible blood may be provided as a life-saving measure. Communication between the transfusion service and the hematologist is critical to assess the risks in these settings. Hemoglobin-based oxygen carriers may provide an important bridging therapy in the future. Requests for "least incompatible" blood do not enhance transfusion safety and often result in unnecessary delays.
antibodies
2026-09-30 | Complement inhibition by sutimlimab in cold agglutinin disease promotes red blood cell agglutination and may lead to circulatory complications, eryptosis and hemolysis.
Sutimlimab, an anti-C1s monoclonal antibody, is approved for the treatment of cold agglutinin disease (CAD). It prevents hemolysis by inhibiting the classical complement pathway. One of its off-target effects may be increasing circulatory complications that have not yet been characterized. We report two patients with CAD who developed unusual widespread skin cyanosis and exacerbated acrocyanosis during sutimlimab treatment. One of the two patients additionally experienced massive intravascular hemolysis, eryptosis and acute renal failure. Serological analyses were conducted using standard techniques, and eryptosis was quantified by flow cytometry with PE-labelled Annexin V. Serological assays using plasma and serum from these two patients and four additional untreated patients (n=6) with CAD were performed. They demonstrated a significant increase in red blood cell (RBC) agglutination in the presence of sutimlimab as well as in the absence of complement activation. The observed increase in RBC agglutination under sutimlimab treatment is likely due to a substantial reduction of C3d deposition on RBCs. This mechanism also represents the most plausible explanation for the side effects observed in some patients with CAD receiving the drug, such as aggravation of circulatory complications, including acrocyanosis, Raynaud's phenomenon, and less commonly, organ dysfunction. Inhibition of early complement components (C1-C3) may therefore not only prevent hemolysis in CAD but paradoxically also promote RBC agglutination, eryptosis, and hemolysis in certain cases. Pre-treatment serological testing with sutimlimab may help predict some of these adverse effects.
2026-09-18 | CD20-positive multiple myeloma complicated by cold agglutinin disease
Cluster of differentiation 20 (CD20) expression is rarely observed in multiple myeloma (MM) and is typically associated with immature plasma cell morphology and aggressive clinical behavior.Cold agglutinin disease (CAD) is also uncommon in MM and usually suggests other hematologic malignancies.We present a rare case of CD20-positive MM complicated by CAD in a 77-year-old woman who initially had pancytopenia, bone pain, and renal failure.Diagnostic work-up revealed light chain MM with kappa restriction, cast nephropathy, and diffuse CD20 expression in plasma cells.She was treated with bortezomib, cyclophosphamide, and dexamethasone (VCD), achieving hematologic improvement and partial renal recovery.During the third cycle, she developed severe anemia and hemolysis due to cold agglutinins, which were managed successfully with corticosteroids and supportive care.Retrospective immunohistochemistry confirmed CD20 positivity.This case underscores the diagnostic and therapeutic complexity of atypical MM presentations and highlights the importance of re-evaluating immunophenotypic features when the clinical course deviates from expectations.While CD20-targeted therapies are not routinely used in MM, their relevance in selected subtypes warrants further exploration.Our case illustrates the potential for paraneoplastic hemolysis and phenotypic diversity in MM, emphasizing the need for a multidisciplinary approach to diagnosis and management.
2026-09-08 | Complement targeting in autoimmune diseases.
Complement is a central effector of cell and tissue injury in hematological and autoimmune diseases, and recent intensive research brought new inhibitors to the clinic. This review summarizes complement-mediated mechanisms across hematological, systemic, and kidney-specific autoimmune diseases, appraises emerging biomarker strategies, and evaluates these therapies. For years, clinical complement inhibition was possible only at C5, first in paroxysmal nocturnal hemoglobinuria. The arsenal has now expanded to the initiation pathways: sutimlimab (anti-C1s) is effective in the hematological autoimmune condition cold agglutinin disease, pegcetacoplan (C3-inhibitor) in C3 glomerulopathy and immune-complex membranoproliferative glomerulonephritis, and oral iptacopan (Factor B-inhibitor) reduces proteinuria in immunoglobulin A nephropathy and C3 glomerulopathy. Nevertheless, challenges remain. Avacopan (C5aR1-inhibitor) faces proposed withdrawal after trial manipulation and hepatotoxicity, and although complement is central to systemic lupus erythematosus and contributes to membranous nephropathy, no effective strategy has yet emerged. Recognizing complement's role in the pathophysiology of hematological and autoimmune diseases has driven effective new therapies. Comprehensive profiling complement biomarkers, now feasible through complementomics in fluids and tissues, may reveal responsive endotypes and optimal cascade steps to target in diseases where complement is implicated but trials have not yet matched the right drug to the right patients.
2026-09-04 | Cold agglutinin disease: pathophysiology, diagnosis, and the evolving therapeutic landscape.
Cold agglutinin disease (CAD) is a rare form of autoimmune hemolytic anemia (AIHA) that accounts for approximately 15%-25% of AIHA cases and is characterized by two interdependent features: a clonal bone marrow B-cell lymphoproliferative disorder producing monoclonal immunoglobulin M (IgM)-κ autoantibodies, and complement-mediated hemolysis driven by the classical pathway. Cold agglutinins bind to erythrocytes at low temperatures and trigger C1-initiated complement activation, predominantly leading to C3b-mediated extravascular hemolysis in the liver, with intravascular hemolysis occurring chiefly during acute exacerbations. CAD must be distinguished from cold agglutinin syndrome (CAS), which occurs secondary to infection, malignant lymphoma, or other disorders, and is managed by treating the underlying cause. The 2022 World Health Organization classification recognized CAD-associated lymphoproliferative diseases as distinct entities. Beyond anemia, patients experience disabling cold-induced circulatory symptoms, profound fatigue, and elevated thromboembolic risk. Diagnosis rests on evidence of hemolysis, a monospecific direct antiglobulin test result positive for C3d but negative for immunoglobulin G (IgG), a cold agglutinin titer ≥ 1:64, and bone marrow evaluation; thermal amplitude can predict clinical severity better than titer alone. Corticosteroids and splenectomy are generally ineffective and not recommended. Contemporary management combines B-cell-directed therapy with complement inhibition, the latter being transformed by the anti-C1s antibody, sutimlimab. This review summarizes the pathophysiology, diagnostic approaches, and rapidly evolving treatment landscapes for CAD, including emerging complement- and clone-directed agents.
2026-08-19 | Combination therapy of sutimlimab and rituximab can lead to stable remission in autoimmune hemolytic anemia: a case series.
Autoimmune hemolytic anemia (AIHA) is associated with a significant impairment of quality of life for affected patients and can lead to life-threating hemolytic crises. Complement-mediated destruction of antibody-opsonized erythrocytes is a central pathomechanism in many cases of AIHA. Complement inhibition is therefore a promising and logical therapeutic strategy. Sutimlimab, a monoclonal antibody that targets complement factor C1s was approved in 2022 and can effectively inhibit hemolysis. However, this therapy must be administered as a permanent treatment and is only approved for the specific subtype cold agglutinin disease. In this case series, we report on a novel combination therapy of sutimlimab and rituximab, which led to rapid and durable remission in three patients suffering from severe autoimmune hemolytic anemia (two patients with cold agglutinin syndrome and one patient with primary warm AIHA). In two of these patients, treatment with sutimlimab could be discontinued without any recurrence to date. The other patient is also in remission but with ongoing therapy. This highly informative case series reports on an innovative therapeutic concept and may form the basis for further clinical studies in AIHA.
small molecules
2026-07-21 | Concurrent Cold Autoimmune Hemolytic Anemia, Painless Thyroiditis, and Deep Vein Thrombosis Following Mycoplasma pneumoniae Pneumonia: A Rare Case of Multi-Organ Immune Complications.
A 22-year-old woman developed palpitations, fatigue, and right leg pain 18 days after suffering from Mycoplasma pneumoniae (MP) pneumonia. Laboratory tests revealed severe hemolytic anemia with elevated lactate dehydrogenase levels, a C3b/C3d-positive direct antiglobulin test, and high cold agglutinin titers, confirming cold autoimmune hemolytic anemia. Thyroid studies showed asymptomatic thyrotoxicosis without tenderness, which was consistent with painless thyroiditis. Venous ultrasonography revealed deep vein thrombosis in the right popliteal and soleal veins. She improved with cold avoidance and apixaban treatment. This case underscores that multi-organ immune complications can emerge during the subacute phase of an MP infection.
2026-06-11 | 20 | Atypical presentation of anaemia in an older woman on direct oral anticoagulants: the importance of differential diagnosis
Introduction. Anaemia in older adults on direct oral anticoagulants is attributed to occult bleeding; however, such diagnostic anchoring may impede the timely recognition of rarer aetiologies. Objectives. To report a case of severe haemolytic anaemia masquerading as gastrointestinal bleeding, underscoring the importance of differential diagnosis in older adults. Materials and Methods. An 88-year-old female on anticoagulants for atrial fibrillation presented with severe anaemia (haemoglobin 7.0 g/dL). In the context of suspected haemorrhage, such drugs were discontinued, and four red blood cell units were transfused. Subsequently, new-onset jaundice and laboratory findings (markedly elevated indirect bilirubin and lactate dehydrogenase, undetectable haptoglobin, and hyperferritinaemia) revealed overt haemolysis. Computed tomography and endoscopy excluded neoplasms or active bleeding. Reassessment confirmed haemolytic anaemia with a negative direct antiglobulin test (Coombs) and a minimal monoclonal immunoglobulin M (IgM) kappa component. Infectious/autoimmune screenings and targeted quantification of cold agglutinin titres were performed. Results. Tests for Epstein-Barr virus, Cytomegalovirus, and Mycoplasma pneumoniae yielded negative results. Notably, the cold agglutinin titre was markedly elevated (1:2048). Following the diagnosis of cold agglutinin disease (CAD) and primary hypothyroidism, steroid therapy (methylprednisolone) and erythropoietin were initiated. Anticoagulation was safely resumed with low-molecular-weight heparin. Haemoglobin stabilised at 9.7 g/dL with remission of haemolysis. The patient was discharged asymptomatic and strictly advised to avoid cold exposure. Conclusions. In older anticoagulated patients with severe anaemia, the prompt evaluation of haemolysis indices and cold agglutinins (even with a negative Coombs test) is of paramount clinical importance to avoid inappropriate transfusions and ensure correct therapeutic management.
2025-12-29 | Autoimmune Hemolytic Anemia in Non-Hodgkin's Lymphoma: Pathogenesis, Diagnosis, and Management.
Autoimmune hemolytic anemia (AIHA) is an acquired hemolytic disorder caused by autoantibodies and/or complement-mediated destruction of red blood cells (RBCs), often driven by dysregulated B lymphocyte activity. A notable clinical association exists between AIHA and lymphoproliferative disorders (LPD), particularly chronic lymphocytic leukemia, and non-Hodgkin's lymphoma (NHL). To summarize the clinicopathological link, prevalence, pathogenesis, and management strategies of AIHA associated with NHL. This narrative review synthesizes evidence from 20 peer-reviewed studies published between 2011 and 2024, identified through PubMed, Google Scholar, and manual citation tracking. Eligible studies were restricted to English-language articles addressing the prevalence, pathogenesis, clinical features, diagnosis, or treatment of AIHA in NHL. Approximately 7%-10% of NHL patients develop coexisting AIHA, while up to 20% of AIHA patients are eventually diagnosed with lymphoma. The reported incidence of AIHA among NHL patients varies widely (0.23%-15.7%), reflecting methodological and population differences. Proposed mechanisms include chronic antigen stimulation and dysregulated antibody production. The coexistence of both conditions complicates management: Treatment generally prioritizes NHL-directed therapy, while glucocorticoids and rituximab are commonly used for AIHA control. AIHA and NHL share overlapping immunopathological pathways with important clinical implications. Early recognition of AIHA in NHL is essential to optimize patient outcomes. Future priorities include developing biomarkers to identify high-risk patients and conducting large-scale randomized trials to validate complement inhibitors for cold agglutinin disease (CAD).
2025-12-05 | Management of autoimmune hemolytic anemia.
Autoimmune hemolytic anemia (AIHA) is caused by premature erythrocyte destruction mediated by autoantibodies (auto-Ab) with or without complement activation. The most frequent form (60%-70% of cases) is warm AIHA (wAIHA), driven by immunoglobulin G auto-Ab that react at body temperature. Cold agglutinin disease (CAD, 20%-25%) is the second most common form and is caused by immunoglobulin M auto-Ab that usually react at temperatures <20°C and strongly activate complement. Rarer forms (5%-10%) include mixed AIHAs (wAIHA plus CAD), and paroxysmal cold hemoglobinuria. Here, we present the management of wAIHA, as CAD is discussed separately. Approximately 50% of wAIHA are primary, whereas the remainder are secondary to various conditions (infections, lymphoproliferative disorders, systemic or organ-specific autoimmune diseases, congenital immunodeficiencies, hematopoietic stem-cell transplantation, and several drugs, including immune checkpoint inhibitors). The disease is highly heterogeneous, ranging from fully compensated to life-threatening, and frequently has a relapsing course. Standard first-line therapy includes steroids with or without intravenous immunoglobulin, transfusions when anemia is clinically significant, prophylactic anticoagulation for severe hemolysis, and recombinant erythropoietin when reticulocytopenia/inadequate bone marrow compensation is present. For severe cases, high-dose steroids and plasma-exchange may be considered. Rituximab is now the preferred second-line option for relapsed/refractory patients, comparing favorably with the traditional splenectomy. The latter is increasingly reserved for later lines together with classic immunosuppressants. Several novel treatments are in development for refractory wAIHA, encompassing drugs targeting B-cells (parsaclisib, ibrutinib, rilzabrutinib, zanubrutinib, obexelimab, ianalumab, povetacicept), plasma cells (bortezomib, daratumumab), spleen tyrosine kinase (fostamatinib, sovleplenib), and the neonatal Fc receptor (nipocalimab).
2025-12-01 | COLD AGGLUTININ DISEASE ASSOCIATED WITH COVID-19 INFECTION IN A PEDIATRIC PATIENT: A RARE CASE PRESENTING WITH SEVERE HEMOLYTIC ANEMIA AND LOBAR PNEUMONIA
Cold agglutinin disease (CAD) is a form of autoimmune hemolytic anemia caused by antibodies—typically immunoglobulin M (IgM), and less frequently IgA or IgG—that target antigens on the surface of erythrocytes. Although the etiology may involve infections or immunologic disorders, most cases are idiopathic. The clinical picture results from hemolysis triggered by antibodies that become active at cold temperatures, leading to degenerative changes in the erythrocyte membrane and autoagglutination. This causes a drop in erythrocyte count and hematocrit, while MCV, MCH, and MCHC values appear markedly elevated. Peripheral blood smears often reveal erythrocyte agglutination. Here in, we present a case of cold agglutinin disease secondary to COVID-19 infection. A 14-year-old previously healthy girl was initially treated with amoxicillin-clavulanate for upper respiratory tract infection symptoms, including fever and cough. Her symptoms worsened, and she tested positive for COVID-19 at an outside hospital. She was diagnosed with lobar pneumonia, and significant anemia noted during follow-up prompted her referral to our institution, Türkiye. Upon admission to our pediatric intensive care unit, three consecutive hemogram samples were clotted and could not be analyzed. Venous blood gas revealed hemoglobin (Hb) of 4.2 g/dL. Biochemical analyses showed LDH: 724 U/L (range 110-295 U/L), total bilirubin: 1.85 mg/dL (range 0.3-1.2 mg/dL), direct bilirubin: 0.29 mg/dL (range 0-0.2 mg/dL), and haptoglobin: 0.38 g/L (range 0.35-2.5 g/L). Direct Coombs test was negative. Peripheral smear demonstrated erythrocyte agglutination clusters. Blood samples were delivered to the laboratory in warm water immediately after collection to prevent in vitro agglutination. Repeat tests showed Hb: 8.2 g/dL, MCV: 100 fL, and a markedly elevated MCHC of 683 g/dL. Quantitative cold agglutinin testing could not be performed due to technical limitations at our center. In addition to pneumonia treatment, the patient was started on methylprednisolone at 2 mg/kg/day for presumed cold agglutinin disease. She was discharged on day 10 of treatment and her steroid therapy was tapered and discontinued by day 21. At follow-up on day 21, the patient’s hemoglobin had increased to 13.9 g/dL, and no erythrocyte agglutination was observed on peripheral smear. This case highlights a rare pediatric presentation of cold agglutinin disease associated with COVID-19 infection, complicated by severe hemolysis and lobar pneumonia. Early recognition and a multidisciplinary approach including corticosteroids and supportive care played a critical role in the patient's favorable outcome.
cell therapies
2026-06-11 | Therapeutic plasma exchange for refractory Mycoplasma pneumoniae-associated cold agglutinin syndrome: A case report.
Cold agglutinin syndrome (CAS) secondary to Mycoplasma pneumoniae typically self-resolves with antimicrobial therapy and supportive care. Therapeutic plasma exchange (TPE) has been described as an adjunct therapy in refractory CAS, but there is limited data on its use in M. pneumoniae-associated CAS. A 26-year-old male developed severe hemolytic anemia 3 weeks after initial M. pneumoniae diagnosis. Initial hemoglobin was 8.2 g/dL with marked hemolysis (lactate dehydrogenase 1398 U/L, total bilirubin 4.0 mg/dL, haptoglobin <10 mg/dL). Antibody screen was positive for cold antibody. Direct antiglobulin test was C3-positive. Despite appropriate antimicrobial therapy, he required 17 units of packed red blood cells over 20 days of admission. TPE was initiated on day 11 for refractory hemolysis. Four sessions were performed (on days 11, 14, 17, 18). Antibody screens became negative post-TPE and markers of hemolysis improved. Following the final 1.5 plasma volume exchange, the patient achieved his longest transfusion-free interval (5 days). Research flow cytometry demonstrated elevated surface IgG and C3 on red cells pre-exchange that decreased over the course of TPEs but remained above baseline at discharge. The patient required three additional units of red cell transfusions post-discharge but achieved transfusion independence by day 30. Total transfusion requirement was 20 units. This case of M. pneumoniae-associated CAS highlights atypical features including failure of antimicrobial therapy and supportive care alone, exceptional transfusion needs, and ongoing hemolysis despite TPE. TPE may serve as adjunctive therapy in transfusion-dependent refractory CAS in the setting of M. pneumoniae infection.
2026-04-11 | CD19 CAR-T therapy induces remission in refractory autoimmune hemolytic anemia with ITP and antiphospholipid syndrome.
Autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP), and antiphospholipid antibody syndrome (APLAS) are B cell-driven autoimmune diseases defined by pathogenic autoantibodies. CD19-directed chimeric antigen receptor (CAR)-T cells have recently demonstrated the ability to reset dysregulated B cells and induce long-lasting remission in refractory systemic autoimmune diseases. Evidence for efficacy in severe, treatment-refractory AIHA, however, is limited. We report the clinical course of a 47-year-old woman with life-threatening cold- and warm-agglutinin AIHA refractory to nine prior treatment lines, accompanied by ITP and APLAS. In an uncontrolled flare, she received a fludarabine/cyclophosphamide-containing lymphodepletion followed by autologous CD19-directed, 4-1BB-costimulated CAR-T cells (zorpocabtagene-autoleucel [Zorpo-cel], 1 × 106/kg) on the basis of compassionate use. Treatment efficacy and safety were assessed over an 11-month follow-up period. Zorpo-cel showed a rapid and sustained B cell depletion. Transfusion independence was achieved by day 7, with hemoglobin normalization by day 25, including resolution of hemolysis markers. Cold-agglutinin titers decreased, and previously elevated antiphospholipid antibodies normalized without recurrence throughout 11 months of follow-up. ITP stabilized. No cytokine release syndrome or neurotoxicity occurred. Mild transaminase elevation and thrombocytopenia were observed, most likely correlating with pre-existing severe iron overload due to erythrocyte transfusions. This case demonstrates that CD19-directed CAR-T cell therapy can induce rapid, durable remission of severe, refractory cold-agglutinin AIHA and simultaneously improve coexisting APLAS and ITP on a favorable toxicity profile. However, more data from controlled clinical trials are needed for final conclusions. This work was funded by Deutsche Forschungsgemeinschaft and Deutsche Krebshilfe.
2026-03-12 | Mixed Autoimmune Hemolytic Anemia With Refractory Cold Agglutinin Syndrome in a Child Successfully Treated With Serial Whole Blood Exchange Transfusions and Immunosuppression.
Mixed autoimmune hemolytic anemia can manifest with severe intra- and extravascular hemolysis, with autoagglutination contributing to vaso-occlusive microangiopathic phenomena. We present a case of mixed autoimmune haemolytic anemia with unusually severe cold agglutinin syndrome causing cutaneous, cerebral, ocular, and aural manifestations of microvasculopathy and massive intravascular haemolysis, requiring 6 double-volume whole-blood exchanges over 8 days to temporise severe hemolysis and autoagglutination while immunosuppression with high-dose steroids, rituximab, and bortezomib took effect. Whole-blood exchange permitted fluid-neutral clearance of preformed antibodies and antibody-coated red cells, with dramatic resolution of microvasculopathy and hemolysis, before discharge home on oral steroid therapy.
2025-11-24 | Precision targeting of autoreactive B cells in systemic lupus erythematosus using anti-9G4 idiotope synthetic immune receptor T cells.
Chimeric antigen receptor (CAR)-T cell therapies that broadly target B cells can achieve complete remission in severe systemic lupus erythematosus (SLE) but carry an increased risk of infection and cytokine-related toxicities that limit their use. Alternative strategies that combine the potency of immune effector cell therapies with more precise targeting approaches have the potential to control disease without the challenges of broad immunosuppression. B cells expressing immunoglobulin heavy variable gene 4-34 (IGHV4-34)-derived B cell receptors (BCRs) are a major source of disease-relevant autoantibodies in lupus and other autoimmune diseases. Here, we exploit a common feature of IGHV4-34 BCRs, namely the 9G4 idiotope (9G4id), to develop precision cellular immunotherapies that target autoreactive B cells. Anti-9G4 CAR-T cells and anti-9G4 chimeric T cell receptor (cTCR) T cells, integrating anti-9G4 antibody fragments into a re-engineered TCR scaffold, eliminated autoreactive Ramos B cells expressing SLE patient-derived 9G4id BCRs with equal potency, while sparing non-9G4 Ramos B cells. Using SLE patient PBMCs, autologous anti-9G4 cTCR-T cells and anti-9G4 CAR-T cells selectively depleted primary human 9G4id B cells, while maintaining total B cell numbers. Similarly, anti-9G4 T cells eliminated B cells expressing 9G4id BCRs from patients with cold agglutinin disease and Burkitt lymphoma. Compared to broad targeting with CD19 CAR-T cells, anti-9G4 T cell therapies showed lower cytokine release (~6-8-fold for interferon [IFN]-γ). In addition, anti-9G4 cTCR-T cells showed ~17-fold lower IFN-γ secretion compared to anti-9G4 CAR-T cells, despite achieving similar cytotoxicity. Together, our findings suggest that anti-9G4 precision cellular therapies provide a strategy to selectively target pathogenic B cells in SLE, while minimizing risks of infection and cytokine-related toxicities.
2025-10-26 | CD19 CAR-T induces complete and durable remission in cold agglutinin syndrome associated relapse and refractory diffuse large B cell lymphoma
Primary cold agglutinin disease (CAD), a well-characterized indolent B cell clonal disorder, and secondary cold agglutinin syndrome (CAS), which frequently brings on by underlying conditions like i...
proteins
2026-07-28 | Discovery and engineering of novel IgM proteases for the treatment of autoimmune and inflammatory diseases 2253144
Abstract Introduction IgM is a multifunctional immunoglobin that acts as the first line of defense against systemic pathogens. IgM’s multimeric structure, together with its complement binding ability, makes IgM a highly potent inflammation driver. The presence of autoreactive IgM antibodies causing complement dependent damage has been described in inflammatory and autoimmune conditions such as Cold Agglutinin Disease (CAD) and Multifocal Motor Neuropathy (MMN) . For this reason, the development of IgM autoantibodies degrading therapy represents an attractive approach. Methods Employing Seismic’s IMPACT platform and evolutionary screening, we identified several novel and selective IgM proteases. Discovered proteases cleave soluble IgM in plasma and the IgM BCR in B cells from healthy individuals. Results CAD is an autoimmune hemolytic anemia, caused by IgM autoantibodies that bind to red blood cells (RBC), causing agglutination and activate complement cascade resulting in RBC death. Seismic’s IgM protease cleaves RBC bound IgM, preventing agglutination in whole blood from CAD donors, an unmet need not targeted by current approved treatment. In addition, IgM cleavage reduced cold-induced complement deposition on RBC from CAD patients. Conclusion Further engineering and optimization with our IMPACT Platform for the novel proteases is currently under way. Funding Source n/a Topic Categories Therapeutic Approaches to Autoimmunity (THER)
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.
2024-09-04 | When you think you should transfuse…don't!
A 48-year-old female presented to the emergency department with severe fatigue. Admission laboratory test results were hemoglobin 6.6 g/dL, platelet count 287,000/μL, and white blood cell count 25,200/μL. Lactate dehydrogenase was elevated at 898 U/L, haptoglobin was markedly decreased (< 31 mg/dL), indirect bilirubin was elevated (5.3 mg/dL), and the absolute reticulocyte count was low at 0.0050/μL. A sample was sent to the immunohematology reference laboratory. The direct antiglobulin test immunoglobulin G was negative; C3 was 1+. All cells were reactive at immediate spin phase, indirect antiglobulin testing (IAT) with polyethylene glycol, with low ionic strength saline, neat, prewarm, and in the solid phase. All cells were nonreactive at IAT-ficin. Additional testing included a cold antibody titer that was 1:4096 and thermal amplitude studies demonstrating reactivity of 2+ at 37°C. These results were consistent with a clinically significant anti-Pr and cold agglutinin disease (CAD). Although rituximab is effective in autoimmune hemolytic anemia, this may take weeks. The patient was treated with pegcetacoplan, a pegylated peptide that targets C3 inhibiting hemolysis. The patient was discharged on day 29 with a hemoglobin of 8 g/dL. This is a report of one of the first patients successfully treated with pegcetacoplan for CAD.
2014-08-22 | Peptide Inhibitor of Complement C1, a Novel Suppressor of Classical Pathway Activation: Mechanistic Studies and Clinical Potential
The classical pathway of complement plays multiple physiological roles including modulating immunological effectors initiated by adaptive immune responses as well as an essential homeostatic role in the clearance of damaged self-antigens. However, dysregulated classical pathway activation is associated with antibody-initiated, inflammatory diseases processes like cold agglutinin disease (CAD), acute intravascular hemolytic transfusion reaction (AIHTR) and acute/hyperacute transplantation rejection. To date, only one putative classical pathway inhibitor, C1 esterase inhibitor (C1-INH), is currently commercially available and its only approved indication is for replacement treatment in hereditary angioedema (HAE), which is predominantly a kinin pathway disease. Given the variety of disease conditions in which the classical pathway is implicated, development of therapeutics that specifically inhibit complement initiation represents a major unmet medical need. Our laboratory has identified a peptide that specifically inhibits the classical and lectin pathways of complement. In vitro studies have demonstrated that these Peptide Inhibitors of Complement C1 (PIC1) bind to the collagen-like region of the initiator molecule of the classical pathway, C1q. PIC1 binding to C1q blocks activation of the associated serine proteases (C1s-C1r-C1r-C1s) and subsequent downstream complement activation. Rational design optimization of PIC1 has resulted in the generation of a highly potent derivative of fifteen amino acids. PIC1 inhibits classical pathway mediated complement activation in ABO incompatibility in vitro as well as inhibiting classical pathway activation in vivo in rats. This review will focus on the pre-clinical development of PIC1 and discuss its potential as a therapeutic in antibody-mediated classical pathway disease, specifically AIHTR.
2005-07-01 | Treatment of Autoimmune Hemolytic Anemia
The appropriate therapy of autoimmune hemolytic anemia (AIHA) is dependent on the correct diagnosis and classification of this family of hemolytic disorders. Although the majority of cases are warm AIHA, there are several distinct types of cold AIHA and a number of drug-induced etiologies of AIHA, which must be investigated to determine if stopping a drug will induce a remission. In warm AIHA, corticosteroids are standard, followed by consideration of splenectomy in recalcitrant cases. If steroids and splenectomy are insufficient, other forms of immunosuppressive therapy are typically initiated. In cold AIHA, keeping the patient warm in often sufficient, but therapy directed at an underlying lympholiferative disorder may be helpful. Brisk hemolysis, inadequate responses to therapy, and worsening anemia require transfusion therapy. Although the pretransfusion workup is made difficult by the presence of the autoantibody, transfusion services can usually provide blood safe for transfusion by excluding underlying alloantibodies. When transfusion is urgently required and compatible blood cannot be located, incompatible blood may be provided as a life-saving measure. Communication between the transfusion service and the hematologist is critical to assess the risks in these settings. Hemoglobin-based oxygen carriers may provide an important bridging therapy in the future. Requests for "least incompatible" blood do not enhance transfusion safety and often result in unnecessary delays.
antibodies
2026-09-30 | Complement inhibition by sutimlimab in cold agglutinin disease promotes red blood cell agglutination and may lead to circulatory complications, eryptosis and hemolysis.
Sutimlimab, an anti-C1s monoclonal antibody, is approved for the treatment of cold agglutinin disease (CAD). It prevents hemolysis by inhibiting the classical complement pathway. One of its off-target effects may be increasing circulatory complications that have not yet been characterized. We report two patients with CAD who developed unusual widespread skin cyanosis and exacerbated acrocyanosis during sutimlimab treatment. One of the two patients additionally experienced massive intravascular hemolysis, eryptosis and acute renal failure. Serological analyses were conducted using standard techniques, and eryptosis was quantified by flow cytometry with PE-labelled Annexin V. Serological assays using plasma and serum from these two patients and four additional untreated patients (n=6) with CAD were performed. They demonstrated a significant increase in red blood cell (RBC) agglutination in the presence of sutimlimab as well as in the absence of complement activation. The observed increase in RBC agglutination under sutimlimab treatment is likely due to a substantial reduction of C3d deposition on RBCs. This mechanism also represents the most plausible explanation for the side effects observed in some patients with CAD receiving the drug, such as aggravation of circulatory complications, including acrocyanosis, Raynaud's phenomenon, and less commonly, organ dysfunction. Inhibition of early complement components (C1-C3) may therefore not only prevent hemolysis in CAD but paradoxically also promote RBC agglutination, eryptosis, and hemolysis in certain cases. Pre-treatment serological testing with sutimlimab may help predict some of these adverse effects.
2026-09-18 | CD20-positive multiple myeloma complicated by cold agglutinin disease
Cluster of differentiation 20 (CD20) expression is rarely observed in multiple myeloma (MM) and is typically associated with immature plasma cell morphology and aggressive clinical behavior.Cold agglutinin disease (CAD) is also uncommon in MM and usually suggests other hematologic malignancies.We present a rare case of CD20-positive MM complicated by CAD in a 77-year-old woman who initially had pancytopenia, bone pain, and renal failure.Diagnostic work-up revealed light chain MM with kappa restriction, cast nephropathy, and diffuse CD20 expression in plasma cells.She was treated with bortezomib, cyclophosphamide, and dexamethasone (VCD), achieving hematologic improvement and partial renal recovery.During the third cycle, she developed severe anemia and hemolysis due to cold agglutinins, which were managed successfully with corticosteroids and supportive care.Retrospective immunohistochemistry confirmed CD20 positivity.This case underscores the diagnostic and therapeutic complexity of atypical MM presentations and highlights the importance of re-evaluating immunophenotypic features when the clinical course deviates from expectations.While CD20-targeted therapies are not routinely used in MM, their relevance in selected subtypes warrants further exploration.Our case illustrates the potential for paraneoplastic hemolysis and phenotypic diversity in MM, emphasizing the need for a multidisciplinary approach to diagnosis and management.
2026-09-08 | Complement targeting in autoimmune diseases.
Complement is a central effector of cell and tissue injury in hematological and autoimmune diseases, and recent intensive research brought new inhibitors to the clinic. This review summarizes complement-mediated mechanisms across hematological, systemic, and kidney-specific autoimmune diseases, appraises emerging biomarker strategies, and evaluates these therapies. For years, clinical complement inhibition was possible only at C5, first in paroxysmal nocturnal hemoglobinuria. The arsenal has now expanded to the initiation pathways: sutimlimab (anti-C1s) is effective in the hematological autoimmune condition cold agglutinin disease, pegcetacoplan (C3-inhibitor) in C3 glomerulopathy and immune-complex membranoproliferative glomerulonephritis, and oral iptacopan (Factor B-inhibitor) reduces proteinuria in immunoglobulin A nephropathy and C3 glomerulopathy. Nevertheless, challenges remain. Avacopan (C5aR1-inhibitor) faces proposed withdrawal after trial manipulation and hepatotoxicity, and although complement is central to systemic lupus erythematosus and contributes to membranous nephropathy, no effective strategy has yet emerged. Recognizing complement's role in the pathophysiology of hematological and autoimmune diseases has driven effective new therapies. Comprehensive profiling complement biomarkers, now feasible through complementomics in fluids and tissues, may reveal responsive endotypes and optimal cascade steps to target in diseases where complement is implicated but trials have not yet matched the right drug to the right patients.
2026-09-04 | Cold agglutinin disease: pathophysiology, diagnosis, and the evolving therapeutic landscape.
Cold agglutinin disease (CAD) is a rare form of autoimmune hemolytic anemia (AIHA) that accounts for approximately 15%-25% of AIHA cases and is characterized by two interdependent features: a clonal bone marrow B-cell lymphoproliferative disorder producing monoclonal immunoglobulin M (IgM)-κ autoantibodies, and complement-mediated hemolysis driven by the classical pathway. Cold agglutinins bind to erythrocytes at low temperatures and trigger C1-initiated complement activation, predominantly leading to C3b-mediated extravascular hemolysis in the liver, with intravascular hemolysis occurring chiefly during acute exacerbations. CAD must be distinguished from cold agglutinin syndrome (CAS), which occurs secondary to infection, malignant lymphoma, or other disorders, and is managed by treating the underlying cause. The 2022 World Health Organization classification recognized CAD-associated lymphoproliferative diseases as distinct entities. Beyond anemia, patients experience disabling cold-induced circulatory symptoms, profound fatigue, and elevated thromboembolic risk. Diagnosis rests on evidence of hemolysis, a monospecific direct antiglobulin test result positive for C3d but negative for immunoglobulin G (IgG), a cold agglutinin titer ≥ 1:64, and bone marrow evaluation; thermal amplitude can predict clinical severity better than titer alone. Corticosteroids and splenectomy are generally ineffective and not recommended. Contemporary management combines B-cell-directed therapy with complement inhibition, the latter being transformed by the anti-C1s antibody, sutimlimab. This review summarizes the pathophysiology, diagnostic approaches, and rapidly evolving treatment landscapes for CAD, including emerging complement- and clone-directed agents.
2026-08-19 | Combination therapy of sutimlimab and rituximab can lead to stable remission in autoimmune hemolytic anemia: a case series.
Autoimmune hemolytic anemia (AIHA) is associated with a significant impairment of quality of life for affected patients and can lead to life-threating hemolytic crises. Complement-mediated destruction of antibody-opsonized erythrocytes is a central pathomechanism in many cases of AIHA. Complement inhibition is therefore a promising and logical therapeutic strategy. Sutimlimab, a monoclonal antibody that targets complement factor C1s was approved in 2022 and can effectively inhibit hemolysis. However, this therapy must be administered as a permanent treatment and is only approved for the specific subtype cold agglutinin disease. In this case series, we report on a novel combination therapy of sutimlimab and rituximab, which led to rapid and durable remission in three patients suffering from severe autoimmune hemolytic anemia (two patients with cold agglutinin syndrome and one patient with primary warm AIHA). In two of these patients, treatment with sutimlimab could be discontinued without any recurrence to date. The other patient is also in remission but with ongoing therapy. This highly informative case series reports on an innovative therapeutic concept and may form the basis for further clinical studies in AIHA.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
0 orphan drug designations.
0 orphan drug designations.
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.