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
0
drugs
With orphan designations
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
403 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:
403 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:
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.
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)
2026-07-24 | Temperature Safeguards and Peri-Procedural Strategies for Stem Cell Collection in Cold Agglutinin Disease: A Case Report and Literature Review.
Cold agglutinins can result in red blood cell (RBC) agglutination and lysis at low temperatures. Temperature sensitivity during stem cell mobilization, processing, and infusion poses unique procedural challenges in patients with active cold agglutinins. A 49-year-old man presented at an outside hospital with severe hemolysis and was found to have an anti-I cold agglutinin and a component of warm autoimmune hemolytic anemia, together with a positive COVID and Rhinovirus test. He was treated with RBC transfusions, steroids, and Rituximab. Bone marrow evaluation several months later at our institution demonstrated IgA-kappa multiple myeloma and a rare, atypical B-cell population of unclear significance. After induction therapy, autologous peripheral blood stem cell transplantation was recommended. The primary concerns were cold-induced agglutination during apheresis collection of hematopoietic progenitor cells and during graft handling. This required coordination across hematology, apheresis, and cell therapy teams. The patient received cyclophosphamide for cytoreduction, granulocyte colony-stimulating factor for mobilization, and sutimlimab for complement inhibition. The collection was performed using practical temperature mitigation strategies including environmental warming and insulation of extracorporeal components. The product was processed using prewarmed equipment, and cryopreservation was performed per institutional protocol. A total of 5.61 × 106 CD34+ cells/kg were collected without circuit alarms or visible agglutination. Conditioning with high-dose melphalan and autologous infusion was completed without complication, with successful engraftment. This case highlights the feasibility of pragmatic, multidisciplinary temperature management strategies during stem cell collection and processing in patients with cold agglutinin disease.
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.
2026-07-08 | Sutimlimab for cold agglutinin disease: an updated perspective from approval to real-world clinical treatment.
Sutimlimab, a classical complement pathway (CP) inhibitor, was approved in 2022 in the US, EU, and Japan for the treatment of cold agglutinin disease (CAD), a rare form of autoimmune hemolytic anemia (AIHA) characterized by CP‑mediated extravascular hemolysis and circulatory symptoms related to IgM‑mediated red blood cell (RBC) agglutination. This review reexamines the clinical trial data and compares those findings with published real‑world experience (RWE), providing clinicians with efficacy and safety data that extend beyond the clinical trial experience in this rare AIHA. The first-in-human trials, the two seminal clinical trials (CARDINAL and CADENZA), and the published post‑marketing RWE are presented. Literature searches for CAD and sutimlimab were conducted in PubMed and in abstracts from ASH and EHA from 2016 to present. All articles and abstracts regarding sutimlimab and CAD were included. Long-term data from clinical trials and published RWE support the safety and efficacy of sutimlimab. Targeting the CP as primary therapy for CAD offers a unique, targeted management strategy that minimizes exposure to immunosuppressive regimens. The rapid onset of sutimlimab's activity provides a potentially lifesaving treatment option in situations where immediate control of hemolysis is critical. Opportunities remain to increase our understanding of the role of complement inhibition combined with immunosuppressive therapy in CAD. The impact of complement inhibition on morbidity and mortality in CAD remains to be determined.
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.
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)
2026-07-24 | Temperature Safeguards and Peri-Procedural Strategies for Stem Cell Collection in Cold Agglutinin Disease: A Case Report and Literature Review.
Cold agglutinins can result in red blood cell (RBC) agglutination and lysis at low temperatures. Temperature sensitivity during stem cell mobilization, processing, and infusion poses unique procedural challenges in patients with active cold agglutinins. A 49-year-old man presented at an outside hospital with severe hemolysis and was found to have an anti-I cold agglutinin and a component of warm autoimmune hemolytic anemia, together with a positive COVID and Rhinovirus test. He was treated with RBC transfusions, steroids, and Rituximab. Bone marrow evaluation several months later at our institution demonstrated IgA-kappa multiple myeloma and a rare, atypical B-cell population of unclear significance. After induction therapy, autologous peripheral blood stem cell transplantation was recommended. The primary concerns were cold-induced agglutination during apheresis collection of hematopoietic progenitor cells and during graft handling. This required coordination across hematology, apheresis, and cell therapy teams. The patient received cyclophosphamide for cytoreduction, granulocyte colony-stimulating factor for mobilization, and sutimlimab for complement inhibition. The collection was performed using practical temperature mitigation strategies including environmental warming and insulation of extracorporeal components. The product was processed using prewarmed equipment, and cryopreservation was performed per institutional protocol. A total of 5.61 × 106 CD34+ cells/kg were collected without circuit alarms or visible agglutination. Conditioning with high-dose melphalan and autologous infusion was completed without complication, with successful engraftment. This case highlights the feasibility of pragmatic, multidisciplinary temperature management strategies during stem cell collection and processing in patients with cold agglutinin disease.
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.
2026-07-08 | Sutimlimab for cold agglutinin disease: an updated perspective from approval to real-world clinical treatment.
Sutimlimab, a classical complement pathway (CP) inhibitor, was approved in 2022 in the US, EU, and Japan for the treatment of cold agglutinin disease (CAD), a rare form of autoimmune hemolytic anemia (AIHA) characterized by CP‑mediated extravascular hemolysis and circulatory symptoms related to IgM‑mediated red blood cell (RBC) agglutination. This review reexamines the clinical trial data and compares those findings with published real‑world experience (RWE), providing clinicians with efficacy and safety data that extend beyond the clinical trial experience in this rare AIHA. The first-in-human trials, the two seminal clinical trials (CARDINAL and CADENZA), and the published post‑marketing RWE are presented. Literature searches for CAD and sutimlimab were conducted in PubMed and in abstracts from ASH and EHA from 2016 to present. All articles and abstracts regarding sutimlimab and CAD were included. Long-term data from clinical trials and published RWE support the safety and efficacy of sutimlimab. Targeting the CP as primary therapy for CAD offers a unique, targeted management strategy that minimizes exposure to immunosuppressive regimens. The rapid onset of sutimlimab's activity provides a potentially lifesaving treatment option in situations where immediate control of hemolysis is critical. Opportunities remain to increase our understanding of the role of complement inhibition combined with immunosuppressive therapy in CAD. The impact of complement inhibition on morbidity and mortality in CAD remains to be determined.
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