An Overview of Cold Agglutinin Disease

Jeremy Lorber, MD, explains what is known about the pathophysiology of a rare autoimmune hemolytic anemia, cold agglutinin disease.

Neil Minkoff, MD: Hello, and welcome to this AJMC® Peer Exchange program titled, “Strategies in Managing Cold Agglutinin Disease.” I’m Dr Neil Minkoff, the chief medical officer of Coeus Healthcare and Consulting. Joining me today in our virtual discussion are my colleagues, Dr Jeremy Gleeson, a medical director at ABQ Health Partners, part of Optum; Dr Jeremy Lorber, an assistant professor in the Department of Medicine at Tower Hematology Oncology at Cedars-Sinai Medical Center; Dr Kevin Stephens, regional chief medical officer at UnitedHealthcare; and Dr Mihir Raval, clinical assistant professor at New York Oncology Hematology. Together, we’ll be exploring an overview of the burden of cold agglutinin disease, review available treatment options, and try to explore clinical and payer considerations to emerging therapies. I’d like to thank everyone here for joining me, and with that, maybe we can jump right in. One of the things that I think is interesting is that this is not a particularly well understood disease state, even among normally very well-read clinicians. I was wondering if maybe we could just start by kind of highlighting what the actual burden of disease is for cold agglutinin disease. Dr. Lorber, can you start to lead us in that discussion?

Jeremy Lorber, MD: Sure. It is a rare disease, so it’s not common, and for most patients it’s not something they ever need to worry about. But depending on the study, looking at the prevalence, and it varies in various countries, about 5 to 20 per million people will have cold agglutinin disease, or CAD. It’s a chronic disease, so the burden of disease is accumulated over many years. Symptoms like anemia, fatigue, and symptoms related to the cold, which we’ll get into in a bit, can be quite burdensome for the patient and the health care system with frequent transfusions, and doctor and even sometimes hospital visits.

Neil Minkoff, MD: Are there particular patient characteristics that you think are associated with this disease state or things that help tip you off in terms of making the diagnosis?

Jeremy Lorber, MD: Not really. It’s very rare, so there aren’t little hints that say, “This type of patient will be more likely to have cold agglutinin disease.” It’s more common in females. It’s not something you typically see diagnosed in the very young; the median age of diagnosis is around the sixth or seventh decade of life. Cold agglutinin disease, when we’re defining primary cold agglutinin disease, doesn’t necessarily have a background disease to it, which is something else that can be called secondary cold agglutinin disease or syndrome, where that oftentimes has a background in an autoimmune disease. Somebody with lupus may have that, but with real primary CAD, there aren’t real patient types that may tip you off to the diagnosis.

Neil Minkoff, MD: And the underlying pathophysiology?

Jeremy Lorber, MD: Cold agglutinin disease falls within the category of autoimmune hemolytic anemias. It’s not the most common. It’s a more rare subtype, and what it is, it’s caused by antibodies called cold agglutinins that are targeting normal antigens that I would classify as ubiquitous in our red blood cells. The antigens that they target are normal, that’s not the disease. The disease is the production of these abnormal antibodies. They are typically categorized as an IgM [immunoglobulin M] antibody, that’s the heavy chain, and they bind to these antigens on red blood cells, and when they do this, a few things can happen. They can agglutinate, which means sort of gather other red blood cells, and you can even see this under the microscope. They also activate the classical pathway of a complement cascade, so they recruit C1, C4, C2, and eventually C3. When these red blood cells are coded with C3b from the complement pathway, they’re recognized extravascularly, so mainly in the liver, and our macrophage system gets rid of these red blood cells when they shouldn’t, when these are typically healthy red blood cells. Thus, that leads to the anemia and the hemolysis, and the agglutination due to the IgM on the red blood cells leads to the cold symptoms that we see in cold agglutinin disease.

Transcript edited for clarity.

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