When it comes to exceedingly rare diseases, one naturally turns to the existing medical literature to gain a better understanding of them. What can be frustrating is when the rare diseases under investigation do not possess a solid body of medical literature that can be readily pored over; these diseases, in which studies conducted to explore them are scarce, are truly “rare diseases” in every sense of the word. 

Cold agglutinin disease (CAD), a subset of autoimmune hemolytic anemia, certainly fits the bill for this kind of disease. Because it is a rare subcategory of a rare but more well-known disease, very few medical researchers devote entire studies to exploring it. 

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In an interconnected world in which the whole body of human knowledge is usually at one’s fingertips, some have the assumption that most diseases are neatly classified, with an expected disease course, and a fixed number of drugs commonly used to treat them. Physicians and patients alike can sometimes assume that medicine can be “Wikipedia-ed”. Granted, most medical conditions do have their own Wikipedia entry, but dig deeper and you will sometimes find gaps in knowledge with phrases such as “Some scientists speculate,” and “Conflicting evidence suggests,” and “This aspect of the disease warrants further study.” 

Many researchers try to tame the Wild West of rare diseases, to “civilize” them so that significant inroads can be made and neat categories conjured up. This is indeed a worthy endeavor. However, this effort should be carried out with a healthy dose of humility: understanding everything we need to know about rare diseases such as CAD would probably require a few lifetimes’ worth of effort. 

Geographical Differences in CAD Prevalence

Sigbjørn Berentsen, MD, PhD, and colleagues sought to add to the scarce medical resources devoted to CAD with the publication of a paper titled “Cold agglutinin disease revisited: a multinational, observational study of 232 patients.” In it, the research team discussed CAD in a level of detail that yields important information for physicians treating patients with CAD.

The study, published in Blood, recruited patients with CAD from Norway, Lombardy (northern Italy), United Kingdom, Finland, and Denmark. The purpose of the study was clear: “to improve our knowledge of the epidemiologic, clinical, and laboratory findings in CAD.“

“We also wanted to provide “real-world” information on the long-term outcomes of previously studied therapies, with focus on the rituximab-fludarabine and rituximab-bendamustine combinations,” the authors wrote. 

One of the most striking results in terms of the epidemiology of the disease was that the prevalence and incidence of CAD was 4 times higher in Norway compared to Lombardy, suggesting that geographical/climate variation may impact the distribution of patients with this disease. An explanation for this discrepancy is that the lower outdoor temperature in parts of Norway compared to Lombardy allows the disease to present more symptomatically, since it is temperature-sensitive.

In a separate paper, Dr. Berentsen (one of the primary experts on CAD) wrote about the characteristics of the disease: 

  • CAD is mediated by autoantibodies that function best at a temperature of 0o-4oC, which is the temperature optimum for antigen-antibody reaction.
  • CAD accounts for 25% to 35% of autoimmune hemolytic anemias. 
  • Cold agglutinins are able to agglutinate red blood cells and are cold-reactive antibodies. 
  • Hemolysis in CAD is mediated by the classical complement pathway and can generate anaphylatoxins (such as C3a and, to some extent, C5a). 
  • To diagnose CAD, these 4 criteria must be present: chronic hemolysis, cold agglutinin titer ≥64 at 4oC, polyspecific direct antiglobalization test (DAT) positive, and monospecific DAT strongly positive for C3d. 

Variations in Treatment Outcomes

Let’s take a look at the study performance of the 2 drug combinations investigated—rituximab-bendamustine and rituximab-fludarabine. It is important to note that the inclusion and outcomes criteria were identical, and the baseline characteristics and demographics were likewise similar. The differences in outcomes were as follows:

  • The overall response rates were 78% with rituximab-bendamustine and 62% with rituximab-fludarabine. 
  • The complete response rates were 53% with rituximab-bendamustine and 38% with 38%.
  • The estimated 5-year sustained remission rate was 77% with rituximab-bendamustine and 71% with rituximab-fludarabine. 
  • The median estimated response duration with rituximab-bendamustine was not reached after 88 months. With rituximab-fludarabine, the median estimated response duration was 77 months. 

The authors of the study wrote that the higher overall response rate with rituximab-bendamustine “can be explained, however, by the long time to response (TTR) and time to best response.” In other words, different drugs respond differently in the length of time that they were under investigation. However, it should be noted that based on this study, both therapy combinations were efficacious in treating CAD.

Read more about CAD treatment

What more is there to know about CAD? Plenty. For a start, we need a clearer picture of why CAD specifically develops as a subset of autoimmune hemolytic anemia as opposed to the warm-antibody autoimmune hemolytic anemia. We also need to know if there are other drugs that are able to terminate CAD symptoms—and do so permanently. Until then, the work of researchers on this subject continues. 


Berentsen S, Barcellini W, D’Sa S, et al. Cold agglutinin disease revisited: a multinational, observational study of 232 patientsBlood. 2020;136(4):480-488. doi:10.1182/blood.2020005674

Berentsen S. New insights in the pathogenesis and therapy of cold agglutinin-mediated autoimmune hemolytic anemiaFront Immunol. 2020;11:590. doi:10.3389/fimmu.2020.00590