CAD and cryoglobulinemia often co-exist, report suggests

More than half of CAD patients in study had the related autoimmune disorder

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Among people with cold agglutinin disease (CAD), more than half were found to have a related autoimmune disorder called cryoglobulinemia, which affected symptom presentation but did not appear to affect survival.

That’s according to a small study in which 59% of CAD patients tested positive for cryoglobulins, the antibodies that cause cryoglobulinemia.

Also, acrocyanosis — a bluish skin discoloration that occurs when blood vessels are blocked — thickened blood, and severe and painful lack of blood flow to the fingers (digital ischemia) were seen more often in patients with both conditions than in those with CAD alone.

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These findings highlight the high frequency of cryoglobulinemia among CAD patients and suggest it may influence the latter’s presentation, the researchers noted while calling for more research to assess the impact of cryoglobulins in CAD.

The results were published recently in the British Journal of Haematology as a letter to the editor, “Cold agglutinin disease and cryoglobulinemia: A frequent coexistence with clinical impact.”

CAD is a rare autoimmune disorder in which self-reactive antibodies called cold agglutinins bind to red blood cells at cold temperatures, promoting their clumping and destruction.

This leads to anemia, which can be defined by lower-than-normal counts of red blood cells or hemoglobin, the protein in these cells that helps carry oxygen throughout the body. Red blood cell clumps also can block blood vessels.

CAD symptoms include fatigue, pain, and circulation problems, and the disease can be secondary to infections, cancer, or other autoimmune diseases. Sometimes the cause is unknown.

Like CAD, cryoglobulinemia is caused by self-reactive antibodies that react to cold temperatures, but it is does not cause red blood cell destruction. Instead, antibodies called cryoglobulins become solid or gel-like in the cold and cause inflammation and blockage in blood vessels. It often is preceded by a viral infection with hepatitis C.

Similar symptoms in both conditions

Both conditions can affect circulation, leading to similar symptoms such as Raynaud’s phenomenon, when the blood vessels constrict in cold temperatures. However, cryoglobulinemia also is associated with other symptoms not typical in CAD, such as thickened blood (hyperviscosity) and kidney damage.

The two conditions have been found to coexist in some patients, and a recent study reported that among 134 patients with cryoglobulinemia, 15% also had CAD.

However, the fact that both diseases are very rare and “likely underdiagnosed,” coupled with their substantial clinical overlap, can make it difficult to accurately determine how often they co-exist and how this influences symptoms and prognosis, the researchers noted.

Now, a team of scientists at the University College London Hospital, in the U.K., examined the frequency of cryoglobulinemia in 41 CAD patients (23 women and 18 men) who were screened for cryoglobulin antibodies at the researchers’ hospital from 2016 and 2023. Their median age at CAD diagnosis was 66 (range 41-80 years).

Cryoglobulin testing was performed as part of routine screening for 90% of patients, and because of specific symptoms, such as progressive cold symptoms, kidney impairment, or hyperviscosity in the remaining 10%.

Overall, some type of cryoglobulin antibodies were detected in 24 patients (59%), none of whom had a history of hepatitis C or HIV infection.

Acrocyanosis observed in 73% of the CAD patients

Cold-induced acrocyanosis was seen in 73% of the CAD patients, with a significantly higher frequency in those with concurrent cryoglobulinemia (88%) than in those with CAD alone (53%).

Hyperviscosity and severe digital ischemia leading to tissue death were observed exclusively in patients who also had cryoglobulinemia (13%-17%), and did not occur in any of those with only CAD.

While this difference did not reach statistical significance, it “suggests the addition of cryoglobulinaemia affects the clinical [profile] of CAD,” the team wrote.

Rates of blood clots and other blood markers were not significantly different between the two groups.

While 12 patients (29%) were left untreated, the remaining 71% received a median of two lines of therapy for CAD. This most often involved rituximab (41.5%), a therapy that works to kill antibody-producing B-cells, leading to a response in 47% of treated patients.

A treatment response was defined as an increase or a normalization of blood hemoglobin levels with no need for blood transfusions, as well as a reduction in circulatory symptoms for those experiencing them.

Rituximab with plasma exchange was effective

A combination of rituximab with plasma exchange — a blood cleaning procedure — was more effective, leading to such a response in five of six treated people (83%).

Complement inhibitor therapy, such as the CAD-approved Enjaymo (sutimlimab-jome), was given to 12 patients, and was effective for half of them.

During a median follow-up of 76 months (a little more than six years) since CAD diagnosis, seven patients died: one due to CAD, four due to infection, and two due to other causes. A total of 81% patients were alive after five years, and the presence of cryoglobulinemia did not influence survival.

These results indicate that “in CAD, there is a high proportion of coexistent cryoglobulinaemia,” the researchers wrote, adding that higher frequency in this study relative to previous reports may be the “result of routine screening for cryoglobulin in all CAD patients.”

Screening CAD patients for cryoglobulin antibodies

As such, CAD patients “should be screened for cryoglobulins, particularly if they have circulatory symptoms,” they added.

Among the study’s limitations, the researchers noted its retrospective nature and the fact that symptoms may be attributed wrongfully to CAD when they are actually signs of cryoglobulinemia. As such, these findings “should be replicated in other [groups of patients],” the team wrote.

“Further research should investigate whether the cold agglutinin and cryoglobulin represent [different] properties of the same [self-reactive antibody] and explore the influence of cryoglobulins on CAD,” the researchers concluded.