Study of IgM-related blood condition supports CAD as separate disease
Research explores clinical, lab features of CAD patients with, without IgM-MGUS
Among people who meet the criteria for a blood condition called IgM monoclonal gammopathy of undetermined significance (IgM-MGUS), those with cold agglutinin disease (CAD) show distinct clinical and laboratory features from those without, a study shows.
IgM-MGUS is marked by the excessive production of immunoglobulin M (IgM), a type of infection-fighting antibody. The abnormal antibodies that drive CAD also are of the IgM type, and the two conditions sometimes coexist.
While the presence of other IgM-related disorders was not as distinguishable, “cases of CAD show distinct features, warranting their recognition as a separate [condition],” the researchers wrote.
The study, “IgM monoclonal gammopathy of undetermined significance: clinicopathologic features with and without IgM-related disorders,” was published in Haematologica.
IgMs are a type of antibody produced by the immune system in response to a threat. When IgM or fragments of it are found at higher-than-normal levels in the bloodstream, it is a sign of IgM-MGUS. Their production is driven by the excessive growth and activity of immune B-cells and their activated, antibody-producing form, called plasma cells.
IgM-MGUS is linked to the later development of certain B-cell associated cancers. While most people with IgM-MGUS do not experience symptoms, some patients develop IgM-related disorders.
One of these conditions is CAD, in which self-reactive IgM antibodies, called cold agglutinins, attack red blood cells at cold temperatures. Research indicates that CAD patients may have distinct clinical and laboratory features from other IgM-MUS patients.
“It is currently unclear whether other forms of [IgM-related conditions] may show distinctive [clinical] findings compared to asymptomatic IgM MGUS patients,” the researchers wrote.
Now, a team of researchers at Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, in Ohio, set out to learn more about the clinical features of IgM-MGUS with or without IgM-related disorders, including CAD.
To do so, they looked at bone marrow samples (where most abnormal B-cell growth happens) and clinical information previously collected from a group of 191 people with IgM-MUS seen at their clinic from 2002 to 2021.
Among them, 82 people (43%) were determined to have an IgM-related disorder, including 10 people with CAD (5%); six were men and four were women. They had a mean age of 69.6 years at the time of sample collection.
Differences in IgM in the blood
People with CAD had significantly lower concentrations of IgM in the blood relative to those without CAD, as well as lower levels of hemoglobin, a protein on red blood cells that helps carry oxygen.
Evidence of white blood cell clumps were observed more often in CAD patients than non-CAD patients, although the difference failed to reach statistical significance. Specifically, these aggregates were found in 60% of CAD patients compared with 30.4% of people without CAD.
Evidence of the presence of malignant B-cells and malignant plasma cells was found in three and four CAD patients, respectively.
None of the three tested CAD patients were positive for a mutation in the MYD88 gene that has been linked to B-cell-associated cancers. The mutation was found in 66% of patients without CAD.
Over a median follow-up of 3.16 years, CAD patients did not show any signs of progression toward cancer in the bone marrow. Among all patients without CAD, only two people showed signs of progression.
Characteristics of the 72 patients with IgM-MGUS associated with other IgM-related disorders, including peripheral neuropathy or cryoglobulinemia, were largely similar to those without any of these disorders.
Peripheral neuropathy is characterized by damage in the nerves outside the brain and spinal cord, while cryoglobulinemia is a condition where antibody clumps form at low temperatures and can cause inflammation and organ damage.
“Our results confirm the distinctive nature of CAD compared to IgM MGUS,” the researchers wrote, noting that the findings support guidelines that recognize CAD as a distinct disorder.
Additional studies are needed to determine if CAD may have more similarities to other types of B-cell associated cancers, such as marginal zone lymphoma, the team added.
About the Author
