CAD 4 Times More Prevalent in Colder Climates, European Study Finds

The prevalence of cold agglutinin disease (CAD) is four times higher in colder climates than in warmer areas, according to a study from Europe.

The findings also showed that a combination of rituximab with bendamustine is a safe and effective therapy for people with CAD.

The study, titled “Cold agglutinin disease revisited: A multinational, observational study of 232 patients,” was published in the journal Blood.

CAD is a form of autoimmune hemolytic anemia, in which self-directed antibodies called cold agglutinins attack and destroy red blood cells at low body temperatures.

“Although seasonal variations of hemolysis [destruction of red blood cells] have been documented in individual cases, no direct evidence has been published for the notion that CAD is more prevalent or severe in colder climates,” the researchers wrote.

To expand knowledge of CAD’s clinical features and evaluate the long-term outcomes of some therapies used to treat the disease, the team reviewed the medical records of 232 CAD patients.

Patients included in the study were being followed at 24 clinical centers across five countries — the U.K., Norway, Italy, Denmark, and Finland — between June 2017 and January 2019.

From the total group of participants (mean age 68 at diagnosis and 76 at study start), 207 had a confirmed diagnosis of CAD, and 25 had probable CAD.

At baseline, the patients’ mean hemoglobin level of 9.3 g/decilitre (dL) was below the normal range (12–17.5 g/dL). The levels were lower than 8 g/dL in 26.7% of the patients.

During follow-up, 38 events of venous thrombosis — a medical condition in which a blood clot forms and clogs veins in the body, blocking blood flow — were reported in 30 patients (12.9%).

Additional analyses revealed that over the course of eight years, the number of venous thrombosis events observed was higher than expected (14 vs. 8.4), suggesting that CAD patients had an increased risk of these events compared to individuals from the general population.

In colder climates (Norway), the incidence of CAD (1.9 cases per million, per year) and prevalence (20 cases per million) were both approximately four times higher than in warmer climates (Lombardy, Italy), where the incidence was 0.48 cases per million, per year, and prevalence was 5 cases per million.

“Probably, the 7 C lower outdoor temperature in representative parts of Norway as compared to Lombardy is associated with more symptomatic disease, resulting in a higher proportion of patients being diagnosed,” the investigators wrote.

However, they added that differences in genetic background and other features in the two groups of patients could not be completely ruled out as explanations for the findings.

The study also included follow-up data from all 45 patients who participated in the Nordic 2017 rituximab-bendamustine trial (NCT02689986), as well as all 29 who participated in the Norwegian 2010 rituximab-fludarabine trial (NCT00373594).

A total of 35 participants (78%) in the Nordic 2017 trial responded to treatment, with 24 (53%) achieving complete responses, meaning complete disease eradication.

As for those participating in the Norwegian 2010 study, 18 (62%) responded to treatment, and 11 (38%) attained a complete response.

The estimated five-year sustained remission rate was slightly higher among patients receiving the rituximab-bendamustine combo (77%) compared with those receiving the rituximab-fludarabine treatment (71%). Median estimated response duration was longer with rituximab-bendamustine.

Safety assessments indicated that the rituximab-bendamustine combo was associated with a lower risk of long-term adverse effects compared to the other regimen.

“Based on the balance between efficacy, short-term toxicity, and risk of long-term adverse effects, our results show that the use of rituximab plus bendamustine is safe and highly efficacious in relatively fit patients who require therapy for CAD,” the investigators wrote.