Abstract artist Betty Usdan-Zwickler of Boca Raton, Florida, has a passion for color, texture, and textiles that’s evident in her vibrant mixed media collage and fiber creations. She’s explored painting, wood sculpting, printmaking, and photography, and has shown her art at 175 exhibitions throughout the United States.
But Usdan, 83, is also known for something else: she’s a fierce advocate for fellow patients with cold agglutinin disease (CAD). For years, she’s worked closely with Sigbjørn Berentsen, MD, PhD, a hematologist and senior researcher at Norway’s Haugesund Hospital.
After a bout of mycoplasma pneumonia in her early 30s, she became mildly anemic. Uncomfortable with the winter weather, she left her native New York City in 1975 for Florida.
“I couldn’t stand the cold. I was always freezing,” Usdan told Rare Disease Advisor. “I was also low in hemoglobin. Unfortunately, my doctors automatically assumed that I was iron-deficient, so they prescribed iron supplements, which in my case never worked.”
Yet for years after relocating to the Sunshine State, Usdan continued to suffer. In 2000, she was referred to a hematologist, who suspected internal bleeding, a likely cause for most anemias. Following a battery of tests, Usdan was finally diagnosed at age 62 with CAD.
“I was reassured that I could live a normal lifespan with lifestyle modifications—keeping warm at all times, no cold drinks or ice, being well-rested, getting regular blood checks, and having only warmed transfusions and infusions,” she said.
In 2002, Usdan was put on epoetin alfa (Procrit®), a bone marrow stimulator for red cell production. This continued for 7 years with weekly or biweekly self-injections to help raise her hemoglobin levels, until her doctor took her off the medication due to side effects.
Coping With a Debilitating Disease
As her disease progressed, Usdan received periodic infusions of rituximab, an intravenous infusion developed by Biogen/Idec in collaboration with Genentech to treat non-Hodgkin’s lymphoma, rheumatoid arthritis, and other conditions. Usdan’s last such infusion was in 2016; she stopped receiving them because her hemoglobin level increased each week so that by week 4, she was back at her normal, which is around 10 grams per deciliter.
“It’s not a cure, it’s only a treatment,” she said. “Right now, I take only folic acid because it’s a blood builder.”
Even now, whenever Usdan visits a shopping mall, she must wrap herself in sweaters and scarves due to the air-conditioning.
“Everyone else is wearing short sleeves,” said the grandmother of 5. “I hardly ever wear a dress because my legs are cold.”
Like other CAD patients, Usdan’s hemoglobin level drops when she has a bacterial or viral infection; upon healing, it goes back up. The normal range of hemoglobin for women is 12.0 to 15.5 grams per deciliter.
“When my hemoglobin trends downward from the mid-9s and lower, my CAD symptoms are extreme fatigue, heartbeat whooshing sounds in my ears, breathlessness upon physical exertion, paleness, and very rarely, hemoglobinuria—brown urine,” she said. “I am happy that I can function well with a hemoglobin level in the 10s, but I always do have the fatigue factor.”
Usdan, a longtime CAD advocate, is certainly no stranger to these issues. In 2007, she and 2 other CAD patients supported by the National Organization for Rare Diseases (NORD) created a dedicated website for CAD patients as well as a private Facebook group called CADdy Chatter.
That group, which now has around 1300 members, evolved in 2019 into the nonprofit Cold Agglutinin Disease Foundation. Headquartered in Cherry Hill, New Jersey, it consists entirely of volunteers and strives to advance knowledge about CAD for doctors, researchers, patients, and caregivers.
“It took 20 years following my CAD diagnosis to form a CAD Foundation . . . for a surge of interest by drug companies globally to commit to discover and develop treatments for rare diseases,” said Usdan, who still works full-time as an artist from her home studio in Florida. She is no longer affiliated with the CAD Foundation, though she stays in touch with the other cofounders.
Sanofi is currently awaiting FDA approval of its C1s inhibitor sutimlimab. Its recent CADENZA study, involving 42 CAD patients, showed that sutimlimab reduced the destruction of red blood cells in patients with CAD within one week of starting treatment.
“Travel is a very big problem. People with CAD are restricted,” she said. “I would not go to a third-world country ever, because if I get sick and have to go to a hospital, it could be a disaster.”
Decades of Research on CAD
Dr. Berentsen’s interest in the disease began in 1992, when he began treating 3 patients at University Hospital in the Norwegian city of Trondheim.
“I realized there was an unmet need for education among doctors and even among hematologists, and also an unmet need for treatment among patients,” he said. ”So I started from there, publishing a small case report on those 3 patients. And then afterwards I did 2 large studies and several prospective trials on therapies and coping with this new disease.”
Dr. Berentsen has since studied CAD extensively. The author of several published studies on B-cell-directed therapies for CAD, he’s also lectured at the American Society of Hematology, which held its most recent annual meeting in Atlanta in December 2021.
Not surprisingly, Dr. Berentsen said, CAD is more common in countries with colder climates. If someone with CAD moves from a cold place to a warmer one, the patient will still have the disorder, but the symptoms will often be milder.
His lab recently did a study comparing Norway to northern Italy, which is 6 °C warmer on average, and found that CAD was 4 times more prevalent in Norway.
“The implication is that patients living in colder climates will more often need therapy, and they will have a poorer quality of life,” he said. “At least we think so.”
Dr. Berentsen said that when he started studying CAD, corticosteroids such as prednisone or prednisolone were the only therapies available. Neither was particularly effective, he said, and while rituximab did relieve symptoms, “the duration of the response was, I would say, disappointingly short, with a median of 1 year. It was the first effective therapy, but it’s not an optimum therapy. On the other hand, it’s usually well-tolerated, and there are few side effects.”
The Norwegian researcher has specific advice for CAD sufferers: “You must protect yourself from cold ambient temperatures. People living in cold climates should use warm clothing, and especially protect hands, feet, face, nose, and ears from the cold.”
“For some patients, taking food from the freezer, and even from the refrigerator, may induce symptoms. They often have a special kind of bluish discoloring of face, hands, and feet called acrocyanosis,” he added. ”People often think that protection from cold will protect them from those symptoms. That is correct, but protection from cold will also, to some degree, protect them from the hemolytic anemia, the red blood cells, that leads to anemia.”