Reaching into a freezer bare-handed is something some people with cold agglutinin disease (CAD) are advised to avoid. A 2020 review by the Norwegian hematologist Sigbjørn Berentsen notes that some patients should wear gloves even to take food from the fridge or freezer. Heading into winter, people with CAD are dealing with 2 different problems at once. The 2 main kinds of treatment, Enjaymo (sutimlimab) and regimens built on rituximab, do not act on those problems the same way.
Cold Agglutinin Disease Causes 2 Problems, and Only 1 Is Driven by Complement
Cold agglutinin disease is caused by an antibody called IgM that sticks to red blood cells when they cool. That antibody does 2 separate kinds of damage, and a 2026 review by Berentsen and Vos in the British Journal of Haematology treats them as distinct processes.
The first is red blood cell destruction, which doctors call hemolysis. The stuck antibody switches on complement, a part of the immune system that tags the cells so the liver removes them. The result is anemia, tiredness and sometimes dark urine. The second is the antibody gluing red cells into clumps in the coolest parts of the body. That slows blood flow and can turn fingers, toes, ears and the nose blue or numb in the cold.
How cold is cold depends on the person. Berentsen's 2020 review explains that antibodies still reacting above about 28-30°C (82-86°F) can clump red cells in the fingers and ears even on a mild day. In some people the reaction reaches close to body temperature. Jeanette, an 81-year-old American, shared her story for Rare Disease Day in 2023. She wrote that her reaction had progressed until temperatures in the low 70s set it off.
The line between a harmless cold antibody and one that causes disease, about 28-30°C, is warmer than a typical room. Sources: Berentsen's 2020 review (thermal amplitude, the 4°C test and fridge gloves), the British Society for Haematology's 2017 guideline (heart surgery) and Jeanette's Rare Disease Day story.
“My body reacts to cold everywhere that cold contacts my skin.”
Jeanette, living with cold agglutinin disease, Rare Disease Day, 2023
Does Cold Agglutinin Disease Get Worse in Winter?
Patients report worse cold-triggered symptoms in winter, but in a US study of 594 patients' health records, hemoglobin in cold agglutinin disease held steady across the seasons (Röth et al., 2022). Median hemoglobin was 9.87g/dL in summer and 9.86g/dL in winter. LDH, a blood marker of red cell breakdown, was higher in winter at 367 against 309 U/L.
Hospital visits, transfusions and blood clots were no more common in winter in that study, which its authors summed up as hemolysis that persists year round. Three of its authors worked for Sanofi, which owned Enjaymo at the time, and it measured blood tests and hospital use rather than how people felt.
Patients describe winter very differently, as a 2020 survey shows. It reached 50 American adults with CAD through the Cold Agglutinin Disease Foundation and a Sanofi patient website, and Sanofi paid for it (Joly et al., 2022). Of the 47 who named something that made symptoms worse, 83% named cold temperatures, 68% winter and 55% air conditioning. Avoiding the cold was the most common way they managed the disease, used by 82%.
Some people with CAD have gone much further than gloves. Of the 50, 16 had moved because of the disease, 9 for part of each year and 7 for good. Another 20 of the 34 who had not moved said they wanted to. Jeanette and her husband spent winters in Mexico, and she wrote that she still walked 5 miles a day in any weather, covered up against the cold.
The year-round hemolysis carries a risk that has nothing to do with cold fingers. A 10-year study of US insurance records compared 608 people with CAD with 5,873 similar people without it (Broome et al., 2020). Clots in a vein, artery or the brain showed up in 29.6% against 17.6%, a risk about 1.9 times higher after adjustment.
What to Tell a Hospital, a Lab or a Surgeon About Cold Agglutinin Disease
Medical care brings its own cold exposures, from transfusions to operating rooms, and the guidelines treat them seriously. The British Society for Haematology's 2017 guideline on primary autoimmune hemolytic anemia recommends keeping patients at normal body temperature during and right after surgery. It also advises considering a blood warmer for transfusions, while noting that evidence of benefit is limited.
Berentsen's 2020 review is blunter about transfusions, saying most literature recommends an in-line blood warmer and keeping the patient and the transfusion arm warm. It reports that acute flares have followed when those steps were skipped, and that a fatal outcome has been reported. Heart surgery needs the most planning, since cold heart-protection solutions can cool the heart to 8-12°C. The British guideline asks every heart surgery unit to have a policy for cold agglutinins.
Blood tests need the same care, because of what cold does inside a sample tube. When a sample cools before it is run, clumped red cells can make the red cell count look falsely low and the cell size falsely high. In a child described by St. Jude Children's Research Hospital, whose cold agglutinins followed an infection, the clumping disappeared once the blood was warmed to 37°C (Inaba et al., 2005). Jeanette found her own diagnosis this way, years after being told she had Raynaud's, through a note in old lab reports that her sample had been warmed to 37 degrees. The test that confirms CAD runs the other way and measures the antibody at 4°C. The standard definition calls for a titer, or antibody level, of 64 or higher (Berentsen, 2020).
Fever can set off a flare without any cold at all. In Berentsen's 2006 study of 86 Norwegian patients, 74% had worse hemolysis during feverish illnesses.
Rituximab, Rituximab With Bendamustine or Enjaymo for Cold Agglutinin Disease
No published trial has compared rituximab, rituximab with bendamustine and Enjaymo directly, and Berentsen's 2023 review says the choice should rest on an individual assessment. Not everyone needs a drug at all, since his 2020 review says treatment is not indicated for mild anemia or compensated hemolysis without troublesome symptoms.
Rituximab and Rituximab With Bendamustine, Aimed at the Antibody Source
Rituximab removes the B cells that make the cold antibody, and in most people with CAD those cells form a slow-growing clonal disorder in the bone marrow. Given alone to 27 patients over 37 courses, it brought a response after 54% of courses (Berentsen et al., 2004). Responses took a median of 1.5 months to arrive and lasted a median of 11 months.
Adding the chemotherapy drug bendamustine made responses deeper and much longer lasting. In a Nordic trial of 45 patients given 4 monthly cycles, 71% responded and 40% had a complete response (Berentsen et al., 2017). With longer follow-up, 78% had responded and 53% completely, and an estimated 77% of responders were still in remission at 5 years (Berentsen et al., 2020). The cost was side effects, since severe drops in infection-fighting white cells hit 33% of patients and 11% had an infection.
Responses to the combination can take months to arrive. Jeanette finished her 4 cycles in July 2022, and a month later her cold antibody levels had not fallen. Her doctor told her that results can take up to a year.
Enjaymo (Sutimlimab), Aimed at Complement
Enjaymo was approved in 2022 and is now sold by Recordati Rare Diseases. It blocks C1s, an early step of the classical complement pathway, so red cell destruction slows quickly while the drug is given. In the placebo-controlled CADENZA trial, 73% of patients on Enjaymo reached the main goal against 15% on placebo (Enjaymo label). Fatigue scores improved by 10.8 points against 1.9, on a 52-point scale.
The effect lasts only as long as the infusions continue, and hemolysis returned by about 9 weeks after the last dose in both main trials. Serious infections occurred in 15% of trial patients, and 1 died of a Klebsiella pneumonia. The label calls for pneumococcal and meningococcal vaccines at least 2 weeks before the first dose. Acrocyanosis, a bluish color of the skin and lips, and Raynaud's phenomenon were each reported in 18% of CADENZA patients on Enjaymo against none on placebo.
“B-cell-directed approaches should be preferred over complement-mediated therapies.”
Sigbjørn Berentsen, on patients with marked or severe circulatory symptoms, HemaSphere, 2023
The same review says Enjaymo should be considered first, where available and affordable, when a rapid response is needed. It is often the best second option when the cold symptoms are not disabling, provided Enjaymo has not already failed. It also frames rituximab with bendamustine as a good first treatment for fit patients with moderate to severe disease, and rituximab alone as an option for frail patients.
The First Year on Each Cold Agglutinin Disease Treatment, Counted in Visits
By Trial Friend's count from the label and published regimens, a first year on Enjaymo means 27 infusion visits. Rituximab alone takes 4 and rituximab with bendamustine takes 8 treatment days. Enjaymo is given in weeks 0 and 1 and then every 2 weeks through week 51, which makes 27, while rituximab alone is 4 weekly infusions. The combination gives rituximab and bendamustine on day 1 and bendamustine again on day 2, across 4 monthly cycles (checked November 2, 2026).
Those counts measure the time a treatment takes, not how well it works. Enjaymo's visits continue for as long as it is used, while the rituximab regimens end after a fixed course and are repeated only if the disease returns. Most insurer policies Trial Friend read for Enjaymo do not require trying rituximab first, though Geisinger does and Kaiser Permanente Northwest does for chronic anemia. Some plans, including Humana, Centene and Geisinger, do not cover Enjaymo alongside rituximab. Recordati Rare Diseases Patient Solutions, at 1-833-223-2428, runs a free 30-day starter supply for first-time users.
Quick Answers on Cold Agglutinin Disease
Is cold agglutinin disease a type of cancer?
Cold agglutinin disease is not usually treated as a cancer. Most people with it, though, have a slow-growing group of identical B cells in the bone marrow making the cold antibody. In the 2006 Norwegian study, 76% had marrow findings of a low-grade lymphoma. Later work described it as a distinct bone marrow disorder of its own, which is why a B-cell treatment like rituximab works.
How common is cold agglutinin disease?
Cold agglutinin disease affects about 16 people per million in Norway, with about 1 new case per million each year (Berentsen et al., 2006). Half of patients there were 67 or older when it began. A 5-country study found it about 4 times as common in colder climates, 20 against 5 cases per million (Berentsen et al., 2020).
Can Enjaymo be stopped once hemoglobin is normal?
Enjaymo can be stopped, but the label says hemolysis tends to come back, and hemoglobin fell by about 2.3-2.4g/dL within the 9 weeks after the last dose in its trials. The label tells doctors to watch for returning hemolysis and says restarting Enjaymo can be considered.
Why do blood test results look strange in cold agglutinin disease?
Blood that cools in the tube can clump, so an analyzer may report a falsely low red cell count and falsely high cell size. Warming the sample to 37°C before testing reverses the clumping, and British guidance asks labs to warm samples from people with CAD to 37°C before testing.
The next development in cold agglutinin disease may be a pill. Annexon said in August 2026 that dosing was complete in its study of ANX1502, an oral drug aimed at the same C1s step as Enjaymo. The company expects to give an update in the fall of 2026. If it works, it would act on the complement half of the disease, and the cold-triggered half would still need the antibody-lowering treatments covered above. Open studies are on the cold agglutinin disease trials page, including an early-stage trial recruiting at 4 US sites.