CAD secondary to lupus appears to affect only women, study finds
Duo calls case series spanning nearly 75 years 'the largest' to date
Few cases of cold agglutinin disease (CAD) secondary to systemic lupus erythematosus, or SLE, have been reported over the past seven decades, but all occurred in women, according to a study by two researchers in Colombia.
In addition to describing two new cases of CAD secondary to SLE — the most common form of lupus — the researchers reviewed the demographic, clinical, and treatment data of these and the 11 other cases reported between 1950 and 2023. Altogether, the researchers found 13 cases of patients with CAD secondary to lupus over the nearly 75 years.
Besides discovering that all cases reported to date involved women, the duo found that CAD was diagnosed for each, in general, at the beginning of the patient’s SLE journey. Further, being older than 50 was associated with more severe CAD-related anemia, or low counts of red blood cells, the researchers found.
“As a strength of this study, it stands out that it is the largest series of cases described in the literature,” the team wrote, adding that “it’s of valuable importance to consolidate information on this group of patients, in such a way that it allows improving the diagnostic approach, therapeutic approach, prognosis and quality of life.”
The study, “Autoimmune haemolytic anaemia due to cold agglutinins associated with systemic lupus erythematosus. Case presentation and literature review,” was published in the Colombian Journal of Rheumatology.
Researchers detail 2 new cases, bringing total reported to 13
A rare autoimmune disease, CAD is caused by the production of self-reactive antibodies, called cold agglutinins, that bind to red blood cells at cold temperatures. This leads to the cells’ clumping, or aggregation, and destruction, known as hemolysis.
Key signs and symptoms of CAD include anemia and Raynaud’s phenomenon, which occurs when the body’s extremities become numb and/or discolored in response to cold temperatures.
While it can occur on its own — when it’s thus known as primary CAD — the disease also can develop secondary to another condition, such as infections, cancers, or other autoimmune diseases such as SLE. In such cases, it’s called secondary CAD.
CAD secondary to SLE can affect many parts of the body, including the skin, joints, kidneys, and blood. The researchers noted that it “is infrequent and is only described in case reports.”
Here, the duo described two new cases of CAD secondary to SLE.
The first involved a woman, 76, diagnosed with SLE, who had anemia and signs of red blood cell clumping. She did not have circulation problems like Raynaud’s or acrocyanosis, where fingers or toes turn bluish in the cold.
Blood testing revealed high levels of anti-nuclear antibodies, or ANAs, a type of self-reactive antibodies that are a hallmark of lupus.
Despite treatment with anti-inflammatory and immunosuppressive medications, namely prednisolone and azathioprine, the woman showed no improvement, with relapsing anemia that required frequent hospital visits and blood transfusions.
After three years, doctors started her on rituximab, a medication that depletes antibody-making B-cells. Rituximab, commonly used in CAD and other autoimmune diseases, is sold as Rituxan, among other brand names, and biosimilars are available. There were “no clear data on response to such management,” the researchers wrote.
A year later, the woman was hospitalized for severe hemolysis, with low levels of hemoglobin, which is the protein in red blood cells that carries oxygen. A direct Coombs test, which detects antibodies and other immune proteins attached to red blood cells, was positive, as was testing for cold agglutinins, confirming a diagnosis of CAD secondary to SLE.
The woman received another immunosuppressive treatment, called cyclophosphamide, that slightly increased, but did not normalize, her hemoglobin levels. It did eliminate the need for hospitalizations. Another dose of rituximab maintained that response. The patient later died from COVID-19 complications.
Rituximab worked without need for corticosteroids in 5 of 6 patients
The second case involved a 29-year-old woman who developed painful joint inflammation over six months. She was initially misdiagnosed with rheumatoid arthritis and given immunosuppressive treatment, to which she did not adhere.
Later, she began experiencing other symptoms, including weight and hair loss, jaundice, which is a yellowing of the skin and whites of the eyes, difficulty breathing, and acrocyanosis.
Blood testing revealed severe anemia, with very low hemoglobin levels. She tested positive on a direct Coombs test and for the presence of ANAs and cold agglutinins. Based on these findings, the woman was diagnosed with CAD secondary to SLE.
She received prednisolone, hydroxychloroquine — a medication sometimes used in SLE — and rituximab. Her condition improved and her hemoglobin levels increased to near normal. After nine months, she had fully recovered.
[CAD] associated with SLE is an infrequent manifestation, which notably affects middle-aged women.
In reviewing these two cases and the 11 other reports previously published, the researchers found that all involved women. Their median age was 42, ranging from 17 to 77. In three-quarters of the cases, symptoms of CAD manifested early in the course of SLE. In the other cases, CAD developed within five years of the SLE diagnosis.
Women older than 50 were more likely to have severe CAD-related anemia when they were admitted to the hospital.
Corticosteroids were used as first-line treatment in all cases. Rituximab was associated with better responses relative to the other treatments used, resulting in five complete responses and one partial response.
The researchers noted that rituximab appeared to work well “without the need for immunosuppressants other than corticosteroids in 5 of the 6 cases described.”
“[CAD] associated with SLE is an infrequent manifestation, which notably affects middle-aged women,” the team concluded.
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