Rituximab helps treat CAD linked to long-term immunosuppression: Case
Disorder developed as a result of treatment for 2 other autoimmune diseases
Written by |
Rituximab plus glucocorticoids led to sustained disease remission in an older woman who developed cold agglutinin disease (CAD) and severe kidney disease after receiving long-term immunosuppressive treatment for two other autoimmune diseases, a study shows.
“Rituximab combined with glucocorticoids led to a prompt and marked improvement in anemia and [kidney] lesions, resulting in sustained remission of both CAD and [C3 glomerulonephritis, a type of kidney disease] while maintaining … remission” of rheumatoid arthritis, one of the woman’s autoimmune conditions, researchers wrote. “Accumulation of similar cases will be essential to refine disease classification and to optimize therapeutic strategies for immune-mediated overlap disorders.”
The woman’s case was described in the study, “A case of concurrent cold agglutinin disease and C3 glomerulonephritis requiring differentiation from other iatrogenic immunodeficiency-associated lymphoproliferative disorder in a patient with rheumatoid arthritis and Sjögren’s disease,” which was published in Immunological Medicine.
Rituximab commonly used off-label for CAD
CAD is a rare autoimmune disease caused by self-reactive antibodies called cold agglutinins that bind to red blood cells at cold temperatures, causing them to clump and be marked for destruction (hemolysis). This process involves a group of immune proteins called the complement system.
CAD signs and symptoms include anemia (low red blood cell counts), fatigue, shortness of breath, and skin discoloration upon cold exposure.
The disease is thought to result from excessive, but non-cancerous, growth of cold agglutinin-producing B-cells. These immune cells typically produce antibodies to protect the body against infections, but in autoimmune diseases, they produce self-reactive antibodies that target healthy cells.
Rituximab (marketed as Rituxan and MabThera, with biosimilars available) is a therapy commonly used off-label for CAD and other autoimmune diseases. It works by killing B-cells, the immune cells that produce self-reactive antibodies.
Woman had been diagnosed with rheumatoid arthritis, Sjögren’s disease
In this study, a team of researchers at the Kawasaki Medical School in Japan reported the case of a 69-year-old woman in whom rituximab effectively treated CAD that developed as a result of long-term immunosuppressive treatment for other autoimmune diseases.
The woman had a diagnosis of two autoimmune diseases: rheumatoid arthritis, which affects the joints, and Sjögren’s disease, which mainly affects the glands that produce tears and saliva. She had been treated with methotrexate for 16 years and infliximab (sold as Remicade) for 13 years to suppress the immune system.
About three months before she was admitted to the researchers’ hospital, she noticed a purple, net-like rash during winter. This rash, called livedo reticularis, can occur when cold restricts blood flow. She also became increasingly tired.
Over the next two months, her kidney function gradually worsened. Three days before admission, she developed shortness of breath with physical activity.
At admission, blood tests showed low numbers of red blood cells, immune cells, and platelets (blood fragments involved in blood clotting). Doctors first thought this was caused by methotrexate suppressing her bone marrow (where blood cells are produced), especially because her kidney problems could increase the therapy’s toxicity.
The doctors decided to stop methotrexate and infliximab, and she received calcium folinate, a form of folic acid that reduces methotrexate’s side effects. Her white blood cell and platelet counts improved, but her anemia and kidney function did not.
CAD remained in remission a year later
Further testing showed several signs of CAD, including red blood cells clumping at room temperature, a positive direct Coombs test indicating complement proteins bound to red blood cells, and high levels of cold agglutinins. These findings confirmed a diagnosis of CAD.
She also had high levels of monoclonal IgM-kappa, a type of antibody typically linked to CAD and made by a single clone of B-cells. Because doctors found no signs of infection or cancer, they considered CAD to be an iatrogenic immunodeficiency-associated lymphoproliferative disorder, which refers to an abnormal growth of immune cells caused by long-term immunosuppressive treatment for autoimmune diseases.
A kidney biopsy was performed to understand the woman’s worsening kidney function. It showed signs of C3 glomerulonephritis, a serious disease that damages the kidney’s filtering units and is driven by abnormal complement activation.
After about three weeks in the hospital, she was started on glucocorticoids, a type of anti-inflammatory and immunosuppressive treatment. Because warming alone did not adequately control hemolysis, she received four weekly infusions of rituximab.
This case suggests the potential of rituximab to possibly contribute to controlling both [disease-causing] axes.
After this combined treatment, her anemia lessened, her monoclonal IgM-kappa levels decreased, and her kidney function returned to normal.
“By hospital day 51, both anemia and [kidney] function had stabilized, and the patient was discharged home,” the researchers wrote.
Six months later, she received a second course of rituximab as maintenance treatment, and started to reduce her daily dose of glucocorticoids, as long-term treatment can cause serious side effects. One year later, rheumatoid arthritis, CAD, and C3 glomerulonephritis remained in remission.
This case suggests that long-term immunosuppression may have triggered abnormal B-cell growth and complement activation that led to CAD and C3 glomerulonephritis. Targeting B-cells with rituximab successfully treated the two conditions, leading to lasting remission.
“This case suggests the potential of rituximab to possibly contribute to controlling both [disease-causing] axes,” the researchers concluded.
