Autoimmune haemolytic anaemia is a rare blood disorder where the body’s own immune system attacks healthy red blood cells, causing them to break down faster than they can be replaced. While this condition can be serious if left untreated, a range of established treatments and emerging therapies in clinical trials offer hope for managing symptoms, improving quality of life, and addressing the underlying immune dysfunction.
Understanding Treatment Goals in Autoimmune Haemolytic Anaemia
When someone is diagnosed with autoimmune haemolytic anaemia, the primary aim of treatment is to stop the destruction of red blood cells and allow the body to restore healthy levels. The approach taken depends on several factors, including the type of AIHA a person has, how severe the anaemia (low red blood cell count) is, and whether there is an underlying condition causing the immune reaction. In some cases, AIHA develops without an obvious cause, known as primary AIHA, while in others it is linked to conditions such as blood cancers, autoimmune diseases, infections, or certain medications, referred to as secondary AIHA.[1][2]
Treatment decisions are also influenced by the temperature at which the damaging antibodies become active. Warm autoimmune haemolytic anaemia, the most common form, involves antibodies that attack red blood cells at normal body temperature. Cold autoimmune haemolytic anaemia, also called cold agglutinin disease, occurs when antibodies become active at cooler temperatures, often causing symptoms when a person is exposed to cold environments.[1][5]
Medical societies and clinical guidelines recommend a stepwise approach to treatment, starting with medications that suppress the immune system and progressing to more targeted therapies or surgical options if initial treatments do not work. Alongside established treatments, researchers are actively investigating new drugs and approaches in clinical trials, aiming to provide safer, more effective options for people living with this condition.[4][10]
Standard Treatment Approaches for Autoimmune Haemolytic Anaemia
First-Line Treatment with Corticosteroids
For most people with warm autoimmune haemolytic anaemia, treatment begins with corticosteroids, which are medications that suppress the immune system’s production of harmful antibodies. The most commonly used corticosteroids are prednisone, prednisolone, and methylprednisolone. These drugs work by reducing the immune response that causes red blood cells to be destroyed. Clinical studies show that corticosteroids are effective in about 70 to 85 percent of patients with warm AIHA.[10][12]
Doctors typically start with high doses of corticosteroids to quickly bring the immune reaction under control. Once symptoms improve and red blood cell counts stabilize, the dose is gradually reduced over a period of six to twelve months. This slow tapering is important because stopping corticosteroids too quickly can cause symptoms to return. However, despite their effectiveness, corticosteroids are not suitable for long-term use because they can cause significant side effects.[10][11]
Common side effects of prolonged corticosteroid use include weight gain, mood changes, increased blood sugar levels, high blood pressure, weakened bones (osteoporosis), increased risk of infections, and changes in appearance such as a rounded face. Because of these potential complications, doctors aim to use the lowest effective dose for the shortest time possible.[5][10]
Treatment for Underlying Conditions
When AIHA is secondary to another condition, treating the underlying cause is essential. For example, if AIHA develops due to a viral infection such as Epstein-Barr virus or hepatitis, the anaemia often resolves once the infection is successfully treated. Similarly, if certain medications such as penicillin or other antibiotics are triggering the immune reaction, stopping the offending drug may lead to improvement.[1][2]
In cases where AIHA is linked to autoimmune diseases like systemic lupus erythematosus or rheumatoid arthritis, managing the primary autoimmune condition with appropriate therapies can help control the haemolytic anaemia. Similarly, when AIHA occurs alongside blood cancers such as chronic lymphocytic leukaemia or lymphoma, treatment of the cancer may improve or resolve the anaemia.[2][3]
Second-Line Therapies When Corticosteroids Are Not Enough
Unfortunately, not all patients respond well to corticosteroids, and some experience relapses when the dose is reduced. For these individuals, doctors turn to second-line therapies. The traditional sequence of second-line treatment includes splenectomy (surgical removal of the spleen), rituximab (a targeted antibody therapy), and immunosuppressive drugs.[10][12]
Splenectomy involves removing the spleen, an organ that plays a key role in filtering and destroying red blood cells. By removing the spleen, doctors can reduce the rate at which damaged red blood cells are destroyed. Splenectomy is effective in approximately two out of three patients with warm AIHA, and about 20 percent of patients may experience long-term remission. The procedure can be performed laparoscopically through small incisions or as an open surgery. Recovery typically takes four to six weeks. However, removing the spleen increases the risk of infections, particularly from certain bacteria, and patients may require vaccinations and preventive antibiotics.[10][18]
Rituximab is a monoclonal antibody that targets B-cells, the immune cells responsible for producing the harmful antibodies. By depleting these B-cells, rituximab can help reduce the destruction of red blood cells. It is given as an intravenous infusion, often in combination with corticosteroids or as a single therapy. Studies show that rituximab is effective in about 80 to 90 percent of patients with warm AIHA. Because of its effectiveness and relatively favorable side effect profile, rituximab is increasingly being used earlier in the treatment sequence, sometimes even as a first-line therapy alongside corticosteroids.[4][10][11]
Other immunosuppressive drugs that may be used include azathioprine, cyclophosphamide, cyclosporin, and mycophenolate mofetil. These medications work by dampening the overall immune response, but they can have significant side effects such as increased infection risk, liver or kidney problems, and bone marrow suppression. They are typically reserved for patients who do not respond to other treatments.[10][12]
Additional Treatment Options
In some cases, doctors may use intravenous immunoglobulin (IVIG), a preparation of antibodies collected from blood donors. IVIG can provide temporary improvement in some patients, although responses are often short-lived. Another option is danazol, a synthetic hormone that can help reduce red blood cell destruction, though it is used less frequently today.[5][10]
For patients with severe, life-threatening anaemia, blood transfusions may be necessary to quickly restore red blood cell levels. However, transfusions do not address the underlying immune problem and provide only temporary relief. In autoimmune haemolytic anaemia, finding compatible blood can be challenging because the antibodies may also attack transfused red blood cells. Doctors use the least incompatible blood available and administer transfusions slowly to minimize the risk of rapid destruction.[5][11]
Treatment for Cold Agglutinin Disease
Cold autoimmune haemolytic anaemia requires a different approach. Corticosteroids are generally less effective for this type, and splenectomy is rarely helpful. Instead, rituximab is now recommended as the first-line treatment for primary cold agglutinin disease. It can be used alone or in combination with other drugs such as bendamustine, a chemotherapy agent that targets abnormal B-cells. Patients are also advised to avoid cold exposure, as this can trigger symptoms.[4][10][12]
In addition to B-cell targeted therapies, complement inhibitors are emerging as an important treatment option for cold agglutinin disease. These drugs target the complement system, a part of the immune system that contributes to red blood cell destruction in cold AIHA.[4][13]
Treatment in Clinical Trials: New Horizons for AIHA
While established treatments have helped many patients, there is still a significant need for more effective and safer therapies, particularly for those who do not respond to current options or who experience frequent relapses. Clinical trials are exploring a range of innovative approaches, from new drugs targeting specific immune pathways to therapies that remove harmful antibodies from the bloodstream.[4][13]
Complement Inhibitors: Targeting the Immune Cascade
One of the most promising areas of research involves drugs that inhibit the complement system, a series of proteins in the blood that, when activated, can lead to the destruction of red blood cells. In autoimmune haemolytic anaemia, especially the cold antibody type, the complement system plays a central role in damaging red blood cells. By blocking specific steps in this cascade, complement inhibitors can help prevent haemolysis (the breaking down of red blood cells).[4][13]
One such drug is BIVV009, also known as sutimlimab, a monoclonal antibody that specifically inhibits C1s, an enzyme early in the complement pathway. In clinical trials, sutimlimab has shown the ability to stabilize patients with acute severe haemolysis and improve clinical outcomes in cold agglutinin disease. The drug is now entering Phase III studies, which are large-scale trials designed to confirm effectiveness and safety before seeking regulatory approval. Phase III trials compare the new treatment with standard care and involve hundreds or thousands of patients.[4][13]
The advantage of complement inhibitors is that they can rapidly reduce haemolysis without broadly suppressing the immune system, potentially reducing the risk of infections compared to traditional immunosuppressive drugs. These therapies are especially valuable for patients with cold agglutinin disease, where other treatments have had limited success.[13]
Rituximab in Combination Therapy
Although rituximab is already used in clinical practice, researchers are continuing to study its optimal use through clinical trials. One area of investigation is the use of rituximab as a first-line treatment in combination with corticosteroids for warm AIHA. A Phase III randomized trial involving 64 patients compared rituximab plus prednisolone to prednisolone alone. After 12 months, 75 percent of patients who received the combination therapy had a satisfactory response, compared to only 36 percent of those who received prednisolone alone. After 36 months, about 70 percent of patients in the combination group remained in remission, versus about 45 percent in the prednisolone-only group. These results support the early use of rituximab alongside corticosteroids, potentially improving long-term outcomes and reducing the need for additional therapies.[11]
Novel B-Cell Targeting Agents
Beyond rituximab, researchers are exploring other drugs that target B-cells, the immune cells responsible for producing the autoantibodies. These include newer monoclonal antibodies and small molecules that can more selectively or potently deplete B-cells or interfere with their function. While these agents are still in earlier phases of clinical testing (Phase I and Phase II), they hold promise for patients who do not respond to rituximab or who experience side effects from it.[13]
Phase I trials primarily focus on determining the safety of a new drug and finding the appropriate dose. Phase II trials assess whether the drug is effective and continue to monitor safety in a larger group of patients. If these trials are successful, the drugs move to Phase III for broader testing.[4]
Treatments Targeting Extravascular Haemolysis
Most red blood cell destruction in warm AIHA occurs in the spleen and liver, a process known as extravascular haemolysis. Researchers are developing drugs that can interfere with this process by preventing the immune system’s macrophages (a type of white blood cell) from recognizing and destroying antibody-coated red blood cells. These therapies are still in early-stage development but represent a novel approach to reducing haemolysis without removing the spleen or broadly suppressing the immune system.[13]
Therapies to Remove IgG Antibodies
Another innovative approach involves physically removing the harmful antibodies from the blood. One experimental technique uses drugs or devices that target and eliminate IgG antibodies, the type of antibody most commonly involved in warm AIHA. By reducing the level of these antibodies in the bloodstream, the rate of red blood cell destruction can be slowed. This approach is being tested in clinical trials and may offer a rapid way to control severe or refractory cases.[13]
High-Dose Cyclophosphamide and Alemtuzumab
For patients with severe, life-threatening AIHA that does not respond to any other treatments, doctors may consider last-resort options such as high-dose cyclophosphamide or alemtuzumab. Cyclophosphamide is a powerful chemotherapy drug that can reset the immune system, while alemtuzumab is a monoclonal antibody that targets a broad range of immune cells. Both treatments carry significant risks, including severe infections and bone marrow suppression, and are only used when all other options have been exhausted.[10][12]
Patient Eligibility and Trial Locations
Clinical trials for autoimmune haemolytic anaemia are conducted at specialized medical centers around the world, including locations in Europe, the United States, and other regions. Eligibility for these trials depends on factors such as the type of AIHA, previous treatments received, disease severity, and overall health. Patients interested in participating in clinical trials should discuss options with their healthcare team, who can help identify appropriate studies and provide guidance on enrollment.[4][13]
Most Common Treatment Methods
- Corticosteroid Therapy
- Prednisone, prednisolone, and methylprednisolone are the first-line treatments for warm autoimmune haemolytic anaemia, effective in 70 to 85 percent of patients by suppressing antibody production.[10][12]
- High doses are given initially and then slowly tapered over six to twelve months to prevent relapse.[10]
- Side effects include weight gain, mood changes, high blood sugar, weakened bones, and increased infection risk, limiting long-term use.[5][10]
- Rituximab (Monoclonal Antibody Therapy)
- Rituximab targets B-cells, the immune cells producing harmful antibodies, and is effective in 80 to 90 percent of warm AIHA cases.[4][10]
- It is increasingly used as first-line therapy in combination with corticosteroids or as a second-line treatment after corticosteroid failure.[11]
- For cold agglutinin disease, rituximab is now the recommended first-line treatment, either alone or combined with bendamustine.[4][12]
- Splenectomy (Surgical Removal of the Spleen)
- Splenectomy is effective in approximately two out of three patients with warm AIHA, with about 20 percent achieving long-term remission.[10][18]
- The procedure reduces red blood cell destruction but increases the risk of infections, requiring vaccinations and preventive antibiotics.[10][18]
- Recovery typically takes four to six weeks, with laparoscopic procedures allowing faster recovery than open surgery.[18]
- Immunosuppressive Drugs
- Azathioprine, cyclophosphamide, cyclosporin, and mycophenolate mofetil are used for refractory or relapsed cases after other treatments have failed.[10][12]
- These drugs suppress the overall immune response but carry risks such as increased infections, liver or kidney problems, and bone marrow suppression.[10]
- Complement Inhibitors (in Clinical Trials)
- Blood Transfusions
- Intravenous Immunoglobulin (IVIG) and Danazol
