An autoimmune disease is one where antibodies are produced which attack an element of our own body. Antibodies are the molecules produced by our immune system which are designed to recognize and destroy ‘foreign’ material. For example, we normally make antibodies to recognize bacteria or viruses, a crucial step in allowing our immune system to identify and destroy the disease. However, if the body ‘incorrectly’ makes antibodies against cells or molecules which belong to us then that part of the body is attacked, leading to an auto-immune disease. More well-known autoimmune diseases include rheumatoid arthritis or inflammatory bowel disease. However, auto-immune diseases can also attack the skin, the thyroid gland and even the blood cells. Autoimmune hemolytic anemia (AIHA) occur when the body produces antibodies which recognize our own red blood cells. These antibodies then attach to the red blood cells and ‘burst’ (or hemolyse) them. As the body cannot keep up with the rate of destruction of red blood cells, the patient becomes anemic – and may suffer with symptoms including shortness of breath, fatigue and fainting. In the most severe cases, there may not be sufficient red cells to transport oxygen to the tissues and the person becomes critically unwell.
Autoimmune hemolytic anemais are rare, affecting one to three people per 100,000 each year , with adults more commonly affected than children. The onset is most often gradual, with slowly developing symptoms, but occasionally the condition present with a rapidly progressing anaemia and can be life-threatening. Patients may need transfusion of red blood cells to lessen their symptoms, but this is not a cure and is used only while waiting for other treatments to become effective. Sadly, much of the treatment for these rare conditions is not evidenced-based, and may not always be effective. Auto-immune hemolytic anemias have a mortality of around 11% in adults .
AIHA are classed as ‘warm’ or ‘cold’ depending on the temperature at which the auto-antibody is effective. For people with cold AIHA keeping warm and preventing exposure may be enough to keep the disease at bay. Medical treatment is mainly based on experience and case-reports rather than large trials, due in part to the rare nature of the conditions.
AIHA can occur either as a ‘primary’ disorder – that is one which happens in isolation without the patient having any other illness, or ‘secondary’ to a range of other conditions including leukemias, and other auto-immune conditions such as Crohn’s disease. The underlying cause of the anemia may affect how responsive it is to treatment, although as with many things about the treatment of these rare conditions, much remains unclear .
The first treatment given to most patients is steroids. These act by suppressing the whole immune system, thus reducing the production of the auto-antibody. Reports on the effectiveness of steroids vary widely, and can depend on the type of anemia (cold or warm), or whether the patient has another disease . Steroids are generally given at a high dose to start with, until some response is seen, most patients will respond in the second or third week of treatment . Once the haemoglobin level has risen to an acceptable level, the steroids are slowly reduced. The data from trials and reports which have been published suggest that patients do best if steroids are carried on for a long time and reduced very gradually. Even so, only one in three will remain disease free in the longer-term .
Second-line treatment options
The traditional treatment if steroids fail, or if the patient experiences multiple relapses is to offer a splenectomy. The theory behind this is that the spleen both produces antibodies and acts to ‘clean’ the blood of damaged red blood cells. If it recognises red cells with antibodies attached as abnormal it will help to destroy them, worsening the patient’s anemia. By removing the spleen the symptoms may be controlled. Only very few studies have been carried out on the effectiveness of splenectomy for AIHA, but those that have suggest up to 80% of patients may be helped, and some stay in remission for many years . Of course, surgery also carries risks – and complications such as infection or bleeding can occur. Of particular concern following a splenectomy is that the patient is at risk from overwhelming bacterial infection, although immunisations before surgery and regular low-dose antibiotics are often recommended, such infections can still happen.
More recently, new treatments have started to be used such as rituximab, a monoclonal antibody which specifically targets a molecule on the surface of B cells. This medication has the advantage of being more selective, rather than reducing the function of the whole immune system, it targets the specific part which causes the problem in most patients. This of course means the rest of the system is able to fight off infections in the normal way. A recently published small randomised trial looked at the use of rituximab (along with standard steroid treatment) for patients with warm hemolytic anemia. They found that rituximab significantly increased the proportion of patients responding to treatment (from 31% to 75%), increased the number remaining disease free at a year, and was associated with fewer severe infections than treatment with steroid alone . There is a growing impression that given few side-effects and high numbers of patients responding to treatment, rituximab should be used earlier in the treatment of autoimmune anemias .
Many other solutions have been tried for patients who remain resistant to first- or second-line therapy. A range of so-called ‘steroid sparing’ agents may be used in an attempt to reduce the steroid dose, and therefore the side-effects. As a last resort chemotherapy agents such as cyclophosphamide may be tried. These agents effectively kill off the bone marrow – once the treatment is stopped regeneration of the bone marrow is encouraged by using granulocyte colony stimulating factor. The hope is that the ‘new’ bone marrow will regenerate free from any harmful auto-antibodies. Whilst chemotherapy like this can be effective, the side-effects can be extremely challenging to cope with, and potentially dangerous.
As a final step, hematopoietic stem cell transplantation has been described in a few patients with auto-immune anemia. This treatment is potentially life-threatening, and should probably be reserved as a very last resort in challenging patients .
There is much still to be understood about the treatment of autoimmune hemolytic anemias. Current treatment is based on personal experience and case-series rather than more accurate randomized trials. One of the problems with undertaking larger, more powerful studies is that conditions are rare, meaning studies would need to be conducted across many centres, and over many years. As such, first-line treatment continues to be steroids to ‘damp down’ the harmful immune response, followed by either surgery or other medications. As experience with newer monoclonal antibody medication grows, it may be used earlier in the progression of the condition to try and achieve a good response without some of the significant side-effects which come with a more traditional approach.
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