NORD gratefully acknowledges James Bruce Bussel, MD, Weill Medical College of Cornell University, for assistance in the preparation of this report.
Evans syndrome is a rare disorder in which the body’s immune system produces antibodies that mistakenly destroy red blood cells, platelets and sometimes certain white blood cell known as neutrophils. This leads to abnormally low levels of these blood cells in the body (cytopenia). The premature destruction of red blood cells (hemolysis) is known as autoimmune hemolytic anemia or AIHA. Thrombocytopenia refers to low levels of platelets (idiopathic thrombocytopenia purpura or ITP in this instance). Neutropenia refers to low levels of certain white blood cells known as neutrophils. Evans syndrome is defined as the association of AIHA along with ITP; neutropenia occurs less often. In some cases, autoimmune destruction of these blood cells occurs at the same time (simultaneously); in most cases, one condition develops first before another condition develops later on (sequentially). The symptoms and severity of Evans syndrome can vary greatly from one person to another. Evans syndrome can potentially cause severe, life-threatening complications. Evans syndrome may occur by itself as a primary (idiopathic) disorder or in association with other autoimmune disorders or lymphoproliferative disorders as a secondary disorder. (Lymphoproliferative disorders are characterized by the overproduction of white blood cells.) The distinction between primary and secondary Evans syndrome is important as it can influence treatment.
Evans syndrome was first described in the medical literature in 1951 by Dr. Robert Evans and associates. For years, the disorder was considered a coincidental occurrence of AIHA with thrombocytopenia and/or neutropenia. However, researchers now believe that the disorder represents a distinct condition characterized by a chronic, profound (more than in ITP or AIHA alone) state of immune system malfunction (dysregulation).
The symptoms and severity of Evans syndrome can vary greatly from one person to another as can the onset, course and duration of the disorder. Most individuals exhibit a chronic course with periods of worsening symptoms (exacerbation) and remissions usually induced transiently by treatment. Most symptoms are caused by low levels of specific blood cells in the body. These blood cells perform specific functions. Red blood cells deliver oxygen to the body and remove carbon dioxide, platelets assist in clotting to stop blood loss, and white blood cells help to fight infection.
Some individuals with Evans syndrome may first present with accelerated destruction of red blood cells faster than the body can replace them. Low levels of circulating red blood cells, known as anemia, can cause a variety of symptoms including fatigue, pale skin color (pallor), lightheadedness, shortness of breath, dark colored urine, and a rapid heartbeat. Some individuals may develop yellowing of the skin and especially the whites of the eyes (jaundice).
Other individuals may first present with low levels of platelets, known as thrombocytopenia. Thrombocytopenia may cause tiny reddish or purple spots on the skin (petechiae), larger purplish discoloration on the skin caused by bleeding from ruptured blood vessels into subcutaneous tissue (ecchymosis), and purpura, a rash consisting of purple spots cause by internal bleeding from small blood vessels. Affected individuals may be more susceptible to bruising following minimal injury and spontaneous bleeding from the mucous membranes.
Low levels of white blood cells, known as neutropenia, occurs less frequently in individuals with Evans syndrome than anemia or thrombocytopenia. Individuals with neutropenia may be susceptible to recurrent infections. General symptoms may include fever, a general feeling of poor health (malaise) and sores (ulcers) on the mucous membranes of the mouth.
Additional symptoms that may occur in individuals with Evans syndrome include enlargement of the lymph nodes, spleen and liver. These findings may come and go or, in some cases, may only occur during acute episodes.
All too often, patients with Evans syndrome may not respond to treatment (refractory Evans syndrome) and can eventually progress to cause life-threatening complications including sepsis, severe bleeding (hemorrhaging) episodes, and significant cardiovascular problems including heart failure.
The exact, underlying cause of Evans syndrome is unknown. Evans syndrome is an autoimmune disorder. It occurs when the immune system produces antibodies that mistakenly attack healthy tissue, specifically red blood cells, platelets and sometimes certain white blood cells.
The immune system normally responds to foreign substances by producing specialized proteins called antibodies. Antibodies work by destroying foreign substances directly or coating them with a substance that marks them for destruction by white blood cells. When antibodies target healthy tissue they may be referred to as autoantibodies. Researchers believe that a triggering event (such as an infection or an underlying disorder) may induce the immune system to produce autoantibodies in Evans syndrome.
Evans syndrome may occur in combination with another disorder as a secondary condition. Secondary Evans syndrome can be associated with other disorders including autoimmune lymphoproliferative syndrome (ALPS), lupus, antiphospholipid syndrome, Sjogren’s syndrome, common variable immunodeficiency, IgA deficiency, certain lymphomas, and chronic lymphocytic leukemia. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
The incidence and prevalence of Evans syndrome is unknown. The disorder can affect children or adults.
A diagnosis of Evans syndrome is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation, and a variety of specialized tests. No specific test is conclusive for Evans syndrome and a diagnosis is made after excluding other possible diagnoses. Specifically, a diagnosis of Evans syndrome may be made when autoimmune hemolytic anemia (with a positive direct coombs test) and thrombocytopenia (ITP) occur in the same patient even if not at the same time.
Clinical Testing and Workup
Laboratory studies include a complete blood count (CBC), which can reveal low levels of red blood cells, platelets and white blood cells. Another blood test known as a direct antiglobulin test or DAT is used to determine whether the amount of certain antibodies is higher than normal. A variety of different tests may be administered to rule out other conditions. Such tests can include a bone marrow biopsy, additional antibody assays, and computed tomography (CT) scans of the chest, abdomen and pelvis.
Some physicians recommend that children with Evans syndrome be screened for ALPS because of the high prevalence of these two disorders occurring together. Screening involves testing for the presence of double negative ??T-cells (DNTs) by flow cytometry, the presence of which is indicative of ALPS.
There is no cure for Evans syndrome and treatment is often challenging. Treatment is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, hematologists, pediatric hematologists, immunologists, rheumatologists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment.
Most affected individuals require treatment, although, in rare cases, spontaneously remission has been reported. A variety of different therapies have been used to treat individuals with Evans syndrome and their effectiveness among affected individuals has been highly variable. Some individuals have long remissions of the disorder; others experience chronic problems with no remission.
Consequently, specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease severity; blood cell count levels; the presence or absence of certain symptoms; an individual’s age and general health; and/or other elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.
First-line therapy for Evans syndrome often consists of corticosteroids such as prednisolone. Corticosteroids help to suppress the immune system and decrease the production of autoantibodies. Initial results are often effective.
Intravenous immunoglobulin (IVIg) therapy has also been used to treat individuals with Evans syndrome. IVIg therapy modifies the activity of the immune system. IVIg is a solution containing antibodies donated from healthy individuals and delivered directly into a vein.
Surgical removal of the spleen (splenectomy) has been used to treat some individuals with Evans syndrome. Most reports are inconclusive and anecdotal and the effectiveness of the procedure is difficult to determine because of the simultaneous (concomitant) use of other therapies such as drugs. Splenectomy is generally reserved for individuals who do not respond to other therapeutic options (refractory Evans syndrome). In children, splenectomy rarely produces long term remission of symptoms. In adults, the effectiveness varies and symptoms usually return at some point. Therefore, it is usually delayed as long as possible and every effort is made not to perform it.
During an acute episode, blood and/or platelet transfusions may be necessary to address symptoms. However, the use of blood or platelet transfusions should be avoided as much as possible.
New therapies are being explored for Evans syndrome. Rituximab appears to be a highly effective treatment for patients with Evans syndrome. Rituximab is classified as a monoclonal antibody or biologic therapy – medications that act like antibodies, but are artificially created in a lab. Initial studies have shown that the drug is generally safe and effective. Advantages of rituximab are that it avoids serious immunosuppression and side effects associated with other immunosuppressive agents. The disadvantage is that in cases of Evans syndrome in which underlying ALPS is the cause it appears likely that hypogammaglobulinemia will develop and may persist in rituximab-treated patients. Hypogammaglobulinemia is a condition in which the body’s immune system does not produce sufficient antibodies, potentially leaving affected individuals susceptible to bacterial infections and to a lesser extent certain viral infections.
Additional medications have been studied in small case series of individuals with Evans syndrome. The next agent that appears to be relatively effective in this disorder is mycophenolate mofetil. These drugs may be used alone or in combination (multi-agent therapy) as second-line therapies for individuals with Evans syndrome who do not respond to corticosteroids or IVIg therapy. More research is necessary to determine the long-term safety and effectiveness of these potential therapies for individuals with Evans syndrome.
Some individuals with Evans syndrome have been treated with allogeneic or autologous stem cell transplantation. Stem cells are special cells found in the bone marrow that manufacture different types of blood cells (i.e. red blood cells, white blood cells and platelets). In autologous stem cell transplantation, an affected individual’s stem cells are removed after prior treatment, usually with drugs. These healthy stem cells are later re-infused into the bone marrow after the disorder has progressed. In allogeneic stem cell transplantation, stem cells are donated from another person, usually from a closely matched family member. These procedures have generally been used as a last resort for individuals who have failed to respond to other forms of treatment. They have produced mixed results and more experience is necessary to determine their potential effectiveness as a treatment for Evans syndrome.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
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For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
RareConnect offers a safe patient-hosted online community for patients and caregivers affected by this rare disease. For more information, visit www.rareconnect.org.
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