What is an autoimmune disease? 

Autoimmune diseases occur when the body malfunctions and is unable to distinguish foreign cells from its own healthy cells, leading to an attack on itself by mistake. 

What is Evans Syndrome?

Evans syndrome (ES) is a rare autoimmune disease in which the body mistakenly attacks its own blood cells. Evans syndrome is characterised by two or more symptoms of cytopenia: a condition presented by low blood count levels, including red blood cells (resulting in anaemia), white blood cells (resulting in neutropenia), and/or platelets (resulting in thrombocytopenia).¹  

ES is a complex disorder. It can occur as primary Evans syndrome, where there are no associated underlying autoimmune disorders, or can be more complex and occur as secondary Evans syndrome, where other autoimmune disorders, immunodeficiencies, or malignancy are present.² Thus, highlighting the complexity of the condition and the importance of identifying associated conditions for diagnosis and treatment. Scientists often categorise the condition as idiopathic (having no cause); however, secondary ES is commonly associated with:^1,2

• Systemic lupus erythematosus (SLE)
• Common variable immunodeficiency (CVID)
• Non-Hodgkin lymphoma
• Viral infections (including HIV, Hepatitis C)
• Chronic lymphocytic leukaemia

This article discusses the associated connections between Evans syndrome and lupus, CVID, and various other autoimmune disorders, the diagnosis of the condition, possible treatments and its prognosis. 

Understanding Evans Syndrome 

The coexistence of autoimmune haemolytic anaemia (AIHA) and immune thrombocytopenia (ITP), and often neutropenia, is what defines Evans syndrome. It’s the body’s immune system attacking red blood cells, platelets and sometimes white blood cells at the same time.

Autoimmune Haemolytic Anaemia (AIHA)

Autoimmune haemolytic anaemia is a rare blood disorder that causes a reduced number of red blood cells in the body. In AIHA, the immune system identifies its own red blood cells as foreign invader cells and creates antibodies to attack them. The red blood cells are therefore broken down at a quicker rate than they are created, resulting in anaemia.³

Immune Thrombocytopenia (ITP)

Immune thrombocytopenia is an illness in which the immune system mistakenly attacks the body’s platelet cells. This results in low levels of platelets in the blood, which are responsible for blood clotting. If there are not enough of them, it causes excessive bleeding and bruising.⁴

Neutropenia 

Neutropenia is a condition categorised by a low level of neutrophils (a type of white blood cell) in the blood, which are primary responders in fighting invading microorganisms that cause infections and inflammation. Therefore, the recurrence of infections is likely.⁵   

Pathophysiology: Blood Cell Lines Under Immune Attack 

The standard mechanism of the immune system is to protect the body against harmful, invading substances such as bacteria, viruses, and toxins. These invading substances carry antigens which trigger the production of antibodies, produced by immune cells (white blood cells), which seek out the antigens to destroy them. However, when an individual has an autoimmune disorder, their immune system loses the ability to distinguish between healthy cells and harmful antigens, consequently causing an attack on healthy cells. 

The cause of autoimmune disorders is unknown. Most research suggests that it is a result of a combination of genetic and environmental factors, such as certain bacteria, medications, diet, toxin exposure, and genetic predispositions.⁶

Clinical presentation of Evans syndrome

The clinical presentation of Evans syndrome varies depending on which type of blood cells are affected:²

• When red blood cells are affected, causing anaemia (AIHA), symptoms of fatigue, pallor (pale skin), dizziness and shortness of breath are common
• When clotting cells (platelets) are affected in immune thrombocytopenia (ITP), increased bruising and bleeding arise 
• Neutropenia, the least common cytopenia, has symptoms that include recurrent infections and mouth sores 

Challenges of Evans Syndrome 

Individuals with ES face a complex set of challenges. These can include managing the symptoms of severe bleeding, increased risk of infections, possible blood clots and cardiovascular problems. Relapses are also common, and there is also a greater likelihood of developing additional autoimmune disorders, such as systemic lupus erythematosus (SLE).^2,7 

ES not only presents with severe symptoms but is also a fluctuating condition that is challenging to diagnose, requiring a combination of blood tests and the exclusion of other causes.  

Evans Syndrome and Autoimmune Diseases

Primary Evans syndrome refers to the condition having no known cause or associated diseases, whereas secondary Evans syndrome occurs due to underlying conditions such as systemic lupus erythematosus (SLE).⁸ The autoimmune dysregulation that is present in other diseases can also trigger the production of antibodies to attack blood cells, resulting in ES. The shared issue of autoimmune diseases is this broken mechanism of knowing which cells to attack

As the process of distinguishing between self and non-self cells doesn’t work as it should, several things can go wrong in the body. Here are some of the key players involved in this malfunction:

T-cells

A type of white blood cell that actively works as part of the immune system to destroy infected cells. In autoimmune conditions, these T-cells are overreactive, destroying more cells, and ordering other types of white blood cells (B cells) to produce antibodies against the body's own healthy cells.⁹ 

Cytokines

The increased chemical signals sent from T-cells are carried out by cells called cytokines, resulting in an imbalance of more cells. Cytokines act as inflammatory markers; when there is a cellular imbalance in the blood, they cause more inflammation in the body, which can lead to autoimmune diseases.¹⁰

In Evans syndrome specifically, it is mainly the red blood cells and platelets that are attacked. The same immune problems can cause other autoimmune diseases, depending on which cells are targeted.

Genetic and Environmental Factors and Autoimmune Diseases

The immune system, genetic factors and environmental factors all contribute to the development of autoimmune diseases. Researchers have discovered that genetic predispositions often increase the likelihood of the development of autoimmune diseases and account for around 30%.¹² Similarly, environmental factors involving chemical/toxin exposure, dietary factors and infections are also accountable for impacting autoimmune disease and subsequently influence genetic predispositions, triggering immune system dysregulation.¹¹ 

Evans Syndrome and Lupus (Systemic Lupus Erythematosus) 

Similarly to Evans syndrome, lupus also causes haematological (blood) complications by triggering the production of antibodies targeting its own blood cells. Both conditions often present with overlapping symptoms, such as anaemia and thrombocytopenia.¹³

In some cases, lupus may present as Evans syndrome or vice versa, as both diseases are immunity-related. For both diseases, the treatments involve suppression of the immune system using immunosuppressant drugs. However, Evans syndrome, either on its own or in combination with Lupus, requires more specialised treatments due to frequent relapses and increased mortality.¹⁴

Unlike in ES, where the clinical presentation of cytopenias is the distinguishing feature of the condition, in lupus, the cytopenias, although common, do not define the manifestation of the disease.¹⁵ 

Evans syndrome and Common Variable Immunodeficiency

Common variable immunodeficiency (CVID) is a rare condition that occurs due to a deficiency of specific antibodies known as immunoglobulins, which are cells that fight infection, resulting in increased susceptibility to infections.¹⁶

Evans syndrome can often be a secondary complication of CVID, due to the dysregulation of immune cell production. Both disorders share similar clinical presentations; sometimes this overlap can be the initial or only presentation of CVID. This similarity can make it especially challenging to diagnose the conditions, particularly when the conditions coexist. 

Other Associated Autoimmune Diseases

Other autoimmune disorders, such as rheumatoid arthritis, autoimmune thyroid disease, type 1 diabetes, coeliac disease and primary immunodeficiency syndrome, are considered primary conditions that can result in ES. Due to the malfunction of the immune system arising from these autoimmune diseases, there is an increase in antibody production and attack on the body's blood cells. As the body's own cells are attacked, this gives rise to conditions such as AIHA and IPT, therefore allowing the diagnosis of Evans syndrome. Recognising these connections can help healthcare providers to form a better understanding of patients’ overall health and choose the most effective treatment.

Diagnosis and Clinical Approach

When two types of cytopenia are found and Evans syndrome is suspected, a variety of blood tests can be done, including:^7,17

• Complete Blood Count (CBC) 
• Coombs test, a test that identifies the presence of antibodies that attack red blood cells, causing anaemia
• Reticulocyte count, a test that measures if the body is producing enough red blood cells

In addition to these, an extensive look into the medical history of the patient will be carried out to rule out possible secondary causes of the symptoms, such as HIV, malignancies, or infections.  A well-established diagnosis is essential to ensure that appropriate treatment is provided, as there is a wide range of treatment options for various autoimmune diseases or immune deficiencies. 

Treatment 

Although there is currently no cure for Evans syndrome, treatment usually focuses on managing symptoms and controlling the immune system with immunosuppressant drugs.  Blood transfusions may also be used when necessary. The standard medications include corticosteroids and intravenous immunoglobulin therapy (IVIg), which is a transfusion of antibodies.  

If the standard treatment is not effective, monoclonal antibodies such as rituximab may be offered as an alternative. In some severe cases of ES, a splenectomy may also be suggested if medication alone is not enough.⁷ Ongoing monitoring and working closely with the healthcare team are important to find the right treatment for each individual.
Prognosis and Outcomes

Evans syndrome can lead to serious complications, such as bleeding and infections. However, when treatment is provided, patients often respond well, making symptoms more manageable. The condition often includes periods of remission and flare-ups, when symptoms can be mild to more severe.⁷ The increased likelihood of developing additional autoimmune disorders, such as SLE, can also impact a patient's long-term health.²

This highlights the importance of early diagnosis as well as having a knowledgeable, multidisciplinary healthcare team. Such an approach is essential, not only for treating and managing primary ES, but also secondary ES, addressing any underlying autoimmune conditions. 

Summary 

Evans syndrome is a complex autoimmune disorder that shares immune pathways with conditions like lupus and common variable immunodeficiency. The unpredictable nature of the syndrome and its risk of relapse or flare-ups create difficulties and highlight the significance of early diagnoses and a multidisciplinary approach for treatment and management of the cytopenias and any additional autoimmune conditions. Continued research into the causes and treatments for ES offers hope for even better outcomes in the future.