Continuing Education Activity

Evans syndrome is an autoimmune condition that presents with two or more cytopenias, which commonly include autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP), with or without immune neutropenia. This activity reviews the presentation, evaluation, and management of Evans syndrome and stresses the role of an interprofessional team approach to the care of affected patients.

Objectives:

• Describe the pathogenesis of Evans syndrome.
• Summarize the characteristics of Evans syndrome that differentiate it from other causes of anemia.
• Review the management of Evans syndrome.
• Explain a structured interprofessional team approach to provide effective care to and appropriate surveillance of patients with Evans syndrome.

Introduction

Evans syndrome is an autoimmune condition that presents with two or more cytopenias, which commonly includes autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP), with or without immune neutropenia (only in 15% of cases, according to a report) [1]. The type of AIHA that presents in Evans syndrome is warm AIHA, in which IgG antibodies react with red blood cell (RBC) surface antigens at body temperature, as opposed to cold AIHA. In ITP, the immune system is directed against GPIIb/IIIa on the platelets. 

Recently, a proposition has been laid out to classify the condition as primary (idiopathic) or secondary (associated with an underlying disorder) [1]. Secondary Evans syndrome has been associated with diseases such as systemic lupus erythematosus (SLE), common variable immunodeficiency (CVID), and autoimmune lymphoproliferative syndrome (ALPS) in [2] Non-Hodgkin lymphoma (NHL) in patients older than 50 years, chronic lymphocytic leukemia (CLL), viral infections (such as HIV, hepatitis C) and following allogeneic hematopoietic cell transplantation. Identifying Evans syndrome as secondary when associated with a disease is important because cytopenias have been observed to be more severe when with Evans syndrome in contrast to when presenting alone as AIHA or ITP. Also, the treatment options differ according to the classification.

Etiology

The exact cause of this condition is unknown, which is why it is usually considered an idiopathic condition. It is an autoimmune disease in which B cells produce auto-antibodies that attack own cells, in this case, red blood cells, platelets, and white blood cells. More recently, there has been speculation that the condition is likely a result of excessive immune dysregulation.

Epidemiology

Evans syndrome is rare, diagnosed in less than 5% of all patients with either ITP or AIHA at the onset. The mean age at the time of diagnosis is 52 years, and like most other autoimmune conditions, it is more prevalent in females; the sex ratio is 3:2 in females to males.[1] Although usually considered a disease of children, adults are also be affected by Evans syndrome. It is generally a sporadic condition, and there are no genes identified to associate with the condition. It can rarely be inherited when it is called "familial Evans syndrome." Some of these cases have been reported to co-occur with other disorders, such as heart defects, [3] or with inherited disorders such as hereditary spastic paraplegia.[4]

Pathophysiology

Presentations of Evans syndrome can vary, being self-controlled in some cases and relapsing-remitting in others. Many cases respond to treatment transiently, but relapses are very common.

History and Physical

Signs and symptoms of Evans syndrome are variable and depend on the type of blood cell lines that are affected. In the presence of AIHA, they can present with fatigue, pallor, dizziness, shortness of breath, and limitation of physical activity. Physical examination usually shows pallor and jaundice. The spleen can be enlarged. Easy bruising or bleeding on minor injuries, petechiae, and purpura occur in those with ITP and recurrent infections in those with neutropenia.

ITP in Evans syndrome, in some cases, has been reported to be severe enough to lead to a life-threatening hemorrhage.[1] There have been cases of increased risk of ischemic complications such as events related to acute coronary syndrome or cerebrovascular events secondary to AIHA, frequently in those older than 60 years.[1]

Evaluation

Once anemia is diagnosed on complete blood count and differential, if Evans syndrome is suspected, further workup such as levels of lactate dehydrogenase, haptoglobin, bilirubin, and the reticulocyte count is usually required to evaluate for hemolysis. Positive direct antiglobulin test (DAT) and spherocytes on peripheral smear further confirm warm AIHA. Evans syndrome is a diagnosis of exclusion. Therefore, ruling out common etiologies such as cold agglutinin disease, thrombotic thrombocytopenic purpura (TTP) through careful evaluation of the peripheral blood smear, infectious causes (such as HIV, Hepatitis C), other autoimmune conditions and malignancies are required before the diagnosis of Evans syndrome can be made.

There are no established guidelines regarding which tests should be performed in patients suspected to have secondary Evans syndrome to look for an underlying disease. However, with common disorders such as SLE, ALPS in young patients, a minimal workup to evaluate for malignancy, including a chest and abdominal computed tomography scan, should be performed.

Treatment / Management

Management of Evans syndrome is challenging as many patients are refractory to common treatments that work very well with isolated AIHA. Treatment depends on various factors, including the severity of the condition, presenting signs and symptoms, and patient co-morbidities. Symptomatic management such as transfusions is required in those with low blood counts presenting with symptoms secondary to anemia or bleeding in those with thrombocytopenia.

For definitive management, first-line treatment is usually corticosteroids or intravenous immunoglobulin (IVIG). Steroids are given at 1 to 2 mg/kg per day tapered over weeks in isolated ITP or over months when warm AIHA is present. In the presence of ITP, IVIG is used relatively more frequently compared with patients with isolated AIHA.

Although most patients have been observed to respond to corticosteroids initially, the duration of response can vary, and more than half relapse, making the use of additional or alternative treatment options imperative.[1]

Rituximab or splenectomy may be considered in those refractory to the standard treatment or if steroid-dependent (that is, at least prednisone greater than or equal to 15 mg required daily to prevent relapse). Again, the responses can be variable. Rituximab is usually preferred due to increased response and particularly when Evans syndrome is likely secondary to an underlying condition such as a malignancy or SLE, and also in those at increased risk of infections due to co-morbidities making it necessary to avoid splenectomy.[5] Its combined use with steroids has been reported to have remission rates as high as 76%, according to one study [6]. Splenectomy is becoming less frequent now, usually reserved for those refractory to medical treatment due to low response rates, higher relapse, and increased risk of increased sepsis. Danazol has frequently been used as a second-line treatment option, especially with its corticosteroid-sparing effects.[1]

Immunosuppressive drugs can be used in those unresponsive to corticosteroids or rituximab. Various immunosuppressants have been tried, but cyclosporin A [6] and mycophenolate mofetil [7] are the preferred ones due to their increased efficacy in autoimmune conditions. Others that have also been used include cyclophosphamide, [8] azathioprine [9], and sirolimus.[10] The choice of immunosuppressant is dependant on patient factors, co-morbidities, and disease severity. Hematopoietic stem cell transplant has been used very rarely as a last resort in those unresponsive to all medical treatments. Both autologous and allogeneic stem cell transplantation has been tried in a small number of patients, with mixed results.[9]

Differential Diagnosis

• Autoimmune lymphoproliferative syndrome (ALPS)
• Thrombotic thrombocytopenic purpura (TTP)
• Systemic lupus erythematosus (SLE)
• Antiphospholipid syndrome (APLA)
• Sjogren syndrome
• Common variable immunodeficiency (CVID)
• IgA deficiency
• Lymphomas
• Chronic lymphocytic leukemia (CLL)

Prognosis

Those with Evans syndrome mostly require some treatment. Even with treatment, responses can be variable, and relapses are common. They are more prone to developing other autoimmune disorders such as SLE [1]. According to a study done on patients with Evans syndrome, only 32% were in remission off treatment at a median follow-up of 4.8 years.[1]

Pearls and Other Issues

• Evans syndrome is an autoimmune condition that presents with two or more cytopenias, which commonly includes autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP), with or without immune neutropenia.
• It can be primary (or idiopathic) or secondary (i.e., associated with an underlying disorder). When secondary, it has been associated with diseases such as systemic lupus erythematosus (SLE), common variable immunodeficiency (CVID), and autoimmune lymphoproliferative syndrome (ALPS) in younger patients, non-Hodgkin lymphoma (NHL) in patients older than 50 years, and chronic lymphocytosis leukemia (CLL).
• Because it is an idiopathic condition, other common diagnoses should be ruled out before diagnosing the condition.
• Corticosteroids and IVIG are the first-line treatment options for Evans syndrome. Rituximab is the preferred second-line treatment. Other treatment options include splenectomy, danazol, and immunosuppressants.
• Even with treatment, responses can be variable, and relapses are common, commonly requiring multimodal management.

Enhancing Healthcare Team Outcomes

Evans syndrome is difficult to diagnose and manage; thus it is best treated by an interprofessional team that includes nurses and pharmacists. The condition is usually managed with corticosteroids and other immunosuppressive agents. However, the response is not predictable or consistent.

The outcomes for patients with Evans syndrome are guarded; those who respond to treatment have favorable outcomes.

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References

1.

Michel M, Chanet V, Dechartres A, Morin AS, Piette JC, Cirasino L, Emilia G, Zaja F, Ruggeri M, Andrès E, Bierling P, Godeau B, Rodeghiero F. The spectrum of Evans syndrome in adults: new insight into the disease based on the analysis of 68 cases. Blood. 2009 Oct 08;114(15):3167-72. [PubMed: 19638626]

2.

Seif AE, Manno CS, Sheen C, Grupp SA, Teachey DT. Identifying autoimmune lymphoproliferative syndrome in children with Evans syndrome: a multi-institutional study. Blood. 2010 Mar 18;115(11):2142-5. [PubMed: 20068224]

3.

Ahmed FE, Albakrah MS. Neonatal familial Evans syndrome associated with joint hypermobility and mitral valve regurgitation in three siblings in a Saudi Arab family. Ann Saudi Med. 2009 May-Jun;29(3):227-30. [PMC free article: PMC2813659] [PubMed: 19448367]

4.

Ahmed FE, Qureshi IM, Wooldridge MA, Pejaver RK. Hereditary spastic paraplegia and Evans's syndrome. Acta Paediatr. 1996 Jul;85(7):879-81. [PubMed: 8819560]

5.

Crowther M, Chan YL, Garbett IK, Lim W, Vickers MA, Crowther MA. Evidence-based focused review of the treatment of idiopathic warm immune hemolytic anemia in adults. Blood. 2011 Oct 13;118(15):4036-40. [PubMed: 21778343]

6.

Bader-Meunier B, Aladjidi N, Bellmann F, Monpoux F, Nelken B, Robert A, Armari-Alla C, Picard C, Ledeist F, Munzer M, Yacouben K, Bertrand Y, Pariente A, Chaussé A, Perel Y, Leverger G. Rituximab therapy for childhood Evans syndrome. Haematologica. 2007 Dec;92(12):1691-4. [PubMed: 18055994]

7.

Emilia G, Messora C, Longo G, Bertesi M. Long-term salvage treatment by cyclosporin in refractory autoimmune haematological disorders. Br J Haematol. 1996 May;93(2):341-4. [PubMed: 8639426]

8.

Kotb R, Pinganaud C, Trichet C, Lambotte O, Dreyfus M, Delfraissy JF, Tchernia G, Goujard C. Efficacy of mycophenolate mofetil in adult refractory auto-immune cytopenias: a single center preliminary study. Eur J Haematol. 2005 Jul;75(1):60-4. [PubMed: 15946312]

9.

Mathew P, Chen G, Wang W. Evans syndrome: results of a national survey. J Pediatr Hematol Oncol. 1997 Sep-Oct;19(5):433-7. [PubMed: 9329465]

10.

Chang DK, Yoo DH, Kim TH, Jun JB, Lee IH, Bae SC, Kim IS, Kim SY. Induction of remission with intravenous immunoglobulin and cyclophosphamide in steroid-resistant Evans' syndrome associated with dermatomyositis. Clin Rheumatol. 2001;20(1):63-6. [PubMed: 11254245]

Disclosure: Hira Shaikh declares no relevant financial relationships with ineligible companies.

Disclosure: Prerna Mewawalla declares no relevant financial relationships with ineligible companies.