Practice Essentials
Evans syndrome is the presence of simultaneous or sequential direct Coombs-positive autoimmune hemolytic anemia (AIHA) in conjunction with immune-mediated thrombocytopenia, with no known underlying etiology. [1, 2, 3]
Signs and symptoms
Manifestations of Evans syndrome may include the following, in descending order of frequency:
-
Thrombocytopenia
-
Anemia
-
Neutropenia
-
Pancytopenia
Signs of thrombocytopenia include purpura, petechiae, and ecchymoses. Signs of anemia include pallor, fatigue, and light-headedness. Jaundice may indicate hemolysis.
Potential complications of Evans syndrome include the following:
-
Hemorrhage with severe thrombocytopenia
-
Serious infection in patients with neutropenia
See Presentation for more detail.
Diagnosis
Laboratory studies that may be considered include the following:
-
Complete blood count (CBC)
-
Reticulocyte count
-
Coombs test (direct antiglobulin test)
-
Tests for antineutrophil, and antiplatelet antibodies
-
Lupus antibody (lupuslike inhibitor) and antinuclear antibody (ANA) tests
-
Measurement of serum immunoglobulins
-
Flow cytometry of blood samples
-
Gene mutation studies
Bone marrow aspiration helps reveal aplastic anemia or an infiltrative disorder. It is usually indicated for excluding infiltrative processes in patients who present with pancytopenia.
See Workup for more detail.
Management
Medical therapy is the mainstay of management. In patients admitted for severe anemia or thrombocytopenia, the following are indicated:
-
Stabilization of respiratory and cardiovascular functions
-
Transfusion of blood products, if needed
-
Pharmacologic therapy
Commonly used agents are as follows:
-
Prednisone (most commonly used first-line agent)
-
Intravenous immune globulin (IVIg; for those with persistent immune cytopenia and those who require prolonged or high doses of steroids)
Other pharmacologic therapies that have been tried include the following:
-
Alemtuzumab
-
Danazol
-
Cyclosporine
-
Azathioprine
-
Cyclophosphamide
-
Vincristine
-
6-mercaptopurine
-
Sirolimus
-
Mycophenolate mofetil
-
Bortezomib
-
Rituximab
Additional therapies have included the following:
-
Splenectomy (has no clearly established role in treatment but may be considered in refractory cases)
-
Autologous and allogeneic stem cell transplantation
See Treatment and Medication for more detail.
Background
Evans syndrome is the coexistence of simultaneous or sequential direct Coombs-positive autoimmune hemolytic anemia (AIHA) with immune-mediated thrombocytopenia. [4, 2, 3] In the initial description by Evans et al in 1951, [5] the anemia and thrombocytopenia varied with respect to time of onset, course, and duration. Spontaneous remission and exacerbation were common, and a few patients had neutropenia. [1]
Although Evans syndrome seems to be a disorder of immune regulation, the exact pathophysiology is unknown, and the underlying etiology is unclear. Autoantibodies targeting different antigenic determinants on red blood cells (RBCs) and platelets are assumed to cause isolated episodes of hemolytic anemia and thrombocytopenia, respectively. The typical clinical course is chronic and relapsing, and therapy is generally progressive and of poor outcome.
Pathophysiology
The exact pathophysiology of Evans syndrome is unknown, although the mechanism generally seems to be related to the one associated with autoimmune hemolytic anemia and immune thrombocytopenia. In these disorders, non–cross-reacting autoantibodies are directed against antigens specific to RBCs, platelets, or neutrophils. [6] Wang et al demonstrated decreased serum levels of immunoglobulin G (IgG), immunoglobulin M (IgM), and immunoglobulin A (IgA) in these patients. [7, 8] The cytopenias that occur with Evans syndrome may be related to T-cell abnormalities; decreases in helper T cells and increases in suppressor T cells were noted in these patients.
Savasan et al observed that more than half of the patients with Evans syndrome had evidence of lymphoid hyperactivity. [9] Teachey et al demonstrated that more than half (58%) of patients with Evans syndrome might have autoimmune lymphoproliferative syndrome (ALPS), a novel finding with potentially important therapeutic implications. [10] Several cases of Evans syndrome have also been reported in association with the group of lymphoproliferative disorders known as Castleman disease. [11, 12, 13, 14]
Programmed cell death (apoptosis) of activated lymphocytes is critical to immune homeostasis. The cell surface protein Fas (CD95) and its ligand play a pivotal role in regulating lymphocyte apoptosis, and defective expression of either Fas or Fas ligand results in marked overaccumulation of mature lymphocytes and autoimmune disease in mice. Some study results suggest that defective lymphocyte apoptosis caused by mutations of the FAS gene can result in severe ALPS in humans.
Teachey et al screened 12 children by using flow cytometry for CD4/CD8 (double-negative) T cells and using the definitive test for ALPS (ie, defective in vitro Fas-mediated apoptosis). [10] Six patients had elevated numbers of double-negative T cells and defective Fas-mediated apoptosis, and 1 had a borderline elevation; thus, 7 patients with Evans syndrome had evidence suggestive of ALPS, which, in turn, suggests that there may be some overlap between Evans syndrome and ALPS. This may explain the severe clinical course in some patients with Evans syndrome.
A study by Rivalta et al indicated that in children with Evans syndrome, the disorder is frequently the initial expression of an immunologic or rheumatologic disease. Out of 12 pediatric patients with Evans syndrome, five (42%) were found to have a primary immunodeficiency, including three with common variable immunodeficiency, one with ALPS, and one with Rubinstein-Taybi syndrome. Of the three patients (25%) with a rheumatologic disorder, two had systemic lupus erythematosus, and one had mixed connective tissue disease. [15]
Etiology
The etiology of Evans syndrome remains unknown. Autoantibodies are directed against antigens specific to RBCs, platelets, or neutrophils, but these autoantibodies do not cross-react.
Many patients have associated disorders (eg, systemic lupus erythematosus [SLE] and other autoimmune diseases, chronic lymphadenopathy, or hypogammaglobulinemia). [16, 17, 18] Acquired cytopenias occur in association with sex-linked agammaglobulinemia, common variable immunodeficiency, and IgA deficiency.
Evans syndrome has been diagnosed in a child with insulin-dependent diabetes mellitus, [19] in another after an autologous bone marrow transplant for recurrent Hodgkin disease, [20] and in a child with celiac disease. [21] Familial occurrences of Evans syndrome, though rare, have been previously described. [22, 23] Additionally, some overlap appears to exist between Evans syndrome and primary immunodeficiency syndromes associated with genetic mutations in the genes LRBA, CTLA4, PI3K, and STAT3. [6] As further understanding of the genetic landscape underlying immune dysregulation syndrome is achieved, we may better grasp the links between genetic mutations and the risk of developing Evans Syndrome.
Most patients with Evans syndrome have decreased levels of serum IgG, IgM, and IgA and decreased in vitro synthesis of IgG, IgM, or both.
Decreased helper T cell populations and increased suppressor T cell populations that are similar to levels found in congenital hypoplastic anemia and amegakaryocytic thrombocytopenia have been observed. This finding has led to speculation that the cytopenias in Evans syndrome may relate to T-cell abnormalities.
As noted (see Pathophysiology), numerous patients with Evans syndrome may have ALPS. [10]
The role of childhood immunizations in the development of Evans syndrome has been investigated, but no specific associations have been reported. However, case reports suggest that immunizations may trigger the development of this disease in susceptible individuals.
Epidemiology
United States statistics
In the United States, Evans syndrome is uncommon but not rare; its exact frequency is unknown. Pirofsky estimated the minimal annual incidence of immune hemolytic anemia to be 1 case per 80,000 US residents (mostly adults). [24] In a combined series of 1064 patients with childhood immune thrombocytopenia, only 9 had autoimmune hemolytic anemia associated with immune thrombocytopenia; however, thrombocytopenia occurs relatively often in patients with autoimmune hemolytic anemia. Frequencies of 1.6-59.4% have been reported in adults.
Pui et al first described 7 children with Evans syndrome out of 164 cases of immune thrombocytopenia and 15 cases of AIHA. [25] Habibi et al observed that 10 of 46 children with prolonged chronic AIHA had thrombocytopenia. [26]
International statistics
In a report from Malaysia by Ng, Evans syndrome was diagnosed in 12 of 220 adult patients with immune thrombocytopenia and 102 with AIHA. [27]
Age-related demographics
Evans syndrome occurs in individuals of all ages. In a 1997 survey of North American pediatric hematologists, the median reported age at diagnosis was 7.7 years (range, 0.2-26.6 years). [28] This late presentation age may indicate that the disease was undiagnosed until the second presentation of cytopenia, which usually occurred months to years after the first presentation.
Sexual differences in incidence
No sexual predilection is known in Evans syndrome. AIHA affects boys more frequently than girls, in a ratio of 1.4:1. Among adults, however, AIHA affects women more often than men. In a study by Genty et al, 67% of cases occurred in women. [29]
Racial differences in incidence
Of 42 patients reported in a national survey, 29 were white, 7 were black, and 6 had other racial backgrounds. [28] This distribution could suggest either a preponderance among whites or a reporting bias. As individual conditions, AIHA and immune thrombocytopenia have no racial predilection.
Prognosis
The characteristic clinical course of Evans syndrome includes periods of remission and exacerbation. Patients rarely do well without treatment, and responses to therapy are variable and often disappointing. On occasion, Evans syndrome can be fatal.
Recurrences of thrombocytopenia and anemia are common, as are episodes of hemorrhage and serious infections. In a national survey by Mathew et al, recurrences of thrombocytopenia were documented in 60% of Evans syndrome patients; the number of reported recurrent episodes was 1-20. [28] AIHA recurred in 31% of patients; the number of episodes ranged from 1 to 8. Neutropenia recurred in 15% of patients.
Treatment occasionally provides complete resolution. In a median follow-up study of 42 patients (age, 4 months to 18.9 years) that spanned 3 years, 3 patients (7%) had died, 20 (48%) had active disease and remained on some treatment, and 5 (12%) had persistent disease but were not receiving any treatment. [28] The remaining 14 (33%) had no evidence of disease for 1.5 months to 5 years (median, 1 year).
In the national survey, each patient received a median of 5 (range, 1-12) treatment modalities, either in combination or sequentially. [28] Only 1 patient received no treatment; this patient’s hemoglobin levels were 9-13.2 g/dL and platelet counts were 9-208,000/µL during follow-up examinations over 11 years.
Long-term survival data are limited. In patients followed for a median range of 3-8 years, mortality ranged from 7-36%. [28] The main causes of death were hemorrhage and sepsis. None of these patients developed any malignancy.
Patient Education
Patients and their families must be educated about the chronic nature of Evans syndrome, which can include periods of remission and exacerbation. It is important that the clinician explain potential adverse effects of medications, especially long-term steroids, whenever a steroid is administered to treat an exacerbation.
