Evans Syndrome

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.

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]

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.

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.

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.

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.

In a national survey, thrombocytopenia was the presenting feature in 76% of patients with Evans syndrome, and anemia was the presenting feature in 67% of these patients.[28] In addition, 24% of patients had neutropenia, and 14% had pancytopenia.

Evans syndrome is a diagnosis of exclusion. Confounding disorders, such as infections, rheumatologic diseases, and malignancies, can present with autoimmune cytopenias and must be ruled out.

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 – The national survey reported hemorrhage in 29% of patients,[28] with 2 deaths resulting from severe GI bleeding and a third death from acute intracranial bleeding

• Serious infection in patients with neutropenia – The national survey showed invasive infections in 29% of patients, including pneumonia, sepsis, meningitis with Streptococcus pneumoniae, localized abscess, and osteomyelitis[28] ; one patient died of presumed sepsis and liver failure 9 years after splenectomy

Typical blood tests include a complete blood count (CBC), a reticulocyte count, examination of a blood smear, and the Coombs test (direct antiglobulin test). Additional studies that may be prudent are as follows:

• Measurement of serum immunoglobulins

• Serum markers for conditions such as systemic lupus erythematosus (SLE)

• Peripheral blood T-cell subsets using flow cytometry

• Bone marrow examination

In patients with Evans syndrome, the CBC and the reticulocyte count reveal anemia, thrombocytopenia, neutropenia, or combined cytopenias; the reticulocyte count increases if the patient has anemia. Features of hemolysis include a raised reticulocyte count, an increase in unconjugated bilirubin, and decreased haptoglobins.

Finding spherocytes on a blood smear in the presence of thrombocytopenia is a significant clue that an immune hemolytic anemia is ongoing, especially if the reticulocyte count is elevated. Moreover, the presence of large platelets on the smear may suggest an immune etiology to the thrombocytopenia, while, in the presence of cytopenia, blood smear examination could help to rule out malignant disease or suggest the presence of one.

In Evans syndrome, the Coombs test result (ie, direct antiglobulin test result) is almost invariably positive (often weakly) and may be positive for immunoglobulin G (IgG), complement, or both. Indirect antiglobulin test findings may also be positive in 52-83% of patients.

Various antibodies directed against red blood cells (RBCs), white blood cells (WBCs), and platelets (eg, antineutrophil, and antiplatelet antibodies) are noted in association with Evans syndrome.

In a study by Fagiolo that included 32 adults, as many as 91% had antiplatelet antibodies that were demonstrable by thromboagglutination and indirect antiglobulin consumption tests.[30] About 81% had leukocyte antibodies that were detectable by cytotoxicity testing. However, the intervals between the detection of antibodies and the demonstration of leukopenia or thrombocytopenia varied. No relation was established between the leukocyte antibodies and platelet antibodies (alone or in combination) and the type of RBC antibodies.

A subsequent study by Kakaiya et al reported that the antibodies directed against RBCs and platelets were different.[31] Pegels et al confirmed this finding: In absorption and elution experiments, they found that the autoantibodies were directed against specific antigens on RBCs, platelets, and WBCs and that the autoantibodies did not cross-react.[32] These findings raise questions about the clinical utility of these tests.

In a study by Pui et al, platelet antibodies were found in only 2 of 6 children tested.[25] Antineutrophil antibodies were positive in 3 of 4 patients with neutropenia. Therefore, positive antibody results are useful, but negative results provide little clinical information.

Lupus antibody (lupuslike inhibitor) and antinuclear antibody (ANA) tests are used to detect SLE. T-cell and B-cell function tests for quantitative immunoglobulins are performed to evaluate for hypogammaglobulinemia and perturbations in T-cell numbers. Flow cytometry of blood samples is indicated to look for double negatives. Gene mutation studies are used to detect known conditions such as autoimmune lymphoproliferative syndrome (ALPS).

Bone marrow aspiration helps to reveal aplastic anemia or an infiltrative disorder. It is usually indicated if reticulocytopenia is present or for excluding infiltrative processes in patients who present with pancytopenia. Bone marrow examination is usually not indicated in classic cases when patients present with autoimmune hemolytic anemia (AIHA) or immune thrombocytopenia.

Bone marrow studies may reveal erythroid hyperplasia and, occasionally, hypoplasia if AIHA is the predominant finding. Normal levels or increased numbers of megakaryocytes confirm that thrombocytopenia is caused by increased destruction in the blood.

Management of Evans syndrome is challenging. Although almost all patients require therapy at some time during the course of the disease, the search for a consistent, effective, and nontoxic therapy continues. Medical therapy is the mainstay of management. Response to therapy varies even within the same individual, and the disease is characterized by periods of remission and exacerbation. No randomized trials have been conducted in patients with Evans syndrome, and the evidence for treatment is based on case reports, case series, and retrospective studies.

Patients admitted for severe anemia or thrombocytopenia should have respiratory and cardiovascular functions stabilized first; should receive blood product transfusions, if needed, after consultation with a pediatric hematologist; and should then be started on therapy with steroids or intravenous (IV) immune globulin (IVIg).

A study by Fan et al indicated that while glucocorticoid therapy is effective against AIHA, patients with Evans syndrome require longer treatment than do those with AIHA alone.[33]

In classic cases (ie, presenting with either autoimmune hemolytic anemia [AIHA] or immune thrombocytopenia), bone marrow aspiration is not indicated. When a patient has pancytopenia at presentation or when the diagnosis of immune thrombocytopenia is unconfirmed, bone marrow examination may help exclude an infiltrative pathology or an aplastic marrow. Bone marrow examination may be indicated in unusual cases, in cases refractory to treatment, or in cases when a peripheral blood smear suggests immature myeloid cells.

Additional therapies include splenectomy, administration of immunomodulatory agents, and hematopoietic stem cell transplantation.[34] Autologous and allogeneic stem cell transplantation have been used in a small number of patients (14 patients aged 5-52 years), with mixed results.[35]

Prednisone (eg, 1-2 mg/kg divided 2 or 3 times daily) is the most commonly used first-line agent and often effectively controls acute episodes of Evans syndrome. Although some patients are successfully weaned off steroids, relapses may occur in other individuals when prednisone is tapered or stopped. Accordingly, an alternate-day steroid regimen is advised, if feasible.

Patients with persistent immune cytopenia and those who require prolonged or high doses of steroids may benefit from IVIg (eg, 1-2 g/kg/day for 1-2 days.[36, 37] Thrombocytopenia is more responsive to this therapy than is hemolysis. Long-term control of thrombocytopenia is reportedly achieved with interval doses of IVIg.

Other therapies reported to be effective in small series include treatments with the following immunomodulating agents[28] :

• Alemtuzumab

• Danazol

• Cyclosporine[38]

• Azathioprine

• Cyclophosphamide

• Vincristine

• 6-mercaptopurine

• Sirolimus

• Mycophenolate mofetil

• Bortezomib

• Rituximab

In one study,[28] where plasmapheresis was performed in 3 patients, 1 patient had transient responses, at best, to tacrolimus, protein A-Sepharose column plasmapheresis, whole-blood exchange transfusion, and total nodal irradiation. Another patient showed some response to treatment with a combination of Rh D immunoglobulin (anti-D), methotrexate, prednisone, and folic acid (responses to these agents varied).

Rituximab has shown varying results in refractory Evans syndrome.[39, 40, 41, 42, 43, 44, 45] At present, this agent seems to be used as a second-line therapy. Rituximab is approved for the treatment of relapsed and refractory B-cell non-Hodgkin lymphoma. Its binding to cells expressing CD20 results in cell death via a combination of mechanisms (eg, antibody-dependent cell cytotoxicity, complement activation, and apoptosis). Hence, it has been used to treat various autoimmune disorders mediated by autoantibodies.

Galor et al reported the successful use of rituximab in a patient with Evans syndrome.[39] Mantadakis et al reported the successful use of this agent in a patient with long-lasting Evans syndrome refractory to standard treatments; the patient responded well to rituximab and then responded again when relapse occurred 7 months later.[40] In contrast, Grossi et al treated 2 patients with rituximab without success.[46] In fact, the patients had a worsening of their anemia.

Zecca et al described the weekly use of rituximab in 5 children with Evans syndrome, all of whom were successfully treated.[41] In a retrospective review of patients at the Mayo Clinic, Shanafelt reported responses in one, but not both, of the cytopenias among 3 patients with Evans syndrome.[42]

A review by Norton and Roberts of the use of rituximab in 18 patients (age, 0.3-65 years) yielded encouraging results, with sustained complete remission lasting as long as 17 months.[47] In a pediatric prospective series by Rao et al, 2 patients with Evans syndrome were treated with rituximab; 1 had a partial response, and 1 had no response.[44] Complications associated with rituximab in these studies have been minimal; the most common is infusion-associated reaction.

A prospective study by Ducassou et al reported that in children treated with rituximab, those with isolated AIHA responded better than did those with AIHA associated with Evans syndrome. The rate of complete response to rituximab was 74% in children with isolated AIHA, compared with 40% in those with Evans syndrome, while the rates of 6-year relapse-free survival were 53% and 36%, respectively.[48]

Another agent that has been tried is alemtuzumab, a humanized immunoglobulin G (IgG) monoclonal antibody specific for the CD52 antigen present on T cells and B cells. Willis et al reported on the use of alemtuzumab in 3 patients with Evans syndrome; though a response was seen in 2 patients, both experienced relapses within 3 months.[49]

One pilot study showed that a multiagent approach may be effective in patients with Evans syndrome.[50] Transfusions of red blood cells (RBCs) and platelets were also used as adjuncts to treatment.

In a multicenter study of 156 children with Evans syndrome, Aladjidi et al found that at least one second-line immune treatment (eg, azathioprine, anti-D, cyclosporine, colchicine, hydroxychloroquine, mycophenolate mofetil, rituximab, thrombopoietin-receptor agonists, splenectomy) was needed in 108 cases (69%).[51]

Splenectomy does not have a clearly established role in the treatment of Evans syndrome, but it may be considered in refractory cases. Splenectomy may improve the CBC and reduce steroid dependence; however, relapses are common and, in most cases, occur within 1-2 months after the procedure.

According to a national survey, splenectomy provided a reported duration of response that ranged from 1 week to 5 years; however, the median response duration was just 1 month.[28]  A retrospective study by Sulpizio et al indicated that the 1-year remission rate following splenectomy is greater in patients with immune thrombocytopenia than in those with Evans syndrome. The investigators reported that the initial and 1-year response rates after splenectomy were 85.7% and 42.8%, respectively, in patients with Evans syndrome, compared with 90.9% and 70.1% in the immune thrombocytopenia cohort. Thus, the study found the 1-year postsplenectomy relapse rate in Evans syndrome to be 42.8%.[52]

The risk of postsplenectomy sepsis appears to be increased in children with Evans syndrome, especially those with pancytopenia. Prior to splenectomy, all patients should be immunized against S pneumoniae, Haemophilus influenzae type b, and Neisseria meningitidis. Additionally, postsplenectomy antibiotic prophylaxis may be indicated, potentially for the patient's lifetime.

Dietary restrictions are not usually required. Patients receiving steroid therapy should have some restrictions placed on their salt, sugar, and fluid intake to prevent excessive fluid retention.

Activities may have to be restricted depending on symptoms, the age of the patient, and the degree of thrombocytopenia and anemia.

The following consultations may be considered as appropriate:

• Pediatric hematologist

• Pediatric oncologist

• Rheumatologist

• Immunologist

A patient may be discharged if he or she is clinically stable (eg, if blood counts are rising). Weekly follow-up is recommended with blood counts and physical examinations until counts become stable or return to reference ranges. Subsequent follow-up care may be arranged at intervals of 2-4 weeks. More frequent follow-up care may be indicated for patients with clinical or laboratory signs of recurrence (eg, when steroids are tapered).

Prednisone, the most commonly used first-line agent for Evans syndrome, often effectively controls acute episodes, though relapses may be frequent when patients are weaned off prednisone. Intravenous immune globulin (IVIg) may help patients who depend on steroids.

Class Summary

Steroids are the usual initial therapy for Evans syndrome. They possess anti-inflammatory properties and cause profound and varied metabolic effects. They modify the immune response of the body to diverse stimuli.

Prednisone (Rayos)

Prednisone is a commonly used steroid that interferes with macrophage Fc gamma and C3b receptors responsible for destruction of red blood cells and platelets. It may work by decreasing abnormal immunoglobulin G (IgG) production that may be responsible for destruction of the cells. Prednisone can increase vascular stability and ameliorate endothelial abnormalities associated with thrombocytopenia; it also helps decrease clearance of opsonized platelets.

Class Summary

This is a purified preparation of gamma globulin. It is derived from large pools of human plasma and is composed of 4 subclasses of antibodies, approximating the distribution of human serum.

Immune globulin intravenous (Carimune NF, Bivigam, Hizentra, Gammagard, Octagam)

IVIg neutralizes circulating myelin antibodies through anti-idiotypic antibodies. It down-regulates proinflammatory cytokines (eg, interferon gamma), blocks Fc receptors on macrophages, suppresses inducer T and B cells, and augments suppressor T cells. IVIg also blocks the complement cascade and promotes remyelination. In addition, it may increase IgG in cerebrospinal fluid.