Primary Evans syndrome in an adult man

Abstract

Evans syndrome (ES) is a simultaneous or subsequent development of two haematological disorders, autoimmune haemolytic anaemia (AIHA) and immune thrombocytopenia (ITP). It can be primary (idiopathic) or secondary (associated with an underlying disease). Primary Evans is a diagnosis of exclusion and has a poorer prognosis than AIHA or ITP alone. We present a 55-year-old man who presented with weakness and lethargy and was diagnosed to be suffering from primary ES.

Background

Evans syndrome (ES) is a rare chronic, relapsing and remitting combination of two immune dysregulated haematological diseases—autoimmune haemolytic anaemia (AIHA) and immune thrombocytopenia (ITP).¹ There may be associated autoimmune neutropenia also. Direct anti-human globulin positivity is commonly seen with anti-immunoglobulin G (IgG) antisera in warm AIHA and anti-C3d in cold agglutinin disease. It may be secondary to some other associated condition or may be primary when there is no other underlying disease.^{2 3} Primary disease usually manifests in childhood but may be seen in adults also.^{4 5} We present a case of primary ES in a 55-year-old man who failed to respond to first-line and second-line therapy and required splenectomy for maintenance of cells counts.

Case presentation

A 55-year-old man presented to us with generalised weakness and lethargy for the past 1 month. He was detected to have anaemia and thrombocytopenia. He did not have any bleeding manifestations. There was no history of photosensitivity, alopecia, joint pains, oral ulcers, easy bruising or any other systemic symptoms. There was no history of fever, vomiting or diarrhoea. There was no history of intake of any drug prior to onset of disease. He had significant pallor but no lymphadenopathy or organomegaly.

Investigations

His investigations at the time of presentation showed severe anaemia with haemoglobin 46 g/L, mean corpuscular volume 111.4 fL, mean corpuscular haemoglobin (MCH) 37.4 and MCH concentration 33.6 g/dL. Corrected reticulocyte count was 10% with absolute reticulocyte count of 126 000/mm^3. Peripheral blood smear showed predominantly macrocytic and normochromic cells, moderate anisopoikilocytosis in the form of macro-ovalocytes, microcytes, elliptical cells and tear drop cells. Platelet count was 6×10⁹/L and total leucocyte count was 5500 mm³. Direct antiglobulin test (DAT) for IgG was positive. Lactate dehydrogenase was 623 IU/L. Liver functions showed: total bilirubin as 1.2 mg/dL with indirect bilirubin 0.70 mg/dL, aspartate aminotransferase 38 IU/L, alanine aminotransferase 24 IU/L and serum protein 6.45 g/dL. Renal function tests were normal. Coagulation profile was normal. His serum iron and vitamin B₁₂ were within normal limits. Bone marrow smear and biopsy showed normal cellularity with predominantly normoblastic erythropoiesis and normal thrombopoiesis and myeloid cell lineage. His viral markers (for hepatitis B and C and for HIV) were negative and thyroid functions were normal. Antinuclear antibody, rheumatoid factor and lupus anticoagulant test were negative. Anticitrullinated protein antibodies and M components were not done as patient could not afford. Chest X-ray and ultrasound of the abdomen were unremarkable and there was no hepatosplenomegaly. Urine microscopic examination was also normal without any evidence of haemoglobinuria.

Differential diagnosis

As the index patient had DAT positivity along with haemolytic anaemia so was diagnosed as AIHA. Along with AIHA, the patient had severe thrombocytopenia in peripheral smear with a reactive bone marrow. Conditions that cause concurrent haemolytic anaemia and thrombocytopenia can be classified into non-immune and immune conditions. Various non-immune causes are haemolytic uraemic syndrome (HUS), acquired thrombotic thrombocytopenic purpura (TTP) and Kasabach-Merritt syndrome (KMS).⁶ In HUS, there is a history of vomiting, diarrhoea and fever and is accompanied by acute renal failure and negative Coombs Test. TTP also has negative DAT and is associated with neurological and renal impairment. KMS is associated with giant haemangiomas. Paroxysmal nocturnal haemoglobinuria (PNH), Zieve’s syndrome and haemophagocytic lymphohistiocytosis usually cause haemolytic anaemia but occasionally may have thrombocytopenia but DAT is negative. A patient with PNH in the absence of aplastic anaemia may present with thrombosis or anaemia.⁷ Glucose-6-phosphate dehydrogenase deficiency can also cause non-immune haemolytic anaemia. Vitamin B₁₂ deficiency may show non-immune haemolysis in addition to megaloblastic anaemia. A combined immune cytopenia can also be caused by systemic lupus erythematosus, antiphospholipid syndrome, AIDS and common variable immunodeficiency.^{1 5 8} The absence of ANA and lupus anticoagulant antibody, viral markers and a history of recurrent infections ruled out these diseases. Paroxysmal cold haemoglobinuria also shows AIHA and thrombocytopenia but immunopositivity to anti-C3d is seen. We considered a possibility of ES after exclusion of other disorders based on clinical features and investigations. ES-like disease may also be secondary to lymphoproliferative diseases (absence of B symptoms, with no lymphadenopathy, changes in peripheral smear and bone marrow of lymphoproliferative changes), multicentric Castleman’s disease, solid organ malignancy and inflammatory bowel disease, post interleukin-2 therapy for renal cell carcinoma or following autologous or allogeneic stem cell transplantation.^{5 8} After excluding all of these underlying diseases, a diagnosis of primary ES was made.

Treatment

The patient was transfused multiple units of both packed red blood cells (RBCs) and platelets during the course of treatment. Blood was transfused after being washed and careful cross matching and premedication with pheniramine maleate. Maximum blood transfused was 1 mL/kg/hour. While the haemoglobin level improved, platelet count never increased beyond 8000 mm³.

Therefore, he was given pulse methylprednisolone (1 g for 3 days) followed by oral prednisolone, but there was no improvement in the platelet counts even after 3 weeks. Subsequently, he was infused four cycles of rituximab (375 mg/m² weekly), but he still failed to respond even after 4 months. We then had to perform splenectomy, which led to improvement in platelets to 25 000 mm³ after 7 days of splenectomy. The patient was maintained on 50 mg two times per day azathioprine for 2 months to suppress the peripheral circulating immunoglobulins.

Outcome and follow-up

Platelet count increased to 25 000 mm³ 7 days after splenectomy and further increased after 1 month to 49 000 mm³. Haemoglobin also improved to 8.3 g/dL within 1 month post splenectomy. The patient is maintained on prophylactic antibiotics post splenectomy and is on regular follow-up.

Discussion

ES is an uncommon chronic relapsing haematologic disorder characterised by the sequential or simultaneous development of AIHA, ITP and/or immune neutropenia. It was first described by Robert Evans in 1951.¹ Incidence of ES was 1.84 cases per million with a prevalence of 21.30 per million as observed in 2016.⁵ Among isolated autoimmune cytopenia ES represents 0.3%–7% of AIHA and 2%–2.7% of ITP.¹ It can be classified into primary or idiopathic type and secondary type when it is associated with some underlying disease. Primary ES is a diagnosis of exclusion. Neutropenia occurs in up to 18%–20% of patients at presentation.⁸ Development of second cytopenia may occur months to years after first immune cytopenia and may lead to a delay in the diagnosis.¹ ITP is suspected in rapidly evolving thrombocytopenia with no underlying hepatic, splenic, drug-related or haematological malignancy. Clinically, ES presents with features of either haemolytic anaemia, thrombocytopenia or with both.

Secondary ES is associated with an autoimmune, infectious or lymphoproliferative disease, vaccination, drugs or immunodeficiency disorder. Almost half the cases of ES have been observed to be secondary to some underlying cause.¹

In ES, there are abnormalities in both cellular and humoral immunity.⁹ IgG (warm AIHA) autoantibodies seen in ES fix the complement system and cause RBC destruction via the antibody-dependent cellular cytotoxicity (ADCC) which are phagocytosed by monocyte–macrophage leading to extravascular haemolysis in spleen (warm AIHA) or liver in the case of C3b-mediated ADCC. Genetic mutations (TNFRSF6, CTLA4, STAT3, PIK3CD, CBL, ADAR1, LRBA, RAG1 and KRAS) may predispose to paediatric ES. In AIHA, destruction of RBCs is through T helper 2 (Th2) humoral response which increases antibody-mediated mechanism of RBC destruction. There is reduced interferon-γ levels also which further increases Th2 response. There is increased cellular immunity also (cytotoxic CD8+ T lymphocytes, natural killer cells and activated macrophages). Increased Th1 activity further boosts the cellular immunity. Transforming growth factor-β elevation in ES leads to Th17 differentiation which amplifies the proinflammatory and autoimmune responses. A reduced pool of T regulatory cells further leads to increased autoimmune response.⁹ In ES, ITP occurs due to antibodies against glycoproteins (GPs) produced by platelets, especially GP IIb/IIIa. This leads to premature destruction of platelets.

A complete blood count should be obtained with peripheral blood film examination for features of AIHA (polychromasia, spherocytes). Haemoglobin at time of presentation is the most important prognostic indicator of AIHA in ES. Features of haemolysis should be sought including a raised reticulocyte count, unconjugated hyperbilirubinemia and decreased haptoglobins.⁷ Reticulocyte count is a marker of bone marrow activity, so absolute reticulocyte count and Bone Marrow Responsiveness Index (BMRI) should be calculated. BMRI<121 signifies reticulocytopenia which is a poor prognostic indicator.¹⁰ DAT is commonly positive in AIHA but may be occasionally negative.¹ The indirect antiglobulin test may also be positive.

Prognosis and treatment of primary and secondary ES is different. So, before establishing a diagnosis of primary ES secondary ES should be ruled out. Major causes of death are bleeding, infections and haematological malignancies.⁵ Median survival of ES is comparable to AIHA but is lower than ITP and general population. Mortality is maximum in first year of diagnosis of disease.^{2 5 8}

Prednisolone in a dosage of 1 mg/kg/day is the first line of treatment. Tapering should be started after 14–21 days. Steroids should then be gradually tapered and stopped over a period of about 4–6 months. For patients unresponsive to first-line therapy, early relapsed or requiring inacceptable high doses (more than 10–15 mg prednisone per day), second-line therapy is indicated. Rituximab in a dose of 375 mg/m² weekly for 4 consecutive weeks is the second line of treatment. Median time to response is 4–6 weeks following the first dose, although responses after 3–4 months are not uncommon. Retreatment of relapsing patients can be done. Rituximab is a costly drug and patient at times is not able to afford it. Rituximab has been used as first-line drug.^{11 12} Other second-line options include splenectomy or alternative immunosuppression such as azathioprine, cyclosporine and mycophenolate. Approximately 70% respond and 40% achieve complete remission following splenectomy. Other drugs which can be considered are cyclophosphamide, continuous low-dose prednisone, danazol, haematopoietic stem cell transplantation and bortezomib.^{13 14} For patients in whom AIHA resolves and only platelet refractoriness remains (eg, in our patient), thrombopoietin analogues (romiplostim, eltrombopag, avatrombopag, etc) have mostly replaced splenectomy as the second-line therapy due to long-term complications of splenectomy.¹⁵ But these drugs are not readily available and are costly so we may have to perform splenectomy. Lifelong prophylactic folic acid supplementation is also required in ES.

Learning points.

• There are a number of non-immune and immune disorders which need to be excluded before making a diagnosis of Evans syndrome (ES). Further primary ES is diagnosed by exclusion of secondary ES.

• Steroids are the first line of treatment and have to be given for a long time.

• Rituximab has replaced splenectomy as second-line therapy.

• Patients with persistent thrombocytopenia can be given thrombopoietin analogues instead of doing splenectomy.

• Lifelong supplementation with folic acid should be given.

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