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Dr. Rasyidah Hasan Harahap dr. Savita Handayani,SpPD dr. Savita Handayani, SpPD
Evans Syndrome
Rasyidah Hasan Harahap, Senior Tawarta Keliat, Andri Iskandar Mardia,
Henny Syahrini Lubis, Savita Handayani, Dairion Gatot
Division Of Hematology & Oncology, Department Of Internal Medicine,
Unversity of North Sumatera / H. Adam Malik Central Hospital
1. INTRODUCTION
Evans syndrome (ES) is an uncommon autoimmune disease that was defined by
Robert Evans in 1951 when he studied the relationship between autoimmune hemolytic
anemia (AIHA) and immune thrombocytopenic purpura (ITP). He described the first
diagnosis criteria of ES, including the presence of anemia, reticulocytosis, increased
blood bilirubin and fecal urobilinogen, no family history of hemolytic diseases,
evidence of antibodies against erythrocytes at 37°C, hemolysis of transfused
erythrocytes, the presence of purpura, prolonged bleeding time, bone marrow aspiration
with normal or increased number of megakaryocytes and the absence of exogenous
toxic agents or a baseline disease. Evans divided five groups of patients and
demonstrated the presence of a serum agglutinating factor in patients with ITP1 based
on previously reported observations in guinea pigs and rabbits.2 Some authors modified
the definition of Evans as a destruction of at least two hematological blood lineages, as
observed in patients with neutropenia, hemolytic anemia and thrombocytopenia.3,4
Importantly, AIHA is a complex syndrome with a warm, cold,mixed and biphasic
thermal behavior of antibodies, but only warm ones characterize ES (Perez et al, 2018).
Evans syndrome is a rare diagnosis although the exact frequency is unknown. A
review of adult patients with immunocytopenias from 1950 to 1958 included 399 cases
of AIHA and 367 cases of thrombocytopenia; only six of these 766 patients had Evans
1
syndrome (Norton, 2005). In the United States, Evans syndrome is uncommon but not
rare; its exact frequency is unknown. Familial occurence is rare. In a report from
Malaysia, ES was diagnosed in 12 of 220 adults patients with immune
trhrombocytopenia and 102 with AIHA. Evans syndrome occurs in individuals of all
ages. In a 1997 survey of North American pediatric hematologist, the median reported
age at diagnosis was 7.7 years (range 0.2-26.6 years). This late presentation age may
indicate that the disease was undiagnosed until the second presentation of cytopenia,
which usually occured months to years after the first presentation. Evans syndrome in
adults has been anecdotally reported. No sexual predilection is known in Evans
syndrome. AIHA affects boys more frequently than girls, in ratio of 1.4:1. Among
adults, however, AIHA affect women more often than men. In a study by genty et al,
67% of cases occured in woman (Mathew, 2016)(Ng SC, 1992).
2. CASE REPORT
A 27-years-old female presented with progressive pallor, mild jaundice, passage
of tea-coloured urine and generalized weakness. She had all of this symptoms since a
month ago. In the last two weeks reddish spot appear on the legs and there is no others
bleeding history. Fever history was unclear. There was no history of chronic contact
with chemical material and family history of immune disorders.
The typical course of ES is characterized by an heterogeneous chronic disease
with clinical variability at onset, spontaneous remissions and exacerbations (Jamie,
2015). Its worldwide frequency is unknown; however, research of ES in AIHA is
available in some cohorts that report an incidence of about37%–73% in this setting.6,7
A higher rate in female gender has been reported in 60%–70% of ES patients.5,8 (Perez
et al,2018)
Several authors have proposed different disease pathways, summarized by the
presence of immune dysregulation with antibodies against erythrocytes, platelets and/or
granulocytes17 and decreased CD4:CD8 ratio. The pathophysiology of ES remains
unknown. Deficiency of CTLA-4 (CD152) and LRBA, Deficit of tripeptidyl peptidase
2(TPP2),decreased CD4/CD8 ratio are theoretically extrapolated to the disease (Perez,
2018).
2
On physical examination, she was found severely pale, subfebrile, tachycardia
with moderate volume pressure, tachypnea, but her blood pressure was found normal
and stable, yellowish icteric, jaundice, spenomegaly matched to schuffner II, pale and
cold on extremities, ptechiae on both lower extremities, markly on the site of blood
puncture. No lymphadenopathy was found. Also there was no blood or black stool on
digital rectal examination.
Complete blood examination detected severe anemia (hemoglobin 4 g/dL) with
MCV 99 fl; MCH 31,6 pg; MCHC 31,9 g%, low erythrocyte count (1,3 x 106 /mm3),
leucocytosis (16.780/mm3) with normal differential count, reduced platelet count
(13.000/mm3). Peripheral blood morphology revealed revealed a polychromatic anemia,
anisocytosis, with trombocytopenia. Hemostatic panel in normal value. Fibrinogen in
normal level (280 mg/dL) with D-Dimer was highly increased (9987 ng/mL). there is no
lengthening of bleeding time. Other laboratory finding include high level of LDH (1696
IU/L), albumin 2,0, Bilirubin indirect increased (Bilirubin total 2,4; indirect 1,8; SGOT
15 U/L ; SGPT 16 U/L), ALP 31 U/L. Iron profiles showed an increased of ferritin (
1406 ng/mL ; SI 46 mg/mL ; TIBC 255 µg/mL) with increased of reticulocyte count (17
%). Renal function test and electrolyte was found at normal range at that time.
The diagnosis of Evans syndrome was made after laboratory finding detected a
positive direct anti-globulin tes (coomb’s test) and after excluding other possible
etiologies such as systemic lupus erythemtosus (SLE) ANA test : 16,8 (negative) ; Viral
Marker : HBsAg (-) ; Anti HCV (-) ; IgM Anti HAV (-), and peripheral blood
examination of malaria was negative. Chest X-ray was normal while ultrasonogram of
whole abdomen revealed splenomegaly without focal lession and congestion. From
bone marrow aspiration, increased number of megakaryocytes in whole field of view.
As the treatment for this patient, we started an intravenous injection of
methylprednisolon 250 mg bid for three days, and as it’s dose reduced to 125 mg bid on
fourth day, mycophenolate mofetil 500mg bid were the added on seventh day.
Supportive medication were given as transfussion with washed red blood cells.
After several days of treatment, the patients’s clinical conditon seen improve.
Tachycardi, tahcypnoe, icteric, jaundice and weakness slowly disappear and discharge
from hospital after 14 days of hospitalization.
3
3. DISCUSSION
Evans syndrome is an uncommon condition defined by the combination (either
simultaneously or sequentially) of immune thrombocytopenia (ITP) and autoimmune
haemolytic anaemia (AIHA) with a positive direct antiglobulin test (DAT) in the
absence of known underlying aetiology. This condition generally runs a chronic course
and is characterised by frequent exacerbations and remissions (Norton, 2005).
The typical course of ES is characterized by an heterogeneous chronic disease
with clinical variability at onset, spontaneous remissions and exacerbations (Jamie et
al,2015). Its worldwide frequency is unknown; however, research of ES in AIHA is
available in some cohorts that report an incidence of about 37%–73% in this setting
(Aladjidi, 2011). A higher rate in female gender has been reported in 60%–70% of ES
patients (Bernard, 2018) (Perez et al,2018)(Dhingra, 2008).
For diagnose, an exhaustive clinical history must be taken to determine the risk
factors for developing ES, such as infections, malignancies, autoimmune diseases,
recent vaccinations, drugs or a family history of immune disorders (Norton 2005),
complemented with a thorough physical examination focused on signs of anemia or
thrombocytopenia. It is important to mention that primary ES is a diagnosis of exclusion
and secondary ES must be searched for to determine a baseline disease because
treatment and responses considerably differ between primary and secondary ES (Perez,
2018).Clinical presentation includes the usual features of haemolytic anaemia: pallor,
lethargy, jaundice, heart failure in severe cases; and thrombocytopenia: petechiae,
bruising, mucocutaneous bleeding. Examination may reveal lymphadenopathy,
hepatomegaly and/or splenomegaly (Teachey et al, 2005). The lymphadenopathy and
organomegaly may be chronic or intermittent and in some cases may only be apparent
during episodes of acute exacerbation (Norton, 2005).
In this case, hemolytic anemia and thrombocytopenia were came
simultaneously. Clinical presentation of anemia an trombositopenia such as general
weakness, tea-coloured urine, ptechiae, icteric, splenomegaly, pale, met the clinical
criteria of Evan syndrome. Characterization of laboratory features requires a complete
blood count and direct examination of peripheral blood; anemia, thrombocytopenia,
reticulocytosis, poikilocytosis, mainly due to the presence of spherocytes, increased
indirect bilirubin and lactate dehydrogenase and a positive direct anti-human globulin
4
test (DAT) test confirming ongoing immune hemolysis are to be expected (Dhingra,
2008)(Miano, 2016). Additional studies can include the detection of antibodies against
platelets (PA-IgG), documented in 35% of individuals, mostly type anti-IIb-IIIa.9 Anti-
granulocyte antibodiescan be detected in some patients, but a lack of these antibodies
does not exclude neutrophil involvement. Other antibodies must be considered to
identify main autoimmune diseases associated with ES. The main laboratory and
diagnostic work up is shown in Figure 1 (Perez 2018).
5
syndrome subsequently determined by positive result of coomb’s test and after having
excluded other possible causes like systemic lupus erythematosis, malaria, viral
infection, malignancies, etc. Unfortunately, we did not performe several important
laboratory examination such total immunoglobulins which could have made a better
diagnosis due to limitation of our facilities. Bone marrow study in this case showed
increased number of megakaryocytes in whole field of view.
The management of Evans syndrome remains a challenge. The syndrome is
characterised by periods of remission and exacerbation and response to treatment varies
even within the same individual (Norton, 2005). There are no clinical trials available for
ES treatment and indications for starting therapy have not been established by evidence-
based studies. Few retrospective reports and small cohorts have documented responses
which are summarized in Table 1. It is reasonable to treat patients with clinically
significant decreased platelet and hemoglobin levels; nevertheless, as observed in ITP,
the decision to start therapy in non-symptomatic patients varies in each case depending
on physician experience.11 (Perez, 2018)(Norton, 2005).
First-line treatments
Steroids. It is postulated that steroids inhibit the ability of macrophages for clearing
platelets and erythrocytes.86 Prednisolone or prednisone at 1–2 mg/kg/day (must be
administrated in all cases, and in patients with severe clinical manifestations, an initial
dose of 4–6 mg/kg/day within the first 72 hours is recommended Norton, 2005)(Miano,
2016)(Perez, 2018). The initial response rate documented for patients who receive
steroids at 1–2 mg/kg/day is about 82%–83%. A regimen including a prednisolone
megadose of 30 mg/kg/day for 3 days, then 20 mg/kg/day for 4 days, followed by
progressive tapering to 10, 5, 2, 1 mg/kg/ week has been administered and most patients
have shown complete response. Three weeks after starting treatment patients need a re-
evaluation; if complete response is achieved, slow tapering within 6 months is necessary
to avoid adverse effects (Perez, 2018). In patients with a partial response, the initial
dose of prednisolone must continue for two more consecutive weeks.11 If no response
is achieved, it is mandatory to start second-line therapy(Miano, 2016)(Perez, 2018). A
loss of response is mainly associated with tapering the steroid dose or viral infections.6
IVIG may be added if ITP is prevalent.87 In cases where thrombocytopenia
6
predominates, the presence of hepatomegaly has beenmrelated to a good response
(Perez, 2018).
Intravenous immunoglobulin. Concentrated IgG from human plasma donors acts by
blocking the FC receptor on the macrophages,89 which remains a controversial therapy.
In some centers, it is recommended as a first-line treatment together with steroids, and
in others as a complementary drug in severe thrombocytopenic patients (Perez, 2018).
Table 1 Second-line therapeutic options for patients with Evans syndrome (Perez, 2018)
Abbreviations: AIHA, autoimmune hemolytic anemia; b.d., twice daily; CR, complete
response; ES, Evans syndrome; ITP, immune thrombocytopenic purpura; IV, intravenous; N/A,
not available; NR, no response; PR, partial response.
Second-line treatment
Rituximab Rituximab is a chimeric anti-CD20 targeted drug that has been increasingly
used as the second-line treatment in steroidrefractory or relapsing ES. It has an
immunosuppressive effect with B-cell depletion in peripheral blood after one infusion.
7
Previous study reported the outcome of six patients with ES treated at our institution,
four women and two men with an age range of 10–42 years. Three received steroids as
the first-line treatment and low doses of rituximab, 100 mg/week/4 weeks, as the
second-line treatment with a good clinical response; after second relapse,however, two
patients required splenectomy (Perez, 2018).
Mycophenolate mofetil The 2-morpholinoethyl ester of mycophenolic acid is a
selective, competitive immunosuppressant prodrug that reduces lymphocyte
proliferation by inhibition of inosine monophosphate dehydrogenase.107 Some authors
have shown its efficacy in autoimmune cytopenias.12,107 Both patients received MMF
at 50 mg/kg/day, while the second patient also received cyclosporine (Perez, 2018).
Cyclosporine. Cyclosporine has been used in small series of patients with ES since
1994. It is an immunosuppressive drug whose mechanism of action is that it inhibits the
activation of T-cells.. If administered, continuous monitoring of serum concentrations of
cyclosporine is mandatory due to the severe adverse effects associated with its
administration, including malignancy and nephrotoxicity, which have been observed
after administration of low doses of cyclosporine (6 mg/kg/day) after 20 years of
treatment (Perez, 2018).
Splenectomy Splenectomy was the only option in refractory relapsing patients before
the introduction of rituximab, being classically considered as a second-line treatment in
patients with autoimmune cytopenias, achieving a response of 60%–75% in AIHA and
ITP,101 while in ES, the responses are documented to be considerably heterogeneous,
between 0% and 66% (Perez, 2018) (Duperier, 2003)(Li, 2014). Recently, splenectomy
has been replaced by rituximab due to the risks of the surgical procedure. It is important
to mention that in children <6 years of age, it is not a recommended option because of a
higher risk of septicemia/ meningitis with S. pneumoniae, Neisseria meningitidis or
Haemophilus influenzae with both classic and laparoscopic techniques (Perez, 2018)
(Leone, 2015). Also, splenectomy is contraindicated in patients with ALPS due to an
elevated risk of sepsis and recurrent multilineage cytopenias (Perez, 2018)(Price, 2010).
Third-line treatments
Cyclophosphamide Cyclophosphamide is a powerful alkylating agent with antimitotic
and immunomodulatory effects, is used in cancer and autoimmune diseases. It is able to
suppress an ongoing immune response. Current results suggest that cyclophosphamide
8
can induce remission in ES patients and it could be administered as a third–fourth-line
option in refractory cases (Perez, 2018).
Alemtuzumab. A humanized monoclonal antibody against CD52 has recently been
tested for AIHA and ITP and was found to show a good response. This antibody exerts
its action through depleting lymphocytes; recently, we studied this therapeutic option in
refractory ITP and AIHA at 10 mg on days 1 and 3 administered subcutaneously in
combination with subcutaneous rituximab at 100 mg/week/month, and the response was
100% (Perez, 2018).
Thrombopoietin-receptor agonists. Second generation of thrombopoietin receptor
agonists, romiplostim and eltrombopag, had a potential effect stimulating
thrombopoiesis as observed in ITP, and recently in ES, as documented in a patient
refractory to steroids, splenectomy, IVIG and rituximab who received eltrombopag,
romiplostim plus steroids with a duration of remission of 40 days at the last follow-up,
suggesting that the combination of drugs (Perez, 2018).
Hematopoietic stem cell transplantation. Scarce reports have documented the use of
stem cell transplantation in ES. The main benefit of allogeneic HSCT is that it currently
constitutes the only curative treatment option for ES by resetting the immune
system;138 thus, this therapy could be a valuable alternative for patients with multiple
relapses,with severe complications affecting their quality of life and/or if a lack of
response to immunosuppressive drugs exists (Perez, 2018).
For this patient, we started an intravenous injection of methylprednisolon 250
mg bid for three days, and as it’s dose reduced to 125 mg bid on fourth day,
mycophenolate mofetil 500mg bid were the added in seventh day. Supportive
medication were given as transfussion with washed red blood cells. After several days
of treatment, the patients’s clinical conditon seen improve. Tachycardi, tahcypnoe,
icteric, jaundice and weakness slowly disappear and discharge from hospital after 14
days of hospitalization.
9
Figure 1 Management of Evans syndrome: a sequential approach. (Norton, 2005)
*Multiagent therapy: steroids/IVIG/vincristine/danazol/ciclosporin (Scaradavou & Bussel,
1995); vincristine/methylprednisolone/cyclosporin.
4. CONCLUSION
ES is a rare disease with a heterogeneous course characterized by multiple relapses
during lifetime, despite multimodal treatment. A combination of genetic and epigenetic
factors appears to be involved in its pathogenesis, and the knowledge of its precise
etiology will help to design specific targeted therapies with less-severe adverse effects,
significantly improving patients quality of life.
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