Excerpt from Evans Syndrome

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Background

In 1951, Evans and colleagues described a group of patients whose clinical course was characterized by immune thrombocytopenia and autoimmune hemolytic anemia (AIHA).¹ The anemia and thrombocytopenia varied in time of onset, course, and duration. Spontaneous remission and exacerbation were common, and a few patients had neutropenia.

Evans syndrome is the coexistence of simultaneous or sequential direct Coombs-positive AIHA in conjunction with immune-mediated thrombocytopenia, with no known underlying etiology. The typical clinical course is chronic and relapsing, and therapy is generally progressive and poor. Although Evans syndrome seems to be a disorder of immune regulation, the exact pathophysiology is unknown. Autoantibodies targeted at different antigenic determinants on red cells and platelets are assumed to cause isolated episodes of hemolytic anemia and thrombocytopenia, respectively.

Pathophysiology

The etiology of Evans syndrome is unknown. Noncrossreacting autoantibodies are directed against antigens specific to red cells, platelets, or neutrophils. Wang et al demonstrated decreased levels of serum immunoglobulin (Ig) G, IgM, and IgA in these patients.^{2, 3} The cytopenias that occur with Evans syndrome may be related to T-cell abnormalities because decreased T-helper cells and increased T-suppressor 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.⁴ Teachey et al demonstrated that numerous patients (58%) with Evans syndrome may have autoimmune lymphoproliferative syndrome, a novel finding that may have important therapeutic implications.⁵

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. The results of recent studies suggest that defective lymphocyte apoptosis caused by mutations of the Fas gene can result in a severe autoimmune lymphoproliferative syndrome in humans. 

Teachey et al screened 12 children using flow cytometry for CD4/CD8 (double-negative) T cells and using the definitive test for autoimmune lymphoproliferative syndrome (ie, defective in vitro Fas-mediated apoptosis).⁵ Six patients had elevated numbers of these double negative T cells and defective Fas-mediated apoptosis and one patient had borderline elevation; this suggests that 7 patients with Evans syndrome (58%) had evidence suggestive of autoimmune lymphoproliferative syndrome. This finding suggests Evans syndrome and autoimmune lymphoproliferative syndrome may have some overlap.

Frequency

United States

Evans syndrome is an uncommon but not rare condition; its exact frequency is unknown. Familial occurrence is rare.

Pirofsky estimated the minimal annual incidence of immune hemolytic anemia to be one case per 80,000 US residents (mostly adults).⁶ 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.⁷ Habibi et al observed that 10 of 46 children with prolonged chronic AIHA had thrombocytopenia.⁸

International

In a report from Malaysia by Ng, Evans syndrome was diagnosed in 12 of 220 adult patients with immune thrombocytopenia and 102 with AIHA.⁹

Mortality/Morbidity

Evans syndrome has a chronic, relapsing, and sometimes fatal course.

• According to Mathew et al, the course of Evans syndrome is characterized by recurrences of thrombocytopenia in 60% of patients; the number of reported recurrent episodes was 1-20.¹⁰ AIHA recurred in 31% of patients; the number of episodes was 1-8. Neutropenia recurred in 15% of patients.
• In a median follow-up study of 42 patients (aged 4 m to 18.9 y) 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.¹⁰ The remaining 14 (33%) had no evidence of disease for 1.5 months to 5 years (median 1 y). Fourteen (33%) had no evidence of disease for 1.5 months to 5 years (median 1 year).

Race

• Of 42 patients reported in a national survey, 29 were white, 7 were black, and 6 had other racial backgrounds.¹⁰ This distribution could suggest a preponderance among whites or a reporting bias.
• As individual conditions, AIHA and immune thrombocytopenia have no racial predilection.

Sex

• No predilection is known in Evans syndrome; AIHA affects boys more frequently than girls at a ratio of 1.4:1.
• Among adults, AIHA affects women more often than men. In one study from Genty et al, 67% of cases occurred in women.¹¹

Age

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 y).¹⁰ This late presentation age may indicate the disease was undiagnosed until the second presentation of cytopenia, which was usually months to years after the first presentation.
• Evans syndrome in adults has been anecdotally reported.

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