Dierickx_EU Haematology 04/03/2010 16:17 Page 12
Anaemia
Figure 1: Pathogenetic Mechanisms in Autoimmune Haemolytic Anaemia and Immune Thrombocytopenic Purpura
Auto-antigen RBC
Macrophage
THR
Peptides
Fc-receptor
APC
Auto-antibody
MHC II
CD40
CD80
CD154
CD28
TCR
CD154 CD40
B
T
Cytokines
(IL-2, IFN-γ, etc.)
Platelet (THR) and red blood cell (RBC) antigens are cleaved by antigen-presenting cells (APCs) and presented as peptides on their surface via major histocompatibility complex (MHC) class II
molecules. This complex is recognised by the T-cell receptor (TCR) of the CD4-positive T-helper (Th) cell. Additional co-stimulatory signals are provided by CD80–CD28 and CD40–CD154
interactions. The activated Th cells produce activating cytokines (such as interleukin-2 and interferon-gamma), which cause activation and differentiation of B cells, leading to auto-antibody
production. Auto-antigens on the surface of platelets and RBCs are recognised by the Fab part of the auto-antibodies. Auto-antibody-coated platelets and RBCs are then recognised by
macrophages of the mononuclear phagocytic system via Fc-receptors on their surface, are internalised and eventually undergo phagocytosis.
Evidence on the use of rituximab in AIHA is mainly based on Whether rituximab can be used as a splenectomy-sparing second-line
retrospective case reports and case series, with only a few therapy in warm AIHA has yet not been studied properly. However, in
prospective trials. Nevertheless, based on these rather small series, ITP – which can be considered the platelet analogue of AIHA –
information on about 300 patients has been reported, leading to rituximab is now considered a valuable alternative in patients not fit
overall response rates of more than 60%, with complete response enough to undergo or refusing splenectomy.
18,19
rates exceeding 25%.
4,12
However, these numbers need to be
interpreted with caution, as patients not responding are unlikely to Unlike ITP, identification of possible clinical or biochemical parameters
be reported in case reports and smaller series. able to predict outcomes following rituximab treatment have been
poorly investigated. In both trials by Berentsen et al. in primary
Although patients experiencing warm AIHA can often be treated CAD and in the Belgian retrospective registry, no such parameters
successfully with corticosteroids and/or splenectomy, these could be identified.
12,13,15
treatment options are very disappointing in primary cold agglutinin
disease (CAD). CAD has traditionally been treated upfront with Response duration in AIHA patients treated with rituximab has shown
cytotoxic therapy, displaying a substantial toxicity profile. Recent considerable variation, ranging from one month to more than eight
findings using rituximab in CAD showing overall response rates of years, with most patients showing responses exceeding more than
50–65% in retrospective and prospective uncontrolled trials have led one year. Although rituximab can induce durable responses in a
to the general assumption that rituximab, either in monotherapy or proportion of patients with AIHA, most patients will eventually
combined with alkylating agents or purine analogues, should be used relapse. However, re-treatment with rituximab in previously
as a first-line treatment in CAD.
12–15
responding patients having lost their response seems feasible,
leading to comparable response rates and sometimes even longer
AIHA is a well-known complication of lymphoproliferative disorders, response duration.
4,12
especially chronic lymphocytic leukaemia (CLL). Based on its potent
activity in these disorders, either in monotherapy or combined with Rituximab in Evans Syndrome
chemotherapeutic agents, rituximab has been used in lympho- Evans syndrome (ES) is a rare autoimmune disorder characterised by
proliferative-disorder-associated AIHA. The combined immuno- simultaneous or sequential occurrence of ITP and AIHA. Although
chemotherapeutic regimen rituximab–cyclophosphamide–dexa- initially by definition considered as an idiopathic (‘primary’ ES)
methasone in particular seems to be associated with very high and disorder, the existence of ‘secondary’ ES has recently been
durable responses in CLL-associated AIHA.
16,17
recognised.
20,21
Michel et al. reported on a large database of 68 ES
12 EUROPEAN HAEMATOLOGY
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