Warm Autoimmune Hemolytic Anemia: Recent Progress in Understanding the Immunobiology and the Treatment

Barros, Melca Maria Oliveira; Blajchman, Morris A.; Bordin, José Orlando

doi:10.1016/j.tmrv.2010.03.002

Cited by 96 publications

(105 citation statements)

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“…Moreover, a substantial number of them remain in remission for years without medication, with a presumed cure rate of up to 20%. 2,22,23 It is worth mentioning that patients with persistent or recurrent hemolysis after splenectomy often require lower doses of corticosteroids than before surgery.2 A drawback of splenectomy is the lack of reliable predictors of the outcome, since its effectiveness is not related to disease duration, response to steroids nor the extent of splenic sequestration. 24 Moreover, splenectomy may be associated with surgical complications (pulmonary embolism, intra-abdominal bleeding, abdominal abscess, abdominal wall hematoma), although laparoscopic intervention has lowered the surgical risk compared to conventional surgery (0.5-1.6% vs. 6%).…”

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confidence: 99%

Treatment of autoimmune hemolytic anemias

2014

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Autoimmune hemolytic anemia (AIHA) is a relatively uncommon disorder caused by autoantibodies directed against self red blood cells. It can be idiopathic or secondary, and classified as warm, cold (cold hemagglutinin disease (CAD) and paroxysmal cold hemoglobinuria) or mixed, according to the thermal range of the autoantibody. AIHA may develop gradually, or have a fulminant onset with life-threatening anemia. The treatment of AIHA is still not evidence-based. The first-line therapy for warm AIHA are corticosteroids, which are effective in 70-85% of patients and should be slowly tapered over a time period of 6-12 months. For refractory/relapsed cases, the current sequence of second-line therapy is splenectomy (effective approx. in 2 out of 3 cases but with a presumed cure rate of up to 20%), rituximab (effective in approx. 80-90% of cases), and thereafter any of the immunosuppressive drugs (azathioprine, cyclophosphamide, cyclosporin, mycophenolate mofetil). Additional therapies are intravenous immunoglobulins, danazol, plasma-exchange, and alemtuzumab and high-dose cyclophosphamide as last resort option. As the experience with rituximab evolves, it is likely that this drug will be located at an earlier point in therapy of warm AIHA, before more toxic immunosuppressants, and in place of splenectomy in some cases. In CAD, rituximab is now recommended as first-line treatment. ABSTRACT Treatment of warm AIHAThe traditional treatment of AIHA includes corticosteroids, splenectomy and conventional immunosuppressive drugs. Over recent years, some new therapies have become available and there has been some evidence of success. These therapies are primarily used in patients who are not candidates for or fail to respond to splenectomy, those who relapse after splenectomy, and those who cannot maintain stable hemoglobin levels without unacceptably high doses of corticosteroids. First-line therapy CorticosteroidsThere is general agreement that corticosteroids represent the first-line treatment for patients with warm antibody type AIHA, albeit their use is based on experience rather than hard evidence. In fact, there is little published information on their effectiveness, 1,16,17 and this is not supported by clinical trials. Corticosteroids, usually prednisone, are given at the initial dose of 1.0-1.5 mg/kg/day for 1-3 weeks until hemoglobin levels greater than 10 g/dL are reached. Response occurs mainly during the second week, and if none or minimal improvement is observed in the third week, this therapy is assumed to be ineffective. After stabilization of hemoglobin, prednisone should be gradually and slowly tapered off at 10-15 mg weekly to a daily dose of 20-30 mg, then by 5 mg every 1-2 weeks until a dose of 15 mg, and subsequently by 2.5 mg every two weeks with the aim of withdrawing the drug. Although one might be tempted to discontinue steroids more rapidly, AIHA patients should be treated for a minimum of three or four months with low doses of prednisone (≤10 mg/day).1 In fact, patients receiving low doses of cortico...

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confidence: 99%

Treatment of autoimmune hemolytic anemias

2014

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“…1 In warm AIHA, mainly polyclonal RBC autoantibodies of IgG class and sometimes of IgA class are involved and react optimally around 37°C. 2 Sensitization of RBC with this type of antibodies will lead to destruction via IgG-Fc receptors (FcγR) or IgA-Fc receptors (FcαR), respectively, on phagocytes, mainly in the spleen. Autoantibodies in so-called cold AIHA react optimally at temperatures below 30°C and are mainly of IgM class.…”

Section: Introductionmentioning

confidence: 99%

Complement deposition in autoimmune hemolytic anemia is a footprint for difficult-to-detect IgM autoantibodies

et al. 2015

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© F e r r a t a S t o r t i F o u n d a t i o nwhich leads to remission in 50% of patients. 7 Rituximab has also been seen to be a successful treatment for IgGmediated AIHA, 8 and -despite its high cost and side effects -is recommended as second-line therapy in steroid-refractory AIHA. Cold (IgM-mediated) AIHA usually does not respond to prednisone. In some cases hemolysis can be prevented by protection from cold, but otherwise the therapeutic anti-CD20 antibody rituximab seems to be a promising strategy for treatment of this group of patients, showing a response rate of around 50%. 9,10 In general, patients with mixed AIHA initially respond well to steroids, but usually go on to develop chronic hemolysis. 11,12 To determine the optimal therapy, it is crucial to identify the causative RBC autoantibodies correctly, and to evaluate the presence of anti-RBC IgM autoantibodies in AIHA. However, with the current diagnostic techniques, it can be challenging to detect IgM because of its frequently low avidity. Moreover, a distinction is not routinely made between IgG and IgM in the IAT and can be difficult. We, therefore, studied alternative methods to detect autoantibodies in AIHA, focusing on the detection of IgM. First, we adapted the DAT and IAT to a fluorescence-activated cell sorting (FACS)-based assay, since a similar strategy had previously been shown to be successful for the detection of IgG and C3 on RBC.13-16 Secondly, we studied a method for detecting IgM based on the presence of deposited complement factors on patients' RBC. It is known that IgM activates complement more efficiently than IgG and it has been shown that if a patient's serum induces hemolysis in vitro, this is often caused by anti- RBC IgM 17 . Instigated by this, we studied whether the presence or extent of complement C3 deposition, as routinely measured in the DAT, can indicate the presence of anti-RBC IgM by separating IgG and IgM in the sera from AIHA patients and subsequently testing which fractions of the samples activated complement. Methods Patients' materialFor the FACS-based IAT and DAT studies, anonymized residual samples from patients with AIHA (34 and 50 patients, respectively) were used. The samples were collected in 2013 and 2014 and had been sent in for diagnostic tests to the Dutch reference laboratory for immunohematology and had a positive DAT for at least C3d and positivity in the hemolysin test. For the fractionation/depletion experiments, 16 additional samples were used that were positive for at least C3d in the DAT. Details can be found in Online Supplementary Table S1. The presence of clinical hemolysis was confirmed using the following parameters, if available: low hemoglobin, high lactate dehydrogenase, decreased haptoglobin, increased indirect bilirubin or a confirmed diagnosis by the treating physician.Fractionation of serum or eluate from patients with autoimmune hemolytic anemia AIHA patients' serum, recalcified plasma or eluate was filtered through a 0.22 μm filter before loading 0.5 mL on a 10/30...

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“…The auto-antibodies in AIHA are classified in warm and cold antibodies, depending on the optimal temperature they bind to RBCs (37 °C or lower, respectively). The warm antibodies are usually of IgG isotype and the cold antibodies of the IgM isotype 8,9 . AIHA can be secondary to e.g.…”

Section: Introductionmentioning

confidence: 99%

“…AIHA can be secondary to e.g. lymphoprolyferative disorders, connective tissue diseases, solid tumors, infections or drugs, but in 50% of the cases AIHA is idiopathic 9 .…”

Section: Introductionmentioning

confidence: 99%

Methods for Quantitative Detection of Antibody-induced Complement Activation on Red Blood Cells

Meulenbroek

Wouters

2014

JoVE

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Antibodies against red blood cells (RBCs) can lead to complement activation resulting in an accelerated clearance via complement receptors in the liver (extravascular hemolysis) or leading to intravascular lysis of RBCs. Alloantibodies (e.g. ABO) or autoantibodies to RBC antigens (as seen in autoimmune hemolytic anemia, AIHA) leading to complement activation are potentially harmful and can be -especially when leading to intravascular lysis -fatal 1 . Currently, complement activation due to (auto)-antibodies on RBCs is assessed in vitro by using the Coombs test reflecting complement deposition on RBC or by a nonquantitative hemolytic assay reflecting RBC lysis [1][2][3][4] . However, to assess the efficacy of complement inhibitors, it is mandatory to have quantitative techniques. Here we describe two such techniques. First, an assay to detect C3 and C4 deposition on red blood cells that is induced by antibodies in patient serum is presented. For this, FACS analysis is used with fluorescently labeled anti-C3 or anti-C4 antibodies. Next, a quantitative hemolytic assay is described. In this assay, complement-mediated hemolysis induced by patient serum is measured making use of spectrophotometric detection of the released hemoglobin. Both of these assays are very reproducible and quantitative, facilitating studies of antibody-induced complement activation. Video LinkThe video component of this article can be found at

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Warm Autoimmune Hemolytic Anemia: Recent Progress in Understanding the Immunobiology and the Treatment

Cited by 96 publications

References 105 publications

Treatment of autoimmune hemolytic anemias

Treatment of autoimmune hemolytic anemias

Complement deposition in autoimmune hemolytic anemia is a footprint for difficult-to-detect IgM autoantibodies

Methods for Quantitative Detection of Antibody-induced Complement Activation on Red Blood Cells

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