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Ann Thorac Surg 2002;74:1240-1242
© 2002 The Society of Thoracic Surgeons
a Division of Cardiothoracic Surgery, University of Tennessee, Memphis, Tennessee, USA
b Baptist Hospital/University of Tennessee Heart Transplant Program, Memphis, Tennessee, USA
Accepted for publication May 1, 2002.
* Address reprint requests to Dr Garrett, 80 Humphreys Blvd, Suite 300, Memphis, TN 38120 USA
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Abstract |
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Introduction |
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Although vascular rejection is much less frequent than cellular rejection, the clinical consequences are no less devastating. Without specific treatment, vascular rejection can produce graft loss or death [3, 4]. Patients with three or more episodes of vascular rejection in the first 3 months (either alone or mixed with cellular rejection) have a fourfold higher risk of the development of coronary allograft vasculopathy [2]. Episodes of vascular rejection are a powerful predictor of future coronary allograft vasculopathy even when considered separate from other associations (degree of human lymphocyte antigen mismatch, serum human lymphocyte antigen or endothelial antibodies after transplantation, cytomegalovirus infection, cellular rejection frequency, dyslipidemia). Treatment of humoral rejection has been based primarily on plasmapheresis to lower the circulating immunoglobulin levels followed by high-dose cyclophosphamide to reduce the B-cell population with modest success. OKT3 (murine monoclonal antibody) has also been used but with little success. The only alternative after failure of treatment has been retransplantation.
CD20 is a 35,000-kDa nonglycosylated tetra spanning cell membrane phosphoprotein that has both amino and carboxy termini within the cytoplasm [5]. CD20 appears to be involved in the regulation of B-cell development and differentiation and may mediate some of its effects by functioning as a calcium channel [5]. CD20 is exposed in most mature B lymphocytes but is down-regulated during terminal differentiation into plasma cells [5].
Rituximab (Genentech, Inc, South San Francisco, CA) is a genetically engineered chimeric murine-human anti-CD20 monoclonal antibody. This antibody retains murine antigen-combining variable regions grafted onto a human constant region with human IgG 1-Fc domains [5]. The human Fc region interacts more effectively than murine Fc regions with human complement and effector cells, resulting in augmentation of complement-mediated lysis and antibody-dependent cellular toxicity [5]. In addition, antibody binding to CD20 induces signal transduction events that raise intracellular calcium ion levels and lead to apoptosis.
Rituximab is generally administered as an intravenous dose of 375 mg/m2 weekly for 4 consecutive weeks [6]. The toxicity profile is mild. The most common adverse reactions are fever, chills, and hives during the first infusion. Subsequent infusions can be associated with less frequent and milder symptoms [6]. The most serious side effects are bronchospasm, hypotension, neutropenia, and thrombocytopenia, each occurring in less than 2% of patients [6]. Circulating B-lymphocytes are saturated with very small doses (5 to 10 mg/m2), but lymph nodes are not completely saturated at a dose of 800 mg/m2 [5]. B-cell counts drop dramatically but return to normal within 6 to 9 months after treatment. Infectious complications are rare, which is likely related to the preservation of nearly normal serum immunoglobulin levels in rituximab-treated patients, presumably because plasma cells are not affected [5].
Rituximab was first introduced for the treatment of B-cell non-Hodgkin’s lymphoma, and the response rate was 50%. Because of its selective toxicity to normal B cells, rituximab has been used in the treatment of autoimmune thrombocytopenic purpura, IgM-type chronic demyelinating peripheral neuropathy, myasthenia gravis, lymphoproliferative disease both de novo and after stem cell transplantation, and purging of mature B cells from the bloodstream prior to stem cell mobilization [5]. On the basis of this experience and the mechanism of humoral rejection, it seemed likely that rituximab would be a useful adjunct in the treatment of humoral rejection in cardiac transplant recipients.
A 55-year-old woman with a history of hypertension and eight pregnancies was seen in 1999 with worsening congestive heart failure secondary to a known idiopathic cardiomyopathy. Left ventricular ejection fraction had deteriorated to 0.20 when she was listed as a Status II candidate for cardiac transplantation on September 30, 1999. Her condition continued to deteriorate, and she required continuous intravenous infusion of dobutamine hydrochloride, 10 µg · kg-1 · min-1, and milrinone lactate, 3 µg · kg-1 · min-1, on December 28, 1999, which elevated her status to 1B. She underwent orthotopic cardiac transplantation on January 29, 2000, with an ischemic time of 175 minutes. Panel-reactive antibodies prior to transplantation were 0. The donor tested positive for toxoplasmosis, and the patient tested negative. Immunosuppression was managed with cyclosporine, prednisone, and mycophenolate mafetil.
Over the next 2 months, four endomyocardial biopsies were performed. After three, the specimens revealed grade 0 to 1A cellular rejection and after one, mild 1B rejection. All specimens were negative for IgG and complement. Left ventricular ejection fraction ranged between 0.55 and 0.60. On April 3, 2000 (65 days after transplantation), a routine biopsy specimen revealed a grade 1A cellular rejection but markedly positive staining for complement and negative staining for IgG. This was associated with a decrease in left ventricular ejection fraction to 0.35. Cardiac catheterization revealed normal coronary arteries.
Because vascular rejection associated with a reduced left ventricular ejection fraction was suspected, the patient underwent four daily plasmapheresis treatments followed by 800 mg of intravenous administration of cyclophosphamide. Repeat biopsy specimens obtained 1 week and 3 weeks later confirmed grade 0 cellular rejection with negative IgG and complement staining, and left ventricular ejection fraction gradually increased to 0.45.
However, by May 23, 2000 (day 115 after transplantation), ejection fraction had again decreased to 0.30 and was associated with positive complement staining of the biopsy specimen without major cellular rejection. The patient again underwent two series of four daily plasmapheresis treatments over the next 4 weeks. Repeat biopsy specimens taken 2 and 6 weeks later were normal, and there was a gradual increase in ejection fraction to 0.55. However, at a routine biopsy 10 weeks after the last course of therapy on September 11, 2000 (day 226 after transplantation), the specimen was again positive for complement with grade 0 cellular rejection and a reduced ejection fraction of 0.30. She again underwent four daily plasmapheresis treatments over the next week.
Because it appeared that conventional therapy had been unsuccessful and that the only future option was retransplantation, rituximab therapy was considered. After informed consent was obtained from the patient, rituximab was administered at a dose of 375 mg/m2 for a total intravenous dose of 750 mg weekly for 4 weeks. The last dose was administered on October 23, 2000 (day 268 after transplantation). No adverse reactions occurred with intravenous administration. Flow cytometry demonstrated marked reduction in the B-cell population by CD20 marker. After administration of rituximab, left ventricular ejection fraction increased to 0.60. All subsequent biopsy specimens over the next year revealed grade 0 to 1A cellular rejection with no evidence of IgG or complement staining. One year after rituximab therapy, the patient had a toxoplasmosis infection, which responded to antimicrobial therapy.
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Patients who are successfully treated for vascular rejection with rituximab will require careful reevaluation, as B-cell populations rebound 9 months after therapy. Even if a repeat course of drug therapy is required, however, toxicity and complications of therapy appear minimal. The long-term impact on lymphoproliferative disorders is unknown.
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