Rheumatology Advance Access originally published online on November 23, 2008
Rheumatology 2009 48(2):198-199; doi:10.1093/rheumatology/ken421
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Severe acute thrombotic exacerbation in two cases with anti-phospholipid syndrome after retreatment with rituximab in phase I/II clinical trial for refractory systemic lupus erythematosus
1Division of Rheumatology and Clinical Immunology, Department of Medicine, 2Department of Pathology, Saitama Medical Center, Saitama Medical University, Saitama, and 3First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
Correspondence to: T. Takeuchi, Division of Rheumatology and Clinical Immunology, Department of Medicine, Saitama Medical Center, Saitama Medical University, 1981 Kamoda, Kawagoe, Saitama, 350-8550, Japan. E-mail: tsutake{at}saitama-med.ac.jp
SIR, Rituximab is a chimeric mouse human monoclonal antibody against CD20 on B cells that has been approved for treatment for non-Hodgkin's lymphoma and RA in the US/EU: its safety and efficacy in SLE has been reported previously [1, 2]. We report herein two cases of SLE, with APS, who developed severe flare after re-treatment with rituximab.
Summarized clinical courses are shown in Fig. 1. Case 1 was a 24-yr-old female with a 9-yr history of thrombocytopenia, who had been treated with corticosteroids, immunosuppressants, intravenous immunoglobulin and platelet transfusion. Two years prior, thrombocytopenia, fever, erythema and polyarthritis were gradually progressing and the first rituximab treatment regimen—two infusions of 1000 mg separated by 14 days—was applied in a Japanese Phase I/II clinical trial in SLE [3]. Rituximab effectively depleted B cells and a significant improvement of clinical manifestations observed; however, a pharmacokinetic examination found early clearance of rituximab due to human anti-chimeric antibody (HACA). The serum level of rituximab became undetectable 5 weeks after the second infusion with quantifiable HACA (287 ng/ml). Rituximab usually remains detectable for as long as 4–6 months post-treatment. Sixteen months after the first rituximab therapy, lacunar infarctions associated with APS appeared and SLE activity also began to increase, for which a second course of rituximab treatment was initiated. The first infusion was well tolerated, but a severe infusion reaction with rash and dyspnea occurred at the time of the second infusion. A modest level of HACA was detectable just before the first infusion (37.6 ng/ml), but this increased markedly (71 700 ng/ml) 3 weeks after the second infusion; however, an attempted rituximab administration completed with concomitant intravenous corticosteroid rescue. A third course of rituximab therapy was administered 7 months after the second course, but severe infusion reactions developed both at the first and second infusions, and a temporal stop/resume of rituximab infusion, repeated several times, with intravenous steroid rescue was performed. The serum level of HACA was 295 ng/ml before the first rituximab infusion and 324 ng/ml 3 weeks after the second infusion, with no detectable rituximab suggesting complete neutralization by HACA. One week after completion of this third regimen, high fever and headache emerged and a diagnosis of acute meningitis was made from an examination of cerebrospinal fluid. Paraplegia of the legs with pain suddenly developed, and an MRI confirmed transverse myelitis, which is known to be a clinical manifestation associated with APS as well as with SLE, in the spinal cord. Corticosteroid pulse, plasma exchange, cyclophosphamide pulse and intrathecal MTX therapy were sequentially administered, but the paraplegia did not ameliorate.
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APS is a prothrombotic disorder consisting of vascular occlusions in the presence of aPLs, which are auto-antibodies mediating the activation of platelets and endothelial cells. While expression of tissue factor is known to be critical triggering blood clotting cascade in APS, its expression can be up-regulated by stimuli such as lipopolysccaharides, activated complements and pro-inflammatoly cytokines, like TNF-
[4].
Given the pathophysiological mechanisms of thrombotic events in APS, it is most likely that the severe infusion reactions associated with the rituximab administration could have a causal relationship with the above onset of transverse myelitis, as it is reported that serum levels of TNF- increased significantly in association with the infusion reactions due to rituximab [5]; moreover, the immune complex composed of rituximab and HACA could activate the complement process, both of which could be enough to trigger a prothrombotic state in APS.
Our second case was a 39-yr-old female with a previous history of deep vein thrombosis that had reoccurred several times prior to the rituximab treatment; she developed a pulmonary embolism 7 months after retreatment with rituximab. An autopsy confirmed catastrophic APS. She had also developed HACA after the first course of rituximab treatment; however, she received a subsequent retreatment without any infusion-related reactions. Clinical meanings of HACA seemed different in this subject from the first subject, and it was not potential enough to neutralize rituximab as the HACA became detectable a few months after rituximab disappeared from the serum. A causality relationship between embolism and rituximab is unverifiable as the event was observed 7 months after rituximab retreatment and her previous thrombotic history. The study was approved by the local hospital institutional review board, and both patients described here gave informed consent before treatment.
While preliminary data suggest that B-cell depletion therapy with rituximab may be effective for the treatment of various auto-immune diseases including SLE, its safety and efficacy should be examined thoroughly in a placebo-controlled large-scale clinical study, which is now on-going in the United States and Japan.
Also, it is emphasized that a number of newly developed biological products are now available for treatment of various unmet medical conditions, some of which are also known to elicit infusion reactions, and special attention should be paid to such biological protein-derived products when applied to the patients with thrombotic disposition like APS for development of severe infusion reactions.
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The authors wish to thank the members of the steering committee of the study: Prof. T. Koike of Hokkaido University School of Medicine, Prof. N. Miyasaka of Tokyo Medical and Dental University, Prof. K. Yamamoto of Tokyo University School of Medicine, Prof. T. Mimori of Kyoto University School of Medicine, Prof. T. Sumida of Tsukuba University School of Medicine and Prof. N. Nishimoto of Osaka University School of Medicine, and those of an independent data-monitoring committee, Dr H. Hashimoto, Dr K. Toyama and Dr M. Hara.
Disclosure statement: The authors have declared no conflicts of interest. T.T. and Y.T. are also a member and chairperson of the Steering Committee, respectively.
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TopAcknowledgementsReferences |
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