NDT Advance Access originally published online on January 9, 2006
Nephrology Dialysis Transplantation 2006 21(3):577-579; doi:10.1093/ndt/gfk042
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A new treatment for TTP?
Service de Néphrologie, Hôpital Necker, AP-HP, Université Paris V-René Descartes, Paris, France
Correspondence and offprint requests to: Fadi Fakhouri. Email: fakhouri{at}necker.fr
Keywords: monoclonal antibody; rituximab; thrombotic thrombocytopenic purpura (TTP)
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Pathophysiology of TTP |
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 Top Pathophysiology of TTP Therapeutic considerationsTreatment of relapses with...Prevention of relapsing TTPReferences |
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Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease that mainly affects adult patients. It is characterized by microangiopathic haemolytic anaemia, thrombocytopenia, neurological disturbances and renal failure [1]. These symptoms are related to the presence of von Willebrand factor (VWF)-rich platelet thrombi in the arterioles and capillaries.
The VWF, a multimeric plasma glycoprotein secreted mainly by endothelial cells, is crucial for both platelet adhesion and aggregation, especially at the high shear rates in the microvasculature. The VWF is secreted in the form of high molecular weight multimers with a high potency to aggregate platelets. Thus, the size of VWF multimers is physiologically regulated in vivo by a specific metalloprotease, The ADAMTS13 (A Desintegrin And Metalloprotease with a ThromboSpondin-like domain), that cleaves the largest multimers in order to prevent the spontaneous formation of platelet thrombi in the microcirculation. The absence of ADAMTS13 activity in the plasma leads to the persistence of high molecular weight VWF multimers with ensuing platelet aggregation and thrombotic microangiopathy. The ADAMTS13 may be deficient in rare cases due to a mutation in the corresponding gene (Upshaw–Schulman syndrome) or, more frequently, to circulating, mostly inhibitory auto-antibodies (Abs) directed against ADAMTS13.
In 33% to 90% of cases, idiopathic TTP is related to a severe functional deficiency of ADAMTS13 in plasma due to circulating (Abs) to ADAMTS13 [2].
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Therapeutic considerations |
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TopPathophysiology of TTPTherapeutic considerationsTreatment of relapses with...Prevention of relapsing TTPReferences |
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Plasma therapy including both plasma infusion and plasma exchange (PE) has dramatically improved TTP prognosis, decreasing the mortality rate from 90% to less than 20% [3]. However, a subset of patients with acquired TTP requires very long-term plasma therapy to prevent fatal outcome and to achieve a sustained remission. In these patients, complementary treatments including immunosuppressive agents (corticosteroids, vincristine, cyclophosphamide, azathioprine, cyclosporine A), high dose intravenous immunoglobulin, staphylococcal protein A immunoadsorption and splenectomy have been proposed [4–8]. The efficacy of these treatments has not been proved in prospective studies. Besides, in spite of all these therapeutic options, about one third of all acquired TTP patients develop multiple relapses or persistent disease [1].
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Treatment of relapses with rituximab |
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TopPathophysiology of TTPTherapeutic considerationsTreatment of relapses with...Prevention of relapsing TTPReferences |
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Rituximab is an anti-CD20 monoclonal Ab that induces a sustained depletion of B cells. It has dramatically improved the management of CD20-positive lymphoproliferative disorders [9]. It is also increasingly used in various autoimmune disorders such as rheumatoid arthritis, systemic lupus erythematous, etc. especially in severe forms resistant to conventional immunosuppressive treatment [10–12].
It has also been used as a curative treatment in small retrospective cohorts of patients with acute refractory TTP associated with a severe ADAMTS13 deficiency related to inhibitory anti-ADAMTS13 Abs (reviewed in [13]). Twenty-five out of 26 patients achieved complete remission and their follow-up revealed long-term remission in most cases. However, rituximab has never been used as a prophylactic treatment in patients with highly recurrent TTP out of an acute episode.
We conducted a multicentric prospective open-label study in order to (i) test the efficiency of rituximab in patients with an acute refractory TTP and (ii) to evaluate the use of rituximab as a prophylactive treatment in selected patients with recurrent TTP out of an acute episode.
This study included 11 adult patients with (i) at least an episode of TTP defined by a microangiopathic haemolytic anaemia (haemoglobin <10 g/dl, LDH >460 IU/l, undetectable serum haptoglobin and the presence of schizocytes on blood smear) and a thrombocytopenia (platelets <50 x 109/l), eventually associated with visceral ischaemic signs and (ii) an undetectable ADAMTS13 plasma activity (<5%; normal: 50–150%) related to a circulating anti-ADAMTS13 inhibitory Ab detected on at least two assays.
Six patients were included during an acute TTP episode that was uncontrolled despite at least three weeks of PE. Five patients were included during a clinical remission of a severe relapsing TTP with persistent anti-ADAMTS13 antibody.
All patients received four weekly infusions of rituximab (375 mg/m2). At inclusion in the study, immunosuppressive treatments had been stopped since at least one month (range: 1–24 months).
The aim of the treatment was to restore an ADAMTS13 activity >10%. This threshold was chosen based on observations made in patients with congenital TTP due to ADAMTS13 gene mutations and treated with prophylactic FFP infusions [14].
In all patients enrolled during an acute TTP episode, rituximab induced a clinical remission (i.e. disappearance of clinical signs and normalization of platelet count and LDH level) in 5–14 days after the 4th rituximab infusion.
In the 11 included patients, a recovery of a significant ADAMTS13 plasma activity along with the disappearance of anti-ADAMTS13 antibodies was obtained as early as 8 weeks after rituximab treatment. No TTP relapse occurred during a follow-up that ranged from 12 to 18 months. In three patients, maintenance rituximab infusions were necessary during follow-up as the restoration of a normal B cell count was followed by the reappearance of anti-ADAMTS13 antibodies and a decrease in ADAMTS13 activity.
Most patients with acquired TTP, which are due to anti-ADAMTS13, are to be considered and treated as suffering from an autoimmune disease. Based on previously published series and case reports as well as on our prospective data, rituximab is probably the optimal first-line and single treatment of acute refractory TTP. Indeed, in the presence of high-titer anti-ADAMTS13 antibodies, FFP infusions and PE rarely lead to the disappearance of these antibodies and ADAMTS13 plasma activity remains undetectable ([15] and personal data). The optimal timing for the use of rituximab is still debated: after at least 3 weeks of plasma therapy or earlier in patients with high-titer anti-ADAMTS13 antibodies.
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Prevention of relapsing TTP |
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TopPathophysiology of TTPTherapeutic considerationsTreatment of relapses with...Prevention of relapsing TTPReferences |
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Rituximab is also a promising prophylactic treatment in patients with frequently relapsing TTP and persistent anti-ADAMTS13 antibodies despite previous immunosuppressive treatments. In these patients, the relapse rate is high (43%) and may justify prophylactic treatment with rituximab.
A maintenance treatment with rituximab is necessary in some patients with severe TTP as the recovery of a normal B cell count is frequently but not constantly associated with the reappearance of anti-ADAMTS13 antibodies (Figure 1). The modalities of this treatment are still open to debate. What is the optimal time (before or after the recovery of B cells? before or after the reappearance of autoantibodies?), frequency (every 6 months?) and dose (one perfusion?) of maintenance therapy? What will be the impact of such treatment on the incidence of anti-rituximab antibodies and on the subsequent efficacy of the drug?
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) or fresh frozen plasma infusions (
) and (ii) remission (#). Abbreviations: R: relapse; RTX: rituximab; S: splenectomy; Ab: antibodies. The length of the solid bars indicates the duration of TTP relapses.Despite these promising data, the impact of rituximab on long-term evolution of TTP remains to be ascertained. Thus, extended follow-up is necessary in order to evaluate whether rituximab significantly decreases the frequency of TTP relapses.
In summary, rituximab is an effective first-line curative therapy in patients with acute refractory TTP related to anti-ADAMTS13 antibodies. It may prove a helpful treatment in selected patients with severe relapsing TTP and persistent anti-ADAMTS13 antibodies.
Conflict of interest statement. None declared.
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References |
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[Abstract/Free Full Text]
Accepted in revised form: 12.12.05
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