Thrombotic thrombocytopenic purpura (TTP) is a rare disorder characterized by thrombocytopenia, microangiopathic haemolytic anaemia, neurological and renal abnormalities and fever1, with a mortality rate, in the absence of treatment, of almost 90%. Since such criteria do not distinguish TTP from haemolytic uraemic syndrome (HUS), the comprehensive term TTP-HUS is more approriate2. The standard therapy is urgent plasma exchange (PE)1, which reduces mortality to 10% or less3–9. Because of its dramatic effect on short and long-term outcome, it is now accepted that PE can be begun, in the absence of an alternative diagnosis, even when not all of the above criteria are fulfilled3,4,6,9,10. The evident advantage of early initiation of therapy along with the decreased diagnostic threshold has resulted in a 7-fold increase of patients treated with PE for TTP-HUS from 1981 to 199711.
The symptoms of TTP are related to the presence of von Willebrand factor (VWF)-rich platelet thrombi in arterioles and capillaries. VWF is a multimeric plasma glycoprotein crucial for both platelet adhesion and aggregation, especially at the high shear rates present in the microvasculature. The size of VWF multimers is physiologically regulated in vivo by a specific metalloprotease, ADAMTS-13 (a disintegrin-like and metalloprotease with thrombospondin type 1 repeats)12.
A severe deficiency of ADAMTS-13 (< 5% of normal activity) may be specific for TTP13 and it has been proposed that severe ADAMTS-13 deficiency now defines TTP14,15. Because ADAMTS-13 deficiency, whether idiopathic or caused by an autoantibody, provides a possible explanation for the effectiveness of PE (removal of the autoantibody by apheresis; supply of ADAMTS-13 by plasma replacement), it has been suggested that the levels of this metalloprotease can be used to guide treatment decisions14,16–19. At present it is not possible to establish the sensitivity of ADAMTS-13 deficiency for identifying patients who may respond to PE. In seven reports, 45% to 100% of patients with TTP were reported to have severe deficiency of ADAMTS-13 activity19–25 while such a high rate has not been described in those with HUS19,20,23. However, the interpretation of these studies is limited by the absence of explicit criteria for distinguishing patients with TTP from patients with HUS. PE has been proven effective even in patients without deficiency of ADAMTS-13 activity, which makes it difficult to understand how PE is benificial2. In conclusion, the role of ADAMTS-13 activity in the diagnosis and treatment decisions in patients with TTP or HUS remains unknown.
Therapy with PE should be implemented in all patients with TTP-HUS and continued until the resolution of signs and/or symptoms and normalisation of laboratory tests; this can require long-term therapy. PE has some other disadvantages: first of all, it is not a risk-free procedure since a substantial number of major complications have been reported26,27. Furthermore, about 10% to 20% of TTP-HUS patients do not respond or have only an incomplete response2. Various different types of immunosuppressive treatment have been proposed for refractory patients14,29,30,32, including steroids and immunosuppressive or immune-modulating agents; however, the lack of robust data does not allow proper suggestion of such agents in the setting of acute refractory or chronic relapsing TTP28,32. Splenectomy has been proposed for patients with refractory or relapsing TTP, with reported remission rates of 50–100%29, but relapses have occurred in a considerable proportion of patients, most of them with severe ADAMTS-13 deficiency2,29,33,35. It has recently been shown that splenectomy can cause the disappearance of antibodies, normalisation of ADAMTS-13 activity and clinical remission in cases of refractory/relapsing TTP associated with anti-ADAMTS-13 autoantibodies. Other authors reported a low frequency of relapses in a large cohort of patients who underwent splenectomy30.
Rituximab, a chimaeric monoclonal antibody directed against the CD20 antigen present on B lymphocytes, is used in lymphoma patients and those with rheumatoid arthritis33. Its action relies on clearance of the B lymphocytes responsible for antibody production by complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity or directly by inducing apoptosis31,33. The understanding that ADAMTS-13 deficiency could be antibody-mediated first provided the rationale for the use of rituximab in TTP-HUS12, but its reported effectiveness even in TTP-HUS patients without antibody-mediated ADAMTS-13 deficiency as well as in cases of refractory/relapsing cases makes this monoclonal antibody a very attractive therapeutic agent33–35. The data suggest that the drug may not simply decrease ADAMTS-13 autoantibody production by depleting B cells, but that it may have additional mechanisms of action. Kameda et al.34 suggested that B-cell depletion by rituximab reduces excessive cytokine production in patients with secondary TTP, thus containing the level of VWF multimers within the normal range. At present, only data from case series have been published and many questions remain open regarding the target population, timing of initiation, duration of treatment and concomitant PE34–49. Here we describe four patients with refractory/relapsing idiopathic TTP-HUS who were successfully treated with rituximab (Table I).