Background Thrombotic microangiopathy (TMA) is characterized by microvascular thrombosis with thrombocytopenia, haemolytic anemia, and red blood cell fragmentation. TMA is often reported to develop under various clinical conditions such as malignant hypertension, stem cell transplantation, pregnancy, drug-induced, and connective tissue diseases (CTD). TMA is associated with deficiency of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member-13 (ADAMTS-13) induced by its inhibitor. Excessive production of ultra-large von Willebrand factor multimers (UL-VWFMs) also induced TMA. Plasma exchange (PE) is the standard treatment for TMA patients, and PE treatment can reduce mortality from 90% to less than 20% ¹⁾. However, some cases without the deficiency of ADAMTS-13 activity are resistant to PE treatment in TMA associated with CTD (CTD-TMA) ²⁾. Recently, rituximab (RTX), anti-CD20 monoclonal antibody, is known as effective treatment for patients with refractory CTD-TMA. RTX is considered to affect on immune response by not only depleting B cells but modulating antigen-presenting cell function and release of inflammatory or immunomodulatory cytokines, and normalizing the abnormal auto-reactive T-cell response through co-stimulatory signals ³⁾.

Objectives We investigate the efficacy and safety of RTX treatment (two doses of RTX, 375 mg/m² once per week) for CTD-TMA with refractory to PE treatment.

Methods We enrolled six CTD-TMA patients with refractory to PE treatment. We examined the ADAMTS-13 activity, its inhibitor and UL-VWFMs at TMA onset.In addition, we investigated as follow subjects; efficacy of RTX treatment, duration from initial RTX treatment to complete remission (CR), duration of sustained CR, relapse and adverse events.

Results Five patients were female and one was male with average age of 41.5 years. CTD included three systemic lupus erythematosus, two Sjögren's syndrome and one mixed connective tissue disease. No abnormality of ADAMTS-13 activity was observed in five patients. ADAMTS-13 inhibitor was also not detected these five patients. UL-VWFMs were detected with two patients with neither deficiency of ADAMTS-13 activity nor presence of its inhibitor. In all patients, the cytopenia such as anemia and thrombocytopenia was improved immediately after the initial RTX administration. In addition, five of six patients could achieve CR within two weeks, and they have sustained in CR for at least 24 weeks. After 24 weeks, one of five patients who achieved CR relapsed, but she could achieve 2nd-CR after RTX re-treatment.Refractory CTD-TMA was controlled with RTX treatment, and serious complications were not occurred.

Conclusions We suggest that RTX treatment could be expected the efficacy and safety for the refractory CTD-TMA patients regardless of ADAMTS-13 activity levels. It is possible that RTX treatment might be first line treatment strategy for CTD-TMA patients.

References

1. Sadler JE. Von Willebrand factor, ADAMTS-13, and thrombotic thrombocytopenic purpura. Blood 2008; 112(1): 11-18.

2. T Matsuyama. Heterogeneous pathogenic processes of thrombotic microangiopathies in patients with connective tissue diseases. Thromb Haemost 2009; 102: 371-378.

3. Stasi R. Rituximab in autoimmune hematologic disease:not just a matter of B cells. Semin Hematol 2010; 47: 170-179.

Disclosure of Interest None declared