Background Recently, it has been described in many reports that B cell has important roles in connective tissue disease (CTD). Rituximab (RTX), anti-CD20 monoclonal antibody is widely known as effective for patients with several autoimmune hematological disorders including thrombotic microangiopathy (TMA) through not only B cell depletion but reducing antigen-presenting cell function, complement hyperactivation, release of inflammatory cytokines and abnormal auto-reactive T cell response through co-stimulatory signals.1) TMA is developed in CTD occasionally. CTD-TMA especially with normal activity of von Willebrand factor cleaving protease, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member-13 (ADAMTS-13) is often resistant for plasma exchange (PE) conducted for thrombotic thrombocytopenic purpura with ADAMTS-13 inhibitor and lack of ADAMTS-13 activity as a first-line treatment.2) It has been reported that the autoantibodies other than ADAMTS-13 inhibitor, complement hyperactivation, and excessive inflammatory cytokines production associated with refractory TMA.3)
Objectives We investigate the efficacy and the long-term prognosis of RTX treatment for refractory TMA associated with CTD.
Methods We enrolled 7 CTD-TMA patients (SLE; 3, SS; 2, MCTD; 1, DM; 1) with refractory to PE treatment between 2006 and 2015. We examined the ADAMTS-13 activity, its inhibitor and ultra-large von Willebrand factor multimers (UL-VWFMs) at TMA onset. RTX was given 375mg/m2 per a dose. We defined complete response (CR) as platelet counts >150×109/l for more than 3 consecutive days, with normal levels of serum LDH and an absence of TMA-related symptoms. We considered CR continued more than 30 days after RTX treatment as remission. In addition, we investigated as follow subjects; duration from initial RTX treatment to CR, duration of sustained CR, relapse and adverse events.
Results No abnormality of ADAMTS-13 activity was observed 6 patients. The thrombocytopenia was improved immediately within 2–3 weeks after the initiation of RTX and hemolytic anemia and neuropsychiatric manifestations were improved following after the recovery of thrombocytopenia, respectively. 6 patients could achieve CR. They who achieved CR all have sustained long-term remission by only 1 or 2 doses of RTX administration and there was no relapse. RTX was partial response for 1 patient with insufficient recovery of thrombocytopenia but detectable serum haptoglobin and she was reported with controllable bacterial pneumonia.
Conclusions We suggest that RTX treatment has efficacy with high response rate and long-term remission for the refractory CTD-TMA patients. Moreover, RTX treatment can be the first-line treatment for CTD-TMA.
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Tomomi Matsuyama, Masataka Kuwana, Masanori Matsumoto, et.al. Heterogeneous pathogenic processes of thrombotic microangiopathies in patients with connective tissue diseases. Thromb Haemost. 2009; 102: 371–378.
Marina Noris, Federica Mescia, Giuseppe Remuzzi. STEC-HUS, atypical HUS and TTP are all diseases of complement activation. Nat. Rev. Nephrol. 2012; 8: 622–633.
Disclosure of Interest None declared