Controlling chronic TTP

Comment on Fakhouri et al, page 1932

For patients who have thrombotic thrombocytopenic purpura (TTP) associated with acquired severe ADAMTS13 deficiency, rituximab may be effective for helping to establish remission and prevent recurrence.

The effectiveness of plasma exchange treatment for thrombotic thrombocytopenic purpura (TTP) is established,¹  but the value of additional therapies remains unclear. Additional therapy is an important issue for patients who have difficulty achieving a remission or who have multiple relapses. For patients whose TTP is associated with severe acquired ADAMTS13 (a disintegrin-like and metalloprotease [reprolysin type] with thrombospondin type 1 motif 13) deficiency and an anti-ADAMTS13 inhibitory antibody, the presumed autoimmune etiology provides a rationale for immunosuppressive treatment. In this issue, Fakhouri and colleagues describe their experience with rituximab in 11 consecutive patients, all of whom had TTP associated with undetectable ADAMTS13 and anti-ADAMTS13 inhibitory activity, even if they had been in remission with no clinical evidence of TTP for 1 to 19 months. The authors report success in all 11 patients: 6 who were treated for acute episodes and 5 who were in remission but for whom prophylactic therapy seemed appropriate because of a history of 4 to 15 previous episodes over 4 to 28 years. The report is the first to describe rituximab therapy for prevention of relapse.

Readers should note several limitations of this study. First, describing rituximab as “curative” therapy is an overstatement; “remission” is a more accurate term, since patients with severe ADAMTS13 deficiency may have recurrent episodes. Although the authors conclude that “rituximab is a promising first-line immunosuppressive treatment,” glucocorticoids (used in all of their patients) are actually the “first-line” immunosuppressive treatment. What the authors suggest is that rituximab may be the next agent to try if glucocorticoids and plasma exchange are ineffective. Although rituximab appeared to be effective in preventing or at least deferring relapses, the follow-up time of 6 to 11 months is short, especially since many of their patients appeared to have declining ADAMTS13 activity during the course of follow-up. The authors define a “biologic remission” as ADAMTS13 activity more than 10% with no detectable inhibitor, but the prognostic value of ADAMTS13 measurements remains unclear. In this and other reports,²  patients were observed to have undetectable ADAMTS13 activity for prolonged periods, with or without a demonstrable inhibitor, but no evidence of TTP. Also, patients may have acute episodes of TTP when ADAMTS13 activity is detectable by current assays.²  Finally, this experience may not be relevant for the many patients currently treated for TTP who do not have severe ADAMTS13 deficiency.² 

What is the long-term prognosis for patients with severe ADAMTS13 deficiency who achieve a remission? The experience of the Oklahoma Thrombotic Thrombocytopenic Purpura-Hemolytic Uremic Syndrome (TTP-HUS) Registry is that half will have a recurrent acute episode. Most relapses occur within the first year, and many patients may have only one recurrence, but the course is unpredictable.²  For example, one of our patients (described on our website as “Emily's Story”³ ) had 5 episodes during her first year of illness but has had no further episodes following a splenectomy and cholecystectomy in 2000. Is her durable remission related to her splenectomy? Is it related to the cholecystectomy and removal of a source of chronic inflammation? Or is this simply the natural history of her TTP?

Although the report by Fakhouri and colleagues adds further support for a role for rituximab in the management of patients who have a prolonged course and difficulty achieving a remission, maintenance or prophylactic treatment with rituximab may have more risk than benefit for many patients until we have more accurate prognostic ability. ▪