Relapse Rate in Survivors of Acute Autoimmune Thrombotic Thrombocytopenic Purpura Treated with or without Rituximab

Abstract

Background: Autoimmune thrombotic thrombocytopenic purpura (iTTP) is caused by autoantibody-mediated severe a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13 (ADAMTS13) deficiency leading to micro-angiopathic haemolytic anaemia (MAHA) and thrombocytopenia with organ damage. Patients survive with plasma exchange (PEX), fresh frozen plasma replacement and corticosteroid treatment. Anti-CD20 monoclonal antibody rituximab is increasingly used in patients resistant to conventional PEX or relapsing after an acute bout.

Objective: This retrospective observational study focused on the relapse rate and possible influencing factors including treatment with rituximab first introduced in 2003.

Patients and methods: Seventy patients treated between January 2003 and November 2014 were evaluated. Number, duration, clinical manifestations, laboratory data and treatment of acute episodes were documented. Diagnostic criteria of acute iTTP were thrombocytopenia, MAHA, increased lactate dehydrogenase and severe ADAMTS13 deficiency.

Results: Fifty-four female and 16 male patients had a total of 224 acute episodes over a median observation period of 8.3 years. The relapse rate was 2.6% per month, for women 2.4% and for men 3.5% per month. Since 2003, 17 patients with a first iTTP episode were treated with rituximab, whereas 28 were not. There was a trend towards lower relapse rates after rituximab treatment over the ensuing years. However, this was statistically not significant.

Conclusion: This analysis does not show a significant reduction of acute iTTP relapses by rituximab given during an acute bout. Initial episodes are characterized by more severe clinical signs compared with the less severe relapses. Furthermore, men suffer significantly more frequent and considerably more serious acute relapses.

Fig. 1

Patients' recruitment. *Five autoimmune thrombotic thrombocytopenic purpura (iTTP) patients consulted the UMC after having survived their first acute episode. At the time of consultation they showed a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13 (ADAMTS13) activities of 16, 19, 15, 17 and 18%, with/ without weak ADAMTS13 inhibitors. All other iTTP patients had documented severe ADAMTS13 deficiency (< 10%) during acute episode.

Fig. 2

Treatment of acute autoimmune thrombotic thrombocytopenic purpura (iTTP) episodes.

Fig. 3

Frequency of the different clinical severity scores at first, second and all following bouts in 70 autoimmune thrombotic thrombocytopenic purpura (iTTP) patients. During the first iTTP manifestation, the proportion of severe episodes was higher than during 1st relapse and all subsequent relapses. Absolute numbers in a total of 219 bouts: 1st manifestation: laboratory (0): n  = 1, mild (1): n  = 11, moderate (2): n  = 22, severe (3): n  = 34; 1st relapse: laboratory (0): n  = 2, mild (1): n  = 19, moderate (2): n  = 8, severe (3): n  = 7, death (4): n  = 1; all further relapses: laboratory (0): n  = 18, mild (1): n  = 64, moderate (2): n  = 11, severe (3): n  = 14, death (4): n  = 1.

Fig. 4

Event history of all autoimmune thrombotic thrombocytopenic purpura (iTTP) patients with detailed therapy data. Acute iTTP episodes of all 70 patients from the first day of first acute thrombotic thrombocytopenic purpura (TTP) episode until end of observation time in days. Patients were pseudonymized with a number code. Men are listed (above dotted horizontal line no. 19–156) in the upper part and women in the lower part of the figure (below dotted line no. 2–155). Acute iTTP episodes are represented by a black dot. If being treated by rituximab, this circle is bordered by red rectangles. Empty circles represent the last day of observation. Two patients died during a relapse (Died): including one woman following her first acute TTP relapse (no. 82). She had denied plasma products for religious beliefs. One man did not survive his 13th acute TTP episode (no. 44).

Fig. 5

Kaplan–Meier estimates of relapse-free survival of 45 autoimmune thrombotic thrombocytopenic purpura (iTTP) patients with a first disease bout since 2003. Relapse-free survival of iTTP patients receiving rituximab ( n  = 17) (upper dotted curve) compared with iTTP patients who did not receive rituximab ( n  = 28) (lower curve) during their first acute thrombotic thrombocytopenic purpura (TTP) bout. Vertical bars denote censored patients not having suffered from relapse. There was no statistical difference between these groups ( p -value = 0.131).