The Prognostic Effects of Anti-ADAMTS13 IgG, IgA and IgM Antibody Subclasses In Acute Idiopathic TTP and the Effect of Rituximab,
Authors: McDonald Vickie , Machin Samuel J , Mackie Ian J , Scully Marie A 
Published: October 2019

Abstract
Abstract 3305
Acquired idiopathic TTP is associated with severe ADAMTS13 (A13) deficiency/anti-A13 IgG antibodies. Management is with plasma exchange (PEX) and immunosuppression. Rituximab is known to induce a sustained remission by eradicating the A13 inhibitor. We studied the prognostic value of anti-A13 IgG subclasses and the effect of rituximab on these antibodies. Anti-A13 IgG subclasses were detected using ELISA: microtitre plates coated with rADAMTS13 and antibody detected using biotinylated monoclonal anti-IgG1-4. Results: 70 acute episodes from a 4 year period were analysed. In addition, 23 deaths and 25 relapsed TTP episodes were selected to ensure adequate numbers in these groups for comparison. The median ADAMTS13 activity was <5% and the median IgG anti-ADAMTS13 was 48.5% (7–164.3%, normal <4%). The total IgG positively and significantly correlated with the number of IgG subclasses present. Increasing levels of IgG1-3 were associated with increasing total IgG however the levels of IgG4 did not correlate with total IgG levels. IgG4 and IgG1 inversely correlated with each other. IgG4 was the predominant subclass (74%), followed by IgG1 (73%), IgG2 (69%) and IgG3 (50%). This pattern was similar for de novo and relapsed cases and for men and women. The percentage of patients with 1,2,3 and 4 subclasses concurrently was 14, 29, 32 and 25% respectively showing that this is a polyclonal disease. De novo presentations were more likely to present with a greater number of subclasses than relapses. The mortality increased with increasing numbers of subclasses: 1 subclass 0%, 2 subclasses 15%, 3 subclasses 24% and 4 subclasses 31% mortality. The presence of IgG2 but not the other subclasses was associated with mortality (OR 12.4, p 0.018). IgG2 also correlated with cardiac disease. Higher IgG1 and 2 levels were seen in those with neurological and cardiac involvement. IgG2 and IgG4 significantly correlated with the number of PEX to remission (p<0.0001 and p 0.027 respectively). The median number of PEX increased with increasing numbers of IgG subclasses at presentation: one subclass 8.85, two subclasses 11.25, three subclasses 16 and four subclasses 24. 28% patients had IgA anti-ADAMTS13 at presentation and 7.9% had IgM. The total anti-ADAMTS13 IgG was higher in those with IgA (80%) compared to those without (39.6%, p 0.0004). The median PEX was not influenced by the presence of IgA (22 vs 15, p0.49). There was no influence of IgA on mortality however all of the relapses occurred in the IgA negative group.
A subset of 64 (48F/16M; 47de novo/17relapses; 3 deaths; median PEX 16) episodes had received weekly rituximab, median 4 doses, range 2–8. Of these patients, 60.9, 62.5, 42.2 and 81.3% patients had IgG 1, 2, 3 &4 respectively at presentation. On completing rituximab the %patients with IgG1, 2, 3 &4 was 48.1, 23.1, 3.8 and 51.9. By 6 months the percentages were 30.8, 12.8, 0 and 15 and at 12 months were 26.5, 6.1, 4.1 and 12.2. 25% patients had all 4 subclasses at presentation compared to 2% at 12months. The median A13 activity at 12 months was lower in those with persistent subclasses (63%) compared to those with none (77%) but the difference did not reach significance (p=0.06). Not all patients with antibody levels above the limit of detection had low A13 activity so clearly some antibodies are non-inhibitory. The median anti-A13 IgG subclass levels all fell with therapy (by >50% after 2 rituximab doses). 5.8% patients with no subclasses at 12months relapsed compared to 17.6% of those with detectable subclasses.
In conclusion, TTP is a polyclonal disease. The presence of increased numbers of IgG anti-ADAMTS13 subclasses is associated with increased mortality and increased PEX requirement. Rituximab leads to the eradication of most anti-A13 subclasses but IgG1&4 are more likely to remain above the normal range despite clinical remission and in some cases normalisation of ADAMTS13 activity. Persistence of antibodies in remission leads to an increased risk of relapse. IgA at presentation is associated with may protect from relapse.

Disclosures:
Off Label Use: This talk contains discussion of the off license use of rituximab in TTP.