iTPP: nature vs nurture?

In this issue of Blood, Chaturvedi et al¹ present a retrospective analysis of a large idiopathic thrombotic thrombocytopenic purpura (iTPP) cohort. This large US multicenter study confirms that race impacts the relapse risk and response to rituximab in iTTP.

Over the past 30 years, the survival for those with iTPP improved dramatically. Plasma exchange² was a major advance, resulting in improved rates of response and survival compared with plasma infusion. The latest major advance, caplacizumab, which improved normalization of the platelet count, decreased the recurrence rate of iTPP and the need for plasma exchange,³ came into general clinical use after the 2020 end date for this study. Rituximab and steroids were the mainstays of treatment during the 25 years covered by this study.

Chaturvedi et al have documented statistically significant differences in iTTP between those described as Black vs White. Blacks are overrepresented in iTPP registries but disparities in outcome have not been fully explored.⁴ In this study, the authors found no significant differences in treatment exposure between Black and White patients. However, Black patients were more likely to have a shorter time to relapse and less of a response to rituximab.

Martino et al previously proposed that a low natural frequency of HLA-DRB1*04 in Black ethnicity may account for the greater risk of TTP, but with better overall survival compared with White patients.⁵ There are also differences in B-cell repletion in other disease conditions by race, such as multiple sclerosis and neuromyelitis optica. The reason for differences in B cells is not clear but activating factors could play a role. In a relatively small cohort, B cells from Blacks had lower anti-immunoglobulin D (IgD)-induced phosphorylation of multiple B-cell receptor pathway components, including the membrane proximal proteins Syk and SFK as well as proteins in the PI3K pathway (S6 and Akt), the MAPK pathways (Erk and p38), and the nuclear factor-κB pathway.⁶ Racial differences in B-cell receptor signaling kinetic profiles were observed, and the frequency of IgD⁺ B cells differed by race and correlated with B-cell receptor pathway activation. Thus, the race-related difference in B-cell receptor pathway activation appears to be attributable at least in part to a race-associated difference in IgD⁺ B-cell frequencies.⁶ 

If genetic differences do exist between Blacks and Whites, perhaps single nucleotide polymorphisms are more common in Blacks that are influenced by environmental exposure. In the United States, Blacks are more likely to live in poverty and areas with more toxic stress.⁷ Environmental exposure to acute and chronic stressors is associated with more chronic disease, more health complications, and a shorter lifespan.⁸ The current study did not include any measure of socioeconomic status, so no conclusion can be made about the association between income, education, environment, and so on, and the outcomes of people with iTTP. Racial disparities in cancer survival in the United States are well documented and has also been linked to sociodemographic and neighborhood characteristics. The combination of biologic factors and environmental exposures likely contribute to these health outcomes.

The results of this retrospective analysis are provocative. As with many other diseases and treatments, variations in disease incidence, severity, and response to treatment varies within and between races. Other investigators have identified single nucleotide polymorphisms associated with the levels of ADAMTS13⁹ and von Willebrand factor,¹⁰ race, sex, and the incidence and severity of disease. These data are hypotheses generating. One general hypothesis is that there are specific genetic disease related modifiers that are encoded in the genome. Another hypothesis is that socioeconomic differences in access to care, adherence to therapies, or environmental exposures affect outcomes. Given the status of iTPP as a rare disease, collaborative efforts are needed to collect both biologic samples for genetic analyses and more sociodemographic and environmental measures to better understand the drivers of the disease and the response to treatment. The task ahead will be to define the mechanisms by which ethnicity and environment affect responses and durations of responses with iTPP. Although this work is under way, Black patients with iTTP require closer monitoring for relapse and may benefit from alternative therapy if the response to rituximab is not satisfactory.