Y. Benhamou

Preemptive rituximab infusions after remission efficiently prevent relapses in acquired thrombotic thrombocytopenic purpura

In acquired thrombotic thrombocytopenic purpura (TTP), the persistence of severe ADAMTS13 deficiency (<10%) during remission is associated with more relapse. Preemptive (ie, after remission) administration of rituximab in these patients to prevent relapses remains controversial. We performed a cross-sectional analysis of 12-year follow-up data to compare the relapse incidence with or without preemptive rituximab infusion. Among 48 patients who experienced at least one episode of acquired TTP followed by severe ADAMTS13 deficiency during remission, 30 received preemptive rituximab (group 1); the other 18 did not (group 2). After a median of 17 months (interquartile range [IQR], 11-29) following rituximab, the relapse incidence decreased from 0.57 episodes/year (IQR, 0.46-0.7) to 0 episodes/year (IQR, 0-0.81) (P < .01) in group 1. ADAMTS13 activity 3 months after the first rituximab infusion increased to 46% (IQR, 30%-68%). Nine patients required additional courses of rituximab. In 5 patients, ADAMTS13 activity failed to increase durably. Four patients experienced manageable adverse effects. In group 2, the relapse incidence was higher (0.5 relapses/year; IQR, 0.12-0.5; P < .01). Relapse-free survival was longer in group 1 (P = .049). A persistent severe ADAMTS13 deficiency during TTP remission should prompt consideration of preemptive rituximab to prevent relapses.

Development and validation of a predictive model for death in acquired severe ADAMTS13 deficiency-associated idiopathic thrombotic thrombocytopenic purpura: the French TMA Reference Center experience

Background Acquired thrombotic thrombocytopenic purpura is still associated with a 10–20% death rate. It has still not been possible to clearly identify early prognostic factors of death. This study involved thrombotic thrombocytopenic purpura patients with acquired severe (<10% of normal activity) ADAMTS13 deficiency and aimed to identify prognostic factors associated with 30-day death. Design and Methods The study involved a prospective cohort of patients and was carried out between October 2000 and August 2010. A validation cohort of patients was set up from September 2010 to August 2011. Altogether, 281 (analysis cohort) and 66 (validation cohort) consecutive adult thrombotic thrombocytopenic purpura patients with acquired severe ADAMTS13 deficiency were enrolled. The study evaluated 30-day mortality after treatment initiation according to characteristics at inclusion. Results Non-survivors (11%) were older (P=10−6) and more frequently presented arterial hypertension (P=5.10−4) and ischemic heart disease (P=0.013). Prognosis was increasingly poor with age (P=0.004). On presentation, cerebral manifestations were more frequent in non-survivors (P=0.018) and serum creatinine level was higher (P=0.008). The most significant independent variables determining death were age, severe cerebral involvement and LDH level 10 N or over. A 3-level risk score for early death was defined and confirmed in the validation cohort using these variables, with higher values corresponding to increased risk of early death. Conclusions A risk score for early death was defined in patients with thrombotic thrombocytopenic purpura and validated on an independent cohort. This score should help to stratify early treatment and identify patients with a worse prognosis.

Cardiac troponin-I on diagnosis predicts early death and refractoriness in acquired thrombotic thrombocytopenic purpura. Experience of the French Thrombotic Microangiopathies Reference Center

Cardiac involvement is a major cause of mortality in patients with thrombotic thrombocytopenic purpura (TTP). However, diagnosis remains underestimated and delayed, owing to subclinical injuries. Cardiac troponin‐I measurement (cTnI) on admission could improve the early diagnosis of cardiac involvement and have prognostic value.

Rituximab in autoimmune thrombotic thrombocytopenic purpura: A success story

Despite a significant improvement of thrombotic thrombocytopenic purpura (TTP) prognosis since the use of plasma exchange, morbidity and mortality remained significant because of poor response to standard treatment or exacerbations and relapses. Rituximab, a chimeric monoclonal antibody directed against the B-lymphocyte CD20 antigen, has shown a particular interest in this indication. Recent studies also reported strong evidence for its efficiency in the prevention of relapses. This review addresses these recent progresses and still opened questions in this topic: should rituximab be proposed in all patients at the acute phase? Should all patients benefit from a preemptive treatment? Is the infectious risk acceptable in this context?

Adult-onset renal thrombotic microangiopathy and pulmonary arterial hypertension in cobalamin C deficiency

An 18-year-old man presented in January, 2015, with 48 h of worsening dyspnoea and 1 month of lower limb oedema. He had had language retardation diagnosed at age 3 years, attributed to an emotional shock after the death of his brother, but he had had no specifi c investigations. On admission he was apyrexial with blood pressure 210/100 mm Hg and bilateral basal crackles on auscultation of the chest. Urine dipstick showed microscopic haematuria and proteinuria. Investigations (appendix) showed haemolytic anaemia and mild thrombocytopenia, and renal failure with nephrotic syndrome and haematuria. 3 days after admission, because of progressive renal failure and dyspnoea, and concerns about renal thrombotic microangiopathy (TMA), he was transferred to the medical intensive care unit (ICU) of our hospital. CT scan showed normal kidney morphology and pulmonary oedema. Echocardiography showed raised systolic pulmonary artery pressure with left ventricular hypertrophy without systolic dysfunction. The eye fundus was normal. We started intravenous methylprednisolone, plasma exchange, and haemodialysis in view of features of rapidly progressive glomerulonephritis. Autoimmune investigations were negative. Renal histology done 48 h after admission to ICU showed major stenosing fi broproliferative myxoid lesions in the interlobular arteries, consistent with renal TMA. The glomeruli had an ischaemic appearance with thickened, ribbon-like glomerular basement membranes; there was no proliferation, intracapillary thrombosis, or glomerular endothelial lesion. Immunofl uorescence showed granular glomerular deposits of IgM, without IgG or C3. We ruled out thrombotic thrombocytopenic purpura (TTP) because ADAMTS 13 activity was greater than 10%, and Shiga-toxin related haemolytic uraemic syndrome on PCR for Shiga-like toxin. We could identify no obvious cause of secondary renal TMA so considered the possibility of complement-mediated haemolytic and uraemic syndrome. The patient’s brother had died at the same age, from pulmonary veno-occlusive disease associated with hypertrophic cardiomyopathy. 1 year previously he had been diagnosed with end-stage kidney disease of unknown origin; he had had no history of cognitive impairment. Autopsy showed pulmonary capillary haemangiomatosis and renal lesions, similar to those of his brother. No specifi c biochemical or genetic analysis had been done, and the diagnosis was inconclusive. Workup for cobalamin C (cblC) defi ciency in our patient showed raised concentrations of plasma homocysteine, methylmalonic acid, and propionylcarnitine. We started high-dose intramuscular hydroxycobalamin, and oral betaine and folinic acid. Haemolysis improved within 1 week and he was transferred to the nephrology department on day 10 where his haemodialysis was continued every other day. Right heart catheterisation on day 12 showed mild postcapillary pulmonary hypertension. CT showed no sign of pulmonary veno-occlusive disease. He was discharged 1 month after admission to ICU, with total plasma homocysteine 33 μmol/L (target <70 μmol/L). 5 months later he stopped dialysis with serum creatinine stable around 147 μmol/L. Brain MRI was normal. Genetic analyses confi rmed a compound heterozygosity in MMACHC, with c.271dupA and c.82-12_82-9delTTTC sequence variants, inherited from the patient’s mother and father, respectively. CblC defi ciency, the most common inherited disease of vitamin B12 metabolism, is related to variants in MMACHC. Signs are abnormal concentrations of downstream metabolites of the cobalamin pathway (appendix) with normal vitamin B12. The most frequent and severe presentation occurs in neonates. Pulmonary artery hypertension (PAH) and renal TMA have been described in early-onset cblC defi ciency, whereas isolated neuropsychiatric symptoms prevail in adult-onset forms. A case of adult-onset renal TMA had similar renal outcomes to our patient. The family history and coexistence of a specifi c glomerulopathy in our patient suggest that PAH, renal TMA, and the glomerular lesions are consequences of the variants in MMACHC. This association has been reported in a series of children aged 1–14 years. The glomerular lesions in our case are similar to those described in a 16-year-old with renal failure and a biochemical profi le characteristic of cblC defi ciency, with membrano proliferative lesions with intramembranous granular deposits. How specifi c sequence variants in MMACHC might cause renal and pulmonary vasculopathy is unclear. Hyperhomocysteinaemia alone cannot be the cause because PAH and TMA are usually absent in disorders with very high homocysteine concentrations, such as cystathionine synthase defi ciency. We speculate that endothelial dysfunction, triggered by intracellular and systemic consequences of MMACHC variants, could promote thrombosis, vasoconstriction, and vascular smooth muscle cell proliferation. The c.271dupA variant is the most frequent genetic abnormality described in cblC defi ciency, especially in neonates. The c.82-12_82-9delTTTC variant has been described in only three patients who presented late, possibly because of splicing defects resulting from this intronic deletion. Adult-onset renal thrombotic microangiopathy and pulmonary arterial hypertension in cobalamin C defi ciency

Are platelet transfusions harmful in acquired thrombotic thrombocytopenic purpura at the acute phase? experience of the French thrombotic microangiopathies reference center

enzyme inhibitors or angiotensin receptor blockers highlights the need for close BP monitoring, and dose adjustments in the peri-ASCT setting. A retrospective, non-validated study of 163 patients, without a multivariate analysis, found inferior progression-free survival and overall survival with the use of angiotensinconverting-enzyme inhibitors [7]. Although the current study includes a heterogeneous group of MM patients, there was no significant difference in progression-free survival for those who had early ASCT (more than half of whom were on maintenance therapy), with the use of angiotensin-converting-enyzme inhibitors or angiotensin receptor blockers or in the presence of hypotension. Eighteen patients met criteria for hypotension based on discontinuation of antiHTNs. Perhaps if these medications had not been discontinued, more adverse events would have occurred. The 43% incidence of hypotension associated with high-dose chemotherapy has significant implications for BP monitoring and anti-HTN adjustment, in a patient population that is often fatigued/deconditioned, hypovolemic, febrile, and thrombocytopenic and therefore at a high fall risk without early intervention.

Efficacy of a rituximab regimen based on B cell depletion in thrombotic thrombocytopenic purpura with suboptimal response to standard treatment: Results of a phase II, multicenter noncomparative study.

The standard four‐rituximab infusions treatment in acquired thrombotic thrombocytopenic purpura (TTP) remains empirical. Peripheral B cell depletion is correlated with the decrease in serum concentrations of anti‐ADAMTS13 and associated with clinical response. To assess the efficacy of a rituximab regimen based on B cell depletion, 24 TTP patients were enrolled in this prospective multicentre single arm phase II study and then compared to patients from a previous study. Patients with a suboptimal response to a plasma exchange‐based regimen received two infusions of rituximab 375 mg m−2 within 4 days, and a third dose at day +15 of the first infusion if peripheral B cells were still detectable. Primary endpoint was the assessment of the time required to platelet count recovery from the first plasma exchange. Three patients died after the first rituximab administration. In the remaining patients, the B cell‐driven treatment hastened remission and ADAMTS13 activity recovery as a result of rapid anti‐ADAMTS13 depletion in a similar manner to the standard four‐rituximab infusions schedule. The 1‐year relapse‐free survival was also comparable between both groups. A rituximab regimen based on B cell depletion is feasible and provides comparable results than with the four‐rituximab infusions schedule. This regimen could represent a new standard in TTP. This trial was registered at www.clinicaltrials.gov (NCT00907751). Am. J. Hematol. 91:1246–1251, 2016.

Infliximab improves endothelial dysfunction in a mouse model of antiphospholipid syndrome: Role of reduced oxidative stress

Antiphospholipid syndrome (APS), induces endothelial dysfunction, oxidative stress and systemic inflammation that may be mediated by TNFα. Thus, we investigated the possible protective effect of the anti-TNFα antibody infliximab (5μg/g) on endothelial function in a mouse APS model (induced by injection of purified human anti-β2GP1-IgG). Seven days after anti-β2GPI-IgG injection, we observed an increase in plasma sVCAM-1 and sE-selectin levels and in aortic mRNA expression of VCAM-1 and E-selectin. This was associated with a decreased endothelium-dependent relaxation of isolated mesenteric arteries to acetylcholine, together with decreased mesenteric eNOS mRNA expression and increased eNOS uncoupling, accompanied by increased iNOS and gp91phox mRNA and increased left ventricular GSH/GSSH ratio. Infliximab significantly improved the NO-mediated relaxing responses to acetylcholine, and induced a decrease in iNOS and gp91phox mRNA expression. The õpro-adhesive and pro-coagulant phenotypes induced by the anti-β2GP1-IgG were also reversed. This study provides the first evidence that TNFα antagonism improves endothelial dysfunction in APS and suggests that endothelial dysfunction is mediated by TNFα and oxidative stress. Therefore, infliximab may be of special relevance in clinical practice.

Twice-daily therapeutical plasma exchange-based salvage therapy in severe autoimmune thrombotic thrombocytopenic purpura: the French TMA Reference Center experience

Daily therapeutic plasma exchange (TPE) and rituximab improved thrombotic thrombocytopenic purpura (TTP) prognosis. In the more severe cases, salvage therapies including twice‐daily TPE and/or cyclophosphamide may be proposed and require evaluation.

Statines en prévention primaire des événements cardiovasculaires

Cardiovascular events are the second leading cause of death in France. The assessment of overall cardiovascular risk using a personalized assessment with weighting risk factors can predict the risk of cardiovascular events in ten years. The validated treatments to reduce cardiovascular mortality in primary prevention are few. The use of statins in primary prevention is discussed. We report in this review the updated conclusions from clinical trials regarding the treatment with statins in primary prevention.