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The immunosuppressive treatment of immune-mediated thrombotic thrombocytopenic purpura (iTTP) in patients with intolerance or refractoriness to the B-cell depleting monoclonal antibody rituximab remains debated. Daratumumab, a plasma cell-directed monoclonal antibody targeting CD38, represents a therapeutic option, but data are scarce. The French Thrombotic Microangiopathies Reference Center conducted a nationwide survey on iTTP patients treated with daratumumab. Nine episodes from seven patients were identified. Treatment was administered for A Disintegrin And Metalloproteinase with ThromboSpondin-1 motifs, 13th member (ADAMTS13) relapses while patients were otherwise in clinical response (N = 8), or during the acute phase of the disease following rituximab intolerance (N = 1). Patients have received a median of three previous therapeutic lines. ADAMTS13 activity improved in eight cases following daratumumab administration, including three cases where ADAMTS13 normalized. ADAMTS13 relapses occurred in three patients; in two cases, retreatment with daratumumab was successful. Median ADAMTS13 relapse-free survival was not reached; 12-month ADAMTS13 relapse-free survival was 56%. Daratumumab-related adverse events occurred in five cases and were non-severe infusion-related reactions in all cases. These results suggest that daratumumab may be an effective treatment option for iTTP patients with intolerance or refractoriness to rituximab.
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OBJECTIVES: The association between immune-mediated thrombotic thrombocytopenic purpura (iTTP) and Sjögren disease (SjD) has been poorly investigated. This study presents the first retrospective cohort of iTTP-SjD aiming to identify risk factors for iTTP occurrence in SjD patients and examine their clinical course. METHODS: Patients with iTTP-SjD were identified within the French TTP Registry based on American College of Rheumatology/European League Against Rheumatism 2016 criteria. A comparative analysis was conducted with two control groups comprising primary SjD (pSjD) patients from the French ASSESS cohort and idiopathic iTTP patients from the French TTP Registry. Demographic, clinical and biological data were retrospectively collected. RESULTS: Thirty iTTP-SjD patients were included and compared with 65 pSjD and 45 idiopathic iTTP patients. The majority of iTTP-SjD patients (n=18) were diagnosed with SjD at the time of iTTP diagnosis. In comparison with the pSjD cohort, iTTP-SjD patients were diagnosed with SjD at a younger age (p=0.039) and showed a higher prevalence of anti-SjS-related antigen A antibody positivity and xerostomia (p=0.015, p=0.035, respectively). EULAR Sjogren's Syndrome Disease Activity Index showed similar activity levels between the two groups. iTTP-SjD patients were treated with plasma exchange (n=28), corticosteroids, rituximab (n=19) and caplacizumab (n=3). In comparison with the idiopathic iTTP cohort, mortality rates (log-rank tests, p=0.228), biological and clinical iTTP relapses (multivariate analysis, p=0.181) were comparable and short-term outcomes (survival at day 30, relapse) were favourable. CONCLUSION: iTTP can be a rare complication in patients with SjD. Further studies involving larger cohorts and long-term follow-up are warranted to confirm these findings and to explore the efficacy of immunomodulators and caplacizumab in iTTP-SjD patients.
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Púrpura Trombocitopénica Trombótica , Síndrome de Sjögren , Humanos , Síndrome de Sjögren/complicaciones , Síndrome de Sjögren/diagnóstico , Síndrome de Sjögren/mortalidad , Síndrome de Sjögren/inmunología , Femenino , Masculino , Persona de Mediana Edad , Adulto , Pronóstico , Estudios Retrospectivos , Púrpura Trombocitopénica Trombótica/diagnóstico , Púrpura Trombocitopénica Trombótica/terapia , Púrpura Trombocitopénica Trombótica/epidemiología , Sistema de Registros , Factores de Riesgo , Anciano , Francia/epidemiología , Rituximab/uso terapéuticoRESUMEN
Background: The COVID-19 pandemic related to SARS-CoV-2 virus was responsible for global pandemic. The severe form of the disease was linked to excessive activation of immune pathways together with a systemic cytokine storm response and thrombotic venous or arterial complications. Factors predicting severe outcomes including venous and/or pulmonary thrombosis (VT) and death were identified, but the prognostic role of their combination was not addressed extensively. Objectives: We investigated the role of prognostic factors from the coagulation or inflammatory pathways to better understand the outcome of the disease. Methods: For this, we prospectively studied 167 SARS-CoV-2-positive patients from admission in intensive care units (ICU) or emergency departments from four academic hospitals over a 14-month period. Besides standard biology, we assessed serum concentrations of inflammatory markers, coagulation factors and peripheral blood cells immunophenotyping. Results: Thirty-nine patients (23.3%) developed VT and 30 patients (18%) died. By univariate analysis, C-reactive protein (CRP) level > 150 mg/L, interleukin-6 (IL-6) ≥ 20 pg/mL, D-dimers > 1,500 µg/L, ADAMTS13 activity ≤ 50%, Von. Conclusion: A combination of coagulation and inflammatory markers can refine the prognostication of severe outcome in COVID-19, and could be useful for the initial evaluation of other types of viral infection.
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BACKGROUND: The immune form of thrombotic thrombocytopenic purpura (iTTP) and the hemolytic and uremic syndrome (HUS) are two major forms of thrombotic microangiopathy (TMA). Their treatment has been recently greatly improved. In this new era, both the prevalence and predictors of cerebral lesions occurring during the acute phase of these severe conditions remain poorly known. AIM: The prevalence and predictors of cerebral lesions appearing during the acute phase of iTTP and Shiga toxin-producing Escherichia coli-HUS or atypical HUS were evaluated in a prospective multicenter study. METHODS: Univariate analysis was performed to report the main differences between patients with iTTP and those with HUS or between patients with acute cerebral lesions and the others. Multivariable logistic regression analysis was used to identify the potential predictors of these lesions. RESULTS: Among 73 TMA cases (mean age 46.9 ± 16 years (range 21-87 years) with iTTP (n = 57) or HUS (n = 16), one-third presented with acute ischemic cerebral lesions on magnetic resonance imagery (MRI); two individuals also had hemorrhagic lesions. One in ten patients had acute ischemic lesions without any neurological symptom. The neurological manifestations did not differ between iTTP and HUS. In multivariable analysis, three factors predicted the occurrence of acute ischemic lesions on cerebral MRI: (1) the presence of old infarcts on cerebral MRI, (2) the level of blood pulse pressure, (3) the diagnosis of iTTP. CONCLUSION: At the acute phase of iTTP or HUS, both symptomatic and covert ischemic lesions are detected in one third of cases on MRI. Diagnosis of iTTP and the presence of old infarcts on MRI are associated with the occurrence of such acute lesions as well as increased blood pulse pressure, that may represent a potential target to further improve the therapeutic management of these conditions.
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Enfermedades del Sistema Nervioso Autónomo , Síndrome Hemolítico-Urémico , Púrpura Trombocitopénica Trombótica , Trombosis , Humanos , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Púrpura Trombocitopénica Trombótica/complicaciones , Púrpura Trombocitopénica Trombótica/epidemiología , Púrpura Trombocitopénica Trombótica/diagnóstico , Estudios Prospectivos , Síndrome Hemolítico-Urémico/complicaciones , Síndrome Hemolítico-Urémico/epidemiología , Síndrome Hemolítico-Urémico/diagnóstico , InfartoRESUMEN
The therapeutic landscape of thrombotic thrombocytopenic purpura (TTP) is rapidly changing with the recent availability of new targeted therapies. This progressive shift from empiricism to pathophysiology-based treatments reflects an intensive interaction between the continuous findings in the field of basic science and an efficient collaborative clinical research and represents a convincing example of the strength of translational medicine. Despite the rarity of TTP, national and international efforts could circumvent this limitation and shed light on the epidemiology, clinical presentation, prognosis, and long-term outcome of this disease. Importantly, they also provided high-quality results and practice changing studies for the benefit of patients. We report here the most recent therapeutic findings that allowed progressively improving the prognostic of TTP, both at the acute phase and through long-term outcome.