Prevalence and cost of sickle cell disease in France: real-world analysis using data from the Echantillon Généraliste des Bénéficiaires.

Sickle cell disease (SCD) is a genetic disorder of the hemoglobin resulting in chronic anemia, hemolysis, and vaso-occlusions. Its treatment mostly relies on hydroxycarbamide, transfusions, and stem cell transplantation. This study aimed at describing the epidemiology and management of SCD in adolescent and adult patients in France. This was a retrospective study performed among SCD patients aged ≥12 years between 2016 and 2018 and controls. SCD patients were matched on a 1:3 ratio with a group of individuals with no diagnosis of SCD, referred as control group. The matching of SCD patients and controls was a direct matching based on age, sex, CMU-c status (which corresponds to free-of-charge complementary coverage for people with low resources) and geographical region of residence. SCD patients and their matched controls were followed-up for the same amount of time by adjusting controls' follow-up period to that of the associated patients. This study used claims data from the French representative 1/97th sample of health data system. The main outcomes were the patients' characteristics and treatments received, healthcare consumptions and related costs among SCD cases and controls. Between 2016 and 2018, 151 patients with ≥6 months of follow-up were identified out of the total population of 732,164 individuals. SCD prevalence extrapolated to the entire population [95% CI] was 19,502 [19,230, 19,778] in 2018. The median (Q1-Q3) age at inclusion date was 37.0 (25.0-48.0) years, with 69.5% of patients being female. The mean (SD) reimbursed cost over follow-up was €24,310 (89,167), mostly represented by hospitalization costs accounting for €21,156 (86,402). A switch in SCD management was observed with age, as younger patients presented more frequent hospitalizations and acute procedures, while older ones had more frequent medical visits and paramedical care. Mean (SD) annual costs were €25,680 (91,843) and vs. €3,227 (23,372) for patients and controls, respectively (p < 0.001), representing an extra cost of almost €150 million over the entire SCD population. This study highlighted the important costs related to SCD and the related medical need with treatment alternatives, which could be filled by the emergence of new therapies.

Epidemiology and disease burden of sickle cell disease in France: A descriptive study based on a French nationwide claim database.

CONTEXT: Sickle cell disease (SCD) is a severe hematological disorder. The most common acute complication of SCD is vaso-occlusive crisis (VOC), but SCD is a systemic disease potentially involving all organs. SCD prevalence estimates rely mostly on extrapolations from incidence-based newborn screening programs, although recent improvements in survival may have led to an increase in prevalence, and immigration could account for a substantial number of prevalent patients in Europe. The primary objective of this study was to estimate SCD prevalence in France. METHODS: A cross-sectional observational study was conducted using a representative sample of national health insurance data. SCD patients followed up in France between 2006 and 2011 were captured through hydroxyurea reimbursement and with the International Classification of Diseases (ICD-10) SCD specific code D570.1.2, excluding code D573 (which corresponds to sickle cell trait (SCT)). Nevertheless, we assumed that ICD-10 diagnosis coding for inpatient stays could be imperfect, with the possibility of SCT being miscoded as SCD. Therefore, prevalence was analyzed in two groups of patients [with at least one (G1) or two (G2) inpatient stay] based on the number of SCD-related inpatient stays in the six-year study period, assuming that SCT patients are rarely rehospitalized compared to SCD. The prevalence of SCD in the sample, which was considered to be representative of the French population, was then extrapolated to the general population. The rate of vaso-occlusive crisis (VOC) events was estimated based on hospitalizations, emergencies, opioid reimbursements, transfusions, and sick leave. RESULTS: Based on the number of patients identified for G1 and G2, the 2016 French prevalence was estimated to be between 48.6 per 100,000 (G1) or 32,400 patients and 29.7 per 100,000 (G2) or 19,800 patients. An average of 1.51 VOC events per year were identified, with an increase frequency of 15 to 24 years of age. The average annual number of hospitalizations was between 0.70 (G1) and 1.11 (G2) per patient. Intensive care was observed in 7.6% of VOC-related hospitalizations. Fewer than 34% of SCD patients in our sample received hydroxyurea at any point in their follow-up. The annual average cost of SCD care is €5,528.70 (G1) to €6,643.80 (G2), with most costs arising from hospitalization and lab testing. CONCLUSION: Our study estimates SCD prevalence in France at between 19,800 and 32,400 patients in 2016, higher than previously published. This study highlights the significant disease burden associated with vaso-occlusive events.

Magnetic Resonance Imaging Assessment of Kidney Oxygenation and Perfusion During Sickle Cell Vaso-occlusive Crises.

BACKGROUND: Our understanding of the pathophysiologic processes underlying sickle cell nephropathy remains incomplete. We performed a pilot study to investigate the potential value of magnetic resonance imaging (MRI) for the assessment of kidney oxygenation and detection of potential changes to tissue perfusion and cellular integrity during a vaso-occlusive crisis. STUDY DESIGN: A case-control study. SETTING & PARTICIPANTS: 10 homozygous patients with sickle cell disease (SCD), without kidney disease (based on estimated glomerular filtration rate and albuminuria), underwent renal MRI during a vaso-occlusive crisis episode. The imaging data obtained were compared with those for a second MRI performed at steady state (median, 56 [IQR, 37-72] days after the vaso-occlusive crisis MRI). The control group consisted of 10 apparently healthy individuals. MEASUREMENTS: Deoxyhemoglobin level assessed by R2* value was calculated using the blood oxygen level-dependent technique. The intravoxel incoherent motion diffusion-weighted imaging technique was used to calculate D, D*, and F parameters. RESULTS: Median medullary R2* values on steady-state MRI were significantly higher for patients with SCD than for controls (P=0.01) and did not change significantly during the vaso-occlusive crisis. No significant differences in median cortical R2* values were observed. Both cellular integrity (D) and local perfusion (D* and F) were significantly altered in medullary and cortical areas during vaso-occlusive crises in comparison to steady state in patients with SCD. These parameters did not differ significantly between patients with SCD assessed at steady state and the control group. LIMITATIONS: Small sample size, estimation of glomerular filtration rate according to CKD-EPI creatinine equation without adjustment for race. CONCLUSIONS: Deoxyhemoglobin levels in the medullary area are higher in patients with SCD, during vaso-occlusive crises and at steady state, than in controls. Alterations to the tissue perfusion and cellular integrity of renal parenchyma are a common finding during vaso-occlusive crises that provide additional evidence that a vaso-occlusive crisis may be associated with subclinical kidney injury detectable on MRI.

A potent oral P-selectin blocking agent improves microcirculatory blood flow and a marker of endothelial cell injury in patients with sickle cell disease.

Abnormal blood flow accounts for most of the clinical morbidity of sickle cell disease (SCD) [1,2]. Most notably, occlusion of flow in the microvasculature causes the acute pain crises [3] that are the commonest cause for patients with SCD to seek medical attention [4] and major determinants of their quality of life [5]. Based on evidence that endothelial P-selectin is central to the abnormal blood flow in SCD we provide results from four of our studies that are germane to microvascular blood flow in SCD. A proof-of-principle study established that doses of heparin lower than what are used for anticoagulation but sufficient to block P-selectin improved microvascular blood flow inpatients with SCD. An in vitro study showed that Pentosan Polysulfate Sodium (PPS) had greater P-selectin blocking activity than heparin. A Phase I clinical study demonstrated that a single oral dose of PPS increased microvascular blood flow in patients with SCD. A Phase II clinical study that was not completed documented that daily oral doses of PPS administered for 8 weeks lowered plasma levels of sVCAM-1 and tended to improve microvascular blood flow in patients with SCD. These data support the concept that P-selectin on the microvascular endothelium is critical to both acute vascular occlusion and chronically impaired microvascular blood flow in SCD. They also demonstrate that oral PPS is beneficial to microvascular sickle cell blood flow and has potential as an efficacious agent for long-term prophylactic therapy of SCD.

A randomized, controlled clinical trial of ketoprofen for sickle-cell disease vaso-occlusive crises in adults.

Vaso-occlusive crisis (VOC) is the primary cause of hospitalization of patients with sickle-cell disease. Treatment mainly consists of intravenous morphine, which has many dose-related side effects. Nonsteroidal antiinflammatory drugs have been proposed to provide pain relief and decrease the need for opioids. Nevertheless, only a few underpowered trials of nonsteroidal antiinflammatory drugs for sickle-cell VOC have been conducted, and conflicting results were reported. We conducted a phase 3, double-blind, randomized, placebo-controlled trial with ketoprofen (300 mg/day for 5 days), a nonselective cyclooxygenase inhibitor, for severe VOC in adults. A total of 66 VOC episodes were included. The primary efficacy outcome was VOC duration. The secondary end points were morphine consumption, pain relief, and treatment failure. Seven VOC episodes in each group were excluded from the analysis because of treatment failures. No significant between-group differences were observed for the primary outcome or the secondary end points. Thus, although ketoprofen was well-tolerated, it had no significant efficacy as treatment of VOC requiring hospitalization. These findings argue against its systematic use in this setting.