End points for sickle cell disease clinical trials: patient-reported outcomes, pain, and the brain

To address the global burden of sickle cell disease (SCD) and the need for novel therapies, the American Society of Hematology partnered with the US Food and Drug Administration to engage the work of 7 panels of clinicians, investigators, and patients to develop consensus recommendations for clinical trial end points. The panels conducted their work through literature reviews, assessment of available evidence, and expert judgment focusing on end points related to: patient-reported outcomes (PROs), pain (non-PROs), the brain, end-organ considerations, biomarkers, measurement of cure, and low-resource settings. This article presents the findings and recommendations of the PROs, pain, and brain panels, as well as relevant findings and recommendations from the biomarkers panel. The panels identify end points, where there were supporting data, to use in clinical trials of SCD. In addition, the panels discuss where further research is needed to support the development and validation of additional clinical trial end points

Saudi SCD patients’ symptoms and quality of life relative to the number of ED visits

Background Individuals living with sickle cell disease (SCD) have significantly increased emergency department (ED) use compared to the general population. In Saudi Arabia, health care is free for all individuals and therefore has no bearing on increased ED visits. However, little is known about the relationship between quality of life (QoL) and frequency of acute care utilization in this patient population. Methods A cross-sectional study was conducted on 366 patients with SCD who attended the outpatient department at King Fahad Hospital, Hofuf, Saudi Arabia. Data were collected through self-administered surveys, which included: demographics, SCD-related ED visits, clinical issues, and QoL levels. We assessed the ED use by asking for the number of SCD-related ED visits within a 6-month period. Results The self-report survey of ED visits was completed by 308 SCD patients. The median number of SCD-related ED visits within a 6-month time period (IQR) was four (2-7 visits). According to the unadjusted negative binomial model, the rate of SCD-related ED visits increased by (46, 39.3, 40, and 53.5 %) for patients with fever, skin redness with itching, swelling, and blood transfusion, respectively. Poor QoL tends to increase the rate of SCD-related ED visits. Well education and poor general health positively influenced the rate of SCD-related ED visits. Well education tends to increase the rate of SCD-related ED visits by 50.2 %. The rate of SCD-related ED visits decreased by 1.4 % for every point increase in general health. Conclusion Saudi patients with sickle cell disease reported a wide range of SCD-related ED visits. It was estimated that six of 10 SCD patients had at least three ED visits within a 6-month period. Well education and poor general health resulted in an increase in the rate of SCD-related ED visits

Increased clearance of morphine in sickle cell disease: Implications for pain management

Acute vaso-occlusive painful episodes associated with sickle cell disease (SCD) are frequently treated with morphine. Many SCD individuals require relatively higher doses of morphine to achieve optimal analgesia. We studied pharmacokinetics of morphine in SCD to explore if altered disposition could be a factor for increased requirement of morphine in this population. The study subjects were in steady state of health to avoid the effect of hemodynamic changes associated with vaso-occlusion on morphine disposition. The plasma concentrations of morphine and its major metabolites were measured at timed intervals in 21 SCD subjects after they received a single 0.1 mg/ Kg infusion of morphine sulfate. USCPACK software was used to fit candidate pharmacokinetic models. Non-compartmental pharmacokinetic parameters for morphine were calculated. Morphine clearance was 2.4 – 3.6 L/h, half-life was 0.3 – 0.7 hours, AUC(0−∞) was 27.7 – 42.5 ng*h/mL, and volume of distribution was 0.96 – 3.38 L/kg. Clearance of morphine in the study population was 3 – 10 folds higher than published estimates in the non-SCD population, with correspondingly lower AUC and half-life. Volume of distribution was similar. This observation suggests that due to increased clearance SCD individuals may require higher dose and frequency of morphine to achieve comparable plasma levels

UGT2B7 promoter variant-840G > A contributes to the variability in hepatic clearance of morphine in patients with sickle cell disease

The purpose of the study was to determine if UDP-glucuronosyltransferase (UGT) 2B7 allelic variants encoding for UGT2B7, primary enzyme responsible for morphine glucuronidation contribute to the variability in the hepatic clearance of morphine in sickle cell disease (SCID). Twenty-four hour PK study of morphine and UGT2B7 variants genotyping was performed in 20 SCD patients in a steady state of health. Presence of the -840G allele (GG and GA) was associated with lower morphine metabolites/morphine AUC ratio compared with AA genotype (1.8 +/- 0.5 vs. 3.0 +/- 1.8 for M6G/M and 10.1 +/- 2.7 vs. 15.7 +/- 9.4 for M3G/M) (P = 0.03). Presence of UGT2B7 -840G allele is associated with significantly reduced glucuronidation of morphine and thus contributes to the variability in hepatic clearance of morphine in SCD

A GCH1 haplotype confers sex-specific susceptibility to pain crises and altered endothelial function in adults with sickle cell anemia.

GTP cyclohydrolase (GCH1) is rate limiting for tetrahydrobiopterin (BH4) synthesis, where BH4 is a cofactor for nitric oxide (NO) synthases and aromatic hydroxylases. GCH1 polymorphisms are implicated in the pathophysiology of pain, but have not been investigated in African populations. We examined GCH1 and pain in sickle cell anemia where GCH1 rs8007267 was a risk factor for pain crises in discovery (n = 228; odds ratio [OR] 2.26; P = 0.009) and replication (n = 513; OR 2.23; P = 0.004) cohorts. In vitro, cells from sickle cell anemia subjects homozygous for the risk allele produced higher BH4. In vivo physiological studies of traits likely to be modulated by GCH1 showed rs8007267 is associated with altered endothelial dependent blood flow in females with SCA (8.42% of variation; P = 0.002). The GCH1 pain association is attributable to an African haplotype with where its sickle cell anemia pain association is limited to females (OR 2.69; 95% CI 1.21-5.94; P = 0.01) and has the opposite directional association described in Europeans independent of global admixture. The presence of a GCH1 haplotype with high BH4 in populations of African ancestry could explain the association of rs8007267 with sickle cell anemia pain crises. The vascular effects of GCH1 and BH4 may also have broader implications for cardiovascular disease in populations of African ancestry

Uric Acid as a Potential Biomarker of Pulmonary Arterial Hypertension in Patients with Sickle Cell Disease

Serum uric acid (UA) is emerging as a strong and independent marker for pulmonary arterial hypertension (PAH). PAH is well recognized as a life threatening complication of sickle cell disease (SCD). However, the association between UA and PAH in SCD is unknown. We reviewed electronic medical records (EMR) of 559 consecutive adult SCD patients from Kings County Hospital Center (KCHC) between January 2005 and February 2010. Patients (n = 96) with measurement of UA in close temporal proximity to the transthoracic echocardiography (TTE) were identified. PAH was defined as pulmonary artery systolic pressure (PASP) ≥30 mm Hg. Patients (n = 16) with other risk factors which may cause PAH and chronic renal insufficiency were excluded. In 18 patients, TTE could not measure PASP. Finally, 62 patients were selected. Statistical analysis was performed using Student t tests, Pearson correlation coefficient and multivariate regression analysis. Out of 62 patients, 30 had PAH. Patients with PAH had a higher UA level (8.67 ± 4.8 vs. 5.35 ± 2.1, P = 0.001). We found strong positive correlation between the UA level and PASP (r = 0.71; P < 0.0001). This correlation was independent of diuretic use. UA could be a potential marker for PAH in SCD. However, its’ prognostic and pathophysiologic role in SCD patients with PAH needs to be further investigated