Clinical and Genetic Profiles of the Aging Sickle Cell Patient

Abstract The life expectancy of many patients with sickle cell disease (SCD) is well into the 5th and 6th decade, but this remains extremely variable. Little is known about the biological factors that protect certain SCD patients from early demise while others never reach mid-adulthood. Recently, McKerrell and colleagues (2004) compared the clinical and laboratory profiles of SCD patients aged 40 years and over with SCD patients who were between 21 and 30 years of age. Similarly, we have compared clinical and genetic correlates of older SCD patients (50 years and over) with those of younger patients (18–30 years). Among 514 patients in our total study population, 49 (10%) were categorized as “older” and 194 (38%) were categorized as “younger.” Older SCD patients had lower hemoglobin (older: 7.8 ± 1.1 vs. younger: 8.5 ± 1.2, p=0.004), platelet count (older: 372 ± 126 vs. younger: 460 ± 225, p=0.02), MCV (older: 92 ± 12 vs. younger: 89 ± 9, p=0.08), MCHC (older: 33.6 ± 1.4 vs. younger: 34.3 ± 1.8, p=0.05), and WBC (older: 10.2 ± 2.7 vs. younger: 13.1 ± 4.1, p<0.001). Older patients also had lower total bilirubin (p=0.01), and increased alkaline phosphatase (p=0.0002) and creatinine (p=0.0002), which was associated with poorer creatinine clearance (p<0.0001). The older SCD patients also had increased systolic (p<0.0001) and diastolic (p=0.008) blood pressure, decreased O2 saturation (p=0.03), and a history of fewer pain episodes per year requiring medical treatment (p<0.0001). Many of our findings are consistent with those of McKerrell et al. (2004). In order to identify genetic factors associated with longevity in SCD, we examined 155 SNPs in a total of 41 genes, primarily involved in red blood cell adhesion and inflammation pathways. Chi Square tests of association were constructed for the genotypes of each SNP with the two clinical categories: “older” and “younger.” When the number of rare homozygotes was less than 5 individuals, we combined those individuals with the heterozygote individuals for analysis. All p-values are uncorrected for multiple testing. We found putative associations with 5 SNPs in 3 genes. Three non-coding SNPs in Klotho, not in linkage disequilibrium, exhibited different genotype frequencies in the older versus younger SCD patients (p=0.007, p=0.01 and p=0.01). Similarly, a single non-coding SNP in NOS2A (p=0.02) and TGFBR2 (p=0.02) also exhibited significantly different genotype frequencies in the older versus younger patients. These data support the clinical findings in aging SCD patients reported by McKerrell and colleagues (2004), and they also suggest that genetic factors contribute to variability in longevity in SCD. Interestingly, multiple SNPs in Klotho exhibited differing genotype frequencies in older versus younger patients. Mutations in Klotho have been previously associated with aging-related phenotypes in mice. A better understanding of the biological mechanisms associated with longevity in SCD may help identify those at risk for early demise and in need of more specialized medical care

Priapism in SCD: Clinical and Genetic Correlations

Abstract Priapism is a complication of sickle cell disease (SCD) that occurs due to obstruction of the corpora cavernosa of the penis. We have studied priapism in relation to several clinical and genetic factors in 249 adult male patients with SCD, 92 (37%) of whom reported a positive history of priapism. The mean age of male patients without a history of priapism was 35.2 years (± 10.8 years) compared with a mean age of 36.4 years (± 11.3 years) in male patients with a positive history of priapism. Because of the possible relationship with nitric oxide biology, we examined the co-occurrence of priapism with proteinuria, leg ulcers and stroke. Of the males with a positive history of priapism, 20% also had a history of 2+ or greater proteinuria, compared to a presence of 2+ or greater proteinuria in only 10% of males without a history of priapism (p=0.03). Similarly, 34% of males with a positive history of priapism also had a history of leg ulcers, compared to the presence of leg ulcers in 22% of males without priapism (p=0.03). No statistically significant association between the occurrence of priapism and stroke was observed. In an effort to identify genetic risk factors for priapism, we examined 262 single nucleotide polymorphisms (SNPs) in a total of 56 genes, primarily involved in red blood cell adhesion and inflammation pathways. Chi Square tests of association were constructed for the genotypes of each SNP with two clinical categories: patients with a positive history of priapism and patients without a history of priapism. When the frequency of rare homozygotes was less than five individuals, we combined these rare homozygote individuals with heterozygote individuals for analysis. All p-values were uncorrected for multiple testing. We found associations with 12 SNPs in 8 genes: SLC4A2 (p=0.003); ITGAV (p=0.004 and p=0.02 for two different SNPs); F13A1 (p=0.004 and p=0.02 for two different SNPs); AQP1 (p=0.01 and p=0.04 for two different SNPs); TGFBR2 (p=0.01 and p=0.02 for two different SNPs); ADRB2 (p=0.03); MGC (p=0.04); and ARG2 (p<0.05). These genes are involved in a variety of functions, including adhesion, coagulation, signal transduction, NO biology and immune response. We examined 21 non-coding SNPs in the Klotho gene, but we did not find an association between priapism and Klotho, as was recently reported by Nolan and colleagues (2005). The only possible trend for association we observed in Klotho was at marker rs1888057 (p=0.07); we did not observe association with the SNP (rs2249358) (p=0.82) Nolan and colleagues found associated with priapism. These data support our over-arching hypothesis that genetic factors mediate the variability and risk of developing organ-specific complications of SCD. A better understanding of the genetic factors that contribute to the occurrence of complications such as priapism should ultimately lead to a better understanding of SCD pathophysiology as well as to improved treatment for patients with SCD

A double-blind, randomized, multicenter phase 2 study of prasugrel versus placebo in adult patients with sickle cell disease

Abstract Background Platelet activation has been implicated in the pathogenesis of sickle cell disease (SCD) suggesting antiplatelet agents may be therapeutic. To evaluate the safety of prasugrel, a thienopyridine antiplatelet agent, in adult patients with SCD, we conducted a double-blind, randomized, placebo-controlled study. Methods The primary endpoint, safety, was measured by hemorrhagic events requiring medical intervention. Patients were randomized to prasugrel 5 mg daily (n = 41) or placebo (n = 21) for 30 days. Platelet function by VerifyNow® P2Y12 and vasodilator-stimulated phosphoprotein assays at days 10 and 30 were significantly inhibited in prasugrel- compared with placebo-treated SCD patients. Results There were no hemorrhagic events requiring medical intervention in either study arm. Mean pain rate (percentage of days with pain) and intensity in the prasugrel arm were decreased compared with placebo. However, these decreases did not reach statistical significance. Platelet surface P-selectin and plasma soluble P-selectin, biomarkers of in vivo platelet activation, were significantly reduced in SCD patients receiving prasugrel compared with placebo. In sum, prasugrel was well tolerated and not associated with serious hemorrhagic events. Conclusions Despite the small size and short duration of this study, there was a decrease in platelet activation biomarkers and a trend toward decreased pain.</p

A double-blind, randomized, multicenter phase 2 study of prasugrel versus placebo in adult patients with sickle cell disease

Background Platelet activation has been implicated in the pathogenesis of sickle cell disease (SCD) suggesting antiplatelet agents may be therapeutic. To evaluate the safety of prasugrel, a thienopyridine antiplatelet agent, in adult patients with SCD, we conducted a double-blind, randomized, placebo-controlled study. Methods The primary endpoint, safety, was measured by hemorrhagic events requiring medical intervention. Patients were randomized to prasugrel 5 mg daily (n = 41) or placebo (n = 21) for 30 days. Platelet function by VerifyNow® P2Y12 and vasodilator-stimulated phosphoprotein assays at days 10 and 30 were significantly inhibited in prasugrel- compared with placebo-treated SCD patients. Results There were no hemorrhagic events requiring medical intervention in either study arm. Mean pain rate (percentage of days with pain) and intensity in the prasugrel arm were decreased compared with placebo. However, these decreases did not reach statistical significance. Platelet surface P-selectin and plasma soluble P-selectin, biomarkers of in vivo platelet activation, were significantly reduced in SCD patients receiving prasugrel compared with placebo. In sum, prasugrel was well tolerated and not associated with serious hemorrhagic events. Conclusions Despite the small size and short duration of this study, there was a decrease in platelet activation biomarkers and a trend toward decreased pain

2016 American College of Rheumatology/European League Against Rheumatism Criteria for Minimal, Moderate, and Major Clinical Response in Adult Dermatomyositis and Polymyositis: An International Myositis Assessment and Clinical Studies Group/Paediatric Rheumatology International Trials Organisation Collaborative Initiative

Objective: To develop response criteria for adult dermatomyositis (DM) and polymyositis (PM). Methods: Expert surveys, logistic regression, and conjoint analysis were used to develop 287 definitions using core set measures. Myositis experts rated greater improvement among multiple pairwise scenarios in conjoint analysis surveys, where different levels of improvement in 2 core set measures were presented. The PAPRIKA (Potentially All Pairwise Rankings of All Possible Alternatives) method determined the relative weights of core set measures and conjoint analysis definitions. The performance characteristics of the definitions were evaluated on patient profiles using expert consensus (gold standard) and were validated using data from a clinical trial. The nominal group technique was used to reach consensus. Results: Consensus was reached for a conjoint analysis\u2013based continuous model using absolute percent change in core set measures (physician, patient, and extramuscular global activity, muscle strength, Health Assessment Questionnaire, and muscle enzyme levels). A total improvement score (range 0\u2013100), determined by summing scores for each core set measure, was based on improvement in and relative weight of each core set measure. Thresholds for minimal, moderate, and major improvement were 6520, 6540, and 6560 points in the total improvement score. The same criteria were chosen for juvenile DM, with different improvement thresholds. Sensitivity and specificity in DM/PM patient cohorts were 85% and 92%, 90% and 96%, and 92% and 98% for minimal, moderate, and major improvement, respectively. Definitions were validated in the clinical trial analysis for differentiating the physician rating of improvement (P &lt; 0.001). Conclusion: The response criteria for adult DM/PM consisted of the conjoint analysis model based on absolute percent change in 6 core set measures, with thresholds for minimal, moderate, and major improvement