Continued improvement in disease manifestations of acid sphingomyelinase deficiency for adults with up to 2 years of olipudase alfa treatment: open-label extension of the ASCEND trial.

BACKGROUND: Olipudase alfa is a recombinant human acid sphingomyelinase enzyme replacement therapy for non-central-nervous-system manifestations of acid sphingomyelinase deficiency (ASMD). The ASCEND randomized placebo-controlled trial in adults with ASMD demonstrated reductions in sphingomyelin storage, organomegaly, interstitial lung disease and impaired diffusion capacity of the lung (DLCO), during the first year of olipudase alfa treatment. In an ongoing open-label extension of the ASCEND trial, individuals in the placebo group crossed over to olipudase alfa, and those in the olipudase alfa group continued treatment. RESULTS: Thirty-five of 36 participants continued in the extension trial, and 33 completed year 2. Change-from-baseline results are presented as least-square mean percent change ± SEM. Improvements in the cross-over group after 1 year of treatment paralleled those of the olipudase alfa group from the primary analysis, while clinical improvement continued for those receiving olipudase alfa for 2 years. In the cross-over group, percent-predicted DLCO increased by 28.0 ± 6.2%, spleen volume decreased by 36.0 ± 3.0% and liver volume decreased by 30.7 ± 2.5%. For those with 2 years of olipudase alfa treatment, the percent predicted DLCO increased by 28.5 ± 6.2%, spleen volume decreased by 47.0 ± 2.7%, and liver volume decreased by 33.4 ± 2.2%. Lipid profiles and elevated liver transaminase levels improved or normalized by 1 year and remained stable through 2 years of treatment. Overall, 99% of treatment-emergent adverse events were mild or moderate, with one treatment-related serious adverse event (extrasystoles; previously documented cardiomyopathy). No individual discontinued due to an adverse event. CONCLUSION: Treatment with olipudase alfa is well tolerated and reduces manifestations of chronic ASMD with sustained efficacy. Trial registration NCT02004691 registered 9 December 2013, https://clinicaltrials.gov/ct2/show/NCT02004691.

Olipudase alfa enzyme replacement therapy for acid sphingomyelinase deficiency (ASMD): sustained improvements in clinical outcomes after 6.5 years of treatment in adults.

BACKGROUND: Enzyme replacement therapy with olipudase alfa, a recombinant human acid sphingomyelinase (rhASM), is indicated for non-central nervous system manifestations of acid sphingomyelinase deficiency (ASMD) in children and adults. An ongoing, open-label, long-term study (NCT02004704) assessed the safety and efficacy of olipudase alfa in 5 adults with ASMD. RESULTS: After 6.5 years of treatment, there were no discontinuations, no olipudase-alfa-related serious adverse events, and no new safety signals compared to earlier assessments. Most treatment-emergent adverse events were mild in intensity (1742/1766, 98.6%). Among treatment-related adverse events (n = 657), more than half were considered infusion-associated reactions (n = 403, 61.3%) such as headache, nausea, abdominal pain, arthralgia, pyrexia, and fatigue. No patient developed neutralizing anti-drug antibodies to cellular uptake, and there were no clinically significant adverse changes in vital signs, hematology, or cardiac safety parameters. Improvements (decreases) in spleen and liver volumes progressed through 6.5 years (mean changes from baseline of -59.5% and -43.7%, respectively). There was a mean increase in diffusing capacity of the lung for carbon monoxide from baseline of 55.3%, accompanied by improvements in interstitial lung disease parameters. Lipid profiles at baseline indicated dyslipidemia. All patients had sustained decreases in pro-atherogenic lipid levels and increases in anti-atherogenic lipid levels following olipudase alfa treatment. CONCLUSIONS: Olipudase alfa is the first disease-specific treatment for ASMD. This study demonstrates that long-term treatment with olipudase alfa is well-tolerated and is associated with sustained improvements in relevant disease clinical measures. NCT02004704 registered 26 November 2013, https://clinicaltrials.gov/ct2/show/NCT02004704?term=NCT02004704&draw=2&rank=1 .

Long-term safety and clinical outcomes of olipudase alfa enzyme replacement therapy in pediatric patients with acid sphingomyelinase deficiency: two-year results.

BACKGROUND: Olipudase alfa is a recombinant human acid sphingomyelinase (ASM) enzyme replacement therapy (ERT) for non-central-nervous-system manifestations of acid sphingomyelinase deficiency (ASMD). We report 2-year cumulative safety and efficacy data after olipudase alfa treatment in 20 children (four adolescents [12-17 year], nine children [6-11 year], and seven infants/early child [1-5 year]) with baseline splenomegaly and growth deficits who completed the 1-year ASCEND-Peds clinical trial (NCT02292654) and who continue to receive olipudase alfa in a long-term study (NCT02004704). Efficacy endpoints include spleen and liver volumes, diffusing capacity of the lung for carbon monoxide (DLCO), high-resolution computed tomography (HRCT) lung imaging, lipid profiles, liver function tests, and height Z-scores. RESULTS: All 20 former ASCEND-Peds patients completed at least 2 years of olipudase alfa treatment. No patient discontinued and no new safety issue arose during the second year of treatment; 99% of adverse events were mild or moderate. During year 2, one patient had two treatment-related serious events of hypersensitivity that resolved. Mean reductions from baseline in spleen and liver volumes were 61% and 49%, respectively (p < 0.0001) and mean percent-predicted-DLCO increased by 46.6% (p < 0.0001) in nine patients who performed the test at baseline. Lipid profiles and elevated liver transaminase levels that improved or normalized by 1 year remained stable. Mean height Z-scores improved in all age groups (mean change from baseline 1.17, P < 0.0001). CONCLUSION: Olipudase alfa was generally well-tolerated during 2 years of treatment. Improvements in clinically relevant disease endpoints observed during the first year of treatment were maintained or augmented in the second year. Trial registration NCT02004704 registered 26 Nov 2013, https://clinicaltrials.gov/ct2/show/record/NCT02004704 .

A randomized, placebo-controlled clinical trial evaluating olipudase alfa enzyme replacement therapy for chronic acid sphingomyelinase deficiency (ASMD) in adults: One-year results.

PURPOSE: This trial aimed to assess the efficacy and safety of olipudase alfa enzyme replacement therapy for non-central nervous system manifestations of acid sphingomyelinase deficiency (ASMD) in adults. METHODS: A phase 2/3, 52 week, international, double-blind, placebo-controlled trial (ASCEND; NCT02004691/EudraCT 2015-000371-26) enrolled 36 adults with ASMD randomized 1:1 to receive olipudase alfa or placebo intravenously every 2 weeks with intrapatient dose escalation to 3 mg/kg. Primary efficacy endpoints were percent change from baseline to week 52 in percent predicted diffusing capacity of the lung for carbon monoxide and spleen volume (combined with splenomegaly-related score in the United States). Other outcomes included liver volume/function/sphingomyelin content, pulmonary imaging/function, platelet levels, lipid profiles, and pharmacodynamics. RESULTS: Least square mean percent change from baseline to week 52 favored olipudase alfa over placebo for percent predicted diffusing capacity of the lung for carbon monoxide (22% vs 3.0% increases, P = .0004), spleen volume (39% decrease vs 0.5% increase, P < .0001), and liver volume (28% vs 1.5% decreases, P < .0001). Splenomegaly-related score decreased in both groups (P = .64). Other clinical outcomes improved in the olipudase alfa group compared with the placebo group. There were no treatment-related serious adverse events or adverse event-related discontinuations. Most adverse events were mild. CONCLUSION: Olipudase alfa was well tolerated and associated with significant and comprehensive improvements in disease pathology and clinically relevant endpoints compared with placebo in adults with ASMD.

Pregnancy outcomes following exposure to abatacept during pregnancy.

OBJECTIVE: To characterize pregnancy outcomes following maternal and paternal exposure to abatacept, using clinical trial and post-marketing data available to the manufacturer. METHODS: All confirmed cases of pregnancy with outcome data reported to the manufacturer up to September 1, 2014 were included. Sources included clinical trials, spontaneously reported (unsolicited) post-marketing cases, and the Organization of Teratology Information Specialists registry. Details recorded included number of live births, spontaneous abortions and terminations, pregnancy complications, and congenital anomalies. RESULTS: A total of 161 pregnancies with known outcomes were identified between 1995 and September 2014: 151 were following maternal exposure to abatacept and 10 were following paternal exposure. Seven of 86 (8.1%) live births following maternal exposure had congenital anomalies (cleft lip/cleft palate, congenital aortic anomaly, meningocele, pyloric stenosis, skull malformation, ventricular septal defect/congenital arterial malformation, and Down׳s syndrome with premature rupture of membranes at 17 weeks that resulted in a live birth via cesarean section and subsequent infant death). In addition, 59 of the 151 (39.0%) cases with maternal exposure resulted in abortions (40 spontaneous and 19 elective). Of the 10 pregnancies with paternal exposure, there were nine live births and one elective abortion, with no congenital abnormalities identified and no fetal deaths. CONCLUSIONS: Based on these data, there does not appear to be a pattern of congenital anomalies following maternal or paternal exposure to abatacept. No cases of vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, renal anomalies, or limb abnormalities (VACTERL) were noted. Spontaneous abortion rates were within expected range. Abatacept should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.

Necrotizing Fasciitis of the Chest Wall: Report of Pediatric Cases.

Necrotizing fasciitis is a soft tissue infection uncommonly described in children and is associated with significant morbidity and mortality if not treated early and aggressively. Reports of cases involving the upper torso are rare in general. In adults, necrotizing fasciitis is most commonly described in the abdomen, perineum, and extremities. For children, particularly neonates, necrotizing fasciitis most commonly involves the trunk presenting as omphalitis. In this report, we describe 2 pediatric cases of necrotizing fasciitis of the chest wall that presented within 6 months from each other at Los Angeles County Hospital/University of Southern California Pediatric Emergency Department. Both cases involved previously healthy children with above normal body mass indices of 36 and 25.6, respectively. These cases are noteworthy because of the rarity of necrotizing fasciitis among children especially in the chest wall, atypical presentation with nonspecific symptoms which made the diagnosis challenging, and suggestion that obesity may be a potential risk factor. Despite the rarity of this disease, the information presented in these cases may aid in raising the index of suspicion for diagnosis of necrotizing fasciitis.

Evidence That in Uncontrolled Diabetes, Hyperglucagonemia Is Required for Ketosis but Not for Increased Hepatic Glucose Production or Hyperglycemia.

Several lines of evidence implicate excess glucagon secretion in the elevated rates of hepatic glucose production (HGP), hyperglycemia, and ketosis characteristic of uncontrolled insulin-deficient diabetes (uDM), but whether hyperglucagonemia is required for hyperglycemia in this setting is unknown. To address this question, adult male Wistar rats received either streptozotocin (STZ) to induce uDM (STZ-DM) or vehicle and remained nondiabetic. Four days later, animals received daily subcutaneous injections of either the synthetic GLP-1 receptor agonist liraglutide in a dose-escalating regimen to reverse hyperglucagonemia or its vehicle for 10 days. As expected, plasma glucagon levels were elevated in STZ-DM rats, and although liraglutide treatment lowered glucagon levels to those of nondiabetic controls, it failed to attenuate diabetic hyperglycemia, elevated rates of glucose appearance (Ra), or increased hepatic gluconeogenic gene expression. In contrast, it markedly reduced levels of both plasma ketone bodies and hepatic expression of the rate-limiting enzyme involved in ketone body production. To independently confirm this finding, in a separate study, treatment of STZ-DM rats with a glucagon-neutralizing antibody was sufficient to potently lower plasma ketone bodies but failed to normalize elevated levels of either blood glucose or Ra. These data suggest that in rats with uDM, hyperglucagonemia is required for ketosis but not for increased HGP or hyperglycemia.

Cardiac dysfunction associated with a nucleotide polymerase inhibitor for treatment of hepatitis C.

UNLABELLED: Treatment for chronic hepatitis C virus (HCV) infection is evolving from interferon (IFN)-based therapy to direct-acting antiviral (DAA) agents, yet some safety concerns have arisen involving cardiac toxicity. In this study, we sought to better understand the potential off-target toxicities of new DAAs. We retrospectively evaluated the clinical and pathological findings of the sentinel case in a phase II study that led to clinical development discontinuation for BMS-986094, an HCV nucleotide polymerase (nonstructural 5B) inhibitor. We also report on outcomes from other patients in the same study, including electrocardiogram changes, cardiovascular biomarkers, and transthoracic echocardiograms. Thirty-four patients received IFN-free BMS-986094 regimens. Six patients had left ventricular ejection fractions (LVEFs) <30%, 8 had LVEFs 30%-50%, and 11 required hospitalization for suspected cardiotoxicity. Of the patients with LVEF <50%, 6 had normalization of systolic function after a median of 20 days. T-wave inversions were the most sensitive predictor of LVEF dysfunction. B-type natriuretic peptide levels increased over time and correlated with the degree of LVEF dysfunction. Pathological analysis of cardiac tissue revealed severe myocyte damage with elongated myofibrils without gross necrosis. These findings were consistent with some results of recent primate studies that were conducted to further investigate the potential mechanisms of BMS-986094 toxicity. CONCLUSION: A novel nucleotide analog polymerase inhibitor developed for HCV treatment may cause a toxic cardiomyopathy. Ongoing surveillance of DAAs for cardiotoxicities may be beneficial, especially among patients at higher risk for cardiovascular disease.

Nephrolithiasis and renal failure among patients exposed to atazanavir, other PIs and PI-free regimens.

INTRODUCTION: Recent single-site studies and case reports have linked atazanavir (ATV) with the occurrence of nephrolithiasis. The purpose of this study was to estimate and compare the incidence rate of nephrolithiasis and to characterize the occurrence of subsequent renal failure among patients on ATV, other protease inhibitors (PIs) and PI-free regimens using real world data. MATERIALS AND METHODS: This was a retrospective cohort analysis using claims data from a US commercial and a US public health insurance database (Medicaid) spanning 2003-2011 and 2006-2011, respectively. We identified adult HIV patients who were prescribed ATV, other PIs or PI-free regimens with at least 6 months of continuous enrolment prior to the index claim. Nephrolithiasis was defined as an inpatient or outpatient ICD-9 diagnosis code for nephrolithiasis or an associated condition, plus an imaging/corrective procedure code. Renal failure was also identified using diagnosis codes among patients experiencing nephrolithiasis. Hazard ratios were estimated using propensity score (PS) adjusted Cox regression, crude and adjusted for demographics, baseline comorbidities and comedications. RESULTS: A total of 14,477 patients (ATV: 4,150; other PIs: 4,153; PI-free: 6,174) were identified in the commercial database: 83% male and 20% age ≥50 years. In the Medicaid database, 9,104 patients (ATV: 3,460; other PIs: 3,117; PI-free: 2,527) were identified: 53% male and 25% age ≥50 years. There were significant baseline differences in demographics, comorbidities and concomitant medications among the three cohorts. In adjusted analyses, ATV use was not significantly associated with nephrolithiasis when compared to other PIs. When ATV was compared to PI-free regimens, a positive association was observed in the commercial insurance but not the Medicaid database. In both databases, previous history of nephrolithiasis was the strongest predictor of nephrolithiasis in the ATV/PI-free regimens contrast, but not the ATV/other PIs contrast. For the renal failure outcomes, there were insufficient cases across all cohorts to conduct crude or adjusted analyses (see Table 1). CONCLUSIONS: In this analysis of two large real world databases, we did not find evidence of an increased risk of nephrolithiasis among patients on ATV compared to other PIs. However, when ATV was compared to PI-free regimens, the results differed across the two databases, requiring further study. Additionally, renal failure following nephrolithiasis was infrequent and not significantly different across the three cohorts.

Point-of-care ultrasound in diagnosing pyomyositis: a report of three cases.

BACKGROUND: Pyomyositis is a bacterial infection of skeletal muscle that often results in deep intramuscular abscesses. The absence of external dermatologic manifestations in the early stages of pyomyositis makes this a challenging diagnosis. In addition, physical examination findings can be difficult to distinguish from more common processes, such as soft-tissue cellulitis. Clinicians can fail to diagnose this serious disease in a timely manner, resulting in delayed treatment and potential clinical deterioration from sepsis. Although advanced imaging modalities, such as computed tomography (CT) and magnetic resonance imaging (MRI) provide excellent detail, ultrasound (US) can also be used to detect this disease. US can be performed expeditiously at the bedside and is less expensive than CT or MRI. It allows the clinician to examine the deeper tissue planes of muscle, in which purulent fluid collections will develop as pyomyositis advances. CASE REPORT: Three patients presenting with leg pain were evaluated with point-of-care (POC) US and diagnosed with pyomyositis. The early diagnosis of this condition prompted rapid treatment with administration of appropriate antibiotics and involvement of orthopedic surgery. Aspiration of fluid allowed for detailed fluid analysis and bacterial cultures. Additional diagnostic imaging was performed, confirming the initial US diagnosis. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: POC US can be helpful in identifying and further delineating intramuscular abscesses and can subsequently lead to expedited and appropriate care in patients who present with extremity pain, but lack significant dermatologic changes.

Comparison of accidental and nonaccidental traumatic head injury in children on noncontrast computed tomography.

OBJECTIVE: Mixed-density convexity subdural hematoma and interhemispheric subdural hematoma suggest nonaccidental head injury. The purpose of this retrospective observational study is to investigate subdural hematoma on noncontrast computed tomography in infants with nonaccidental head injury and to compare these findings in infants with accidental head trauma for whom the date of injury was known. PATIENTS AND METHODS: Two blinded, independent observers retrospectively reviewed computed tomography scans with subdural hematoma performed on the day of presentation on 9 infant victims of nonaccidental head injury (mean age: 6.8 months; range: 1-25 months) and on 38 infants (mean age: 4.8 months; range: newborn to 34 months) with accidental head trauma (birth-related: 19; short fall: 17; motor vehicle accident: 2). RESULTS: Homogeneous hyperdense subdural hematoma was significantly more common in children with accidental head trauma (28 of 38 [74%]; nonaccidental head trauma: 3 of 9 [33%]), whereas mixed-density subdural hematoma was significantly more common in cases of nonaccidental head injury (6 of 9 [67%]; accidental head trauma: 7 of 38 [18%]). Twenty-two (79%) subdural hematomas were homogeneously hyperdense on noncontrast computed tomography performed within two days of accidental head trauma, one (4%) was homogeneous and isodense compared to brain tissue, one (4%) was homogeneous and hypodense, and four (14%) were mixed-density. There was no statistically significant difference in the proportion of interhemispheric subdural hematoma, epidural hematoma, calvarial fracture, brain contusion, or subarachnoid hemorrhage. CONCLUSIONS: Homogeneous hyperdense subdural hematoma is more frequent in cases of accidental head trauma; mixed-density subdural hematoma is more frequent in cases of nonaccidental head injury but may be observed within 48 hours of accidental head trauma. Interhemispheric subdural hematoma is not specific for inflicted head injury.

Central projections of melanopsin-expressing retinal ganglion cells in the mouse.

A rare type of ganglion cell in mammalian retina is directly photosensitive. These novel retinal photoreceptors express the photopigment melanopsin. They send axons directly to the suprachiasmatic nucleus (SCN), intergeniculate leaflet (IGL), and olivary pretectal nucleus (OPN), thereby contributing to photic synchronization of circadian rhythms and the pupillary light reflex. Here, we sought to characterize more fully the projections of these cells to the brain. By targeting tau-lacZ to the melanopsin gene locus in mice, ganglion cells that would normally express melanopsin were induced to express, instead, the marker enzyme beta-galactosidase. Their axons were visualized by X-gal histochemistry or anti-beta-galactosidase immunofluorescence. Established targets were confirmed, including the SCN, IGL, OPN, ventral division of the lateral geniculate nucleus (LGv), and preoptic area, but the overall projections were more widespread than previously recognized. Targets included the lateral nucleus, peri-supraoptic nucleus, and subparaventricular zone of the hypothalamus, medial amygdala, margin of the lateral habenula, posterior limitans nucleus, superior colliculus, and periaqueductal gray. There were also weak projections to the margins of the dorsal lateral geniculate nucleus. Co-staining with the cholera toxin B subunit to label all retinal afferents showed that melanopsin ganglion cells provide most of the retinal input to the SCN, IGL, and lateral habenula and much of that to the OPN, but that other ganglion cells do contribute at least some retinal input to these targets. Staining patterns after monocular enucleation revealed that the projections of these cells are overwhelmingly crossed except for the projection to the SCN, which is bilaterally symmetrical.

Differential effects of a centrally acting fatty acid synthase inhibitor in lean and obese mice.

C75 is a potent inhibitor of fatty acid synthase that acts centrally to reduce food intake and body weight in mice; a single dose causes a rapid (>90%) decrease of food intake. These effects are associated with inhibition of fasting-induced up-regulation and down-regulation, respectively, of the expression of orexigenic (NPY and AgRP) and anorexigenic (POMC and CART) neuropeptide messages in the hypothalamus. Repeated administration of C75 at a submaximal level, however, differentially affected food intake of lean and obese mice. With lean mice, C75 suppressed food intake by approximately 50% and, with obese mice (ob/ob and dietary-induced obesity), by 85-95% during the first day of treatment. Lean mice, however, became tolerant/resistant to C75 over the next 2-5 days of treatment, with food intake returning to near normal and rebound hyperphagia occurring on cessation of treatment. In contrast, ob/ob obese mice responded to C75 with a >90% suppression of food intake throughout the same period with incipient tolerance becoming evident only after substantial weight loss had occurred. Dietary-induced obese mice exhibited intermediate behavior. In all cases, a substantial loss of body weight resulted. Pair-fed controls lost 24-50% less body weight than C75-treated mice, indicating that, in addition to suppressing food intake, C75 may increase energy expenditure. The decrease in body weight by ob/ob mice was due primarily to loss of body fat. In contrast to the short-term effects of C75 on "fasting-induced" changes of hypothalamic orexigenic and anorexigenic neuropeptide mRNAs, repeated administration of C75 either had the inverse or no effect as tolerance developed.

Effect of a fatty acid synthase inhibitor on food intake and expression of hypothalamic neuropeptides.

The fatty acid synthase inhibitor, C75, acts centrally to reduce food intake and body weight in mice. Here we report the effects of C75 on the expression of key orexigenic [neuropeptide Y (NPY), agouti-related protein (AgRP), and melanin-concentrating hormone] and anorexigenic [pro-opiomelanocortin (POMC) and cocaine-amphetamine-related transcript (CART)] neuropeptide messages in the hypothalami of lean and obese (ob/ob) mice. In lean mice, C75 rapidly and almost completely blocked food intake and prevented fasting-induced up-regulation of hypothalamic AgRP and NPY mRNAs, as well as down-regulation of CART and POMC mRNAs. Thus, in lean mice C75 seems to interrupt the fasting-induced signals that activate expression of NPY and AgRP and suppression of POMC and CART. In obese mice, C75 rapidly suppressed food intake, reduced body weight, and normalized obesity-associated hyperglycemia and hyperinsulinemia. Like its effect in lean mice, C75 prevented the fasting-induced increase of hypothalamic NPY and AgRP mRNAs in obese mice, but had no effect on the expression of POMC and CART mRNAs. The suppressive effect of C75 on food intake in lean mice seems to be mediated both by NPY/AgRP and POMC/CART neurons, whereas in obese mice the effect seems to be mediated primarily by NPY/AgRP neurons. In both lean and obese mice, C75 markedly increased expression of melanin-concentrating hormone and its receptor in the hypothalamus.