Early-onset emphysema attributed to α-1 antitrypsin deficiency (AATD) is frequently overlooked and undertreated. RAPID-RCT/RAPID-OLE, the largest clinical trials of purified human α-1 proteinase inhibitor (A1 -PI; 60 mg kg-1  week-1 ) therapy completed to date, demonstrated for the first time that A1 -PI is clinically effective in slowing lung tissue loss in AATD. A posthoc pharmacometric analysis was undertaken to further explore dose, exposure and response.

Neuromuscular ultrasound is a noninvasive investigation, which can be easily performed at the bedside on the ICU. A reduction in muscle thickness and increase in echo intensity over time have been described in ICU patients, but the relation to ICU-acquired weakness (ICU-AW) is unknown. We hypothesized that quantitative assessment of muscle and nerve parameters with ultrasound can differentiate between patients with and without ICU-AW. The aim of this cross-sectional study was to investigate the diagnostic accuracy of neuromuscular ultrasound for diagnosing ICU-AW.

Despite the high prevalence of depressive symptoms in Fabry disease (FD), it is unclear which patient characteristics are important in relation to these symptoms. Additionally, the impact of coping styles in relation to depressive symptoms in FD has been unexplored. Determining the impact of different factors relating to depressive symptoms in FD can guide both prevention and treatment of these symptoms.

The two main objectives of this analysis were to (i) characterize the relationship between immunoglobulin (Ig) exposure and chronic inflammatory demyelinating polyneuropathy (CIDP) disease severity using data from 171 patients with CIDP who received either subcutaneous Ig (IgPro20; Hizentra® ) or placebo (PATH study), and to (ii) simulate and compare exposure coverage with various dosing approaches considering weekly dosing to be the reference dose. IgG pharmacokinetic (PK) parameters, including those from a previous population PK model, were used to predict individual IgG profile and exposure metrics. Treatment-related changes in Inflammatory Neuropathy Cause and Treatment (INCAT) scores were best described by a maximum effect (Emax ) model as a function of ΔIgG (total serum IgG at INCAT score assessment minus baseline IgG levels before intravenous Ig restabilization). Simulations indicate that flexible dosing from daily to biweekly (every other week) provide an exposure coverage equivalent to that of a weekly Ig dose.

There are few reports of in vivo muscle strength measurements in animal models of ICU-acquired weakness (ICU-AW). In this study we investigated whether the Escherichia coli (E. coli) septic peritonitis mouse model may serve as an ICU-AW model using in vivo strength measurements and myosin/actin assays, and whether development of ICU-AW is age-dependent in this model.

To characterize relationships between apolipoprotein A-I (apoA-I) exposure and cholesterol efflux capacity (CEC) and covariate effects following CSL112 (apoA-I [human]) administration in an integrated population including acute myocardial infarction (AMI) patients.

Flexible dosing of IgPro20 (Hizentra®, CSL Behring, King of Prussia, Pennsylvania) maintains normal serum immunoglobulin G (IgG) levels in patients with primary immunodeficiencies (PID). Until now, clinical trials testing the pharmacokinetic (PK) characteristics of serum IgG of weekly and biweekly subcutaneous IgG therapy were not published. This is the first study assessing PK characteristics following weekly and biweekly IgPro20 in patients with PID. The PK study was conducted in 2 parts: weekly dosing (12 weeks) and biweekly dosing (up to 12 months). Serum IgG concentration-time data were analyzed using noncompartmental methods to generate PK parameters. Fifteen patients provided PK samples for both dosing regimens. For weekly and biweekly regimens, mean doses per infusion were 109 and 213 mg/kg, respectively, and median tmax was 2.0 and 3.02 days, respectively. The mean Ctrough values were similar in weekly and biweekly regimens (10.21 and 10.13 g/dL, respectively). The geometric mean ratios (GMRs) with 90% confidence intervals of biweekly to weekly Cmax and Ctrough were 1.10 (1.06-1.13) and 0.98 (0.95-1.01), respectively. The GMR of dAUC was 1.07 (1.03-1.10). This PK analysis demonstrated similar systemic IgG exposure after weekly and biweekly IgPro20 dosing with an equivalent monthly dose in patients with PID.

The peripheral nerve contains both nonmyelinating and myelinating Schwann cells. The interactions between axons, surrounding myelin, and Schwann cells are thought to be important for the correct functioning of the nervous system. To get insight into the genes involved in human myelination and maintenance of the myelin sheath and nerve, we performed a serial analysis of gene expression of human sciatic nerve and cultured Schwann cells. In the sciatic nerve library, we found high expression of genes encoding proteins related to lipid metabolism, the complement system, and the cell cycle, while cultured Schwann cells showed mainly high expression of genes encoding extracellular matrix proteins. The results of our study will assist in the identification of genes involved in maintenance of myelin and peripheral nerve and of genes involved in inherited peripheral neuropathies.

To investigate the long-term safety and efficacy of weekly subcutaneous IgPro20 (Hizentra, CSL Behring) in chronic inflammatory demyelinating polyneuropathy (CIDP).

In patients with chronic inflammatory demyelinating polyneuropathy (CIDP), intravenous immunoglobulin (IVIG) is recommended to be periodically reduced to assess the need for ongoing therapy. However, little is known about the effectiveness of restabilization with IVIG in patients who worsen after IVIG withdrawal. In the Polyneuropathy And Treatment with Hizentra (PATH) study, the pre-randomization period included sudden stopping of IVIG followed by 12 weeks of observation. Those deteriorating were then restabilized with IVIG. Of 245 subjects who stopped IVIG, 28 did not show signs of clinical deterioration within 12 weeks. Two hundred and seven received IVIG restabilization with an induction dose of 2 g/kg bodyweight (bw) IgPro10 (Privigen, CSL Behring, King of Prussia, Pennsylvania) and maintenance doses of 1 g/kg bw every 3 weeks for up to 13 weeks. Signs of clinical improvement were seen in almost all (n = 188; 91%) subjects. During IVIG restabilization, 35 subjects either did not show CIDP stability (n = 21, analyzed as n = 22 as an additional subject was randomized in error) or withdrew for other reasons (n = 14). Of the 22 subjects who did not achieve clinical stability, follow-up information in 16 subjects after an additional 4 weeks was obtained. Nine subjects were reported to have improved, leaving a maximum of 27 subjects (13%) who either showed no signs of clinical improvement during the restabilization phase and 4 weeks post-study or withdrew for other reasons. In conclusion, sudden IVIG withdrawal was effective in detecting ongoing immunoglobulin G dependency with a small risk for subjects not returning to their baseline 17 weeks after withdrawal.

Fabry disease (FD) is a rare lysosomal storage disorder that might result in, amongst other complications, early stroke and white matter lesions (WMLs). More insight in WMLs in FD could clarify the role of WMLs in the disease presentation and prognosis in FD. In this systematic review we assessed the prevalence, severity, location and course of WMLs in FD. We also systematically reviewed the evidence on the relation between WMLs, disease characteristics and clinical parameters.

The Polyneuropathy And Treatment with Hizentra (PATH) study required subjects with chronic inflammatory demyelinating polyneuropathy (CIDP) to show dependency on immunoglobulin G (IgG) and then be restabilized on IgG before being randomized to placebo or one of two doses of subcutaneous immunoglobulin (SCIG). Nineteen of the 51 subjects (37%) randomized to placebo did not relapse over the next 24 weeks. This article explores the reasons for this effect. A post-hoc analysis of the PATH placebo group was undertaken. A literature search identified other placebo-controlled CIDP trials for review and comparison. In PATH, subjects randomized to placebo who did not relapse were significantly older, had more severe disease, and took longer to deteriorate in the IgG dependency period compared with those who relapsed. Published trials in CIDP, whose primary endpoint was stability or deterioration, had a mean non-deterioration (placebo effect) of 43%, while trials with a primary endpoint of improvement had a placebo response of only 11%. Placebo is an important variable in the design of CIDP trials. Trials designed to show clinical improvement will have a significantly lower effect of this phenomenon than those designed to show stability or deterioration.

In the PREDICT study, a randomised controlled trial comparing dexamethasone with prednisolone in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), almost a quarter of patients deteriorated soon after starting treatment. The primary objective of this post-hoc analysis was to test the hypothesis that a focal demyelination pattern is associated with early deterioration after corticosteroid treatment and to explore whether various clinical characteristics are associated with deterioration after corticosteroid treatment.