Real-World Adherence to OnabotulinumtoxinA Treatment for Spasticity: Insights From the ASPIRE Study.

Abstract Objective To identify baseline characteristics and treatment-related variables that affect adherence to onabotulinumtoxinA treatment from the Adult Spasticity International Registry (ASPIRE) study. Design Prospective, observational registry (NCT01930786). Setting International clinical sites. Participants Adults with spasticity (N=730). Interventions OnabotulinumtoxinA at clinician's discretion. Main Outcome Measures Clinically meaningful thresholds used for treatment adherent (≥3 treatment sessions during 2-year study) and nonadherent (≤2 sessions). Data analyzed using logistic regression and presented as odds ratios (ORs) with 95% confidence intervals (CIs). Treatment-related variables assessed at sessions 1 and 2 only. Results Of the total population, 523 patients (71.6%) were treatment adherent with 5.3±1.6 sessions and 207 (28.4%) were nonadherent with 1.5±0.5 sessions. In the final model (n=626/730), 522 patients (83.4%) were treatment adherent and 104 (16.6%) were nonadherent. Baseline characteristics associated with adherence: treated in Europe (OR=1.84; CI, 1.06-3.21; P=.030) and use of orthotics (OR=1.88; CI, 1.15-3.08; P=.012). Baseline characteristics associated with nonadherence: history of diplopia (OR=0.28; CI, 0.09-0.89; P=.031) and use of assistive devices (OR=0.51; CI, 0.29-0.90; P=.021). Treatment-related variables associated with nonadherence: treatment interval ≥15 weeks (OR=0.43; CI, 0.26-0.72; P=.001) and clinician dissatisfaction with onabotulinumtoxinA to manage pain (OR=0.18; CI, 0.05-0.69; P=.012). Of the population with stroke (n=411), 288 patients (70.1%) were treatment adherent with 5.3±1.6 sessions and 123 (29.9%) were nonadherent with 1.5±0.5 session. In the final stroke model (n=346/411), 288 patients (83.2%) were treatment adherent and 58 (16.8%) were nonadherent. Baseline characteristics associated with adherence: treated in Europe (OR=2.99; CI, 1.39-6.44; P=.005) and use of orthotics (OR=3.18; CI, 1.57-6.45; P=.001). Treatment-related variables associated with nonadherence: treatment interval ≥15 weeks (OR=0.42; CI, 0.21-0.83; P=.013) and moderate/severe disability on upper limb Disability Assessment Scale pain subscale (OR=0.40; CI, 0.19-0.83; P=.015). Conclusions These ASPIRE analyses demonstrate real-world patient and clinical variables that affect adherence to onabotulinumtoxinA and provide insights to help optimize management strategies to improve patient care

Effect of dimethyl fumarate on lymphocyte subsets in patients with relapsing multiple sclerosis.

Background: In patients treated with dimethyl fumarate, absolute lymphocyte count decline typically occurs during the first year and then plateaus; early drops have been associated with the development of severe prolonged lymphopenia. Objective: We investigated the effect of dimethyl fumarate on absolute lymphocyte counts and CD4+/CD8+ T cells in patients with relapsing-remitting multiple sclerosis treated with dimethyl fumarate in routine practice. Methods: Lymphocyte data were collected via medical chart abstraction. Primary endpoint: change from baseline in absolute lymphocyte count and CD4+/CD8+ counts at 6-month intervals following dimethyl fumarate initiation. Results: Charts of 483 patients were abstracted and 476 patients included in the analysis. Mean baseline absolute lymphocyte count (2.23 × 10 Conclusion: Dimethyl fumarate-associated decline in absolute lymphocyte count in the first 12 months correlated with decline in CD4+ and CD8+ T cells and was independent of prior natalizumab. Absolute lymphocyte count monitoring continues to be an effective strategy to identify patients at risk of prolonged lymphopenia

Effect of natalizumab on disease progression in secondary progressive multiple sclerosis (ASCEND). a phase 3, randomised, double-blind, placebo-controlled trial with an open-label extension

Background: Although several disease-modifying treatments are available for relapsing multiple sclerosis, treatment effects have been more modest in progressive multiple sclerosis and have been observed particularly in actively relapsing subgroups or those with lesion activity on imaging. We sought to assess whether natalizumab slows disease progression in secondary progressive multiple sclerosis, independent of relapses. Methods: ASCEND was a phase 3, randomised, double-blind, placebo-controlled trial (part 1) with an optional 2 year open-label extension (part 2). Enrolled patients aged 18–58 years were natalizumab-naive and had secondary progressive multiple sclerosis for 2 years or more, disability progression unrelated to relapses in the previous year, and Expanded Disability Status Scale (EDSS) scores of 3·0–6·5. In part 1, patients from 163 sites in 17 countries were randomly assigned (1:1) to receive 300 mg intravenous natalizumab or placebo every 4 weeks for 2 years. Patients were stratified by site and by EDSS score (3·0–5·5 vs 6·0–6·5). Patients completing part 1 could enrol in part 2, in which all patients received natalizumab every 4 weeks until the end of the study. Throughout both parts, patients and staff were masked to the treatment received in part 1. The primary outcome in part 1 was the proportion of patients with sustained disability progression, assessed by one or more of three measures: the EDSS, Timed 25-Foot Walk (T25FW), and 9-Hole Peg Test (9HPT). The primary outcome in part 2 was the incidence of adverse events and serious adverse events. Efficacy and safety analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01416181. Findings: Between Sept 13, 2011, and July 16, 2015, 889 patients were randomly assigned (n=440 to the natalizumab group, n=449 to the placebo group). In part 1, 195 (44%) of 439 natalizumab-treated patients and 214 (48%) of 448 placebo-treated patients had confirmed disability progression (odds ratio [OR] 0·86; 95% CI 0·66–1·13; p=0·287). No treatment effect was observed on the EDSS (OR 1·06, 95% CI 0·74–1·53; nominal p=0·753) or the T25FW (0·98, 0·74–1·30; nominal p=0·914) components of the primary outcome. However, natalizumab treatment reduced 9HPT progression (OR 0·56, 95% CI 0·40–0·80; nominal p=0·001). In part 1, 100 (22%) placebo-treated and 90 (20%) natalizumab-treated patients had serious adverse events. In part 2, 291 natalizumab-continuing patients and 274 natalizumab-naive patients received natalizumab (median follow-up 160 weeks [range 108–221]). Serious adverse events occurred in 39 (13%) patients continuing natalizumab and in 24 (9%) patients initiating natalizumab. Two deaths occurred in part 1, neither of which was considered related to study treatment. No progressive multifocal leukoencephalopathy occurred. Interpretation: Natalizumab treatment for secondary progressive multiple sclerosis did not reduce progression on the primary multicomponent disability endpoint in part 1, but it did reduce progression on its upper-limb component. Longer-term trials are needed to assess whether treatment of secondary progressive multiple sclerosis might produce benefits on additional disability components. Funding: Biogen

Signaling Domain of Sonic Hedgehog as Cannibalistic Calcium-Regulated Zinc-Peptidase

<div><p>Sonic Hedgehog (Shh) is a representative of the evolutionary closely related class of Hedgehog proteins that have essential signaling functions in animal development. The N-terminal domain (ShhN) is also assigned to the group of LAS proteins (LAS = Lysostaphin type enzymes, D-Ala-D-Ala metalloproteases, Sonic Hedgehog), of which all members harbor a structurally well-defined center; however, it is remarkable that ShhN so far is the only LAS member without proven peptidase activity. Another unique feature of ShhN in the LAS group is a double- center close to the zinc. We have studied the effect of these calcium ions on ShhN structure, dynamics, and interactions. We find that the presence of calcium has a marked impact on ShhN properties, with the two calcium ions having different effects. The more strongly bound calcium ion significantly stabilizes the overall structure. Surprisingly, the binding of the second calcium ion switches the putative catalytic center from a state similar to LAS enzymes to a state that probably is catalytically inactive. We describe in detail the mechanics of the switch, including the effect on substrate co-ordinating residues and on the putative catalytic water molecule. The properties of the putative substrate binding site suggest that ShhN could degrade other ShhN molecules, e.g. by cleavage at highly conserved glycines in ShhN. To test experimentally the stability of ShhN against autodegradation, we compare two ShhN mutants <i>in vitro</i>: (1) a ShhN mutant unable to bind calcium but with putative catalytic center intact, and thus, according to our hypothesis, a constitutively active peptidase, and (2) a mutant carrying additionally mutation E177A, i.e., with the putative catalytically active residue knocked out. The <i>in vitro</i> results are consistent with ShhN being a cannibalistic zinc-peptidase. These experiments also reveal that the peptidase activity depends on .</p></div

Statistical comparisons of zinc center geometries.

<p>(A) RMSDs between zinc centers from LAS enzyme X-ray structures to ShhN in states Ca0 (red), Ca1 (blue), Ca2 (grey) sampled by molecular dynamics. (B) RMSDs between zinc centers from MD simulations of LAS enzymes and MD simulations of ShhN in states Ca0, Ca1, Ca2.</p

Switch mechanism triggered by Ca2 calcium ion.

<p>(A) ShhN zinc center in states Ca0 (X-ray structure 1vhh, red), Ca1 (X-ray structure 3n1r, blue), Ca2 (X-ray structure 3d1m, black). Putative catalytic water from 1vhh is close to the zinc ion. From Ca0 to Ca1 and Ca2, E127 carboxylate is drawn towards and drags H-bound H135 side chain with it, away from substrate and the active E177. While Ca0 and Ca1 superimpose well, Ca2 is clearly different. (B) Central components of the switch mechanisms in states Ca0 and Ca2. (C) Distances between H-bonded E127 carboxylate-O and H135 imidazole-proton, and between substrate-clamping side chains of H135 and catalytically active E177. Red (Ca0) and black (Ca2) points are sampled by MD simulations. Green triangle (Ca0) and green square (Ca2) are the corresponding values directly taken from X-ray structures 1vhh and 3d1m, respectively.</p

Phylogenetic tree of all 30 reviewed full length Hedgehog proteins from UniProtKB.

<p>The vertebrate Hedgehogs (bottom subtree) are clearly separated from the <i>Drosophila</i> Hedgehogs (top subtree). In all vertebrates the full catalytic motif is absolutely conserved (red), except in rat with one conservative exchange (blue).</p

Zinc centers of peptidases and ShhN.

<p>The four examples shown are Thermolysin (A), ShhN (B), and LAS peptidases <i>Streptomyces albus G</i> D-Ala-D-Ala Carboxypeptidase (PDB: 1lbu) (C), and L-alanoyl-D-glutamate endopeptidase of a bacteriophage (PDB: 2vo9) (D). Numbers on dashed lines are characteristic distances in 0.1 nm.</p

<i>In vitro</i> tests of ShhN mutant stabilities against proteolysis.

<p>The logarithm of protein content (relative to maximum protein content) is plotted over time. Proteins are (E177A, red) and (E177, blue). Straight red and blue lines are least squares fits to the measurements, shaded areas around these lines are 95% confidence intervals for the corresponding linear models. All data refer to measurements at .</p