Early initiation of enzyme replacement therapy for the mucopolysaccharidoses.

The mucopolysaccharidoses (MPS), a group of rare genetic disorders caused by defects in glycosaminoglycan (GAG) catabolism, are progressive, multi-systemic diseases with a high burden of morbidity. Enzyme replacement therapy (ERT) is available for MPS I, II, and VI, and may improve walking ability, endurance, and pulmonary function as evidenced by data from pivotal trials and extension studies. Despite these demonstrable benefits, cardiac valve disease, joint disease, and skeletal disease, all of which cause significant morbidity, do not generally improve with ERT if pathological changes are already established. Airway disease improves, but usually does not normalize. These limitations can be well understood by considering the varied functions of GAG in the body. Disruption of GAG catabolism has far-reaching effects due to the triggering of secondary pathogenic cascades. It appears that many of the consequences of these secondary pathogenic events, while they may improve on treatment, cannot be fully corrected even with long-term exposure to enzyme, thereby supporting the treatment of patients with MPS before the onset of clinical disease. This review examines the data from clinical trials and other studies in human patients to explore the limits of ERT as currently used, then discusses the pathophysiology, fetal tissue studies, animal studies, and sibling reports to explore the question of how early to treat an MPS patient with a firm diagnosis. The review is followed by an expert opinion on the rationale for and the benefits of early treatment.

High hsCRP is associated with reduced lung function in structural firefighters.

BACKGROUND: To assess the association between markers of systemic inflammation and pulmonary function in a population of structural firefighters. METHODS: We studied male career members of a large Midwestern fire department with questionnaires, spirometry, and high-sensitivity C-reactive protein (hsCRP) as a biomarker of systemic inflammation. We examined percent predicted forced expiratory volume in 1 s (FEV1 %-predicted) and forced vital capacity (FVC%-predicted). RESULTS: Complete data were available for 401 firefighters. Higher hsCRP levels were associated with lower lung function values, after adjusting for confounding variables. Specifically, for every twofold increase in log10-hsCRP, FEV1 %-predicted decreased by a mean 1.5% (95% CI: 0.4, 2.6%) and FVC%-predicted decreased by a mean 1.4% (95% CI: 0.4, 2.3%). CONCLUSION: hsCRP as a biomarker of systemic inflammation may indicate reduced lung function in structural firefighters.

Genome-wide association study identifies TH1 pathway genes associated with lung function in asthmatic patients.

BACKGROUND: Recent meta-analyses of genome-wide association studies in general populations of European descent have identified 28 loci for lung function. OBJECTIVE: We sought to identify novel lung function loci specifically for asthma and to confirm lung function loci identified in general populations. METHODS: Genome-wide association studies of lung function (percent predicted FEV1 [ppFEV1], percent predicted forced vital capacity, and FEV1/forced vital capacity ratio) were performed in 4 white populations of European descent (n = 1544), followed by meta-analyses. RESULTS: Seven of 28 previously identified lung function loci (HHIP, FAM13A, THSD4, GSTCD, NOTCH4-AGER, RARB, and ZNF323) identified in general populations were confirmed at single nucleotide polymorphism (SNP) levels (P < .05). Four of 32 loci (IL12A, IL12RB1, STAT4, and IRF2) associated with ppFEV1 (P < 10(-4)) belong to the TH1 or IL-12 cytokine family pathway. By using a linear additive model, these 4 TH1 pathway SNPs cumulatively explained 2.9% to 7.8% of the variance in ppFEV1 values in 4 populations (P = 3 × 10(-11)). Genetic scores of these 4 SNPs were associated with ppFEV1 values (P = 2 × 10(-7)) and the American Thoracic Society severe asthma classification (P = .005) in the Severe Asthma Research Program population. TH2 pathway genes (IL13, TSLP, IL33, and IL1RL1) conferring asthma susceptibility were not associated with lung function. CONCLUSION: Genes involved in airway structure/remodeling are associated with lung function in both general populations and asthmatic subjects. TH1 pathway genes involved in anti-virus/bacterial infection and inflammation modify lung function in asthmatic subjects. Genes associated with lung function that might affect asthma severity are distinct from those genes associated with asthma susceptibility.

The relationship between anti-idursulfase antibody status and safety and efficacy outcomes in attenuated mucopolysaccharidosis II patients aged 5 years and older treated with intravenous idursulfase.

In the pivotal phase II/III trial of idursulfase administered intravenously to treat mucopolysaccharidosis II, approximately half of the patients developed antibodies to idursulfase. This post-hoc analysis of data from the phase II/III trial and extension study examined the relationship between antibody status and outcomes. A total of 63 treatment-naïve patients received 0.5 mg/kg of intravenous idursulfase weekly for two years. Thirty-two patients (51%) were positive for anti-idursulfase IgG antibodies, 23 of whom (37%) became persistently positive. All patients who developed an antibody response did so by their scheduled Week 27 study visit. Positive antibody status appeared to have no statistically significant effect upon changes in six-minute walk test distance, percent predicted forced vital capacity, or liver and spleen volume. All patients showed significant decreases in urinary GAG levels, although the antibody positive group maintained somewhat higher urinary GAG levels than their antibody-negative counterparts at the end of study (138.7 vs. 94.7 µg/mg creatinine, p = 0.001). Antibody positivity was not associated with a higher event rate for serious adverse events. Among patients who had no prior infusion-related reactions, antibody positive patients were 2.3 times more likely to have a first infusion-related reaction than those who would remain negative (p = 0.017); the risk increased to 2.5 times more likely for those who were persistently positive (p = 0.009). These differences in risk disappeared among patients with a previous infusion-related reaction, likely because of preventive measures. A genotype analysis for the 36 patients with available data found that patients with nonsense or frameshift mutations may be more likely to develop antibodies, to experience infusion-related reactions, and to have a reduced uGAG response than those with missense mutations, suggesting the possibility that antibodies are not a driver of clinical outcomes but rather a marker for genotype.

Pamrevlumab, a Fully Human Monoclonal Antibody Targeting Connective Tissue Growth Factor, for Non-Ambulatory Patients with Duchenne Muscular Dystrophy.

BACKGROUND: Duchenne muscular dystrophy (DMD) is a neuromuscular disease stemming from dystrophin gene mutations. Lack of dystrophin leads to progressive muscle damage and replacement of muscle with fibrotic and adipose tissue. Pamrevlumab (FG-3019), a fully human monoclonal antibody that binds to connective tissue growth factor (CTGF), is in Phase III development for treatment of DMD and other diseases. METHODS: MISSION (Study 079; NCT02606136) was an open-label, Phase II, single-arm trial of pamrevlumab in 21 non-ambulatory patients with DMD (aged≥12 years, receiving corticosteroids) who received 35-mg/kg intravenous infusions every 2 weeks for 2 years. The primary endpoint was change from baseline in percent predicted forced vital capacity (ppFVC). Secondary endpoints included other pulmonary function tests, upper limb function and strength assessments, and changes in upper arm fat and fibrosis scores on magnetic resonance imaging. RESULTS: Fifteen patients completed the trial. Annual change from baseline (SE) in ppFVC was -4.2 (0.7) (95% CI -5.5, -2.8). Rate of decline in ppFVC in pamrevlumab-treated patients was slower than observed in historical published trials of non-ambulatory patients. MISSION participants experienced slower-than-anticipated muscle function declines compared with natural history and historical published trials of non-ambulatory patients with DMD. Pamrevlumab was well-tolerated. Treatment-emergent adverse events were mild to moderate, and none led to study discontinuation. CONCLUSIONS: nti-CTGF therapy with pamrevlumab represents a potential treatment for DMD. The lack of internal control group limits the results.

Body mass index-percent forced vital capacity-respiratory hospitalization: new staging for idiopathic pulmonary fibrosis patients.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is relentless progressive interstitial lung disease. Evaluating predictor of mortality for IPF patients is crucial. The aim of this study was to evaluate the serial trend of important indicators of prognosis and create a useful staging method for IPF patients. METHODS: We retrospectively searched medical records, pulmonary function tests (PFTs), and chest high resolution computed tomography (HRCT) scans from January 1, 2008 through June 30, 2015 at our hospital. We also evaluated the same parameters 1-year later. RESULTS: We identified 65 IPF patients. The mean age was 71.9±1.8 years (range, 22-85 years). In terms of PFTs, mean percent predicted forced vital capacity (%FVC) was 69.8±2.7. Baseline mean body mass index (BMI) was 24.3±0.6 kg/mm2. Mean survival was 39.2 months (range, 0.9-158.9 months). Cox proportional hazard ratios (HRs) showed the following to be predictors of mortality in IPF patients: 1-year BMI (HR: 0.899; 95% CI: 0.825-0.979; P=0.021); 1-year %FVC (HR: 0.932; 95% CI: 0.887-0.979; P=0.005) and 1-year respiratory hospitalization (HR: 3.307; 95% CI: 2.149-5.090; P<0.001). On the basis of these date, we created a new staging method for predicting mortality for IPF patients, consisting of delta BMI, delta %FVC and respiratory hospitalization within a year following diagnosis of IPF (BFR staging). We stratified patients into one of three groups according to the composite points. Mean survival of stages 1, 2, and 3 was 77.9 (30.8-158.9), 43.9 (0.9-145.2) and 14.8 (3.5-32) months (P<0.001), respectively. CONCLUSIONS: In our cohort of IPF patients, this new staging method, including delta BMI and delta %FVC and respiratory hospitalization within 1-year showed a clear survival difference.