Identification of serum microRNAs as potential biomarkers in Pompe disease

Altres ajuts: This study was supported by a grant from Sanofi-Genzyme (GZ-2015-11342) to Dr. Gallardo and has been registered in Clinicaltrials.gov (identifier NCT03045042).This study was supported by a grant from Sanofi-Genzyme (GZ-2015-11342) to Dr. Gallardo and has been registered in Clinicaltrials.gov (identifier NCT03045042).To analyze the microRNA profile in serum of patients with Adult Onset Pompe disease (AOPD). We analyzed the expression of 185 microRNAs in serum of 15 AOPD patients and five controls using microRNA PCR Panels. The expression levels of microRNAs that were deregulated were further studied in 35 AOPD patients and 10 controls using Real-Time PCR. Additionally, the skeletal muscle expression of microRNAs which showed significant increase levels in serum samples was also studied. Correlations between microRNA serum levels and muscle function test, spirometry, and quantitative muscle MRI were performed (these data correspond to the study NCT01914536 at ClinicalTrials.gov). We identified 14 microRNAs that showed different expression levels in serum samples of AOPD patients compared to controls. We validated these results in a larger cohort of patients and we found increased levels of three microRNAs, the so called dystromirs: miR-1-3p, miR-133a-3p, and miR-206. These microRNAs are involved in muscle regeneration and the expression of these was increased in patients' muscle biopsies. Significant correlations between microRNA levels and muscle function test were found. Serum expression levels of dystromirs may represent additional biomarkers for the follow-up of AOPD patients

Effectiveness of a multidisciplinary BIOPSYCHOSOCIAL intervention for non-specific SUBACUTE low back pain in a working population : a cluster randomized clinical trial

BACKGROUND: Low back pain (LBP) is a multifactorial condition with individual and societal impact that affects populations globally. Current guidelines for the treatment of LBP recommend pharmacological and non-pharmacological strategies. The aim of this study was to compare usual clinical practice with the effectiveness of a biopsychosocial multidisciplinary intervention in reducing disability, severity of pain and improving quality of life in a working population of patients with subacute (2-12 weeks), non-specific LBP. METHODS: Longitudinal cluster randomized clinical trial conducted in 39 Primary Health Care Centres (PHCC) of Barcelona, with patients aged 18-65 years (n = 501; control group = 239; 26 PHCC, intervention group = 262; 13 PHCC). The control group received usual clinical care. The intervention group received usual clinical care plus a biopsychosocial multidisciplinary intervention, which consisted of physiotherapy, cognitive-behavioural therapy and medication. The main outcomes were changes in the Roland Morris Disability Questionnaire (RMDQ), and the minimal clinically important differences. Secondary outcomes were changes in the McGill Pain (MGPQ) and Quality of Life (SF-12) questionnaires. Assessment was conducted at baseline, 3 and 12 months. Analysis was by intention-to-treat and analyst-blinded. Multiple imputations were used. RESULTS: Of the 501 enrolled patients, 421 (84%) provided data at 3 months, and 387 (77.2%) at 12 months. Mean age was 46.8 years (SD: 11.5) and 64.7% were women. In the adjusted analysis of the RMDQ outcome, only the intervention group showed significant changes at 3 months (- 1.33 points, p = 0.005) and at 12 months (- 1.11 points, p = 0.027), but minimal clinically important difference were detected in both groups. In the adjusted analysis of the RMDQ outcome, the intervention group improvement more than the control group at 3 months (- 1.33 points, p = 0.005) and at 12 months (- 1.11 points, p = 0.027). The intervention group presented a significant difference. Both groups presented a minimal clinically important difference, but more difference in the intervention group. The intervention group presented significant differences in the MGPQ scales of current pain intensity and VAS scores at 3 months. No statistically significant differences were found in the physical and mental domains of the SF-12. CONCLUSIONS: A multidisciplinary biopsychosocial intervention in a working population with non-specific subacute LBP has a small positive impact on disability, and on the level of pain, mainly at short-term, but no difference on quality of life. TRIAL REGISTRATION: ISRCTN21392091 (17 oct 2018) (Prospectively registred

Study protocol of effectiveness of a biopsychosocial multidisciplinary intervention in the evolution of non-speficic sub-acute low back pain in the working population : cluster randomised trial

Background: Non-specific low back pain is a common cause for consultation with the general practitioner, generating increased health and social costs. This study will analyse the effectiveness of a multidisciplinary intervention to reduce disability, severity of pain, anxiety and depression, to improve quality of life and to reduce the incidence of chronic low back pain in the working population with non-specific low back pain, compared to usual clinical care. Methods/Design: A Cluster randomised clinical trial will be conducted in 38 Primary Health Care Centres located in Barcelona, Spain and its surrounding areas. The centres are randomly allocated to the multidisciplinary intervention or to usual clinical care. Patients between 18 and 65 years old (n = 932; 466 per arm) and with a diagnostic of a non-specific sub-acute low back pain are included. Patients in the intervention group are receiving the recommendations of clinical practice guidelines, in addition to a biopsychosocial multidisciplinary intervention consisting of group educational sessions lasting a total of 10 hours. The main outcome is change in the score in the Roland Morris disability questionnaire at three months after onset of pain. Other outcomes are severity of pain, quality of life, duration of current non-specific low back pain episode, work sick leave and duration, Fear Avoidance Beliefs and Goldberg Questionnaires. Outcomes will be assessed at baseline, 3, 6 and 12 months. Analysis will be by intention to treat. The intervention effect will be assessed through the standard error of measurement and the effect-size. Responsiveness of each scale will be evaluated by standardised response mean and receiver-operating characteristic method. Recovery according to the patient will be used as an external criterion. A multilevel regression will be performed on repeated measures. The time until the current episode of low back pain takes to subside will be analysed by Cox regression. Discussion: We hope to provide evidence of the effectiveness of the proposed biopsychosocial multidisciplinary intervention in avoiding the chronification of low back pain, and to reduce the duration of non-specific low back pain episodes. If the intervention is effective, it could be applied to Primary Health Care Centres

PDGF-BB serum levels are decreased in adult onset Pompe patients

Adult onset Pompe disease is a genetic disorder characterized by slowly progressive skeletal and respiratory muscle weakness. Symptomatic patients are treated with enzymatic replacement therapy with human recombinant alfa glucosidase. Motor functional tests and spirometry are commonly used to follow patients up. However, a serological biomarker that correlates with the progression of the disease could improve follow-up. We studied serum concentrations of TGFβ, PDGF-BB, PDGF-AA and CTGF growth factors in 37 adult onset Pompe patients and 45 controls. Moreover, all patients performed several muscle function tests, conventional spirometry, and quantitative muscle MRI using 3-point Dixon. We observed a statistically significant change in the serum concentration of each growth factor in patients compared to controls. However, only PDGF-BB levels were able to differentiate between asymptomatic and symptomatic patients, suggesting its potential role in the follow-up of asymptomatic patients. Moreover, our results point to a dysregulation of muscle regeneration as an additional pathomechanism of Pompe disease

Identification of serum microRNAs as potential biomarkers in Pompe disease

Coinvestigators – The Spanish Pompe Study Group: Miguel Angel Barba-Romero; Joseba Barcena; María Rosario Carzorla; Carlota Creus; Jaume Coll-Canti; Noemí de Luna; Manuel Díaz; Cristina Domínguez; Roberto Fernández Torrón; María José García Antelo; Josep María Grau; María Teresa Gómez Caravaca; Juan Carlos León Hernández; Adolfo López de Munain; Francisco Antonio Martinez-García; Yolanda Morgado; Antonio Moreno; Germán Morís; Miguel Angel Muñoz-Blanco; Andres Nascimento; Carmen Paradas; José Luis Parajua Pozo; Luis Querol; Arturo Robledo-Strauss; Ricard Rojas García, Ricard; Íñigo Rojas-Marcoso; José Antonio Salazar; Mercedes Usón[Objective] To analyze the microRNA profile in serum of patients with Adult Onset Pompe disease (AOPD). [Methods] We analyzed the expression of 185 microRNAs in serum of 15 AOPD patients and five controls using microRNA PCR Panels. The expression levels of microRNAs that were deregulated were further studied in 35 AOPD patients and 10 controls using Real‐Time PCR. Additionally, the skeletal muscle expression of microRNAs which showed significant increase levels in serum samples was also studied. Correlations between microRNA serum levels and muscle function test, spirometry, and quantitative muscle MRI were performed (these data correspond to the study NCT01914536 at ClinicalTrials.gov). [Results] We identified 14 microRNAs that showed different expression levels in serum samples of AOPD patients compared to controls. We validated these results in a larger cohort of patients and we found increased levels of three microRNAs, the so called dystromirs: miR‐1‐3p, miR‐133a‐3p, and miR‐206. These microRNAs are involved in muscle regeneration and the expression of these was increased in patients' muscle biopsies. Significant correlations between microRNA levels and muscle function test were found. [Interpretation] Serum expression levels of dystromirs may represent additional biomarkers for the follow‐up of AOPD patients.This study was supported by a grant from Sanofi‐Genzyme (GZ‐2015‐11342) to Dr. Gallardo and has been registered in Clinicaltrials.gov (identifier NCT03045042)

Follow‐up of late‐onset Pompe disease patients with muscle magnetic resonance imaging reveals increase in fat replacement in skeletal muscles

Altres ajuts: This investigation was sponsored by the following grants, one from Sanofi Genzyme and another from the Spanish Ministry of Health, Fondos FEDER-ISCIII. Isabel Illa has received speaker honorarium from Grifols and Sanofi-Genzyme. Jordi Díaz-Manera has received speaker honorarium from PTC Therapeutics and Sanofi-Genzyme. The authors of this manuscript certify that they comply with the ethical guidelines for authorship and publishing in the Journal of Cachexia, Sarcopenia, and Muscle.42Altres ajuts: MSCBS/PI18-01525Altres ajuts: MSCBS/PI18-0111Late-onset Pompe disease (LOPD) is a genetic disorder characterized by progressive degeneration of the skeletal muscles produced by a deficiency of the enzyme acid alpha-glucosidase. Enzymatic replacement therapy with recombinant human alpha-glucosidase seems to reduce the progression of the disease; although at the moment, it is not completely clear to what extent. Quantitative muscle magnetic resonance imaging (qMRI) is a good biomarker for the follow-up of fat replacement in neuromuscular disorders. The aim of this study was to describe the changes observed in fat replacement in skeletal muscles using qMRI in a cohort of LOPD patients followed prospectively. A total of 36 LOPD patients were seen once every year for 4 years. qMRI, several muscle function tests, spirometry, activities of daily living scales, and quality-of-life scales were performed on each visit. Muscle MRI consisted of two-point Dixon studies of the trunk and thigh muscles. Computer analysis of the images provided the percentage of muscle degenerated and replaced by fat in every muscle (known as fat fraction). Longitudinal analysis of the measures was performed using linear mixed models applying the Greenhouse-Geisser test. We detected a statistically significant and continuous increase in mean thigh fat fraction both in treated (+5.8% in 3 years) and in pre-symptomatic patients (+2.6% in 3years) (Greenhouse-Geisser p < 0.05). As an average, fat fraction increased by 1.9% per year in treated patients, compared with 0.8% in pre-symptomatic patients. Fat fraction significantly increased in every muscle of the thighs. We observed a significant correlation between changes observed in fat fraction in qMRI and changes observed in the results of the muscle function tests performed. Moreover, we identified that muscle performance and mean thigh fat fraction at baseline visit were independent parameters influencing fat fraction progression over 4 years (analysis of covariance, p < 0.05). Our study identifies that skeletal muscle fat fraction continues to increase in patients with LOPD despite the treatment with enzymatic replacement therapy. These results suggest that the process of muscle degeneration is not stopped by the treatment and could impact muscle function over the years. Hereby, we show that fat fraction along with muscle function tests can be considered a good outcome measures for clinical trials in LOPD patients

Identification of serum microRNAs as potential biomarkers in Pompe disease

Altres ajuts: This study was supported by a grant from Sanofi-Genzyme (GZ-2015-11342) to Dr. Gallardo and has been registered in Clinicaltrials.gov (identifier NCT03045042).To analyze the microRNA profile in serum of patients with Adult Onset Pompe disease (AOPD). We analyzed the expression of 185 microRNAs in serum of 15 AOPD patients and five controls using microRNA PCR Panels. The expression levels of microRNAs that were deregulated were further studied in 35 AOPD patients and 10 controls using Real-Time PCR. Additionally, the skeletal muscle expression of microRNAs which showed significant increase levels in serum samples was also studied. Correlations between microRNA serum levels and muscle function test, spirometry, and quantitative muscle MRI were performed (these data correspond to the study NCT01914536 at ClinicalTrials.gov). We identified 14 microRNAs that showed different expression levels in serum samples of AOPD patients compared to controls. We validated these results in a larger cohort of patients and we found increased levels of three microRNAs, the so called dystromirs: miR-1-3p, miR-133a-3p, and miR-206. These microRNAs are involved in muscle regeneration and the expression of these was increased in patients' muscle biopsies. Significant correlations between microRNA levels and muscle function test were found. Serum expression levels of dystromirs may represent additional biomarkers for the follow-up of AOPD patients

Assessment of disease progression in dysferlinopathy. A 1-year cohort study

Jain COS Consortium.[Objective] To assess the ability of functional measures to detect disease progression in dysferlinopathy over 6 months and 1 year.[Methods] One hundred ninety-three patients with dysferlinopathy were recruited to the Jain Foundation's International Clinical Outcome Study for Dysferlinopathy. Baseline, 6-month, and 1-year assessments included adapted North Star Ambulatory Assessment (a-NSAA), Motor Function Measure (MFM-20), timed function tests, 6-minute walk test (6MWT), Brooke scale, Jebsen test, manual muscle testing, and hand-held dynamometry. Patients also completed the ACTIVLIM questionnaire. Change in each measure over 6 months and 1 year was calculated and compared between disease severity (ambulant [mild, moderate, or severe based on a-NSAA score] or nonambulant [unable to complete a 10-meter walk]) and clinical diagnosis.[Results] The functional a-NSAA test was the most sensitive to deterioration for ambulant patients overall. The a-NSAA score was the most sensitive test in the mild and moderate groups, while the 6MWT was most sensitive in the severe group. The 10-meter walk test was the only test showing significant change across all ambulant severity groups. In nonambulant patients, the MFM domain 3, wrist flexion strength, and pinch grip were most sensitive. Progression rates did not differ by clinical diagnosis. Power calculations determined that 46 moderately affected patients are required to determine clinical effectiveness for a hypothetical 1-year clinical trial based on the a-NSAA as a clinical endpoint.[Conclusion] Certain functional outcome measures can detect changes over 6 months and 1 year in dysferlinopathy and potentially be useful in monitoring progression in clinical trials.[ClinicalTrials.gov identifier] NCT01676077.The estimated US $4 million needed to fund this study is being provided by the Jain Foundation. The John Walton Centre Muscular Dystrophy Research Centre is part of the MRC Centre for Neuromuscular Diseases (grant MR/K000608/1)

Effectiveness of a multidisciplinary BIOPSYCHOSOCIAL intervention for non-specific SUBACUTE low back pain in a working population : a cluster randomized clinical trial

BACKGROUND: Low back pain (LBP) is a multifactorial condition with individual and societal impact that affects populations globally. Current guidelines for the treatment of LBP recommend pharmacological and non-pharmacological strategies. The aim of this study was to compare usual clinical practice with the effectiveness of a biopsychosocial multidisciplinary intervention in reducing disability, severity of pain and improving quality of life in a working population of patients with subacute (2-12 weeks), non-specific LBP. METHODS: Longitudinal cluster randomized clinical trial conducted in 39 Primary Health Care Centres (PHCC) of Barcelona, with patients aged 18-65 years (n = 501; control group = 239; 26 PHCC, intervention group = 262; 13 PHCC). The control group received usual clinical care. The intervention group received usual clinical care plus a biopsychosocial multidisciplinary intervention, which consisted of physiotherapy, cognitive-behavioural therapy and medication. The main outcomes were changes in the Roland Morris Disability Questionnaire (RMDQ), and the minimal clinically important differences. Secondary outcomes were changes in the McGill Pain (MGPQ) and Quality of Life (SF-12) questionnaires. Assessment was conducted at baseline, 3 and 12 months. Analysis was by intention-to-treat and analyst-blinded. Multiple imputations were used. RESULTS: Of the 501 enrolled patients, 421 (84%) provided data at 3 months, and 387 (77.2%) at 12 months. Mean age was 46.8 years (SD: 11.5) and 64.7% were women. In the adjusted analysis of the RMDQ outcome, only the intervention group showed significant changes at 3 months (- 1.33 points, p = 0.005) and at 12 months (- 1.11 points, p = 0.027), but minimal clinically important difference were detected in both groups. In the adjusted analysis of the RMDQ outcome, the intervention group improvement more than the control group at 3 months (- 1.33 points, p = 0.005) and at 12 months (- 1.11 points, p = 0.027). The intervention group presented a significant difference. Both groups presented a minimal clinically important difference, but more difference in the intervention group. The intervention group presented significant differences in the MGPQ scales of current pain intensity and VAS scores at 3 months. No statistically significant differences were found in the physical and mental domains of the SF-12. CONCLUSIONS: A multidisciplinary biopsychosocial intervention in a working population with non-specific subacute LBP has a small positive impact on disability, and on the level of pain, mainly at short-term, but no difference on quality of life. TRIAL REGISTRATION: ISRCTN21392091 (17 oct 2018) (Prospectively registred