Predictors of Loss of Ambulation in Duchenne Muscular Dystrophy: A Systematic Review and Meta-Analysis.

Objective: The objective of this study was to describe predictors of loss of ambulation in Duchenne muscular dystrophy (DMD). Methods: This systematic review and meta-analysis included searches of MEDLINE ALL, Embase, and the Cochrane Database of Systematic Reviews from January 1, 2000, to December 31, 2022, for predictors of loss of ambulation in DMD. Search terms included "Duchenne muscular dystrophy" as a Medical Subject Heading or free text term, in combination with variations of the term "predictor". Risk of bias was assessed using the Newcastle-Ottawa Scale. We performed meta-analysis pooling of hazard ratios of the effects of glucocorticoids (vs. no glucocorticoid therapy) by fitting a common-effect inverse-variance model. Results: The bibliographic searches resulted in the inclusion of 45 studies of children and adults with DMD from 17 countries across Europe, Asia, and North America. Glucocorticoid therapy was associated with delayed loss of ambulation (overall meta-analysis HR deflazacort/prednisone/prednisolone: 0.44 [95% CI: 0.40-0.48]) (n = 25 studies). Earlier onset of first signs or symptoms, earlier loss of developmental milestones, lower baseline 6MWT (i.e.,<350 vs. ≥350 metres and <330 vs. ≥330 metres), and lower baseline NSAA were associated with earlier loss of ambulation (n = 5 studies). Deletion of exons 3-7, proximal mutations (upstream intron 44), single exon 45 deletions, and mutations amenable of skipping exon 8, exon 44, and exon 53, were associated with prolonged ambulation; distal mutations (intron 44 and downstream), deletion of exons 49-50, and mutations amenable of skipping exon 45, and exon 51 were associated with earlier loss of ambulation (n = 13 studies). Specific single-nucleotide polymorphisms in CD40 gene rs1883832, LTBP4 gene rs10880, SPP1 gene rs2835709 and rs11730582, and TCTEX1D1 gene rs1060575 (n = 7 studies), as well as race/ethnicity and level of family/patient deprivation (n = 3 studies), were associated with loss of ambulation. Treatment with ataluren (n = 2 studies) and eteplirsen (n = 3 studies) were associated with prolonged ambulation. Magnetic resonance biomarkers (MRI and MRS) were identified as significant predictors of loss of ambulation (n = 6 studies). In total, 33% of studies exhibited some risk of bias. Conclusion: Our synthesis of predictors of loss of ambulation in DMD contributes to the understanding the natural history of disease and informs the design of new trials of novel therapies targeting this heavily burdened patient population.

Factors Associated with Respiratory Health and Function in Duchenne Muscular Dystrophy: A Systematic Review and Evidence Grading.

BACKGROUND: Despite advances in the medical management of the disease, respiratory involvement remains a significant source of morbidity and mortality in children and adults with Duchenne muscular dystrophy (DMD). OBJECTIVE: The objective of this systematic literature review was to synthesize and grade published evidence of factors associated with respiratory health and function in DMD. METHODS: We searched MEDLINE, Embase, and the Cochrane Library for records of studies published from January 1, 2000 (to ensure relevance to current care practices), up until and including December 31, 2022, reporting evidence of prognostic indicators and predictors of disease progression in DMD. The quality of evidence (i.e., very low to high) was assessed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework. RESULTS: The bibliographic search strategy resulted in the inclusion of 29 articles. In total, evidence of 10 factors associated with respiratory health and function in patients with DMD was identified: glucocorticoid exposure (high- to very low-quality evidence), DMD mutations (low-quality evidence), DMD genetic modifiers (low-quality evidence), other pharmacological interventions (i.e., ataluren, eteplirsen, idebenone, and tamoxifen) (moderate- to very low-quality evidence), body mass index and weight (low-quality evidence), and functional ability (low-quality evidence). CONCLUSIONS: In conclusion, we identified a total of 10 factors associated with respiratory health in function in DMD, encompassing both pharmacological therapies, genetic mutations and modifiers, and patient clinical characteristics. Yet, more research is needed to further delineate sources of respiratory heterogeneity, in particular the genotype-phenotype association and the impact of novel DMD therapies in a real-world setting. Our synthesis and grading should be helpful to inform clinical practice and future research of this heavily burdened patient population.

Timing of Clinical Interventions in Patients With Duchenne Muscular Dystrophy: A Systematic Review and Grading of Evidence.

BACKGROUND: Clinical medical management guidelines of Duchenne muscular dystrophy (DMD) emphasize prevention and early identification and treatment. OBJECTIVE: The objective of our study was to review, synthesize, and grade published evidence of the impact of the timing of clinical interventions in DMD. METHODS: We searched PubMed, Embase, and the Cochrane Library for records published from inception up until November 19, 2021, reporting evidence of the impact of the timing of clinical interventions in DMD. We assessed the quality of evidence using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework. RESULTS: We included 12 publications encompassing 1,623 patients with DMD from seven countries (Australia, France, Germany, Italy, Japan, the United Kingdom, and the United States of America). Six (50%) studies reported evidence of an impact of the timing of initiation of glucocorticoids on loss of ambulation, cardiomyopathy, fractures, forced vital capacity, and height and BMI; four (33%) of cardiac medication (i.e., angiotensin-converting enzyme inhibitors, ß-blockers, and eplerenone) on left ventricular size and function and survival; one (8%) of lower limb surgery on motor quotient and loss of ambulation; and one (8%) of ataluren on lower extremity and motor function. The overall quality of the body of evidence was low. CONCLUSION: While there is a clinical rationale for anticipatory diagnostic and therapeutic strategies, evidence of the impact of the timing of initiation of treatments in patients with DMD is still emerging. Further research of this topic is warranted to inform treatment guidelines in this indication.

Clinical course of multiple sclerosis and labour-force absenteeism: a longitudinal population-based study.

BACKGROUND AND PURPOSE: Multiple sclerosis (MS) is a chronic neurological disease associated with substantial disability and morbidity. The objective of our study was to assess the long-term consequences of MS clinical course on sick leave and disability pension. METHODS: Patients with relapsing-remitting MS (RRMS), secondary progressive MS (SPMS) and primary progressive MS (PPMS) were identified through the Swedish Multiple Sclerosis Registry. We calculated the mean annual prevalence and number of sick leave and disability pension days by clinical course, age and year pre- and post-diagnosis, and compared outcomes using Welch's t-tests and ANOVA models, mixed-effects regression and survival analysis. RESULTS: The sample included 5371 patients (4568 with RRMS, 390 with SPMS and 413 with PPMS). The mean annual number of days with sick leave and disability pension ranged from 101 at 1 year after diagnosis to 164 after 11 years for patients with RRMS. Corresponding estimates for PPMS were 188 and 311 days. Higher levels of absenteeism were observed in patients with PPMS versus RRMS 7 years before diagnosis for sick leave (P < 0.025) and 10 years before diagnosis for disability pension (P < 0.034). Differences between SPMS and PPMS were minor. CONCLUSIONS: Patients with RRMS had substantially lower levels of sick leave and disability pension over time compared with their counterparts with SPMS and PPMS, whereas labour-force absenteeism was similar for patients with SPMS and PPMS. These findings contribute to the understanding of the impact of MS on socioeconomic outcomes and help inform the discussion on the clinical classification of different courses of the disease.

Residual effect after oral bisphosphonate treatment and healthy adherer effects--the Swedish Adherence Register Analysis (SARA).

UNLABELLED: Little is known of the effect of alendronate and risedronate on osteoporotic fractures after discontinuation of therapy. We found that time on treatment was significantly inversely associated with the incidence of hospitalized fractures during posttreatment follow-up. Our results will inform health economic analysis of osteoporosis interventions. INTRODUCTION: Real-world persistence to treatment of osteoporosis is well-understood, but little is known of the posttreatment residual effect on fractures. The objective of this study was to investigate the residual effect of alendronate and risedronate on fractures and assess whether a healthy adherer effect confounds the association between persistence and residual anti-fracture effect. METHODS: A treatment-naïve cohort from the Swedish Prescribed Drug Register was identified through prescriptions for alendronate or risedronate between 2005 and 2009. Persistence was estimated, and patients were stratified by time on treatment (<1 month, 1-6 months, 7-12 months, and >12 months). Survival analysis was used to study hospitalized fractures and mortality up to 18 months after treatment discontinuation. RESULTS: The crude incidence proportion of fractures the first 6 months after treatment discontinuation ranged from 2.26% (<1 month of treatment) to 1.16% (>12 months). The corresponding estimates for month 7 to 12 after discontinuation was 3.18 to 1.96%, and for month 13 to 18 after discontinuation 2.69 to 1.95%. Adjusted regression results showed that patients persisting with therapy for >12 months had 60% lower fracture risk the first six months after treatment discontinuation (RR 0.40, p = 0.001). Patient characteristics, including prevalent fractures and co-morbidities, and posttreatment mortality were comparable across persistence durations, and we found no evidence of a healthy adherer effect. CONCLUSIONS: Time on bisphosphonate treatment was significantly inversely associated with the incidence of hospitalized fractures during posttreatment follow-up. We found no evidence of a healthy adherer effect confounding the relationship between treatment persistence and fracture risk.

The association between automatic generic substitution and treatment persistence with oral bisphosphonates.

UNLABELLED: Automatic generic substitution of alendronate products, used to reduce drug costs, and medication persistence was studied retrospectively between 2006 and 2009. During this period the number of, and the rate of substitution between, alendronate products increased while persistence decreased. Patient preferences should be considered when designing and evaluating generic policies. INTRODUCTION: Automatic generic substitution (AGS) was implemented in Sweden in 2002. The objective of this study was to investigate the association between AGS and persistence with alendronate treatment of primary osteoporosis in Sweden. METHODS: An open historical cohort of women and men (n = 36,433) was identified in the Swedish Prescribed Drug Register through filled prescriptions for alendronate or risedronate between 2005 and 2009. Co-morbidity data was extracted from the National Patient Register. The association between AGS and medication persistence was investigated using non-parametric and parametric survival analysis. RESULTS: Between 2006 and 2009, the number of alendronate products increased from 15 to 25, the proportion of prescriptions constituting a substitution increased from 10.8% to 45.2%, and the proportion of patients persisting with alendronate treatment for 12 months fell from 66.9% to 51.7%. Patients starting alendronate treatment in 2006 had lower risk of stopping treatment compared with those starting in 2007 (HR 1.34, 95% CI 1.29-1.39), 2008 (HR 1.49, 95% CI 1.43-1.55), and 2009 (HR 1.50, 95% CI 1.40-1.60). No difference was observed in persistence with proprietary risedronate during the same period. Individuals who had their alendronate product substituted at the first prescription refill had significantly higher probability of discontinuation (HR 1.25, 95% CI 1.20-1.30). CONCLUSION: AGS causes increased product substitution which appears to be associated with reduced treatment persistence. Poor health outcomes and associated costs due to forgone drug exposure should be taken into account in the design and evaluation of policies implemented to encourage utilisation of generic medicines.

Adherence to treatment of primary osteoporosis and its association to fractures--the Swedish Adherence Register Analysis (SARA).

SUMMARY: Osteoporosis treatments reduce the risk of fractures. The objective of this study was to investigate adherence to treatment of osteoporosis and its association to fractures in Sweden. Adherence to treatment of osteoporosis in Sweden is poor, and time on treatment was found to be significantly associated with fracture incidence. INTRODUCTION: The objective of this study was to estimate persistence and compliance to treatment of primary osteoporosis in Sweden. A second aim was to investigate the determinants of non-persistence and the association between adherence and fracture incidence. METHODS: Patients were identified through filled prescriptions for alendronate, risedronate, strontium ranelate, and raloxifene between 2005 and 2009 from the Swedish Prescribed Drug Register. Persistence was investigated using survival analysis. Medication possession ratio (MPR) was used to measure compliance in persistent patients. The outcome measure in the analysis of adherence and fracture incidence was hospitalized osteoporotic fractures. RESULTS: The final cohort consisted of 56,586 treatment-naïve patients (mean age 71, 86% women). A total of 51%, 35%, 25%, and 14% were still on treatment (switching allowed) after 1, 2, 3, and 4 years, respectively. Average MPR in persistent patients was 94.2% (CI(95) 94.2-94.3%). Compared with <1 month of therapy, treatment for 1 month to 1 year, 1 to 2 years, and 2 to 3 years was associated with a lower 3-year fracture incidence (HR 0.86, p = 0.091; HR 0.67, p < 0.001; and HR 0.59, p < 0.001, respectively). No significant relationship was identified between MPR and fracture risk. CONCLUSIONS: Persistence to treatment of osteoporosis in Sweden is poor and approximately 50% of all treatment-naïve patients discontinue therapy within 1 year. Average refill compliance, estimated only while the patients were persistent, was found to be close to perfect. A strong association was identified between treatment persistence and fracture incidence, which calls for action to improve the current situation.