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Prognostic indicators of disease progression in Duchenne muscular dystrophy: A literature review and evidence synthesis

  • Nermina Ferizovic ,

    Roles Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing

    nermina.ferizovic@hotmail.co.uk

    Affiliations MAP BioPharma Ltd, Cambridge, England, United Kingdom, BresMed Health Solutions, Sheffield, England, United Kingdom

  • Jessica Summers,

    Roles Conceptualization, Data curation, Formal analysis, Methodology, Validation, Writing – review & editing

    Affiliation MAP BioPharma Ltd, Cambridge, England, United Kingdom

  • Igor Beitia Ortiz de Zárate,

    Roles Conceptualization, Methodology, Writing – review & editing

    Affiliation PTC Therapeutics France SAS, Paris, France

  • Christian Werner,

    Roles Conceptualization, Formal analysis, Validation, Writing – review & editing

    Affiliation PTC Therapeutics Germany GmbH, Frankfurt/Main, Germany

  • Joel Jiang,

    Roles Methodology, Validation, Writing – review & editing

    Affiliation PTC Therapeutics, South Plainfield, New Jersey, United States of America

  • Erik Landfeldt ,

    Contributed equally to this work with: Erik Landfeldt, Katharina Buesch

    Roles Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing

    Affiliation ICON plc, Stockholm, Sweden

  • Katharina Buesch

    Contributed equally to this work with: Erik Landfeldt, Katharina Buesch

    Roles Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing

    Affiliation PTC Therapeutics Switzerland GmbH, Zug, Switzerland

Abstract

Background

Duchenne muscular dystrophy (DMD) is a rare, severely debilitating, and fatal neuromuscular disease characterized by progressive muscle degeneration. Like in many orphan diseases, randomized controlled trials are uncommon in DMD, resulting in the need to indirectly compare treatment effects, for example by pooling individual patient-level data from multiple sources. However, to derive reliable estimates, it is necessary to ensure that the samples considered are comparable with respect to factors significantly affecting the clinical progression of the disease. To help inform such analyses, the objective of this study was to review and synthesise published evidence of prognostic indicators of disease progression in DMD. We searched MEDLINE (via Ovid), Embase (via Ovid) and the Cochrane Library (via Wiley) for records published from inception up until April 23 2021, reporting evidence of prognostic indicators of disease progression in DMD. Risk of bias was established with the grading system of the Centre for Evidence-Based Medicine (CEBM).

Results

Our search included 135 studies involving 25,610 patients from 18 countries across six continents (Africa, Asia, Australia, Europe, North America and South America). We identified a total of 23 prognostic indicators of disease progression in DMD, namely age at diagnosis, age at onset of symptoms, ataluren treatment, ATL1102, BMI, cardiac medication, DMD genetic modifiers, DMD mutation type, drisapersen, edasalonexent, eteplirsen, glucocorticoid exposure, height, idebenone, lower limb surgery, orthoses, oxandrolone, spinal surgery, TAS-205, vamorolone, vitlolarsen, ventilation support, and weight. Of these, cardiac medication, DMD genetic modifiers, DMD mutation type, and glucocorticoid exposure were designated core prognostic indicators, each supported by a high level of evidence and significantly affecting a wide range of clinical outcomes.

Conclusion

This study provides a current summary of prognostic indicators of disease progression in DMD, which will help inform the design of comparative analyses and future data collection initiatives in this patient population.

1. Introduction

Duchenne muscular dystrophy (DMD) is a rare, neuromuscular disease characterised by progressive muscle degeneration caused by mutations in the X-linked DMD gene [1, 2]. The DMD gene encodes dystrophin, a structural protein which forms part of complexes predominantly found in muscle cells where it plays a significant role in the stabilisation of cell membranes [3]. To date, over 1,100 mutations have been identified, including 891 responsible for DMD phenotypes [4]. The incidence of DMD has been estimated at between 1 in 3,500 and 5,000 live male births [5, 6].

Patients with DMD are diagnosed around the age of four years, but many boys show symptoms earlier due to proximal muscle weakness resulting in delayed physical milestones (e.g., walking, running, and climbing stairs). As the disease progresses, patients become non-ambulatory usually in their early teens, followed by increasing loss of upper limb strength and function [711]. Respiratory and cardiac decline ensue, with patients eventually requiring mechanical ventilation support for survival [9, 10]. The median life expectancy at birth is around 30 years [12]. At present, there is no cure for DMD, and standard of care is mainly aimed at managing disease symptoms and promoting patient quality of life [13].

In medical research, it is occasionally necessary to pool patient-level data from different studies to indirectly assess the efficacy of a treatment due to low statistical power because of small patient samples and/or the absence of direct comparators in randomised controlled trials (RCTs). To minimize bias in such analyses, it is important to ensure that the populations to be compared are sufficiently homogeneous with respect to factors that would be expected to directly or indirectly affect outcomes of interest [14]. For example, in the context of DMD, it would be relevant to adjust any indirect comparison for the current age of the patient, among other factors, given the progressive, age-related nature of the disease. However, to date, no study has systematically reviewed the body of evidence for factors affecting disease progression outcomes in DMD. To bridge this evidence gap, the objective of this study was to review and synthesise the published evidence on prognostic indicators of disease progression in DMD.

2. Methods

This literature review was conducted and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [15]. The study protocol is not publicly available due to intellectual property restrictions.

2.1. Search strategy

We searched MEDLINE (via Ovid), Embase (via Ovid) and the Cochrane Library (via the Wiley online platform) for records of studies published from inception up until April 23 2021, reporting evidence of prognostic indicators of disease progression in DMD. The search string contained “Duchenne muscular dystrophy” as a Medical Subject Heading term or free text term in combination with variations of the free text term “prognostic indicator”. For example, the MEDLINE population terms were: 1. “exp Muscular Dystrophy, Duchenne/”, 2. “(Duchenne and dystro*).mp.” and 3. “1 or 2”. These were combined with the prognostic indicator terms; 4. “(prognos* or (disease adj3 course) or (disease adj3 impact) or natural history or (disease adj3 predict*) or (disease adj3 outcome) or (disease adj3 progres*)).mp.” and 5. “3 and 4”. Then the searches filtered out irrelevant study designs with the following; 6. “(comment or letter or editorial or notes or review).pt.”, 7. “(exp animals/ or exp invertebrate/ or animal experiment/ or animal model/) and (human/)” and 8. “(exp animals/ or exp invertebrate/ or animal experiment/ or animal model/) not 7”, 9. “6 or 8” and 10. “5 not 9”. Full search strings are provided in S1 Appendix.

2.2. Selection criteria

Eligibility criteria based on the Population, Intervention, Comparison, Outcomes and Study design (PICOS) framework for study inclusion are presented in Table 1. Only English language texts were included. For the purposes of this review, a prognostic indicator was defined as any factor, either endogenous or exogenous, affecting the clinical progression of disease.

2.3. Screening and data extraction

One investigator (NF) initially screened article titles and abstracts for eligibility, and subsequently reviewed full-text versions of selected records. The reason for exclusion was recorded and confirmed by a second investigator (JS). For all articles that met the inclusion criteria upon full-text review, the following information was extracted into a pre-designed data extraction form: Author, year, geographical setting, study design, interventions, patient sample population characteristics, disease progression outcome measures, prognostic indicators, and the impact of the prognostic indicators on disease progression. For the purpose of this review, we only considered statistically significant prognostic indicators (as reported in the included studies).

We synthesised extracted evidence of the impact of identified prognostic indicators of disease progression in DMD into eight outcome categories: cardiac health and function, loss of independent ambulation, lower extremity and motor function, muscle strength, respiratory health and function, scoliosis, survival, and upper extremity function. Although loss of ambulation is a clinical milestone within the lower extremity and motor function domain, we decided to report evidence separately for this factor given its central role in DMD research (e.g., as a primary endpoint in RCTs). Due to the monotonic progression of DMD, we did not consider current age a prognostic factor of interest, nor bisphosphonate therapy because of the negative impact from both glucocorticoids and DMD on bone health [13].

2.4. Level of evidence

The level of evidence of included studies was established using a modified version of the grading system of the Centre for Evidence-Based Medicine (CEBM) [16]. Specifically, five levels of evidence were designated based on study design: (1) systematic review of randomised trials or n-of-1 trials, (2) randomised trial or observational study with dramatic effect, (3) non-randomised controlled cohort/follow-up study, (4) case-series, case-control studies, or historically controlled studies, and (5) mechanism-based reasoning. For reporting purposes, we categorised evidence levels 1 and 2 as “high level of evidence”, level 3 as “moderate level of evidence”, and levels 4 and 5 as “low level of evidence”.

3. Results

The search was performed on April 26 2021, and resulted in the identification of 3,018 publications (including journal articles and congress/conference abstracts) reporting evidence of prognostic indicators of disease progression in DMD (Fig 1). Of these, 740 records were duplicates, 1,966 excluded following title and abstract screening, and 312 selected for full-text review. An additional 54 articles were included from the reference searches of identified systematic literature reviews (SLRs) and meta-analyses (MAs). Finally, 294 publications were considered for data extraction, with 135 studies reporting statistically significant prognostic indicators of disease progression that were subsequently included for evidence synthesis and grading. Summary details of the included studies are presented in Table 2. Identified studies encompassed 25,610 patients with DMD from 18 countries (Argentina, Australia, Belgium, Canada, China, Denmark, Egypt, France, Germany, Holland, India, Italy, Japan, Korea, Sweden, Turkey, the United Kingdom and the United States).

thumbnail
Fig 1. PRISMA diagram of the selection process of the included publications.

Note: † Studies reporting evidence of statistically significant prognostic indicator of disease progression in DMD. Systematic literature reviews (SLRs). Meta-analyses (MAs).

https://doi.org/10.1371/journal.pone.0265879.g001

thumbnail
Table 2. Characteristics of included studies and identified prognostic indicators in DMD.

https://doi.org/10.1371/journal.pone.0265879.t002

We identified a total of 23 prognostic indicators of disease progression in DMD. Endogenous indicators included age at diagnosis, age at onset of symptoms, DMD genetic modifiers, DMD mutation type, height, weight and body mass index (BMI). Exogenous indicators included ataluren treatment, ATL1102, cardiac medication, drisapersen, edasalonexent, eteplirsen, glucocorticoid exposure (including age at glucocorticoid treatment initiation, dose, duration of exposure, pharmacological agent, and regimen), idebenone, lower limb surgery, orthoses, oxandrolone, spinal surgery, TAS-205, vamorolone, vitlolarsen, and ventilation support. The evidence for these prognostic indicators across the pre-defined outcome categories is summarised below and illustrated in Fig 2.

thumbnail
Fig 2. Evidence of prognostic indicators of disease progression in DMD.

Note: Numbers shown in the coloured squares refer to the number of studies reporting of the specific indicator. † Angiotensin-converting enzyme (ACE) inhibitors, beta blockers, and/or diuretics. ‡ Age at treatment initiation, dose, duration of exposure, pharmacological agent, and regimen. Duchenne muscular dystrophy (DMD).

https://doi.org/10.1371/journal.pone.0265879.g002

3.1. Cardiac health and function

We identified 29 studies presenting evidence of prognostic indicators of disease progression in DMD measured in terms of cardiac health and function [1745, 91, 111, 199]. In total, seven prognostic indicators were identified: BMI, cardiac medication, DMD genetic modifiers, DMD mutation type, glucocorticoid exposure, idebenone and ventilation support (Table 2). Angiotensin-converting enzyme (ACE) inhibitors, including timing of treatment initiation, have been shown to be significantly associated with improved left ventricular ejection fraction (LVEF) [CEBM Evidence Level 2] [29, 3234, 4244], and left ventricular end diastolic and systolic dimension (LVEDd/LVESd) [Level 2]; [30, 31, 45] and left ventricular free wall systolic myocardial velocity [Level 2] [30], beta blockers, when administered in combination with ACE inhibitors, with improved LVEF [Level 4] [3235], left ventricular fractional shortening (LVFS) [Level 2] [31], LVEDd and LVESd [Level 2] [35], left ventricular myocardial performance index (LVMPI) [Level 4] [35], and left ventricular sphericity index [Level 4];[35] beta blockers with reduced heart failure and arrhythmia [Level 3] [37], and improved LVMPI [Level 2]; [30] timing of unspecified cardiac medication with later onset of cardiomyopathy [Level 4]; [38] eplerenone (EPL) with improved left ventricular systolic strain, LVEF, and end systolic volume (ESV) [Level 2]; [36] and ventilation support in combination with cardiac medication with decreased LVEF and left atrium diameter [Level 4] [39]. Glucocorticoid exposure has been shown to be significantly associated with improved LVEF [Level 4] [1719, 21, 22, 25], LVFS [Level 3] [1719, 2527], LVEDd [Level 4] [19, 25, 26], meridional wall stress (mWS) [Level 4] [26], stabilisation of velocity of circumferential fibre shortening (VCFc) [Level 4] [26], reduction in cardiomyopathy [Level 4] [18, 20, 25, 199], and increases in summed rest score [Level 3] [24], as well as increased risk of cardiomyopathy [Level 4] [28], and decline in LVEF [Level 4] [23] linked to duration of glucocorticoid exposure. Idebenone improves peak systolic radial strain in the LV inferolateral wall [Level 2] [111]. BMI is prognostic of cardiomyopathy [Level 4] [41]. Finally, mutations in exons 51 and 52, as well as latent transforming growth factor beta-binding protein 4 (LTBP4), have been shown to be significantly associated with improved or sustained cardiac health and function [Level 4];[21, 22, 35]; mutations in exons 12, 14, 15, 16, and 17 with increased risk of cardiomyopathy [Level 4] [35]. and deletions in exon 53 with lower LVEF and higher contracture score compared with deletions not treatable by exon 53 skipping [Level 4] [91]. The ACTN3 null genotype is associated with earlier onset of cardiac dysfunction specifically, lower LV dilation-free rate [Level 4] [40].

3.2. Loss of independent ambulation

We identified 35 studies presenting evidence of prognostic indicators of disease progression in DMD measured in terms of loss of independent ambulation [11, 1820, 38, 46, 51, 6166, 6891, 109, 126130, 192, 193, 199]. In total, nine prognostic indicators were identified: age at diagnosis, age at onset of symptoms, ataluren treatment, DMD genetic modifiers, DMD mutation type, glucocorticoid exposure, eteplirsen treatment, height, and weight (Table 2). Prolonged independent ambulation was found in patients with later onset of symptoms [Level 2]; [83, 84] patients treated with glucocorticoids, including age at treatment initiation, duration of exposure, and pharmacological agent [Level 2]; [11, 1820, 38, 46, 51, 6164, 66, 7082, 88, 199]; ataluren treatment [Level 2] [87, 109, 110, 192, 193]; eteplirsen treatment [Level 2] [126130]; LTBP4 genotype [Level 2]; [65] lower limb surgery [Level 2] [89, 90] and mutations in exons 44 [Level 2] [11, 67, 73, 86, 88] and exons 3–7 [Level 2]; [11, 88] exon 8 [Level 4] [86, 88]; exon 45 [Level 4] [88, 199]; exon 53 [Level 4] [91];and the minor allele at rs1883832 [Level 4] [85]. Earlier loss of ambulation was found in patients with TG/GG genotype at the rs28357094 secreted phosphoprotein 1 (SPP1) promoter [Level 2]; [6366] exon 51 skipping and exon 49–50 deletions [Level 4] [88]; and deletions in the dystrophin gene [Level 4] [61]. Older age at diagnosis (>4 years) has been shown to be a predictor of later loss of ambulation [Level 5] [74]. Finally, greater weight and lower height have been shown to predict delayed time to loss of ambulation in patients treated with glucocorticoids [Level 4] [68, 69].

3.3. Lower extremity and motor function

We found 47 studies presenting evidence of prognostic indicators of disease progression in DMD measured in terms of lower extremity and motor function [47, 51, 71, 7577, 7982, 87, 92, 96, 101, 119131, 136, 138, 140, 141, 143146, 150152, 160186, 188198, 200202]. In total, twelve prognostic indicators were identified: ataluren treatment, BMI, DMD genetic modifiers, DMD mutation type, drisapersen treatment, eteplirsen treatment, glucocorticoid exposure, height, TAS-205 treatment, vamorolone treatment, vitlolarsen treatment, and weight (Table 2). Glucocorticoid treatment, including dose, duration of exposure, and regimen, have been shown to be significantly associated with improvement in motor function as measured using the Scott functional score [Level 2] [140, 143], the Vignos scale [Level 4] [71, 96], muscle function measure [Level 4] [171, 172], improvements in the NorthStar Ambulatory Assessment (NSAA) scale [Level 1] [7577, 131, 163167, 170], the 6-minute walk test (6MWT) including duration of glucocorticoid exposure [Level 1] [131, 163166, 175, 177179], 10 Meter Walk/Run Test (10WRT) [Level 2] [7981, 92, 96, 138, 174], 100 metre walk/run test [Level 3] [174], 9 metre walk/run test [Level 2] [47, 141, 144, 145], unspecified walking test [Level 4] [71], Supine-to-Stand (STS) test [Level 1] [47, 51, 71, 82, 92, 96, 101, 131, 136, 138, 141, 143, 145, 146, 160, 163166], and 4-Stairs Climb Test (4SCT) including duration of exposure [Level 1] [47, 71, 82, 92, 96, 101, 131, 138, 141, 144, 145, 161, 163166, 176]. Ataluren treatment has been shown to be significantly associated with better performance in timed function tests, including the 4SCT [Level 2] [87, 150, 189193], the STS test [Level 3] [87, 192, 193], the 10WRT [Level 2] [150, 189191], the NSAA [Level 2] [186188], and the 6MWT [Level 2]; [150, 180185, 189191] treatment with TAS-205 has been shown to increase muscle volume index [Level 2] [196]; treatment with vitlolarsen associated with improved 10WRT, 6MWT, STS and NSAA [Level 2] [152]; treatment with vamorolone improves 6MWT [Level 3] [197] STS [197, 198], 10WRT [197, 198], 4SCT and NSAA [Level 4] [198]; treatment with drisapersen improves STS and 6MWT [Level 2] [168, 169, 200202]. Eteplirsen treatment improves 6MWT [Level 2] [119130, 162]. Greater height and weight have been shown to be significantly associated with decline in the 6MWT [Level 4]; [175] similarly, height, weight BMI and glucocorticoid exposure including duration are predictive of 4SC [Level 4] [161]. Finally, skip exon mutations has been shown to be significantly associated with 6MWT performance [Level 4] and [194, 195] Dp140 deletions associated with lower NSAA scores [Level 4] [151].

3.4. Muscle strength

We found 26 studies presenting evidence of prognostic indicators of disease progression in DMD measured in terms of muscle strength [18, 47, 71, 79, 80, 91, 92, 100, 101, 135149, 153159]. In total, five prognostic indicators were identified: DMD genetic modifiers, DMD mutation type, edasalonexent, glucocorticoid exposure and oxandrolone (Table 2). Specifically, glucocorticoid treatment, including dose, duration of exposure, and regimen, have been shown to be associated with muscle strength as quantified by the Medical Research Council (MRC) muscle power assessment scale [Level 2] [18, 71, 100, 135, 136, 138, 158], quantitative muscle testing (QMT) [Level 2] [92, 139], muscle mass as given by creatine excretion [Level 2] [137, 139, 142], manual muscle testing (MMT) [Level 2] [92, 139, 142, 145], myometric evaluation [Level 2] [140146], unspecified muscle strength testing [Level 2] [101, 137], grip and pinch strength [Level 2] [47, 140, 141], Lovett’s test [Level 4]; [79, 80] and transverse relaxation time constant [Level 3] [159]. Edasalonexent improves the transverse relaxation time constant [Level 2] [153157]. Oxandrolone improves muscle strength as given by MMT [Level 4] [149] and an unspecified measure [Level 2] [148]. Finally, GT/GG genotypes at the rs28357094 SPP1 promoter have been shown to be significantly associated with lower composite MRC scores and grip strength compared with the TT genotype [Level 4] [147]. and exon 53 deletions with lower pinch strength compared to all mutations not treatable by exon 53 skipping [Level 4] [91].

3.5. Respiratory health and function

We identified 35 studies presenting evidence of prognostic indicators of disease progression in DMD measured in terms of respiratory health and function [1719, 21, 22, 28, 38, 47, 71, 77, 82, 92, 94118, 132134, 145, 199, 203]. In total, eight prognostic indicators were identified: ataluren treatment, DMD genetic modifiers, DMD mutation type, eteplirsen treatment, glucocorticoid exposure, idebenone treatment, ventilation support and weight (Table 2). Specifically, ataluren treatment has been shown to be significantly associated with improved forced vital capacity (FVC) [Level 2]; [103, 104, 109, 110] glucocorticoid treatment, including dose, duration of exposure, and regimen, with improved maximum inspiratory pressure (MIP) [Level 2] [92, 95, 96], maximum expiratory pressure (MEP) [Level 4] [94, 95], peak cough flow (PCF) [Level 4]; [94, 95] FVC [Level 2]; [17, 18, 21, 22, 38, 47, 71, 77, 82, 9699, 101, 145] forced expiratory volume in 1 second (FEV1) [Level 2] [96, 107], maximum voluntary ventilation (MVV) [Level 2], [92, 101, 102], FVC [Level 4] [107], reduced need for ventilation [Level 4] [199] and peak expiratory flow rate (PEFR) [Level 3] [96, 98100, 107] and pulmonary function preservation [Level 4] [19]. Duration of glucocorticoid exposure has also been linked to declining FVC levels [Level 4] [28]. Eteplirsen has been shown to be associated with an attenuation in respiratory function [Level 4] [108, 118] and reduced decline in FVC [Level 2] [113117] and MEP [Level 2] [116, 117]; and idebenone reduces the decline in respiratory function as given by FVC [Level 2] [203], FEV1 [Level 2] [112] and PEF [Level 2] [111, 112, 133] as well as reducing bronchopulmonary adverse events [Level 2] [132]. Weight has been shown to be a significant predictor of need for full-time ventilation support [Level 4] [105]. Ventilation support has been shown to reduce the rate of decline of FVC [Level 4] [106]. Finally, Gly16 beta2-adrenergic receptor (ADRB2) polymorphism has been shown to be significantly associated with increased risk of requiring nocturnal ventilation support (compared with the Arg16 polymorphism) [Level 4] [105]; dystrophin protein 140 (Dp140)-related mutations with lower FVC [Level 4] [21, 22]; mutations in exon 44 with lower FVC, FEV1 and PEF [Level 4] [107]; skip 51 and 53 mutations with decreased FEV1, PEF and FVC [Level 4] [107]; splice site, skip 8 and skip 44 with increased FVC [Level 4] [107]; skip 8 and splice site mutations with increased FEV1 and increased PEF [Level 4] [107]; nonsense mutation with decreased FEV1 and FVC [Level 4] [107]; dominant G genotype at rs28357094 in the SPP1 promoter with reduced FVC and PEF [Level 4] [107]; additive T genotype at rs1883832 in the CD40 5’ untranslated region with reduced FVC, FEV1 and PEF [Level 4] [107];mutations in exon 8 with improved PEF [Level 4]; [21, 22]; cDMD deficit with worsened respiratory function [Level 3] [134]; and SPP1 and cluster of differentiation 40 (CD40) polymorphisms with reduced FVC and PEF, respectively [Level 4] [21, 22] with both mutations associated with NIV initiation [Level 4] [107].

3.6. Scoliosis

We identified 7 studies presenting evidence of prognostic indicators of disease progression in DMD measured in terms of risk of scoliosis [18, 4650, 199]. In total, two prognostic indicators were identified: glucocorticoid exposure, and orthoses (Table 2). Specifically, glucocorticoid treatment, including duration of exposure, have been shown to significantly reduce the risk of developing scoliosis, including the degree of scoliosis and the need for spinal surgery [Level 3] [18, 4650, 199]. Time in orthoses has been shown to be significantly related to scoliosis severity [Level 4] [50].

3.7. Survival

We identified 13 studies presenting evidence of prognostic indicators of disease progression in DMD measured in terms of survival [25, 42, 43, 49, 5160]. In total, five prognostic indicators were identified: cardiac medication, glucocorticoid exposure, left ventricular assist devices, spinal surgery, and ventilation support (Table 2). Specifically, prolonged survival was found in patients treated with ACE inhibitors [Level 2] [42, 43] ACE inhibitors in combination with beta blockers, including timing of treatment initiation [Level 4]; [52] in patients treated with glucocorticoids (including duration of exposure) [Level 2]; [25, 49, 51] in patients receiving ventilation support [Level 4]; [5359] and in those undergoing spinal surgery in combination with ventilation support [Level 4] [55].; and in those implanted with left ventricular assist devices in combination with cardiac medication [Level 4] [60].

3.8. Upper extremity function

We identified 5 studies presenting evidence of prognostic indicators of disease progression in DMD measured in terms of upper extremity function [51, 92, 93, 96, 140]. In total, two prognostic indicators were identified: glucocorticoid exposure (including pharmacological agent) and ATL1102 treatment (Table 2). Glucocorticoid treatment has been shown to significantly retain hand-to-mouth function as measured using the Brooke score [Level 2]; [51, 92, 96, 140] and deflazacort (DFZ) exposure significantly delays loss of hand-to-mouth function compared to prednisone (PDN) [Level 2] [51]. Treatment with ATL1102 improves upper limb function in non-ambulant boys as given by performance of upper limb (PUL) scores [Level 2] [93].

4. Discussion

In many disease areas, including DMD, RCTs are commonly unavailable, resulting in the need to indirectly compare treatment effects, for example, by pooling individual patient-level data from multiple sources. However, to derive reliable estimates, it is necessary to ensure that the samples considered are comparable with respect to factors significantly affecting the clinical progression of the disease. To help inform such analyses, the objective of this study was to review and synthesise the published evidence of prognostic indicators of disease progression in DMD. From our literature search, we identified 23 factors significantly affecting disease progression outcomes in DMD, namely age at diagnosis, age at onset of symptoms, ataluren treatment, ATL1102, BMI, cardiac medication, DMD genetic modifiers, DMD mutation type, drisapersen, edasalonexent, eteplirsen, glucocorticoid exposure, height, idebenone, lower limb surgery, orthoses, oxandrolone, spinal surgery, TAS-205, vamorolone, vitlolarsen, ventilation support, and weight. Of these, two endogenous and two exogenous core prognostic indicators were designated, each supported by a high level of clinical evidence.

The most commonly examined prognostic indicator identified in the literature related to treatment with glucocorticoids–the cornerstone of the current pharmacological management of DMD. This core exogenous factor was found to significantly impact a wide range of disease progression outcomes, including loss of independent ambulation, lower extremity and motor function, muscle strength, respiratory health and function, survival, and upper extremity function (high level of evidence); cardiac health and function (moderate level of evidence); and possibly risk of developing scoliosis (low level of evidence). The body of evidence, spanning a total of 73 individual studies, encompassed various commonly reported features of glucocorticoid therapy, such as age at treatment initiation, dose, duration of exposure, pharmacological agent, and regimen.

The second exogenous core prognostic indicator of disease progression in DMD was cardiac medication, supported by data from a total of 13 studies of varying levels of evidence (Fig 2). As expected, this indicator only concerned cardiac health and function (with the exception of a single study of low evidence level showing an impact on survival). Even so, bearing in mind that cardiomyopathy has emerged as one of the leading causes of death in the aging DMD population in the presence of the routine use of mechanical ventilation support [12], the significance of this indicator should not be underestimated, in particular when comparing samples encompassing patients residing in more advanced stages of the disease.

The two endogenous core prognostic indicators of disease progression in DMD identified in our review were DMD genetic modifiers and DMD mutation type. Although more research is needed to quantify the impact of specific modifiers and mutations, emerging data show that these genetic aspects may play a non-trivial role in the overall progression of the disease. These findings underscore the importance of collecting genetic data from DMD patients as part of studies and patient registries.

Our study is subject to three specific limitations. First, our review did not cover grey literature, which means that evidence for some indicators of disease progression in DMD might have not been fully identified. However, given the comprehensive scope of our search and the limited body of clinical evidence disseminated in non-indexed journals, the impact of this limitation is expected to be negligible (in particular in terms of detecting novel prognostic indicators currently not included in our synthesis). Second, for interpretation of results, it is important to keep in mind that our study did not seek to assess the efficacy or effectiveness of current disease interventions, nor the sensitivity of specific indicators, but rather identify factors that have been shown to significantly alter the clinical progression of DMD (irrespective of magnitude). Although we only considered statistically significant factors, this means that it is not possible to discern the relative clinical importance, or relevance, of included indicators. Finally, the fact that we only reported statistically significant and not also non-significant results means that we were more likely to accept false positive than false negative conclusions of specific indicators. That being said, collating and synthesizing also non-significant results, of which a non-trivial proportion (β) would be expected to be false, were outside the scope of this review.

In conclusion, we identified a total of 23 prognostic indicators of disease progression in DMD, of which cardiac medication, DMD genetic modifiers, DMD mutation type, and glucocorticoid exposure were designated core indicators significantly affecting a wide range of clinical outcomes. Our up-to-date summary of prognostic indicators in DMD should be helpful to inform the design of comparative analyses and future data collection initiatives in this patient population.

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