2.1. Review questions

The research questions addressed in this systematic review are:

1. the prevalence and the incidence of DMD in Italy;
2. the quality of life of patients with DMD and their caregivers in Italy;
3. the adherence to the different management strategies for DMD in Italy, such as pharmacotherapy, physiotherapy and occupational therapy, and to identify factors that could facilitate or hamper the adherence;
4. the economic impact of DMD in Italy.

2.2. Literature searches

Systematic literature searches were performed in PubMed, Embase and Web of Science to retrieve studies published from January 2010 to January 2023. Only articles written in English or Italian were considered. The full search strategies are described in S2 Appendix.

2.3. Inclusion criteria

• Research question 1 (epidemiology): we included both secondary studies (systematic or narrative reviews) and primary studies (cross-sectional, cohort) describing prevalence and/or incidence of DMD in Italy;
• Research question 2 (quality of life): studies of any design assessing the quality of life of DMD patients and their caregivers, both comparative (e.g. DMD vs healthy subjects) or not;
• Research question 3 (adherence): studies of any design assessing the adherence to the different management strategies for DMD in Italy;
• Research question 4 (economic impact): economic studies describing comparative economic evaluations (e.g. cost-effectiveness studies) or cost of illness analyses.

For all the research questions, only studies performed in Italy, or international multicenter studies with at least one Italian centre were included.

2.4. Literature screening process

The study selection process was performed independently by two review authors. Any disagreement was solved through discussion and, in the event of no agreement, a third reviewer was involved. Initially, the reviewers screened the records reading titles and abstracts, according to predefined inclusion criteria. Later, they evaluated the full-text of the potential eligible studies. The final studies included in the review have been described in the main text and in the tables, while a list of excluded studies along with the reasons for their exclusion is available as supplementary material (S3 Appendix). Bibliographic references were managed using the EndNote X7.4 software.

2.5. Data extraction

Data extraction was performed by one reviewer and verified by another reviewer using a standardized form. The following general information were extracted from the included studies: bibliographic data (first author, publication year and title), study characteristics (study design, study objective, location, study period, sample size), participant characteristics (type of disease, mean age), study outcomes (incidence/prevalence, quality of life scores, adherence measures, economic measures).

In addition, for each research question we extracted the following specific information:

• Research question 1 (epidemiology), secondary studies: number of included studies and their bibliographic references, epidemiological estimates (prevalence in the general population, birth prevalence, incidence). Primary studies: study population (N), epidemiological estimates.
• Research question 2 (quality of life): methods used for assessing QoL, subjects interviewed (patients and/or caregivers), presence of a reference population (e.g. healthy subjects), results.
• Research question 3 (adherence): definition of non-adherence, percentage of non-adherent patients, reasons for non-adherence, factors influencing (barriers / facilitators) the adherence.
• Research question 4 (economic impact): type of economic analysis, type of costs (direct, indirect, non-healthcare costs), discount rate, economic perspective, reference year, results.

2.6. Quality assessment of included studies

The quality assessment was performed by one reviewer and verified by another reviewer, using checklists specific to the study design of included studies. In particular, the following checklists were used: for systematic reviews, the JBI Critical Appraisal Checklist for Systematic Reviews and Research Synthesis [15]; for prevalence studies, the checklist by Hoy et al. [16]; for qualitative studies, the Critical Appraisal Skills Programme (CASP) checklist [17]; for economic studies, the Consensus Health Economic Criteria (CHEC) list [18].

2.7. Strategy for data synthesis

In our study protocol, we anticipated that a quantitative synthesis of the results through a meta-analysis would only be carried out if three or more included studies reported on the same outcome for any research question; moreover, to be combined, the studies should have to be similar in terms of PICO (patient/population, intervention, comparator, outcome). Assuming a high level of heterogeneity between the included studies, it was planned to perform random effects meta-analyses, providing cumulative estimates along with 95% confidence intervals. The heterogeneity between the included studies would have been assessed using the I² statistic, considering a statistical significance level of p <0.05 for all analyses. The STATA 13/SE software was indicated for the statistical analyses. It was also specified in the protocol that, in all the cases where a meta-analysis was not considered feasible, the results would have been presented narratively.

3.1. Epidemiology

We included 3 studies: a systematic review and meta-analysis [3], a systematic review [19], and an observational prevalence study [20]. The characteristics of the two reviews are described in the Table 1, while the observational study results are described in the main text.

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Table 1. Characteristics of included secondary studies for epidemiology.

https://doi.org/10.1371/journal.pone.0287774.t001

The systematic review of Crisafulli et al. [3] reported a pooled global DMD prevalence from 22 studies of 7.1 cases (95% CI: 5.0–10.1) per 100,000 males and 2.8 cases (95% CI: 1.6–4.6) per 100,000 in the general population. Two out of 22 were Italian studies: Danieli et al. [21], through a retrospective chart review of patients hospitalized in 4 districts of Veneto region in the years 1952–1972, found a period prevalence of 3.4 (95% CI: 2.8–4.2) cases per 100,000 males and females of any age; Siciliano et al. [22], in a study conducted in Pisa (Tuscany) in the year 1997, reported a point prevalence of 1.7 (95% CI: 1.1–2.6) per 100,000 males and females of any age.

The review also reported a pooled global DMD birth prevalence from 29 studies of 19.8 cases (95% CI:16.6–23.6) per 100,000 live male births. Six Italian studies were included: the two studies by Danieli et al. [21, 23] (Veneto region, years 1952–1972) reported a period prevalence of 28.2 per 100,000 live male births; Bertolotto et al. [24] (Turin, years 1955–1974) a period prevalence of 24.2 per 100,000 live male births; Nigro et al. [25] (Campania region, years 1969–1980) a period prevalence of 21.7 per 100,000 live male births; Mostacciuolo et al. (1987) [26] (5 districts in the Veneto region, years 1955–1984) a period prevalence of 26.0 per 100,000 live male births; Merlini et al. [27] (Bologna, years 1970–1982) a period prevalence of 25.8 per 100,000 live male births.

All meta-analyses showed a substantial between-study heterogeneity (≥90%). Meta-regressions highlighted that the only covariate that reduced the heterogeneity of about 45% was the year in which the study began and its duration; older studies reported a higher DMD birth prevalence.

The methodological quality of the included studies was assessed through a modified version of the STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) checklist; 36/44 (82%) studies were considered of moderate quality, 8/44 (18%) studies of low quality, while no study was of high quality.

The systematic review by Theadom et al. [19] describes the prevalence of all types of muscular dystrophies and includes 38 studies in the qualitative synthesis, 22 (58%) of which reporting the DMD prevalence. The included studies reported a prevalence range in the general population of 1.0–7.7 cases per 100,000. Considering only the studies with low risk of bias, the prevalence range narrows to 1.7–4.2 / 100,000.

This review included 5 Italian studies [21, 22, 24, 26, 27] that reported a DMD prevalence range of 1.7–3.4 per 100,000; all of these studies were also included in the Crisafulli review [3].

The quality assessment showed that 15/38 studies were considered having a low risk of bias, 14/38 an unclear risk of bias, and 9/38 a high risk of bias.

The last included study was the observational study of Mostacciuolo et al. (1993) [20], that updates a previous study above described [26] by using Western blot and DNA analyses as diagnostic criteria. The epidemiological estimates concern the incidence rate in the period 1959–1968 and the prevalence rate in the year 1980, in five districts of Veneto region. The reported DMD prevalence in the general population is 3.3 per 100,000, while the birth prevalence is 26.0 per 100,000 live male births.

3.2. Quality of life

To address the research question 2 (quality of life), we identified 8 studies. The main characteristics of included studies are reported in Table 2.

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Table 2. Characteristics of included studies for quality of life.

https://doi.org/10.1371/journal.pone.0287774.t002

The study by Baiardini et al. [28] was carried out in an Italian centre located in Genova (Liguria region) and investigated the health-related quality of life and its possible determinants in 27 Duchenne muscular dystrophy children and in their parents. The tools used were the Children Health Questionnaire (CHQ)—Parent Form 50 and the Family Strain Questionnaire (FSQ); both questionnaires were completed by caregivers. Patients scored significantly lower than reference values of healthy subjects in 10 out of 15 CHQ dimensions. The use of a wheelchair (p <0.02) and pulmonary ventilator (p <0.001) are significantly associated with a lower health-related quality of life. Conversely, FSQ scores are not affected by patient characteristics.

The multicenter study by Cavazza et al. [29] was aimed to determine the health-related quality of life of DMD patients and their caregivers in eight European countries. The Italian participants were 87 patients and 61 caregivers who filled out the EQ-5D, Barthel Index and Zarit Burden Interview questionnaires. As for the EQ-5D, the Italian adult patients obtained an average EQ-5D VAS score lower than the average score of the other countries (45.4 vs. 50.5) while for the caregivers the EQ-5D VAS score was higher than the international mean score (78.2 vs. 74.7). The average Barthel Index of the Italian population indicates severe dependence while the Zarit Burden Interview average score shows a mild-to-moderate burden. With reference to the entire study population, the authors conclude that the HRQoL of people with DMD is much lower than that of the general population and that patients with DMD rate their health status as more harm to their physical than mental health.

Crescimanno et al. [30] conducted a study in an Italian centre located in Palermo (Sicily) involving 48 long-term ventilated adult DMD patients, aimed to assess their QoL and possible determinants. The QoL was evaluated by the Neuromuscular Quality of Life questionnaire (INQoL); in addition, four other questionnaires were administered to assess their sleep quality, psychological status and symptoms of autonomic impairment. The overall INQoL score (42.8 ± 19.2) indicates a moderately altered quality of life, mainly due to high scores in the domains related to physical health (e.g. weakness, pain) and activities of daily living; on the other hand, the psychosocial domain appears to be much less affected by the disease. Loss of independence was the most important concern (mean score: 81.1 ± 21.2). Respiratory and muscular dysfunction and subjective sleep quality were severely impaired, and significantly correlated with several aspects of QoL; symptoms of sleepiness, psychological distress or autonomic dysfunction were marginally correlated to QoL.

The multicenter study by Landfeldt et al. (2014) [31] was carried out in Germany, Italy, United Kingdom (UK), and United States (USA), with the aim to estimate the cost of illness and economic burden of DMD. The QoL was assessed through the Health Utilities Index (for patients) and the EQ -5D (for caregivers). The patients’ quality of life was similar across countries and significantly lower than the reference values of the general population. In particular, the Health Utilities Index for Italian patients was 0.52 (0.45–0.58), compared to a reference value of 0.94 for healthy boys aged 15–19. As for the Italian caregivers, the EQ-5D score obtained was 0.84 (0.81–0.86). On average, the loss of caregiver quality of life compared to the general population was 0.11 points (average score for patients of all countries).

The two papers by Magliano et al. [32, 33] described a cross-sectional study carried out in eight tertiary neuromuscular Italian centers from January to December 2012, that involved 502 families of patients with DMD, BMD, and LGMD. The first paper (2014) [32] was aimed to compare the burden in parents and healthy siblings of 4–17 year-old patients with DMD (n = 246) and BMD (n = 90). Parents filled out the Family Problems Questionnaire (FPQ) and the Social Network Questionnaire (SNQ) questionnaires. The mean burden of parents of DMD children was significantly higher [mean (SD): 1.8 (0.5)] compared to BMD [1.4 (0.4); p <0.05]. Parents of patients with DMD reported a higher burden with regard to the feeling of loss (84.3% DMD vs 57.4% BMD), social stigma (44.2% DMD vs 5.5% BMD) and neglect of hobbies (69.0% DMD vs 32.5% BMD). However, 66% of DMD parents and 62.4% of BMD parents reported that the caregiving experience had a positive impact on their lives. A minority of parents believed that the disease has a negative influence on the psychological well-being (31.0% DMD vs 12.8% BMD) and on the social life of healthy siblings (25.7% vs 18.4%).

The other paper by Magliano et al. (2015) [33] included 502 parents (333 DMD, 129 BMD, 40 LGMD) that completed the FPQ and SNQ questionnaires; in addition to the items considered in the previous study (2014) [32], this paper describes the answers to an additional open-ended question that asks key relatives what they suggest to improve care-givers’ quality of life. Most of relatives (77%) reported feelings of loss, 74% stated they cried or felt depressed and 59% neglected their hobbies. The burden was higher in relatives of patients with DMD than in patients with LGMD and BMD, respectively (burden of practical activities, mean [SD]: 1.7 [0.6] vs 1.2 [0.4] vs 1.4 [0.5], p <0.0001; psychological burden: 2.0 [0.6] vs. 1.9 [0.5], vs. 1.7 [0.5], p <0.0001). As for the answers to the open question, 43% of caregivers suggested improvements in the quality of care, 33% suggested improvements in welfare policies, 30% recommended providing psychological support to families and patients and 19% suggested greater investment in rare disease research. In addition, regression analyses showed a higher practical and psychological burden among relatives who were unemployed, who did not live with a partner, relatives of patients with higher level of functional disabilities, who spent more daily time in caregiving, having fewer social contacts, and who perceived that they had lower levels of support for the patient’s emergencies from their social network.

The multicenter study by Messina et al. [34] involved 98 ambulant boys with DMD from 10 Italian centers, with the aim to assess if 12 month changes in function, assessed by 6MWT, NSAA, 10 meter timed walk/run and Gowers test, were associated to changes on HRQoL. At baseline, PedsQL items correlated with nearly all functional measures, i.e. worse functional measures corresponded to lower QoL levels. The Child Self-Report reports a significant decrease between baseline and 12 months on the PedsQL GCS (74.5 to 71.5; p = 0.04) and its first domain Physical Function Score (68.9 to 64.4; p = 0.03), corresponding to the decrease in functional outcome measures, indicating a decrease in QoL during the follow-up period. Conversely, the correlation between 12-month changes in PedsQL items and functional measures was not significant for almost all items. Similar results were obtained on the Parent Proxy-Report.

The paper of Orcesi et al. of 2014 [35] describes the development of The Strips Of Life with Emoticons Questionnaire (SOLE), a child-centred, multidimensional self-assessment tool for measuring quality of life in children with neuromuscular disorders. The questionnaire was tested in 78 children with neuromuscular disorders and 81 healthy children. Patients were recruited from 6 Italian tertiary centres, while controls (healthy children) were recruited from 4 nursery and primary schools in 2 areas of northern Italy (near Pavia and Turin). The neuromuscular disorders considered were: DMD n = 43; BMD n = 3; Duchenne-Becker muscular dystrophy n = 3; spinal muscular atrophy type II (SMA) n = 14; SMA type III n = 4; congenital myopathy n = 4; girdle dystrophy n = 3; congenital muscular dystrophy n = 1; myotonic dystrophy n = 1; myasthenia gravis n = 1; Emery-Dreifuss muscular dystrophy n = 1.

The mean total score of the SOLE questionnaire was significantly lower in children with neuromuscular disorders (141.9 ± 20.8) than in controls (163.7 ± 18.0) (p <0.001). Similar results were obtained by selecting only the DMD patients and comparing them with the males of the control group (43 DMD cases vs 44 controls): the mean total SOLE score was significantly lower in the DMD group (141.0 ± 20.5) than the control group (159.7 ± 18.2) (p <0.001).

3.3. Adherence

To address the research question 3 (adherence), we identified only the study by Landfeldt et al. of 2015 [11], aimed at comparing the experience reported by the patient (or his family) regarding the medical management of DMD in Germany, Italy, UK and USA, with the recommendations of clinical guidelines for the diagnosis and management of DMD, produced by an international, multidisciplinary group of experts [4, 36]. A total of 770 patient-caregiver pairs completed the questionnaire; of these, 122 couples (16%) were Italian. The questionnaire asked questions about the patient, his health status, visits to doctors and other healthcare providers related to DMD, clinical tests and assessments, drug use, and access to medical aids and devices. The study highlighted a low adherence to the guidelines in all four countries. In particular, with reference to Italian couples, the percentage of patients undergoing visits by a general practitioner or paediatrician in the last six months was 34% (42/122) and this rate is the lowest observed (Germany 66%, UK 62%, USA 60%). Furthermore, despite the importance of routine follow-up due to the side effects associated with glucocorticoids, less than 27% (21/78) of Italian patients taking this class of drugs had visited a neuromuscular specialist in the last six months. Again, the Italian rate is the lowest observed among the countries (72% in Germany, 68% in UK, 62% in USA). Furthermore, it emerged that only 50% (25/50) of Italian patients with scoliosis had been visited by a physiotherapist in the last six months, compared to 80% in Germany, 55% in UK and 48% in USA. The rate of scoliosis patients visited by an orthopaedist in the last six months is also lower for Italian patients than in other countries: 18% (9/50) against 37% in Germany, 23% in UK, 29% in USA. Regarding the evaluation of lung function, also recommended every six months, the observed rate among Italian patients was 66% (37/56), compared to 81% in Germany, 61% in the UK and 62% in the USA. The observed rate among Italian ventilated patients was 46% (11/24), while it was 62% in Germany, 43% in the UK and 66% in USA. The study also reported that, despite the recommendations, the use of glucocorticoids was also highly variable among countries. In particular, Deflazacort was the most used drug in Italy (as well as in Germany and USA, whereas prednisolone was mostly prescribed in UK) according to an alternate-day dosing schedule. However, this scheme was not the most used in other countries where daily (USA) or intermittent (Germany and UK) administration prevails.

The access rate to orthotic devices and mobility aids also appeared variable: in particular, the Italian proportion was 65% for orthoses (Germany 29%, UK 65%, USA 70%) and 26% for wheelchairs; the latter is the lowest observed (Germany 55%, UK 76%, USA 58%).

3.4. Economic impact

To address the research question 4 (economic impact), we identified 3 studies (Table 3).

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Table 3. Characteristics of included studies for economic impact.

https://doi.org/10.1371/journal.pone.0287774.t003

The study by Cavazza et al. [29] was aimed at determining the economic burden of DMD from a societal perspective, and measuring the health-related quality of life (HRQoL) of patients with DMD in Europe (see QoL paragraph). As for the Italian patients, the study reported average annual total costs per patient of € 41,547 (SD 35,811) in the year 2012; specifically, € 63,559 (SD 36,672) referring to adult patients and € 34,543 (SD 33,182) to paediatric patients. The annual direct healthcare costs per patient (e.g. drugs, exams, medical visits, etc.) amount to € 9,744 (SD 10,002), that is 23% of the total costs; in particular, € 20,601 (SD 11,230) if referring only to the adults and € 6,289 (SD 6,583) if referring only to children. Direct non-healthcare costs (e.g. professional and informal care) were much higher, being equal to 76% of the total costs (whole population: € 31,518, SD 32,408; adults: € 41,776, SD 33,691; children: € 28,258, SD 31,552). The labour productivity loss due to sick leave was on average €1,181 (SD 2,706) for adult patients, equal to approximately 2% of their total costs. The study also reports that, in all countries (except for Bulgaria), the average annual cost per patient with DMD is about ten times higher than the total per capita public health expenditure estimated by the World Health Organization.

The cross-sectional study by Landfeldt et al. of 2014 [31] estimated the total cost of illness and the economic burden of DMD from the perspective of the society and caregiver households. The study identified DMD patients through national registries in Germany, Italy, UK and USA, collecting questionnaires for a total of 770 patient-caregiver pairs; of these, 122 couples (16%) were Italian. As for Italy, the study reported an estimated total burden of illness for the society of Int$ (international dollar) 80,120 (71,030–89,190). The total annual cost per patient amounts to Int$ 42,140 (36,940–47,730) and include annual direct costs (medical and non-medical) per patient equal to Int$ 23,920 (20,420–28,300) (57% of the total cost), and indirect costs, due to losses of productivity, equal to Int$ 18,220 (15,430–21,380) (43%). In addition, intangible costs due to reduced quality of life (e.g. due to pain or anxiety) were estimated in Int$ 37,980 (32,400–43,550). The study also reports the annual family burden, due to out-of-pocket expenditures, income loss and reduced quality of life. This cost is estimated to be Int$ 58,440 (IC 50,200–68,900). In Italy, the annual direct cost per DMD patient was 8 times higher than the average public health expenditure per capita, while it was 10, 16 and 7 times higher than the average health expenditure per capita in Germany, UK and USA, respectively.

The study by Landfeldt et al. of 2017 [37] described an economic model for estimating the average annual cost of mortality caused by DMD in Germany, Italy, the UK and USA, according to a societal perspective. The life-years lost due to DMD in the reference year (2012) were estimated based on the incidence of the condition, which for Italy amount to 3,313 (IC 3,297–3,329) life-years, and subsequently the mortality cost was calculated using a willingness-to-pay (WTP) of € 75,000 per life-year gained. The national cost of DMD mortality in Italy was therefore estimated at € 248.5 (CI 247–250) million.

4.1. Strengths and limitations

This review is based on a study protocol registered in the PROSPERO database; the reporting of the review follows the PRISMA guidelines; a comprehensive literature search was performed in three large electronic databases; the literature selection process, data extraction and quality assessment were performed by two independent reviewers.

Potential limitations concern the time horizon considered for the literature search (2010–2023) and that we considered only published studies, without searching the grey literature; these limitations could have reduced the sensitivity of the search.