Healthcare resource utilisation and direct medical cost for individuals with 5q spinal muscular atrophy in Sweden.

BACKGROUND: Spinal muscular atrophy (SMA) is a rare, progressive, neuromuscular disorder. Recent advances in treatment require an updated assessment of burden to inform reimbursement decisions. OBJECTIVES: To quantify healthcare resource utilisation (HCRU) and cost of care for patients with SMA. METHODS: Cohort study of patients with SMA identified in the Swedish National Patient Registry (2007-2018), matched to a reference cohort grouped into four SMA types (1, 2, 3, unspecified adult onset [UAO]). HCRU included inpatient admissions, outpatient visits, procedures, and dispensed medications. Direct medical costs were estimated by multiplying HCRU by respective unit costs. Average annual HCRU and medical costs were modelled for SMA versus reference cohorts to estimate differences attributable to the disease (i.e., average treatment effect estimand). The trajectory of direct costs over time were assessed using synthetic cohorts. RESULTS: We identified 290 SMA patients. Annualised HCRU was higher in SMA patients compared with reference cohorts. Highest risk ratios were observed for inpatient overnight stays for type 1 (risk ratio [RR]: 29.2; 95% confidence interval [CI]: 16.0, 53.5) and type 2 (RR: 23.3; 95% CI: 16.4,33.1). Mean annual direct medical costs per patient for each year since first diagnosis were greatest for type 1 (€114,185 and SMA-attributable: €113,380), type 2 (€61,876 and SMA-attributable: €61,237), type 3 (€45,518 and SMA-attributable: €44,556), and UAO (€4046 and SMA-attributable: €2098). Costs were greatest in the 2-3 years after the first diagnosis for all types. DISCUSSION AND CONCLUSION: The economic burden attributable to SMA is significant. Further research is needed to understand the burden in other European countries and the impact of new treatments.

The role of ataluren in the treatment of ambulatory and non-ambulatory children with nonsense mutation duchenne muscular dystrophy - a consensus derived using a modified Delphi methodology in Eastern Europe, Greece, Israel and Sweden.

BACKGROUND: This paper details the results of an evaluation of the level of consensus amongst clinicians on the use of ataluren in both ambulatory and non-ambulatory patients with nonsense mutation Duchenne muscular dystrophy (nmDMD). The consensus was derived using a modified Delphi methodology that involved an exploration phase and then an evaluation phase. METHODS: The exploration phase involved 90-minute virtual 1:1 interviews of 12 paediatric neurologists who cared for 30-120 DMD patients each and had patient contact every one or two weeks. The respondents managed one to ten nmDMD patients taking ataluren. The Discussion Guide for the interviews can be viewed as Appendix A. Following the exploration phase interviews, the interview transcripts were analysed by an independent party to identify common themes, views and opinions and developed 43 draft statements that the Steering Group (authors) reviewed, refined and endorsed a final list of 42 statements. Details of the recruitment of participants for the exploration and evaluation phases can be found under the Methods section. RESULTS: A consensus was agreed (> 66% of respondents agreeing) for 41 of the 42 statements using results from a consensus survey of healthcare professionals (n = 20) experienced in the treatment of nmDMD. CONCLUSIONS: The statements with a high consensus suggest that treatment with ataluren should be initiated as soon as possible to delay disease progression and allow patients to remain ambulatory for as long as possible. Ataluren is indicated for the treatment of Duchenne muscular dystrophy that results from a nonsense mutation in the dystrophin gene, in ambulatory patients aged 2 years and older (see Summary of Product Characteristics for each country).

Bisphosphonates in Glucocorticoid-Treated Patients With Duchenne Muscular Dystrophy: A Systematic Review and Grading of the Evidence

BACKGROUND AND OBJECTIVES: Bisphosphonates are routinely used to treat osteoporosis in patients with Duchenne muscular dystrophy (DMD), a rare, severely debilitating neuromuscular disease. We sought to synthesize and grade benefits and harms evidence of bisphosphonates in glucocorticoid-treated patients with DMD. METHODS: In this systematic review (PROSPERO identifier: CRD42020157606), we searched MEDLINE, CINAHL, Embase, PsycINFO, Web of Science, and CENTRAL for articles published from inception up to and including March 31, 2023, reporting results in any language from any study type. Quality of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluations framework. RESULTS: We identified 19 publications involving 1,010 children and adults from 12 countries across all inhabited continents except South America. We found high-quality evidence that bisphosphonates significantly increase the areal lumbar spine bone mineral density (BMD) Z score in glucocorticoid-treated patients with DMD. The greatest improvements were recorded in controlled settings among patients treated with intravenous zoledronate. Evidence of benefits to fracture risks was inconclusive and/or of low quality, primarily due to lack of controlled data and small samples. Bisphosphonates were generally well-tolerated, although adverse events related to the first infusion (i.e., "acute phase reaction") were frequently reported. DISCUSSION: There is high-quality evidence supporting the use of bisphosphonates to increase the areal lumbar spine BMD Z score in patients with DMD and glucocorticoid-induced osteoporosis. Our synthesis and grading affirm current recommendations put forward in the 2018 DMD Clinical Care Considerations and should be helpful in raising awareness about anticipated benefits of bisphosphonates, prevailing unmet needs, and potential safety issues in their use.

Health-related quality of life of children with spinal muscular atrophy in Sweden: A prospective cohort study in the era of disease-modifying therapy.

The objective of this study was to estimate change over time in health-related quality of life (HRQoL) of children with spinal muscular atrophy (SMA) in Sweden. Children with SMA were identified via the National Patient Register by the National Board of Health and Welfare in Sweden. Patient HRQoL was caregiver proxy-assessed using the Pediatric Quality of Life Inventory 4.0 Generic Core Scales at baseline, as well as at 6, 12, and 18 months of follow-up. Results were stratified by SMA type. Mothers and fathers to 27 children with SMA (mean patient age: 9.17 years; 59% female) participated in the study. All patients received disease-modifying therapy. At baseline, across SMA types, the mean total score was estimated at between 52.68 and 59.19, Physical Functioning score at between 26.39 and 40.34, Emotional Functioning score at between 66.82 and 68.57, Social Functioning score at between 55.00 and 70.45, and School Functioning score at between 70.45 and 78.33. The mean annual total score change was estimated at -2.03 for SMA type I, 4.11 for SMA type II, and 1.12 for SMA type III. In conclusion, we show that SMA has a detrimental impact on HRQoL that extends above and beyond somatic disability. Children with SMA type II experienced a dramatic increase in HRQoL over time, predominantly related to improvement in physical and social functioning. Our data helps quantify the patient burden of disease and adds to the rapidly expanding body of evidence of the effectiveness of recently approved disease-modifying therapies for SMA.

Genome sequencing with comprehensive variant calling identifies structural variants and repeat expansions in a large fraction of individuals with ataxia and/or neuromuscular disorders.

Introduction: Neuromuscular disorders (NMDs) have a heterogeneous etiology. A genetic diagnosis is key to personalized healthcare and access to targeted treatment for the affected individuals. Methods: In this study, 861 patients with NMDs were analyzed with genome sequencing and comprehensive variant calling including single nucleotide variants, small insertions/deletions (SNVs/INDELs), and structural variants (SVs) in a panel of 895 NMD genes, as well as short tandem repeat expansions (STRs) at 28 loci. In addition, for unsolved cases with an unspecific clinical presentation, the analysis of a panel with OMIM disease genes was added. Results: In the cohort, 27% (232/861) of the patients harbored pathogenic variants, of which STRs and SVs accounted for one-third of the patients (71/232). The variants were found in 107 different NMD genes. Furthermore, 18 pediatric patients harbored pathogenic variants in non-NMD genes. Discussion: Our results highlight that for children with unspecific hypotonia, a genome-wide analysis rather than a disease-based gene panel should be considered as a diagnostic approach. More importantly, our results clearly show that it is crucial to include STR- and SV-analyses in the diagnostics of patients with neuromuscular disorders.

Caregiver Burden of Spinal Muscular Atrophy: A Systematic Review.

OBJECTIVE: The objective of our study was to review, synthesize, and grade published evidence of caregiver burden of spinal muscular atrophy (SMA), a rare autosomal-recessive neuromuscular disease. METHODS: We searched Embase and PubMed for full-text articles published from inception up until 28 February, 2022, reporting results from studies of caregiver burden (i.e., negative aspects of providing informal care) in SMA. Two investigators independently screened article titles and abstracts for eligibility, reviewed full-text versions of selected records, extracted the data, and assessed risk of bias using the Newcastle-Ottawa Scale. The evidence was synthesized to answer the following questions: (1) In which geographical settings have the caregiver burden of SMA been studied? (2) What aspects of the caregiver burden of SMA have been investigated? (3) What instruments have been used to measure the caregiver burden of SMA? (4) What is known of the caregiver burden of SMA? (5) How is the caregiver burden of SMA impacted by available disease-modifying drugs? RESULTS: We identified 15 publications, covering samples from a total of ten countries (i.e., Australia, Canada, China, France, Germany, Romania, Spain, Turkey, the UK, and the USA), reporting estimates of caregiver burden derived using data recorded via surveys or interviews. The most common instruments used to measure caregiver burden were the Zarit Caregiver Burden Interview, the EQ-5D-5L, and the PedsQL Family Impact Model. Caregiving in SMA was found to be associated with reduced health-related quality of life, impaired family function, depression and anxiety, strain, and stress, as well as a substantial impact on work life and productivity. Evidence of the impact of disease-modifying drugs on caregiver burden in SMA was scarce. CONCLUSIONS: Caregivers to patients with SMA were found to be subject to a significant burden, including impaired health-related quality of life, reduced work ability and productivity, and financial stress, and many devote a substantial proportion of their time to provide informal care. Yet, the current body of literature is relatively scarce and more research is needed to better understand the clinical implications of informal caregiving in SMA and the relationship between caregiver burden and SMA types, as well as the impact of new disease-modifying treatments. Our synthesis will be helpful in informing clinical and social support programs (e.g., the routine screening of depression among caregivers, as well as financial support schemes to help manage the long-term day-to-day care) directed towards families caring for patients with SMA.

Survival in patients diagnosed with SMA at less than 24 months of age in a population-based setting before, during and after introduction of nusinersen therapy. Experience from Sweden.

INTRODUCTION: Clinical trials have demonstrated a positive effect of nusinersen therapy on survival of infants with SMA type 1. However, there is a lack of data outside clinical trials on how the introduction of nusinersen has affected the survival of patients with SMA. We therefore set out to analyse survival in patients diagnosed at less than 24 months before, during and after the introduction of nusinersen in a nationwide population-based real-world setting. METHODS: SMA patients diagnosed before the age of 24 months in the time period between February 21, 2000 and December 19, 2019 were identified using ICD-codes, and medical procedures for identification of treatment utilizing information from the public available National Patient Registry held by the National Board of Health and Welfare. Data was divided into 3 different calendar periods (before, during, and after introduction of nusinersen treatment in Sweden). Time to Event analysis was then applied. RESULTS: A total of 155 patients were enrolled in the study, and median follow-up was 1.14 years (inter-quartile range (IQR): 0.27-8.37 years). Data did not provide conclusive evidence that survival differed between the calendar periods (P-value from the log-rank test = 0.419) and while hazards were lower in the middle period, HR 0.70 (95% CI: 0.34-1.47), and 3, HR 0.71 (95% CI: 0.28-1.77) compared to the first period, all confidence intervals were wide., However, nusinersen treatment was associated with a decreased mortality rate, HR 0.05 (95% CI: 0.01-0.37). CONCLUSION: SMA patients receiving nusinersen therapy had a dramatically increased overall survival compared to patients not receiving therapy. This indicates that nusinersen treatment has an effect on survival, in patients diagnosed with SMA, in a nationwide real-world setting. Larger studies are warranted.

Disease Modifying Therapies for the Management of Children with Spinal Muscular Atrophy (5q SMA): An Update on the Emerging Evidence.

SMA (5q SMA) is an autosomal recessive neuromuscular disease with an estimated incidence of approximately 1 in 11,000 live births, characterized by progressive degeneration and loss of α-motor neurons in the spinal cord and brain stem, resulting in progressive muscle weakness. The disease spectrum is wide, from a serious congenital to a mild adult-onset disease. SMA is caused by biallelic mutations in the SMN1 gene and disease severity is modified primarily by SMN2 copy number. Before the advent of specific disease altering treatments, SMA was the second most common fatal autosomal recessive disorder after cystic fibrosis and the most common genetic cause of infant mortality. Nusinersen, risdiplam, and onasemnogene abeparvovec are presently the only approved disease modifying therapies for SMA, and the aim of this review is to discuss their mode of action, effects, safety concerns, and results from real-world experience. All exert their action by increasing the level of SMN protein in lower motor neuron. Nusinersen and risdiplam by modifying the SMN2 gene product, and onasemnogene abeparvovec by delivering SMN1 gene copies into cells. All have an established clinical efficacy. An important feature shared by all three is that early intervention is associated with a better treatment outcome, such that in cases where treatment is initiated in an early pre-symptomatic period, it may result in normal - or almost normal - motor development. Thus, early diagnosis followed by swift initiation of treatment is fundamental for the treatment response and consequently long-term prognosis in SMA type 1, and probably SMA type 2. The same principle similarly applies to the milder phenotypes. All three therapies are relatively novel, with risdiplam being the latest addition. Except for nusinersen, real-world data are still scarce, and long-term data are quite naturally lacking.

Assessment of face validity of a disease model of nonsense mutation Duchenne muscular dystrophy: a multi-national Delphi panel study.

OBJECTIVE: The objective of this study was to assess the face validity of a disease model evaluating the cost-effectiveness of ataluren for the treatment of nonsense mutation Duchenne muscular dystrophy (nmDMD). METHODS: This was a Delphi panel study comprising of physicians with first-hand experience of ataluren for the treatment of nmDMD. Consensus was sought for previously unvalidated model data, including patient health status and quality of life measured using the Health Utility Index (HUI), mortality, informal caregiving, and the expected benefit of early ataluren treatment across four states: (1) ambulatory, (2) non-ambulatory, not yet requiring ventilation support, (3) non-ambulatory, night-time ventilation support, and (4) non-ambulatory, full-time ventilation support. RESULTS: Nine experts from five countries participated in the Delphi panel. Consensus was obtained for all questions after three panel rounds (except for two HUI-questions concerning hand function [dexterity]). Consensus HUI-derived utilities for state (1) were 1.0000 for ataluren on top of best supportive care (BSC) and 0.7337 for BSC alone. Corresponding estimates for state (2) were 0.3179 and 0.2672, for state (3) 0.1643 and 0.0913, and for state (4) -0.0732 and -0.1163. Consensus mortality rates for states (1), (2), and (3) were 4%, 13%, and 33%, and life expectancy in state (4) was agreed to be 3 years. Panelists further agreed that two informal caregivers typically provide day-to-day care/support to patients with nmDMD, and that starting treatment with ataluren at 2 versus 5 years of age would be expected to delay loss of ambulation by an additional 2 years, and initiation of night-time and full-time ventilation support by an additional 3 years, respectively. LIMITATIONS: The main limitation concerns the size of the Delphi panel, govern primarily by the rarity of the disease. CONCLUSION: This study confirms the face validity of key clinical parameters and assumptions underlying the ataluren cost-effectiveness model.

Parents' advice to other parents of children with spinal muscular atrophy: Two nationwide follow-ups.

Being a parent of a child with spinal muscular atrophy (SMA), a disease that causes progressive muscle weakness, involves a range of challenges. The purpose of this study was to explore what advice parents of children with severe SMA, in absence of effective therapies, would like to give to other parents. This study derives from two nationwide parental surveys in Sweden and Denmark, where content analysis was used to analyse one open-ended question about parents' advice to other parents. Ninety-five parents (parents of children diagnosed with SMA type 1 or 2, for whom respiratory support was considered during first year of life) participated (response rate: 84%). Of these 95 parents, 81 gave written advice to other parents. Advice covered coping with everyday life with the ill child, existential issues of living with and losing a child with SMA and involvement in care of the child. Parents highlighted leading normal lives insofar as possible, for example, trying to see healthy aspects in their child, not only focusing on care and treatment. Shared advice can be related to resilience strategies to parents, which can help healthcare professionals and others to support parents in similar situations.

"Suddenly we have hope that there is a future": two families' narratives when a child with spinal muscular atrophy receives a new drug.

Purpose: This study aims to explore negotiations of hope in everyday life for families where a child with spinal muscular atrophy (SMA) has received a new drug treatment.Methods: A narrative design was used, drawing on interviews and participant observations in two families with children with SMA, types 1-2, to situate family experiences of hope in everyday life. Narrative analysis was used on the data.Results: Results are presented as stories, with details about situations and contexts, to illustrate how hope was used by families to reconstruct their own family narratives.Conclusions: Hope was negotiated and struggled with in different ways by different family members, but contributed to each person's own way of dealing with the disease and outlook for the future.

Costs of Illness of Spinal Muscular Atrophy: A Systematic Review.

OBJECTIVES: The objective of our study was to conduct a systematic literature review of estimates of costs of illness of spinal muscular atrophy (SMA). METHODS: We searched MEDLINE (through PubMed), CINAHL, Embase, Web of Science, National Health Service Economic Evaluation Database, and the National Health Service Health Technology Assessment Database for studies published from inception up until 31 August, 2020, reporting direct medical, direct non-medical, and/or indirect costs of any phenotype of SMA. Two reviewers independently screened records for eligibility, extracted the data, and assessed studies for risk of bias using the Newcastle-Ottawa Scale. Costs were adjusted and converted to 2018 US dollars. RESULTS: The search identified 14 studies from eight countries (Australia, France, Germany, Italy, Spain, Sweden, the UK, and the USA). The mean per-patient annual direct medical cost of illness was estimated at between $3320 (SMA type III, Italy) and $324,410 (SMA type I, USA), mean per-patient annual direct non-medical cost between $25,880 (SMA types I-III, Spain) and $136,800 (SMA type I, Sweden), and mean per-patient annual indirect cost between $9440 (SMA type I, Germany) and $74,910 (SMA type II, Australia). Most studies exhibited a risk of bias. CONCLUSIONS: The current body of evidence of costs of illness of SMA is relatively scarce and characterized by considerable variability across geographical settings and disease phenotypes. Our review provides data pertaining to the economic impact of SMA, which is of particular relevance in light of emerging treatments and ongoing research in this field, and underscores the substantial unmet medical need in this patient population.

FLNC Expression Level Influences the Activity of TEAD-YAP/TAZ Signaling.

Filamin C (FLNC), being one of the major actin-binding proteins, is involved in the maintenance of key muscle cell functions. Inherited skeletal muscle and cardiac disorders linked to genetic variants in FLNC have attracted attention because of their high clinical importance and possibility of genotype-phenotype correlations. To further expand on the role of FLNC in muscle cells, we focused on detailed alterations of muscle cell properties developed after the loss of FLNC. Using the CRISPR/Cas9 method we generated a C2C12 murine myoblast cell line with stably suppressed Flnc expression. FLNC-deficient myoblasts have a significantly higher proliferation rate combined with an impaired cell migration capacity. The suppression of Flnc expression leads to inability to complete myogenic differentiation, diminished expression of Myh1 and Myh4, alteration of transcriptional dynamics of myogenic factors, such as Mymk and Myog, and deregulation of Hippo signaling pathway. Specifically, we identified elevated basal levels of Hippo activity in myoblasts with loss of FLNC, and ineffective reduction of Hippo signaling activity during myogenic differentiation. The latter was restored by Flnc overexpression. In summary, we confirmed the role of FLNC in muscle cell proliferation, migration and differentiation, and demonstrated for the first time the direct link between Flnc expression and activity of TEAD-YAP\TAZ signaling. These findings support a role of FLNC in regulation of essential muscle processes relying on mechanical as well as signaling mechanisms.

Two New Cases of Hypertrophic Cardiomyopathy and Skeletal Muscle Features Associated with ALPK3 Homozygous and Compound Heterozygous Variants.

Hypertrophic cardiomyopathy associated with damaging variants in the ALPK3 gene is a fairly recent discovery, and only a small number of patients have been described thus far. Here we present two additional patients with hypertrophic cardiomyopathy caused by biallelic variants in ALPK3. Genetic investigation was performed using a targeted gene panel consisting of known cardiomyopathy-associated genes and whole exome sequencing. The patients showed a large difference in the age of onset, and both presented with extracardiac features that are often seen in ALPK3 patients. The patient with the later onset showed milder extracardiac symptoms, such as decreased muscle tone and distal muscular dystrophy, but had fast progression of cardiac complications leading to the need of heart transplantation. This study further elucidates the variability of both symptoms and age of onset among these patients.

Genetic Spectrum of Left Ventricular Non-Compaction in Paediatric Patients.

INTRODUCTION: Left ventricular non-compaction (LVNC) represents a genetically heterogeneous cardiomyopathy which occurs in both children and adults. Its genetic spectrum overlaps with other types of cardiomyopathy. However, LVNC phenotypes in different age groups can have distinct genetic aetiologies. The aim of the study was to decipher the genetic spectrum of LVNC presented in childhood. Patient Group and Methods: Twenty patients under the age of 18 years diagnosed with LVNC were enrolled in the study. Target sequencing and whole-exome sequencing were performed using a panel of 108 cardiomyopathy-associated genes. Pathogenic, likely pathogenic, and variants of unknown significance found in genes highly expressed in cardiomyocytes were considered as variants of interest for further analysis. RESULTS: The median age at presentation was 8.0 (0.1-17) years, with 6 patients presenting before 1 year of age. Twelve (60%) patients demonstrated reduced ejection fraction. Right ventricular (RV) dilation was registered in 6 (30%), often in combination with reduced RV contractility (25%). Almost half (45%) of the patients demonstrated biventricular involvement already at disease presentation. For pathogenic and likely pathogenic variants, the positive genotyping rate was 45%, and these variants were found mainly in non-contractile structural sarcomeric genes (ACTN2, MYPN, and TTN) or in metabolic and signal transduction genes (BRAF and TAZ). Likely pathogenic TAZ variants were detected in all 5 patients suspected of having Barth syndrome. No pathogenic or likely pathogenic variants were found in genes encoding for sarcomeric contractile proteins, but variants of unknown significance were detected in 3 out of 20 patients (MYH6, MYH7, and MYLK2). In 4 patients, variants of unknown significance in ion-channel genes were detected. CONCLUSION: We detected a low burden of contractile sarcomeric variants in LVNC patients presenting below the age of 18 years, with the major number of variants residing in non-contractile structural sarcomeric genes. The identification of the variants in ion-channel and related genes not previously associated with LVNC in paediatric patients requires further examination of their functional role.

Meta-analyses of ataluren randomized controlled trials in nonsense mutation Duchenne muscular dystrophy.

Aim: Assess the totality of efficacy evidence for ataluren in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD). Materials & methods: Data from the two completed randomized controlled trials (ClinicalTrials.gov: NCT00592553; NCT01826487) of ataluren in nmDMD were combined to examine the intent-to-treat (ITT) populations and two patient subgroups (baseline 6-min walk distance [6MWD] ≥300-<400 or <400 m). Meta-analyses examined 6MWD change from baseline to week 48. Results: Statistically significant differences in 6MWD change with ataluren versus placebo were observed across all three meta-analyses. Least-squares mean difference (95% CI): ITT (n = 342), +17.2 (0.2-34.1) m, p = 0.0473; ≥300-<400 m (n = 143), +43.9 (18.2-69.6) m, p = 0.0008; <400 m (n = 216), +27.7 (6.4-49.0) m, p = 0.0109. Conclusion: These meta-analyses support previous evidence for ataluren in slowing disease progression versus placebo in patients with nmDMD over 48 weeks. Treatment benefit was most evident in patients with a baseline 6MWD ≥300-<400 m (the ambulatory transition phase), thereby informing future trial design.

European ad-hoc consensus statement on gene replacement therapy for spinal muscular atrophy.

Spinal muscular atrophy (SMA) used to be one of the most common genetic causes of infant mortality. New disease modifying treatments have changed the disease trajectories and most impressive results are seen if treatment is initiated in the presymptomatic phase of the disease. Very recently, the European Medicine Agency approved Onasemnogene abeparvovec (Zolgensma®) for the treatment of patients with SMA with up to three copies of the SMN2 gene or the clinical presentation of SMA type 1. While this broad indication provides new opportunities, it also triggers discussions on the appropriate selection of patients in the context of limited available evidence. To aid the rational use of Onasemnogene abeparvovec for the treatment of SMA, a group of European neuromuscular experts presents in this paper eleven consensus statements covering qualification, patient selection, safety considerations and long-term monitoring.

Economic Costs of Myasthenia Gravis: A Systematic Review.

OBJECTIVES: The objective of our study was to conduct a systematic literature review of economic costs (henceforth costs) associated with myasthenia gravis (MG). METHODS: We searched MEDLINE (through PubMed), CINAHL, Embase, PsycINFO, and Web of Science for studies reporting costs of MG published from inception up until March 18, 2020, without language restrictions. Two reviewers independently screened records for eligibility, extracted the data, and assessed included studies for risk of bias using the Newcastle-Ottawa Scale. Costs were inflated and converted to 2018 United States dollars ($). RESULTS: The search identified 16 articles for data extraction and synthesis. Estimates of costs of MG were found for samples from eight countries spanning four continents (Europe, North America, South America, and Asia). Across studies, the mean per-patient annual direct medical cost of illness was estimated at between $760 and $28,780, and cost per hospitalization between $2550 and $164,730. The indirect cost of illness was estimated at $80 and $3550. Costs varied considerably by patient characteristics, and drivers of the direct medical cost of illness included intravenous immunoglobulin and plasma exchange, myasthenic crisis, mechanical ventilatory support, and hospitalizations. CONCLUSIONS: We show that the current body of literature of costs of MG is sparse, limited to a few geographical settings and resource categories, mostly dated, and subject to non-trivial variability, both within and between countries. Our synthesis will help researchers and decision-makers identify gaps in the local health economic context of MG and inform future cost studies and economic evaluations in this patient population.