Idiopathic hypersomnia (IH) is a rare neurological sleep disorder, characterized by excessive daytime sleepiness despite normal sleep duration, that can significantly impact patient\'s lives. The burden of IH goes beyond excessive daytime sleepiness, pervading all aspects of everyday life. Characteristic and burdensome symptoms of IH include sleep inertia/drunkenness, long sleep duration, and daytime cognitive dysfunction. This systematic review assessed current knowledge regarding IH diagnostic challenges and burden of illness. Literature searches for original epidemiological, clinical, humanistic, or economic research relevant to IH published between 2012 and 2022 in MEDLINE, Embase, Cochrane, gray literature (diagnostic criteria and treatment guidelines), conferences (2019-2022), and clinical trial databases yielded 97 articles. Findings indicate that IH remains a poorly defined diagnosis of exclusion that is difficult to distinguish from narcolepsy type 2 because of symptom overlap and inadequacies of objective testing. Consequently, individuals with IH endure diagnostic delays of up to 9 years. The economic burden of IH has not been characterized to any appreciable extent. Pharmacological treatment options can improve symptoms and functional status, but rarely restores normal levels of functioning. These findings highlight the need to reclassify central disorders of hypersomnolence. Further collaboration is now required between research groups to identify and validate objective markers to help redefine diagnostic criteria for IH. This would move IH into a position that could benefit from future targeted therapeutic interventions. The study was funded by Takeda Development Center Americas, Inc.

BACKGROUND: This systematic study aims to assess the global epidemiologic, economic, and humanistic burden of illness associated with all types of hereditary angioedema.
METHODS: A systematic search for articles reporting the epidemiologic, economic, and humanistic burden associated with patients with HAE was conducted using English and Chinese literature databases from the inception to May 23, 2022. The selected studies were assessed for their quality and risk of bias. The study was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses and registered with the International Prospective Register of Systematic Reviews (PROSPERO; CRD42022352377).
RESULTS: In total, 65 articles that met the search inclusion criteria reported 10,310 patients with HAE, of whom 5861 were female patients. Altogether, 4312 patients (81%) and 479 patients (9%) had type 1 and type 2 HAE, respectively, whereas 422 patients (8%) had HAE-normal C1-INH. The overall prevalence of all types of HAE was between 0.13 and 1.6 cases per 100,000. The mean or median delay from the first onset of a symptom of HAE to confirmed diagnosis ranged from 3.9 to 26 years. The estimated risk of death from asphyxiation was 8.6% for patients with HAE. Hospitalization, medication, unnecessary surgeries, doctor visits, specialist services, and nursing costs are direct expenses that contribute to the growing economic burden. The indirect cost accounted mostly due to missing work ($3402/year) and loss of productivity ($5750/year). Furthermore, impairment of QoL as reported by patient-reported outcomes was observed. QoL measures identified depression, anxiety, and stress to be the most common symptoms for adult patients and children.
CONCLUSIONS: This study highlights the importance of early diagnosis and the need for improving awareness among health care professionals to reduce the burden of HAE on patients and society.

BACKGROUND: Tumor-induced osteomalacia (TIO) is an ultra-rare, paraneoplastic syndrome caused by tumors that secrete fibroblast growth factor 23 (FGF23). Initial signs and musculoskeletal symptoms can be non-specific and unrecognized, leading to long delays in diagnosis and treatment, which results in severe and progressive disability in patients with TIO. This review aimed to identify published evidence on healthcare resource use in TIO to better understand the burden of the disease.
METHODS: A targeted literature review was conducted to identify publications reporting on disease characteristics and healthcare resource use associated with TIO.
RESULTS: In total, 414 publications were included in the review, of which 376 were case reports. From the case reports, data on 621 patients were extracted. These patients had a mean (standard deviation) age of 46.3 (15.8) years; 57.6% were male. Mean time from first symptoms to diagnosis of TIO was 4.6 (4.7) years and, in cases where imaging tests were reported, patients underwent a mean of 4.1 (2.7) procedures. Tumor resection was attempted in 81.0% of patients and successful in 67.0%. Fracture was reported in 49.3% of patients. Results from association analyses demonstrated that longer time to diagnosis was associated with poorer tumor resection outcomes and a higher probability of tumor recurrence. Unfavorable tumor resection outcomes were associated with greater use of pharmacologic treatment and a greater likelihood of orthopedic surgery.
CONCLUSIONS: TIO is associated with a substantial healthcare resource burden. Improvements in the diagnostic process could lead to better management of TIO, thereby benefiting patients and reducing that burden.

This systematic literature review evaluated frontline treatment burden in pediatric and adolescent/young adult (AYA) patients with high-risk classical Hodgkin lymphoma (cHL) among studies originating from the United States. Data were extracted from 32 publications (screened: total, n = 3115; full-text, n = 98) representing 12 studies (randomized controlled trials [RCTs], n = 2; non-comparative, non-randomized, n = 7; observational, n = 3). High-risk disease definitions varied across studies. Five-year event-free survival (EFS)/progression-free survival (PFS) was 86%-100% and 79%-94%, and complete response rates were 35%-100% and 5%-64% for brentuximab vedotin (BV)-containing and chemotherapy-alone regimens, respectively. In identified RCTs, BV-containing compared with chemotherapy-alone regimens demonstrated significantly longer 3-year EFS/5-year PFS. Hematological and peripheral neuropathy were the most commonly reported adverse events of interest, although safety data were inconsistently reported. Few studies evaluated humanistic and no studies evaluated economic burden. Results from studies with the highest quality of evidence indicate an EFS/PFS benefit for frontline BV-containing versus chemotherapy-alone regimens for pediatric/AYA patients with high-risk cHL.

OBJECTIVE: Leptomeningeal disease (LMD) is associated with poor survival and health-related quality of life (HRQoL). There is an urgent need for clinical research in this area to improve the outcomes. The purpose of this study is to summarize the areas of active clinical research in LMD, identify the knowledge gap, and suggest future research directions.
METHODS: A narrative review of clinical trials in LMD was conducted based on a search in clinicatrials.gov using the search term \"leptomeningeal\" under \"condition or disease\". Clinical trials in patients with LMD arising from solid malignancy that were labelled as \"not yet recruiting\", \"recruiting\", \"enrolling by invitation\" or \"active, not recruiting\" were included. Studies which were deemed to have significant impact on future research direction in LMD were selected for discussion.
UNASSIGNED: A total of 38 clinical trials were included. Of these 38 trials, 19 are discussed in this review, with focus on their research questions and impact on future research directions. Most of the studies that were not selected for discussion focused on biomarker-driven interventions. Four key areas of research were identified, namely the (I) diagnosis, response assessment or molecular profiling of LMD (n=2); (II) advances in radiotherapy (n=3); (III) intrathecal treatment (n=13); (IV) novel drug carrier for systemic treatment (n=1). The research questions in the 19 discussed clinical trials included the tumour microenvironment of LMD, the role of novel molecular techniques in LMD, combination of radiotherapy with drugs, and cell-based immunotherapy. Among these 19 studies, 11 were phase 1 trials, 3 were phase 2 or phase 1/2 trials, 2 were phase 3 or phase 2/3 trials and the study phase was not reported in the remaining 3 studies. The existing knowledge gaps are discussed, including the lack of primary site-specific prognostic tools, cost-effectiveness studies, dedicated HRQoL assessment tools for LMD and sequencing of treatment.
CONCLUSIONS: The current clinical trials in LMD offer the promise to improve the diagnosis and treatment outcomes of patients with LMD. More research is needed to overcome the potential hurdles in the current treatment and bridge the knowledge gaps as identified in this review, to improve patients\' quantity and quality of survival.

Low back pain (LBP) is a common health problem, and the leading cause of activity limitation and work absence among people of all ages and socioeconomic strata. This study aimed to analyse the clinical and economic burden of LBP in high income countries (HICs) via systematic review and meta-analysis.
A literature search was carried out on PubMed, Medline, CINAHL, PsycINFO, AMED, and Scopus databases was from inception to March 15th, 2023. Studies that assessed the clinical and economic burden of LBP in HICs and published in English language were reviewed. The methodological quality of the included studies was assessed using the Newcastle-Ottawa quality assessment scale (NOS) for cohort studies. Two reviewers, using a predefined data extraction form, independently extracted data. Meta-analyses were conducted for clinical and economic outcomes.
The search identified 4,081 potentially relevant articles. Twenty-one studies that met the eligibility criteria were included and reviewed in this systematic review and meta-analysis. The included studies were from the regions of America (n = 5); Europe (n = 12), and the Western Pacific (n = 4). The average annual direct and indirect costs estimate per population for LBP ranged from € 2.3 billion to € 2.6 billion; and € 0.24 billion to $8.15 billion, respectively. In the random effects meta-analysis, the pooled annual rate of hospitalization for LBP was 3.2% (95% confidence interval 0.6%-5.7%). The pooled direct costs and total costs of LBP per patients were USD 9,231 (95% confidence interval -7,126.71-25,588.9) and USD 10,143.1 (95% confidence interval 6,083.59-14,202.6), respectively.
Low back pain led to high clinical and economic burden in HICs that varied significantly across the geographical contexts. The results of our analysis can be used by clinicians, and policymakers to better allocate resources for prevention and management strategies for LBP to improve health outcomes and reduce the substantial burden associated with the condition.
https://www.crd.york.ac.uk/prospero/#recordDetails?, PROSPERO [CRD42020196335].

BACKGROUND: Angiographic vasospasm (VSP), the narrowing of intracranial arteries, is a complication of aneurysmal subarachnoid hemorrhage (aSAH) and often results in delayed cerebral ischemia (DCI) and cerebral infarction. The objective of this systematic review was to summarize the clinical burden of angiographic VSP and its related complications (DCI and cerebral infarction) after aSAH.
METHODS: Systematic searches of MEDLINE, Embase, and the Cochrane Library were conducted (in January 2021) in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to identify studies reporting clinical outcomes of angiographic VSP and its related complications after aSAH. Study outcomes included measures of functional status (modified Rankin Scale [mRS], Glasgow Outcome Scale [GOS], extended Glasgow Outcome Scale [GOS-E], modified Barthel Index, or the modified National Institutes of Health Stroke Scale), cognitive status (Montreal Cognitive Assessment or the Mini Mental State Exam), clinical events (rebleeding), and mortality. Study selection, data extraction, and qualitative analyses were conducted.
RESULTS: Of 5704 abstracts reviewed, 110 studies were selected: 20 comparative and 39 regression-based studies were included in the qualitative synthesis, 51 descriptive studies were excluded. Most studies (51) were observational and conducted in a single country (53). The occurrence of angiographic VSP and its related complications after aSAH resulted in significantly poorer functional outcomes in three of nine comparative and 11 of 13 regression-based studies, measured by the mRS, and in five of six comparative and eight of nine regression-based studies, measured by the GOS and GOS-E. Angiographic VSP and its related complications were significantly associated with poor cognitive status in all five regression-based studies. Numerically or significantly higher mortality rates in patients with versus those without angiographic VSP and its related complications were reported in five of ten comparative studies and in eight of nine regression-based studies. Six studies looked at specific VSP populations (e.g., by severity or timing of VSP).
CONCLUSIONS: Patients with angiographic VSP and its related complications often had poor functional, neurological, and cognitive outcomes and reduced odds of survival both in hospital and at follow-up. We estimate that angiographic VSP and its related complications, DCI and cerebral infarction, lead to an approximately threefold higher odds of poor functional and cognitive outcomes, and about a twofold increase in the odds of death.
Aneurysmal subarachnoid hemorrhage is a medical emergency in which an aneurysm, a weakened outpouching of a cerebral blood vessel, ruptures causing bleeding in the subarachnoid space. Components from the bleeding can trigger a process leading to the constriction of cerebral arteries, called angiographic vasospasm. Angiographic vasospasm is a frequent occurrence after aneurysmal subarachnoid hemorrhage and can also result in delayed cerebral ischemia and cerebral infarction, which can severely impact patients’ health. This study summarizes the published literature to describe the clinical burden that patients may experience due to angiographic vasospasm, delayed cerebral ischemia, and cerebral infarction after aneurysmal subarachnoid hemorrhage. The evidence from these studies emphasizes numerous clinical consequences that patients may experience. These patients may suffer from diminished neurological and intellectual activity, leading to disability and a loss of functional independence in everyday activities. Angiographic vasospasm and its related complications also reduce the chances of survival, both in the hospital and at follow-up. The considerable clinical burden associated with angiographic vasospasm, delayed cerebral ischemia, and cerebral infarction highlights the importance of their prevention.

BACKGROUND: Although previously regarded as a children\'s disease, it is clear that atopic dermatitis (AD) is also highly prevalent in adults. Because AD is not associated with mortality, it is usually neglected compared with other, fatal diseases. However, several studies have highlighted that AD burden is significant due to its substantial humanistic burden and psychosocial effects. This study aims to summarize and quantify the clinical, economic, and humanistic burden of AD in adults and adolescents.
METHODS: A systematic literature search was performed in PubMed, Scopus, Cochrane, Centre for Reviews and Dissemination (CRD), EconPapers, The Professional Society for Health Economics and Outcomes Research (ISPOR), The National Institute for Health and Care Excellence (NICE), and The Canadian Agency for Drugs and Technologies in Health (CADTH). Studies were included if they reported clinical, economic, or humanistic effects of AD on adults or adolescents, from January 2011 to December 2020. The Grading of Recommendations Assessment tool was used to assess risk of bias for the included studies. Regression models were used to explain the correlation between factors such as disease severity and quality of life (QoL).
RESULTS: Among 3400 identified records, 233 studies were included. Itch, depression, sleep disturbance, and anxiety were the most frequently reported parameters related to the clinical and humanistic burden of AD. The average utility value in studies not stratifying patients by severity was 0.779. The average direct cost of AD was 4411 USD, while the average indirect cost was 9068 USD annually.
CONCLUSIONS: The burden of AD is significant. The hidden disease burden is reflected in its high indirect costs and the psychological effect on QoL. The magnitude of the burden is affected by the severity level. The main limitation of this study is the heterogeneity of different studies in terms of data reporting, which led to the exclusion of potentially relevant data points from the summary statistics.
Atopic dermatitis is a very common skin disease among children and adults. The disease is nonfatal but may lead to patients and families having a low quality of life and decreased productivity, especially in its severe state. Because atopic dermatitis is more common in children than adults, most published research is directed to studying the effect of the disease on children. Atopic dermatitis affects patients’ health, quality of life, financial state, and productivity. Therefore, our study aims to study and quantify the burden caused by the disease represented in the clinical burden, humanistic burden, and economic burden. We conducted a systematic literature review to determine all relevant studies providing specific values for the burden. The studies included are those providing information on the percentage of patients affected by specific symptoms, costs paid for treatment, number of days of productivity lost due to the disease, and quality-of-life questionnaire results for patients with atopic dermatitis or their caregivers. We analyzed the data from all relevant studies to calculate average values and quantify the burden. The results of our study should help healthcare sector decision-makers in understanding the real effect of the disease on adults and adolescents and rearrange their priorities for treating different diseases based on the specific burden of each disease.

BACKGROUND: Patients with higher-risk myelodysplastic syndromes (HR-MDS), if left untreated, have lower overall survival (OS), progress to acute myeloid leukemia (AML), and increased burden.
OBJECTIVE: This systematic literature review (SLR) identified comprehensive evidence of clinical burden of disease among patients with lower to HR-MDS.
METHODS: Literature search of English publications from 2011-2021 was conducted in Embase®, MEDLINE® and MEDLINE®-In-process to identify relevant studies fulfilling pre-defined inclusion criteria. Data on study characteristics, patient demographics and clinical burden were extracted.
RESULTS: A total of 67 studies fulfilled the eligibility criteria. Patients with HR-MDS had lower OS and were four-times less likely to survive compared with lower-risk MDS (LR-MDS) over 85 months (HR, 4.46; CI, 2.8-7.1; p<0.001). Presence of comorbidities, karyotyping and transfusion dependency were predictive of low survival with HR-MDS. Progression to AML was time-dependent and significantly associated with decreased survival (HR, 1.80; CI, 1.27-2.55; p<0.001). Patients with HR-MDS had a high propensity and took less time for AML transformation than patients with LR-MDS. The AML transformation rate increased by 1.5-fold among HR-MDS patients, from first to second year of MDS diagnosis. Cardiovascular disorders and diabetes were common comorbidities, while anemia, thrombocytopenia and neutropenia constituted a major symptom burden. The impact of IPSS-R categories on EuroQoL-5D scoring, was only marginal, and varied per age, gender, comorbidities and transfusion requirement (p<0.001). Among patients with HR-MDS, blood transfusion led to reduction in symptoms of anemia and fatigue (p=0.016). Low quality of life (QoL) was associated with reduced survival. Age, gender, comorbidities and blood transfusion (p<0.001) significantly impacted QoL.
CONCLUSIONS: There is a substantial clinical burden with MDS; age, gender, cytogenetics, comorbidities and blood transfusion being the predominant factors that predict survival and QoL among these patients. A significant proportion of patients with MDS transform to AML. Thus, there is a clearly identified need for more frontline therapies focusing on improving symptoms and OS, particularly among patients with HR-MDS.

While the clinical manifestations of myasthenia gravis (MG) are well understood, its humanistic impact is not. The objective of this systematic literature review (SLR) was to provide a comprehensive understanding of the humanistic burden of MG with regards to psychological symptoms and health-related quality of life (HRQoL) according to patients and caregivers.
A systematic search was conducted on December 27, 2019, in MEDLINE and Embase to identify English-language studies that were published from January 1, 2009-December 27, 2019 and presented relevant information on the humanistic burden among adults with MG and their caregivers. Title/abstract and full-text screening was performed by two investigators, with any discrepancies resolved by a third investigator.
Sixty-seven publications were included in the SLR. Compared with the general population, patients with MG experienced worse HRQoL. Studies reporting on psychological symptoms of MG, including depression, anxiety, fatigue, and sleep, were heterogeneous in terms of the scales and instruments used to assess patients, as well as the patient populations themselves. However, in general those with more severe symptoms and hospitalization days had worse depression and anxiety, and fatigue and sleep improved with disease remission and/or improvement. Scores were worse for females compared with males and where evaluated, HRQoL scores generally improved following treatment.
While the literature demonstrates that symptoms associated with MG get better with disease improvement and remission, additional options in efficacious therapy that adequately address the disease-related symptoms and also improve HRQoL may contribute to beneficial outcomes in a greater number of patients with MG.