Therapeutic inhibition of isocitrate dehydrogenase mutations in glioma and cholangiocarcinoma: new insights and promises-a narrative review.

BACKGROUND AND OBJECTIVE: The identification of mutation hot spots in the isocitrate dehydrogenase (IDH) genes is one of the most important cancer genome-wide sequencing discoveries with relevant impact in the treatment of some orphan tumors. These genes were mostly found mutated in lower-grade gliomas (LGGs), acute myeloid leukaemia (AML), myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPNs) and in cholangiocarcinoma. This aberrant genomic condition represents a therapeutic target of great interest in cancer research, especially in AML, given the limitations of currently approved therapies in this field. In this review, we investigate the role of IDH mutation and the mutant IDH (mIDH)- targeted therapies for cholangiocarcinoma and glioma. METHODS: Here, we provide an overview of the IDH mutation role and discuss its role in tumorigenesis and progression of some solid cancers, in which the therapeutic strategy can be completely changed thanks to these brand-new therapeutic options. KEY CONTENT AND FINDINGS: The encouraging early clinical data demonstrated to be a proof of concept for investigational mIDH1/2 inhibitors in tumors with a paucity of therapeutic possibilities. CONCLUSIONS: Moreover, we list the most important randomised clinical trials still active with their preliminary results.

Virtual screening, molecular docking and dynamics simulation studies to identify potential agonists of orphan receptor GPR78 targeting CNS disorders.

G protein-coupled receptors (GPCRs) are important targets in drug discovery because of their roles in physiological and pathological processes. Orphan GPCRs are GPCR proteins for which endogenous ligands have not yet been identified and they present interesting avenues for therapeutic intervention. This study focuses on GPR78, an orphan GPCR that is expressed in the central nervous system and linked to neurological disorders. GPR78 has no reported crystal structure and there is limited research. In this study, we have predicted the three dimensional model of GPR78 and its probable binding pocket. Structure-based virtual screening was carried out using the ChemDiv and Enamine REAL databases, followed by induced-fit docking studies to identify potential lead compounds with favorable interactions. These lead compounds were then embedded into a POPC lipid bilayer for a 200 ns molecular dynamics simulation. Free energy landscapes and MM-PBSA analyses were performed to assess the binding energies and conformational dynamics. The results highlight the dynamic nature of GPR78 in the presence of lead compounds and show favorable binding interactions. This study aims to predict a reliable three dimensional model of GPR78 and identify novel lead compounds through a comprehensive in silico approach. The identification of these potential GPR78 agonists represents a significant step in the development of new therapeutics for neurological disorders, highlighting the therapeutic potential of orphan GPR78 in CNS disorders.

Clinico-epidemiological characteristics of adolescents and young adults living with HIV in Ghana.

Introduction: sub-Saharan Africa is experiencing a boom in the number of adolescents and young adults living with HIV (AYALHIV). Existing HIV intervention programs are mainly for children and adults living with HIV, with little attention paid to AYALHIV. Characterizing this population is necessary for planning, and designing, AYALHIV-centered HIV intervention programs. Methods: a retrospective single-center, hospital-based chart review was conducted at the largest HIV clinic in Ghana. We examined routinely collected data for AYALHIV (aged 10-24 years) on antiretroviral therapy (ART) for at least 1 year and in active care from 1st January to 31st December 2019. Data was collected using a structured data extraction form. The Chi-square and the Student´s t-test were used to compare characteristics between adolescents and young adults. Results: of 252 AYALHIV, 68% (172/252) were adolescents with a median age of 17 years (IQR 13-19); 32% were young adults with a median age of 22 years (IQR: 20-24). Most (56.7% (143/252)) AYALHIV were female. Almost 40% were orphans. Eighty-six percent of AYALHIV had HIV type I infection. The commonest mode of HIV acquisition among adolescents was vertical transmission (70.5%) and that among young adults was via unprotected sex (31.3%). Eighty-eight percent (88%) of AYALHIV were on non-nucleoside reverse transcriptase inhibitors-based regimen. The viral suppression rate among AYALHIV was 78%. Conclusion: the study shows there is a growing population of AYALHIV most of which are adolescents. About two-fifths were orphans. Policymakers and HIV programs should ensure AYALHIV-centred interventions are developed for this vulnerable population.

Health Outcomes of Elder Orphans: An Umbrella and Scoping Review of the Literature.

Objectives: As the population of elder orphans grows, little research has investigated the health outcomes of these socially and physically isolated older adults without caregiving support. Umbrella and scoping reviews were performed for studies examining health outcomes of older adults experiencing elements of elder orphanhood. Methods: Studies published 2010- June 2021 and indexed on PubMed, Web of Science, CINAHL, Medline, or SocINDEX were eligible. Results of included studies were examined both by individual category and overall to determine overlapping outcomes. Results: Umbrella review returned 1,686 studies, with 14 meeting criteria for social isolation (n=10) and physical isolation (n=4). The scoping review of studies examining unmet caregiving need returned 3,741 results: five met inclusion criteria. Discussion: Included studies reviewed differing health outcomes in older adults, with a focus on dementia, frailty, and healthcare utilization. Further studies are needed that appraise targeted policies and interventions to improve health outcomes of elder orphans.

Orphan and paediatric medical devices in Europe: recommendations to support their availability for on-label and off-label clinical indications.

INTRODUCTION: The Medical Device Regulation (EU)745/2017, increased the regulatory requirements and thus the time and the cost associated with marketing medical devices. For a majority of medical device manufacturers, this has lead to reconsiderations of their product portfolio. The risk of important or essential devices being withdrawn is particularly relevant for pediatric patients and other rare disease patients where limited numbers of devices can be sold and hence the investment needed may not be recovered. This generates critical challenges and opportunities from a regulatory and public health perspective. AREAS COVERED: This paper is based upon the experience of the authors who contributed to working groups, guidance development and research related to orphan and pediatric devices. We examine the use of medical devices in orphan and pediatric conditions, the relevant aspects of regulations and associated guidance, and we suggest possible policy and practice interventions to ensure the continued availability of essential devices for children and people with rare diseases. EXPERT OPINION: We recommend a more proactive approach to identifying devices at risk and essential devices, increasing the use of exceptional market approvals, expanding the role of expert panels, engaging with the rare disease communities and supporting registries and standards.

Rare diseases: What rheumatologists need to know?

Although the terms "rare diseases" (RD) and "orphan diseases" (OD) are often used interchangeably, specific nuances in definitions should be noted to avoid misconception. RD are characterized by a low prevalence within the population, whereas OD are those inadequately recognized or even neglected by the medical community and drug companies. Despite their rarity, as our ability on discovering novel clinical phenotypes and improving diagnostic tools expand, RD will continue posing a real challenge for rheumatologists. Over the last decade, there has been a growing interest on elucidating mechanisms of rare autoimmune and autoinflammatory rheumatic diseases, allowing a better understanding of the role played by immune dysregulation on granulomatous, histiocytic, and hypereosinophilic disorders, just to name a few. This initiative enabled the rise of innovative targeted therapies for rheumatic RD. In this review, we explore the state-of-the art of rare RD and the critical role played by rheumatologists in healthcare. We also describe the challenges rheumatologists may face in the coming decades.

Uncovering the knowledge about systemic amyloidosis relevant to the rheumatologists.

Amyloidosis is a localized or systemic disease caused by deposition of proteins in the extracellular space of various organs and tissues. As part of the disease, proteins that were originally soluble misfold and acquire a fibrillar conformation that renders them insoluble and resistant to proteolysis. Systemic amyloidosis is a rare, often underdiagnosed condition. In recent years, the incidence of newly diagnosed cases of amyloidosis has been increasing in association with the aging of the population and greater access to diagnostic tests. From a clinical perspective, systemic amyloidosis is frequently associated with involvement of the kidneys (causing nephrotic syndrome), heart (cardiac failure and arrhythmia), and peripheral nervous system (sensorimotor polyneuropathy and autonomic dysfunction). This condition is important to the rheumatologist for several reasons, such as its systemic involvement that mimics autoimmune rheumatic diseases, its musculoskeletal manifestations, which when recognized can allow the diagnosis of amyloidosis, and also because reactive or secondary AA amyloidosis is a complication of rheumatic inflammatory diseases. The treatment of amyloidosis depends on the type of amyloid protein involved. Early recognition of this rare disease is fundamental for improved clinical outcomes.

Exosomal miR-205-5p contributes to the immune liver injury induced by trichloroethylene: Pivotal role of RORα mediating M1 Kupffer cell polarization.

Trichloroethylene (TCE) is a common environmental contaminant that can induce occupational dermatitis medicamentosa-like TCE (ODMLT), where the liver damage is the most common complication. The study aims to uncover the underlying mechanism of TCE-sensitization-induced liver damage by targeting specific exosomal microRNAs (miRNAs). Among the enriched serum exosomal miRNAs of ODMLT patients, miR-205-5p had a significant correlation coefficient with the liver function damage indicators. Moreover, retinoic acid receptor-related orphan receptor α (RORα) was identified as a direct target of miR-205-5p via specific binding. Further experiments showed that kupffer cells (KCs) underwent M1 phenotypic and functional changes in liver injury induced by TCE which were alleviated by reducing the expression of miR-205-5p. However, this alleviation was reversed by the RORα antagonist SR1001. In vitro experiments showed that miR-205-5p promoted M1 polarization of macrophages and enhanced the secretion of inflammatory factors by regulating RORα. An increase in RORα reversed the polarization direction of M1-type macrophages and reduced the secretion of proinflammatory factors. In addition, pretreatment of mice with SR1078, a specific RORα agonist, effectively blocked M1 polarization of KCs and reduced the severity of TCE-induced liver injury. Our study uncovers that miR-205-5p regulates KC M1 polarization by targeting RORα in immune liver injury induced by TCE sensitization, providing new insight into the molecular mechanisms and new therapeutic targets for ODMLT.

Impact of Hand Hygiene Interventions on Handwashing Practices and Microbial Risk: A Study in an Orphanage-based School in Pakistan.

BACKGROUND: Orphaned children are often deprived of quality care, making them more susceptible to diseases due to inadequate hand hygiene. OBJECTIVE: The present study aimed to assess the prevalence of hand hygiene practices and detect bacterial loads on children's hands before and after hygiene interventions in an orphanage school. METHOD: The study enrolled all the orphan children registered with the Save Our Souls (SOS) children's orphanage School in Pakistan. The WHO standard checklist for assessing handwashing practices and swab samples from the hand were collected to evaluate the impact of hand-hygiene practices on bacterial load before and after the intervention. The Quantitative Microbial Risk Assessment (QMRA) model was used to predict the health risk. RESULT: The study identified the two most common bacteria: S. aureus and E. coli. Before exposure to the intervention, S. aureus contamination was observed in both groups: intervention (1261 CFU/Hand) and control (1008 CFU/Hand) while E. coli in children's hands were prevalent in the intervention (1042 CFU/Hand) and control (1798 CFU/Hand) groups. The bacterial contamination was significantly reduced after the intervention (S. aureus 166 CFU/ml and E. coli 185 CFU/ml). The higher bacterial ingestion rate was attributed to hand contamination and increased bacteria transfer from hand to mouth. CONCLUSION: The implementation of the multicomponent hand hygiene intervention showed improvement in accessibility to hand hygiene resources and practices. The findings underscore the need for hygiene interventions in orphanage schools to improve health and educational outcomes.

Advanced Regenerative Medicines for Rare Diseases: A Review of Industry Sponsors Investment Motivations.

Despite regulatory changes designed to stimulate investment in therapies for rare diseases, many of these conditions lack government-approved treatments. Advanced regenerative medicines, which are therapies and clinical interventions aimed at healing or replacing damaged or defective human cells, tissues, and organs, offer great promise for addressing many rare diseases. A major challenge facing advanced regenerative medicines for rare diseases is securing financial support to assist in bringing a therapy to market. This paper describes the factors cited by pharmaceutical industry players globally for sponsoring the development of advanced regenerative medicines for rare diseases. The paper examines the motivations of 53 sponsors that meet the latter criteria. The motivations behind investments were broadly similar amongst sponsors and map closely onto regulatory requirements for clinical development and marketing authorization of advanced therapeutic products, including the presence of accelerated or attenuated pathways for regulatory approval, use for indications with high unmet medical needs, and/or that have advantages over existing therapies, and robust preclinical data. Other factors include availability of investment incentives and opportunities for off-label use in the post-approval stages.

Single-cell RNA-Seq analysis of molecular changes during radiation-induced skin injury: the involvement of Nur77.

Introduction: Ionizing radiation has been widely used in industry, medicine, military and agriculture. Radiation-induced skin injury is a significant concern in the context of radiotherapy and accidental exposure to radiation. The molecular changes at the single-cell level and intercellular communications during radiation-induced skin injury are not well understood. Methods: This study aims to illustrate this information in a murine model and human skin samples from a radiation accident using single-cell RNA sequencing (scRNA-Seq). We further characterize the functional significance of key molecule, which may provide a potential therapeutic target. ScRNA-Seq was performed on skin samples from a nuclear accident patient and rats exposed to ionizing radiation. Bioinformatic tools were used to analyze the cellular heterogeneity and preferential mRNAs. Comparative analysis was performed to identify dysregulated pathways, regulators, and ligand-receptor interactions in fibroblasts. The function of key molecule was validated in skin cells and in three mouse models of radiation-induced skin injury. Results: 11 clusters in human skin and 13 clusters of cells in rat skin were depicted respectively. Exposure to ionizing radiation caused changes in the cellular population (upregulation of fibroblasts and endothelial cells, downregulation of keratinocytes). Fibroblasts and keratinocytes possessed the most interaction pairs with other cell lineages. Among the five DEGs common to human and rat skins, Nur77 was highly expressed in fibroblasts, which mediated radiosensitivity by cell apoptosis and modulated crosstalk between macrophages, keratinocytes and endothelial cells in radiation-induced skin injury. In animal models, Nur77 knock-out mice (Nur77 -/-) showed more severe injury after radiation exposure than wild-type counterparts in three models of radiation-induced skin injury with complex mechanisms. Conclusion: The study reveals a single-cell transcriptional framework during radiation-induced skin injury, which provides a useful resource to uncover key events in its progression. Nur77 is a novel target in radiation-induced skin injury, which provides a potential therapeutic strategy against this disease.

Food and Drug Administration (FDA) Approvals of Biological Drugs in 2023.

An increase in total drug (small molecules and biologics) approvals by the Food and Drug Administration (FDA) was seen in 2023 compared with the previous year. Cancer remained the disease most targeted by monoclonal antibodies (mAbs), followed by autoimmune conditions. Our data reveal the prevalence of approvals for biologics even during years when the total number of authorizations was low, such as in 2022. Over half the drugs that received the green light in 2023 benefited from expedited programs, as the incidence of many diseases increased. In addition, over half of the biologics approved received Orphan Drug Designation from the FDA. This narrative review delves into details of the most significant approvals in 2023, including mAbs, enzymes, and proteins, explaining their mechanisms of action, differences from previous drugs, placebo, and standards of care, and outcomes in clinical trials. Given the varying number of drugs authorized annually by the U.S. health authority, this review also examines the limits of external influences over the FDA's decisions and independence regarding drug approvals and withdrawals.

[Corrigendum] miR-382 inhibits migration and invasion by targeting ROR1 through regulating EMT in ovarian cancer.

Following the publication of the above article, an interested reader drew to the authors' attention that certain of the Transwell migration and invasion assay data panels shown in Figs. 3E and G and 7E and G on p. 1754 and 1757 respectively contained overlapping data panels, both within Fig. 3 and between Figs. 3 and 7, such that data which were intended to represent the results of differently performed experiments had apparently been derived from the same original sources. Specifically, the 'con' and 'pre-con' data panels in Fig. 3 were overlapping, as were the 'pre-con' and 'pcDNA.1-ROR1' panels comparing Fig. 3 with Fig. 7, and the Editorial Office subsequently pointed out to the authors that the 'con' and 'pre-con' data panels in Fig. 3E also contained an overlapping edge. After having examined their original data, the authors realized that these figures were inadvertently assembled incorrectly. The corrected versions of Figs. 3 and 7 are shown on the next page, now showing the correct data for the 'con' experiment in Fig. 3E, the 'pre-con' experiment in Fig. 3G, and the 'pcDNA.1-ROR1' panel in Fig. 7G. 'The authors are grateful to the Editor of International Journal of Oncology for granting them the opportunity to publish this corrigendum, and all the authors agree with its publication; furthermore, they apologize to the readership of the journal for any inconvenience caused. [International Journal of Oncology 48: 181-190, 2016; DOI: 10.3892/ijo.2015.3241].

Value contribution of etranacogene dezaparvovec gene therapy in moderately severe and severe haemophilia B through multi-criteria decision analysis.

INTRODUCTION: The value of gene therapies for haemophilia needs to be assessed holistically. AIM: To determine the value of etranacogene dezaparvovec (ED) compared to current extended half-life (EHL) recombinant factors (rFIX), using multi-criteria decision analysis (MCDA). METHOD: MCDA EVIDEM methodology adapted to orphan drugs was used, with nine quantitative criteria and four contextual criteria. The MCDA framework was rated by 28 multidisciplinary experts. Descriptive statistics were performed for quantitative and qualitative criteria. RESULTS: Haemophilia B (HB) was considered a severe disease (mean ± SD: 4.3 ± 0.7) with some unmet needs (mean ± SD 3.3 ± 0.9). Experts found ED more effective (mean ± SD 2.0 ± 2.3) and provide better quality of life (QoL) (mean ± SD: 1.8 ± 1.5) than the comparative HB treatments but with safety uncertainties (mean ± SD -1.2 ± 1.8). ED could lead to medical cost and non-medical cost savings over time (mean ± SD: 1.6 ± 2.0 and 2.0 ± 1.5, respectively). The quality of the evidence was high (mean ± SD: 3.9 ± 0.9). ED was considered aligned with the priorities of the National Health System (NHS) and the specific interests of patients. ED's value contribution was 0.45 (+1 = highest value). CONCLUSIONS: ED brings added value in the treatment of moderately severe and severe HB (sHB) compared to current EHL rFIX, addressing the severity of the disease and increasing efficacy and patients' QoL especially related to the single dose and low bleeding rate. Concerns about long-term safety need to be addressed.

Budget impact analysis of high-priced orphan medicinal products intended for the treatment of rare diseases in China: evidence from a densely populated metropolis of Chengdu.

BACKGROUND: An increasing number of orphan medicinal products (OMPs) are being included in social health insurance schemes, significantly improving access to medicines for patients with rare diseases. However, high-priced OMPs are still not covered, primarily due to health equity controversies and inadequate data systems required for economic evaluation. The aim of this study was to estimate the burden of drug expenditures and the size of the reimbursement budget required for high-priced OMPs from the perspectives of society and healthcare payers. METHODS: The study performed a budget impact analysis using data from multiple sources to estimate the reimbursement budget for high-priced OMPs in Chengdu, a densely populated metropolis in China. The budget analysis consisted of three main elements: the number of patients, the price of drugs, and the simulated policy scenario. By adjusting the combinations of these elements, the budget fluctuations for payers were estimated. Furthermore, the study predicted the budget trend for the next three years to validate its sustainability. RESULTS: The analysis indicated that 98 rare disease patients in Chengdu required high-priced OMPs in 2019. This suggested a projected budget of CNY 179 million for these patients without reimbursement policies, from a societal perspective. Under six assumed policy scenarios, this budget ranged from CNY 32 million to CNY 156 million. Over the next three years, the annual budget was estimated to range from CNY 200 million to CNY 1.303 billion. CONCLUSION: Integration of multi-source data helps to obtain more scientifically reliable results on budget impacts. The study found that the budgetary impacts of high-priced OMPs on society and payers are relatively limited. Health policymakers can choose appropriate reimbursement strategies based on financial affordability among a diverse mix of elements. The results of related studies provided insights for optimizing the allocation of health resources and improving patient access to medications.

Diet and Nutrients in Rare Neurological Disorders: Biological, Biochemical, and Pathophysiological Evidence.

Background/Objectives: Rare diseases are a wide and heterogeneous group of multisystem life-threatening or chronically debilitating clinical conditions with reduced life expectancy and a relevant mortality rate in childhood. Some of these disorders have typical neurological symptoms, presenting from birth to adulthood. Dietary patterns and nutritional compounds play key roles in the onset and progression of neurological disorders, and the impact of alimentary needs must be enlightened especially in rare neurological diseases. This work aims to collect the in vitro, in vivo, and clinical evidence on the effects of diet and of nutrient intake on some rare neurological disorders, including some genetic diseases, and rare brain tumors. Herein, those aspects are critically linked to the genetic, biological, biochemical, and pathophysiological hallmarks typical of each disorder. Methods: By searching the major web-based databases (PubMed, Web of Science Core Collection, DynaMed, and Clinicaltrials.gov), we try to sum up and improve our understanding of the emerging role of nutrition as both first-line therapy and risk factors in rare neurological diseases. Results: In line with the increasing number of consensus opinions suggesting that nutrients should receive the same attention as pharmacological treatments, the results of this work pointed out that a standard dietary recommendation in a specific rare disease is often limited by the heterogeneity of occurrent genetic mutations and by the variability of pathophysiological manifestation. Conclusions: In conclusion, we hope that the knowledge gaps identified here may inspire further research for a better evaluation of molecular mechanisms and long-term effects.

Preclinical Detection of Early Glomerular Injury in Children with Kidney Diseases-Independently of Usual Markers of Kidney Impairment and Inflammation.

Glomerular kidney diseases typically begin insidiously and can progress to end stage kidney failure. Early onset of therapy can slow down disease progression. Early diagnosis is required to ensure such timely therapy. The goal of our study was to evaluate protein biomarkers (BMs) for common nephropathies that have been described for children with Alport syndrome. Nineteen candidate BMs were determined by commercial ELISA in children with congenital anomalies of the kidneys and urogenital tract, inflammatory kidney injury, or diabetes mellitus. It is particularly essential to search for kidney disease BMs in children because they are a crucial target group that likely exhibits early disease stages and in which misleading diseases unrelated to the kidney are rare. Only minor differences in blood between affected individuals and controls were found. However, in urine, several biomarker candidates alone or in combination seemed to be promising indicators of renal injury in early disease stages. The BMs of highest sensitivity and specificity were collagen type XIII, hyaluronan-binding protein 2, and complement C4-binding protein. These proteins are unrelated to inflammation markers or to risk factors for and signs of renal failure. In conclusion, our study evaluated several strong candidates for screening for early stages of kidney diseases and can help to establish early nephroprotective regimens.

A scoping review of the role of managed entry agreements in upcoming drugs for amyotrophic lateral sclerosis: learning from the case of spinal muscular atrophy.

Introduction: The therapeutic options for spinal muscular atrophy (SMA) are encouraging. However, there is currently no cure for amyotrophic lateral sclerosis (ALS). The clinical and economic uncertainty surrounding innovative treatments for rare neurodegenerative diseases makes it necessary to understand managed entry agreements (MEAs). The aim of this study was to review whether models of MEAs in SMA could be extrapolated to ALS. Methods: We performed a scoping review with information on MEAs on SMA in Web of Science (WOS), PubMed, Lyfegen Library, the National Institute for Health and Care Excellence (NICE), and the Canadian Agency for Drugs and Technologies in Health (CADTH). Results: We found 45 results in WOS and PubMed. After an initial survey, 10 were reviewed to assess eligibility, and three were selected. We obtained 44 results from Lyfegen Library, and three results each from NICE and CADTH. Conclusion: The main objective of MEAs is to reduce uncertainty in the financing of drugs with a high budgetary impact and clinical concerns, as is the case with drugs for SMA and ALS. While the information available on MEAs in SMA is scarce, some conceptual models are publicly available. MEAs for long-term treatments for SMA could be used for the design of MEAs in ALS because of their similarities in economic and clinical uncertainty.

Theranostics vs theratyping or theranostics plus theratyping?

Treating all people with Cystic Fibrosis (pwCF) to the level of benefit achieved by highly efficient CFTR modulator therapies (HEMT) remains a significant challenge. Theratyping and theranostics are two distinct approaches to advance CF treatment. Both theratyping in cell lines and pwCF-derived biomaterials theranostics have unique strengths and limitations in the context of studying and treating CF. The challenges, advantages and disadvantages of both approaches are discussed here. While theratyping in cell lines offers ease of use, cost-effectiveness, and standardized platforms for experimentation, it misses physiological relevance and patient-specificity. Theranostics, on the other hand, provides a more human-relevant model for personalized medicine approaches but requires specialized expertise, resources, and access to patient samples. Integrating these two approaches in parallel and leveraging their respective strengths may enhance our understanding of CF and facilitate the development of more effective therapies for all pwCF.

Identifying health inequities faced by older adults with rare diseases: A systematic literature review and proposal for an ethical spectrum and resource allocation framework.

Ageism in healthcare has received increased attention in recent years, but literature focusing on how it affects individuals living with rare diseases remains scant. The rare disease population already faces obstacles when navigating health systems, and ageism has the potential to exacerbate existing health inequities. We conducted a systematic review of peer-reviewed and gray literature on health inequities in rare disease populations, seeking to identify publications that reported primary or secondary data on the equitable or inequitable treatment of these populations, or that discussed related regulatory, moral, or philosophical issues. Our aims were to understand how health inequities in these populations arise, how they are justified from societal points of view, how they manifest themselves in laws and regulations, and what effects they have on health care access and health outcomes. We retrieved information from 63 publications, which we inductively synthesized into five categories: ethical discussions, societal preferences, regulations, access to care, and health outcomes. Integrating insights from these categories, we developed an Ethical Spectrum and Resource Allocation Framework, which explains the emergence of equity issues and how they are manifested in health systems. By providing a better understanding of the root causes of health inequities, particularly among older adults, the framework can inform health policymaking, improving access to care and health outcomes for rare disease patients.