Why are rare diseases underdiagnosed? A clinical management study on detection of primary biliary cholangitis in primary care.

Background: There are about 7,000 rare diseases that affect 10% of the world population. Primary biliary cholangitis, an autoimmune chronic liver disease of the interlobular bile ducts, is one of the most common causes of chronic cholestasis. However, it is a rare, often underdiagnosed and undertreated, disease which can lead to cirrhosis and liver failure. We aimed to assess the proportion of undetected primary biliary cholangitis patients in primary care through a clinical management process. Methods: We made two extractions of the clinical data concerning liver diseases, risk factors and laboratory tests from the databases of a sample of general practitioners, with a check and correction of mistakes. The clinical data of the patients without liver disease and major risk factors, and with serum Alkaline Phosphatase above the laboratory reference values, were re-evaluated by each general practitioner with an expert gastroenterologist. The patients with elevated Alkaline Phosphatase values and without evidence of intrahepatic or extrahepatic causes of cholestasis were considered suspected for primary biliary cholangitis and assessed for antimitochondrial antibodies test and specialist' s evaluation, according to present guidelines. Results: A total of 20,480 adults attending 14 general practitioners in the province of Brescia, Northern Italy, were included in the study. Nine patients had a prior primary biliary cholangitis diagnosis, with a prevalence of 43.9/100000. After excluding 2094 (10.2%) patient with liver diseases or other causes of cholestasis, 121 subjects with Alkaline Phosphatase above the reference values were re-evaluated by the general practitioners and gastroenterologist, and 27 patients without symptoms or signs of cholestasis were considered suspected for primary biliary cholangitis: 9 of them were tested for antimitochondrial antibodies, and three new primary biliary cholangitis cases were detected (+33%). Discussion and Conclusions: This study shows that there is a not negligible burden of undetected cases of adult rare diseases that can be diagnosed in primary care, through a disease management procedure, without modifying the routine clinical practice.

Clinical description and evaluation of 30 pediatric patients with ultra-rare diseases: A multicenter study with real-world data from Saudi Arabia.

BACKGROUND: With the advancement of next-generation sequencing, clinicians are now able to detect ultra-rare mutations that are barely encountered by the majority of physicians. Ultra-rare and rare diseases cumulatively acquire a prevalence equivalent to type 2 diabetes with 80% being genetic in origin and more prevalent among high consanguinity communities including Saudi Arabia. The challenge of these diseases is the ability to predict their prevalence and define clear phenotypic features. METHODS: This is a non-interventional retrospective multicenter study. We included pediatric patients with a pathogenic variant designated as ultra-rare according to the National Institute for Clinical Excellence's criteria. Demographic, clinical, laboratory, and radiological data of all patients were collected and analyzed using multinomial regression models. RESULTS: We included 30 patients. Their mean age of diagnosis was 16.77 months (range 3-96 months) and their current age was 8.83 years (range = 2-15 years). Eleven patients were females and 19 were males. The majority were of Arab ethnicity (96.77%). Twelve patients were West-Saudis and 8 patients were South-Saudis. SCN1A mutation was reported among 19 patients. Other mutations included SZT2, ROGDI, PRF1, ATP1A3, and SHANK3. The heterozygous mutation was reported among 67.86%. Twenty-nine patients experienced seizures with GTC being the most frequently reported semiology. The mean response to ASMs was 45.50% (range 0-100%). CONCLUSION: The results suggest that ultra-rare diseases must be viewed as a distinct category from rare diseases with potential demographic and clinical hallmarks. Additional objective and descriptive criteria to detect such cases are needed.

Introducing the PLOS collection on rare cancer.

Rare cancers are defined by low incidence rates, and may lack evidence that supports uniform standards of care and relevant clinical guidelines. Rare cancers may represent up to 24% of all cancers, yet remain understudied and underappreciated in terms of their clinical and ultimately societal impact. The PLOS Rare Cancer Collection brings together a broad range of research endeavors that are being undertaken in rare cancers research ranging from basic biological evaluations to therapeutic drug development. This Overview presents a brief background to the Collection and highlights the contributions of included articles.

Global health for rare diseases through primary care.

Rare diseases affect over 300 million people worldwide and are gaining recognition as a global health priority. Their inclusion in the UN Sustainable Development Goals, the UN Resolution on Addressing the Challenges of Persons Living with a Rare Disease, and the anticipated WHO Global Network for Rare Diseases and WHO Resolution on Rare Diseases, which is yet to be announced, emphasise their significance. People with rare diseases often face unmet health needs, including access to screening, diagnosis, therapy, and comprehensive health care. These challenges highlight the need for awareness and targeted interventions, including comprehensive education, especially in primary care. The majority of rare disease research, clinical services, and health systems are addressed with specialist care. WHO Member States have committed to focusing on primary health care in both universal health coverage and health-related Sustainable Development Goals. Recognising this opportunity, the International Rare Diseases Research Consortium (IRDiRC) assembled a global, multistakeholder task force to identify key barriers and opportunities for empowering primary health-care providers in addressing rare disease challenges.

Monkeypox Outbreak 2022, from a Rare Disease to Global Health Emergence: Implications for Travellers.

Monkeypox (mpox), a zoonotic disease caused by the monkeypox virus (MPXV), poses a significant public health threat with the potential for global dissemination beyond its endemic regions in Central and West Africa. This study explores the multifaceted aspects of monkeypox, covering its epidemiology, genomics, travel-related spread, mass gathering implications, and economic consequences. Epidemiologically, mpox exhibits distinct patterns, with variations in age and gender susceptibility. Severe cases can arise in immunocompromised individuals, underscoring the importance of understanding the factors contributing to its transmission. Genomic analysis of MPXV highlights its evolutionary relationship with the variola virus and vaccinia virus. Different MPXV clades exhibit varying levels of virulence and transmission potential, with Clade I associated with higher mortality rates. Moreover, the role of recombination in MPXV evolution remains a subject of interest, with implications for understanding its genetic diversity. Travel and mass gatherings play a pivotal role in the spread of monkeypox. The ease of international travel and increasing globalization have led to outbreaks beyond African borders. The economic ramifications of mpox outbreaks extend beyond public health. Direct treatment costs, productivity losses, and resource-intensive control efforts can strain healthcare systems and economies. While vaccination and mitigation strategies have proven effective, the cost-effectiveness of routine vaccination in non-endemic countries remains a subject of debate. This study emphasizes the role of travel, mass gatherings, and genomics in its spread and underscores the economic impacts on affected regions. Enhancing surveillance, vaccination strategies, and public health measures are essential in controlling this emerging infectious disease.

Haemoglobinopathies and other rare anemias in Spain: ten years of a nationwide registry (REHem-AR).

REHem-AR was created in 2013. The progressive implementation of neonatal screening for haemoglobinopathies in Spanish autonomous communities where the registry had not been implemented, as well as the addition of new centres during this period, has considerably increased the sample of patients covered. In this study, we update our previous publication in this area, after a follow-up of more than 5 years. An observational, descriptive, multicentre and ambispective study of adult and paediatric patients with haemoglobinopathies and rare anaemias registered in REHem was performed. The data are from a cross-sectional analysis performed on 1 June, 2023. The study population comprised 1,756 patients, of whom 1,317 had SCD, 214 had thalassaemia and 224 were diagnosed with another condition. Slightly more than one third of SCD patients (37%) were diagnosed based on neonatal bloodspot screening, and the mean age at diagnosis was 2.5 years; 71% of thalassaemia patients were diagnosed based on the presence of anaemia. Vaso-occlusive crisis and acute chest syndrome continue to be the most frequent complications in SCD. HSCT was performed in 83 patients with SCD and in 50 patients with thalassaemia. Since the previous publication, REHem-AR has grown in size by more than 500 cases. SCD and TM are less frequent in Spain than in other European countries, although the data show that rare anaemias are frequent within rare diseases. REHem-AR constitutes an important structure for following the natural history of rare anaemias and enables us to calculate investment needs for current and future treatments.

Increase transparency and reproducibility of real-world evidence in rare diseases through disease-specific Federated Data Networks.

PURPOSE: In rare diseases, real-world evidence (RWE) generation is often restricted due to small patient numbers and global geographic distribution. A federated data network (FDN) approach brings together multiple data sources harmonized for collaboration to increase the power of observational research. In this paper, we review how to increase reproducibility and transparency of RWE studies in rare diseases through disease-specific FDNs. METHOD: To be successful, a multiple stakeholder scientific FDN collaboration requires a strong governance model in place. In such a model, each database owner remains in full control regarding the use of and access to patient-level data and is responsible for data privacy, ethical, and legal compliance. Provided that all this is well documented and good database descriptions are in place, such a governance model results in increased transparency, while reproducibility is achieved through data curation and harmonization, and distributed analytical methods. RESULTS: Leveraging the OHDSI community set of methods and tools, two rare disease-specific FDNs are discussed in more detail. For multiple myeloma, HONEUR-the Haematology Outcomes Network in Europe-has built a strong community among the data partners dedicated to scientific exchange and research. To advance scientific knowledge in pulmonary hypertension (PH) an FDN, called PHederation, was established to form a partnership of research institutions with PH databases coming from diverse origins.

Time trend analysis of rare cancer incidence 2011-2018: Nationwide population-based cancer registries in Japan.

Rare cancers collectively account for a significant proportion of the overall cancer burden in Japan. We aimed to describe and examine the incidence of each rare cancer and the temporal changes using the internationally agreed rare cancer classification. Cancer cases registered in regional population-based cancer registries from 2011 to 2015 and the National Cancer Registry (NCR) from 2016 to 2018 were classified into 18 families, 68 Tier-1 cancer groupings, and 216 single cancer entities based on the RARECAREnet list. Crude incidence rates and age-standardized incidence rates (ASR) were calculated for Tier-1 and Tier-2 cancers. The annual percent change and the 95% and 99% confidence limits for annual ASR for each of the 68 Tier-1 cancers were estimated using the log-linear regression of the weighted least squares method. The differences in ASRs between 2011 and 2018 were evaluated as an absolute change. A total of 5,640,879 cases were classified into Tier-1 and Tier-2 cancers. The ASRs of 18 out of 52 Tier-1 cancers in the rare cancer families increased, whereas the ASR for epithelial tumors of gallbladder decreased. The ASRs of 6 out of the 16 Tier-1 cancers in the common cancer families increased, whereas those of epithelial tumors of stomach and liver decreased. There was no significant change in the incidence of the other 40 Tier-1 cancers. The incidence of several cancers increased due to the dissemination of diagnostic concepts, improved diagnostic techniques, changes in coding practice, and the initiation of the NCR.

Impact of the COVID-19 pandemic on lung transplant patients and on a cohort of patients with rare lung disease: A single-center study.

INTRODUCTION: Due to the COVID-19 pandemic, France underwent several lockdown periods during 2020. Our aim was to evaluate its clinical and social impact on lung transplant (LT) patients treated at Strasbourg University Hospital, by comparing three periods: first lockdown (T1: March-May 2020), end of the first lockdown (T2: May-October 2020), and second lockdown (T3: November-December 2020) and the incidence of COVID-19 infections. A cohort of patients with rare lung disease (RLD) was also studied during T2. METHODS: We used clinical and paraclinical data collected during routine follow-up. A questionnaire was submitted to each patient at each period to assess their lifestyle, adherence to protective measures against COVID-19, contacts with their family and friends, and contagion risk. The incidence of new COVID-19 cases was also assessed. RESULTS: Overall, 283 LT and 57 RLD patients were included. We observed only eight COVID-19 cases over the three periods (n = 4 during T1, n = 0 during T2, and n = 4 during T3) in LT patients, with 37.5 % of patients hospitalized, no ICU transfers, and 100 % favorable outcomes. No case of COVID-19 was diagnosed in the RLD cohort. When comparing the three periods in the LT group, fewer patients limited their out-of-home activities during T2 (p < 0.0001). The frequency of these activities increased after the first lockdown, for the purchase of basic necessities (p < 0.0001), and professional activity continued (p = 0.008). We observed a significant increase in unscheduled medical consultations and in the prescription of anti-infective treatments during the end of the lockdown (p = 0.0002 and p = 0.005, respectively). Adherence to lockdown and to protective measures was high in both groups of patients. CONCLUSION: COVID-19 incidence remained low in both groups and there were significant lifestyle evolutions in LT patients and in those with RLD between first and second lockdown.

Longitudinal natural history studies based on real-world data in rare diseases: Opportunity and a novel approach.

Growing interest in therapeutic development for rare diseases necessitate a systematic approach to the collection and curation of natural history data that can be applied consistently across this group of heterogenous rare diseases. In this study, we discuss the challenges facing natural history studies for leukodystrophies and detail a novel standardized approach to creating a longitudinal natural history study using existing medical records. Prospective studies are uniquely challenging for rare diseases. Delays in diagnosis and overall rarity limit the timely collection of natural history data. When feasible, prospective studies are often cross-sectional rather than longitudinal and are unlikely to capture pre- or early- symptomatic disease trajectories, limiting their utility in characterizing the full natural history of the disease. Therapeutic development in leukodystrophies is subject to these same obstacles. The Global Leukodystrophy Initiative Clinical Trials Network (GLIA-CTN) comprises of a network of research institutions across the United States, supported by a multi-center biorepository protocol, to map the longitudinal clinical course of disease across leukodystrophies. As part of GLIA-CTN, we developed Standard Operating Procedures (SOPs) that delineated all study processes related to staff training, source documentation, and data sharing. Additionally, the SOP detailed the standardized approach to data extraction including diagnosis, clinical presentation, and medical events, such as age at gastrostomy tube placement. The key variables for extraction were selected through face validity, and common electronic case report forms (eCRF) across leukodystrophies were created to collect analyzable data. To enhance the depth of the data, clinical notes are extracted into "original" and "imputed" encounters, with imputed encounter referring to a historic event (e.g., loss of ambulation 3 months prior). Retrospective Functional Assessments were assigned by child neurologists, using a blinded dual-rater approach and score discrepancies were adjudicated by a third rater. Upon completion of extraction, data source verification is performed. Data missingness was evaluated using statistics. The proposed methodology will enable us to leverage existing medical records to address the persistent gap in natural history data within this unique disease group, allow for assessment of clinical trajectory both pre- and post-formal diagnosis, and promote recruitment of larger cohorts.

Incidence, prevalence, and pattern of medical service utilization of children's rare lung diseases in South Korea.

INTRODUCTION: Children's rare lung diseases are a heterogeneous group of rare lung diseases with significant morbidity and mortality. There is very limited information on the incidence and prevalence of children's rare lung diseases in Asia. We investigated the nationwide incidence, prevalence, and pattern of medical service utilization of children's rare lung diseases in Korea. METHODS: We studied patients who were diagnosed with rare lung diseases coded per International Statistical Classification of Diseases and Related Health Problems, 10th Edition and registered in the national rare diseases database of confirmed patients. Data was extracted from the Korean National Health Insurance Service Claims database over 2019-2021. RESULTS: Average incidence rate was 12.9 new cases per million children per year, and average prevalence rate was 60.2 cases per million children during the study period of 2019-2021. We found that more than 65% of new cases were diagnosed before 2 years of age. ChILD, primary ciliary dyskinesia, and cystic fibrosis were usually diagnosed after 6 years of age. Congenital airway and lung anomalies were often diagnosed before 2 years of age. Busan and Gyeongsangnam-do residents tended to visit hospitals near their place of residence, while residents of other areas tended to visit hospitals in Seoul regardless of their area of residence. CONCLUSIONS: We examined the epidemiology of rare lung diseases in children in South Korea. Our estimation of the incidence and prevalence could be used for sustainable health care and equitable distribution of health care resources.

Cluster analysis and visualisation of electronic health records data to identify undiagnosed patients with rare genetic diseases.

Rare genetic diseases affect 5-8% of the population but are often undiagnosed or misdiagnosed. Electronic health records (EHR) contain large amounts of data, which provide opportunities for analysing and mining. Data mining, in the form of cluster analysis and visualisation, was performed on a database containing deidentified health records of 1.28 million patients across 3 major hospitals in Singapore, in a bid to improve the diagnostic process for patients who are living with an undiagnosed rare disease, specifically focusing on Fabry Disease and Familial Hypercholesterolaemia (FH). On a baseline of 4 patients, we identified 2 additional patients with potential diagnosis of Fabry disease, suggesting a potential 50% increase in diagnosis. Similarly, we identified > 12,000 individuals who fulfil the clinical and laboratory criteria for FH but had not been diagnosed previously. This proof-of-concept study showed that it is possible to perform mining on EHR data albeit with some challenges and limitations.

Primary Sjögren's syndrome in Italy: Real-world evidence of a rare disease through administrative healthcare data.

OBJECTIVES: Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease with significant impact on morbidity, mortality, and quality of life. This study aimed to evaluate epidemiology, healthcare needs and related costs of pSS patients from the Italian National Health Service perspective. METHODS: From the Fondazione Ricerca e Salute's database (∼5 million inhabitants/year), pSS prevalence in 2018 was calculated. Demographics, mean healthcare consumptions and direct costs at one year following index date (first in-hospital diagnosis/disease waiver claim) were analysed through an individual direct matched pair case-control analysis (age, sex, residency). RESULTS: In Italy, 3.8/10,000 inhabitants were identified as affected by pSS (1,746 case: 1,746 controls) in 2018. In the year following index date, 53.7% of cases and 42.7% of controls received ≥1 drug (p<0.001); mean per capita cost was €501 and €161, respectively (p<0.01). At least one hospitalization occurred to 7.8% of cases and 3.9% of controls (p<0.001) with mean per capita costs of €416 and €129, respectively (p = 0.46). At least one outpatient specialist service was performed in 49.8% of cases and 30.6% of controls (p<0.001); mean per capita costs were €200 and €75, respectively (p<0.01). Overall, mean annual costs were €1,171 per case and €372 per control (p < 0.01). CONCLUSION: According to results of this population-based study, the prevalence of pSS in Italy appears to be consistent with the definition of rare disease. Patients with pSS have higher pharmacological, in-hospital and outpatient specialist care needs, leading to three-times higher overall cost for the INHS, compared to the general population.