A scoping review of health literacy in rare disorders: key issues and research directions.

BACKGROUND: The ability to find, understand, appraise and utilise health information is crucial among individuals living with rare disorders. The aim of this study was to give a comprehensive overview of the literature on health literacy in adult persons with rare disorders. METHODS: We applied a scoping review methodology and performed a systematic search in 2021 in bibliographic databases. Searches were conducted in Medline (Ovid), Embase (Ovid), PsycInfo (Ovid), CINAHL (ebsco), and ERIC (Ovid). References were sorted and evaluated for inclusion using EndNote and Covidence. This review was guided by the question "What are the characteristics of research on health literacy in rare disorders?" RESULTS: The database searches yielded 75 eligible reports. A total of 6223 individuals with rare disorders were represented alongside 1707 caregivers. The reports in this review have included study participants representing a total of 80 different rare disorders with unique ORPHA and ICD-10 codes. The results revealed that persons with rare disorders often exhibit gaps in health literacy through a lack of knowledge and access to information related to self-management, their own diagnosis and health, as well as daily coping and social rights. In addition, the importance of aid and information from healthcare personnel and the significance of getting social support from others in the same situation were accentuated. CONCLUSION: This review emphasizes the importance of reinforcing health literacy among persons with rare disorders through peer support and education. This is the first review to give a comprehensive and state-of-the-art overview of literature investigating health literacy among persons with rare disorders and offers a basis for further research.

Health service utilization, economic burden and quality of life of patients with mucopolysaccharidosis in China.

BACKGROUND: Patients with mucopolysaccharidosis (MPS) often face delayed diagnoses, limited treatment options and high healthcare costs, that may significantly affect patients' quality of life. The objective of this study was to understand medical service utilization related to diagnosis and treatment, economic burden during diagnosis period, and health-related quality of life among MPS patients in China. METHODS: A series of patients diagnosed with MPS registered in the national patient organization were recruited for a cross-sectional survey from May to July 2019. Information were collected from patients or their parents via phone interview, including demographic data, utilization of services related to diagnosis and treatment, total cost during the period of MPS diagnosis and health-related quality of life (HRQoL). HRQoL was assessed by PedsQL 4.0 Generic Core Scale (PedsQL) and 36-item short-form health survey (SF-36) depending on the age of patients with MPS and compared with the general Chinese population. RESULTS: A total of 180 MPS patients (50, 67, 15, 46, 1 and 1 for type I, II, III, IV, VI and VII), with a mean age of 9.54 years and 137 (76.11%) males, were included in analysis. The mean age at first visit to a medical doctor for MPS related symptoms was 3.65 ± 2.58 years old, while only 12 patients (6.67%) were diagnosed on their first visit. The mean diagnostic delay, which is defined as the time between the first visit to a medical doctor for MPS related symptoms and the final diagnosis, was 9.42 months, with no significant difference between types. The average number of misdiagnosis was 4.56. Before the confirmed diagnosis, the patients made an average of 6.31 visits and visited 4.3 hospitals. During diagnosis period, the mean of ¥81,086.72 direct medical costs accounted for 63.75% of the total cost. Only 32.78% of the patients had ever received specific treatments. The mean scores of PedsQL and SF-36 of patients were significantly lower than the Chinese norms. Household annual income per person, specific treatment use and MPS subtype were significantly associated HRQoL of patients. CONCLUSION: The results highlight challenges faced by MPS patients in terms of diagnosis, access to specific treatments, economic burden and low HRQoL. There is an urgent need to improve early detection and diagnosis, create fair and consistent mechanisms to increase access to specialized treatment and reduce the economic burden of MPS patients in China.

A machine learning model for early diagnosis of type 1 Gaucher disease using real-life data.

OBJECTIVE: The diagnosis of Gaucher disease (GD) presents a major challenge due to the high variability and low specificity of its clinical characteristics, along with limited physician awareness of the disease's early symptoms. Early and accurate diagnosis is important to enable effective treatment decisions, prevent unnecessary testing, and facilitate genetic counseling. This study aimed to develop a machine learning (ML) model for GD screening and GD early diagnosis based on real-world clinical data using the Maccabi Healthcare Services (MHS) electronic database, which contains twenty years of longitudinal data on approximately 2.6 million patients. STUDY DESIGN AND SETTING: We screened the MHS database for patients with GD between January 1998 and May 2022. Eligible controls were matched by year of birth, sex, and socioeconomic status in a 1:13 ratio. The data were partitioned into 75% training and 25% test sets and trained to predict GD using features obtained from medical and laboratory records. Model performances were evaluated using the area-under-the receiver-operating-characteristic curve (AUROC) and the area-under-the-precision-recall curve (AUPRC). RESULTS: We detected 264 confirmed patients with GD to which we matched 3429 controls. The best model performance (which included known GD signs and symptoms, previously unknown clinical features, and administrative codes) on the test set had an AUROC = 0.95 ± 0.03 and AUPRC = 0.80 ± 0.08, which yielded a median GD identification of 2.78 years earlier than the clinical diagnosis (25th-75th percentile: 1.29-4.53). CONCLUSIONS: Using an ML approach on real-world data led to excellent discrimination between GD patients and controls, with the ability to detect GD significantly earlier than the time of actual diagnosis. Hence, this approach might be useful as a screening tool for GD and lead to earlier diagnosis and treatment. Furthermore, advanced ML analytics may highlight previously unrecognized features associated with GD, including clinical diagnoses and health-seeking behaviors.

Anything is better than nothing': exploring attitudes towards novel therapies in leukodystrophy clinical trials.

BACKGROUND/AIM: Leukodystrophies comprise a group of genetic white matter disorders that lead to progressive motor and cognitive impairment. Recent development of novel therapies has led to an increase in clinical trials for leukodystrophies. To enable recruitment of individuals with a leukodystrophy into clinical trials, clinical trial acceptability should be ascertained. We sought therefore, to identify the motivations for and barriers to clinical trial participation in addition to clinical trial features that may be of concern to individuals with a leukodystrophy and/or their carers. METHODS: Adults with a leukodystrophy and parents/carers of individuals with a leukodystrophy were recruited through the Australian Leukodystrophy Registry and through online advertisements. Qualitative semi-structured interviews were used to explore participants views on what clinical trials involve, the perceived risks and benefits of clinical trials, their desire to participate in clinical trials and their personal experience with leukodystrophy. Thematic analysis of data was performed with co-coding of interview transcripts. RESULTS: 5 interviews were held with parents of children with leukodystrophy, 4 with parents of adults with leukodystrophy and 3 with adults diagnosed with leukodystrophy. Motivations for clinical trial enrolment include access to potentially lifesaving novel treatments and improved prognostic outcomes. Participants were concerned about adverse clinical trial outcomes, including side effects and exacerbation of illness. Despite this, majority of participants were willing to try anything in clinical trials, demonstrating a high tolerance for first in human trials and trials utilising invasive treatment options. CONCLUSIONS: Interviewees communicated a strong desire to participate in interventional clinical trials involving novel therapies. To support enrolment into future leukodystrophy clinical trials we suggest the provision of transparent information regarding clinical trial treatments, consideration of alternative trial control measures, and inclusion of treating clinicians in the trial recruitment process. Clinicians play an integral role in initiating transparent conversations regarding trial risks and adverse outcomes.

Compound heterozygosity for two variants in BMP5 in human skeletal dysostosis with atrioventricular septal defect.

The growth and development of the skeleton is regulated by bone morphogenetic proteins of which several are linked to genetic skeletal disorders. So far, no human skeletal malformations have been associated with variants in BMP5. Here, we report a patient with biallelic loss of function variants in BMP5 and a syndromic phenotype including skeletal dysostosis, dysmorphic features, hypermobility, laryngo-tracheo-bronchomalacia and atrioventricular septal defect. We discuss the phenotype in relation to the known tissue-specific expression of Bmp5 and similar morphological abnormalities previously reported in experimental animal models. Our findings suggest a new association between BMP5 variants and a range of developmental anomalies, involving ears, heart and skeleton, thereby increasing understanding of BMP5's role in human development.

Nodular Mucinosis of the Breast: A Case Report.

This article presents a rare case of nodular mucinosis of the breast, typically manifested as a painless subcutaneous mass in young women. We describe the clinical scenario of a 48-year-old woman who previously underwent benign nodule resection in her 20s at the identical site where nodular mucinosis subsequently developed. This recurrence at the previous resection site underscores the unusual nature of the condition and emphasizes the need for continued vigilance in monitoring patients with a history of such lesions.

Past, current, and future trends in the prevalence of primary sclerosing cholangitis and inflammatory bowel disease across England (2015-2027): a nationwide, population-based study.

Background: Primary sclerosing cholangitis (PSC) is one of the leading indications for liver transplantation in Europe, and a major risk factor for cancer in inflammatory bowel disease (IBD). However, it is not known how the epidemiology of PSC will change as that of IBD evolves. The aim of this study is to provide nationwide statistics on the past and current prevalence of PSC and IBD across England, and forecast how this is likely to change over time. Methods: We accessed and analysed a nationwide population-based administrative healthcare registry, which houses prospectively accrued data since April 1st 2001. In so doing, the past and current prevalence of PSC-IBD and IBD alone was determined among 18-60-year-olds in England, alongside average annual percentage change rates (AAPC), between the 1st of January 2015 and 2020. Past and current prevalence data, alongside trends in incidence and event-free survival rates, were then used to forecast future prevalence between 2021 and 2027. Findings: In 2015, the prevalence of PSC with prior IBD diagnosis was 5.0 per 100,000 population, rising to 5.7 when including those with IBD diagnosed after PSC. In 2020, prevalence increased to 7.6 (8.6 accounting for IBD developing after PSC), yielding an AAPC of 8.8. In 2027, PSC-IBD prevalence is forecast to be 11.7 (95% prediction interval [PI]: 10.8-12.7), and 13.3 when accounting for IBD developing after PSC (AAPC: 6.4; 95% PI: 5.3-7.5). Comparatively, the prevalence of IBD alone rose among 18-60-year-olds from 384.3 in 2015 to 538.7 in 2020 (AAPC 7.0), and forecast to increase to 742.5 by 2027 (95% PI: 736.4-748.0; AAPC: 4.7, 95% PI: 4.6-4.8). Interpretation: The rate of growth in PSC-IBD is predicted to exceed IBD-alone. Further research is needed to understand changes in disease epidemiology, including aetiological drivers of developing (invariably progressive) liver disease in IBD, and the implications of rising case burden on health care resources. Funding: This study was supported by an unrestricted grant provided by Gilead Sciences.

Whole exome sequencing reveals a dual diagnosis of BCAP31-related syndrome and glutaric aciduria III.

Background: Biochemical testing is a common first-tier approach in the setting of genetic evaluation of patients with unexplained developmental delay. However, results can be unclear, and a plan for second-tier analysis must be determined based on the patient's biochemical results and clinical presentation - in many cases, triggering a diagnostic odyssey. Case presentation: A male patient from the United States presenting with unexplained developmental delay, microcephaly, hypotonia, and feeding difficulties was referred for clinical genetic evaluation at age 8 months. Biochemical testing revealed an isolated marked elevation of glutaric acid on urine organic acid profile, without elevations of related metabolites. Further testing included GCDH sequencing, a neurometabolic gene panel, chromosomal microarray, Prader Willi/Angelman testing, and lysosomal disease enzyme panel, all of which were non-diagnostic. The patient had persistent developmental delay and hypotonia, dystonia, sensorineural hearing loss, and abnormal brain myelination on magnetic resonance imaging. Whole exome sequencing (WES) was performed and revealed a dual diagnosis of glutaric aciduria III (GA III) and BCAP31-related disorder, an X-linked intellectual disability syndrome, caused by a novel pathogenic variant. Conclusions: GA III has historically been considered clinically benign, with few reported cases. This patient's presenting symptoms were similar to those commonly seen in GA I and GA II, however the biochemical abnormalities were not consistent with these disorders, prompting additional molecular and biochemical testing. Ultimately, WES confirmed a diagnosis of BCAP31-related syndrome, a rare neurological disorder, which explained the patient's presenting symptoms. WES also identified a secondary diagnosis of GA III. We present a patient with two rare genetic conditions, highlighting the importance of deep phenotyping and the utility of WES in the setting of a patient with dual genetic diagnoses.

Bethlem myopathy: A novel homozygous variant of c.385C>T (p.Arg129Cys) in the COL6A2 gene.

Key Clinical Message: This case highlights the challenges in diagnosing Bethlem myopathy, the need for a high index of suspicion, and the importance of recognizing the diverse clinical presentations of this rare condition. Enhanced understanding can aid in early diagnosis and tailored management. Abstract: Bethlem myopathy (BM), a rare collagen VI-related myopathy, is characterized by progressive muscle weakness and contractures, typically affecting the proximal muscles and joints. This case report presents a 15-year-old girl from Tehran, Iran, with a 5-year history of severe limb pain and progressive weakness. Born to consanguineous parents, the patient displayed delayed walking milestones and significant hypotonia, leading to a waddling gait and lumbar hyperlordosis. Neurological examination revealed marked proximal lower limb weakness, a positive Gowers' sign, and absent myotatic reflexes. Elevated creatine phosphokinase (CPK) levels and electromyography (EMG) results indicated myopathy, while nerve conduction studies showed no neuropathy. Genetic testing revealed a novel homozygous variant of c.385C>T (p.Arg129Cys) in the COL6A2 gene, classified as a variant of uncertain significance (VUS) per American College of Medical Genetics and Genomics (ACMG) guidelines due to its rarity and specific phenotype association. Differential diagnosis is essential to distinguish it from other neuromuscular conditions. Management primarily focuses on symptom relief and enhancing patients' quality of life. This case highlights the challenges in diagnosing BM, the need for a high index of suspicion, and the importance of recognizing the diverse clinical presentations of this rare condition. Enhanced understanding can aid in early diagnosis and tailored management.

Renal Replacement Therapy in Methylmalonic Aciduria-Related Metabolic Failure: Case Report and Literature Review.

BACKGROUND: Methylmalonic Aciduria (MA) without homocystinuria (or isolated MA) is a group of rare inherited metabolic disorders which leads to the accumulation of methylmalonic acid (MMA), a toxic molecule that accumulates in blood, urine, and cerebrospinal fluid, causing acute and chronic complications including metabolic crises, acute kidney injury (AKI), and chronic kidney disease (CKD). Detailed Case Description: Herein, we report a case of a 39-year-old male with MA and stage IV CKD who experienced acute metabolic decompensation secondary to gastrointestinal infection. The patient underwent a single hemodialysis (HD) session to correct severe metabolic acidosis unresponsive to medical therapy and to rapidly remove MMA. The HD session resulted in prompt clinical improvement and shortening of hospitalization. DISCUSSION: MMA accumulation in MA patients causes acute and life-threatening complications, such as metabolic decompensations, and long-term complications such as CKD, eventually leading to renal replacement therapy (RRT). Data reported in the literature show that, overall, all dialytic treatments (intermittent HD, continuous HD, peritoneal dialysis) are effective in MMA removal. HD, in particular, can be useful in the emergency setting to control metabolic crises, even with GFR > 15 mL/min. Kidney and/or liver transplantations are often needed in MA patients. While a solitary transplanted kidney can be rapidly affected by MMA exposure, with a decline in renal function even in the first year of follow-up, the combined liver-kidney transplantation showed better long-term results due to a combination of reduced MMA production along with increased urinary excretion. CONCLUSIONS: Early diagnosis, multidisciplinary management and preventive measures are pivotal in MA patients to avoid recurrent AKI episodes and, consequently, to slow down CKD progression.

Obesity-Related Ciliopathies: Focus on Advances of Biomarkers.

Obesity-related ciliopathies, as a group of ciliopathies including Alström Syndrome and Bardet-Biedl Syndrome, exhibit distinct genetic and phenotypic variability. The understanding of these diseases is highly significant for understanding the functions of primary cilia in the human body, particularly regarding the relationship between obesity and primary cilia. The diagnosis of these diseases primarily relies on clinical presentation and genetic testing. However, there is a significant lack of research on biomarkers to elucidate the variability in clinical manifestations, disease progression, prognosis, and treatment responses. Through an extensive literature review, the paper focuses on obesity-related ciliopathies, reviewing the advancements in the field and highlighting the potential roles of biomarkers in the clinical presentation, diagnosis, and prognosis of these diseases.

Effect of Itraconazole, a CYP3A4 Inhibitor, and Rifampin, a CYP3A4 Inducer, on the Pharmacokinetics of Vatiquinone.

Vatiquinone is a small molecule inhibitor of 15-lipoxygenase in development for patients with Friedreich's ataxia. The objective of this analysis was to determine the effect of a cytochrome P450 isoform 3A4 (CYP3A4) inhibitor and inducer on vatiquinone pharmacokinetics (PKs). The coadministration of 400 mg of vatiquinone with 200 mg of itraconazole (a CYP3A4 inhibitor) resulted in increased maximum observed concentration (Cmax) of vatiquinone and systemic exposure (AUC0-inf) by approximately 3.5- and 2.9-fold, respectively. The coadministration of 400 mg of vatiquinone with 600 mg of rifampin (a CYP3A4 inducer) resulted in decreased vatiquinone Cmax and AUC0-inf by approximately 0.64- and 0.54-fold, respectively. The terminal half-life of vatiquinone was not affected by itraconazole or rifampin. These clinical study results confirm the in vitro reaction phenotyping data that shows that CYP3A4 plays an important role in vatiquinone metabolism. The result of this analysis together with phase 3 efficacy and safety data, population PK analysis, and the exposure-response relationship will determine if the extent of vatiquinone changes in the presence of CYP3A4 inhibitors and inducers are considered clinically relevant.

An Integrated Pipeline for Phenotypic Characterization, Clustering and Visualization of Patient Cohorts in a Rare Disease-Oriented Clinical Data Warehouse.

Rare diseases pose significant challenges due to their heterogeneity and lack of knowledge. This study develops a comprehensive pipeline interoperable with a document-oriented clinical data warehouse, integrating cohort characterization, patient clustering and interpretation. Leveraging NLP, semantic similarity, machine learning and visualization, the pipeline enables the identification of prevalent phenotype patterns and patient stratification. To enhance interpretability, discriminant phenotypes characterizing each cluster are provided. Users can visually test hypotheses by marking patients exhibiting specific keywords in the EHR like genes, drugs and procedures. Implemented through a web interface, the pipeline enables clinicians to navigate through different modules, discover intricate patterns and generate interpretable insights that may advance rare diseases understanding, guide decision-making, and ultimately improve patient outcomes.

Chronic Thromboembolic Pulmonary Hypertension: the therapeutic assessment.

Chronic Thromboembolic Pulmonary Hypertension (CTEPH) is a severe and complex condition that evolves from unresolved pulmonary embolism, leading to fibrotic obstruction of pulmonary arteries, pulmonary hypertension, and potential right heart failure. The cornerstone of CTEPH management lies in a multifaceted therapeutic approach tailored to individual patient profiles, reflecting the disease's heterogeneity. This review delves into the current therapeutic strategies for CTEPH, including surgical pulmonary endarterectomy (PEA), balloon pulmonary angioplasty (BPA), and targeted pharmacological treatments such as PDE5 inhibitors, endothelin receptor antagonists, sGC stimulators, and prostanoids. Lifelong anticoagulation is also highlighted as a preventive strategy against recurrent thromboembolism. Special emphasis is placed on the interdisciplinary nature of CTEPH care, necessitating collaboration among PEA surgeons, BPA interventionists, PH specialists, and thoracic radiologists to ensure comprehensive treatment planning and execution. The review underscores the importance of selecting an appropriate treatment modality based on the patient's specific disease characteristics and the evolving landscape of CTEPH treatment, aiming to improve patient outcomes through integrated care strategies.

Duchenne muscular dystrophy in Saudi Arabia: a review of the current literature.

In the past three decades, significant improvements have occurred in the study of Duchenne muscular dystrophy (DMD). DMD is a rare, severe neuromuscular disease that causes death due to cardiovascular and respiratory complications among affected boys. Since the 1980s, ongoing preclinical and clinical studies have been conducted to explore the disease in depth and discover potential therapeutic strategies. In Saudi Arabia, it is unclear whether health services and research efforts are keeping pace with global achievements. Therefore, this review aims to explore the diagnostic and management strategies and research efforts in Saudi Arabia over the past three decades. I searched the PubMed/Medline, Scopus, and Web of Science databases and included all published articles on the epidemiology, genetics, diagnosis, and management of DMD/BMD in this review. The findings suggest a lack of local standardized diagnostic strategies, a poor understanding of epidemiology and common pathogenic variants, and a critical need for preclinical and clinical research. At the time of writing, no such comprehensive review has been published. Challenges, limitations, and future perspectives are also discussed in this article.

The growing research toolbox for SLC13A5 citrate transporter disorder: a rare disease with animal models, cell lines, an ongoing Natural History Study and an engaged patient advocacy organization.

TESS Research Foundation (TESS) is a patient-led nonprofit organization seeking to understand the basic biology and clinical impact of pathogenic variants in the SLC13A5 gene. TESS aims to improve the fundamental understanding of citrate's role in the brain, and ultimately identify treatments and cures for the associated disease. TESS identifies, organizes, and develops collaboration between researchers, patients, clinicians, and the pharmaceutical industry to improve the lives of those suffering from SLC13A5 citrate transport disorder. TESS and its partners have developed multiple molecular tools, cellular and animal models, and taken the first steps toward drug discovery and development for this disease. However, much remains to be done to improve our understanding of the disorder associated with SLC13A5 variants and identify effective treatments for this devastating disease. Here, we describe the available SLC13A5 resources from the community of experts, to foundational tools, to in vivo and in vitro tools, and discuss unanswered research questions needed to move closer to a cure.

Overview of research in SLC13A5 citrate transporter disorder SLC13A5 citrate transporter disorder is an ultra-rare, neurodevelopmental disorder that severely impacts cognition and motor control. It is characterized by frequent, intractable seizures that develop hours or days after birth, low tone, global developmental delay, a unique, varied, and difficult to categorize movement disorder, limited expressive verbal capabilities, tooth abnormalities, and increased citrate in both the CNS and serum. Seizures are frequently medically intractable, patients are often on multiple antiseizure medications and have frequent emergency room visits and hospitalizations for status epilepticus. SLC13A5 citrate transporter disorder is caused by mutations in the SLC13A5 gene which encodes a sodium-dependent citrate transporter, NaCT. NaCT is responsible for transporting citrate, a key molecule in cellular metabolism, from the extracellular space into cells, especially in the central nervous system and the liver. NaCT has been extensively studied in multiple animal models and affects lifespan and loss of some transporter activity actually improves metabolic syndrome in all animal species tested so far while causing mild neurological dysfunction in rodents. Although not definitively proven, it is presumed that loss of neuronal cell citrate transporter activity in the brain is the cause of seizures. Since the discovery of the disorder in 2014, there has been a rapid expansion in characterization of the disease. This has been aided by development of multiple models and molecular tools for studying wild type and mutant SLC13A5 making it a tractable candidate for therapeutic development. TESS Research Foundation is dedicated to driving SLC13A5 research and supporting children and families living with the disorder. Here, we describe the available SLC13A5 resources from the community of experts, to foundational tools, to in vivo and in vitro tools, and discuss unanswered research questions needed to move closer to a cure.

Expanded carrier screening for inherited genetic disease using exome and genome sequencing.

The goal of this study was to assess the feasibility of using exome (ES) and genome sequencing (GS) in guiding preconception genetic screening (PCGS) for couples who are planning to conceive by creating a workflow for identifying risk alleles for autosomal recessive (AR) and X-linked (XL) disorders without the constraints of a predetermined, targeted gene panel. There were several limitations and challenges related to reporting and the technical aspects of ES and GS, which are listed in the discussion. We selected 150 couples from a cohort of families (trios) enrolled in a research protocol where the goal was to define the genetic etiology of disease in an affected child. Pre-existing, de-identified parental sequencing data were analyzed to define variants that would place the couple at risk of having a child affected by an AR or XL disorder. We identified 17 families who would be selected for counseling about risk alleles. We noted that only 3 of these at-risk couples would be identified if we limited ourselves to the current ACMG-recommended expanded carrier screening gene panel. ES and GS successfully identified couples who are at risk of having a child with a rare AR or XL disorder that would have been missed by the current recommended guidelines. Current limitations of this approach include ethical concerns, difficulties in reporting results including variant calling due to the rare nature of some of the variants, determining which disorders to report, as well as technical difficulties in detecting certain variants such as repeat expansions.

The Health Benefits, Costs, and Cost-Effectiveness of Ultraorphan Drugs.

OBJECTIVES: To examine ultraorphan drugs in terms of incremental health, costs, and cost-effectiveness compared with more prevalent disease drugs. METHODS: We identified Food and Drug Administration drug approvals from 1999 to 2019. For drugs approved for multiple indications, we considered each drug-indication pair separately. Utilizing Food and Drug Administration's orphan drug designation and US disease prevalence, we categorized drug-indication pairs as: ultraorphan (<10 000 patients), "other" orphan (≥10 000 and <200 000), and nonorphan (≥200 000). We searched the PubMed database for cost-effectiveness analyses and comparative effectiveness studies. We excluded manufacturer-funded studies. We extracted estimates of incremental health gains in terms of quality-adjusted life-years (QALYs) and incremental costs associated with drug-indication pairs compared with the standard of care at the time of their approval. We compared QALY gains, added costs, and incremental cost-effectiveness ratios (ICERs) using the Kruskal-Wallis, Mann-Whitney U (MWU), and Kolmogorov-Smirnov (KS) tests. RESULTS: Median incremental QALYs, costs, and ICERs differed across nonorphan, "other" orphan, and ultraorphan categories (Kruskal-Wallis P < .01). Compared with nonorphan drugs, ultraorphan drugs had larger QALY gains (0.700 vs 0.050, MWU P < .01, KS P < .01), larger costs ($172 231 vs $3360, MWU P < .01, KS P < .01), and larger ICERs ($1 216 184/QALY vs $114 061/QALY, MWU P < .01, KS P <.01). Compared with "other" orphan drugs, ultraorphan drugs had larger QALY gains (0.700 vs 0.310, MWU P =.65, KS P =.32), larger costs ($172 231 vs $69 308, MWU P = .03, KS P = .03), and larger ICERs ($1 216 184/QALY vs $223 472/QALY, MWU P <.01, KS P <.01). CONCLUSIONS: Novel ultraorphan drugs typically offer larger incremental health gains than drugs for more prevalent diseases, but because of their substantial added costs, are typically less cost-effective.

Vogt-Koyanagi-Harada Syndrome: A Case Report.

Vogt-Koyanagi-Harada disease (VKH) is a neurological disorder that impacts vision and hearing by causing the immune system to attack melanocytes. Symptoms of the condition include flu-like symptoms, eye pain, headache, and dizziness, which may progress to vitiligo and hearing impairment. The diagnostic criteria include ocular involvement, generalized choroiditis, tinnitus, meningitis, and skin depigmentation. The treatment includes corticosteroids and immunosuppressive drugs. VKH is believed to be an autoimmune condition, possibly triggered by hereditary factors and cross-reactivity with cytomegalovirus. VKH is common in East Asia and India and has a genetic link to certain alleles. Inflammation generated by Th1 in melanocytes results in the production of granulomas. An analysis of a 48-year-old female with VKH disease revealed symptoms of anterior uveitis and subsequent glaucoma. The treatment involved the administration of systemic steroids and intratympanic steroid injections. Biochemical indicators showed signs of inflammation. Timely identification and therapy are essential for managing VKH. Further research is necessary to enhance outcomes for patients with VKH disease.