Physician- and patient-reported perspectives on myasthenia gravis in Europe: a real-world surveyMahic, Milada; Bozorg, Ali; DeCourcy, Jonathan; Golden, Keisha; Gibson, Gregor; Taylor, Christian; Scowcroft, Anna
doi: 10.1186/s13023-023-02727-0pmid: 37386469
BackgroundMyasthenia gravis (MG) is a rare, chronic, debilitating, unpredictable, and potentially life-threatening neuromuscular disease. There is a lack of real-world data on disease management that could be used to further understand and address unmet patient needs and burden. We aimed to provide comprehensive real-world insights in the management of MG in five European countries.MethodsData were collected using the Adelphi Real World Disease Specific Programme™ in MG, a point-in-time survey of physicians and their patients with MG in France, Germany, Italy, Spain, and the United Kingdom (UK). Physician- and patient-reported clinical data were collected, including demographics, comorbidities, symptoms, disease history, treatments, healthcare resource utilization (HCRU), and quality of life outcomes.ResultsIn total, 144 physicians completed 778 patient record forms from March to July 2020 in the UK, and from June to September 2020 in France, Germany, Italy and Spain. Mean patient age at symptom onset was 47.7 years, with a mean time from symptom onset to diagnosis of 332.4 days (10.97 months). At diagnosis, 65.3% of patients were classified as Myasthenia Gravis Foundation of America Class II or above. Mean number of symptoms reported at diagnosis per patient was five, with ocular myasthenia reported in at least 50% of patients. At time of survey completion, the mean number of symptoms reported per patient was five and ocular myasthenia and ptosis were each still present in more than 50% of patients. Acetylcholinesterase inhibitors were the most commonly prescribed chronic treatments in all countries. Of 657 patients treated with chronic treatment at the time of the survey, 62% continued to experience moderate-to-severe symptoms. On average, 3.1 healthcare professionals (HCPs) were involved in patient management, 6.2 consultations were made per patient with any HCP over the last 12 months, and 178 (22.9%) patients were hospitalized in the last 12 months. Overall, HCRU and disease management were similar across all countries.ConclusionsOur findings demonstrated the high burden of MG despite current treatment options for patients with MG.
Pathogenic mechanisms of osteogenesis imperfecta, evidence for classificationYu, Hongjie; Li, Changrong; Wu, Huixiao; Xia, Weibo; Wang, Yanzhou; Zhao, Jiajun; Xu, Chao
doi: 10.1186/s13023-023-02849-5pmid: 37559063
Osteogenesis imperfecta (OI) is a connective tissue disorder affecting the skeleton and other organs, which has multiple genetic patterns, numerous causative genes, and complex pathogenic mechanisms. The previous classifications lack structure and scientific basis and have poor applicability. In this paper, we summarize and sort out the pathogenic mechanisms of OI, and analyze the molecular pathogenic mechanisms of OI from the perspectives of type I collagen defects(synthesis defects, processing defects, post-translational modification defects, folding and cross-linking defects), bone mineralization disorders, osteoblast differentiation and functional defects respectively, and also generalize several new untyped OI-causing genes and their pathogenic mechanisms, intending to provide the evidence of classification and a scientific basis for the precise diagnosis and treatment of OI.
Imerslund-Gräsbeck syndrome: a comprehensive review of reported casesKingma, Sandra D.K.; Neven, Julie; Bael, An; Meuwissen, Marije E.C.; van den Akker, Machiel
doi: 10.1186/s13023-023-02889-xpmid: 37710296
Imerslund-Gräsbeck syndrome (IGS) is a rare autosomal recessive disorder characterized by vitamin B12 malabsorption. Most patients present with non-specific symptoms attributed to vitamin B12 deficiency, and proteinuria. Patients may if untreated, develop severe neurocognitive manifestations. If recognized and treated with sufficient doses of vitamin B12, patients recover completely. We provide, for the first time, an overview of all previously reported cases of IGS. In addition, we provide a complete review of IGS and describe two new patients.
The improvement of motor symptoms in Huntington’s disease during cariprazine treatmentCsehi, Reka; Molnar, Viktor; Fedor, Mariann; Zsumbera, Vivien; Palasti, Agnes; Acsai, Karoly; Grosz, Zoltan; Nemeth, Gyorgy; Molnar, Maria Judit
doi: 10.1186/s13023-023-02930-zpmid: 38041194
BackgroundHuntington’s disease (HD) is a progressive neurodegenerative disease, characterised by motor disturbances and non-motor (i.e., psychiatric) symptoms. Motor symptoms are the hallmark features of HD and take many forms. Their emergence is related to alterations in striatal dopaminergic neurotransmission: dopamine levels increase in the early stages of the disease, while more advanced stages are characterised by reduced dopamine levels. Such a biphasic change potentially explains the alterations in motor symptoms: increased dopamine-production induces hyperkinetic movements early in the disease course, while depleted dopamine storage leads to hypokinetic symptoms in the advanced phase. Dopamine D2-D3 partial agonists could be a promising treatment option in HD, as they have the potential to either elevate or lower the surrounding dopamine levels if the levels are too low or too high, respectively, potentially offering symptom-relief across the illness-course. Therefore, the present study aimed at exploring the effects of cariprazine, a dopamine D2-D3 partial agonist with high affinity to D3 receptors, on motor symptoms associated with HD.MethodsThis was a single-centre, retrospective study where sixteen patients received off-label cariprazine treatment for 12 weeks (1.5-3 mg/day). Motor symptoms were evaluated using the Motor Assessment of the Unified Huntington’s Disease Rating Scale. Least Square (LS) Mean Changes from Baseline (BL) to Week 8 and Week 12 in the Total Motor Score (TMS) were analysed using the Mixed Model for Repeated Measures method. In addition, improvement from BL to Week 8 and 12 was calculated for all motor items.ResultsData of 16 patients were collected, but data of only 15 patients were analysed as one patient dropped out due to non-compliance. Significant changes were observed from BL to Week 8 (LS Mean Change: -9.4, p < 0.0001) and to Week 12 (LS Mean Change: -12.8, p < 0.0001) in the TMS. The improvement was captured in the majority of motor functions, excluding bradykinesia and gait. Mild akathisia was the most commonly reported side-effect, affecting 3 patients.ConclusionThis is the first study investigating the effectiveness of a D2-D3 partial agonist, cariprazine, in the treatment of HD. The findings of this study revealed that cariprazine was effective in the treatment of a wide range of motor symptoms associated with HD.
Trend of clinical trials of new drugs for rare diseases in China in recent 10 yearsPeng, Ai; Fan, Xue; Zou, Linling; Chen, Huan; Xiang, Jin
doi: 10.1186/s13023-023-02713-6pmid: 37170366
BackgroundRare disease is a general term for a disease that affects a small number of people but recognized as a global public health priority. Governments worldwide are paying more and more attention to the academical research and drug investment of rare diseases. The conduct of rare disease clinical trials is still difficult, despite the promotion of government policies and the awakening of social consciousness. In this article, we outlined the characteristics and obstacles of clinical trials of rare diseases in China and expected to provide reference for subsequent clinical trials in this field.ResultsIn recent years, China has made some progress in clinical trials of rare diseases in the past 10 years. There were 481 clinical trials on rare diseases in total, covering more than 10 rare diseases with high incidence. Clinical trial applications on rare diseases for a total of 481 were submitted and with an average annual growth rate of 28.2% from 2013 to 2022. The number of clinical trial application for rare diseases in 2016 dramatically increased by 80% compared to 2015 due to the policy document issued by China for clinical research in rare diseases in 2015. Besides, about 70% of applications registering for clinical trials could recruit subjects as expected. Despite this, the number of clinical trials of rare diseases in China was less compared with the United States, Europe and Japan, and the types of infant drugs were limited to biological products and chemical drugs lacking other new treatments.ConclusionsEfforts have been made in recent years to develop clinical research on rare diseases in China. The number of clinical trials for rare diseases in China was growing steadily every year, which was inseparable from the support of the country, society and rare disease patients. Still, there was a large gap between China and other developed countries in this field and this merit further investigation.
How to START? Four pillars to optimally begin your orphan drug developmentJonker, Anneliene Hechtelt; Batista, Liliana; Gabaldo, Michela; Hivert, Virginie; Ardigo, Diego; ,
doi: 10.1186/s13023-023-02845-9pmid: 37537670
Drug development is a complex, resource intensive and long process in any disease area, and developing medicines to treat rare diseases presents even more challenges due to the small patient populations, often limited disease knowledge, heterogeneous clinical manifestations, and disease progression. However, common to all drug development programs is the need to gather as much information as possible on both the disease and the patients’ needs ahead of the development path definition. Here, we propose a checklist named START, a tool that provides an overview of the key pillars to be considered when starting an orphan drug development: STakeholder mapping, Available information on the disease, Resources, and Target patient value profile. This tool helps to build solid foundations of a successful patient-centered medicines development program and guides different types of developers through a set of questions to ask for guidance through the starting phase of a rare disease therapeutic pathway.
Physicians’ use and perceptions of genetic testing for rare diseases in China: a nationwide cross-sectional studyLiu, Weida; Liu, Peng; Guo, Dan; Jin, Ye; Zhao, Kun; Zheng, Jiayin; Li, Kexin; Li, Linkang; Zhang, Shuyang
doi: 10.1186/s13023-023-02847-7pmid: 37563631
BackgroundGenetic testing can facilitate the diagnosis and subsequent therapeutic management of rare diseases. However, there is a lack of data on the use of genetic testing for rare diseases. This study aims to describe the utilization rate and troubles encountered by clinicians in treating rare diseases with genetic testing.MethodsA cross-sectional electronic questionnaire survey was conducted between June and October 2022 among the medical staff from the hospitals covering all provinces, municipalities, and autonomous regions of China. The survey on genetic testing focused on whether genetic testing was used in the diagnosis and treatment of rare diseases, the specific methods of genetic testing, and the problems encountered when using genetic testing.ResultsA total of 20,132 physicians who had treated rare diseases were included, of whom 35.5% were from the central region, 36.7% were from the eastern region, and 27.8% were from the western region. The total utilization rate of genetic testing for rare diseases was 76.0% (95%CI: 75.4–76.6). The use of genetic testing was highest in the Eastern region (79.2% [95% CI: 78.3–80.1]), followed by the Central (75.9% [95% CI: 74.9–76.9]) and Western regions (71.9% [95% CI: 70.7–73.1]). More than 90% (94.1% [95%CI: 93.4–94.8]) of pediatricians had used genetic testing to treat rare diseases, with surgeons having the lowest use of genetic testing (58.3% [95% CI: 56.6–60.0]). Physicians’ departments and education levels affect the use of genetic testing. Most physicians have used a variety of genetic tests in the management of rare diseases, the most popular methods were “Whole-exome sequencing (Proband)” and “Whole-exome sequencing (families of three or more)”. Doctors have encountered many problems with the use of genetic testing in the diagnosis and treatment of rare diseases, among which the high price was the main concern of medical workers.ConclusionThree-quarters of physicians used genetic testing in rare disease practice, and there were regional differences in the use of genetic testing. Recognition of the utilization of genetic testing can help identify patterns of resource utilization in different regions and provide a more comprehensive picture of the epidemiology of rare diseases in jurisdictions.