Cad Saude Publica. 2022 Jul 15;38(6):e00167721. doi: 10.1590/0102-311XPT167721. eCollection 2022.

ABSTRACT

Public policies that serve the Brazilian population with rare diseases are increasingly discussed, either regarding access to medicines, multidisciplinary care, therapeutic alternatives, or representativeness. Although the Brazilian Ministry of Health published in 2014 the Ordinance n. 199, which instituted the Brazilian National Policy of Integral Care for People with Rare Diseases and approving the Guidelines for Integral Care to People with Rare Diseases under the Brazilian Unified National Health System (SUS), this population remains unaided regarding the peculiarities of their treatments. In this scenario, patient associations began to seek spaces for political representation, increasingly provoking legislative initiatives in the Brazilian National Congress, seeking for alternatives for the millions of Brazilians living with rare diseases. By using a qualitative documentary research, the study considers all projects presented until August 2020 on this topic, identifying the main parliamentarians involved, their biographical characteristics, and at which stage of the public policy cycle this topic is in the Brazilian National Congress; thus, identifying a possible path for the consolidation of a policy. We observed that the actions regarding rare diseases are independent of any political party alignment, being an agenda shared by antagonistic groups. This agenda, however, faces the challenge of having only 18 parliamentarians responsible for 50% of all the legislative matters already presented. Furthermore, we also observed that parliamentarians prefer to boost the debate and give visibility to the subject than to invest in new attempts at legal and regulatory changes.

PMID:35857920 | DOI:10.1590/0102-311XPT167721

Mol Genet Metab. 2022 Aug;136(4):289-295. doi: 10.1016/j.ymgme.2022.07.006. Epub 2022 Jul 8.

ABSTRACT

RNA-based therapies are a new, rapidly growing class of drugs that until a few years ago were being used mainly in research in rare diseases. However, the clinical efficacy of recently approved oligonucleotide drugs and the massive success of COVID-19 RNA vaccines has boosted the interest in this type of molecules of both scientists and industry, as wells as of the lay public. RNA drugs are easy to design and cost effective, with greatly improved pharmacokinetic properties thanks to progress in oligonucleotide chemistry over the years. Depending on the type of strategy employed, RNA therapies offer the versatility to replace, supplement, correct, suppress, or eliminate the expression of a targeted gene. Currently, there are more than a dozen RNA-based drugs approved for clinical use, including some for specific inborn errors of metabolism (IEM), and many other in different stages of development. New initiatives in n-of-1 RNA drug development offer new hope for patients with rare diseases and/or ultra-rare mutations. RNA-based therapeutics include antisense oligonucleotides, aptamers, small interfering RNAs, small activating RNAs, microRNAs, lncRNAs and messenger RNAs. Further research and collaborations in the fields of chemistry, biology and medicine will help to overcome major challenges in their delivery to target tissues. Herein, we review the mechanism of action of the different therapeutic approaches using RNA drugs, focusing on those approved or in clinical trials to treat IEM.

PMID:35849888 | PMC:PMC9264812 | DOI:10.1016/j.ymgme.2022.07.006

Orphanet J Rare Dis. 2022 Jul 19;17(1):281. doi: 10.1186/s13023-022-02426-2.

ABSTRACT

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) disease is a rare genetic disorder with symptoms and complications that can significantly affect patients' daily lives. To date, no scale has been validated to assess the specific symptoms of this disease on the quality of life (QOL) of HHT patients. This makes it difficult for clinicians to accurately measure the quality of life of patients with HHT. The present study aims to develop and validate a QOL measurement tool specific to HHT disease: the QOL questionnaire in HHT (QoL-HHT).

METHODS: A quantitative, non-interventional, multi-center study involving HHT patients in twenty French HHT expert centers was conducted. A calibration sample of 415 HHT patients and a validation sample of 228 HHT patients voluntarily participated in the study. Data were analyzed using exploratory factor analysis (EFA), confirmatory factor analysis (CFA), Exploratory Structural Equation Modeling (ESEM) analyses, reliability analyses, and correlational analyses.

RESULTS: The EFA, CFA and ESEM results allowed us to provide evidence of the factorial structure of a questionnaire composed of 24 items measuring 6 domains of QOL: Physical limitations, social relationships, concern about bleeding, relationship with the medical profession, experience of symptoms, and concern about the evolution of the disease. Cronbach's alpha coefficients (> 0.70) demonstrated reliable internal consistency of all the QoL-HHT scores (dimensions). The results of the test-retest provided further evidence of the reliability of the QOL-HHT scores over time. Correlational analyses provided evidence for the convergent validity of the QoL-HHT scores.

CONCLUSIONS: We developed a simple and quick self-assessment tool to measure quality of life specific to HHT disease. This study demonstrated reliability and validity of our QoL-HHT scores. It is a very promising tool to evaluate the impact of HHT disease on all aspects of the quality of life of HHT patients in order to offer them individualized medico-psycho-social support.

TRIAL REGISTRATION: ClinicalTrials, NCT03695874. Registered 04 October 2018, https://www.

CLINICALTRIALS: gov/ct2/show/NCT03695874.

PMID:35854330 | DOI:10.1186/s13023-022-02426-2

Recenti Prog Med. 2022 Jul-Aug;113(7):451-459. doi: 10.1701/3850.38340.

ABSTRACT

INTRODUCTION: Rare diseases have a high social and health impact. Since 2005, AIFA has been funding independent clinical research. The objective of this paper is to describe data on independent research on rare diseases financed by the Agency.

METHODS: With reference to studies financed by AIFA between 2005-2018 the following data have been collected: financial characteristics, study design, therapeutic area, population included, completion status, availability of study results publications, publication characteristics and conclusions. Data have been analyzed in order to provide information on characteristics and scientific productivity of clinical studies on rare diseases.

RESULTS: Between 2005 and 2018, AIFA published 9 Calls for Funding of Independent Research and financed 282 clinical studies, 111 (about 40%) of which were on a rare disease and/or a rare tumor for a total of € 43,455,438. Studies were interventistic in 93.6% (mainly phase II or III). The most represented therapeutic area was oncology (19.9%), followed by neurology (17.1%), and onco-hematology (16.2%). 28.8% of clinical studies enrolled fragile population (children, elderly, pregnant women). Fourty eight studies (43.2%) completed according to protocol, 8 (7.2%) completed with reduced sample size, 18 (16.2%) were prematurely terminated, while 37 of them are still ongoing. In the subgroup of 74 closed studies at least a scientific publication is available for 49 of them. A total of 81 papers are available including two publications related to ongoing studies (range 1-8; mean 1.5; median 1). Cumulative Impact Factor is 619.269 (range for single paper 0.17-34.492).

DISCUSSION: A good percentage of clinical studies financed by AIFA were on rare diseases and/or rare tumors. Clinical trials were less likely to complete according to protocol than observational ones, in agreement with literature data; on the other hand once completed, clinical trials were more likely to publish research findings. Overall, 66.2% of closed studies has at least one publication; this percentage is higher if we consider the subgroup of clinical trials and if we consider clinical trials completed according to study protocol (95.3%).

PMID:35852081 | DOI:10.1701/3850.38340

Recenti Prog Med. 2022 Jul-Aug;113(7):440-450. doi: 10.1701/3850.38339.

ABSTRACT

INTRODUCTION: Rare disease (RD) patients present complex therapeutic needs. When there are therapeutic options available, orphan drugs (OD) represent only a limited proportion of prescribed treatments. This study aims at investigating the real-world use of treatments considered not replaceable and essential for the care of RD patients, besides their reimbursement status, using data from a RD population-based registry.

METHODS: The study is based on data derived from the Veneto region RD registry. For the period 2019-2020, we have analyzed the prescriptions of treatments defined as essential and not replaceable, besides their reimbursement status, included in therapeutic plans issued by RD expert Centres for patients resident in the Veneto region (north-east of Italy, 4.9 million inh.). The correspondent pharmaceutical costs have been estimated as well.

RESULTS: In the study period there have been 22.186 prescriptions, included in 9,197 therapeutic plans issued for RD patients resident in the monitored area. The plans present a high level of complexity in terms of number and type of prescribed treatments, with 11% of the plans containing 5 or more prescriptions. 3,041 medicinal products have been prescribed in the study period, of whom 41% are drugs. Although these prescriptions are distributed among all the groups of RD patients, only a limited proportion of products (n=10) is responsible of the 50% of all the costs attributable to these treatments. Overall, the annual cost attributable to essential treatments not directly reimbursed by the national health system is quantifiable in 1 million euros per million inhabitants.

CONCLUSIONS: This real-world study offers a snapshot of the complexity of treatments defined as essential, besides their reimbursement status, in therapeutic plans issued by RD expert Centres for a consistent group of RD patients monitored by a population-based registry. It highlights the complexity of the therapeutic approaches put in place for the care of RD patients, including drugs and a variety of other treatments. Population-based registries collecting data on prescribed treatments can contribute to understand the therapeutic needs of RD patients, treatments' accessibility and the impact of prescriptions on the global pharmaceutical costs.

PMID:35852080 | DOI:10.1701/3850.38339

Recenti Prog Med. 2022 Jul-Aug;113(7):430-433. doi: 10.1701/3850.38337.

ABSTRACT

Rare cancers are malignant tumors with an incidence lower than 6/100,000/year at the EU level. Even if more conservative in comparison to the definition used for rare diseases (also from the regulatory point of view), rare cancers defined this way make up more than twenty percent of new cases of malignant tumors in the EU, including Italy. The rarity of a tumor implies that clinical decision-making is more problematic outside reference centers and networks, that available evidence suffers from a higher uncertainty, that organization of health care is more difficult. In 2019, a Joint Action on rare cancers launched by the European Union, run in parallel to a Joint Action on rare diseases, worked out ten categories of recommendations, among which some on the methodology of clinical research and regulatory aspects. In general, it stressed the value of collaborative clinical networks (at the EU level and, more importantly, nationally) around centers of expertise. Working according to a "hub-and-spoke" logic, these networks can improve quality of care while rationalizing health migration. Regarding the regulatory aspects and more in general to the definition of the state of art, in rare cancers the magnitude of clinical benefit should be the same as for common conditions, but the quality of evidence should be accepted to be less stringent in terms of statistical precision. Otherwise, rare cancer patients would be discriminated against in their access to innovative diagnostic and therapeutic options, even when available. Specifically, orphan drugs can suffer from lower interest of pharmaceutical industry. This justifies some privileges they are granted, among which the 10-year market exclusivity is crucial. However, a critical aspect is the perception of the regulatory risk by the industry. This problem could be limited by closer cooperation between regulatory bodies and rare cancer communities and by flexible regulatory mechanisms, in particular in partnership with clinical networks. In Italy, more constructive interpretations of the rules about the compassionate use of drugs, an even application of Law 648 and the future implementation of the new Law on Rare Diseases could help. In general, refining the methodology of clinical research in small samples would be fundamental.

PMID:35852078 | DOI:10.1701/3850.38337

Recenti Prog Med. 2022 Jul-Aug;113(7):425-429. doi: 10.1701/3850.38336.

ABSTRACT

In Europe, diseases are defined as "rare" when they have a prevalence of less than 0.05% in the general population. When available, drugs used to treat such diseases often fall into the category of orphan drugs, i.e. drugs used for the diagnosis, prevention and treatment of rare diseases. Generating evidence about the efficacy and safety of orphan drugs in the pre-marketing phase is challenging due to critical issues related to the rarity of these diseases. This highlights the need to generate robust post-marketing evidence to fill the evidence gap in the pre-marketing phase, with the aim to more accurately define the benefit-risk profile and the cost-effectiveness of orphan drugs in the real-world setting. Real-world data (i.e., the data relating to patient health status and/or the delivery of health care routinely collected from a variety of sources) has significantly increased over the last years and their use is increasingly proposed, including by regulatory agencies, to generate evidence to support the regulatory authorization processes of orphan drugs and to study rare diseases. In this article, the authors describe the main sources of real-world data and their role to support the regulatory authorization processes of orphan drugs.

PMID:35852077 | DOI:10.1701/3850.38336

Recenti Prog Med. 2022 Jul-Aug;113(7):415-424. doi: 10.1701/3850.38335.

ABSTRACT

INTRODUCTION: In the last decades, the development of drugs for rare diseases has been supported by regulatory and financial incentives. On the other hand, public health policies have increasingly taken into account the person affected by a rare disease in their strategies. In this perspective, we examined the relation between the regulatory framework on rare diseases and the regulatory framework on drug approval. Technical proposals have been brought forward to protect the needs of individuals.

RESULTS: The legislative framework on rare diseases has developed both at a European and national level with the aim to strengthen the network of centers for diagnosis and care by increasing the degree of social and health protection, as well as to accelerate the assessment, approval and access to new drugs. Since 2000, 210 orphan drugs have been approved by the European Medicines Agency (EMA) (compared to an estimated 7-8,000 rare diseases). Of the 118 orphan drugs active in the community register as of 2020, 97 (82.2%) were available in Italy: 17 (17.5%) in class A; 58 (59.8%) in class H; 12 (12.4%) in class C; 10 (10.3%) in class C-nn. In 2020, expenditure on drugs with an orphan indication accounted for 6% of the total pharmaceutical expenditure (+47% since 2016). These drugs have benefited from incentives at both European and national levels, as well as inclusion in national early access programs. However, the average duration of the assessment process is above the 100-day limit set by law.

DISCUSSION: The legislation on rare diseases has developed in different directions, and drug legislation has undoubtedly played a major role in terms of the results achieved. However, orphan drugs enter the market with a high price, which increasingly represents a problem of sustainability for health systems but notwithstanding Italy shows a high ratio between the level of social protection and access times. In this perspective, it is necessary to be provided with tools for a better system balance with a view to optimize these timeframes. Introducing in Italy a system for tracking the negotiation process that considers the clock stops as the EMA does, would allow to know at what point the negotiation process is. In addition, once the 100-day period is over (net of any clock stops) and in case of failure to reach a negotiation agreement, a second 60-day negotiation round could be proposed and so on. In this way, all the parts involved the system would have a clear scope of action to conclude the process in a flexible but certain timeframe. In this regard, the joint clinical assessments foreseen by the new HTA Regulations provide an additional opportunity to harmonize central decisions with national requirements.

PMID:35852076 | DOI:10.1701/3850.38335

Recenti Prog Med. 2022 Jul-Aug;113(7):411-414. doi: 10.1701/3850.38334.

ABSTRACT

Rare diseases represent a numerous (more than 30 million patients throughout Europe), diverse (more than 6000 disease ascertained), and complex group of genetic, metabolic, neurologic, congenital and other type of disorders presenting both in pediatric and adult age. Research, education and care are the mainstay of the national rare disease plans of the member states, including Italy. Early diagnosis and multidisciplinary care, particularly in severe or progressive disorder, are mandatory to treat disorders (when a specific treatment is available) and/or avoid life-threatening complications. According to the catchphrase "you can only diagnose what you know", it is intuitive how important is education and the "culture of suspect" in rare disease. In the last decade, a pre- and post-graduate academic planning on rare disease have been set up in Italy, with the aim to be comprehensive and up-to-date with the literature, traversal to both general physicians and all the specialties, longitudinal during all the study courses.

PMID:35852075 | DOI:10.1701/3850.38334

Recenti Prog Med. 2022 Jul-Aug;113(7):407-410. doi: 10.1701/3850.38333.

ABSTRACT

In the past few decades, the regulatory system has changed its approach to speed up the assessment and approval of drugs for the treatment of serious and orphan diseases. However, too early assessments may fail to provide solid evidence to define the therapeutic value of drugs and their fair price. As for rare diseases, patients' expectations amplify such criticalities due to the lack of therapeutic alternatives. The revision of the EU regulation on orphan medicinal products represents an opportunity to promote greater integration between the development and approval of drugs with their subsequent access. For this reason, we propose: 1) establishing a process for evaluating the comparative efficacy and quantification of the therapeutic benefit of a drug at a European level, while addressing incentives towards rarer diseases to support their development and marketing; 2) downsizing the impact of orphan drugs on general sustainability, considering that incentives supporting their development and marketing cannot transform them into new 'blockbusters'. In this perspective, a European procurement - initially intended for drugs for ultra-rare diseases - could improve access by all EU countries through simplifying the burdensome procedures for the pharmaceutical industry; 3) enhancing the contribution of post-authorization research from a public-private partnership perspective to steer the development of drugs already approved towards rarer pathologies or mutations of little commercial interest.

PMID:35852074 | DOI:10.1701/3850.38333

Physiol Rep. 2022 Jul;10(14):e15362. doi: 10.14814/phy2.15362.

ABSTRACT

SLC26A4/Pendrin is the major electroneutral Cl- /HCO3 - exchanger of the apical membrane of the Type B intercalated cell (IC) of the connecting segment (CNT) and cortical collecting duct (CCD). Pendrin mediates both base secretion in response to systemic base load and Cl- reabsorption in response to systemic volume depletion, manifested as decreased nephron salt and water delivery to the distal nephron. Pendrin-mediated Cl- /HCO3 - exchange in the apical membrane is upregulated through stimulation of the β-IC apical membrane G protein-coupled receptor, 2-oxoglutarate receptor 1 (OXGR1/GPR99), by its ligand α-ketoglutarate (αKG). αKG is both filtered by the glomerulus and lumenally secreted by proximal tubule apical membrane organic anion transporters (OATs). OXGR1-mediated regulation of Pendrin by αKG has been documented in transgenic mice and in isolated perfused CCD. However, aspects of the OXGR1 signaling pathway have remained little investigated since its original discovery in lymphocytes. Moreover, no ex vivo cellular system has been reported in which to study the OXGR1 signaling pathway of Type B-IC, a cell type refractory to survival in culture in its differentiated state. As Xenopus oocytes express robust heterologous Pendrin activity, we investigated OXGR1 regulation of Pendrin in oocytes. Despite functional expression of OXGR1 in oocytes, co-expression of Pendrin and OXGR1 failed to exhibit αKG-sensitive stimulation of Pendrin-mediated Cl- /anion exchange under a wide range of conditions. We conclude that Xenopus oocytes lack one or more essential molecular components or physical conditions required for OXGR1 to regulate Pendrin activity.

PMID:35851763 | DOI:10.14814/phy2.15362

Neurology. 2022 Jul 18:10.1212/WNL.0000000000200927. doi: 10.1212/WNL.0000000000200927. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVES: ATP1A3 is associated with a broad spectrum of predominantly neurological disorders, that continues to expand beyond the initially defined phenotypes of Alternating Hemiplegia of Childhood (AHC), Rapid-onset Dystonia Parkinsonism (RDP) and Cerebellar ataxia, Areflexia, Pes cavus, Optic atrophy, Sensorineural hearing loss syndrome (CAPOS). This phenotypic variability makes it challenging to assess pathogenicity of an ATP1A3 variant found in an undiagnosed patient. We describe the phenotypic features of individuals carrying a pathogenic/likely pathogenic ATP1A3 variant and perform a literature review of all ATP1A3 variants published thus far in association with human neurological disease. Our aim is to demonstrate the heterogeneous clinical spectrum of the gene and look for phenotypic overlap between patients that will streamline the diagnostic process.

METHODS: Undiagnosed individuals with ATP1A3 variants were identified within the cohort of the Deciphering Developmental Disorders (DDD) study with additional cases contributed by collaborators internationally. Detailed clinical data was collected with consent through a questionnaire completed by the referring clinicians. PubMed was searched for publications containing the term "ATP1A3" from 2004 to 2021.

RESULTS: Twenty-four individuals with a previously undiagnosed neurological phenotype were found to carry 21 ATP1A3 variants. Eight variants have been previously published. Patients experienced on average 2-3 different types of paroxysmal events. Permanent neurological features were common including microcephaly (7;29%), ataxia (13;54%), dystonia (10;42%) and hypotonia (7;29%). All patients had cognitive impairment. Neuropsychiatric diagnoses were reported in 16 (66.6%) individuals. Phenotypes were extremely varied and most individuals did not fit clinical criteria for previously published phenotypes.On review of the literature, 1108 individuals have been reported carrying 168 different ATP1A3 variants. The most common variants are associated with well-defined phenotypes, while more rare variants often result in very rare symptom correlations, such as are seen in our study.CADD scores of pathogenic and likely pathogenic variants were significantly higher and variants clustered within six regions of constraint.

CONCLUSION: Our study shows that looking for a combination of paroxysmal events, hyperkinesia, neuropsychiatric symptoms, and cognitive impairment, as well as evaluating CADD score and variant location can help identify an ATP1A3-related condition, rather than applying diagnostic criteria alone.

PMID:35851257 | DOI:10.1212/WNL.0000000000200927

Front Endocrinol (Lausanne). 2022 Jun 30;13:905963. doi: 10.3389/fendo.2022.905963. eCollection 2022.

ABSTRACT

BACKGROUND: Multiple endocrine neoplasia type 2A (MEN2A) is a rare syndrome that presents as medullary thyroid carcinoma, pheochromocytoma, and hyperparathyroidism. Experience is lacking in the anesthetic management of patients with this syndrome, particularly in those who present with pheochromocytoma receiving nonpheochromocytoma resection. We aimed to share our experience with the anesthetic management of MEN2A patients.

METHOD: We retrospectively enrolled 24 MEN2A patients who had received different types of surgery at Peking Union Medical College Hospital from January 1, 2015, to December 31, 2021. All the medical records were reviewed and analyzed.

RESULT: In total, 33 surgeries were performed in 24 MEN2A patients, with 20 surgeries comprising pheochromocytoma resection in 17 patients. Most of these patients who had received pheochromocytoma resection had typical hemodynamic changes during surgery and anesthesia. Regarding the other 13 nonpheochromocytoma resections in 13 patients, 10 were performed in patients without pheochromocytoma, and 3 surgeries were performed with either functional primary (1, bilateral tumor whose patient refused adrenalectomy) or metastatic pheochromocytoma (2, unresectable and malign tumors developed years after bilateral adrenalectomy). Regarding the latter 3 patients, 1 showed hypertension and tachycardia during anesthesia induction, 1 showed tachycardia during surgery and the other showed stability during surgery. Patients who had received pheochromocytoma resection (n=17) required longer postoperative hospital stays than those who had received nonpheochromocytoma resection without pheochromocytoma (n=10) (5.8 ± 1.8 vs. 4.3 ± 1.6; P = 0.031).

CONCLUSIONS: Whenever MEN2A patients are diagnosed with pheochromocytoma, surgical resection of the pheochromocytoma remains the primary choice for MEN2A treatment. Nonpheochromocytoma surgeries performed with existing pheochromocytoma could be risky and require full caution and preparation.

PMID:35846296 | PMC:PMC9279605 | DOI:10.3389/fendo.2022.905963

Acta Neuropathol. 2022 Jul 17. doi: 10.1007/s00401-022-02468-7. Online ahead of print.

ABSTRACT

X-linked myotubular myopathy (XLMTM) is a fatal neuromuscular disorder caused by loss of function mutations in MTM1. At present, there are no directed therapies for XLMTM, and incomplete understanding of disease pathomechanisms. To address these knowledge gaps, we performed a drug screen in mtm1 mutant zebrafish and identified four positive hits, including valproic acid, which functions as a potent suppressor of the mtm1 zebrafish phenotype via HDAC inhibition. We translated these findings to a mouse XLMTM model, and showed that valproic acid ameliorates the murine phenotype. These observations led us to interrogate the epigenome in Mtm1 knockout mice; we found increased DNA methylation, which is normalized with valproic acid, and likely mediated through aberrant 1-carbon metabolism. Finally, we made the unexpected observation that XLMTM patients share a distinct DNA methylation signature, suggesting that epigenetic alteration is a conserved disease feature amenable to therapeutic intervention.

PMID:35844027 | DOI:10.1007/s00401-022-02468-7

Pharmacol Res. 2022 Aug;182:106349. doi: 10.1016/j.phrs.2022.106349. Epub 2022 Jul 12.

ABSTRACT

Rare diseases refer to diseases with very low prevalence. Along with the support of national policies and improvement of research capability, a new landscape for orphan drug is emerging in China. To identity unmet clinical needs and provide insight on the development of orphan drugs, we reviewed the changes over time of orphan drug clinical trials in China from 2012 to 2022. A total of 261 trials of 40 drugs were initiated, of which 66.3% trials were sponsored by Chinese local pharmaceutical enterprises. Among the 261 trials, chemical drugs (about 63.6%) and biological products (35.6%) account for the high proportions, and traditional Chinese medicine (0.8%) was the least; the indications mainly focused on homozygous hypercholesterolemia, hemophilia, multiple sclerosis and idiopathic pulmonary fibrosis; single-arm study design was applied to 50% of the clinical trials, with an average sample size of 52 participants. Additionally, totally 122 trials were completed by January 2022, of which the average duration time was 15.7 months for new drug and 3.5 months for generic drug, respectively. The trends over time illustrated that remarkable progress has been achieved in development of orphan drugs in China since 2012. Given the large patient pool and the rising capability of innovation, it is believed that China will contribute more to the global drug pipelines for rare diseases.

PMID:35835367 | DOI:10.1016/j.phrs.2022.106349

BMJ Case Rep. 2022 Jul 14;15(7):e248575. doi: 10.1136/bcr-2021-248575.

ABSTRACT

Benign metastasising leiomyoma (BML) is a rare tumour characterised by extrauterine metastasis of histologically benign leiomyomas. We present a case of BML with pulmonary involvement. A 49-year-old woman presented with large pelviabdominal masses complicated by gross abdominal and lower limb swelling 6 years following open myomectomy. Preoperative CT imaging showed pelviabdominal masses and multiple bilateral pulmonary nodules. Initial impression was that of a stage 4 gynaecological malignancy. Palliative total hysterectomy bilateral salpingo-oophorectomy was performed. Histopathology confirmed benign uterine leiomyomas. Biopsy of pulmonary nodules showed benign leiomyomas, strongly positive for oestrogen and progesterone receptors. Definitive diagnosis of BML was made on histopathology and immunohistochemistry. The patient declined letrozole treatment as she had just undergone bilateral oophorectomy. She opted for conservative monitoring of her lung nodules. CT imaging 7 months postsurgery showed disease regression. She will require long-term surveillance scans to detect disease progression.

PMID:35835485 | DOI:10.1136/bcr-2021-248575

Transl Vis Sci Technol. 2022 Jul 8;11(7):7. doi: 10.1167/tvst.11.7.7.

ABSTRACT

PURPOSE: To test a model of retinal nerve fiber bundle trajectories that predicts the arcuate-shaped patterns seen on optical coherence tomography (OCT) retinal nerve fiber layer (RNFL) probability/deviation maps (p-maps) in glaucomatous eyes.

METHODS: Thirty-one glaucomatous eyes from a database of 250 eyes had clear arcuate-shaped patterns on RNFL p-maps derived from an OCT cube scan. The borders of the arcuate patterns were extracted from the RNFL p-maps. Next, the trajectories from an arcuate model were compared against these borders via a normalized root-mean-square difference analysis. The model's parameter, β, was varied, and the best-fitting, initial clock-hour position of the trajectory to the border was found for each β. Finally, the regions, as determined by the arcuate border's best-fit, initial clock-hour positions, were compared against the abnormal regions on the circumpapillary retinal nerve fiber layer (cpRNFL) profile.

RESULTS: The arcuate model's mean βSup and βInf parameters minimized large differences between the trajectories and the arcuate borders on the RNFL p-maps. Furthermore, on average, 68% of the cpRNFL regions defined by the arcuate border's best-fit, initial clock-hour positions were abnormal (i.e., below the ≤5% threshold).

CONCLUSIONS: The arcuate model performed well in predicting the borders of arcuate patterns seen on RNFL p-maps. It also predicted the associated abnormal regions of the cpRNFL thickness plots.

TRANSLATIONAL RELEVANCE: This model should prove useful in helping clinicians understand topographical comparisons among different OCT representations and should improve structure-structure, as well as structure-function agreement analyses.

PMID:35819291 | DOI:10.1167/tvst.11.7.7

J Thorac Dis. 2022 Jun;14(6):1815-1829. doi: 10.21037/jtd-21-1523.

ABSTRACT

BACKGROUND: Aortic diseases in some orphan rheumatological diseases require medical, surgical or peripheral endovascular intervention because they can be catastrophic. Objectives: to analyze the main clinical and epidemiological characteristics of patients with Takayasu arteritis (TA), Marfan syndrome (MS) and similar conditions that were treated with cardiothoracic surgery and peripheral endovascular intervention.

METHODS: Retrospective and descriptive cohort study that included patients of any age and gender with TA (as per the criteria of the American College of Rheumatology and EULAR/PRINTO), MS (according to Ghent criteria), and similar conditions who underwent cardiothoracic surgery or peripheral endovascular intervention. Data were collected from electronic charts.

RESULTS: A total of 77 patients with TA and 135 patients with MS and similar conditions were included. The frequency of surgical or interventional requirements in patients with TA and MS/similar conditions was 77/364 (21.2%) and 135/300 (45%), respectively; such patients were followed for a median of 6 [2-12] and 3.29 (0.42-6.62) years, with (maximum follow-up range of 47 and 21.37 years, respectively). Aneurysms were present in 11 (14.3%) and 66 (48.9%) in patients with TA and MS/similar conditions, respectively. Aortic, mitral and tricuspid valve damage occurred in 8 (10.4%) patients, 4 (5.2%) patients and 1 (1.3%) patient with TA, respectively; corresponding frequencies in patients with MS/similar conditions were 98 (72.6%), 50 (37.0%) and 20 (14.8%). We identified that 20% of patients with TA died after 5.08 years (95% CI: 0.23-25.42 years) and 20 % of the patients with MS and other similar conditions died after 7.52 years (95% CI: 1.10-9.02 years).

CONCLUSIONS: The frequency of surgical intervention was low in this study. Long-term prognosis is good if surgery is performed in a timely manner. Epidemiological studies provide relevant information for public health decisions related to the management of orphan rheumatological diseases.

PMID:35813724 | PMC:PMC9264075 | DOI:10.21037/jtd-21-1523

Chest. 2022 Jul;162(1):e49-e52. doi: 10.1016/j.chest.2022.01.066.

ABSTRACT

A 29-year-old woman without history of cardiac disease or risk factors sought treatment for sudden onset of chest pain radiating down the back, jaw, and arms, complicated by discomfort in the orthostatic position and severe headache. She had a history of epistaxis since childhood as well as familial history of epistaxis via her mother. BMI was 22 kg/m2, and electrocardiography showed ST segment depression in V1V2 precordial leads and T-wave inversion in inferior leads. Troponin was elevated at 3,700 ng/L (normal, < 34 ng/L), with a peak of 11,115 ng/L.

PMID:35809950 | DOI:10.1016/j.chest.2022.01.066

J Hand Surg Asian Pac Vol. 2022 Jun;27(3):565-569. doi: 10.1142/S2424835522720249.

ABSTRACT

A limitation of finger extension resulting from scarring of the juncturae tendinum (JT) is a rare condition. We report a patient with limitation in active extension of the metacarpophalangeal joint (MCPJ) of the ring finger due to a scarred JT in a 37-year-old man. Surgical exploration showed a hard, fixed and scarred JT in the third intermetacarpal space. After resection of the scarred JT, the patient achieved full range of active extension of the ring finger MCPJ. Scarring of the JT may decrease excursion of the extensor digitorum communis and must be considered as one of the differentials in patients with limitation in MCPJ extension. Level of Evidence: Level V (Therapeutic).

PMID:35808878 | DOI:10.1142/S2424835522720249