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The arduous challenge of seeking for biomarkers in rare diseases
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Sarcoidosis is a rare granulomatous disease that can affect any organ; as other chronic diseases, it leads to increased risk of atherosclerosis and cardiovascular (CV) disease. The aim of our observational study was to define a prognostic stratification model of sarcoidosis patients based on the evaluation of CV risk through common carotid Doppler ultrasound and cardiovascular risk scores assessment; for this reason, a clinical phenotyping of sarcoidosis patients in four subgroups was done, based on the different organ involvement. A cohort of 53 sarcoidosis patients and a cohort of 48 healthy volunteers were enrolled. Results showed that CV risk was higher in sarcoidosis cohort than in the control group when evaluated through CV risk scores and Doppler parameters: peak-systolic velocity (PSV) and end-diastolic velocity (EDV) were significantly lower in sarcoidosis cohort (p = 0.045 and p = 0.017, respectively), whereas intima media thickness (IMT) showed higher values in sarcoidosis group than in controls (p = 0.016). The analysis of sarcoidosis phenotypes showed no significative differences of CV risk among them when CV risk scores were considered, while partial differences emerged by evaluating subclinical atherosclerosis. Results also highlighted a relationship between CV risk score and carotid Doppler ultrasound parameters: EDV showed an inverse correlation with Framingham score (R = - 0.275, p = 0.004), whereas IMT showed a direct one (R = 0.429; p = 0.001); furthermore, an inverse correlation between PSV and EDV and illness duration (R = - 0.298, p = 0.030 and R = - 0.406, p = 0.002, respectively) was found, so suggesting a higher CV risk in patients with a longer story of disease.
Objective
Hereditary hemorrhagic telangiectasia (HHT) is an inherited disease associated with pathogenic variants in TGF-β signaling pathway-related genes, resulting in abnormal vascular development in various organs. Brain arteriovenous malformations (AVMs) may lead to intracranial hemorrhage, and brain abscess or ischemic stroke may result from right to left shunting via pulmonary AVMs. We aimed to investigate the risk for these severe complications in both adult and children HHT patients.
Methods
We conducted a case-control study among participants aged 1-64 years in the MarketScan® Commercial (2006-2019) and Multistate Medicaid Databases
(2011-2019). We identified cases with HHT using International Classification of Diseases diagnosis codes (ICD-9-CM 448.0, ICD-10-CM I78.0). Control patients without HHT coding were frequency matched 10:1 to HHT patients by age, duration of insurance enrollment, sex, and Medicaid status. Outcomes of interest (brain abscess, stroke and intracranial/subarachnoid hemorrhage) were identified using the appropriate ICD-9/10 diagnosis codes. We calculated incidence and standardized rates of the various outcomes and compared rate ratios (RR) between HHT cases and controls.
Results
5796 patients with HHT, of which 588 were children (age <16 years) were matched with 57,960 controls. There was increased incidence of brain abscesses in HHT cases compared with controls, with an RR of 35.6 (95% CI 15.4 – 82.5). No brain abscesses were recorded in children aged 15 years or less. Hemorrhagic strokes/subarachnoid hemorrhages were more common in HHT cases, with an RR of 4.01 (95% CI 2.8 to 5.7) in adults and 60.2 (95% CI 7.2 – 500.4) in children. Ischemic strokes were also more common in cases, with an RR of 3.7 (95% CI 3.0 – 4.5) in adults and 70.4 (95% CI 8.7– 572.3) in children.
Conclusion
We observed much higher incidence of severe CNS vascular complications in HHT patients, particularly in children. Though higher incidence of brain abscesses was noted in adult HHT patients, no brain abscesses were recorded in children, a result that may be considered when surveillance recommendations for this population are revisited.
Sarcoidosis is a chronic granulomatous disease that can virtually affect any organ. Its etiology is unknown, although it has been proposed that environmental or biological agents can act as triggers, ultimately leading to chronic inflammation in genetically predisposed individuals. The main component of sarcoid inflammation is represented by an exaggerated T- lymphocytic cellular response to a putative antigen that could not be efficiently cleared in the patient. However, several clinical and immunological observations, such as the association of sarcoidosis to autoimmune diseases or the presence of autoantibodies in the serum of patients with sarcoidosis, suggest that humoral-mediated immune response might also play a role in the pathogenesis of sarcoidosis. The aim of this review is to deepen the relationship between sarcoidosis and autoimmunity, by analyzing the most recent advances and proposing new fields of research.
There is no single global definition of a rare disease, and for different geographical areas the definition is based on the disease occurrence in that population [...]
There are more than 8000 rare diseases (RDs) that affect >5 % of the world’s population. Many of the RDs have no effective treatment and lack of knowledge creates delayed diagnosis making management difficult. The emerging concept of the personalized medicine allows for early screening, diagnosis, and individualized treatment of human diseases. In this context, the discovery of biomarkers in RDs will be of prime importance to enable timely prevention and effective treatment. Since 80 % of RDs are of genetic origin, identification of new genes and causative mutations become valuable biomarkers. Furthermore, dynamic markers such as expressed genes, metabolites, and proteins are also very important to follow prognosis and response the therapy. Recent advances in omics technologies and their use in combination can define pathophysiological pathways that can be drug targets. Biomarker discovery and their use in diagnosis in RDs is a major pillar in RD research.
Gaucher disease (GD) is the most common lysosomal storage disorder (LSD). Based on a deficient β-glucocerebrosidase it leads to an accumulation of glucosylceramide. Standard diagnostic procedures include measurement of enzyme activity, genetic testing as well as analysis of chitotriosidase and CCL18/PARC as biomarkers. Even though chitotriosidase is the most well-established biomarker in GD, it is not specific for GD. Furthermore, it may be false negative in a significant percentage of GD patients due to mutation. Additionally, chitotriosidase reflects the changes in the course of the disease belatedly. This further enhances the need for a reliable biomarker, especially for the monitoring of the disease and the impact of potential treatments.
Here, we evaluated the sensitivity and specificity of the previously reported biomarker Glucosylsphingosine with regard to different control groups (healthy control vs. GD carriers vs. other LSDs).
Only GD patients displayed elevated levels of Glucosylsphingosine higher than 12 ng/ml whereas the comparison controls groups revealed concentrations below the pathological cut-off, verifying the specificity of Glucosylsphingosine as a biomarker for GD. In addition, we evaluated the biomarker before and during enzyme replacement therapy (ERT) in 19 patients, demonstrating a decrease in Glucosylsphingosine over time with the most pronounced reduction within the first 6 months of ERT. Furthermore, our data reveals a correlation between the medical consequence of specific mutations and Glucosylsphingosine.
In summary, Glucosylsphingosine is a very promising, reliable and specific biomarker for GD.
The authors present the case of three patients from the same family in whom hereditary hemorrhagic telangiectasia (HHT) or Rendu-Osler-Weber syndrome was diagnosed. The disease is rare and occurs with multiple telangiectases of the skin and mucosa, and pulmonary arteriovenous fistulae. The clinical status of our patients included multiple telangiectases of the skin and mucosa, recurrent epistaxis, exertion dyspnea and cyanosis. Polycythemia and hypoxemia were observed in the blood. The clinical status and conventional radiological examination of the thoracic region, with the suspicion of arteriovenous (A-V) fistulae, pointed to HHT. A-V fistulae were confirmed by pulmonary angiography. The pulmonary A-V fistulae were operated in all three patients and diagnosis was confirmed by histopathological examination of the operated samples. Clinical improvement was observed after the operation and cyanosis, dyspnea, hypoxemia and polycythemia disappeared.
Biomarkers are new tools framed in precision and personalized medicine. Hereditary hemorrhagic telangiectasia (HHT) is a rare genetic vascular disease with disturbances in the angiogenic pathways. Descriptive evidence supports that some angiogenesis-related molecules are differently detected in HHT patients compared to healthy subjects. These molecules are also related to diagnosis, prognosis, complications and therapy monitoring in other common vascular diseases. Despite the need for improving knowledge before applying them in daily clinical practice, there are good candidates to be considered as potential biomarkers in HHT and other vascular diseases. In the present review, the authors aim to summarize and discuss current evidence regarding the main putative angiogenic biomarkers by describing the biological role of each biomarker, the evidence related to HHT and their potential use in this and other common vascular diseases from a clinical point-of-view.
Hereditary haemorrhagic telangiectasia (HHT) is a rare vascular multisystemic disease that leads to epistaxis, anaemia due to blood loss, and arteriovenous malformations (AVMs) in organs such as the lungs, liver and brain. HHT prevalence is estimated at 1/6000, i.e. around 85,000 European citizens, and is served by the European Reference Network for Rare Multisystemic Vascular Diseases (VASCERN). HHT treatments depend on clinical manifestations, and span multiple different medical, surgical and interventional disciplines. Separate to local treatments in the nose, in severe settings, intravenous bevacizumab has been proposed as treatment option, and the purpose of the current article is to assess the use of intravenous bevacizumab in patients with HHT in 2021 according to available data.
The levels of the health-related quality of life (HR-QoL) were analyzed in hereditary hemorrhagic telangiectasia (HHT) patients. The Short Form-36 Health Survey (SF-36) was administered to 50 HHT patients and scores were compared to a cohort of 2301 normal subjects. Clinical variables were patient age, illness duration, number of epistaxis episodes in the previous year and hemoglobin levels. Physical functioning, physical role limitations, bodily pain, social functioning, emotional role limitations and the physical component scores were lower among females. In multivariable analyses increasing age was related to lower physical functioning (p < 0.04), physical role limitations (p < 0.008), bodily pain (p < 0.05) and emotional role limitations (p < 0.01), while higher hemoglobin levels improved physical functioning (p < 0.03). The number of epistaxis episodes was negatively associated with physical role limitations (p < 0.009), vitality (p < 0.002), social functioning (p < 0.001), physical component summary (p < 0.001) and bodily pain (p < 0.01). Illness duration was negatively related to the mental component summary (p < 0.004). HHT patients had a lower HR-QoL with respect to normal controls in all domains except for bodily pain. Females had lower scores for several domains. Epistaxis was the most important clinical variable.
Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome)
- Shovlin