Anti-angiogenic effects of biotechnological therapies in rheumatic diseases

Introduction: Angiogenesis plays a key role in the pathogenesis of numerous rheumatic diseases, such as rheumatoid arthritis, psoriatic arthritis, and vasculitides. Therefore, the inhibition of pathological angiogenesis may be considered a useful therapeutical approach in these rheumatic diseases. Methods: This review article is based on a literature research about the role of biotechnological therapies in angiogenesis inhibition. Results and conclusions: Several evidences have demonstrated a role for biotechnological therapies in angiogenesis inhibition. Nevertheless, further research and clinical trials are needed to better quantify the real impact of biotechnological therapies on pathological angiogenesis

Risk factors associated with adverse fetal outcomes in pregnancies affected by Coronavirus disease 2019 (COVID-19): a secondary analysis of the WAPM study on COVID-19.

Objectives To evaluate the strength of association between maternal and pregnancy characteristics and the risk of adverse perinatal outcomes in pregnancies with laboratory confirmed COVID-19. Methods Secondary analysis of a multinational, cohort study on all consecutive pregnant women with laboratory-confirmed COVID-19 from February 1, 2020 to April 30, 2020 from 73 centers from 22 different countries. A confirmed case of COVID-19 was defined as a positive result on real-time reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay of nasal and pharyngeal swab specimens. The primary outcome was a composite adverse fetal outcome, defined as the presence of either abortion (pregnancy loss before 22 weeks of gestations), stillbirth (intrauterine fetal death after 22 weeks of gestation), neonatal death (death of a live-born infant within the first 28 days of life), and perinatal death (either stillbirth or neonatal death). Logistic regression analysis was performed to evaluate parameters independently associated with the primary outcome. Logistic regression was reported as odds ratio (OR) with 95% confidence interval (CI). Results Mean gestational age at diagnosis was 30.6+/-9.5 weeks, with 8.0% of women being diagnosed in the first, 22.2% in the second and 69.8% in the third trimester of pregnancy. There were six miscarriage (2.3%), six intrauterine device (IUD) (2.3) and 5 (2.0%) neonatal deaths, with an overall rate of perinatal death of 4.2% (11/265), thus resulting into 17 cases experiencing and 226 not experiencing composite adverse fetal outcome. Neither stillbirths nor neonatal deaths had congenital anomalies found at antenatal or postnatal evaluation. Furthermore, none of the cases experiencing IUD had signs of impending demise at arterial or venous Doppler. Neonatal deaths were all considered as prematurity-related adverse events. Of the 250 live-born neonates, one (0.4%) was found positive at RT-PCR pharyngeal swabs performed after delivery. The mother was tested positive during the third trimester of pregnancy. The newborn was asymptomatic and had negative RT-PCR test after 14 days of life. At logistic regression analysis, gestational age at diagnosis (OR: 0.85, 95% CI 0.8-0.9 per week increase; pPeer reviewe

Perinatal and 2-year neurodevelopmental outcome in late preterm fetal compromise: the TRUFFLE 2 randomised trial protocol

Introduction: Following the detection of fetal growth restriction, there is no consensus about the criteria that should trigger delivery in the late preterm period. The consequences of inappropriate early or late delivery are potentially important yet practice varies widely around the world, with abnormal findings from fetal heart rate monitoring invariably leading to delivery. Indices derived from fetal cerebral Doppler examination may guide such decisions although there are few studies in this area. We propose a randomised, controlled trial to establish the optimum method of timing delivery between 32 weeks and 36 weeks 6 days of gestation. We hypothesise that delivery on evidence of cerebral blood flow redistribution reduces a composite of perinatal poor outcome, death and short-term hypoxia-related morbidity, with no worsening of neurodevelopmental outcome at 2 years. Methods and analysis: Women with non-anomalous singleton pregnancies 32+0 to 36+6 weeks of gestation in whom the estimated fetal weight or abdominal circumference is <10th percentile or has decreased by 50 percentiles since 18-32 weeks will be included for observational data collection. Participants will be randomised if cerebral blood flow redistribution is identified, based on umbilical to middle cerebral artery pulsatility index ratio values. Computerised cardiotocography (cCTG) must show normal fetal heart rate short term variation (≥4.5 msec) and absence of decelerations at randomisation. Randomisation will be 1:1 to immediate delivery or delayed delivery (based on cCTG abnormalities or other worsening fetal condition). The primary outcome is poor condition at birth and/or fetal or neonatal death and/or major neonatal morbidity, the secondary non-inferiority outcome is 2-year infant general health and neurodevelopmental outcome based on the Parent Report of Children's Abilities-Revised questionnaire. Ethics and dissemination: The Study Coordination Centre has obtained approval from London-Riverside Research Ethics Committee (REC) and Health Regulatory Authority (HRA). Publication will be in line with NIHR Open Access policy. Trial registration number: Main sponsor: Imperial College London, Reference: 19QC5491. Funders: NIHR HTA, Reference: 127 976. Study coordination centre: Imperial College Healthcare NHS Trust, Du Cane Road, London, W12 0HS with Centre for Trials Research, College of Biomedical & Life Sciences, Cardiff University. IRAS Project ID: 266 400. REC reference: 20/LO/0031. ISRCTN registry: 76 016 200

Role of prenatal magnetic resonance imaging in fetuses with isolated mild or moderate ventriculomegaly in the era of neurosonography: international multicenter study

Objectives To assess the role of fetal magnetic resonance imaging (MRI) in detecting associated anomalies in fetuses presenting with mild or moderate isolated ventriculomegaly (VM) undergoing multiplanar ultrasound evaluation of the fetal brain. Methods This was a multicenter, retrospective, cohort study involving 15 referral fetal medicine centers in Italy, the UK and Spain. Inclusion criteria were fetuses affected by isolated mild (ventricular atrial diameter, 10.0–11.9 mm) or moderate (ventricular atrial diameter, 12.0–14.9 mm) VM on ultrasound, defined as VM with normal karyotype and no other additional central nervous system (CNS) or extra‐CNS anomalies on ultrasound, undergoing detailed assessment of the fetal brain using a multiplanar approach as suggested by the International Society of Ultrasound in Obstetrics and Gynecology guidelines for the fetal neurosonogram, followed by fetal MRI. The primary outcome of the study was to report the incidence of additional CNS anomalies detected exclusively on prenatal MRI and missed on ultrasound, while the secondary aim was to estimate the incidence of additional anomalies detected exclusively after birth and missed on prenatal imaging (ultrasound and MRI). Subgroup analysis according to gestational age at MRI (< 24 vs ≥ 24 weeks), laterality of VM (unilateral vs bilateral) and severity of dilatation (mild vs moderate VM) were also performed. Results Five hundred and fifty‐six fetuses with a prenatal diagnosis of isolated mild or moderate VM on ultrasound were included in the analysis. Additional structural anomalies were detected on prenatal MRI and missed on ultrasound in 5.4% (95% CI, 3.8–7.6%) of cases. When considering the type of anomaly, supratentorial intracranial hemorrhage was detected on MRI in 26.7% of fetuses, while polymicrogyria and lissencephaly were detected in 20.0% and 13.3% of cases, respectively. Hypoplasia of the corpus callosum was detected on MRI in 6.7% of cases, while dysgenesis was detected in 3.3%. Fetuses with an associated anomaly detected only on MRI were more likely to have moderate than mild VM (60.0% vs 17.7%; P < 0.001), while there was no significant difference in the proportion of cases with bilateral VM between the two groups (P = 0.2). Logistic regression analysis showed that lower maternal body mass index (adjusted odds ratio (aOR), 0.85 (95% CI, 0.7–0.99); P = 0.030), the presence of moderate VM (aOR, 5.8 (95% CI, 2.6–13.4); P < 0.001) and gestational age at MRI ≥ 24 weeks (aOR, 4.1 (95% CI, 1.1–15.3); P = 0.038) were associated independently with the probability of detecting an associated anomaly on MRI. Associated anomalies were detected exclusively at birth and missed on prenatal imaging in 3.8% of cases. Conclusions The incidence of an associated fetal anomaly missed on ultrasound and detected only on fetal MRI in fetuses with isolated mild or moderate VM undergoing neurosonography is lower than that reported previously. The large majority of these anomalies are difficult to detect on ultrasound. The findings from this study support the practice of MRI assessment in every fetus with a prenatal diagnosis of VM, although parents can be reassured of the low risk of an associated anomaly when VM is isolated on neurosonography

Anti-angiogenic effects of anti–tumor necrosis factor α agents in the treatment of behçet disease

There are accumulating evidences on the role of dysregulated angiogenesis in Behçet disease. By considering that encouraging results are accumulating about the role of anti–tumor necrosis factor α (TNF-α) agents in the treatment of Behçet disease and that there are evidences of a role of anti-TNF-α agents in angiogenesis inhibition, it is conceivable that antiangiogenic effects of anti-TNF-α agents may contribute to the efficacy of these therapeutic arms in Behçet disease

Osteoblast role in osteoarthritis pathogenesis

Even if osteoarthritis pathogenesis is still poorly understood, numerous evidences suggest that osteoblasts dysregulation plays a key role in osteoarthritis pathogenesis. An abnormal expression of OPG and RANKL has been described in osteoarthritis osteoblasts, which is responsible for abnormal bone remodeling and decreased mineralization. Alterations in genes expression are involved in dysregulation of osteoblast function, bone remodeling, and mineralization, leading to osteoarthritis development. Moreover, osteoblasts produce numerous transcription factors, growth factors, and other proteic molecules which are involved in osteoarthritis pathogenesis

Macrophages and angiogenesis in rheumatic diseases

Angiogenesis plays a key role in several rheumatic diseases, including rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, systemic sclerosis, systemic lupus erythematosus, and vasculitides. An imbalance between angiogenic inducers and inhibitors seems to be a critical factor in pathogenesis of these diseases. Macrophages promote angiogenesis during rheumatoid arthritis. In addition, macrophages can produce a variety of pro-angiogenic factors that have been associated with the angiogenic response occurring during other rheumatic diseases. Lastly, macrophages could be a target in the treatment of rheumatoid arthritis and other rheumatic diseases. Nevertheless, further studies are needed to better elucidate the exact role of macrophage in angiogenesis in these diseases

Angiogenesis Dysregulation in the Pathogenesis of Systemic Sclerosis

Systemic sclerosis is a chronic autoimmune connective tissue disease characterized by vascular injury and fibrosis and by an impaired angiogenesis which cannot ensure an efficient vascular recovery. Vascular injury is responsible for hypoxia and tissual ischemia which are the primary triggers for angiogenesis and are not able to induce a compensatory angiogenesis. This review article is focused on current knowledge on the mechanisms responsible for angiogenesis dysregulation in systemic sclerosis

Pathogenesis of ligaments ossification in spondyloarthritis: insights and doubts

Despite intensive research in spondyloarthritis pathogenesis, some important questions still remain unanswered, particularly concerning enthesis new bone formation. Several evidences suggest that it prevalently occurs by endochondral ossification, however it remains to identify factors that can induce and influence its initiation and progression. Recent progress, achieved in animal models and in vitro and genetic association studies, has led us to hypothesize that several systemic factors (adipokines and gut hormones) and local factors (BMP and Wnt signaling) as well as angiogenesis and mechanical stress are involved. We critically review and summarize the available data and delineate the possible mechanisms involved in enthesis ossification, particularly at spinal ligament level.KEY MESSAGES Complete understanding of spondyloarthritis pathophysiology requires insights into inflammation, bone destruction and bone formation, which are all located in entheses and lead all together to ankylosis and functional disability. Several factors probably play a role in the pathogenesis of bone formation in entheses including not only cytokines but also several systemic factors such as adipokines and gut hormones, and local factors, such as BMP and Wnt signaling, as well as angiogenesis and mechanical stress. Data available about pathophysiology of new bone formation in spondyloarthritis are limited and often conflicting and future studies are needed to better delineate it and to develop new therapeutic approaches