Major sickle cell disease syndrome (SCD) is a set of potentially serious and disabling constitutional haemoglobin pathologies characterised by chronic haemolysis and vaso‐occlusion phenomena. If ...expression takes the form of acute vaso‐occlusive crisis, SCD is currently considered to be a chronic systemic pathology, primarily associated with vasculopathy and ischaemia‐reperfusion phenomena. The haemolytic aspect of the disease may be associated with endothelial dysfunctional complications, including leg ulcers, which are a classic spontaneous complication of major SCD. Their frequency, all aetiologies combined, varies considerably according to the series under consideration. Hydroxycarbamide has become the standard treatment for some SCD phenotypes, but has classically been described as one of the causes of leg ulcer. This causality is widely debated and is still difficult to establish because it is a specific complication of the disease. Comorbidity factors (eg, iron deficiency) are also often implicated as causal or aggravating factors so research into all the potential aetiologies of leg ulcers in a sickle cell patient must be exhaustive. We discuss the aetiologies of a leg ulcer in a patient treated by hydrocarbamide for major SCD. The imputation of the drug was established, followed by a marrow allograft in this patient.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
We describe the unusual case of a 78-year-old woman consulting for extensive and painful wound leg ulcerations and calcifications secondary to CREST syndrome that was treated by extracorporeal shock ...wave lithotripsy. This treatment was considered because of the severity of our patient's symptoms and her failure to respond to various medical and surgical treatment.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Substantial placebo response has been observed in trials assessing treatments in Raynaud's Phenomenon (RP), which makes any treatment effect difficult to detect. However, whether this response is due ...to a real placebo effect or to other nonspecific effects, such as regression towards the mean (RTM), has not been explored. Our objectives were to explore and quantify placebo response in RP, and to evaluate the magnitude of RTM contribution.
We combined trial-level and individual-level data from a series of n-of-1 trials and a network meta-analysis, respectively. Main outcomes were the daily frequency and the mean duration of RP attacks, as well as the Raynaud's Condition Score (RCS). We estimated the placebo response by the mean difference between the placebo period (or arm) and the baseline. RTM was estimated by the relationship between placebo response and baseline, and with Galton squeeze plots. Finally, we simulated the effect of the threshold used for inclusion in clinical trials on RTM.
We observed a large and significant placebo response from both individual and trial data for RCS -1.20 (-1.63, -0.77) and -0.65 (-0.89, -0.41) and the daily frequency of RP -0.61 (-0.85, -0.37) and -0.75 (-0.95, -0.54). Outcome at baseline was significantly associated with placebo response, suggesting the presence of RTM. The latter was confirmed on individual data, through Galton squeeze plots.
Placebo response is large in RP trials, and likely due to regression towards the mean rather than ‘true’ placebo effect. This should be carefully considered when designing future trials.
This work has been partially supported by MIAI @ Grenoble Alpes (ANR-19-P3IA-0003).
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Recent controlled trials have assessed the efficacy of phosphodiesterase-5 (PDE-5) inhibitors in secondary Raynaud's phenomenon (RP). However, the conclusions are conflicting, and whether these drugs ...are effective remains unclear. The objective of this meta-analysis was to determine the efficacy of PDE-5 inhibitors on Raynaud's Condition Score (RCS) and frequency and duration of attacks.
A systematic review of articles was performed (sources included Medline, Embase, Web of Science, the Cochrane Central Register of Controlled Trials). Only double-blind, randomised controlled trials (RCTs) were included. Studies were selected independently by two authors using predefined data fields, including study quality indicators.
Six RCTs were included (one with sildenafil, one with modified-release sildenafil, three with tadalafil and one with vardenafil). PDE-5 inhibitors significantly decreased mean RCS by -0.46 (-0.74 to -0.17) (p=0.002), the daily frequency of ischaemic attacks by -0.49 (-0.71 to -0.28) (p<0.0001), and daily duration of RP attacks by -14.62 (-20.25 to -9.00) min (p<0.0001).
PDE-5 inhibitors appear to have significant but moderate efficacy in secondary RP. A further large RCT is needed.
Vascular endothelial-cadherin is the most important transmembrane component of endothelial adherens junctions, exclusively expressed by endothelial cells in all types of vessels. Targeting either the ...extracellular domain or the cytoplasmic tail deleteriously affects the junctional strength and leads to vascular permeability. Recently, cytokine-induced phosphorylation of the vascular endothelial-cadherin cytoplasmic domain was reported to trigger cleavage of its extracellular domain, producing the soluble form of the protein – soluble vascular endothelial-cadherin. Hence, the presence of soluble vascular endothelial-cadherin or auto-antibodies to human vascular endothelial-cadherin in human serum could signalize the presence of vascular abnormalities. This systematic review covers many human studies reporting increased levels of soluble vascular endothelial-cadherin, as well as auto-antibodies to human vascular endothelial-cadherin, which could be promising biomarkers of endothelial dysfunction in a large panel of diseases.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
In conjunction with appropriate wound care, negative pressure wound therapy with instillation and dwell time (NPWTi-d) may be used as an adjunct therapy for acute or hard-to-heal (chronic) wounds, ...especially when infected. However, there are very few data on the use of NPWTi-d in the treatment of fibrinous wounds that are difficult to debride mechanically. The main objective of this study was to describe changes in the fibrin area of such wounds, before and after treatment with NPWTi-d.
This was a monocentric, observational, prospective pilot study evaluating the NPWTi-d medical device. Eligible patients included in the study were those with hard-to-heal lower limb ulcers who had previously undergone unsuccessful specific debridement treatment for their wound, with failure of manual mechanic debridement for at least six weeks' duration, and whose wounds had a fibrinous surface area of >70% of the total wound surface area. The primary endpoint was the difference in the percentage of fibrinous surface area before and after treatment.
A total of 14 patients who received treatment for lower limb ulcers between October 2017 and August 2019 were included in the study. There was a significant shrinkage rate of the fibrinous wound surface between the start and end of treatment (83.6±14.5% and 32.2±19.7%, respectively; p<0.001).
This study showed a significant decrease in fibrin area in wounds treated with NPWTi-d, with good tolerance. We believe that NPWTi-d has its place in the multidisciplinary management of patients with hard-to-heal ulcers. Additional randomised studies are required to confirm these findings.
The authors have no conflicts of interest.
Abstract
Objective
Systemic sclerosis (SSc) is a rare, chronic disease characterized by fibrosis, vascular alterations and digital ulcerations. Few drugs have shown efficacy to enhance wound healing ...of existing SSc-related ulcers. Local delivery of treprostinil, a prostacyclin analogue, may improve wound healing. The present work aimed first at developing a mouse model of SSc-related ulcerations and second at assessing the effect of iontophoresis of treprostinil on wound healing.
Methods
We used two murine models of SSc: chemically induced with HOCl, and urokinase-type plasminogen activator receptor (uPAR)-deficient. Excisional wounding was performed on the dorsal midline with a biopsy punch. Animals were randomized into three groups: treated with electrostimulation alone, with treprostinil iontophoresis or untreated. We assessed wound healing over time, as well as skin microvascular reactivity, inflammation, microvessel density and collagen distribution, before wounding and after re-epithelialization.
Results
uPAR–/– mice, but not HOCl-treated mice, showed impaired wound healing and decreased microvascular reactivity compared with their controls. Treprostinil iontophoresis improved wound healing and microvascular density and decreased inflammation in uPAR–/– mice, while electro-stimulation did not. However, treprostinil had no effect on microvascular reactivity and collagen distribution.
Conclusion
This study suggests that excisional wounds in uPAR–/– mice are a relevant model of SSc-related ulcers. In addition, treprostinil iontophoresis enhances wound healing in this model. Further work in now needed to show whether this effect translates in humans.
BACKGROUNDSeveral sclerosing agents are used to treat chronic venous diseases. Although they do not seem to differ in terms of efficacy, their safety profiles might differ.
OBJECTIVETo compare the ...safety profile of sclerosing agents through an analysis of the World Health Organization pharmacovigilance database.
METHODSThe authors performed a disproportionality analysis using the proportional reporting ratio (PRR) method to compare pharmacovigilance signals between each sclerosing agent among 6 adverse event syndromes of interesthypersensitivity reactions, arterial thromboembolic disorders, venous thromboembolic disorders, cardiac arrhythmias, visual/neurological disturbances, and skin ulcerations. The cutoff for signal detection was defined by a logPRR lower boundary 95% confidence interval (CI) ≥0 and number of cases n ≥3.
RESULTSOf 1,227 Individual Case Safety Reports (ICSRs) identified, after removal of ICSRs with unselected indications, the authors selected 472 reports for the analysis. The authors found that polidocanol is associated with more reporting of venous embolic/thrombotic events (logPRR = 1.38 95% CI 1.27–1.49), ethanolamine with the higher pharmacovigilance disproportionality signal of cardiac arrhythmias (logPRR = 0.80 95% CI 0.51–1.09), and STS with more reporting of allergic reactions (logPRR = 1.79 95% CI 1.59–1.98).
CONCLUSIONThe safety profile of sclerosing agents significantly differs and should guide benefit-risk ratio assessment of such agents.
There is no consensual definition of significant peripheral arterial disease of the upper limbs. Patients with end-stage renal disease are usually explored with Doppler ultrasound, which seems ...insufficient to characterize and quantify the arterial disease in this anatomic site. Candidates for haemodialysis access tend to be increasingly older and have polyvascular disease, and a better assessment of the vascular status of their upper limbs with finger systolic blood pressure is necessary. Photoplethysmography is simple and currently used in practice, but laser Doppler flowmetry may be more sensitive for low values. Our objective is to investigate additional information in the digit assessment over the ultrasound assessment of the upper limbs of patients awaiting haemodialysis and compare digital pressure values taken by photoplethysmography and laser Doppler.
All included patients with end-stage renal disease scheduled for haemodialysis access received a prospective evaluation of their upper limbs with a clinical examination of the hands, an arterial upper limb Doppler ultrasound, and finger systolic blood pressure using photoplethysmography and laser Doppler flowmetry. Significant upper limb arterial disease was defined by a finger systolic blood pressure below 60 mm Hg or a finger brachial pressure index below 0.7.
Twenty-four patients were included in the study. In all, 41.7% of patients (n = 10) had parietal calcifications to the antebrachial arteries on Doppler ultrasound, 8.3% of patients (n = 2) had bilateral finger systolic blood pressure values below 60 mm Hg with laser Doppler flowmetry (but not confirmed with photoplethysmography), and 16.6% of patients (n = 4) had a finger brachial pressure index below 0.7 on both laser Doppler flowmetry and photoplethysmography. While there was an agreement between these two methods, higher values were recorded with photoplethysmography. The Pearson coefficient was 0.493 for the median of basal digital pressures in absolute values and 0.489 for finger brachial pressure index (p < 0.001).
Our study confirms the need to evaluate significant upper limb arterial disease in patients with end-stage renal disease not only with Doppler ultrasound but also with an evaluation of the finger systolic blood pressure. The correlation of the finger systolic blood pressure values using laser Doppler flowmetry and photoplethysmography was poor, which was probably due to an overestimation of the pressures with photoplethysmography. Despite the absence of a gold standard, we suggest that Laser Doppler flowmetry should be used rather than photoplethysmography to better characterize significant peripheral arterial disease of the upper limbs in patients with end-stage renal disease, particularly before creation of a new haemodialysis access.
Protocol Record on clinical trial 38RC19.285.
•11There is no consensual definition of peripheral arterial disease of the upper limbs. Doppler ultrasound may not be the optimal technique to evaluate it. Peripheral arterial disease of the upper limbs in patients with end-stage renal disease is probably underestimated. Microcirculation methods have to be added for a quantitative evaluation. Finger systolic blood pressure is a useful tool, which must be carried out for a quantitative evaluation. There is a poor correlation coefficient of 0.493 (p < 0.001) between laser Doppler flowmetry and photoplethysmography. Laser Doppler flowmetry seems to be better in detecting peripheral arterial disease, as compared to photoplethysmography, which tends to overestimate the raw values.There is no consensual definition of peripheral arterial disease of the upper limbs. Doppler ultrasound may not be the optimal technique to evaluate it.•Peripheral arterial disease of the upper limbs in patients with end-stage renal disease is probably underestimated.•Microcirculation methods have to be added for a quantitative evaluation.•Finger systolic blood pressure is a useful tool, which must be carried out for a quantitative evaluation. There is a poor correlation coefficient of 0.493 (p < 0.001) between laser Doppler flowmetry and photoplethysmography.•Laser Doppler flowmetry seems to be better in detecting peripheral arterial disease, as compared to photoplethysmography, which tends to overestimate the raw values.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Introduction: Cardiovascular adverse effects of COX-2 inhibitors are well described. Nevertheless, no study explored the cutaneous and vascular adverse effects of COX-2 inhibitors 1. The aim of this ...study is to identify and quantify the risk of skin ulcer associated with COX-2 inhibitors in real world setting. Material and methods: A population-based nested case control study was conducted from a representative sample of the French nationwide claims database, “EGB,” for the 2012–2016 period 2. Cases were defined as patients who had consumed at least two boxes of wound dressing during 1 month between 2012 and 2016. The index date was the date of first period of reimbursement of wound dressing for skin ulcer. Up to four potential controls were selected for each case among subjects free from skin ulcers. Conditional logistic models were used to estimate adjusted odds ratios (aORs) and their 95% CIs. Cumulative exposure of drug class was considered using quartile as a categorical variable. The status of exposure was defined using a categorical variable. Results: For diabetes foot ulcers, pressure ulcers, and vascular ulcers, respectively 19,982, 4,584, and 41,632 cases fulfilled the inclusion criteria. Among cases and controls, an increased risk of all types of ulcers was found for a cumulative exposure to COX-2 inhibitors exceeding 90 days with aOR = 1.35 (95% CI 1.03–1.77) for diabetic foot ulcer, aOR = 2.04 (95% CI 1.63–2.56) for pressure ulcers, and aOR = 1.89 (95% CI 1.71–2.11) for vascular ulcers. Current exposure was associated with a higher risk of skin ulcer with aOR = 1.63 (95% CI 1.06–2.49) for diabetic foot ulcer, aOR = 2.20 (95% CI 1.52–3.19) for pressure ulcers, and aOR = 3.0 (95% CI 2.57–3.52) for vascular ulcers. Discussion/Conclusion: Our results suggest that COX-2 inhibitors are associated with a dose and time-dependent risk of skin ulcers. Given the observational nature of this study, we cannot exclude unmeasured and residual confounding.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
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