BACKGROUNDSubstantial 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. METHODSWe 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. FINDINGSWe 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. INTERPRETATIONPlacebo 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. FUNDINGThis 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
The International Union of Phlebology recommends measuring at least D-dimer and fibrinogen levels in the diagnosis of extensive extra-truncular venous malformations, with a surface area of 10 cm
or ...those which are deep, as well as prior to any interventional procedure. The aim of the study was to characterise venous malformations associated with a possible vascular complication.
This study was an observational and multicentre study. The objective was to explore the presence of a possible coagulation disorder among patients with venous malformation. The primary endpoint was to characterise venous malformations with increased D-dimer levels.
The majority of the 72 venous malformations were located in the trunk region, mostly in intramuscular or subcutaneous locations. There were 72 venous malformations with increased D-dimer levels including 3 with biological disseminated intravascular coagulation (elevated D-dimer and fibrinogen <1 g/L). The anticoagulant treatments administered were very heterogeneous in class and dosage, and at the end of the treatment, 17 elevated D-dimers were persistent, 9 venous malformations remained painful and 27 showed thrombotic regression.
Venous vascular malformations are probably underestimated and should probably be explored more systematically in terms of coagulation disorder regardless of size or symptomatology. The therapeutic recommendations to treat localised intravascular coagulation with low-molecular weight are not widely applied. Studies are needed, in particular to assess the role of oral anticoagulants in the management of coagulation disorder among patients with venous malformation.
Aim
Drug‐induced Raynaud's phenomenon (RP) has long been associated with the use of different drugs, including cancer chemotherapy or β‐adrenoceptor blockers. However, sources report extremely ...variable prevalence and the level of evidence for each class is heterogeneous. Moreover, new signals are emerging from case reports and small series. Our objective was therefore to review available evidence about this adverse drug effect and to propose a mechanistic approach of drug‐induced RP.
Methods
A systematic review of English and French language articles was performed through Medline (1946–2015) and Embase (1974–2015). Further relevant papers were identified from the reference lists of retrieved articles.
Results
We identified 12 classes of drugs responsible for RP, with a variety of underlying mechanisms such as increased sympathetic activation, endothelial dysfunction, neurotoxicity or decreased red blood cell deformability. Cisplatin and bleomycin were associated with the highest risk, followed by β‐adrenoceptor blockers. Recent data suggest a possible involvement of tyrosine kinase inhibitors (TKI), through an unknown mechanism.
Conclusion
Drug‐induced RP is a probably underestimated adverse drug event, with limited available evidence regarding its prevalence. Although rare, serious complications like critical digital ischaemia have been reported. When these treatments are started in patients with a history of RP, careful monitoring must be made and, if possible, alternative therapies that do not alter peripheral blood flow should be considered.
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Vascular lesions are frequent in Behçet's disease, and among them, deep venous thrombosis may occur in up to one-third of patients. Treatment is based on immunosuppressive drugs in addition to ...anticoagulants. We report the case of a young woman who presented with an acute iliofemoral venous thrombosis. Acute treatment with endovascular thrombectomy and catheter-directed fibrinolysis failed, probably because of the inflammatory status of the vessel wall. Recanalization with stenting of the obstructed common femoral and iliac veins 1 year later was successful under immunosuppressive therapy. This case suggests that endovascular treatment of venous thrombosis in Behçet's disease may be conducted successfully in nonactive venous lesions under immunosuppressive therapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Obstructive sleep apnea (OSA) is highly prevalent in conditions characterized by fluid overload. Chronic venous insufficiency (CVI) is associated to fluid overload that might interfere with OSA ...occurrence and severity.
A total of 180 patients with symptomatic CVI completed the Berlin questionnaire and were assessed for the presence of symptoms and signs of OSA and fluid shift.
According to the Berlin questionnaire, 59 patients (33%) had high risk of OSA. The predictors of having a positive Berlin questionnaire were male sex, body mass index and symptoms possibly related to fluid shift.
Patients with CVI, a disease characterized by fluid overload, present high risk of OSA, which might be related to fluid shift.
•Chronic venous insufficiency (CVI) presented high risk of OSA.•Patient-reported signs of fluid overload and shift have been correlated with OSA.•CVI patients with clinically detectable fluid overload may have higher risk of OSA.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Finger systolic blood pressure measurement (FSBP) has been shown helpful in the detection of distal arterial insufficiency in upper limbs. This work assesses the possibility to measure FSBP on the ...2nd phalanx instead of the first one in order to improve its sensitivity and to verify this would not alter the repeatability of the measurement.
In this multicenter study, FSBP was measured twice in all fingers but the thumbs in consecutive systemic sclerosis patients on the first phalanx and the second phalanx in alternate order using laser-Doppler flowmetry.
Thirty-seven patients were enrolled. The repeatability of FSBP was excellent and similar on the first and 2nd phalanxes with coefficients of variation respectively of 7.1% and 7.6%. While the correlation between the FSBP at the two sites was fair (Pearson coefficient 0.69; p < 0.001). The agreement was poor, with a mean difference of 14 mm Hg between the two sites. Significantly higher differences were found in fingers with digital ulcers. The ROC curves showed a better prediction of the 2nd phalanx measurements.
FSBP has an excellent repeatability whatever the site of phalanx. However, measurements performed on the 2nd phalanx have a better sensitivity for the prediction of digital ulcers.
•Finger Systolic Blood Pressure with laser doppler detect significant arterial disease in systemic sclerosis patients.•FSBP has an excellent repeatability of the measurements whatever the warming method used and the site of measurement.•Measurements performed on the second phalanx exhibit an excellent repeatability.Measurements performed on the second phalanx have a better sensitivity for the prediction of digital ulcers.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Objective
To evaluate the prevalence and clinical correlates of peripheral arterial disease of the upper limbs in patients with systemic sclerosis (SSc), as detected with finger brachial pressure ...index (FBPI) measurements.
Methods
This work is based on the baseline data of the SCLEROCAP multicenter cohort of SSc patients. Finger systolic blood pressure was measured with laser Doppler flowmetry, and the FBPI was obtained as its ratio over the ipsilateral brachial systolic blood pressure. An FBPI of <0.70 was used as the diagnostic criterion for occlusive arterial disease of the upper limbs. Thus, the prevalence of defined arterial disease as well as its clinical, biologic, and capillaroscopic correlates were evaluated.
Results
Among 326 enrolled patients, 177 (54.3%) met the criterion for arterial disease (FBPI <0.70). No association was found with the type of SSc nor with the type of associated antinuclear antibodies, but a significant association was found with the duration of the disease (P < 0.001), the capillaroscopic pattern (P < 0.001), and most strikingly with the presence of digital ulcers (42.9% versus 13.4%; P < 0.001). A quantitative relationship was found between the FBPI and the prevalence of digital ulcers and was shown to be independent from the capillaroscopic pattern.
Conclusion
This cross‐sectional study shows a high prevalence of arterial disease of the upper limbs in patients with SSc. FBPI appears to be a strong and independent predictor of digital ulcers. This study suggests that both macro‐ and microangiopathy are contributing to the ischemic damage of the fingertips.
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IMPORTANCE: Calcific uremic arteriolopathy (CUA), a rare, potentially fatal, disease with calcium deposits in skin, mostly affects patients with end-stage renal disease who are receiving dialysis. ...Chemical composition and structure of CUA calcifications have been poorly described. OBJECTIVES: To describe the localization and morphologic features and determine the precise chemical composition of CUA-related calcium deposits in skin, and identify any mortality-associated factors. DESIGN, SETTING, AND PARTICIPANTS: A retrospective, multicenter cohort study was conducted at 7 French hospitals including consecutive adults diagnosed with CUA between January 1, 2006, and January 1, 2017, confirmed according to Hayashi clinical and histologic criteria. Patients with normal renal function were excluded. For comparison, 5 skin samples from patients with arteriolosclerosis and 5 others from the negative margins of skin-carcinoma resection specimens were also analyzed. MAIN OUTCOMES AND MEASURES: Localization and morphologic features of the CUA-related cutaneous calcium deposits were assessed with optical microscopy and field-emission–scanning electron microscopy, and the chemical compositions of those deposits were evaluated with μ Fourier transform infrared spectroscopy, Raman spectroscopy, and energy dispersive radiographs. RESULTS: Thirty-six patients (median range age, 64 33-89 years; 26 72% female) were included, and 29 cutaneous biopsies were analyzed. Calcific uremic arteriolopathy and arteriolosclerosis skin calcifications were composed of pure calcium–phosphate apatite. Calcific uremic arteriolopathy vascular calcifications were always circumferential, found in small to medium-sized vessels, with interstitial deposits in 22 (76%) of the samples. A thrombosis, most often in noncalcified capillary lumens in the superficial dermis, was seen in 5 samples from patients with CUA. Except for calcium deposits, the vessel structure of patients with CUA appeared normal, unlike thickened arteriolosclerotic vessel walls. Twelve (33%) patients died of CUA. CONCLUSIONS AND RELEVANCE: Calcific uremic arteriolopathy–related skin calcifications were exclusively composed of pure calcium–phosphate apatite, localized circumferentially in small to medium-sized vessels and often associated with interstitial deposits, suggesting its pathogenesis differs from that of arteriolosclerosis. Although the chemical compositions of CUA and arteriolosclerosis calcifications were similar, the vessels’ appearances and deposit localizations differed, suggesting different pathogenetic mechanisms.
Aim
Peripheral vasoconstriction has long been described as a vascular adverse effect of β‐adrenoceptor blockers. Whether β‐adrenoceptor blockers should be avoided in patients with peripheral vascular ...disease depends on pharmacological properties (e.g. preferential binding to β1‐adrenoreceptors or intrinsic sympathomimetic activity). However, this has not been confirmed in experimental studies. We performed a network meta‐analysis in order to assess the comparative risk of peripheral vasoconstriction of different β‐adrenoceptor blockers.
Method
We searched for randomized controlled trials (RCTs) including β‐adrenoceptor blockers that were published in core clinical journals in the Pubmed database. All RCTs reporting peripheral vasoconstriction as an adverse effect of β‐adrenoceptor blockers and controls were included. Sensitivity analyses were conducted including possibly confounding covariates (latitude, properties of the β‐adrenoceptor blockers, e.g. intrinsic sympathomimetic activity, vasodilation, drug indication, drug doses). The protocol and the detailed search strategy are available online (PROSPERO registry CRD42014014374).
Results
Among 2238 records screened, 38 studies including 57 026 patients were selected. Overall, peripheral vasoconstriction was reported in 7% of patients with β‐adrenoceptor blockers and 4.6% in the control groups (P < 0.001), with heterogeneity among drugs. Atenolol and propranolol had a significantly higher risk than placebo, whereas pindolol, acebutolol and oxprenolol had not.
Conclusion
Our results suggest that β‐adrenoceptor blockers have variable propensity to enhance peripheral vasoconstriction and that it is not related to preferential binding to β1‐adrenoceptors. These findings challenge FDA and European recommendations regarding precautions and contra‐indications of use of β‐adrenoceptor blockers and suggest that β‐adrenoceptor blockers with intrinsic sympathomimetic activity could be safely used in patients with peripheral vascular disease.
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