To assess the efficacy of tocilizumab in patients with Takayasu arteritis (TA).
We conducted a retrospective multicenter study in 46 TA patients treated with tocilizumab. We analyzed factors ...associated with response to tocilizumab (assessed using NIH score).
Forty-six patients with TA were included, with a median age of 43 years 29–54, and 35 (76%) females. We observed a decrease in the median NIH scale (from 3 2–3 at baseline to 0 0–1 and 0 at 3 and 6 months, respectively; p < 0.0001). The daily prednisone dose also decreased from 15 mg 8–19 at baseline to 4 mg 5–21 and 5 mg 4.5–9 at 3 and 6 months, respectively (p < 0.0001) under tocilizumab. The overall tocilizumab failure free survival was 81% CI 95%; 0.7–0.95, 72% CI 95%; 0.55–0.95 and 48% CI 95%; 0.2–0.1 at 12, 24 and 48 months, respectively. The presence of constitutional symptoms (HR 5.6 CI 95%; 1.08–29, p = 0.041), and C-reactive protein level (HR 1.16 CI 95%; 1.01–1.31, P = 0.003) at the time of tocilizumab initiation were significantly associated with tocilizumab event-free survival. The event-free survival was significantly better under tocilizumab therapy in comparison to DMARDs (p = 0.02).
This large multicenter study shows that tocilizumab is efficient and may reduce the incidence of relapses in TA.
•Tocilizumab can lead patients TA to remission in 80%, have steroid sparing effect and a good safety profile.•Tocilizumab can be used in monotherapy and as first line therapy.•Tocilizumab can be used in monotherapy and is effective as first line therapy.
Naringin (NAR) from grapefruit has exhibited potential protective effects against atherosclerosis development. However, specific mechanisms responsible for such effects are poorly understood. Thus, ...we aimed to investigate the antiatherogenic effects of NAR in different mouse models of hypercholesterolemia and decipher its molecular targets in the aorta using transcriptomic approach. Two mouse models of hypercholesterolemia, wild-type mice fed a high-fat/high-cholesterol diet and apolipoprotein E-deficient mice fed a semisynthetic diet, were studied. Mice were fed a respective control diets supplemented or not for 18 weeks with 0.02% of NAR, that is, nutritional supplementation. NAR supplementation reduced plaque progression only in wild-type mice fed the high-fat/high-cholesterol diet (−41%). Consistent with this protective effect, NAR reduced plasma non-high-density lipoprotein cholesterol concentrations as well as biomarkers of endothelial dysfunction. Microarray studies performed on aortas demonstrated differentially expressed genes encoding proteins involved in cell adhesion, actin cytoskeleton organization and cell division. Thus, the changes in gene expression induced by NAR could suggest a limited atherosclerosis progression by preventing immune cell adhesion and infiltration in the intima of vascular wall, as well as smooth muscle cell proliferation. Furthermore, this hypothesis was strengthened by in vitro experiments, which showed the ability of naringenin to reduce monocyte adhesion to endothelial cells and smooth muscle cell proliferation. In conclusion, this study revealed the antiatherogenic effect of NAR supplemented at a nutritionally achievable dose, specifically toward diet-induced atherosclerosis, and depicted its multitarget mode of action at the vascular level.
Primary lymphedema is a rare chronic pathology associated with constitutional abnormalities of the lymphatic system. The objective of this French National Diagnosis and Care Protocol (Protocole ...National de Diagnostic et de Soins; PNDS), based on a critical literature review and multidisciplinary expert consensus, is to provide health professionals with an explanation of the optimal management and care of patients with primary lymphedema. This PNDS, written by consultants at the French National Referral Center for Primary Lymphedema, was published in 2019 ( https://has-sante.fr/upload/docs/application/pdf/2019-02/pnds_lymphoedeme_primaire_final_has.pdf ). Primary lymphedema can be isolated or syndromic (whose manifestations are more complex with a group of symptoms) and mainly affects the lower limbs, or, much more rarely, upper limbs or external genitalia. Women are more frequently affected than men, preferentially young. The diagnosis is clinical, associating mild or non-pitting edema and skin thickening, as confirmed by the Stemmer's sign (impossibility to pinch the skin on the dorsal side or the base of the second toe), which is pathognomonic of lymphedema. Limb lymphoscintigraphy is useful to confirm the diagnosis. Other causes of swelling or edema of the lower limbs must be ruled out, such as lipedema. The main acute lymphedema complication is cellulitis (erysipelas). Functional and psychological repercussions can be major, deteriorating the patient's quality of life. Treatment aims to prevent those complications, reduce the volume with low-stretch bandages, then stabilize it over the long term by exercises and wearing a compression garment. Patient education (or parents of a child) is essential to improve observance.
Objective
To investigate the relationship between vascular damage and fibrosis in systemic sclerosis (SSc) by testing the hypothesis that platelets contribute to skin fibrosis via the activation of ...human dermal microvascular endothelial cells (HDMECs) and subsequent production of profibrotic mediators.
Methods
A total of 203 SSc patients and 30 healthy donors were prospectively enrolled between 2012 and 2015 at the University Hospital of Bordeaux. Immunohistochemistry and immunofluorescence analyses were performed on skin biopsy sections from 18 SSc patients and 5 healthy donors. Serum thymic stromal lymphopoietin (TSLP) levels were measured by enzyme‐linked immunosorbent assay in the entire cohort. HDMECs and fibroblasts were purified from biopsy sections. Extracellular matrix production by cultured fibroblasts was assessed by real‐time quantitative polymerase chain reaction.
Results
Serum TSLP levels were significantly increased in SSc patients compared to healthy donors (P < 0.0001) and were associated with a higher frequency of vasculopathy (P = 0.02). The proportion of TSLP‐positive dermal cells was increased in the skin of SSc patients compared with healthy donors (P < 0.0001) and was correlated with fibrosis (modified Rodnan skin thickness score) (r = 0.6146, P = 0.0001). In SSc dermis, TSLP was mainly expressed by CD31‐positive endothelial cells. In vitro, activated platelets induced TSLP production by HDMECs in an interleukin‐1β–dependent manner. SSc fibroblasts responded differently according to their original TSLP environment.
Conclusion
Taken together, these results identify HDMECs as contributors to TSLP production in SSc and suggest a potential mechanism by which platelets may profoundly affect the fibrotic process in SSc.
Summary Background & aims Blond orange juice is the most consumed fruit juice in the world. It is a source of hesperidin, a bioavailable flavonoid reported to exhibit potential vascular protective ...actions. However, the specific impact on vascular function of Citrus phytomicronutrients, is unknown. For the first time, we investigated the effects of blond orange juice compared with a control beverage mimicking the composition of orange juice (including Vitamin C but no phytomicronutrients), on antioxidant markers, cardiovascular risk factors and endothelial function. Methods Twenty five male volunteers with two cardiovascular risk factors (age over 50 years and LDL-cholesterol between 130 and 190 mg/L) were enrolled in a randomized cross-over study. They received 3 times daily 200 mL of either blond orange juice or control beverage for 4 weeks, spaced by a 5-week wash-out. Endothelial function (flow mediated dilatation and plasma markers), oxidative status, lipid profile and inflammatory markers were assessed. Results Daily intakes of orange juice significantly led to a marked antioxidant effect which was correlated to hesperetin plasma levels and related with a decrease in reactive oxygen species. A tendency towards reduction of endothelial dysfunction and modest increase in plasma apoA-I concentration were also observed. This allows further experiments demonstrating the specific effect of phytomicronutrients from orange juice. Conclusions These findings suggest that daily intake of nutritionally relevant dose of blond orange juice may contribute for a significant antioxidant effect through the phytochemicals contained in. Orange juice may be associated to other healthy foods to achieve a significant effect on the vascular function. This study is recorded in ClinicalTrials.com as NCT00539916.
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.
Subgroups of capillaroscopic scleroderma landscape have been correlated with stages of SSc: two groups for Maricq's classification (slow and active), and three for Cutolo's classification (early, ...active and late). We report inter- and intra-observer agreement for these classifications as a preliminary step in the multicentre prospective SCLEROCAP study, which aims to assess the classification and single capillaroscopic items as prognostic tools for SSc.
SCLEROCAP included 385 patients. Agreement was studied in the first 100 patients, who were independently rated twice by two observers, blind to patients' characteristics; 30 of the patients were rated once by six observers. After consensus meetings, these ratings were held again. Kappa and intraclass correlation coefficients were used to assess agreement.
Interobserver agreement on 100 patients was moderate for Maricq and Cutolo classifications κ 0.47 (0.28, 0.66) and 0.49 (0.33, 0.65), respectively, and became substantial after consensus meetings 0.64 (0.50, 0.77) and 0.69 (0.56, 0.81). Intra-observer agreement between two observers was moderate to substantial: κ 0.54 (0.33, 0.75) and 0.70 (0.57, 0.83) for Maricq's classification; 0.57 (0.38, 0.77) and 0.76 (0.65, 0.87) for Cutolo's. Thirty patients were rated once by each of six observers, and agreement was moderate to substantial: κ 0.57 ± 0.10 (Maricq) and 0.61 ± 0.12 (Cutolo). Agreement was substantial for bushy, giant capillaries and microhaemorrhages, moderate for capillary density and low for oedema, disorganization and avascular areas.
The moderate reproducibility of Maricq and Cutolo classifications might hamper their prognostic value in SSc patients. Consensus meetings improve reliability, a prerequisite for better prognostic performances. A focus on giant capillaries, haemorrhages and capillary density might be more reliable.
The aim of this study was to compare the prognosis of patients according to diabetes status, during a 1-year follow-up after hospital admission for lower extremity artery disease, in the prospective ...COPART (COhorte de Patients ARTériopathes) registry. Inclusion criteria were intermittent claudication, ischemic rest pain, tissue loss, or acute limb ischemia, with radiological and hemodynamic confirmation. Among 2494 patients, 1235 (49.5%) had diabetes. Incidence rates for major adverse cardiovascular events (MACE) were 18.0/100 person-years (95% confidence interval CI, 15.4–21.0) for the diabetes group and 11.1/100 person-years (95% CI, 9.2–13.4) for the non-diabetes group. Incidence rates of all-cause mortality were 29.8/100 person-years (95% CI, 26.5–33.4) for the diabetes group and 19.7/100 person-years (95% CI, 17.2–22.7) for the non-diabetes group. Incidence rates of major limb amputation were 24.2/100 person-years (95% CI, 21.1–27.8) for the diabetes group and 11.6/100 person-years (95% CI, 9.6–14.0) for the non-diabetes group. Diabetes was associated with MACE, adjusted hazard ratio 1.60 (95% CI, 1.16–2.22), and all-cause mortality, unadjusted HR 1.49 (95% CI, 1.24–1.78). In the multivariate analysis, diabetes was no longer associated with major amputation, adjusted HR 1.15 (95% CI, .87–1.51). Patients hospitalized for LEAD with diabetes had a higher risk of MACE than those without diabetes.
The hemodynamic definition of critical limb ischemia (CLI) has evolved over time but remains controversial. We compared the prediction of major amputation by 3 hemodynamic methods. Patients were ...selected from the Cohorte des Patients ARTériopathes cohort of patients hospitalized for peripheral arterial disease. Patients with CLI were enrolled according to the Trans-Atlantic Inter-Society Consensus Document on Management of Peripheral Arterial Disease II definition and followed up for at least 1 year. We compared the major amputation rate according to initial ankle pressure (AP), systolic toe pressure (STP), and forefoot transcutaneous oxygen pressure (TcPO2); 556 patients were included and divided into surgical (264) and medical (292) groups. The AP failed to identify 42% of patients with CLI. After 1 year, 27% of medical and 17% of surgical patients had undergone major amputation. The TP <30 mm Hg predicted major amputation in the whole sample and in the medical group (odds ratio OR 3.5 1.7-7.1 and OR 5 2-12.4, respectively), but AP did not. The TcPO2 <10 mm Hg also predicted major amputation (OR 2.3 1.5-3.5 and OR 3.8 2.1-6.8). The best predictive thresholds to predict major amputation were STP <30 mm Hg and TcPO2 <10 mm Hg. None of these methods performed before surgery was able to predict outcome in the revascularized patients.
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