The disruption of endothelial homeostasis is a major determinant in the pathogenesis of systemic sclerosis (SSc) and is reflected by soluble and cellular markers of activation, injury and repair. We ...aimed to provide a combined assessment of endothelial markers to delineate specific profiles associated with SSc disease and its severity.
We conducted an observational, single-centre study comprising 45 patients with SSc and 41 healthy control subjects. Flow cytometry was used to quantify circulating endothelial microparticles (EMPs) and CD34
progenitor cell subsets. Colony-forming unit-endothelial cells (CFU-ECs) were counted by culture assay. Circulating endothelial cells were enumerated using anti-CD146-based immunomagnetic separation. Blood levels of endothelin-1, vascular endothelial growth factor (VEGF) and soluble fractalkine (s-Fractalkine) were evaluated by enzyme-linked immunosorbent assay. Disease-associated markers were identified using univariate, correlation and multivariate analyses.
Enhanced numbers of EMPs, CFU-ECs and non-haematopoietic CD34
CD45
endothelial progenitor cells (EPCs) were observed in patients with SSc. Patients with SSc also displayed higher serum levels of VEGF, endothelin-1 and s-Fractalkine. s-Fractalkine levels positively correlated with CD34
CD45
EPC numbers. EMPs, s-Fractalkine and endothelin-1 were independent factors associated with SSc. Patients with high CD34
CD45
EPC numbers had lower forced vital capacity values. Elevated s-Fractalkine levels were associated with disease severity, a higher frequency of pulmonary fibrosis and altered carbon monoxide diffusion.
This study identifies the mobilisation of CD34
CD45
EPCs and high levels of s-Fractalkine as specific features of SSc-associated vascular activation and disease severity. This signature may provide novel insights linking endothelial inflammation and defective repair processes in the pathogenesis of SSc.
•Inflammatory myopathies (IM) are rarely associated to myelodysplastic syndromes (MDS).•Dermatomyositis and anti-TIF1g + are the most frequent forms of IM associated to MDS.•Antisynthetase syndrome ...is not observed in MDS patients.•Association with MDS has a negative impact on IM patients’ survival.
Patients with inflammatory myopathies (IM) are known to have an increased risk of developing malignancies. Autoimmune and inflammatory diseases occur in up to 25% of patients with myelodysplastic syndrome (MDS). This study aimed to describe the rare association between IM and MDS.
We report here the main characteristics, treatment, and outcome of 21 patients (11 national cases and 10 additional cases from a literature review) with IM associated to MDS.
Median age of patients at IM diagnosis was 66 years (range 26 – 78). Diagnosis of the two conditions were concomitant in most patients (n=14/21) whereas MDS diagnosis preceded IM diagnosis in 5 patients. Different types of IM were observed but dermatomyositis was the most frequent (59%). Compared to IM without MDS (IM/MDS−), patients with MDS (IM/MDS+) were older (median 66 vs 55, p=0.3), more frequently male (sex ratio M/F 1.125 vs 0.41, p=0.14) and positive for anti-TIF1γ (24% vs 4%, p=0.0039). Antisynthetase syndrome was never observed among IM/MDS+ patients (0% vs 28%, p=0.01). MDS WHO type was not univocal, but the prognostic score was of low risk in almost all cases. IM was usually steroid sensitive (82% of patients) but often steroid dependent (56% of patients). Overall survival of IM patients with MDS was worse compared to patients with IM without MDS (p=0.0002).
IM associated with MDS are mainly represented by dermatomyositis and/or anti-TIF1γ autoantibodies. Antisynthetase syndrome has not been described in association with MDS. Despite low-risk MDS, overall survival of IM patients with MDS is worse than IM patients without MDS.
The association between cancer and sarcoidosis is controversial. Some epidemiological studies show an increase of the incidence of cancer in patients with sarcoidosis but only few cases of ...sarcoidosis following cancer treatment have been reported. We conducted a retrospective case study from internal medicine and oncology departments for patients presenting sarcoidosis after solid cancer treatment. We also performed a literature review to search for patients who developed sarcoidosis after solid cancer. We describe the clinical, biological, and radiological characteristics and outcome of these patients. Twelve patients were included in our study. Various cancers were observed with a predominance of breast cancer. Development of sarcoidosis appeared in the 3 years following cancer and was asymptomatic in half of the patients. The disease was frequently identified after a follow-up positron emission tomography computerized tomography evaluation. Various manifestations were observed but all patients presented lymph node involvement. Half of the patients required systemic therapy. With a median follow-up of 73 months, no patient developed cancer relapse. Review of the literature identified 61 other patients for which the characteristics of both solid cancer and sarcoidosis were similar to those observed in our series. This report demonstrates that sarcoidosis must be considered in the differential diagnosis of patients with a history of malignancy who have developed lymphadenopathy or other lesions on positron emission tomography computerized tomography. Histological confirmation of cancer relapse is mandatory in order to avoid unjustified treatments. This association should be consider as a protective factor against cancer relapse.
Context:
Cyclophosphamide is used for renal and major extrarenal involvement in systemic lupus erythematosus (SLE) and is associated with a risk of premature ovarian failure. There are no data ...available about the relation between anti-Müllerian hormone (AMH) serum levels and the probability of subsequent pregnancy in SLE patients.
Objective:
We analyzed AMH levels and the probability of pregnancy in SLE women exposed to cyclophosphamide.
Design and Setting:
We conducted a matched cohort study in referral centers for SLE.
Patients:
Fifty-six cyclophosphamide-exposed SLE women younger than 40 years of age and 56 control SLE women matched for age within 6 months participated in the study.
Main Outcome Measures:
AMH was measured in samples from the PLUS study (ClinicalTrials.gov no. NCT00413361). All patients were interviewed in May 2012 regarding their obstetric status.
Results:
The mean age ± SD of the 112 patients was 31.6 ± 5.8 years. The mean AMH level was low (1.21 ± 1.01 ng/mL) and was significantly lower in patients exposed to cyclophosphamide (P = .03) and in patients older than 30 years (P = .02). During a median follow-up (interval between sampling and the interview) period of 4.2 (range, 2.5–4.8) years, 38 patients sought to become pregnant, and 32 (84.2%) succeeded. In the univariate analysis, the risk of failure was associated with cumulative cyclophosphamide dose (P = .007) and older age (P = .02), but not with AMH.
Conclusion:
We confirmed that AMH levels are low in SLE patients and decrease significantly with age and cyclophosphamide exposure. Nonetheless, the risk of failure to conceive was low and was predicted by cyclophosphamide exposure and age, but not by AMH levels.
The lupus anticoagulant-hypoprothrombinemia syndrome (LAHS)--the association of acquired factor II deficiency and lupus anticoagulant--is a rare disease drastically different from antiphospholipid ...syndrome in that it may cause predisposition not only to thrombosis but also to severe bleeding. We performed a retrospective study of 8 patients with LAHS referred to 6 French tertiary care centers between January 2003 and February 2011, and a literature review retrieving all related articles published between 1960 and April 2011. Including our 8 new cases, LAHS has been reported in 74 cases. The disease mostly occurs in young adults, with a female to male sex ratio of 1.4. Associated conditions mostly include autoimmune diseases such as systemic lupus erythematosus and infectious diseases. Bleeding is a frequent feature (89% of cases), while arterial and/or venous thrombosis is less common (13%). Factor II level is severely decreased at diagnosis (median value, 11%; range, 1%-40%). LAHS associated with autoimmune diseases is more persistent than LAHS associated with infection, and hemorrhagic complications are more common. Corticosteroids should be considered the first-line treatment, but the thrombotic risk strongly increases during treatment because of the improvement of factor II level. Despite the fact that 50% of patients develop severe bleeding, the mortality rate is <5%, after a median follow-up of 13 months (range, 0.5-252 mo). LAHS associated with autoimmune diseases should be diagnosed and managed carefully because the disease is persistent and severe hemorrhagic complications are common.
Microparticles are small vesicles playing a crucial role in cell communication by promoting prothrombotic and proinflammatory responses. However, the molecular mechanisms underlying their release are ...still elusive. We previously established that thrombin promoted the generation of endothelial microparticles (EMPs). In the present study, gene profiling identified TRAIL/Apo2L, a cytokine belonging to the tumor necrosis factor-alpha superfamily, as a target of thrombin. Thrombin increased the expression of cell-associated and soluble forms of TRAIL (sTRAIL) in HMEC-1 cells and human umbilical vein endothelial cells (HUVECs). Blocking TRAIL by specific antibodies or by small interfering RNA reduced both the number and the procoagulant activity of EMPs released by thrombin. Consistent with an involvement of sTRAIL in thrombin-induced EMP release, we showed that (1) exogenously added sTRAIL generated procoagulant EMPs; (2) supernatants from thrombin-stimulated endothelial cells induced EMP release by HMEC-1 cells and HUVECs, whereas those recovered from TRAIL knockdown endothelial cells displayed no effect. TRAIL/TRAIL-R2 complex mediated EMP release by initiating the recruitment of adaptor proteins and the activation of nuclear factor kappaB. Moreover, sTRAIL modulated intercellular adhesion molecule-1 and interleukin-8 expression induced by thrombin by a downstream pathway involving nuclear factor kappaB activation. Our data reveal a novel mechanism controlling EMP release and identify TRAIL as a key partner in the pathway linking coagulation and inflammation elicited by thrombin.
Giant cell arteritis (GCA) is the most common systemic vasculitis in individuals aged ≥50 years. Its course is marked by a high relapse rate requiring long-term glucocorticoid use with its inherent ...adverse effects. We aimed to identify factors associated with relapses or recurrences in GCA at diagnosis.
We reviewed the medical records of consecutive patients with GCA diagnosed between 2009 and 2019 and followed for at least 12 months. We recorded their characteristics at onset and during follow-up. Factors associated with relapses or recurrences were identified using multivariable analysis.
We included 153 patients, among whom 68% were female with a median age of 73 (47-98) years and a median follow-up of 32 (12-142) months. Seventy-four patients (48.4%) had at least 1 relapse or recurrence. Headache and polymyalgia rheumatica were the most frequent manifestations of relapses. The first relapse occurred at a median time of 13 months after the diagnosis, with a median dose of 5.5 (0-25) mg/d of glucocorticoids.In multivariable analysis, patients with relapses or recurrences had a higher frequency of cough and scalp tenderness at diagnosis (20.3% vs 5.1%; odds ratio OR, 4.73; 95% confidence interval CI, 1.25-17.94; p = 0.022; and 41.9% vs 29.1%; OR, 2.4; 95% CI, 1.07-5.39; p = 0.034, respectively). Patients with diabetes mellitus at diagnosis had fewer relapses or recurrences during follow-up (5.4% vs 19%; OR, 0.24; 95% CI, 0.07-0.83; p = 0.024).
Cough and scalp tenderness at diagnosis were associated with relapses or recurrences, whereas patients with diabetes experienced fewer relapses or recurrences.
Systemic sclerosis (SSc) is a severe and highly heterogeneous disease. The modified Rodnan skin score (mRSS) is a widely used tool for the assessment of the extent and degree of skin thickness. This ...study aimed to identify the classes of patients with early similar skin thickening trajectories without any a priori assumptions and study their associations with organ involvement and survival.
From the French SSc national cohort, patients with a disease duration of less than 2 years at inclusion and with at least 2 mRSS available within the first 4 years of follow-up were enrolled. Classes of patients with similar mRSS trajectories were identified based on a latent class mixed model. The clinical characteristics and survival rate were compared between the obtained classes.
A total of 198 patients fulfilled the inclusion criteria, with a total of 641 mRSS available. The median disease duration and follow-up were 0.8 (interquartile range 0.4; 1.2) and 6.3 (3.8; 8.9) years, respectively. Individual trajectories of mRSS were highly heterogeneous between patients. Models with 1-6 latent classes of trajectories were sequentially assessed, and the 5-class model represented the best fit to data. Each class was characterized by a unique global trajectory of mRSS. The median disease duration did not differ significantly between classes. Baseline organ involvement was more frequent in classes with significant change over time (classes 2-5) than in class 1 (low baseline mRSS without significant change over time). Using Cox regression, we observed a progressively increasing risk of death from classes 1 to 5.
Early identification of clinical phenotype based on skin thickening trajectories could predict morbi-mortality in SSc. This study suggested that mRSS trajectories characterization might be pivotal for clinical practice and future trial designs.
Abstract
Background
A novel multisystem inflammatory syndrome in children (MIS-C) temporally associated with the coronavirus disease 2019 (COVID-19) infection has been reported, arising weeks after ...the peak incidence of COVID-19 infection in adults. Patients with MIS-C have been reported to have cardiac involvement and clinical features overlapping with other acute inflammatory syndromes such as Kawasaki disease, toxic shock syndrome, and macrophage activation syndrome. Multisystem inflammatory syndrome in children may follow COVID-19 infection, most of the time after its asymptomatic form, even though it can lead to serious and life-threatening illness.
Case summary
In this case series, we discuss two cases of young adults with no former medical history who fit with the criteria defined in MIS-C. They both developed a refractory cardiogenic shock and required intensive care treatment including mechanical circulatory support, specifically the use of venous–arterial extracorporeal membrane oxygenation. They were both treated early with intravenous immune globulin and adjunctive high-dose steroids. They recovered ad integrum in less than 2 weeks.
Discussion
Multisystem inflammatory syndrome in children occurs 2–4 weeks after infection with severe acute respiratory syndrome coronavirus 2. Patients with MIS-C should ideally be managed in an intensive care environment since rapid clinical deterioration may occur. It would be preferable to have a multidisciplinary care to improve outcomes. Patients should be monitored for shock. Elucidating the mechanism of this new entity may have importance for understanding COVID-19 far beyond the patients who have had MIS-C to date. The pathogenesis seems to involve post-infectious immune dysregulation so early administration intravenous immune globulin associated with corticosteroids appears appropriate. It implies early recognition of the syndrome even in young adults.
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