Background
Statins possess antithrombotic and profibrinolytic properties. The association between statin use and short‐term outcomes in patients with acute pulmonary embolism (PE) remains unknown.
...Methods
We used the data from the Registro Informatizado de Pacientes con Enfermedad TromboEmbólica registry to compare the 30‐day all‐cause mortality in patients with acute PE according to the use of statins. Secondary outcome was fatal PE. We used cancer‐related mortality as a falsification endpoint.
Results
From January 2009 to April 2021, 31 169 patients with PE were recruited. Of these, 5520 (18%) were using statins at baseline: low intensity: 829, moderate: 3636, high intensity: 1055. Statin users were older and had a higher frequency of diabetes, hypertension, or atherosclerotic disease than non‐users (P <0.001 for all comparisons). During the first 30 days, 1475 patients died (fatal PE, 255). On multivariable analysis, statin users had a lower risk of all‐cause death (odds ratio OR: 0.65; 95% confidence interval CI: 0.56–0.76) and fatal PE (OR: 0.42; 95% CI: 0.28–0.62) than non‐users. The risk for death was lower in patients using either low‐ (OR: 0.51; 95% CI: 0.34–0.77), moderate‐ (OR: 0.68; 95% CI: 0.57–0.81), or high‐intensity statins (OR: 0.68; 95% CI: 0.51–0.92). Results did not change in mixed effects logistic regression models with hospitals as a random effect. Statins were not associated with a significant chance in cancer mortality (falsification endpoint).
Conclusions
PE patients using statins at baseline had a significantly lower risk of dying within the first 30 days than non‐users. Randomized trials are needed to confirm these data.
Old patients receiving anticoagulant therapy for venous thromboembolism (VTE) are at an increased risk for bleeding. We used data from the RIETE registry to assess the prognostic ability of the ...Comorbidity Charlson Index (CCI) to predict the risk for major bleeding in patients aged > 75 years receiving anticoagulation for VTE beyond the third month. We calculated the area under the receiver-operating characteristic curve (AUC), the category-based net reclassification index (NRI) and the net benefit (NB). We included 4303 patients with a median follow-up of 706 days (interquartile range IQR 462–1101). Of these, 147 (3%) developed major bleeding (27 died of bleeding). The AUC was 0.569 (95% CI 0.524–0.614). Patients with CCI ≤ 4 points were at a lower risk for adverse outcomes than those with CCI > 10 (major bleeding 0.81 (95% CI 0.53–1.19) vs. 2.21 (95% CI 1.18–3.79) per 100 patient-years; p < 0.05; all-cause death 1.9 (95% CI 1.45–2.44) vs. 15.67 (95% CI 12.63–19.22) per 100 patient-years; p < 0.05). A cut-off point of 4 points (CCI4) had a sensitivity of 82% (95% CI 75–89) and a specificity of 30% (95% CI 29–31) to predict major bleeding beyond the third month. CCI4 reclassification improved the NB of the RIETE bleeding score to predict bleeding beyond the third month (CCI4 NB 1.78% vs. RIETE NB 0.44%). Although the AUC of the CCI to predict major bleeding was modest, it could become an additional help to select patients aged > 75 years that obtain more benefit of extended anticoagulation, due to a lower risk for bleeding and better survival.
Systemic lupus erythematosus (SLE) is an autoimmune disease with a broad range of clinical manifestations and a heterogeneous disease course. There is no cure for SLE, but current standard ...pharmacotherapies can improve disease prognosis in most patients. However, some patients are refractory to conventional treatments and require alternative treatment options. The present study is aimed at identifying predictors of clinical response to allogeneic bone marrow-derived or umbilical cord-derived mesenchymal stem cell (BM-/UC-MSC) transplant in SLE. All adult patients identified in the Nanjing database with an SLE Disease Activity Index (SLEDAI) score≥8 at baseline that had undergone MSC transplant and who had at least 1 year of follow-up after one or two successive intravenous injections of allogeneic BM-/UC-MSCs (1 million/kg) were analyzed. SLE symptoms and SLEDAI were assessed at baseline and during follow-up to determine low disease activity (LDA) and clinical remission (CR) at 1, 3, 6, and 12 months. Sixty-nine patients were included in the study, with a median (range) SLEDAI of 13 (8-34) at baseline. Among the 69 patients, 40 (58%) achieved LDA and 16 (23%) achieved CR with a SLEDAI of 9 (4–20), 8 (0-16), 6 (0-18), and 5 (0-18) after 1, 3, 6, and 12 months, respectively. Older age (p=0.006) and no arthralgia/arthritis at baseline (p=0.03) were associated with a higher rate of LDA. Achieving CR was associated with older age (p=0.033), no arthralgia/arthritis at baseline (p=0.001), and no prior use of cyclophosphamide (p=0.003) or hydroxychloroquine (p=0.016). Future studies using unique immunosuppressive regimens and allogeneic MSC sources will further elucidate determinants of clinical response to MSC transplant in SLE.
Digital ulcers are the most frequent vascular manifestations of systemic sclerosis (SSc). Clinical features of patients with prior or current digital ulcers have not been extensively described. This ...cross-sectional analysis of a large multicenter cohort compared the characteristics of SSc patients with prior or current digital ulcers with those never affected.
Patients with prior/current digital ulcers or never affected were identified in the cohort of SSc patients enrolled in the French ItinérAIR-Sclérodermie registry. Rodnan skin scores, pulmonary function test results, and clinical and immunological data were analyzed to identify digital ulcerassociated clinical features.
Of 599 SSc patients, 317 had prior or current digital ulcers. These patients were more frequently male, with impaired diffusing capacity for carbon monoxide (DLCO), and higher Rodnan skin scores than patients never affected by digital ulcers. In a multivariate analysis, male gender, early onset of SSc, increased duration of SSc, high Rodnan skin score, and presence of anti-topoisomerase I antibodies (anti-topo I) were associated with prior or current digital ulcers. Comparison of patients with current digital ulcers versus patients never affected indicated that affected patients had increased duration of SSc, impaired DLCO, increased Rodnan score, and younger age at onset of SSc.
Male patients with early onset SSc, more severe skin fibrosis, impaired DLCO, and anti-topo I were most likely to exhibit prior or current digital ulcers. Confirmation of these results in a prospective longitudinal study may enable identification of patients at greatest risk of developing digital ulcers, facilitating management of this disabling complication.
To investigate association between genetic polymorphisms of GST, CYP and renal outcome or occurrence of adverse drug reactions (ADRs) in lupus nephritis (LN) treated with cyclophosphamide (CYC). CYC, ...as a pro-drug, requires bioactivation through multiple hepatic cytochrome P450s and glutathione S transferases (GST).
We carried out a multicentric retrospective study including 70 patients with proliferative LN treated with CYC. Patients were genotyped for polymorphisms of the CYP2B6, CYP2C19, GSTP1, GSTM1 and GSTT1 genes. Complete remission (CR) was defined as proteinuria ≤0.33g/day and serum creatinine ≤124 µmol/l. Partial remission (PR) was defined as proteinuria ≤1.5g/day with a 50% decrease of the baseline proteinuria value and serum creatinine no greater than 25% above baseline.
Most patients were women (84%) and 77% were Caucasian. The mean age at LN diagnosis was 41 ± 10 years. The frequency of patients carrying the GST null genotype GSTT1-, GSTM1-, and the Ile→105Val GSTP1 genotype were respectively 38%, 60% and 44%. In multivariate analysis, the Ile→105Val GSTP1 genotype was an independent factor of poor renal outcome (achievement of CR or PR) (OR = 5.01 95% CI 1.02-24.51) and the sole factor that influenced occurrence of ADRs was the GSTM1 null genotype (OR = 3.34 95% CI 1.064-10.58). No association between polymorphisms of cytochrome P450s gene and efficacy or ADRs was observed.
This study suggests that GST polymorphisms highly impact renal outcome and occurrence of ADRs related to CYC in LN patients.
In patients receiving anticoagulant therapy for venous thromboembolism (VTE), the important issue of anemia influence on the risk of bleeding has not been consistently studied. We used the large ...registry data RIETE (Registro Informatizado Enfermedad Tromboembólica) to compare the rate of major bleeding in patients receiving anticoagulant therapy for VTE according to the presence or absence of anemia at baseline. Patients with or without cancer were separately studied. Until August 2016, 63492 patients had been enrolled. Of these, 21652 (34%) had anemia and 14312 (23%) had cancer. Anemia was found in 57% of the patients with cancer and in 28% without (odds ratio 3.46; 95% CI 3.33–3.60). During the course of anticoagulant therapy, 680 patients with cancer had a major bleeding event (gastrointestinal tract 43%, intracranial 14%, hematoma 12%). Cancer patients with anemia had a higher rate of major bleeding (rate ratio RR: 2.52; 95% CI 2.14–2.97) and fatal bleeding (RR 2.73; 95% CI 1.95–3.86) than those without anemia. During the course of anticoagulation, 1133 patients without cancer had major bleeding (gastrointestinal tract 32%, hematoma 24%, intracranial 21%). Patients with anemia had a higher rate of major bleeding (RR 2.84; 95% CI 2.52–2.39) and fatal bleeding (RR 2.76; 95% CI 2.07–3.67) than those without. On a multivariable analysis, anemia independently predicted the risk for major bleeding in patients with and without cancer (hazard ratios: 1.66; 95% CI 1.40–1.96 and 1.95; 95% CI 1.72–2.20, respectively). During anticoagulation for VTE, both cancer- and non-cancer anemic patients had a higher risk for major bleeding than those without anemia. In anemic patients (with or without cancer), the rate of major bleeding during the course of anticoagulant therapy exceeded the rate of VTE recurrences. In patients without anemia the rate of major bleeding was lower than the rate of VTE recurrences.
Treatment for autoimmune diseases such as systemic lupus erythematosus (SLE), idiopathic inflammatory myositis, and systemic sclerosis often involves long-term immune suppression. Resetting aberrant ...autoimmunity in these diseases through deep depletion of B cells is a potential strategy for achieving sustained drug-free remission.
We evaluated 15 patients with severe SLE (8 patients), idiopathic inflammatory myositis (3 patients), or systemic sclerosis (4 patients) who received a single infusion of CD19 chimeric antigen receptor (CAR) T cells after preconditioning with fludarabine and cyclophosphamide. Efficacy up to 2 years after CAR T-cell infusion was assessed by means of Definition of Remission in SLE (DORIS) remission criteria, American College of Rheumatology-European League against Rheumatism (ACR-EULAR) major clinical response, and the score on the European Scleroderma Trials and Research Group (EUSTAR) activity index (with higher scores indicating greater disease activity), among others. Safety variables, including cytokine release syndrome and infections, were recorded.
The median follow-up was 15 months (range, 4 to 29). The mean (±SD) duration of B-cell aplasia was 112±47 days. All the patients with SLE had DORIS remission, all the patients with idiopathic inflammatory myositis had an ACR-EULAR major clinical response, and all the patients with systemic sclerosis had a decrease in the score on the EUSTAR activity index. Immunosuppressive therapy was completely stopped in all the patients. Grade 1 cytokine release syndrome occurred in 10 patients. One patient each had grade 2 cytokine release syndrome, grade 1 immune effector cell-associated neurotoxicity syndrome, and pneumonia that resulted in hospitalization.
In this case series, CD19 CAR T-cell transfer appeared to be feasible, safe, and efficacious in three different autoimmune diseases, providing rationale for further controlled clinical trials. (Funded by Deutsche Forschungsgemeinschaft and others.).
Women with scleroderma (SSc) maintain significantly higher quantities of persisting fetal microchimerism (FMc) from complete or incomplete pregnancies in their peripheral blood compared to healthy ...women. The non-classical class-I human leukocyte antigen (HLA) molecule HLA-G plays a pivotal role for the implantation and maintenance of pregnancy and has often been investigated in offspring from women with pregnancy complications. However data show that maternal
polymorphisms as well as maternal soluble HLA-G (sHLA-G) expression could influence pregnancy outcome. Here, we aimed to investigate the underlying role of maternal sHLA-G expression and
polymorphisms on the persistence of FMc. We measured sHLA-G levels by enzyme linked immunosorbent assay in plasma samples from 88 healthy women and 74 women with SSc. Male Mc was quantified by DYS14 real-time PCR in blood samples from 58 women who had previously given birth to at least one male child. Furthermore, eight
5'URR/3'UTR polymorphisms, previously described as influencing HLA-G expression, were performed on DNA samples from 96 healthy women and 106 women with SSc. Peripheral sHLA-G was at lower concentration in plasma from SSc (76.2 ± 48.3 IU/mL) compared to healthy women (117.5 ± 60.1 IU/mL,
< 0.0001), independently of clinical subtypes, autoantibody profiles, disease duration, or treatments. Moreover, sHLA-G levels were inversely correlated to FMc quantities (Spearman correlation,
< 0.01). Finally, women with SSc had lower sHLA-G independently of the eight
5'URR/3'UTR polymorphisms, although they were statistically more often homozygous than heterozygous for
polymorphism genotypes -716 (G/T), -201 (G/A), 14 bp (ins/del), and +3,142 (G/A) than healthy women. In conclusion, women with SSc display less sHLA-G expression independently of the eight
polymorphisms tested. This decreased production correlates with higher quantities of persisting FMc commonly observed in blood from SSc women. These results shed some lights on the contribution of the maternal HLA-G protein to long-term persistent fetal Mc and initiate new perspectives in this field.
PDF
