Thrombocytopenia (TP) is considered as a warning sign of high-risk antiphospholipid syndrome (APS) and sometimes a paradoxical sign of anti-thrombosis treatment. Currently, there is an extreme ...paucity of effective and safe drugs for long-term management of TP in primary APS patients; therefore, we explored the efficacy and safety of sirolimus monotherapy.
In this real-world study, we included 7 consecutive patients with primary APS who received sirolimus monotherapy for TP. Oral sirolimus was initiated at a dose of 1-2 mg once daily and then adjusted primarily based on clinical efficacy and tolerance, with consideration of the sirolimus trough concentration of ≤15 ng/ml.
Of included patients, the median age was 58 years with a median disease course of 1.5 years and 4 patients were treatment-naïve. All patients completed 6 months of sirolimus therapy with a median follow-up of 6 months (range: 6-15). All patients received sirolimus monotherapy for TP during the entire follow-up, without any additional agents. Overall, the platelet count exhibited a substantially increasing trend after sirolimus administration during the first 6 months (p < 0.001) and stability later. Specifically, the median platelet count was significantly increased from 59 × 10
/l before sirolimus to 90 × 10
/l at month 1 (p = 0.028), 131 × 10
/l at 3 months (p = 0.028), and 178 × 10
/l at 6 months (p = 0.018). Overall and complete responses were respectively achieved in 6 (85.7%) and 5 (71.4%) patients at month 6. Importantly, overall response was achieved in all 4 treatment-naïve patients. Additionally, there were different extents of decline in the titers of antiphospholipid antibodies after sirolimus treatment. Regarding safety, only one patient experienced an elevated cholesterol level with recovery after atorvastatin treatment.
Sirolimus monotherapy confers good efficacy and tolerance for TP in primary APS patients and therefore may be considered as a first-line therapy.
Immune checkpoint inhibitors (ICIs) have brought impressive benefits to cancer patients, however often accompanied with immune-related adverse events (irAEs). We aimed to investigate the association ...of irAEs with efficacy and overall survival in cancer patients treated by ICIs, and further quantify the association by stratifying subgroups.
PubMed, EMBASE and Cochrane library from database inception to 29 August 2019 were systematically searched. Articles reporting association of objective response rate (ORR), progression-free survival (PFS), overall survival (OS) with irAEs in cancer patients treated with approved ICIs were included. Adjusted odds ratios (OR) with 95% confidential intervals (CIs) were calculated for ORR, and hazard ratios (HR) were used for PFS and OS.
A total of 52 articles comprising 9,156 patients were included. Pooled data demonstrated a statistically significant greater probability of achieving objective tumor response for patients with irAEs compared to those without (OR 3.91, 95% CI 3.05-5.02). In overall meta-analysis, patients who developed irAEs presented a prolonged PFS (HR 0.54; 95% CI 0.46-0.62) and OS (HR 0.51; 95% CI 0.41-0.59). More specifically, irAEs in certain cancer types (NSCLC and melanoma) and organs (skin and endocrine) were robustly associated with better clinical outcomes, while this association needs further verification regarding other tumors. High grade toxicities (G3-5) were not associated with a significantly favorable PFS or OS. Additionally, the association between irAEs and clinical benefit seemed to be more definite in patients receiving PD-(L)1 blockade than CTLA-4 blockade. Pooled data from landmark analyses displayed consistent results.
The occurrence of irAEs predicted improved tumor response and better survival in overall cancer patients treated with ICIs. Notably, the association stayed robust in certain cancer types (NSCLC and melanoma) and organ-specific irAEs (skin and endocrine).
The role of IL-33, particularly in tumor growth and tumor immunity, remains ill-defined. We show that exogenous IL-33 can induce robust antitumor effect through a CD8
T cell-dependent mechanism. ...Systemic administration of rIL-33 alone was sufficient to inhibit growth of established tumors in transplant and de novo melanoma tumorigenesis models. Notably, in addition to a direct action on CD8
T cell expansion and IFN-γ production, rIL-33 therapy activated myeloid dendritic cells (mDCs) in tumor-bearing mice, restored antitumor T cell activity, and increased Ag cross-presentation within the tumor microenvironment. Furthermore, combination therapy consisting of rIL-33 and agonistic anti-CD40 Abs demonstrated synergistic antitumor activity. Specifically, MyD88, an essential component of the IL-33 signaling pathway, was required for the IL-33-mediated increase in mDC number and upregulation in expression of costimulatory molecules. Importantly, we identified that the IL-33 receptor ST2, MyD88, and STAT1 cooperate to induce costimulatory molecule expression on mDCs in response to rIL-33. Thus, our study revealed a novel IL-33-ST2-MyD88-STAT1 axis that restores mDC activation and maturation in established cancer and, thereby, the magnitude of antitumor immune responses, suggesting a potential use of rIL-33 as a new immunotherapy option to treat established cancer.
Paradoxical psoriasis or psoriasiform lesions induced by anti-tumor necrosis factor (anti-TNF) therapies receive increasing attention worldwide. However, no comprehensive meta-analysis investigating ...the incidence estimates and risk factors for anti-TNF-induced psoriasis is currently available. We aimed to precisely quantify its incidence as well as risk factors in patients with inflammatory bowel disease (IBD).
This study was registered on PROSPERO database under review registration number CRD42021233695. The electronic databases PubMed, EMBASE, and the Cochrane library were comprehensively searched for observational studies published as full-length papers in English and reporting the incidence and/or predictors for psoriasis or psoriasiform lesions in IBD patients. A random-effects meta-analysis was performed to calculate the pooled incidence. Pooled odds ratio (OR) and 95% confidence interval for potential predictors were combined using a fixed-effects or random-effects model.
In total, 30 articles comprising 24,547 IBD patients treated by anti-TNF were finally included. The overall pooled incidence of psoriasis and/or psoriasiform lesions following anti-TNF therapy was 6.0% (5.0-7.0%;
= 93.9%), with 6.9% (5.1-8.7%;
= 92.4%) for psoriasiform lesions and 4.6% (3.6-5.6%;
= 93.9%) for psoriasis. Multivariable meta-regression analysis indicated regions and populations that significantly contributed to the heterogeneity. A statistically higher risk for psoriasis or psoriasiform lesions during anti-TNF therapy was observed in female patients (OR 1.46, 1.23-1.73), those who are at a younger age at anti-TNF initiation (OR 1.03, 1.00-1.05), smokers (OR 1.97, 1.56-2.48), ileocolonic Crohn's disease patients (OR 1.48, 1.03-2.13), and those who are using adalimumab or certolizumab (
. infliximab) (OR: 1.48 and 2.87 respectively).
The incidence of psoriasis or psoriasiform lesions was not uncommon in IBD patients following anti-TNF therapy. Female, younger age, smoker, ileocolonic Crohn's disease, and the types of anti-TNF were significantly associated with such risk. These findings may help gastroenterologists to make more individualized decisions and understand the mechanisms of this paradoxical phenomenon.
https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=233695, identifier CRD42021233695.
Background
In patients with rheumatoid arthritis (RA), glucocorticoids (GC) should be firstly discontinued before considering tapering conventional synthetic disease-modifying anti-rheumatic drugs ...(csDMARD) or other biological agents. We aim to determine risk factors for flare after GC withdrawal in RA patients undergoing csDMARDs.
Method
RA patients who discontinued GC with continuation of csDMARD were selected from a longitudinal real-world cohort. Established RA was defined as disease duration over 12 months. Dissatisfied RA control was defined as the proportion of simplified disease activity index (SDAI)-based remission time to total time from GC initiation to discontinuation less than 50%. Logistic regression was used to analyze the independent risk factors for flare after GC discontinuation and results were expressed as odds ratio (OR).
Results
There were 115 eligible RA patients discounted GC with continuation of csDMARDs (methotrexate: 80%; hydroxychloroquine: 61%; csDMARDs combination: 79%). Of these, 24 patients experienced flare after GC discontinuation. Compared with relapse-free patients, flare patients were more likely to have established RA (75% vs. 49%, p=0.025), higher median cumulative prednisolone dosages (3.3g vs. 2.2g, p=0.004), and higher proportion of dissatisfied RA control during GC usage (66% vs. 33%, p=0.038). In multivariate analysis, significantly increased flare risk was predicted by established RA (OR 2.93 1.02-8.43), cumulative prednisolone dose > 2.5g (OR 3.69 1.34-10.19) and dissatisfied RA control (OR 3.00 1.09-8.30). Flare risk was increased with increases in number of risk factors, with highest OR of 11.56 in patients with three risk factors (p for trend=0.002).
Conclusions
Flare following GC withdrawal is not common in RA patients with undergoing csDMARDs therapy. Established RA, higher cumulative GC dose and dissatisfied RA control before GC discontinuation are important factors associated with flare after GC withdrawal.
Overlapping Sjogren's syndrome (SS) is not uncommon in rheumatoid arthritis (RA) and considered as a probable detrimental factor of RA. But data on the impact of overlapping SS on RA therapeutic ...response is limited. Our current study aimed to identify the effect in a real-world cohort from 2009 to 2019.
The medical records of RA patients who visited the rheumatology clinic of our medical center from 2009 to 2019 were reviewed. Their composite disease activity scores at each follow-up point were collected. The therapeutic response between RA patients with SS (RA-SS) and without (RA-noSS) was compared. To correct confounders which may affect the therapeutic response, both propensity score matched and unmatched cohorts were analyzed by using the Cox proportional hazards model.
Among the 1099 RA patients, 129 (11.7%) overlapped with SS were validated by positive anti-SSA or a minor salivary gland biopsy with histological changes suggestive of SS. After propensity score matching based on their baseline characteristics, 126 of 129 RA-SS and 126 of 970 RA-noSS patients were statistically extracted. Overlapping SS was associated with a 29%, 26%, 18%, and 22% lower probability of reaching remission defined by DAS28-ESR, DAS28-CRP, SDAI, and CDAI in RA patients, respectively. Similar decreased probability of reaching low disease activity was also observed. Although ESR was most significantly affected (HR 0.69, 95% CI 0.61-0.79), other component of composite RA disease activity score was also affected by overlapping SS. Stratification by age, RF/ACPA status, or baseline DAS28-CRP was not associated with change of results.
Overlapping SS is associated with lower probability of reaching remission or low disease activity in RA patients and should be regarded as one of the poor prognostic factors.
Post-infarction cardiovascular remodeling and heart failure are the leading cause of myocardial infarction (MI)-driven death during the past decades. Experimental observations have involved ...intestinal microbiota in the susceptibility to MI in mice; however, in humans, identifying whether translocation of gut bacteria to systemic circulation contributes to cardiovascular events post-MI remains a major challenge.
Here, we carried out a metagenomic analysis to characterize the systemic bacteria in a cohort of 49 healthy control individuals, 50 stable coronary heart disease (CHD) subjects, and 100 ST-segment elevation myocardial infarction (STEMI) patients. We report for the first time higher microbial richness and diversity in the systemic microbiome of STEMI patients. More than 12% of post-STEMI blood bacteria were dominated by intestinal microbiota (Lactobacillus, Bacteroides, and Streptococcus). The significantly increased product of gut bacterial translocation (LPS and D-lactate) was correlated with systemic inflammation and predicted adverse cardiovascular events. Following experimental MI, compromised left ventricle (LV) function and intestinal hypoperfusion drove gut permeability elevation through tight junction protein suppression and intestinal mucosal injury. Upon abrogation of gut bacterial translocation by antibiotic treatment, both systemic inflammation and cardiomyocyte injury in MI mice were alleviated.
Our results provide the first evidence that cardiovascular outcomes post-MI are driven by intestinal microbiota translocation into systemic circulation. New therapeutic strategies targeting to protect the gut barrier and eliminate gut bacteria translocation may reduce or even prevent cardiovascular events post-MI.
ObjectiveGlucocorticoids (GC) withdrawal is part of the targets in current recommendations for SLE, but relapse is the most worrying issue. We aimed to investigate the predictors for flare in ...patients with SLE after GC withdrawal.MethodsWe systematically searched PubMed, EMBASE and Cochrane Library as well as Scopus databases up to 9 July 2021 for studies concerning predictive factors of relapses in patients with SLE after GC cessation. Pooled OR and 95% CI were combined using a random-effects or fixed-effects model.Results635 patients with SLE with GC discontinuation in 9 publications were eligible for the final analysis. Of them, 99.5% patients were in clinical remission before GC withdrawal. Serologically active yet clinically quiescent (SACQ) was associated with an increased risk of flare after GC withdrawal (OR 1.78, 95% CI (1.00 to 3.15)). Older age and concomitant use of hydroxychloroquine (HCQ) trended towards decreased risk of flare (weighted mean difference (WMD) −2.04, 95% CI (−4.15 to 0.06) for age and OR 0.50, 95% CI (0.23 to 1.07) for HCQ), yet not statistically significant. No significant association was observed regarding gender (pooled OR 1.75; 95% CI (0.59 to 5.20)), disease duration (WMD −11.91, 95% CI (−27.73 to 3.91)), remission duration (WMD −8.55, 95% CI (−33.33 to 16.23)), GC treatment duration (WMD −10.10, 95% CI (−64.09 to 43.88)), concomitant use of immunosuppressant (OR 0.86, 95% CI (0.48 to 1.53)).ConclusionYounger age and SACQ were potential risk factors of SLE flare among patients who discontinued GC. HCQ, but not immunosuppressant might prevent flare. GC withdrawal should be done with caution in this subgroup of patients.
Pulmonary arterial hypertension (PAH) isa fatal disease characterized by vascular remodeling and chronic inflammation. Macrophages are the key orchestrators of inflammatory and repair responses, and ...have been demonstrated to be vital in the pathogenesis of PAH. However, specific phenotype of macrophage polarization (M1 & M2 macrophage) in the development of PAH and the underlying mechanisms how they work are still largely unclear. A rat model of monocrotaline (MCT) induced PAH was used. Hemodynamic analysis and histopathological experiments were conducted at day 3, 7, 14, 21 and 28, respectively. In PAH rat lung tissue, confocal microscopic images showed that CD68+NOS2+ M1-like macrophages were remarkably infiltrated on early stage, but dramatically decreased in mid-late stage. Meanwhile, CD68+CD206+ M2-like macrophages in lung tissue accumulated gradually since day 7 to day 28, and the relative ratio of M2/M1 macrophage increased over time. Results detected by western blot and immunohistochemistry were consistent. Further vitro functional studies revealed the possible mechanism involved in this pathophysiological process. By using Transwell co-culture system, it was found that M1 macrophages inducedendothelial cellapoptosis, while M2 macrophages significantly promoted proliferation of both endothelial cell and smooth muscle cell.These data preliminarily demonstrated a temporal dynamic change of macrophage M1/M2 polarization status in the development of experimental PAH. M1 macrophages participated in the initial stage of inflammation by accelerating apoptosis of endothelial cell, while M2 macrophages predominated in the reparative stage of inflammation and the followed stage of aberrant tissue remodeling.
Abstract
Objective
To clarify the frequency and outcome of patients with systemic lupus erythematosus (SLE) who achieved the clinical state as serologically active clinically quiescent (SACQ) and to ...identify factors associated with the flare of disease.
Methods
Clinical data of patients diagnosed as SLE and followed in Peking University First Hospital from 2009 to 2015 were retrospectively reviewed. Six hundred eighty-two patients who were followed up for more than 6 months were analyzed. SACQ was defined as an at least a 6-month period with persistent serologic activity and without clinical activity and daily dose of prednisone or equivalent were less than 7.5 mg. Serologically quiescent clinically quiescent (SQCQ) patients served as control groups. Data including demographics, initial symptoms, duration to SACQ, treatments before and after SACQ, and characteristics of the patients suffered from flare were analyzed.
Results
Among the 682 patients, 170 patients were SACQ (24.9%) and 187 patients were SQCQ. SQCQ patients (38.61 ± 15.08 years old) were older at baseline than SACQ patients (38.61 ± 15.08 years vs. 32.09 ± 14.35 years,
p
< 0.001). Of 170 SACQ patients, 32.9% experienced flare that was significantly higher than 15.5% of SQCQ patients (29/187). Corticosteroids (OR 1.323, 95% CI 1.129 to 1.550;
p
= 0.001) was an independent risk factor for flare, while antimalarials (OR 0.045, 95% CI 0.004 to 0.474;
p
= 0.010) and immunosuppressants (OR 0.332, 95% CI 0.156 to 0.706;
p =
0.004) were protective factors in SACQ patients; however, only antimalarials was protective factors in SQCQ patients (OR 0.028, 95% CI 0.001 to 0.743;
p =
0.033).
Conclusion
About one third of SLE patients with SACQ experience flare, significantly more frequent than that of patients with SQCQ. Thus, approach to prevent flare in SACQ patient is required. Maintenance therapy of hydroxychloroquine and immunosuppressant agents may be protective and beneficial treatment strategy in these patients.
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