Clinical recommendations for perioperative immunotherapy-induced adverse events in patients with non-small cell lung cancer.

Perioperative adjuvant treatment has become an increasingly important aspect of the management of patients with non-small cell lung cancer (NSCLC). In particular, the success of immune checkpoint inhibitors, such as antibodies against PD-1 and PD-L1, in patients with lung cancer has increased our expectations for the success of these therapeutics as neoadjuvant immunotherapy. Neoadjuvant therapy is widely used in patients with resectable stage IIIA NSCLC and can reduce primary tumor and lymph node stage, improve the complete resection rate, and eliminate microsatellite foci; however, complete pathological response is rare. Moreover, because the clinical benefit of neoadjuvant therapy is not obvious and may complicate surgery, it has not yet entered the mainstream of clinical treatment. Small-scale clinical studies performed in recent years have shown improvements in the major pathological remission rate after neoadjuvant therapy, suggesting that it will soon become an important part of NSCLC treatment. Nevertheless, neoadjuvant immunotherapy may be accompanied by serious adverse reactions that lead to delay or cancellation of surgery, additional illness, and even death, and have therefore attracted much attention. In this article, we draw on several sources of information, including (i) guidelines on adverse reactions related to immune checkpoint inhibitors, (ii) published data from large-scale clinical studies in thoracic surgery, and (iii) practical experience and published cases, to provide clinical recommendations on adverse events in NSCLC patients induced by perioperative immunotherapy.

Distinctive Clinical Characteristics and Outcome of ILD-Onset Rheumatoid Arthritis and ACPA-Positive ILD: a Longitudinal Cohort of 282 Cases.

The aim of this study is to investigate the clinical features and outcome of interstitial lung disease (ILD)-onset rheumatoid arthritis (RA) and anti-citrullinated protein antibody (ACPA)-positive ILD-only patients. Arthritis-onset and ILD-onset RA-ILD and ACPA-positive ILD-only patients consecutively admitted to Peking Union Medical College Hospital from January 2008 to December 2017 were enrolled and followed-up. Their demographic, clinical, and laboratory features as well as outcome were collected and analyzed. Compared with arthritis-onset RA-ILD (n = 166, median arthritis-to-ILD interval: 60 months), the ILD-onset RA-ILD (n = 75, median ILD-to-arthritis interval: 2 months) had less rheumatoid nodules and higher titer of ACPA, and manifested more stable ILD (median estimated progression-free survival: 120 vs. 100 months, p = 0.019). Elder age (≥ 65 years) at ILD diagnosis and UIP pattern were associated with ILD progression by both univariate and Cox hazards modeling analysis (p < 0.05). In ACPA-positive ILD-only patients (n = 41), arthritis developed in 7 (17.1%) female patients after a median interval of 24 months. ACPA-positive ILD who subsequently developed arthritis exhibited higher frequency of rheumatoid factor (RF), higher titer of ACPA, and higher levels of ESR and CRP (p < 0.05). Multivariate regression analysis showed that positive RF (OR 12.55, 95% CI 1.31 to 120.48) was the independent risk factor for arthritis development in ACPA-positive ILD-only patients. ILD-onset RA-ILD had more stable ILD compared with arthritis-onset RA-ILD. ACPA-positive ILD patients with positive RF are at increased risk of developing RA.

Antagonizing miR-7 suppresses B cell hyperresponsiveness and inhibits lupus development.

OBJECTIVES: The objective of this study was to address the biological function of miR-7 in an animal model of systemic lupus erythematosus. METHODS: MRLlpr/lpr lupus mice were administrated antagomiR-7 or a scramble control by tail vein for 5weeks. Three groups of animals' tissues were assessed for lupus manifestations by immunofluorescence and immunohistochemistry, and serum was examined for levels of autoantibodies and inflammatory cytokines. Splenic B cell subsets were assessed for intracellular expression of PI3K signaling by FACS. Finally, the ability of the miR-7 antagomir to regulate the expansion of T follicular helper (Tfh) cells and B cell hyperresponsiveness was further explored. RESULTS: We found that miR-7 was up-regulated in MRLlpr/lpr lupus mice and directly targeted PTEN mRNA in B cells. Up-regulated miR-7 in MRLlpr/lpr lupus B cells was negatively correlated with PTEN expression. Notably, miR-7 antagomir treatment reduced lupus manifestations in MRLlpr/lpr lupus mice. miR-7-mediated down-regulation of PTEN/AKT signaling promoted B cell differentiation into plasmablasts/plasma cells and spontaneous germinal center (GC) formation, whereas miR-7 antagomir normalized splenic B cell subtypes. Besides suppressing the activation of B cells, miR-7 antagomir intervention also down-regulated STAT3 phosphorylation and production of IL-21 and reduced Tfh expansion. CONCLUSION: The above data have demonstrated the critical roles of miR-7 not only in regulating PTEN expression and also B cell and Tfh cell function in lupus-prone MRLlpr/lpr lupus mice. Furthermore, the disease manifestations in MRLlpr/lpr lupus mice are efficiently improved by miR-7 antagomir, indicating miR-7 as a potential treatment strategy in SLE.

EZH2 deficiency attenuates Treg differentiation in rheumatoid arthritis.

The chromatin modifier enhancer of zeste homolog 2 (EZH2) methylates lysine 27 of histone H3 (H3K27) and regulates T cell differentiation. However, the potential role of EZH2 in the pathogenesis of rheumatoid arthritis (RA) remains elusive. We analyzed EZH2 expression in PBMC, CD4+ T cells, CD19+ B cell, and CD14+ monocytes from active treatment-naïve RA patients and healthy controls (HC). We also suppressed EZH2 expression using EZH2 inhibitor GSK126 and measured CD4+ T cell differentiation, proliferation and apoptosis. We further examined TGFß-SMAD and RUNX1 signaling pathways in EZH2-suppressed CD4+ T cells. Finally, we explored the regulation mechanism of EZH2 by RA synovial fluid and fibroblast-like synoviocyte (FLS) by neutralizing key proinflammatory cytokines. EZH2 expression is lower in PBMC and CD4+ T cells from RA patients than those from HC. EZH2 inhibition suppressed regulatory T cells (Tregs) differentiation and FOXP3 transcription, and downregulated RUNX1 and upregulated SMAD7 expression in CD4+ T cells. RA synovial fluid and fibroblast-like synoviocytes suppressed EZH2 expression in CD4+ T cells, which was partially neutralized by anti-IL17 antibody. Taken together, EZH2 in CD4+ T cells from RA patients was attenuated, which suppressed FOXP3 transcription through downregulating RUNX1 and upregulating SMAD7 in CD4+ T cells, and ultimately suppressed Tregs differentiation. IL17 in RA synovial fluid might promote downregulation of EZH2 in CD4+ T cells. Defective EZH2 in CD4+ T cells might contribute to Treg deficiency in RA.

Metagenomic profiling of the pro-inflammatory gut microbiota in ankylosing spondylitis.

OBJECTIVE: Gut dysbiosis has been reported implicated in ankylosing spondylitis (AS), a common chronic inflammatory disease mainly affects sacroiliac joints and spine. Utilizing deep sequencing on the feces of untreated AS patients, our study aimed at providing an in-depth understanding of AS gut microbiota. METHODS: We analyzed the fecal metagenome of 85 untreated AS patients and 62 healthy controls by metagenomic shotgun sequencing, and 23 post-treatment feces of those AS patients were collected for comparison. Comparative analyses among different cohorts including AS, rheumatoid arthritis and Behcet's disease were performed to uncover some common signatures related to inflammatory arthritis. Molecular mimicry of a microbial peptide was also demonstrated by ELISpot assay. RESULTS: We identified AS-enriched species including Bacteroides coprophilus, Parabacteroides distasonis, Eubacterium siraeum, Acidaminococcus fermentans and Prevotella copri. Pathway analysis revealed increased oxidative phosphorylation, lipopolysaccharide biosynthesis and glycosaminoglycan degradation in AS gut microbiota. Microbial signatures of AS gut selected by random forest model showed high distinguishing accuracy. Some common signatures related to autoimmunity, such as Bacteroides fragilis and type III secretion system (T3SS), were also found. Finally, in vitro experiments demonstrated an increased amount of IFN-γ producing cells triggered by a bacterial peptide of AS-enriched species, mimicking type II collagen. CONCLUSIONS: These findings collectively indicate that gut microbiota was perturbed in untreated AS patients with diagnostic potential, and some AS-enriched species might be triggers of autoimmunity by molecular mimicry. Additionally, different inflammatory arthritis shared some common microbial signatures.

Usefulness of Myocardial Strain and Twist for Early Detection of Myocardial Dysfunction in Patients With Autoimmune Diseases.

Cardiac involvement in autoimmune diseases (AD) is common but underdiagnosed due to a lack of sensitive imaging methods. We aim to evaluate the characteristics of left ventricular (LV) systolic dysfunction in patients with AD using deformational parameters from 2-dimensional speckle-tracking echocardiography (STE). We retrospectively enrolled 86 AD patients and 71 healthy controls. All subjects underwent transthoracic echocardiography and STE to analyze LV strain and twist. A twist-radial displacement loop was constructed to investigate the relation between LV contractility and dimension. In AD patients, 68 had preserved LV ejection fraction (EF ≥ 50%), and 18 had reduced LVEF (EF < 50%). The patients with preserved LVEF exhibited significantly lower values of global longitudinal, circumferential, and radial strain than controls (-19.11 ± 4.18 vs -21.49 ± 2.53%, -25.17 ± 5.04% vs -27.37 ± 2.87%, 17.68 ± 5.69% vs 21.17 ± 6.44%, respectively; all p <0.01) and a marked attenuation in peak twist (14.24 ± 5.57 vs 18.10 ± 5.97, p <0.01) attributed to impaired apical rotation (9.03 ± 5.17 vs 12.79 ± 5.99, p <0.01). AD patients were more likely to present with abnormal loop types with flat ascending slope and delayed peak twist time. In conclusion, abnormal strain and twist precede deterioration in LVEF, suggesting early myocardial involvement in AD. STE can be used as a good alternative for early detection of myocardial dysfunction in AD patients.

Complement C1q synergizes with PTX3 in promoting NLRP3 inflammasome over-activation and pyroptosis in rheumatoid arthritis.

Excessive inflammatory cytokines play crucial roles in the pathogenesis of rheumatoid arthritis (RA), however, the underlying mechanism remains unclear. In this study, we demonstrated that pentaxin 3 (PTX3), an essential component of innate immunity, was elevated in RA and preferentially bound to CD14+ monocytes. C1q promoted the binding and resulted in increased cell proliferation, activation and caspase-1-related late apoptotic cells (7-AAD+annexin V+), as well as enhanced release of inflammatory cytokines including TNF-α, IL-1ß and IL-6. Serum from RA patients, compared with healthy controls, induced gasdermin D (GSDMD)-dependent pyroptosis in monocytes, and this ability was associated with disease activity. Moreover, PTX3 synergized with C1q to promote pyroptosis in RA-serum pre-incubated monocytes by coordinately enhancing NLRP3 inflammasome over-activation and inducing GSDMD cleavage, cell swelling with large bubbles, caspase-1-dependent cell death and inflammatory cytokine release including IL-6. On the other hand, IL-6 promoted PTX3 plus C1q-induced pyroptosis in both normal and RA serum pre-incubated monocytes. These findings collectively implicated an important role of IL-6 in driving PTX3 plus C1q-mediated pyroptosis in RA and shed lights on a potential new treatment strategy targeting pyroptosis-mediated persistent inflammatory cytokine release.

Obstructive uropathy associated with rheumatoid arthritis successfully treated with steroids and immunosuppressive therapy: A case report.

RATIONALE: Urinary obstruction are relatively rare complications of autoimmune diseases including systemic lupus erythematosus and systemic vasculitis. It has never been reported in rheumatoid arthritis (RA). PATIENT CONCERNS: We report a case of a female patient with seropositive RA who presented with gross hematuria associated with worsening joint symptoms, found to have acute kidney injury (AKI), bilateral hydronephrosis with bilateral renal pelvis, and ureteral wall thickening. Uroscopy with biopsy demonstrated inflammation without evidence of malignancy. DIAGNOSES: Rheumatoid arthritis related inflammation and obstruction of the urinary tract. INTERVENTIONS: Prednisone 50 mg daily (tapering began 1 month later), iguratimod 50 mg daily, and leflunomide 20 mg daily were prescribed. OUTCOMES: The patient responded well to steroids and immunosuppressive therapy with complete resolution of hematuria, renal injury, and hydronephrosis. LESSONS: Our case showed that RA might cause local inflammation involving the urinary tract which leads to obstruction and AKI.

Standardized patient methodology in mainland China: a nationwide survey.

BACKGROUND: To describe the current status of standardized patient (SP) practice in mainland China. METHODS: We conducted a nationwide survey in 2016. One hundred and eighty-three SP educators (SPEs) responded to the questionnaire, representing 80 medical centers from 25 provinces in mainland China. All of these centers were affiliated with China Standardized Patients Practice Teaching Guidance. In the survey, we assessed the methods of SPs' recruitment, hourly wage, how SPs were used and challenges of SP role. We also compared these data among the 4 different regions in China. RESULTS: In mainland China, the most frequent range of SPs' age was between 30 and 40 years (24.8%). The SPs were usually recruited by recommendations from the SPEs or a current SP (43.8%), as well as advertising in the hospitals (43.8%). The mean hourly wage was US$12.60 for teaching activities and US$18.82 for medical examinations. The median frequency for training SPs was 12.9 times per year. The SPs were used in areas such as internal medicine (89.6%), surgery (79.2%) and pediatrics (56.3%). The most challenging parts for the SPs were to remember all of the key points of the cases (51.9%) and portraying the emotions of the case (51.9%). Almost half of the SPs reported that, when interacting with medical students, they had difficulty in providing feedback in consistent with students' learning objectives. SPs' gender, age, rewards and scenarios playing were different significantly among the 4 geographic regions in China (P < 0.05). CONCLUSIONS: This survey provided the reliable data on the current situation of SP application in China. SP activities have had an encouraging progress but regional development imbalance.

The efficacy and safety of antithrombotic therapy in patients with positive antiphospholipid antibodies receiving invasive procedures: experience from a single tertiary center.

OBJECTIVES: To evaluate the efficacy and safety of antithrombotic prophylaxis and to explore potential risk factors for thrombotic/bleeding events in patients with positive antiphospholipid (aPL) antibodies receiving invasive procedures. METHOD: All aPL-positive patients who underwent invasive procedures in Peking Union Medical College Hospital, from January 2002 to April 2018, were retrospectively enrolled. Demographic features, clinical features, antiphospholipid antibody profiles, types of invasive procedures, and antithrombotic management, as well as complications and outcomes, were systematically reviewed and recorded. RESULTS: A total of 111 aPL-positive patients with 130 invasive procedures were enrolled. One hundred nine (83.8%) cases were on regular antithrombotic therapy which started at least 1 month prior to the invasive procedures, with 58 (44.6%) receiving anticoagulation therapy, 27 (20.8%) receiving antiplatelet therapy, and 24 (18.5%) receiving both. During the periprocedural period, the median time free of antithrombotic therapy was 2.5 days (interquartile range 1.5-6.0 days). Two (1.5%) periprocedural thrombotic events and 18 (13.8%) bleeding events were identified. Large open/laparoscopic surgeries of the thorax and abdomen were associated with a higher risk of bleeding (OR 3.46, 95% CI 1.24-9.67, p = 0.014). All bleeding events were manageable and not life-threatening. CONCLUSIONS: Aggressive antithrombotic therapy was associated with fewer thrombotic events in aPL-positive patients receiving invasive procedures, but might contribute to an increased bleeding rate, especially in large open surgeries. This study justifies more caution in prophylactic antithrombotic therapy in periprocedural aPL-positive patients.

Renal involvement in primary Sjögren's syndrome: A retrospective study of 103 biopsy-proven cases from a single center in China.

AIM: To retrospectively investigate the features of renal involvements in patients with primary Sjögren's syndrome (pSS) with biopsy results. METHODS: A total of 2096 pSS inpatients at Peking Union Medical College Hospital in China from 2005 to 2015 were identified. Patients with biopsy-proven renal involvement (SS-renal) and matched controls (SS-only) were recruited. The clinical and pathologic features as well as treatments and outcomes were systematically analyzed. RESULTS: One hundred and three pSS nephritis (inpatients had biopsy-proven renal involvement. Tubulointerstitial 53, 51.5%) was the prominent pathologic pattern with glomerulonephritis (GN) present in 50 (48.5%) of the renal lesions. The patterns of GN lesions included membranous nephropathy (37, 35.9%), mesangial proliferative glomerulonephritis (six, 5.8%) or immunoglobulin A nephropathy (three, 2.9%), minimal change disease (four, 3.9%) and focal segmental glomerulosclerosis (three, 2.9%). Compared to SS-only patients, SS-renal patients had fewer dry eyes and positive objective xerostomia (P < 0.05). They presented with a significantly lower incidence of interstitial lung disease (ILD), leukocytopenia and elevated immunoglobulin G levels (P < 0.05). They received a larger initial dosage of corticosteroid and had a higher mortality rate (P < 0.05). CONCLUSION: This Chinese SS-renal population with biopsy results has diverse pathologic patterns and distinct clinical features. They are characterized with prominent renal-associated and mild SS-associated features. They received more vigorous treatment but had poorer prognosis.

Chemotaxis of Vδ2 T cells to the joints contributes to the pathogenesis of rheumatoid arthritis.

OBJECTIVES: To explore the role of Vδ2 T cells in the pathogenesis of rheumatoid arthritis (RA). METHODS: Sixty-eight patients with RA, 21 patients with osteoarthritis and 21 healthy controls were enrolled in the study. All patients with RA fulfilled the 2010 American College of Rheumatology/European League Against Rheumatism criteria for RA. Peripheral Vδ2T population, chemokine receptor expression and proinflammatory cytokine secretion were quantified by flow cytometry. The infiltration of Vδ2 T cells within the synovium was examined by immunohistochemistry and flow cytometry. The effect of tumour necrosis factor (TNF)-α and interleukin (IL)-6 on Vδ2 T migration was determined by flow cytometry and transwell migration assay. RESULTS: Peripheral Vδ2T cells, but not Vδ1 T cells, were significantly lower in patients with RA, which was negatively correlated with disease activity gauged by Disease Activity Score in 28 joints. Vδ2 T cells from RA accumulated in the synovium and produced high levels of proinflammatory cytokines including interferon-γ and IL-17. Phenotypically, Vδ2 T cells from RA showed elevated chemotaxis potential and expressed high levels of chemokine receptors CCR5 and CXCR3, which was driven by increased serum TNF-α through nuclear factor kappa B signalling. In vivo, TNF-α neutralising therapy dramatically downregulated CCR5 and CXCR3 on Vδ2 T cells and repopulated the peripheral Vδ2 T cells in patients with RA. CONCLUSIONS: High levels of TNF-α promoted CCR5 and CXCR3 expression in Vδ2 T cells from RA, which potentially infiltrated into the synovium and played crucial roles in the pathogenesis of RA. Targeting Vδ2 T cells might be a potential approach for RA.

[Toxic megacolon complicated by ulcerative colitis in six patients: a case report and literature review].

OBJECTIVE: To summarize the clinical features of ulcerative colitis (UC) complicated by toxic megacolon for early diagnosis and proper treatment. METHODS: Six cases of toxic megacolon in the patients suffered from UC in Peking Union Medical College Hospital from 1983 to 2010 were analyzed, and related literature was searched and reviewed. RESULTS: The incidence of the toxic megacolon in the patients with UC in our center was 0.7%(6/824), which was lower than those reported in the literature. There were always risk factors triggering the disease. The prognosis of the patients was poor, even after medical care and surgery intervention. Evaluation of the patients and making right timing to perform the surgery would improve the prognosis of the patients in foreign literature. CONCLUSION: It's crucial to make early diagnosis of the toxic megacolon in the patients suffered from UC. The right choice and timing to perform urgent surgery or selective surgery may improve their prognosis.

Are CD4+CD25-Foxp3+ cells in untreated new-onset lupus patients regulatory T cells?

INTRODUCTION: Our previous study has reported that, in patients with untreated new-onset lupus (UNOL), there was an abnormal increase in the number of CD4+CD25-Foxp3+ T cells that correlated with disease activity and significantly decreased after treatment. However, little is known about the nature of this cell entity. The aim of this study was to explore the nature of abnormally increased CD4+CD25-Foxp3+ T cells in UNOL patients. METHODS: The expressions of surface (CD4, CD25, CD127, chemokine receptor 4 [CCR4], glucocorticoid-induced tumor necrosis factor receptor [GITR], and cytotoxic T lymphocyte-associated antigen 4 [CTLA-4]) and intracellular (Foxp3) molecules as well as cytokine synthesis of peripheral blood mononuclear cells from 22 UNOL patients were analyzed by flow cytometry. The proliferative and suppressive capacities of different T-cell subgroups from UNOL patients were also assessed. RESULTS: In UNOL patients, the percentages of CD127(low/-) in CD25(high), CD25(low), and CD25- subpopulations of CD4+Foxp3+ T cells were 93.79% +/- 3.48%, 93.66% +/- 2.31%, and 91.98% +/- 2.14%, respectively (P > 0.05), whereas the expressions of Foxp3 showed significant differences in CD25(high) (91.38% +/- 2.57%), CD25(low) (71.89% +/- 3.31%), and CD25- (9.02% +/- 2.21%) subpopulations of CD4+CD127(low/-) T cells (P < 0.01). The expressions of surface CCR4, GITR, and CTLA-4 on CD4+CD25-Foxp3+ T cells were significantly less than CD4+CD25+Foxp3+ T cells (P < 0.05). Moreover, unlike CD4+CD25+Foxp3+ T cells, CD4+CD25-Foxp3+ T cells also synthesized interferon-gamma, interleukin (IL)-4, IL-2, and IL-17 (P < 0.05), though less than CD4+CD25+Foxp3- T cells. The suppressive capacity was most prominent in CD4+CD25(high)CD127(low/-), followed by CD4+CD25(low)CD127(low/-). CD4+CD25-CD127- T cells showed the least suppressive capacity, which was similar to the effector T cells. CONCLUSIONS: CD4+CD25-Foxp3+ T cells in UNOL patients are different from regulatory T cells, both phenotypically and functionally. CD127 is not an appropriate surface marker for intracellular Foxp3 in CD4+CD25- T cells.