Long noncoding RNA intersectin 1-2 gradually declines during adalimumab treatment, and its reduction correlates with treatment efficacy in patients with ankylosing spondylitis

Previous studies show that long noncoding RNA intersectin 1-2 (lnc-ITSN1-2) promotes the inflammation process and serves as a potential biomarker in autoimmune diseases, except for ankylosing spondylitis (AS). Therefore, this study aimed to explore the correlation of baseline lnc-ITSN1-2 expression with disease risk and activity of AS, and to investigate its longitudinal change with treatment response to a tumour necrosis factor alpha (TNFα) inhibitor in patients with AS. In total, 63 patients with AS receiving 12-week adalimumab treatment were included and their baseline clinical features were collected. Lnc-ITSN1-2 expression in peripheral blood mononuclear cells (PBMC) of patients with AS was detected by reverse transcription quantitative polymerase chain reaction. Meanwhile, Assessment in Spondyloarthritis International Society (ASAS) 40 response was evaluated at week 2 (W2), W4, W8, and W12. According to the ASAS40 response status at W12, patients with AS were classified into responders and non-responders. PBMC lnc-ITSN1-2 expression was also determined in healthy controls (N = 60). Lnc-ITSN1-2 expression was elevated in patients with AS compared to controls (P < 0.001). Baseline lnc-ITSN1-2 expression was positively associated with C-reaction protein (CRP) (P = 0.021), interleukin (IL)-1β (P = 0.020), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score (P = 0.040), and Ankylosing Spondylitis Disease Activity score with C-reactive protein (ASDASCRP) (P = 0.045) in patients with AS. Furthermore, lnc-ITSN1-2 expression declined during the treatment with adalimumab (P < 0.001). Notably, this reduction was more obvious in responders than non-responders. In conclusion, declined lnc-ITSN1-2 expression during the TNFα inhibitor treatment correlates with good treatment efficacy in patients with AS, suggesting its clinical value for AS management.

Features of the pathogenetic mechanisms of tuberculous peritonitis in an experiment

The prevalence of tuberculous peritonitis that has been observed in the recent decades is the result of lymphohematogenous spread of Mycobacterium tuberculosis (MBT) from lungs and other extrapulmonary sources. It is still unclear why certain organs and anatomical regions get involved in the inflammatory process during generalization of the tuberculosis infection. Why do some cases develop into peritoneal tuberculosis and other into kidney tuberculosis? Thus study aimed to investigate the pathogenesis of tuberculous peritonitis in a reproducible biological model. Tuberculous peritonitis was modeled in 18 rabbits (10 in the test group, 8 in control) by intraperitoneal inoculation of the MBT suspension. In order to suppress peritoneal macrophages and major cytokines, test group rabbits were injected with the TNFα inhibitor and iron (III) hydroxide sucrose complex before being infected, while control group rabbits received no immunosuppressive drugs. Autopsy of the control group animals revealed changes characteristic of pulmonary tuberculosis in 37.5% of cases, with no damage to other organs and systems registered. Conversely, test group rabbits had the signs of tuberculous peritonitis in their abdominal cavities. The results of this study suggest that it is the local immunity of an anatomical area that largely determines whether a secondary focus of extrapulmonary tuberculosis infection will develop there or not. For the peritoneum, a smaller pool of peritoneal macrophages and weaker cytokine production is a necessary and sufficient condition to have tuberculous peritonitis developing therein.

Switching from TNFα inhibitor to tacrolimus as maintenance therapy in rheumatoid arthritis after achieving low disease activity with TNFα inhibitors and methotrexate: 24-week result from a non-randomized, prospective, active-controlled trial

Background Tapering or stopping biological disease-modifying anti-rheumatic drugs has been proposed for patients with rheumatoid arthritis (RA) in remission, but it frequently results in high rates of recurrence. This study evaluates the efficacy and safety of tacrolimus (TAC) as maintenance therapy in patients with established RA in remission after receiving combination therapy with tumor necrosis factor inhibitor (TNFi) and methotrexate (MTX). Methods This 24-week, prospective, open-label trial included patients who received TNFi and MTX at stable doses for ≥24 weeks and had low disease activity (LDA), measured by Disease Activity Score-28 for ≥12 weeks. Patients selected one of two arms: maintenance (TNFi plus MTX) or switched (TAC plus MTX). The primary outcome was the difference in the proportion of patients maintaining LDA at week 24, which was assessed using a logistic regression model. Adverse events were monitored throughout the study period. Results In efficacy analysis, 80 and 34 patients were included in the maintenance and switched arms, respectively. At week 24, LDA was maintained in 99% and 91% of patients in the maintenance and switched arms, respectively (odds ratio, 0.14; 95% confidence interval, 0.01–1.59). Drug-related adverse effects tended to be more common in the switched arm than in the maintenance arm (20.9% versus 7.1%, respectively) but were well-tolerated. Conclusion This controlled study tested a novel treatment strategy of switching from TNFi to TAC in RA patients with sustained LDA, and the findings suggested that TNFi can be replaced with TAC in most patients without the patients experiencing flare-ups for at least 24 weeks. Trial registration Korea CDC CRIS, KCT0005868. Registered 4 February 2021—retrospectively registered

Beyond steroids: Immunosuppressants in steroid-refractory/resistant immune related adverse events.

9092 Background: The optimal management for immune related adverse events (irAEs) in patients who do not respond or become intolerant to steroids is unclear. Guidelines suggest additional immunosuppressants based on case reports and expert opinion. Methods: We examined patients with advanced lung cancers at MSK treated with immune checkpoint blockade (ICB) from 2011-2020. Pharmacy records were queried to identify patients who received systemic steroids as well as an additional immunosuppressant (eg TNFα inhibitor, mycophenolate mofetil). Patient records were manually reviewed to examine baseline characteristics, management, and outcomes. Results: Among 2,750 patients with lung cancers treated with ICB, 51 (2%) received both steroids and an additional immunosuppressant for a severe irAE (TNFα inhibitor (73%), mycophenolate mofetil (20%)). The most common events were colitis (53%), pneumonitis (20%), hepatitis (12%), and neuromuscular (10%). At 90 days after start of an additional immunosuppressant, 57% were improved from their irAE, 18% were unchanged, and 25% were deceased. Improvement was more common in hepatitis (5/6) and colitis (18/27) but less common in neuromuscular (1/5) and pneumonitis (3/10). All patients with hepatitis received mycophenolate mofetil 500-1000mg BID for a median of 3 months, range 2-5 months. Of the 18 patients with colitis who improved with a TNFα inhibitor, 10 needed just one dose. Of 13 patients who died, 4 were related to toxicity from immunosuppression (3, infection-related deaths; 1, drug-induced liver injury leading to acute liver failure). Those who died from immunosuppressive therapy received higher amounts of systemic steroids than those who did not (max median 525 vs 132 mg prednisone equivalent, Mann Whitney U p = 0.004, total median 5.9k vs 2.3k mg prednisone equivalent, p = 0.004). Of 31 patients who received at least 3 weeks of prednisone ≥ 20mg, most (90%, 28/31) had at least one side effect that was brought to clinical attention (most commonly altered mood/ sleep, 52%, increase in BMI > 1kg/m2, 45%, and infection, 32%). Conclusions: Steroid-refractory/resistant immune related adverse events are rare. While existing treatments help patients with hepatitis and colitis, most patients with other irAEs remain refractory and/or experience toxicities from immunosuppression. Systemic steroid use likely contributed to side effects and mortality. A more precise understanding of the pathophysiology of specific irAEs is needed to guide biologically informed treatment regimens for severe irAEs to realize the true benefit of ICB therapy.

Gastrointestinal adverse drug reaction profile of etanercept: real world data from patients and healthcare professionals

Objective We aimed to describe the nature and frequency of gastrointestinal adverse drug reactions (GI-ADRs) of etanercept (ETN) using patient-reported and healthcare professional (HCP)-registered data and compared this frequency with the GI-ADR frequency of the widely used TNFα-inhibitor adalimumab. Methods Reported GI-ADRs of ETN for rheumatic diseases were collected from the Dutch Biologic Monitor and DREAM registries. We described the clinical course of GI-ADRs and compared the frequency with adalimumab in both data sources using a Fisher’s exact test. Results Out of 416 patients using ETN for inflammatory rheumatic diseases in the Dutch Biologic Monitor, 25 patients (6%) reported 36 GI-ADRs. In the DREAM registries 11 GI-ADRs were registered for 9 patients (2.3%), out of 399 patients using ETN, with an incidence of 7.14 per 1000 patient years. Most GI-ADRs concerned diarrhoea, nausea and abdominal pain. GI-ADRs led to ETN discontinuation in one patient (4%) and dose adjustment in four (16%) in the Dutch Biologic Monitor. Eight GI-ADRs (73%) led to ETN discontinuation in the DREAM registries. The frequency of GI-ADRs of ETN did not significantly differ from GI-ADRs of adalimumab in both data sources (Dutch Biologic Monitor: ETN 8.7% vs. ADA 5.3%, p=0.07; DREAM: ETN 2.8% vs. ADA 4.7%, p=0.16). Conclusion Most GI-ADRs associated with ETN concerned gastrointestinal symptoms. These ADRs may lead to dose adjustment or ETN discontinuation. The frequency of ETN associated GI-ADRs was comparable to the frequency of adalimumab associated GI-ADRs. Knowledge about these previously unknown ADRs can facilitate early recognition and improve patient communication.

TNF Alpha-Induced SOX2 Expression Promotes Hepatic Steatois in Diet-Induced Obesity Model

Diet-induced obesity can cause metabolic or inflammatory damage on liver. Nonalcoholic fatty liver disease (NAFLD) begins with the fat accumulation in hepatocyte, but can lead to hepatocellular carcinoma (HCC). Sex-determining region Y-box 2 (SOX2) is a critical transcription factor involving regeneration and pluripotency. The expression level of Sox2 is correlated with progression of HCC, and anti-inflammatory effects of Sox2 in mesenchymal stem cells have been found. However, the expression of Sox2 by inflammatory cytokines in hepatocyte in NAFLD or the role of SOX2 in fat accumulation has been rarely reported. Here, we found that high-fat diet feeding, with or without high fructose in drinking water, significantly upregulated SOX2 in the livers of mice. In vitro, treatment with free fatty acids (FFAs) and fructose increased SOX2 expression in FL83B cells compared with the vehicle-treated group. Furthermore, overexpression or knockdown of SOX2 in FL83B cells promoted or suppressed, respectively, triglyceride synthesis and lipid accumulation after FFAs stimulation. The expression levels of several lipogenesis-related molecules were found to be altered by SOX2 expression. In addition, among several cytokines, only the treatment of tumor necrosis factor-alpha (TNFα) increased the SOX2 expression compared with the vehicle-treated control. Further, upregulation of (TNFα) by FFA/fructose was observed, and TNFα and FFA/fructose induced SOX2 expression was abolished by pretreatment of a TNFα inhibitor. Collectively, our findings suggest that TNFα-SOX2 signaling pathway in hepatocyte may be one of targets for early prevention of the development of NAFLD.