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ID PMID Title PublicationDate abstract
32587091 The deubiquitinase USP7 uses a distinct ubiquitin-like domain to deubiquitinate NF-ĸB sub 2020 Aug 14 The transcription factor NF-ĸB is a master regulator of the innate immune response and plays a central role in inflammatory diseases by mediating the expression of pro-inflammatory cytokines. Ubiquitination-triggered proteasomal degradation of DNA-bound NF-ĸB strongly limits the expression of its target genes. Conversely, USP7 (deubiquitinase ubiquitin-specific peptidase 7) opposes the activities of E3 ligases, stabilizes DNA-bound NF-ĸB, and thereby promotes NF-ĸB-mediated transcription. Using gene expression and synthetic peptide arrays on membrane support and overlay analyses, we found here that inhibiting USP7 increases NF-ĸB ubiquitination and degradation, prevents Toll-like receptor-induced pro-inflammatory cytokine expression, and represents an effective strategy for controlling inflammation. However, the broad regulatory roles of USP7 in cell death pathways, chromatin, and DNA damage responses limit the use of catalytic inhibitors of USP7 as anti-inflammatory agents. To this end, we identified an NF-ĸB-binding site in USP7, ubiquitin-like domain 2, that selectively mediates interactions of USP7 with NF-ĸB subunits but is dispensable for interactions with other proteins. Moreover, we found that the amino acids (757)LDEL(760) in USP7 critically contribute to the interaction with the p65 subunit of NF-ĸB. Our findings support the notion that USP7 activity could be potentially targeted in a substrate-selective manner through the development of noncatalytic inhibitors of this deubiquitinase to abrogate NF-ĸB activity.
32473600 Mechanism of baricitinib supports artificial intelligence-predicted testing in COVID-19 pa 2020 Aug 7 Baricitinib is an oral Janus kinase (JAK)1/JAK2 inhibitor approved for the treatment of rheumatoid arthritis (RA) that was independently predicted, using artificial intelligence (AI) algorithms, to be useful for COVID-19 infection via proposed anti-cytokine effects and as an inhibitor of host cell viral propagation. We evaluated the in vitro pharmacology of baricitinib across relevant leukocyte subpopulations coupled to its in vivo pharmacokinetics and showed it inhibited signaling of cytokines implicated in COVID-19 infection. We validated the AI-predicted biochemical inhibitory effects of baricitinib on human numb-associated kinase (hNAK) members measuring nanomolar affinities for AAK1, BIKE, and GAK. Inhibition of NAKs led to reduced viral infectivity with baricitinib using human primary liver spheroids. These effects occurred at exposure levels seen clinically. In a case series of patients with bilateral COVID-19 pneumonia, baricitinib treatment was associated with clinical and radiologic recovery, a rapid decline in SARS-CoV-2 viral load, inflammatory markers, and IL-6 levels. Collectively, these data support further evaluation of the anti-cytokine and anti-viral activity of baricitinib and support its assessment in randomized trials in hospitalized COVID-19 patients.
33027190 Is Patient-reported Penicillin Allergy Independently Associated with Increased Risk of Pro 2020 Dec BACKGROUND: Patients with a patient-reported penicillin allergy may be at greater risk for postoperative prosthetic joint infection (PJI) after total joint arthroplasty of the hip, knee, or shoulder. The increased risk of PJI in these patients has been attributed to these patients receiving a less-effective perioperative antibiotic. However, prior reports did not fully address the clinical characteristics of these unique patients, who may inherently be at greater risk of having a PJI, which may confound prior findings. QUESTIONS/PURPOSES: After controlling for risk factors for PJI such as BMI, anxiety, depression, and other comorbidities, we asked: Are patients with a patient-reported penicillin allergy more likely to have a PJI after THA, TKA, or total shoulder arthroplasty than patients without such a reported allergy? METHODS: We queried patient records from 2010 to 2017 from a nationwide administrative claims database of 122 million patients to adequately power an investigation comparing the 1-year incidence of PJI after TKA, total shoulder arthroplasty, and THA in patients with patient-reported penicillin allergy versus patients without a patient-reported penicillin allergy. Operative treatments for deep joint infection, identified by Current Procedural Terminology and ICD-9 and ICD-10 codes were used as a surrogate for PJI. Clinical characteristics such as age, sex, BMI, length of stay, and Charlson comorbidity index and specific comorbidities including alcohol abuse, anemia, anxiety, cardiac disease, diabetes, immunocompromised status, rheumatoid arthritis, depression, liver disease, chronic kidney disease, tobacco use, and peripheral vascular disease were queried for each study group. The odds of PJI within 1 year of THA, TKA, or total shoulder arthroplasty were compared using multiple logistic regression after adjusting for potential confounders. RESULTS: After adjusting for potential confounding factors such as BMI, anxiety, depression and other comorbidities, we found that patient-reported penicillin allergy was independently associated with an increased odds of PJI after TKA (odds ratio 1.3 [95% confidence interval 1.1 to 1.4]; p < 0.01) and total shoulder arthroplasty (OR 3.9 [95% CI 2.7 to 5.4]; p < 0.01). However, patient-reported penicillin allergy was not independently associated with an increased odds of PJI after THA (OR 1.1 [95% CI 0.9 to 1.3]; p = 0.36) after controlling for the same risk factors. CONCLUSIONS: In this study, we found that patients with patient-reported penicillin allergy were at an increased risk for PJI after TKA and total shoulder arthroplasty, which we suspect-but cannot prove-is likely a function of those patients receiving a second-line antibiotic for presurgical prophylaxis. Since prior research has found that many patients listed in medical records as having a penicillin allergy are in fact not allergic to penicillin, we suggest that surgeons consider preoperative allergy testing, such as using an intraoperative test dose, to aid in choosing the most appropriate antibiotic choice before knee or shoulder arthroplasty and to amend patient medical records based on testing results. Future studies should determine whether this additional diagnostic maneuver is cost-effective. LEVEL OF EVIDENCE: Level III, therapeutic study.
31339007 Activated M2 Macrophages Contribute to the Pathogenesis of IgG4-Related Disease via Toll-l 2020 Jan OBJECTIVE: IgG4-related disease (IgG4-RD) is a unique inflammatory disorder in which Th2 cytokines promote IgG4 production. In addition, recent studies have implicated the Toll-like receptor (TLR) pathway. This study was undertaken to examine the expression of TLRs in salivary glands (SGs) from patients with IgG4-RD. METHODS: SGs from 15 patients with IgG4-RD, 15 patients with Sjögren's syndrome (SS), 10 patients with chronic sialadenitis, and 10 healthy controls were examined histologically. TLR family gene expression (TLR-1 through TLR-10) was analyzed by DNA microarray in the submandibular glands (SMGs). Up-regulation of TLRs was confirmed in SGs from patients with IgG4-RD. Finally, the phenotype of human TLR-7 (huTLR-7)-transgenic C57BL/6 mice was assessed before and after stimulation with TLR agonist. RESULTS: In patients with IgG4-RD, TLR-4, TLR-7, TLR-8, and TLR-9 were overexpressed. Polymerase chain reaction validated the up-regulation of TLR-7 in IgG4-RD compared with the other groups. Immunohistochemical analysis confirmed strong infiltration of TLR-7-positive cells in the SGs of patients with IgG4-RD. Double immunohistochemical staining showed that TLR-7 expression colocalized with CD163+ M2 macrophages. After in vitro stimulation with a TLR-7 agonist, CD163+ M2 macrophages produced higher levels of interleukin-33 (IL-33), which is a Th2-activating cytokine. In huTLR-7-transgenic mice, the focus and fibrosis scores in SMGs, pancreas, and lungs were significantly higher than those in wild-type mice (P < 0.05). Moreover, the concentration of serum IgG, IgG1, and IL-33 in huTLR-7-transgenic mice was distinctly increased upon stimulation with a TLR-7 agonist (P < 0.05). CONCLUSION: TLR-7-expressing M2 macrophages may promote the activation of Th2 immune responses via IL-33 secretion in IgG4-RD.
33322152 Toll-Like Receptor 7 Is Required for Lacrimal Gland Autoimmunity and Type 1 Diabetes Devel 2020 Dec 13 Sjögren syndrome (SS) is an immunologically complex, chronic autoimmune disease targeting lacrimal and salivary glands. Nonobese diabetic (NOD) mice spontaneously develop inflammation of lacrimal and salivary glands with histopathological features similar to SS in humans including focal lymphocytic infiltrates in the affected glands. The innate immune signals driving lymphocytic infiltration of these glands are not well-defined. Here we evaluate the role of Toll-like receptor (TLR) 7 in the development of SS-like manifestations in NOD mice. We created a Tlr7 knockout NOD mouse strain and performed histological and gene expression studies to characterize the effects of TLR7 on autoimmunity development. TLR7 was required for male-specific lacrimal gland inflammation but not for female-specific salivary gland inflammation. Moreover, TLR7 was required for type 1 diabetes development in male but not female NOD mice. RNA sequencing demonstrated that TLR7 was associated with a type I interferon (IFN) response and a type I IFN-independent B cell response in the lacrimal glands. Together these studies identify a previously unappreciated pathogenic role for TLR7 in lacrimal gland autoimmunity and T1D development in male NOD mice adding to the growing body of evidence supporting sex differences in mechanisms of autoimmune disease in NOD mice.
33080929 Systemic Comorbidities in Korean Patients with Rosacea: Results from a Multi-Institutional 2020 Oct 17 Recent evidence links rosacea to systemic disease, but there are not enough methodologic studies addressing this association in Asians. Our aim was to identify rosacea comorbidities in Koreans and establish a reference database. A multi-center, case-control study was performed where a total of 12,936 rosacea patients and 12,936 age- and sex-matched control subjects were identified from 2007 to 2018. Logistic regression was performed to find significant association between rosacea and Sjögren syndrome (odds ratio [OR] 2.05; 95% confidence interval, 1.40-3.00), systemic sclerosis (OR 6.56; 95% CI, 1.50-28.7), rheumatoid arthritis (OR 1.72; 95% CI, 1.50-1.98), ankylosing spondylitis (OR 2.32; 95% CI, 1.42-3.84), autoimmune thyroiditis (OR 1.96; 95% CI, 1.40-2.73), alopecia areata (OR 1.77; 95% CI, 1.27-2.45), vitiligo (OR 1.90; 95% CI, 1.30-2.77), lung cancer (OR 1.54; 95% CI, 1.06-2.21), hepatobiliary cancer (OR 1.38; 95% CI, 1.06-1.77), alcohol abuse (OR 1.59; 95% CI, 1.05-2.39), diabetes mellitus (OR 1.11; 95% 1.02-1.19), obesity (OR 1.72; 95% CI, 1.22-2.41), allergic rhinitis (OR 1.65; 95% CI, 1.54-1.76), allergic conjunctivitis (OR 1.57; 95% CI, 1.27-1.94), chronic rhinosinusitis (OR 1.28; 95% CI, 1.14-1.42), herpes infection (OR 1.69; 95% CI, 1.53-1.86), and human papillomavirus infection (OR 2.50; 95% CI, 2.06-3.02). Higher odds for Sjogren syndrome, systemic sclerosis, ankylosing spondylitis, thyroiditis, vitiligo, hepatobiliary cancer, and obesity was exclusive in female subjects with rosacea, whereas increased prevalence of alopecia areata and alcohol abuse was confined to men. Only those who were 50 years and older exhibited higher odds for vitiligo, lung cancer, and gastroesophageal reflux disease while individuals younger than 50 were exclusively associated with hepatobiliary cancer, allergic conjunctivitis, and irritable bowel syndrome. Our study suggests that Koreans with rosacea are more likely to experience systemic comorbidity. Clinicians should acknowledge these interrelations and employ comprehensive care with an individual-based approach.
33246119 Effects of Salvia officinalis L. and Chamaemelum nobile (L.) extracts on inflammatory resp 2021 Mar 25 ETHNOPHARMACOLOGICAL RELEVANCE: Salvia officinalis L. (sage), and Chamaemelum nobile (L.) (chamomile) have been used traditionally to treat various inflammatory conditions. AIMS: Our study aims to investigate the anti-inflammatory properties of both plant extracts in IL-1β-stimulated neuroblastoma cells (SK-N-SH) and human subcutaneous mature adipocytes, as well as their potential protective effects against mature adipocytes conditioned media (ACM)-induced neuro-inflammation. MATERIALS AND METHODS: Human subcutaneous mature adipocytes and neuroblastoma cells were treated with 5 μg/ml (low dose: LD) and 50 μg/ml (high dose: HD) of each extract, with or without 0.5 ng/ml of human recombinant IL-1β. To understand the cross talk between fat tissue and neuronal cells, SK-N-SH cell line was incubated with ACM 10%, in presence or absence of both extracts LD and HD. Following 4, and 24 h incubation, the released MCP-1, IL-6, IL-8, TNF-α, ICAM-1, VCAM-1 and SAA levels were measured using MSD Cytokines and Chemokines assay kits, and the cells were used for gene expression. RNA was quantified using Qubit™ RNA HS Assay. RNA aliquots were shipped to Eurofins Genomics (Aarhus, Denmark) for expression analysis on the human Clariom™ GO Screen Assay (952,361; ThermoFisher). RESULTS: Chamomile showed stronger effects compared to sage in both cell lines, at 4 and 24 h. Adipocytes acute treatment with sage decreased MCP-1, IL-6, IL-8 (p < 0.001), and TNF-α (p < 0.05) basal levels. This was mirrored at MCP-1 transcriptional level. Chronic treatment with both extracts resulted in a significant reduction in ICAM-1, VCAM-1 and SAA (p < 0.001) levels, in IL-1β-stimulated adipocytes. However, in SK-N-SH cells, sage increased the basal levels of many cytokines and chemokines on both protein and transcriptional levels. This was also observed in IL-1β-stimulated cells. In chamomile treated SK-N-SH cells, acute and chronic treatments decreased MCP-1 (p < 0.001), IL-6 (p < 0.01), TNF-α (p < 0.01), and IL-8 (p < 0.001) basal levels. In IL1-β-stimulated SK-N-SH cells, chamomile HD induced a significant reduction in TNF-α after both acute and chronic treatments respectively, by 52% and 81%. At transcriptional level, this effect was only reflected at 4 h. ICAM-1, VCAM-1 and SAA levels were reduced in most of the studied conditions. In IL-1β treated adipocytes, chamomile showed stronger reduction in MCP-1, ICAM-1 and VCAM-1 expression, however no significant reduction in TNF-α and IL-8 was observed, despite the decrease in basal levels. In SK-N-SH cells, ACM increased MCP-1, IL-6, IL-8, TNF-α, VCAM-1 and SAA levels. Sage HD acute treatment resulted in a reduction of ACM effect on IL-6, IL-8 and VCAM-1, with greater effect of chamomile on MCP-1 (p < 0.05); IL-6 (p < 0.001); TNF-α (p < 0.001); VCAM-1 (p < 0.001); and SAA (p < 0.001). This protective effect was also observed after chronic treatment. However, both extracts potentiated significantly the ACM-pro-inflammatory effect on IL-8 (p < 0.001). CONCLUSIONS: Sage decreased the pro-inflammatory markers mostly in human adipocytes, whereas chamomile showed a strong reduction in both cell populations. Both extracts reduced the ACM-induced inflammation effect and might be used as a preventive treatment for late-life cognitive impairment related to low-grade chronic inflammation associated with obesity. Further studies are needed to investigate their combination on other chronic inflammation-related diseases such as type 2 diabetes or rheumatoid arthritis.
31228185 Targeting protein tyrosine phosphatase PTP-PEST (PTPN12) for therapeutic intervention in a 2020 Apr 1 AIMS: The myocardial ischaemia/reperfusion (I/R) injury is almost inevitable since reperfusion is the only established treatment for acute myocardial infarction (AMI). To date there is no effective strategy available for reducing the I/R injury. Our aim was to elucidate the mechanisms underlying myocardial I/R injury and to develop a new strategy for attenuating the damage it causes. METHODS AND RESULTS: Using a mouse model established by ligation of left anterior descending artery, we found an increase in activity of protein tyrosine phosphatases (PTPs) in myocardium during I/R. Treating the I/R-mice with a pan-PTP inhibitor phenyl vinyl sulfone attenuated I/R damage, suggesting PTP activation to be harmful in I/R. Through analysing RNAseq data, we showed PTPs being abundantly expressed in mouse myocardium. By exposing primary cardiomyocytes ablated with specific endogenous PTPs by RNAi to hypoxia/reoxygenation (H/R), we found a role that PTP-PEST (PTPN12) plays to promote cell death under H/R stress. Auranofin, a drug being used in clinical practice for treating rheumatoid arthritis, may target PTP-PEST thus suppressing its activity. We elucidated the molecular basis for Auranofin-induced inactivation of PTP-PEST by structural studies, and then examined its effect on myocardial I/R injury. In the mice receiving Auranofin before reperfusion, myocardial PTP activity was suppressed, leading to restored phosphorylation of PTP-PEST substrates, including ErbB-2 that maintains the survival signalling of the heart. In line with the inhibition of PTP-PEST activity, the Auranofin-treated I/R-mice had smaller infarct size and better cardiac function. CONCLUSIONS: PTP-PEST contributes to part of the damages resulting from myocardial I/R. The drug Auranofin, potentially acting through the PTP-PEST-ErbB-2 signalling axis, reduces myocardial I/R injury. Based on this finding, Auranofin could be used in the development of new treatments that manage I/R injury in patients with AMI.
33155547 Sustained TNF-α stimulation leads to transcriptional memory that greatly enhances signal 2020 Nov 6 Transcriptional memory allows certain genes to respond to previously experienced signals more robustly. However, whether and how the key proinflammatory cytokine TNF-α mediates transcriptional memory are poorly understood. Using HEK293F cells as a model system, we report that sustained TNF-α stimulation induces transcriptional memory dependent on TET enzymes. The hypomethylated status of transcriptional regulatory regions can be inherited, facilitating NF-κB binding and more robust subsequent activation. A high initial methylation level and CpG density around κB sites are correlated with the functional potential of transcriptional memory modules. Interestingly, the CALCB gene, encoding the proven migraine therapeutic target CGRP, exhibits the best transcriptional memory. A neighboring primate-specific endogenous retrovirus stimulates more rapid, more strong, and at least 100-fold more sensitive CALCB induction in subsequent TNF-α stimulation. Our study reveals that TNF-α-mediated transcriptional memory is governed by active DNA demethylation and greatly sensitizes memory genes to much lower doses of inflammatory cues.
32920132 Biflavonoid-rich fraction from Daphne pseudomezereum var. koreana Hamaya exerts anti-infla 2021 Jan 30 ETHNOPHARMACOLOGICAL RELEVANCE: Daphne pseudomezereum var. koreana Hamaya is distributed in the Gangwon-do of South Korea and is traditionally used to treat chronic inflammatory diseases, including rheumatoid arthritis. AIM OF THE STUDY: We investigated the anti-inflammatory effect of biflavonoid-rich fraction (BF) obtained from an extract of D. pseudomezereum leaves on lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and mouse model of ovalbumin (OVA)-induced allergic asthma. MATERIALS AND METHODS: Neochamaejasmin B (NB) and chamaejasmin D (CD) were spectroscopically characterized as major components of BF obtained from the leaves of D. pseudomezereum. RAW264.7 cells pretreated with NB, CD and BF and activated by LPS (500 ng/ml) were used to assess the anti-inflammatory effects of these materials in vitro. To evaluate the protective effect of BF on allergic asthma, female BALB/c mice were sensitized to OVA by intraperitoneal (i.p.) injection and treated with BF by oral administration (15 or 30 mg/kg). RESULTS: Pretreatment with BF inhibited LPS-stimulated nitric oxide (NO), TNF-α and IL-6, and led to upregulation of heme oxygenase-1 (HO-1) in RAW264.7 macrophages. Orally administered BF significantly inhibited the recruitment of eosinophils and the production of IL-5, IL-6, IL-13 and MCP-1 as judged by the analysis of BALF from OVA-induced asthma animal model. BF also decreased the levels of IgE in the serum of asthmatic mice. BF suppressed the influx of inflammatory cells into nearby airways and the hypersecretion of mucus by the airway epithelium of asthmatic mice. In addition, the increase in Penh in asthmatic mice was reduced by BF administration. Furthermore, BF led to Nrf2 activation and HO-1 induction in the lungs of mice. CONCLUSIONS: These data have shown the anti-asthmatic effects of BF, and therefore we expect that BF may be a potential candidate as a natural drug/nutraceutical for the prevention and treatment of allergic asthma.
32935492 Chitinase 3-Like 1 Contributes to Food Allergy via M2 Macrophage Polarization. 2020 Nov PURPOSE: Food allergy is a hypersensitive immune response to specific food proteins. Chitinase 3-like 1 (CHI3L1, also known as YKL-40 in humans or BRP-39 in mice) is associated with various chronic diseases, such as cancer, rheumatoid arthritis, and allergic disease. CHI3L1 is involved in allergen sensitization and type 2 helper T (Th2) inflammation, but the role of CHI3L1 in food allergy remains unclear. In this study, we sought to investigate the role of CHI3L1 in the development of food allergy. METHODS: We measured serum levels of CHI3L1 in food allergic patients. Food allergy was induced in wild-type (WT) and CHI3L1 null mutant (CHI3L1(-/-)) BALB/c mice with ovalbumin (OVA). We investigated Th2 immune responses, M2 macrophage polarization, and mitogen-activated protein kinase (MAPK)/phosphoinositide 3-kinase (PI3K) signaling pathways, and also performed transcriptome analysis. RESULTS: Serum levels of CHI3L1 were significantly higher in children with food allergy compared with those in healthy controls. Furthermore, CHI3L1 expression levels were elevated in WT mice after OVA treatment. Food allergy symptoms, immunoglobulin E levels, Th2 cytokine production, and histological injury were attenuated in food allergy-induced CHI3L1(-/-) mice compared with those in food allergy-induced WT mice. CHI3L1 expression was increased in OVA-treated WT intestinal macrophages and caused M2 macrophage polarization. Furthermore, CHI3L1 was involved in the extracellular signal-regulated kinases (ERK) and AKT signaling pathways and was associated with immune response and lipid metabolism as determined through transcriptome analysis. CONCLUSIONS: CHI3L1 plays a pivotal role in Th2 inflammation and M2 macrophage polarization through MAPK/ERK and PI3K/AKT phosphorylation in food allergy.
32790935 Extrahepatic autoimmune diseases in primary biliary cholangitis: Prevalence and significan 2021 Apr BACKGROUND AND AIM: The prevalence and clinical significance of extrahepatic autoimmune diseases (EHAIDs) have not been evaluated in a large cohort of primary biliary cholangitis (PBC). METHODS: The medical records of 1554 patients with PBC from 20 international centers were retrospectively reviewed. Development of decompensated cirrhosis (ascites, variceal bleeding, and/or hepatic encephalopathy) and hepatocellular carcinoma were considered clinical endpoints. RESULTS: A total of 35 different EHAIDs were diagnosed in 440 (28.3%) patients with PBC. Patients with EHAIDs were more often female (92.5% vs 86.1%, P < 0.001) and seropositive for anti-mitochondrial antibodies (88% vs 84%, P = 0.05) and antinuclear antibodies and/or smooth muscle antibodies (53.8% vs 43.6%, P = 0.005). At presentation, patients with EHAIDs had significantly lower levels of alkaline phosphatase (1.76 vs 1.98 × upper limit of normal [ULN], P = 0.006), aspartate aminotransferase (1.29 vs 1.50 × ULN, P < 0.001), and total bilirubin (0.53 vs 0.58 × ULN, P = 0.002). Patients with EHAIDs and without EHAIDs had similar rates of GLOBE high-risk status (12.3% vs 16.1%, P = 0.07) and Paris II response (71.4% vs 69.4%, P = 0.59). Overall, event-free survival was not different in patients with and without EHAIDs (90.8% vs 90.7%, P = 0.53, log rank). Coexistence of each autoimmune thyroid diseases (10.6%), Sjögren disease (8.3%), systemic sclerosis (2.9%), rheumatoid arthritis (2.7%), systemic lupus erythematosus (1.7%), celiac disease (1.7%), psoriasis (1.5%), and inflammatory bowel diseases (1.3%) did not influence the outcome. CONCLUSIONS: Our study confirms that EHAIDs are frequently diagnosed in patients with PBC. The presence of EHAIDs may influence the clinical phenotype of PBC at presentation but has no impact on PBC outcome.
31984480 Oral Janus kinase inhibitors for maintenance of remission in ulcerative colitis. 2020 Jan 27 BACKGROUND: Tofacitinib is an oral Janus kinase (JAK) inhibitor which blocks cytokine signaling involved in the pathogenesis of autoimmune diseases including ulcerative colitis (UC). The etiology of UC is poorly understood, however research suggests the development and progression of the disease is due to a dysregulated immune response leading to inflammation of the colonic mucosa in genetically predisposed individuals. Additional medications are currently required since some patients do not respond to the available medications and some medications are associated with serious adverse events (SAEs). JAK inhibitors have been widely studied in diseases including rheumatoid arthritis and Crohn's disease and may represent a promising and novel therapeutic option for the treatment of UC. OBJECTIVES: The primary objective was to assess the efficacy and safety of oral JAK inhibitors for the maintenance of remission in participants with quiescent UC. SEARCH METHODS: We searched the following databases from inception to 20 September 2019: MEDLINE, Embase, CENTRAL, and the Cochrane IBD Group Specialized Register, WHO trials registry and clinicaltrials.gov. References and conference abstracts were searched to identify additional studies. SELECTION CRITERIA: Randomized control trial (RCTs) in which an oral JAK inhibitor was compared with placebo or active comparator in the treatment of quiescent UC were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently screened studies for inclusion and extraction. Bias was assessed using the Cochrane 'Risk of bias' tool. The primary outcome was the proportion of participants who failed to maintain remission as defined by any included studies. Secondary outcomes included failure to maintain clinical response, failure to maintain endoscopic remission, failure to maintain endoscopic response, disease-specific quality of life, adverse events (AEs), withdrawal due to AEs and SAEs. We calculated the risk ratio (RR) and 95% confidence intervals (95% CI) for each dichotomous outcome. Data were analyzed on an intention-to-treat basis. The overall certainty of the evidence supporting the outcomes was evaluated using the GRADE criteria. MAIN RESULTS: One RCT (593 participants) including patients with moderately to severely active UC met the inclusion criteria. Patients were randomly assigned in a 1:1:1 ratio to receive maintenance therapy with tofacitinib at 5 mg twice daily, 10 mg twice daily or placebo for 52 weeks. The primary endpoint was remission at 52 weeks and the secondary endpoints included mucosal healing at 52 weeks, sustained remission at 24 and 52 weeks and glucocorticosteroid-free remission. This study was rated as low risk of bias. The study reported on most of the pre-specified primary and secondary outcomes for this review including clinical remission, clinical response, endoscopic remission, AEs, SAEs and withdrawal due to AEs. However, the included study did not report on endoscopic response or disease-specific quality of life. Sixty-three per cent (247/395) of tofacitinib participants failed to maintain clinical remission at 52 weeks compared to 89% (176/198) of placebo participants (RR 0.70, 95% CI 0.64 to 0.77; high-certainty evidence). Forty-three per cent (171/395) of tofacitinib participants failed to maintain clinical response at 52 weeks compared to 80% (158/198) of placebo participants (RR 0.54, 95% CI 0.48 to 0.62; high-certainty evidence). Eighty-four per cent (333/395) of tofacitinib participants failed to maintain endoscopic remission at 52 weeks compared to 96% (190/198) of placebo participants (RR 0.88, 95% CI 0.83 to 0.92; high-certainty evidence). AEs were reported in 76% (299/394) of tofacitinib participants compared with 75% (149/198) of placebo participants (RR 1.01, 95% CI 0.92 to 1.11; high-certainty evidence). Commonly reported AEs included worsening UC, nasopharyngitis, arthralgia (joint pain)and headache. SAEs were reported in 5% (21/394) of tofacitinib participants compared with 7% (13/198) of placebo participants (RR 0.81, 95% CI 0.42 to 1.59; low-certainty evidence). SAEs included non-melanoma skin cancers, cardiovascular events, cancer other than non-melanoma skin cancer, Bowen's disease, skin papilloma and uterine leiomyoma (a tumour in the uterus). There was a higher proportion of participants who withdrew due to an AE in the placebo group compared to the tofacitinib group. Nine per cent (37/394) of participants taking tofacitinib withdrew due to an AE compared to 19% (37/198) of participants taking placebo (RR 0.50, 95% CI 0.33 to 0.77; moderate-certainty evidence). The most common reason for withdrawal due to an AE was worsening UC. The included study did not report on endoscopic response or on mean disease-specific quality of life scores. AUTHORS' CONCLUSIONS: High-certainty evidence suggests that tofacitinib is superior to placebo for maintenance of clinical and endoscopic remission at 52 weeks in participants with moderate-to-severe UC in remission. The optimal dose of tofacitinib for maintenance therapy is unknown. High-certainty evidence suggests that there is no increased risk of AEs with tofacitinib compared to placebo. However, we are uncertain about the effect of tofacitinib on SAEs due to the low number of events. Further studies are required to look at the long-term effectiveness and safety of using tofacitinib and other oral JAK inhibitors as maintenance therapy in participants with moderate-to-severe UC in remission.
32903098 Omega-3 fatty acid intake suppresses induction of diverse autoantibody repertoire by cryst 2020 Nov Inhalation of crystalline silica (cSiO(2)) in the workplace is etiologically linked to lupus and other autoimmune diseases. Exposing lupus-prone NZBWF1 mice to respirable cSiO(2) unleashes a vicious cycle of inflammation and cell death in the lung that triggers interferon-regulated gene expression, ectopic lymphoid structure (ELS) development, elevation of local and systemic autoantibodies (AAbs), and glomerulonephritis. However, cSiO(2)-induced inflammation and onset of autoimmunity can be prevented by inclusion of the ω-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) into the diet of these mice. Since cSiO(2) both causes cell death and interferes with efferocytosis, secondary necrosis of residual cell corpses might provide a rich and varied autoantigen (AAg) source in the lung. While it is known that the particle induces anti-nuclear and anti-dsDNA AAbs in NZBWF1 mice, the full extent of the cSiO(2)-induced AAb response relative to specificity and isotype is not yet understood. The purpose of this study was to test the hypotheses that cSiO(2) exposure induces a wide spectrum of AAbs in the pulmonary and systemic compartments, and that dietary DHA intervention prevents these changes. Archived tissue fluid samples were obtained from a prior study in which NZBWF1 mice were fed purified isocaloric diets containing no DHA (control) or DHA corresponding calorically to human doses of 2 and 5 g/day. Mice were intranasally instilled with 1 mg cSiO(2) or saline vehicle weekly for 4 weeks, then groups euthanized 1, 5, 9, or 13 weeks post-instillation (PI) of the last cSiO(2) dose. Bronchoalveolar lavage fluid (BALF) and plasma from each time point were subjected to AAb profiling using a microarray containing 122 AAgs. cSiO(2) triggered robust IgG and IgM AAb responses against lupus-associated AAgs, including DNA, histones, ribonucleoprotein, Smith antigen, Ro/SSA, La/SSB, and complement as early as 1 week PI in BALF and 5 weeks PI in plasma, peaking at 9 and 13 weeks PI, respectively. Importantly, cSiO(2) also induced AAbs to AAgs associated with rheumatoid arthritis (collagen II, fibrinogen IV, fibrinogen S, fibronectin, and vimentin), Sjögren's syndrome (α-fodrin), systemic sclerosis (topoisomerase I), vasculitis (MPO and PR3), myositis (Mi-2, TIF1-γ, MDA5), autoimmune hepatitis (LC-1), and celiac disease (TTG). cSiO(2) elicited comparable but more modest IgA AAb responses in BALF and plasma. cSiO(2)-induced AAb production was strongly associated with time dependent inflammatory/autoimmune gene expression, ELS development, and glomerulonephritis. AAb responses were dose-dependently suppressed by DHA supplementation and negatively correlated with the ω-3 index, an erythrocyte biomarker of ω-3 content in tissue phospholipids. Taken together, these findings suggest that cSiO(2) exposure elicits a diverse multi-isotype repertoire of AAbs, many of which have been reported in individuals with lupus and other autoimmune diseases. Furthermore, induction of this broad AAb spectrum could be impeded by increasing ω-3 tissue content via dietary DHA supplementation.
31308211 Suboptimal Immunization Coverage among Canadian Rheumatology Patients in Routine Clinical 2020 May 1 OBJECTIVE: To assess vaccination coverage and predictors of vaccination among a Canadian population of rheumatology patients in routine clinical care. METHODS: In this cross-sectional study, consecutive adult patients presenting to a tertiary rheumatology clinic at the McGill University Health Center between May and September 2015 were asked to fill a survey on vaccination. Patients self-identified as having rheumatoid arthritis (RA), systemic autoimmune rheumatic diseases (SARD), spondyloarthropathies (SpA), or other diseases (OD). Multivariate logistical regression analyses were performed to evaluate patient and physician factors associated with various vaccinations [for influenza, pneumococcus, and hepatitis B virus (HBV)]. Published Quebec general population influenza and pneumococcal vaccination rates in those aged ≥ 65 years were used as comparative baseline rates. RESULTS: Three hundred fifty-two patients were included in the analysis (RA: 136, SARD: 113, SpA: 47, OD: 56). Vaccination rates were reported as follows: (1) influenza: RA 48.5%, SARD 42.0%, SpA 31.9%, OD 88.9%, Quebec general population 58.5%; (2) pneumococcal: RA 42.0%, SARD 37.8%, SpA 29.7%, OD 33.3%, Quebec general population 53.2%; (3) HBV: RA 33.6%, SARD 55.6%, SpA 73.5%, OD 36.8%; and (4) herpes zoster: RA 5.6%, SARD 28.6%, SpA 25.0%, OD 16.7%. Physician recommendation was the strongest independent predictor of vaccination across all vaccine types (influenza: OR 8.56, 95% CI 2.80-26.2, p < 0.001; pneumococcal: OR 314, 95% CI 73.0-1353, p < 0.001; HBV: OR 12.8, 95% CI 5.27-31.1, p < 0.001). Disease group, disease duration, comorbidities, treatment type, and being followed by a primary care physician were not significantly associated with vaccination. CONCLUSION: There is suboptimal immunization coverage among ambulatory rheumatology patients. An important role for patient and physician education is highlighted in our study, especially because physician recommendation of vaccination was strongly predictive of vaccine uptake.
32907830 TREM-2 defends the liver against hepatocellular carcinoma through multifactorial protectiv 2021 Jul OBJECTIVE: Hepatocellular carcinoma (HCC) is a prevalent and aggressive cancer usually arising on a background of chronic liver injury involving inflammatory and hepatic regenerative processes. The triggering receptor expressed on myeloid cells 2 (TREM-2) is predominantly expressed in hepatic non-parenchymal cells and inhibits Toll-like receptor signalling, protecting the liver from various hepatotoxic injuries, yet its role in liver cancer is poorly defined. Here, we investigated the impact of TREM-2 on liver regeneration and hepatocarcinogenesis. DESIGN: TREM-2 expression was analysed in liver tissues of two independent cohorts of patients with HCC and compared with control liver samples. Experimental HCC and liver regeneration models in wild type and Trem-2(-/-) mice, and in vitro studies with hepatic stellate cells (HSCs) and HCC spheroids were conducted. RESULTS: TREM-2 expression was upregulated in human HCC tissue, in mouse models of liver regeneration and HCC. Trem-2(-/-) mice developed more liver tumours irrespective of size after diethylnitrosamine (DEN) administration, displayed exacerbated liver damage, inflammation, oxidative stress and hepatocyte proliferation. Administering an antioxidant diet blocked DEN-induced hepatocarcinogenesis in both genotypes. Similarly, Trem-2(-/-) animals developed more and larger tumours in fibrosis-associated HCC models. Trem-2(-/-) livers showed increased hepatocyte proliferation and inflammation after partial hepatectomy. Conditioned media from human HSCs overexpressing TREM-2 inhibited human HCC spheroid growth in vitro through attenuated Wnt ligand secretion. CONCLUSION: TREM-2 plays a protective role in hepatocarcinogenesis via different pleiotropic effects, suggesting that TREM-2 agonism should be investigated as it might beneficially impact HCC pathogenesis in a multifactorial manner.
33270649 Dose-dependent oral glucocorticoid cardiovascular risks in people with immune-mediated inf 2020 Dec BACKGROUND: Glucocorticoids are widely used to reduce disease activity and inflammation in patients with a range of immune-mediated inflammatory diseases. It is uncertain whether or not low to moderate glucocorticoid dose increases cardiovascular risk. We aimed to quantify glucocorticoid dose-dependent cardiovascular risk in people with 6 immune-mediated inflammatory diseases. METHODS AND FINDINGS: We conducted a population-based cohort analysis of medical records from 389 primary care practices contributing data to the United Kingdom Clinical Practice Research Datalink (CPRD), linked to hospital admissions and deaths in 1998-2017. We estimated time-variant daily and cumulative glucocorticoid prednisolone-equivalent dose-related risks and hazard ratios (HRs) of first all-cause and type-specific cardiovascular diseases (CVDs). There were 87,794 patients with giant cell arteritis and/or polymyalgia rheumatica (n = 25,581), inflammatory bowel disease (n = 27,739), rheumatoid arthritis (n = 25,324), systemic lupus erythematosus (n = 3,951), and/or vasculitis (n = 5,199), and no prior CVD. Mean age was 56 years and 34.1% were men. The median follow-up time was 5.0 years, and the proportions of person-years spent at each level of glucocorticoid daily exposure were 80% for non-use, 6.0% for <5 mg, 11.2% for 5.0-14.9 mg, 1.6% for 15.0-24.9 mg, and 1.2% for ≥25.0 mg. Incident CVD occurred in 13,426 (15.3%) people, including 6,013 atrial fibrillation, 7,727 heart failure, and 2,809 acute myocardial infarction events. One-year cumulative risks of all-cause CVD increased from 1.4% in periods of non-use to 8.9% for a daily prednisolone-equivalent dose of ≥25.0 mg. Five-year cumulative risks increased from 7.1% to 28.0%, respectively. Compared to periods of non-glucocorticoid use, those with <5.0 mg daily prednisolone-equivalent dose had increased all-cause CVD risk (HR = 1.74; 95% confidence interval [CI] 1.64-1.84; range 1.52 for polymyalgia rheumatica and/or giant cell arteritis to 2.82 for systemic lupus erythematosus). Increased dose-dependent risk ratios were found regardless of disease activity level and for all type-specific CVDs. HRs for type-specific CVDs and <5.0-mg daily dose use were: 1.69 (95% CI 1.54-1.85) for atrial fibrillation, 1.75 (95% CI 1.56-1.97) for heart failure, 1.76 (95% CI 1.51-2.05) for acute myocardial infarction, 1.78 (95% CI 1.53-2.07) for peripheral arterial disease, 1.32 (95% CI 1.15-1.50) for cerebrovascular disease, and 1.93 (95% CI 1.47-2.53) for abdominal aortic aneurysm. The lack of hospital medication records and drug adherence data might have led to underestimation of the dose prescribed when specialists provided care and overestimation of the dose taken during periods of low disease activity. The resulting dose misclassification in some patients is likely to have reduced the size of dose-response estimates. CONCLUSIONS: In this study, we observed an increased risk of CVDs associated with glucocorticoid dose intake even at lower doses (<5 mg) in 6 immune-mediated diseases. These results highlight the importance of prompt and regular monitoring of cardiovascular risk and use of primary prevention treatment at all glucocorticoid doses.
32794606 Psychological therapies for the management of chronic pain (excluding headache) in adults. 2020 Aug 12 BACKGROUND: Chronic non-cancer pain, a disabling and distressing condition, is common in adults. It is a global public health problem and economic burden on health and social care systems and on people with chronic pain. Psychological treatments aim to reduce pain, disability and distress. This review updates and extends its previous version, published in 2012. OBJECTIVES: To determine the clinical efficacy and safety of psychological interventions for chronic pain in adults (age > 18 years) compared with active controls, or waiting list/treatment as usual (TAU). SEARCH METHODS: We identified randomised controlled trials (RCTs) of psychological therapies by searching CENTRAL, MEDLINE, Embase and PsycINFO to 16 April 2020. We also examined reference lists and trial registries, and searched for studies citing retrieved trials. SELECTION CRITERIA: RCTs of psychological treatments compared with active control or TAU of face-to-face therapies for adults with chronic pain. We excluded studies of headache or malignant disease, and those with fewer than 20 participants in any arm at treatment end. DATA COLLECTION AND ANALYSIS: Two or more authors rated risk of bias, extracted data, and judged quality of evidence (GRADE). We compared cognitive behavioural therapy (CBT), behavioural therapy (BT), and acceptance and commitment therapy (ACT) with active control or TAU at treatment end, and at six month to 12 month follow-up. We did not analyse the few trials of other psychological treatments. We assessed treatment effectiveness for pain intensity, disability, and distress. We extracted data on adverse events (AEs) associated with treatment. MAIN RESULTS: We added 41 studies (6255 participants) to 34 of the previous review's 42 studies, and now have 75 studies in total (9401 participants at treatment end). Most participants had fibromyalgia, chronic low back pain, rheumatoid arthritis, or mixed chronic pain. Most risk of bias domains were at high or unclear risk of bias, with selective reporting and treatment expectations mostly at unclear risk of bias. AEs were inadequately recorded and/or reported across studies. CBT The largest evidence base was for CBT (59 studies). CBT versus active control showed very small benefit at treatment end for pain (standardised mean difference (SMD) -0.09, 95% confidence interval (CI) -0.17 to -0.01; 3235 participants; 23 studies; moderate-quality evidence), disability (SMD -0.12, 95% CI -0.20 to -0.04; 2543 participants; 19 studies; moderate-quality evidence), and distress (SMD -0.09, 95% CI -0.18 to -0.00; 3297 participants; 24 studies; moderate-quality evidence). We found small benefits for CBT over TAU at treatment end for pain (SMD -0.22, 95% CI -0.33 to -0.10; 2572 participants; 29 studies; moderate-quality evidence), disability (SMD -0.32, 95% CI -0.45 to -0.19; 2524 participants; 28 studies; low-quality evidence), and distress (SMD -0.34, 95% CI -0.44 to -0.24; 2559 participants; 27 studies; moderate-quality evidence). Effects were largely maintained at follow-up for CBT versus TAU, but not for CBT versus active control. Evidence quality for CBT outcomes ranged from moderate to low. We rated evidence for AEs as very low quality for both comparisons. BT We analysed eight studies (647 participants). We found no evidence of difference between BT and active control at treatment end (pain SMD -0.67, 95% CI -2.54 to 1.20, very low-quality evidence; disability SMD -0.65, 95% CI -1.85 to 0.54, very low-quality evidence; or distress SMD -0.73, 95% CI -1.47 to 0.01, very low-quality evidence). At follow-up, effects were similar. We found no evidence of difference between BT and TAU (pain SMD -0.08, 95% CI -0.33 to 0.17, low-quality evidence; disability SMD -0.02, 95% CI -0.24 to 0.19, moderate-quality evidence; distress SMD 0.22, 95% CI -0.10 to 0.54, low-quality evidence) at treatment end. At follow-up, we found one to three studies with no evidence of difference between BT and TAU. We rated evidence for all BT versus active control outcomes as very low quality; for BT versus TAU. Evidence quality ranged from moderate to very low. We rated evidence for AEs as very low quality for BT versus active control. No studies of BT versus TAU reported AEs. ACT We analysed five studies (443 participants). There was no evidence of difference between ACT and active control for pain (SMD -0.54, 95% CI -1.20 to 0.11, very low-quality evidence), disability (SMD -1.51, 95% CI -3.05 to 0.03, very low-quality evidence) or distress (SMD -0.61, 95% CI -1.30 to 0.07, very low-quality evidence) at treatment end. At follow-up, there was no evidence of effect for pain or distress (both very low-quality evidence), but two studies showed a large benefit for reducing disability (SMD -2.56, 95% CI -4.22 to -0.89, very low-quality evidence). Two studies compared ACT to TAU at treatment end. Results should be interpreted with caution. We found large benefits of ACT for pain (SMD -0.83, 95% CI -1.57 to -0.09, very low-quality evidence), but none for disability (SMD -1.39, 95% CI -3.20 to 0.41, very low-quality evidence), or distress (SMD -1.16, 95% CI -2.51 to 0.20, very low-quality evidence). Lack of data precluded analysis at follow-up. We rated evidence quality for AEs to be very low. We encourage caution when interpreting very low-quality evidence because the estimates are uncertain and could be easily overturned. AUTHORS' CONCLUSIONS: We found sufficient evidence across a large evidence base (59 studies, over 5000 participants) that CBT has small or very small beneficial effects for reducing pain, disability, and distress in chronic pain, but we found insufficient evidence to assess AEs. Quality of evidence for CBT was mostly moderate, except for disability, which we rated as low quality. Further trials may provide more precise estimates of treatment effects, but to inform improvements, research should explore sources of variation in treatment effects. Evidence from trials of BT and ACT was of moderate to very low quality, so we are very uncertain about benefits or lack of benefits of these treatments for adults with chronic pain; other treatments were not analysed. These conclusions are similar to our 2012 review, apart from the separate analysis of ACT.
33037005 Fast diagnostic test for familial Mediterranean fever based on a kinase inhibitor. 2021 Jan BACKGROUND AND OBJECTIVE: Familial Mediterranean fever (FMF) is the most frequent hereditary autoinflammatory disease. Its diagnosis relies on a set of clinical criteria and a genetic confirmation on identification of biallelic pathogenic MEFV variants. MEFV encodes pyrin, an inflammasome sensor. Using a kinase inhibitor, UCN-01, we recently identified that dephosphorylation of FMF-associated pyrin mutants leads to inflammasome activation. The aim of this study was to assess whether quantifying UCN-01-mediated inflammasome activation could discriminate FMF patients from healthy donors (HD) and from patients with other inflammatory disorders (OID). METHODS: Real-time pyroptosis and IL-1β secretion were monitored in response to UCN-01 in monocytes from FMF patients (n=67), HD (n=71) and OID patients (n=40). Sensitivity and specificity of the resulting diagnostic tests were determined by receiver operating characteristic curve analyses. RESULTS: Inflammasome monitoring in response to UCN-01 discriminates FMF patients from other individuals. Pyroptosis assessment leads to a fast FMF diagnosis while combining pyroptosis and IL-1β dosage renders UCN-01-based assays highly sensitive and specific. UCN-01-triggered monocytes responses were influenced by MEFV gene dosage and MEFV mutations in a similar way as clinical phenotypes are. CONCLUSIONS: UCN-01-based inflammasome assays could be used to rapidly diagnose FMF, with high sensitivity and specificity.
32231148 BMAL1 Suppresses Proliferation, Migration, and Invasion of U87MG Cells by Downregulating C 2020 Mar 28 Several studies have shown that brain and muscle aryl hydrocarbon receptor nuclear translocator-like 1 (BMAL1), an important molecule for maintaining circadian rhythms, inhibits the growth and metastasis of tumor cells in several types of cancer, including lung, colon, and breast cancer. However, its role in glioblastoma has not yet been established. Here, we addressed the function of BMAL1 in U87MG glioblastoma cells with two approaches-loss and gain of function. In the loss of function experiments, cell proliferation in U87MG cells transfected with small interfering RNA (siRNA) targeting BMAL1 was increased by approximately 24% (small interfering (si)-NC 0.91 ± 0.00 vs. si-BMAL1 1.129 ± 0.08) via upregulation of cyclin B1. In addition, cell migration and invasion of BMAL1 siRNA-treated glioblastoma cells were elevated by approximately 20% (si-NC 51.00 ± 1.53 vs. si-BMAL161.33 ± 0.88) and 209% (si-NC 21.28 ± 1.37 vs. si-BMAL1 44.47 ± 3.48), respectively, through the accumulation of phosphorylated-AKT (p-AKT) and matrix metalloproteinase (MMP)-9. Gain of function experiments revealed that adenovirus-mediated ectopic expression of BMAL1 in U87MG cells resulted in a 19% (Adenovirus (Ad)-vector 0.94± 0.03 vs. Ad-BMAL1 0.76 ± 0.03) decrease in cell proliferation compared with the control via downregulation of cyclin B1 and increased early and late apoptosis due to changes in the levels of BCL2-associated X protein (BAX), B-cell lymphoma 2 (BCL-2), and cleaved caspase-3. Likewise, cell migration and invasion were attenuated by approximately 24% (Ad-vector 55.00 ± 0.00 vs. Ad-BMAL1 41.83 ± 2.90) and 49% (Ad-vector 70.01 ± 1.24 vs. Ad-BMAL1 35.55 ± 1.78), respectively, in BMAL1-overexpressing U87MG cells following downregulation of p-AKT and MMP-9. Taken together, our results suggest that BMAL1 acts as an anti-cancer gene by altering the proliferation, migration, and invasion of glioblastoma cells. Therefore, the BMAL1 gene could be a potential therapeutic target in the treatment of glioblastoma.