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ID PMID Title PublicationDate abstract
30825105 A high-throughput drug screen identifies auranofin as a potential sensitizer of cisplatin 2019 Dec Small cell lung cancer (SCLC) is a highly lethal malignancy with the 5-year survival rate of less than 7%. Chemotherapy-resistance is a major challenge for SCLC treatment in clinic. In the study, we developed a high-throughput drug screen strategy to identify new drugs that can enhance the sensitivity of chemo-drug cisplatin in SCLC. This screen identified auranofin, a US Food and Drug Administration (FDA)-approved drug used therapeutically for rheumatoid arthritis, as a sensitizer of cisplatin. Further study validated that auranofin synergistically enhanced the anti-tumor activity of cisplatin in chemo-resistant SCLC cells, which was accompanied by the enhanced induction of cell cycle arrest and apoptosis. The synergistic action of auranofin and cisplatin was through ROS overproduction, thereby leading to mitochondrial dysfunction and DNA damage. Furthermore, in vivo study demonstrated that the combination treatment of auranofin and cisplatin dramatically inhibited tumor growth in SCLC. Therefore, our study provides a rational basis for further clinical study to test whether auranofin could enhance the sensitivity of cisplatin-based therapy in SCLC patients.
30797069 Sinomenine inhibits osteolysis in breast cancer by reducing IL-8/CXCR1 and c-Fos/NFATc1 si 2019 Apr Sinomenine (SIN) is an anti-inflammatory and antiarthritic alkaloid derived from Sinomenium acutum, and the product Zhengqing Fengtongning produced from SIN has been marketed in China for treating rheumatoid arthritis (RA). Interestingly, we recently found that SIN could significantly ameliorate bone destruction induced by breast cancer cells in mice. Micro-CT examination showed that bone loss of the trabecular bones in tumor-bearing mice was markedly decreased by i.p. treatment of SIN at 150 mg/kg body weight. A mechanistic study demonstrated that SIN could suppress osteoclast formation and bone absorption induced by both MDA-MB-231 cells and MDA-MB-231 cell-conditioned medium (MDA-MB-231 CM) in preosteoclastic RAW264.7 cells. The MDA-MB-231 CM-induced osteoclast-related genes TRAP and OSCAR were obviously downregulated by SIN. In addition, mRNA expression of c-Fos and NFATc1 and nuclear translocation of c-Fos and NFATc1 protein were inhibited by SIN during MDA-MB-231 CM-induced osteoclastogenesis, while NF-κB signaling was not impacted by SIN. More interestingly, SIN was demonstrated to decrease hIL-8 mRNA expression in cultured MDA-MB-231 cells and to inhibit hIL-8 protein expression in MDA-MB-231 cells cocultured with preosteoclastic RAW264.7 cells while simultaneously downregulating CXCR1, the ligand of IL-8 related to bone destruction, during MDA-MB-231 CM-induced osteoclastogenesis. Previously, IL-8/CXCR1 was reported to be associated with the pathogenesis and progression of RA, and SIN was observed to markedly ameliorate bone erosion of RA patients. Our current findings may extend the utilization of SIN to preventing osteoclastogenesis and bone destruction in breast cancer patients and may enable IL-8/CXCR1 to serve as new targets for both anticancer and antiarthritic drug discovery.
30395947 Molecular pharmacology of inflammation: Medicinal plants as anti-inflammatory agents. 2019 Jan Except for an essential step for the pathology of multiple diseases including atherosclerosis and rheumatoid arthritis, inflammation is an imperative therapeutic target for developing novel approaches for pharmacological interventions. Thus, molecular understanding of inflammation not only revealed the mechanisms of drug action and their biological targets but also has spawned innovative maneuvers to influence multifaceted biological systems, providing new prospects for drug designing and suggesting important new implications for existing clinical medicine. Meanwhile, modulation of inflammation with the use of medicinal plants proposed an alternate to conventional therapeutic strategies for numerous ailments, particularly when suppression of inflammation is expected. In modern literature, several species of medicinal plants have been shown substantial antiinflammatory and immunomodulatory actions including inhibitory effects on suppression of cellular and humoral immunity, lymphocyte activation, and propagation of apoptosis. Herein, we reviewed the molecular pharmacology of inflammation, chemical components and biological activities of medicinal plants such as, curcumin from Curcuma longa, and epigallocatechin-3-gallate from Camellia sinensis as well as their mechanism of action during inflammation at molecular level. An extensive review of the literature and electronic databases was conducted, encompassing PubMed, GoogleScholar, ScienceDirect, medlineplus, www.clinicaltrial.gov, www.fda.gov, www.ema.europa.eu, www.drugbank.ca, TrialBulletin.com, www.theplantlist.org, and www.pharmacodia.com for assembling the information. Additionally, data was attained from books, ethnopharmacological literature, and relevant publications for essential elements of molecular mechanisms, signal transduction networks, transcription factors, complement system, reactive species, and clinical trials are selected for substantial understanding of biochemistry, pathophysiology as well as clinical importance of medicinal plants during inflammatory diseases.
30622307 To NET or not to NET:current opinions and state of the science regarding the formation of 2019 Mar Since the discovery and definition of neutrophil extracellular traps (NETs) 14 years ago, numerous characteristics and physiological functions of NETs have been uncovered. Nowadays, the field continues to expand and novel mechanisms that orchestrate formation of NETs, their previously unknown properties, and novel implications in disease continue to emerge. The abundance of available data has also led to some confusion in the NET research community due to contradictory results and divergent scientific concepts, such as pro- and anti-inflammatory roles in pathologic conditions, demarcation from other forms of cell death, or the origin of the DNA that forms the NET scaffold. Here, we present prevailing concepts and state of the science in NET-related research and elaborate on open questions and areas of dispute.
31781316 Tetrandrine Ameliorates Airway Remodeling of Chronic Asthma by Interfering TGF-β1/Nrf-2/H 2019 BACKGROUND: Imbalanced oxidative stress and antioxidant defense are involved in airway remodeling in asthma. It has been demonstrated that Tetrandrine has a potent role in antioxidant defense in rheumatoid arthritis and hypertension. However, the correlation between Tetrandrine and oxidative stress in asthma is utterly blurry. This study aimed to investigate the role of Tetrandrine on oxidative stress-mediated airway remolding. MATERIALS AND METHODS: Chronic asthma was established by ovalbumin (OVA) administration in male Wistar rats. Histopathology was determined by HE staining. Immunofluorescence was employed to detect the expression of α-SMA and Nrf-2. Level of oxidative stress and matrix metalloproteinases were examined by ELISA kits. Cell viability and cell cycle of primary airway smooth muscle cells (ASMCs) were evaluated by CCK8 and flow cytometry, respectively. Signal molecules were detected using western blot. RESULTS: Tetrandrine effectively impairs OVA-induced airway inflammatory and airway remodeling by inhibiting the expression of CysLT1 and CysLTR1. The increase of oxidative stress and subsequent enhancement of MMP9 and TGF-β1 expression were rescued by the administration of Tetrandrine in the rat model of asthma. In in vitro experiments, Tetrandrine markedly suppressed TGF-β1-evoked cell viability and cell cycle promotion of ASMCs in a dose-dependent manner. Furthermore, Tetrandrine promoted Nrf-2 nuclear transcription and activated its downstream HO-1 in vivo and in vitro. CONCLUSION: Tetrandrine attenuates airway inflammatory and airway remodeling in rat model of asthma and TGF-β1-induced cell proliferation of ASMCs by regulating oxidative stress in primary ASMCs, suggesting that Tetrandrine possibly is an effective candidate therapy for asthma.
31601008 Neighborhood Deprivation and Risks of Autoimmune Disorders: A National Cohort Study in Swe 2019 Oct 9 Background: No study to date, as far as we know, has analyzed the potential effect of neighborhood-level deprivation on autoimmune disorders (ADs), when adjusted for individual-level characteristics. Methods: A total of 5.4 million individuals from 8363 neighborhoods, comprising the whole Swedish population (ages 25-74 years), were followed for the period 1 January 2000, until admission due to diagnosis of ADs during the period of the study, or the conclusion of the study (31 December 2010). We used a neighborhood deprivation index, constructed from variables such as low education, low income, unemployment, and social welfare assistance, to assess the level of neighborhood deprivation. Multilevel logistic regression was used in the analysis with individual level characteristics at the first level and level of neighborhood deprivation at the second level. Results: A significant association between level of neighborhood deprivation and ADs was found. The crude odds were 1.32 (95% confidence interval 1.27-1.36) for those residing in the high-deprived neighborhoods compared to those living in low-deprivation neighborhoods. In the full model, where individual level characteristics were taken into account, the odds of ADs were 1.18 (1.14-1.22) in the most deprived neighborhoods. Certain Ads-angiitis hypersensitive (5.14), ankylosing spondylitis (1.66), celiac disease (1.65), Crohn's disease (1.21), diabetes mellitus type 1 (1.45), Graves's disease (1.13), Hashimoto thyroiditis (1.51), psoriasis (1.15), rheumatoid arthritis (1.15), sarcoidosis (1.20), and systemic sclerosis (1.27)-remained significantly associated with high level of neighborhood deprivation after adjustment for the individual-level variables. Conclusion: This study is the largest to date analyzing the potential influence of neighborhood deprivation on ADs. Our results indicate that neighborhood deprivation may affect risk of ADs, independent of individual level sociodemographic characteristics. For health care policies, both individual and neighborhood level approaches seem to be of importance.
31536611 Risk of major autoimmune diseases in female breast cancer patients: A nationwide, populati 2019 BACKGROUND: Breast cancer is one of the most common malignancies among women. However, there remains no consensus in current literature on the incidence of autoimmune diseases among breast cancer patients. The purpose of this study was to evaluate the risks of major autoimmune diseases (MAD) including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjögren's syndrome (SS) and dermatomyositis (DMtis)/polymyositis (PM) in female breast cancer patients. METHODS: Using the Taiwanese National Health Insurance Research Database (NHIRD) records from 2003 to 2013, we identified newly-diagnosed female breast cancer patients and randomly selected females without breast cancer in the period 2007 to 2013 into a control group. We matched the two cohorts using a 1:4 ratio based on age, and the year of index date for comparison of the risk of major autoimmune diseases. We estimated and compared the relative risks of autoimmune diseases in female breast cancer patients and females without breast cancer. RESULTS: A total of 54,311 females with breast cancer and 217,244 matched females without breast cancer were included in this study. For SLE, the incidence rates were 2.3 (breast cancer group) vs. 10.0 (control group) per 100,000 women years; for RA rates were 19.3 (breast cancer group) vs. 42.7 (control group) per 100,000 women years; and for SS rates were 20.5 (breast cancer group) vs. 38.2 (control group) per 100,000 women years. After adjusting for potential confounders, the hazard ratios (95% confidence intervals) for female breast cancer patients vs. control group were 0.04 (0.01-0.24) for SLE; 0.03 (0.02-0.04) for RA; and 0.21 (0.09-0.48) for SS. CONCLUSION: Female breast cancer patients had lower risks of SLE, RA and SS when compared to female individuals without breast cancer. However, there was no significant difference in the risk of developing DMtis/PM between both groups.
31341258 Leflunomide increased the renal exposure of acyclovir by inhibiting OAT1/3 and MRP2. 2020 Jan Rheumatoid arthritis patients can be prescribed a combination of immunosuppressive drug leflunomide (LEF) and the antiviral drug acyclovir to reduce the high risk of infection. Acyclovir is a substrate of organic anion transporter (OAT) 1/3 and multidrug resistance-associated protein (MRP) 2. Considering the extraordinarily long half-life of LEF's active metabolite teriflunomide (TER) and the kidney injury risk of acyclovir, it is necessary to elucidate the potential impact of LEF on the disposition of acyclovir. Here we used a specific MRP inhibitor MK571 and probenecid (OAT1/3 and MRP2 inhibitor) to assess the effects of MRP2 and OAT1/3 on the pharmacokinetics and tissue distribution of acyclovir in rats. We showed that LEF and probenecid, but not MK571 significantly increased the plasma concentration of acyclovir. However, kidney and liver exposures of acyclovir were increased when coadministered with LEF, probenecid or MK571. The kidney/plasma ratio of acyclovir was increased to approximately 2-fold by LEF or probenecid, whereas it was increased to as much as 14.5-fold by MK571. Consistently, these drugs markedly decreased the urinary excretion of acyclovir. TER (0.5-100 μmol/L) dose-dependently increased the accumulation of acyclovir in MRP2-MDCK cells with an IC(50) value of 4.91 μmol/L. TER (5 μmol/L) significantly inhibited the uptake of acyclovir in hOAT1/3-HEK293 cells. These results suggest that LEF/TER increased the kidney accumulation of acyclovir by inhibiting the efflux transporter MRP2, which increased its kidney/plasma ratio and renal injury risk. However, the inhibitory effects of LEF/TER on OAT1/3 reduced the tubular cells' uptake of acyclovir and increased the plasma concentration.
31307110 Association between opioid use disorder and fractures: a population-based study. 2019 Nov AIMS: To test whether fractures and osteoporosis are more prevalent among patients with opioid use disorder (OUD) than patients without OUD in Taiwan. DESIGN: We conducted a retrospective cohort study using data from the National Health Insurance Research Database (NHIRD) in Taiwan. SETTING: Taiwan. PARTICIPANTS: The number of adult patients with OUD and without OUD was 3695 and 14 780, respectively. We established both cohorts from 1 January 1998 to 31 December 2011 to observe the incidence of fracture. The occurrence of fracture was followed-up until the end of 2011. MEASUREMENTS: The primary measure was incidence of fracture. The relative risk of fracture was estimated using the Cox proportional hazard model after adjusting for age, sex, index year and comorbidities. Comorbidities included diabetes mellitus, hyperlipidemia, stroke, chronic obstructive pulmonary disease, heart failure, alcohol-related illness, osteoporosis, end-stage renal disease, obesity and rheumatoid arthritis, using the International Classification of Diseases, 9th revision, clinical modification. FINDINGS: Patients with OUD were 4.13 times more likely to suffer fractures than patients without OUD [incidence rate (IR) per 1000 person-years = 23.0 versus 5.47, adjusted hazard ratio (HR) = 3.74, 95% confidence interval (CI) = 3.27-4.29]. Compared with the control group, the risk of fracture was higher among the patients with OUD. Risk of fracture was higher in male elderly patients with diabetes mellitus, alcohol-related illness or osteoporosis. The cumulative incidences of fracture over 14 years of patients with OUD and without OUD differed significantly. CONCLUSIONS: Taiwanese patients with opioid use disorder appear to have a higher adjusted hazard ratio for fracture than Taiwanese patients without opioid use disorder.
30670317 Non-canonical cholinergic anti-inflammatory pathway-mediated activation of peritoneal macr 2019 Mar The cholinergic anti-inflammatory pathway (CAP) links the nervous and immune systems and modulates innate and adaptive immunity. Activation of the CAP by vagus nerve stimulation exerts protective effects in a wide variety of clinical disorders including rheumatoid arthritis and Crohn's disease, and in murine models of acute kidney injury including ischemia/reperfusion injury (IRI). The canonical CAP pathway involves activation of splenic alpha7-nicotinic acetylcholine receptor (α7nAChR)-positive macrophages by splenic β2-adrenergic receptor-positive CD4+ T cells. Here we demonstrate that ultrasound or vagus nerve stimulation also activated α7nAChR-positive peritoneal macrophages, and that adoptive transfer of these activated peritoneal macrophages reduced IRI in recipient mice. The protective effect required α7nAChR, and did not occur in splenectomized mice or in mice lacking T and B cells, suggesting a bidirectional interaction between α7nAChR-positive peritoneal macrophages and other immune cells including β2-adrenergic receptor-positive CD4+ T cells. We also found that expression of hairy and enhancer of split-1 (Hes1), a basic helix-loop-helix DNA-binding protein, is induced in peritoneal macrophages by ultrasound or vagus nerve stimulation. Adoptive transfer of Hes1-overexpressing peritoneal macrophages reduced kidney IRI. Our data suggest that Hes1 is downstream of α7nAChR and is important to fully activate the CAP. Taken together, these results suggest that peritoneal macrophages play a previously unrecognized role in mediating the protective effect of CAP activation in kidney injury, and that Hes1 is a new candidate pharmacological target to activate the CAP.
31605099 Author Correction: Tubular cell and keratinocyte single-cell transcriptomics applied to lu 2019 Nov An amendment to this paper has been published and can be accessed via a link at the top of the paper.
31542070 Lymphomatoid Papulosis Type B in a Patient with Crohn's Disease Treated with TNF-Alpha Inh 2019 Sep Dear Editor, Lymphomatoid papulosis (LP) is a chronic, recurrent, usually self-limited papulonecrotic or papulonodular skin disease, which belongs to the group of primary cutaneous CD30+ lymphoproliferative disorders (1). Three main histological subtypes of LP have been recognized: type A (histiocytic), type B (mycosis fungoides-like), and type C (anaplastic large cell lymphoma-like). Recently, new histologic LP variants classified as type D (CD8-positive, cytotoxic form) and type E (angioinvasive form) have also been described. The etiology of LP has not been determined to date (2-4). Herein we report a case of LP type B evolving in a patient with Crohn's disease after treatment with infliximab and adalimumab. A 38-year-old man suffering from terminal ileitis form of luminar Crohn's disease for 10 years presented at our department. During the last 10 years, the patient had been treated with a number of conventional disease-modifying anti-inflammatory drugs including non-steroid anti-inflammatory drugs, mesalazine, and immunomodulatory agents such as corticosteroids and azathioprine. As the disease was not sufficiently controlled, TNF-α inhibitor therapy was initiated. Infliximab was administered in standard dosage (5 mg/kg body weight every 8 weeks after the induction period) for one year. Concomitant therapy with azathioprine was established to reduce the risk of adverse immunological reactions. Since the patient showed only partial clinical response, infliximab was switched to adalimumab (40 mg biweekly), resulting in notable improvement. 18 months after the initiation of adalimumab treatment, asymptomatic, small, red to brown papules developed on the extremities. Multiple lesions were observed, initially on the legs, but the symptoms rapidly progressed to the arms and trunk (Figure 1). An acquired ichthyosis further complicated the disease course by extended, extremely xerotic, scaling skin lesions. Neither systemic symptoms nor significant lymphadenopathy was observed. The clinical picture suggested either ichthyosiform mycosis fungoides or a coincidence of LP and acquired ichthyosis. The histology of a typical papule showed perivascular and periadnexal lymphoid infiltration with massive hemorrhage in the dermis. The infiltration was dense, composed of small-to-medium-sized lymphoid cells showing focal significant epidermotropism (Figure 2). Most observed epidermal lymphocytes were CD3+, CD4+, and CD30+, while the dermal infiltration had higher CD4 and lower CD30 expression (10-15%). Polymerase chain reaction (PCR) analysis of skin and peripheral blood samples did not show clonal rearrangement of T-cell receptor gamma (TcRgamma) genes. Normal phenotypes of lymphocyte subsets were detected by flow cytometry of peripheral blood. Ichthyosiform mycosis fungoides was excluded since histology of ichthyosiform skin lesions showed only hyperkeratosis with a reduced granular layer. While the cutaneous CD4+ epidermotropic infiltrate was suspicious of either mycosis fungoides or LP type B, the complexity of clinicopathological data confirmed the diagnosis of LP type B. The peripheral blood counts, serum biochemical tests, and urinalysis were within normal range, while the elevated serum anti-Saccharomyces cerevisiae antibodies (ASCA) of IgG and IgA subclasses indicated the activity of Crohn's disease. Adalimumab and azathioprine were discontinued, and oral budesonide therapy was started in combination with topical corticosteroids and PUVA phototherapy. The skin lesions resolved with hyperpigmentation, and there was no relapse during the twelve-month follow-up. Recent data suggest that LP occurs more commonly in immunocompromised patients, especially in those with solid organ or bone marrow transplants (3). Though TNF-α inhibitors have dramatically advanced the treatment of various diseases, the risk of lymphoma associated with their use remains controversial (5). Several cases of cutaneous lymphoproliferative disorders associated with TNF-α inhibitor treatment have been reported, including two patients with LP (6). One of the two patients with LP received infliximab for Crohn's disease (7), while the other one had juvenile rheumatoid arthritis and received adalimumab (8). Our case is the third report on LP developing under TNF-α inhibitor therapy and the first LP type B in a patient with Crohn's disease treated with infliximab and later with adalimumab. A further interesting aspect of our case is that it also represents an example of the known association of acquired ichthyosis with inflammatory bowel disease (9). Multidisciplinary management was needed to provide optimal care and disease outcome for our patient. Since it is usually difficult to prove causality in most of such cases, it is important to collect similar clinical observations. Acknowledgments: The authors are grateful to Dr. László Bene, Dr. József Szakonyi, and Dr. Fruzsina Kovács for additional medical care of the patient and to Tamás Szaák for the clinical photos. The authors thank Prof. Miklós Sárdy for his critical review of the paper.
31170001 Immune-Related Comorbidities in Childhood-Onset Obsessive Compulsive Disorder: Lifetime Pr 2019 Oct Objective: To evaluate the lifetime prevalence of infectious, inflammatory, and autoimmune disorders in a multisite study of probands with childhood-onset obsessive compulsive disorder (OCD) and their first-degree relatives. Methods: Medical questionnaires were completed by 1401 probands and 1045 first-degree relatives in the OCD Collaborative Genetics Association Study. Lifetime prevalence of immune-related diseases was compared with the highest available population estimate and reported as a point estimate with 95% adjusted Wald interval. Worst-episode OCD severity and symptom dimensions were assessed with the Yale-Brown Obsessive Compulsive Scale (YBOCS) and Symptom Checklist (YBOCS-CL). Results: Probands reported higher-than-expected prevalence of scarlet fever (4.0 [3.1-5.2]% vs. 1.0%-2.0%, z = 1.491, p < 0.001, n = 1389), encephalitis or meningitis (1.4 [0.9-2.1]% vs. 0.1%-0.4%, z = 5.913, p < 0.001, n = 1393), rheumatoid arthritis (1.1 [0.6-2.0]% vs. 0.2%-0.4%, z = 3.416, p < 0.001, n = 949) and rheumatic fever (0.6 [0.3-1.2]% vs. 0.1%-0.2%, z = 3.338, p < 0.001, n = 1390), but not systemic lupus erythematosus, diabetes, asthma, multiple sclerosis, psoriasis, or inflammatory bowel disease. First-degree relatives reported similarly elevated rates of scarlet fever, rheumatic fever, and encephalitis or meningitis independent of OCD status. There was no association between worst-episode severity and immune-related comorbidities, although probands reporting frequent ear or throat infections had increased severity of cleaning-/contamination-related symptoms (mean factor score 2.5 ± 0.9 vs. 2.3 ± 1.0, t = 3.183, p = 0.002, n = 822). Conclusion: These data suggest high rates of streptococcal-related and other immune-mediated diseases in patients with childhood-onset OCD and are consistent with epidemiological studies in adults noting familial clustering. Limitations include potential reporting bias and absence of a control group, underscoring the need for further prospective studies characterizing medical and psychiatric disease clusters and their interactions in children. Such studies may ultimately improve our understanding of OCD pathogenesis and aid in the development of adjunctive immune-modulating therapeutic strategies.
30634574 Identification of the Chemical Constituents of an Anti-Arthritic Chinese Medicine Wen Luo 2019 Jan 10 Wen Luo Yin (WLY), a well-known traditional Chinese medicine formulation, has been used as a complementary therapy for the treatment of rheumatoid arthritis in clinical settings. However, the chemical constituents of WLY remain unclear. In this study, a high-performance liquid chromatography coupled with tandem mass spectrometry method was established to separate and comprehensively identify the chemical constituents of WLY. The analytes were eluted with a mobile phase of acetonitrile and 0.1% aqueous acetic acid. Mass detection was performed in both positive and negative ion mode. The MS/MS fragmentation pathways were proposed for the identification of the components. A total of 42 compounds including sesquiterpenes, alkaloids, biflavonoids, polyacetylenes, phenylpropanoids and acetylenic phenols were identified unambiguously or tentatively according to their retention times and mass behavior with those of authentic standards or literature data. The identification and structural elucidation of chemical constituents may provide important information for quality control and pharmacological research of WLY.
30476584 Safety of Tofacitinib for Treatment of Ulcerative Colitis, Based on 4.4 Years of Data From 2019 Jul BACKGROUND & AIMS: Tofacitinib is an oral, small-molecule inhibitor of JAK approved in several countries for the treatment of ulcerative colitis (UC). We report integrated safety analyses of tofacitinib-treated patients with moderate to severe UC. METHODS: Patients receiving placebo or tofacitinib (5 or 10 mg) twice daily were analyzed as 3 cohorts: induction (phase 2 and 3 induction studies, n = 1220), maintenance (phase 3 maintenance study, n = 592), and overall (patients receiving tofacitinib 5 or 10 mg twice daily in phase 2, phase 3, or open-label, long-term extension studies, n = 1157; 1613 patient-years' exposure). Incidence rates (IRs; patients with events per 100 patient-years of exposure) were evaluated for select adverse events. RESULTS: In the maintenance cohort, IRs for select adverse events were similar among treatment groups, except for a numerically higher IR of herpes zoster infection among patients who received tofacitinib 5 mg twice daily (2.1; 95% CI, 0.4-6.0) and statistically higher IR among patients who received tofacitinib 10 mg twice daily (IR, 6.6; 95% CI, 3.2-12.2) vs placebo (IR, 1.0, 95% CI, 0.0-5.4). For the overall cohort (84% received average dose of tofacitinib 10 mg twice daily), IRs were: death, 0.2 (95% CI, 0.1-0.6); serious infections, 2.0 (95% CI, 1.4-2.8); opportunistic infections, 1.3 (95% CI, 0.8-2.0); herpes zoster infection, 4.1 (95% CI, 3.1-5.2); malignancy (excluding non-melanoma skin cancer), 0.7 (95% CI, 0.3-1.2); non-melanoma skin cancer, 0.7 (95% CI, 0.3-1.2); major adverse cardiovascular events, 0.2 (95% CI, 0.1-0.6); and gastrointestinal perforations, 0.2 (95% CI, 0.0-0.5). CONCLUSIONS: In safety analyses of patients with moderate to severe UC treated with tofacitinib, we observed a dose relationship with herpes zoster infection. Although follow-up time was relatively short, the safety profile of tofacitinib for patients with UC appeared similar to that reported for patients with rheumatoid arthritis and for patients with UC treated with biologic agents, except for the higher IR of herpes zoster infection. ClinicalTrials.gov, no: NCT00787202, NCT01465763, NCT01458951, NCT01458574, and NCT01470612.
30189157 Serum Amyloid A Contributes to Chronic Apical Periodontitis via TLR2 and TLR4. 2019 Jan In the current concept of bacterial infections, pathogen-associated molecular patterns (PAMPs) derived from pathogens and damage-associated molecular patterns (DAMPs) released from damaged/necrotic host cells are crucial factors in induction of innate immune responses. However, the implication of DAMPs in apical and marginal periodontitis is unknown. Serum amyloid A (SAA) is a DAMP that is involved in the development of various chronic inflammatory diseases, such as rheumatoid arthritis. In the present study, we tested whether SAA is involved in the pathogenesis of periapical lesions, using human periapical surgical specimens and mice deficient in SAA and Toll-like receptors (TLR). SAA1/2 was locally expressed in human periapical lesions at the mRNA and protein levels. The level of SAA protein appeared to be positively associated with the inflammatory status of the lesions. In the development of mouse periapical inflammation, SAA1.1/2.1 was elevated locally and systemically in wild-type (WT) mice. Although SAA1.1/2.1 double-knockout and SAA3 knockout mice had redundant attenuation of the extent of periapical lesions, these animals showed strikingly improved inflammatory cell infiltration versus WT. Recombinant human SAA1 (rhSAA1) directly induced chemotaxis of WT neutrophils in a dose-dependent manner in vitro. In addition, rhSAA1 stimulation significantly prolonged the survival of WT neutrophils as compared with nonstimulated neutrophils. Furthermore, rhSAA1 activated the NF-κB pathway and subsequent IL-1α production in macrophages in a dose-dependent manner. However, TLR2/TLR4 double deficiency substantially diminished these SAA-mediated proinflammatory responses. Taken together, the SAA-TLR axis plays an important role in the chronicity of periapical inflammation via induction of inflammatory cell infiltration and prolonged cell survival. The interactions of PAMPs and DAMPs require further investigation in dental/oral inflammation.
30059674 Tofacitinib and TPCA-1 exert chondroprotective effects on extracellular matrix turnover in 2019 Jul OBJECTIVE: Currently, there are no disease-modifying osteoarthritis drugs (DMOADs) approved for osteoarthritis. It is hypothesized that a subtype of OA may be driven by inflammation and may benefit from treatment with anti-inflammatory small molecule inhibitors adopted from treatments of rheumatoid arthritis. This study aimed to investigate how small molecule inhibitors of intracellular signaling modulate cartilage degradation and formation as a pre-clinical model for structural effects. DESIGN: Bovine cartilage explants were cultured with oncostatin M (OSM) and tumour necrosis factor α (TNF-α) either alone or combined with the small molecule inhibitors: SB203580 (p38 inhibitor), R406 (Spleen tyrosine kinase (Syk) inhibitor), TPCA-1 (Inhibitor of κB kinase (Ikk) inhibitor), or Tofacitinib (Tofa) (Janus kinases (Jak) inhibitor). Cartilage turnover was assessed with the biomarkers of degradation (AGNx1 and C2M), and type II collagen formation (PRO-C2) using ELISA. Explant proteoglycan content was assessed by Safranin O/Fast Green staining. RESULTS: R406, TPCA-1 and Tofa reduced the cytokine-induced proteoglycan loss and decreased AGNx1 release 3.7-, 43- and 32-fold, respectively. SB203580 showed no effect. All inhibitors suppressed C2M at a concentration of 3 µM. TPCA-1 and Tofa increased the cytokine reduced PRO-C2 3.5 and 3.7-fold, respectively. CONCLUSION: Using a pre-clinical model we found that the inhibitors TPCA-1 and Tofa inhibited cartilage degradation and rescue formation of type II collagen under inflammatory conditions, while R406 and SB203580 only inhibited cartilage degradation, and SB203580 only partially. These pre-clinical data suggest that TPCA-1 and Tofa preserve and help maintain cartilage ECM under inflammatory conditions and could be investigated further as DMOADs for inflammation-driven osteoarthritis.
31363069 Noncompetitive inhibitors of TNFR1 probe conformational activation states. 2019 Jul 30 Tumor necrosis factor receptor 1 (TNFR1) is a central mediator of the inflammatory pathway and is associated with several autoimmune diseases such as rheumatoid arthritis. A revision to the canonical model of TNFR1 activation suggests that activation involves conformational rearrangements of preassembled receptor dimers. Here, we identified small-molecule allosteric inhibitors of TNFR1 activation and probed receptor dimerization and function. Specifically, we used a fluorescence lifetime-based high-throughput screen and biochemical, biophysical, and cellular assays to identify small molecules that noncompetitively inhibited the receptor without reducing ligand affinity or disrupting receptor dimerization. We also found that residues in the ligand-binding loop that are critical to the dynamic coupling between the extracellular and the transmembrane domains played a key gatekeeper role in the conformational dynamics associated with signal propagation. Last, using a simple structure-activity relationship analysis, we demonstrated that these newly found molecules could be further optimized for improved potency and specificity. Together, these data solidify and deepen the new model for TNFR1 activation.
31287802 The association between insomnia, c-reactive protein, and chronic low back pain: cross-sec 2019 Oct 25 BACKGROUND AND AIMS: Chronic low back pain (chronic LBP) is the number one cause for years lived with disability among 301 diseases and injuries analyzed by The Global Burden of Disease study 2013. Insomnia is highly prevalent among people with chronic LBP. To explain the sleep-pain relationship, theoretical models propose that insomnia symptoms may be associated with increased basal inflammation, operationalized as c-reactive protein (CRP) and lead to further pain and disrupted sleep. We aimed to determine the associations between insomnia, chronic LBP, and inflammation (operationalized as CRP), whilst controlling for age, body mass index, smoking, physical activity, depression, anxiety and osteoarthritis. METHODS: A cross-sectional analysis of the third Nord-Trøndelag Health Study (2006-2008), a rural population survey of 50,666 participants in Norway aged 20-96 years. Insomnia (dichotomous) was defined according to the Diagnostic and Statistical Manual of Mental Disorders 5th Edition, and chronic LBP (dichotomous) as low back pain or stiffness lasting at least 3 months. Data for CRP were obtained from non-fasting serum samples and assessed via latex immunoassay methodology. We excluded participants with the following self-reported chronic somatic diseases: chronic heart failure, chronic obstructive pulmonary disease, rheumatoid arthritis, fibromyalgia or ankylosing spondylosis. Possible associations between presence of insomnia and presence of chronic LBP (dependent), and the level of CRP and presence of chronic LBP (dependent), were assessed using logistic regression models. The possible association between insomnia and CRP (dependent) was assessed using linear regression. Multivariable analyses were conducted adjusting for confounders stated in our aim that achieved p ≤ 0.2 in univariate regressions. We performed stratified analyses for participants with "Normal" (<3 mg/L) "Elevated" (3-10 mg/L) and "Very High" (>10 mg/L) levels of CRP. RESULTS: In our total included sample (n = 30,669, median age 52.6, 54% female), 6.1% had insomnia (n = 1,871), 21.4% had chronic LBP (n = 6,559), and 2.4% had both (n = 719). Twenty four thousand two hundred eighty-eight (79%) participants had "Normal" CRP, 5,275 (17%) had "Elevated" CRP, and 1,136 (4%) had "Very High" CRP. For participants with "Normal" levels of CRP, insomnia was associated with higher levels of CRP (adjusted B = 0.04, 95%CI [0.00-0.08], p = 0.046), but not for people with "Elevated" or "Very High" levels of CRP. There was an association between CRP and presence of chronic LBP in the total sample (adjusted OR = 1.01, [1.00-1.01], p = 0.013) and for people with "Normal" CRP (1.05, [1.00-1.10, p = 0.034]. Insomnia was associated with the presence of chronic LBP in the total sample (adjusted OR = 1.99, 95%CI [1.79-2.21], <0.001) and for people with "Normal", "Elevated" and "Very High". CONCLUSIONS: Individuals with insomnia have twice the odds of reporting chronic LBP. Insomnia, CRP and chronic LBP appear to be linked but the role of CRP appears to be limited. Longitudinal studies may help further explore the causal inference between insomnia chronic LBP, and inflammation. IMPLICATIONS: Given the strong relationship between insomnia and chronic LBP, screening and management of comorbid insomnia and chronic LBP should be considered in clinical practice. Further longitudinal studies are required to explore whether the presence of insomnia and increased inflammation affects the development of chronic LBP.
30951689 Remission of Non-Infectious Anterior Scleritis: Incidence and Predictive Factors. 2021 Mar PURPOSE: To assess how often non-infectious anterior scleritis remits and identify predictive factors. METHODS: Our retrospective cohort study at four ocular inflammation subspecialty centers collected data for each affected eye/patient at every visit from center inception (1978, 1978, 1984, 2005) until 2010. Remission was defined as inactivity of disease off all suppressive medications at all visits spanning at least three consecutive months or at all visits up to the last visit (to avoid censoring patients stopping follow-up after remission). Factors potentially predictive of remission were assessed using Cox regression models. RESULTS: During 1,906 years' aggregate follow-up of 832 affected eyes, remission occurred in 214 (170 of 584 patients). Median time-to-remission of scleritis = 7.8 years (95% confidence interval [CI]: 5.7, 9.5). More remissions occurred earlier than later during follow-up. Factors predictive of less scleritis remission included scleritis bilaterality (adjusted hazard ratio [aHR] = 0.46, 95% CI: 0.32-0.65); and diagnosis with any systemic inflammatory disease (aHR = 0.36, 95% CI: 0.23-0.58), or specifically with Rheumatoid Arthritis (aHR = 0.22), or Granulomatosis with Polyangiitis (aHR = 0.08). Statin treatment (aHR = 1.53, 95% CI: 1.03-2.26) within ≤90 days was associated with more remission incidence. CONCLUSIONS: Our results suggest scleritis remission occurs more slowly in anterior scleritis than in newly diagnosed anterior uveitis or chronic anterior uveitis, suggesting that attempts at tapering suppressive medications is warranted after long intervals of suppression. Remission is less frequently achieved when systemic inflammatory diseases are present. Confirmatory studies of whether adjunctive statin treatment truly can enhance scleritis remission (as suggested here) are needed.