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ID PMID Title PublicationDate abstract
33738083 Bioorthogonally surface-edited extracellular vesicles based on metabolic glycoengineering 2021 Mar Extracellular vesicles (EVs) are essential mediators in intercellular communication that have emerged as natural therapeutic nanomedicines for the treatment of intractable diseases. Their therapeutic applications, however, have been limited by unpredictable in vivo biodistribution after systemic administration. To control the in vivo fate of EVs, their surfaces should be properly edited, depending on the target site of action. Herein, based on bioorthogonal copper-free click chemistry (BCC), surface-edited EVs were prepared by using metabolically glycoengineered cells. First, the exogenous azide group was generated on the cellular surface through metabolic glycoengineering (MGE) using the precursor. Next, PEGylated hyaluronic acid, capable of binding specifically to the CD44-expressing cells, was labelled as the representative targeting moiety onto the cell surface by BCC. The surface-edited EVs effectively accumulated into the target tissues of the animal models with rheumatoid arthritis and tumour, primarily owing to prolonged circulation in the bloodstream and the active targeting mechanism. Overall, these results suggest that BCC combined with MGE is highly useful as a simple and safe approach for the surface modification of EVs to modulate their in vivo fate.
33688619 Telemedicine in the management of rheumatoid arthritis: maintaining disease control with l 2021 OBJECTIVES: We aimed to evaluate the use of an eHealth platform and a self-management outpatient clinic in patients with RA in a real-world setting. The effects on health-care utilization and disease activity were studied. METHODS: Using hospital data of patients with RA between 2014 and 2019, the use of an eHealth platform and participation in a self-management outpatient clinic were studied. An interrupted time series analysis compared the period before and after the introduction of the eHealth platform. The change in trend (relative to the pre-interruption trend) for the number of outpatient clinic visits and the DAS for 28 joints (DAS28) were determined for several scenarios. RESULTS: After implementation of the platform in April 2017, the percentage of patients using it was stable at ∼37%. On average, the users of the platform were younger, more highly educated and had better health outcomes than the total RA population. After implementation of the platform, the mean number of quarterly outpatient clinic visits per patient decreased by 0.027 per quarter (95% CI: -0.045, -0.08, P = 0.007). This was accompanied by a significant decrease in DAS28 of 0.056 per quarter (95% CI: -0.086, -0025, P = 0.001). On average, this resulted in 0.955 fewer visits per patient per year and a reduction of 0.503 in the DAS28. CONCLUSION: The implementation of remote patient monitoring has a positive effect on health-care utilization, while maintaining low disease activity. This should encourage the use of this type of telemedicine in the management of RA, especially while many routine outpatient clinic visits are cancelled owing to COVID-19.
33655803 Host Modulation and Treatment of Periodontal Disease. 2021 Jul Periodontitis is the sixth-most prevalent disease in the world and the first cause for tooth loss in adults. With focus shifted to the inflammatory/immune response in the pathogenesis of periodontitis, there is a critical need to evaluate host modulatory agents. Synthetic and biological disease-modifying antirheumatic drugs are a cornerstone for the treatment of inflammatory diseases. Recent prospective cohort studies showed that synthetic disease-modifying antirheumatic drugs improved periodontal clinical parameters following nonsurgical periodontal treatment in patients with rheumatoid arthritis. Treatment with recombinant humanized monoclonal antibodies against CD20 (rituximab) and IL-6 receptor (tocilizumab), the latter also in clinical trials for the treatment of COVID-19 pneumonia, resulted in decreased periodontal inflammation and improved periodontal status. Studies on the effect of TNF-α inhibitors in patients with periodontitis yielded inconsistent results. Recent data suggest that probiotics provide anti-inflammatory clinical benefit, as do nutritional supplements, such as n-3 fatty acids, when combined with periodontal therapy. Probiotics reduce the production of proinflammatory cytokines/chemokines by suppressing NF-κB pathways and promote the accumulation of T regulatory cells. Statins, like aspirin, have been shown to exhibit anti-inflammatory and bone-preserving actions by upregulating production of Specialized Proresolving Mediators (SPMs). Currently, there is insufficient scientific support for the topical delivery of statins or bisphosphonates as adjuncts to periodontal therapy. Here, we present a critical review of the most recent host modulatory agents applied in humans and the key immune pathways that they target. Emerging evidence from novel drug candidates, including SPMs and complement inhibitors as previously studied in animal models and currently in human clinical trials, suggests future availability of adjunctive therapeutic strategies for the management of periodontitis.
33650674 Acanthopanax senticosus Harms extract causes G0/G1 cell cycle arrest and autophagy via in 2021 Mar Acanthopanax senticosus (Rupr. et Maxim) Harms (ASH), also known as Siberian ginseng or eleuthero, is a hardy shrub native to China, Korea, Russia and the northern region of Japan. ASH is used for the treatment of several diseases such as heart disease, hypertension, rheumatoid arthritis, allergies, chronic bronchitis, diabetes and cancer. In the present study, the inhibitory effect of the root extract of ASH (ASHE) on HuH‑7 and HepG2 liver cancer cells was examined. ASHE suppressed liver cancer cell proliferation by inducing cell cycle arrest at the G0/G1 phase, as well as apoptosis, as indicated by the increased number of Annexin V and 7‑AAD‑positive cells. Furthermore, the expression of LC3‑II, an autophagy marker, in these cells also increased post treatment with ASHE. LC3‑II induction was further enhanced by co‑treatment with chloroquine. Fluorescence and transmission electron micrographs of ASHE‑treated liver cancer cells showed the presence of an increased number of autophagic vesicles. A decreased protein expression level of run domain Beclin‑1‑interacting and cysteine‑rich domain‑containing, an autophagy inhibitor, with no change in RUBCN mRNA expression was observed, indicating activation of the autophagosome‑lysosome fusion step of autophagy. In conclusion, ASHE exerts cytostatic activity on liver cancer cells via both apoptosis and autophagy, and may serve as a potential therapeutic agent for management of liver cancer and autophagy‑related diseases.
33611520 Imputed gene expression risk scores: a functionally informed component of polygenic risk. 2021 May 17 Integration of functional genomic annotations when estimating polygenic risk scores (PRS) can provide insight into aetiology and improve risk prediction. This study explores the predictive utility of gene expression risk scores (GeRS), calculated using imputed gene expression and transcriptome-wide association study (TWAS) results. The predictive utility of GeRS was evaluated using 12 neuropsychiatric and anthropometric outcomes measured in two target samples: UK Biobank and the Twins Early Development Study. GeRS were calculated based on imputed gene expression levels and TWAS results, using 53 gene expression-genotype panels, termed single nucleotide polymorphism (SNP)-weight sets, capturing expression across a range of tissues. We compare the predictive utility of elastic net models containing GeRS within and across SNP-weight sets, and models containing both GeRS and PRS. We estimate the proportion of SNP-based heritability attributable to cis-regulated gene expression. GeRS significantly predicted a range of outcomes, with elastic net models combining GeRS across SNP-weight sets improving prediction. GeRS were less predictive than PRS, but models combining GeRS and PRS improved prediction for several outcomes, with relative improvements ranging from 0.3% for height (P = 0.023) to 4% for rheumatoid arthritis (P = 5.9 × 10-8). The proportion of SNP-based heritability attributable to cis-regulated expression was modest for most outcomes, even when restricting GeRS to colocalized genes. GeRS represent a component of PRS and could be useful for functional stratification of genetic risk. Only in specific circumstances can GeRS substantially improve prediction over PRS alone. Future research considering functional genomic annotations when estimating genetic risk is warranted.
33596941 Tibia stress injury and the imaging appearance of stress fracture in juvenile dermatomyosi 2021 Feb 17 BACKGROUND: Tibial stress injuries are frequent injuries of the lower extremity and the most common causes of exercise-induced leg pain among athletes and military recruits. They sometimes occur in patients with pathological conditions of bone metabolism such as osteoporosis or rheumatoid arthritis, but there are previously no cases reported in juvenile dermatomyositis (JDM). Here we report 6 JDM patients who presented with shin pain, and the imaging appearance of tibial stress fractures or stress reactions. CASE PRESENTATION: All 6 patients with JDM presented with shin pain or tenderness in the anterior tibia without any evidence of excessive exercise or traumatic episode. They were diagnosed with tibial stress injuries based on a combination of radiographs, three-phase bone scans, and magnetic resonance imaging (MRI), and 5 out of 6 patients had been treated with prednisone and/or methotrexate at onset of tibial stress injuries. In one patient, we could not find any abnormalities in his radiograph, but the subsequent MRI showed tibial stress reaction. In all 6 patients, the tibial stress injuries improved with only rest and/or analgesics. CONCLUSION: We experienced 6 children with JDM who presented with shin pain, and who were diagnosed with tibial stress fractures or stress reactions. Their underlying disease and weakness, treatment with glucocorticoid and methotrexate, or inactivity may have resulted in these tibial injuries, and made these patients more predisposed than other children. In addition to preventing JDM patients from getting osteoporosis, we need to consider stress reactions when children with JDM complain of sudden shin pain.
33593350 Cardiovascular and musculoskeletal health disorders associate with greater decreases in ph 2021 Feb 16 BACKGROUND: Good physical capability is an important part of healthy biological ageing. Several factors influencing physical capability have previously been reported. Long-term reports on physical capability and the onset of clinical disorders and chronic diseases are lacking. Decrease in physical capacity has been shown to increase mortality. This study focuses on the prevalence of chronic diseases. The primary objective of the study was to reveal the association between physical capability and morbidity. Secondary objectives included the validity of self-reported physical capability and the association between baseline physical capability and mortality. METHODS: The OSTPRE (Kuopio Osteoporosis Risk Factor and Prevention Study) prospective cohort involved all women aged 47-56 years residing in the Kuopio Province, Finland in 1989. Follow-up questionnaires were mailed at five-year intervals. Physical capability questions were first presented in 1994. From these women, we included only completely physically capable subjects at our baseline, in 1994. Physical capability was evaluated with five scale self-reports at baseline and in 2014 as follows: completely physically capable, able to walk but not run, can walk up to 1000 m, can walk up to 100 m and temporarily severely incapable. The prevalences of selected chronic diseases, with a minimum prevalence of 10% in 2014, were compared with the change in self-reported physical capability. Additionally, associations between long-term mortality and baseline physical capability of the whole 1994 study population sample were examined with logistic regression. The correlation of self-reported physical capability with functional tests was studied cross-sectionally at the baseline for a random subsample. RESULTS: Our study population consisted of 6219 Finnish women with a mean baseline age of 57.0 years. Self-reported physical capability showed statistically significant correlation with functional tests. Cardiovascular diseases and musculoskeletal disorders show the greatest correlation with decrease of physical capability. Prevalence of hypertension increased from 48.7% in the full physical capability group to 74.5% in the "able to walk up to 100 metres" group (p < 0.001). Rheumatoid arthritis showed a similar increase from 2.1 to 7.4% between these groups. Higher baseline body mass index (BMI) decreases long-term capability (P < 0.001). Women reporting full physical capability at baseline had a mortality rate of 15.1%, in comparison to 48.5% in women within the "able to walk up to 100 m" group (p = 0.357). Mortality increased steadily with worsening baseline physical capability. CONCLUSIONS: The results of this study show that chronic diseases, particularly cardiovascular and musculoskeletal disorders, correlate with faster degradation of physical capability in the elderly. Similar results are shown for increase in BMI. We also demonstrate that the risk of mortality over a 20-year period is higher in individuals with poor baseline physical capability.
33590984 [A Rare Yeast: Cases of Rhodotorula mucilaginosa Infection Followed Up in a Tertiary Unive 2021 Jan Rhodotorula species are yeasts that are common in the environment,but are not frequently encountered as an infectious agent in humans. Rhodotorula mucilaginosa, Rhodotorula glutinis and Rhodotorula minuta are the species that cause disease in humans. Although its isolation from mucosa is doubtful in terms of the presence of true infection, it is more frequently encountered in daily practice due to the increasing number of invasive procedures, immune system deficiencies caused by immunosuppressive drugs and diseases. R.mucilaginosa growth isolated from various clinical samples between 2000 and 2018 in a tertiary university hospital was presented in this case report. The first case was an 82-year-old man with chronic lung disease, hypertension, congestive heart failure and acute leukemia causing severe immunosuppression. Use of broad spectrum antibiotics, history of immunosuppressive therapy, presence of jugular catheter were the risk factors in this patient. R.mucilaginosa was isolated from blood culture while the patient was receiving fluconazole treatment for Candida albicans grown in urine culture and the patient died before starting the treatment. The second case was a 34-year-old female patient with congenital heart disease. Discharge was observed at the intracardiac defibrillator site of the patient, a temporary pacemaker was inserted, and she used broad spectrum antibiotics for a long time. When the yeast growth was reported in the blood culture, caspofungin treatment was initiated. Although the treatment was switched to amphotericin B lipid complex after the culture result was reported as R.mucilaginosa, the patient died after 12 hours. The third case was a 70-year-old woman with hypertension, dementia, diabetes mellitus and rheumatoid arthritis admitted to the intensive care unit due to cerebrovascular accident. She received different immunosuppressive treatments and had invasive procedures. R.mucilaginosa was isolated from the blood culture taken from the patient's catheter, and there was no growth in the blood culture obtained from the peripheral vein. Anidulafungin was started empirically, which was changed to amphotericin B lipid complex after the identification of the yeast. The patient died for various reasons 10 days after the antifungal treatment was stopped. Our last case was a 55-year-old woman with metastatic ovarian cancer and secondary ascites. Broad-spectrum multiple antibiotics were used and invasive procedures were performed. R.mucilaginosa and C.albicans were isolated from the urine of the patient who had a urinary catheter. No growth was detected from urine after changing the urinary catheter. Therefore, growths were evaluated as colonization, and fluconazole was administered for C.albicans due to the high risk of invasive infection. The patient was lost for different reasons. The development and diversity of the treatment methods lead to the emergence of some opportunistic infectious agents that were not observed previously. Rhodotorula species are one of the rare agents that have increased over the years. Rhodotorula species should be considered as the cause of an infection if no clinical response is obtained after echinocandin and/or fluconazole treatment in patients with long-term immunosuppression and invasive procedures. Data on clinical pictures, treatment responses, follow-up and treatment results of this rare yeast are still limited. This case series was presented to draw attention to the risk factors related to R.mucilaginosa infection/colonization, clinical characteristics of the patients, follow-up results and treatment options and to contribute to the literature.
33521056 In vitro Dissolution Profile at Different Biological pH Conditions of Hydroxychloroquine S 2020 Hydroxychloroquine sulfate is one of an extensive series of 4-aminoquinolines with antimalarial activity. Moreover, it is used for the treatment of rheumatoid arthritis. Sometimes, hydroxychloroquine sulfate is beneficial for the treatment of autoimmune diseases. Based on recent clinical experiments, it is exploited for the treatment of COVID-19, coronavirus across the globe. The chromatogram separation was achieved by using Agilent, Zorbax C8, 250 mm × 4.6 mm i.d., column. The buffer consists of 0.01 M of 1-pentane sulfonic acid and 0.02% of orthophosphoric acid in purified water. Mixed buffer, acetonitrile, and methanol (800:100:100 v/v). The flow rate was 1.0 ml min(-1), and injection volume was 10 μl. Detection was made at 254 nm by using a dual absorbance detector (DAD). The reversed-phase high-performance liquid chromatography (RP-HPLC) method has been developed and validated as per the current International Conference on Harmonization (ICH) guidelines to estimate hydroxychloroquine sulfate tablets. As part of method validation, specificity, linearity, precision, and recovery parameters were verified. The concentration and area relationships were linear (R (2) > 0.999) over the concentration range of 25-300 μg ml(-1) for hydroxychloroquine (HCQ). The relative standard deviations for precision and intermediate precision were <1.5%. The proposed RP-HPLC generic method was applied successfully to evaluate the in vitro dissolution profile with different pH conditions such as 0.1 N HCl, pH 4.5 acetate buffer, and pH 6.8 phosphate buffers as US-marketed reference products.
33501768 Quantitative modeling predicts competitive advantages of a next generation anti-NKG2A mono 2021 Mar A semimechanistic pharmacokinetic (PK)/receptor occupancy (RO) model was constructed to differentiate a next generation anti-NKG2A monoclonal antibody (KSQ mAb) from monalizumab, an immune checkpoint inhibitor in multiple clinical trials for the treatment of solid tumors. A three-compartment model incorporating drug PK, biodistribution, and NKG2A receptor interactions was parameterized using monalizumab PK, in vitro affinity measurements for both monalizumab and KSQ mAb, and receptor burden estimates from the literature. Following calibration against monalizumab PK data in patients with rheumatoid arthritis, the model successfully predicted the published PK and RO observed in gynecological tumors and in patients with squamous cell carcinoma of the head and neck. Simulations predicted that the KSQ mAb requires a 10-fold lower dose than monalizumab to achieve a similar RO over a 3-week period following q3w intravenous (i.v.) infusion dosing. A global sensitivity analysis of the model indicated that the drug-target binding affinity greatly affects the tumor RO and that an optimal affinity is needed to balance RO with enhanced drug clearance due to target mediated drug disposition. The model predicted that the KSQ mAb can be dosed over a less frequent regimen or at lower dose levels than the current monalizumab clinical dosing regimen of 10 mg/kg q2w. Either dosing strategy represents a competitive advantage over the current therapy. The results of this study demonstrate a key role for mechanistic modeling in identifying optimal drug parameters to inform and accelerate progression of mAb to clinical trials.
33404106 Selective killing of human M1 macrophages by Smac mimetics alone and M2 macrophages by Sma 2021 Oct The inflammatory and anti-inflammatory Mϕs have been implicated in many diseases including rheumatoid arthritis, multiple sclerosis, and leprosy. Recent studies suggest targeting Mϕ function and activation may represent a potential target to treat these diseases. Herein, we investigated the effect of second mitochondria-derived activator of caspases (SMAC) mimetics (SMs), the inhibitors of apoptosis (IAPs) proteins, on the killing of human pro- and anti-inflammatory Mϕ subsets. We have shown previously that human monocytes are highly susceptible whereas differentiated Mϕs (M0) are highly resistant to the cytocidal abilities of SMs. To determine whether human Mϕ subsets are resistant to the cytotoxic effects of SMs, we show that M1 Mϕs are highly susceptible to SM-induced cell death whereas M2a, M2b, and M2c differentiated subsets are resistant, with M2c being the most resistant. SM-induced cell death in M1 Mϕs was mediated by apoptosis as well as necroptosis, activated both extrinsic and intrinsic pathways of apoptosis, and was attributed to the IFN-γ-mediated differentiation. In contrast, M2c and M0 Mϕs experienced cell death through necroptosis following simultaneous blockage of the IAPs and the caspase pathways. Overall, the results suggest that survival of human Mϕs is critically linked to the activation of the IAPs pathways. Moreover, agents blocking the cellular IAP1/2 and/or caspases can be exploited therapeutically to address inflammation-related diseases.
33394977 Thirty- and 90-day Readmissions After Spinal Surgery for Spine Metastases: A National Tren 2021 Jun 15 STUDY DESIGN: Retrospective cohort study. OBJECTIVE: The aim of this study was to investigate differences in 30- and 90-day readmissions for spine metastases treated with decompression and/or fusion spine surgery in a nationwide readmission database. SUMMARY OF BACKGROUND DATA: Patients with metastases to the spine represent a particularly vulnerable patient group that may encounter frequent readmissions. However, the 30- and 90-day rates for readmission following surgery for spine metastases have not been well described. METHODS: The Nationwide Readmission Database years 2013 to 2015 was queried. Patients were grouped by no readmission (non-R), readmission within 30 days (30-R), and readmission within 31 to 90 days (90-R). Weighted multivariate analysis assessed impact of treatment approach and clinical factors associated with 30- and 90-day readmissions. RESULTS: There were a total of 4423 patients with a diagnosis of spine metastases identified who underwent spine surgery, of which 1657 (37.5%) encountered either a 30-or 90-day unplanned readmission (30-R: n = 1068 [24-.1%]; 90-R: n = 589 [13.3%]; non-R: n = 2766). The most prevalent inpatient complications observed were postoperative infection (30-R: 16.3%, 90-R: 14.3%, non-R: 11.5%), acute post-hemorrhagic anemia (30-R: 13.4%, 90-R: 14.2%, non-R: 14.5%), and genitourinary complication (30-R: 5.7%, 90-R: 2.9%, non-R: 6.2%). The most prevalent 30-day and 90-day reasons for admission were sepsis (30-R: 10.2%, 90-R: 10.8%), postoperative infection (30-R: 13.7%, 90-R: 6.5%), and genitourinary complication (30-R: 3.9%, 90-R: 4.1%). On multivariate regression analysis, surgery type, age, hypertension, and renal failure were independently associated with 30-day readmission; rheumatoid arthritis/collagen vascular diseases, and coagulopathy were independently associated with 90-day readmission. CONCLUSION: In this study, we demonstrate several patient-level factors independently associated with unplanned hospital readmissions after surgical treatment intervention for spine metastases. Furthermore, we find that the most common reasons for readmission are sepsis, postoperative infection, and genitourinary complications.Level of Evidence: 3.
34724085 ArthroRad trial: multicentric prospective and randomized single-blinded trial on the effec 2022 Apr PURPOSE: Randomized comparison of the effect of radiotherapy on painful osteoarthritis (OA) applying a standard-dose vs. a very-low-dose regime PATIENTS AND METHODS: Patients with OA of the hand and knee joints were included. Further inclusion criteria: symptoms for more than 3 months, favorable general health status, age above 40 years. Patients with prior local radiotherapy, trauma, rheumatoid arthritis, or vascular diseases were excluded. After randomization (every joint was randomized separately), the following protocols were applied: standard arm: total dose 3.0 Gy, single fractions of 0.5 Gy twice weekly; experimental arm: total dose 0.3 Gy, single fractions of 0.05 Gy twice weekly. The dosage was not known to the patients. The patients were examined 3 and 12 months after radiotherapy. Scores like VAS (visual analogue scale), KOOS-SF (the knee injugy and osteoarthritis outcome score), SF-SACRAH (short form score for the assessment and quantification of chronic rheumatic affections of the hands), and SF-12 (short form 12) were used. RESULTS: A total of 64 knees and 172 hands were randomized. 3.0 Gy was applied to 87 hands and 34 knees, 0.3 Gy was given to 85 hands and 30 knees. After 3 months, we observed good pain relief after 3 Gy and after 0.3 Gy, there was no statistically significant difference. Side effects were not recorded. The trial was closed prematurely due to slow recruitment. CONCLUSION: We found favorable pain relief and a limited response in the functional and quality of life scores in both arms. The effect of low doses such as 0.3 Gy on pain is widely unknown. Further trials are necessary to compare a conventional dose to placebo and to further explore the effect of low doses on inflammatory disorders.
34807366 Physiologically based pharmacokinetic (PBPK) modeling of meloxicam in different CYP2C9 gen 2021 Dec Meloxicam, a non-steroidal anti-inflammatory drug, is used for the treatment of rheumatoid arthritis and osteoarthritis. Cytochrome P450 (CYP) 2C9 and CYP3A4 are major and minor enzymes involved in the metabolism of meloxicam. Impaired enzyme activity of CYP2C9 variants increases the plasma exposures of meloxicam and the risk of adverse events. The objective of our study is to develop and validate the physiologically based pharmacokinetic (PBPK) model of meloxicam related to CYP2C9 genetic polymorphism using the PK-Sim(®) software. In vitro k(cat) of CYP2C9 was optimized in different CYP2C9 genotypes. The demographic and pharmacokinetic dataset for the development of the PBPK model was extracted from two previous clinical pharmacokinetic studies. Thirty-one clinical datasets, representing different dose regimens and demographic characteristics, were utilized to validate the PBPK model. The shapes of simulated plasma concentration-time profiles in each CYP2C9 genotype were visually similar to observed profiles. The predicted exposures (AUC(inf)) of meloxicam in CYP2C9*1/*3, CYP2C9*1/*13, and CYP2C9*3/*3 genotypes were increased by 1.77-, 2.91-, and 8.35-fold compared to CYP2C9*1/*1 genotype, respectively. In all datasets for the development and validations, fold errors between predicted and observed pharmacokinetic parameters were within the two-fold error criteria. As a result, the PBPK model was appropriately established and properly described the pharmacokinetics of meloxicam in different CYP2C9 genotypes. This study is expected to contribute to reducing the risk of adverse events of meloxicam through optimization of meloxicam dosing in different CYP2C9 genotypes.
34716913 A comprehensive review of IL-26 to pave a new way for a profound understanding of the path 2022 Jan Cytokines are considered vital mediators of the immune system. Down- or upregulation of these mediators is linked to several inflammatory and pathologic situations. IL-26 is referred to as an identified member of the IL-10 family and IL-20 subfamily. Due to having a unique cationic structure, IL-26 exerts diverse functions in several diseases. Since IL-26 is mainly secreted from Th17, it is primarily considered a pro-inflammatory cytokine. Upon binding to its receptor complex (IL-10R1/IL-20R2), IL-26 activates multiple signalling mediators, especially STAT1/STAT3. In cancer, IL-26 induces IL-22-producing cells, which consequently decrease cytotoxic T-cell functions and promote tumour growth through activating anti-apoptotic proteins. In hypersensitivity conditions such as rheumatoid arthritis, multiple sclerosis, psoriasis and allergic disease, this cytokine functions primarily as the disease-promoting mediator and might be considered a biomarker for disease prognosis. Although IL-26 exerts antimicrobial function in infections such as hepatitis, tuberculosis and leprosy, it has also been shown that IL-26 might be involved in the pathogenesis and exacerbation of sepsis. Besides, the involvement of IL-26 has been confirmed in other conditions, including graft-versus-host disease and chronic obstructive pulmonary disease. Therefore, due to the multifarious function of this cytokine, it is proposed that the underlying mechanism regarding IL-26 function should be elucidated. Collectively, it is hoped that the examination of IL-26 in several contexts might be promising in predicting disease prognosis and might introduce novel approaches in the treatment of various diseases.
34497607 Baricitinib Attenuates Autoimmune Phenotype and Podocyte Injury in a Murine Model of Syste 2021 OBJECTIVE: Baricitinib, a selective inhibitor for janus kinase (JAK) 1 and JAK2, is approved for use in rheumatoid arthritis. Systemic lupus erythematosus (SLE) is recently regarded as a potential candidate targeted by JAK inhibitors because of the relationship between its pathogenesis and JAK/signal transducer and activator of transcription (STAT) pathway-mediated cytokines such as type I interferons. The objective of this study was to determine whether baricitinib could effectively ameliorate SLE using a murine model. METHODS: To investigate effects of baricitinib on various autoimmune features, especially renal involvements in SLE, eight-week-old MRL/Mp-Fas(lpr) (MRL/lpr) mice were used as a lupus-prone animal model and treated with baricitinib for eight weeks. Immortalized podocytes and primary podocytes and B cells isolated from C57BL/6 mice were used to determine the in vitro efficacy of baricitinib. RESULTS: Baricitinib remarkably suppressed lupus-like phenotypes of MRL/lpr mice, such as splenomegaly, lymphadenopathy, proteinuria, and systemic autoimmunity including circulating autoantibodies and pro-inflammatory cytokines. It also modulated immune cell populations and effectively ameliorated renal inflammation, leading to the recovery of the expression of structural proteins in podocytes. According to in vitro experiments, baricitinib treatment could mitigate B cell differentiation and restore disrupted cytoskeletal structures of podocytes under inflammatory stimulation by blocking the JAK/STAT pathway. CONCLUSIONS: The present study demonstrated that baricitinib could effectively attenuate autoimmune features including renal inflammation of lupus-prone mice by suppressing aberrant B cell activation and podocyte abnormalities. Thus, baricitinib as a selective JAK inhibitor could be a promising therapeutic candidate in the treatment of SLE.
34451835 Janus Kinase Inhibitors and Coronavirus Disease (COVID)-19: Rationale, Clinical Evidence a 2021 Jul 28 We are witnessing a paradigm shift in drug development and clinical practice to fight the novel coronavirus disease (COVID-19), and a number of clinical trials have been or are being testing various pharmacological approaches to counteract viral load and its complications such as cytokine storm. However, data on the effectiveness of antiviral and immune therapies are still inconclusive and inconsistent. As compared to other candidate drugs to treat COVID-19, Janus Kinase (JAK) inhibitors, including baricitinib and ruxolitinib, possess key pharmacological features for a potentially successful repurposing: convenient oral administration, favorable pharmacokinetic profile, multifunctional pharmacodynamics by exerting dual anti-inflammatory and anti-viral effects. Baricitinib, originally approved for rheumatoid arthritis, received Emergency Use Authorization in November 2020 by the Food and Drug Administration in combination with remdesivir for the treatment of COVID-19 in hospitalized patients ≥ 2 years old who require supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation. By July 2021, the European Medicines Agency is also expected to issue the opinion on whether or not to extend its use in hospitalised patients from 10 years of age who require supplemental oxygen. Ruxolitinib, approved for myelofibrosis, was prescribed in patients with COVID-19 within an open-label Emergency Expanded Access Plan. This review will address key milestones in the discovery and use of JAK inhibitors in COVID-19, from artificial intelligence to current clinical evidence, including real world experience, and critically appraise emerging safety issues, namely infections, thrombosis, and liver injury. An outlook to ongoing studies (clinicaltrials.gov) and unpublished pharmacovigilance data is also offered.
34245837 TAK1 in the AP-1 pathway is a critical target of Saururus chinensis (Lour.) Baill in its a 2021 Oct 28 ETHNOPHARMACOLOGICAL RELEVANCE: Saururus chinensis (Lour.) Baill (Saururaceae), also known as Asian lizard's tail, is a plant commonly found in East Asia. Its leaves have been used in traditional medicine to treat many diseases such as edema, pneumonia, hypertension, leproma, jaundice, gonorrhea, and rheumatoid arthritis. AIM OF THE STUDY: Based on the efficacies of S. chinensis, the anti-inflammatory effects of this plant and the molecular mechanism were evaluated using the ethanol extract of S. chinensis leaves (Sc-EE). MATERIALS AND METHODS: The production of pro-inflammatory mediators and cytokines in response to Sc-EE was evaluated using Griess and semi-quantitative reverse transcription-polymerase chain reactions. Furthermore, relevant proteins including c-Jun, c-Fos, p38, JNK, ERK, MEK1/2, MKK3/6, MKK4/7, and TAK1 were detected through immunoblotting. RESULTS: Sc-EE diminished production of nitric oxide (NO); decreased expression levels of cyclooxygenase (COX)-2, interleukin (IL)-6, inducible NO synthase (iNOS), and IL-1β in LPS-stimulated RAW264.7 cells; and attenuated activator protein 1 (AP-1)-mediated luciferase activities. The extract markedly downregulated the phosphorylation of TAK1, upregulated thermal stability of TAK1, and reduced TAK1/AP-1-mediated luciferase activity in LPS-treated RAW264.7 cells and TAK1-overexpressing HEK293T cells. CONCLUSIONS: These results demonstrated that Sc-EE suppresses pro-inflammatory gene expression through blockade of the TAK1/AP-1 pathway in LPS-treated RAW264.7 macrophages, implying that inhibition of TAK1/AP-1 signaling by S. chinensis is a key event in its anti-inflammatory activity.
34228745 Cost-effectiveness analysis of branded and authorized generic celecoxib for patients with 2021 OBJECTIVES: The aim of this study was to examine the cost-effectiveness of branded and authorized generic (AG) celecoxib for chronic pain patients with osteoarthritis (OA), rheumatoid arthritis (RA), and low back pain (LBP), using real-world cost information for loxoprofen and pharmacotherapy for gastrointestinal bleeding. METHODS: This cost-effectiveness analysis was performed as a long-term simulation using the Markov model from the Japanese public healthcare payer's perspective. The analysis was conducted using loxoprofen with real-world weighted price by branded/generic distribution (hereinafter, loxoprofen with weighted price) as a comparator. In the model, we simulated the prognosis of patients with chronic pain by OA, RA, and LBP treated with loxoprofen or celecoxib, over a lifetime period. RESULTS: A cost-increase of 129,688 JPY (1,245.00 USD) for branded celecoxib and a cost-reduction of 6,268 JPY (60.17 USD) for AG celecoxib were recognized per patient in lifetime horizon, compared to loxoprofen with weighted price. No case was recognized to reverse the results of cost-saving by AG celecoxib in one-way sensitivity analysis. The incremental cost-effectiveness ratio of branded celecoxib attained 5,403,667 JPY/QALY (51,875.20 USD/QALY), compared to loxoprofen with the weighted price. CONCLUSION: The current cost-effectiveness analysis for AG celecoxib revealed its good value for costs, considering the patients' future risk of gastrointestinal injury; also, the impact on costs due to AG celecoxib against loxoprofen will be small. It implies that the disadvantage of AG celecoxib being slightly more expensive than generic loxoprofen could be offset by the good cost-effectiveness during the prognosis.
34188480 The Prevalence of Overweight and Obesity Among Women in Jordan: A Risk Factor for Developi 2021 OBJECTIVE: The study aimed to investigate the prevalence of obesity among Jordanian women and its association with a wide range of chronic diseases. METHODS: Subjects were enrolled in the present cross-sectional study based on a random drop-off technique at the Obstetrics and Gynecology clinics at Jordan University Hospital. Initially, any female 18 years of age and older was asked to enroll in the study. Relevant data were gathered using a questionnaire composed of 30 questions, and body mass index (BMI) was determined from each participant's weight and height. The following variables were collected: socio-demographic, chronic diseases, and health status. Each variable's frequencies were reported, and the 95% confidence interval (95% CI) for each variable was calculated. For association analysis, Chi-square analysis was performed with an odds ratio (OR) and 95% CI. Multinomial logistic regression analysis was applied to a combination of independent variables and a dependent condition with covariate factors. RESULTS: The age-standardized prevalence of overweight/obese Jordanian women was 70.6% (95% CI 66.0-74.8%). On the other hand, the age-standardized prevalence of only obese women was 36.4 (95% Cl 31.9-41.2%). Furthermore, the association between age and overweight/obesity was significant (p<0.0001). The percentage of overweight and obesity started to be significant in the 30-39 year age group. Moreover, the OR for obesity ranged from 2.7 to 7.0 (p<0.05-0.01) for those women with only elementary education. Besides, high parity was significantly associated with obesity and elementary education. For chronic conditions, the percentages of hypertension, diabetes, hypertriglyceridemia, osteoporosis, and rheumatoid arthritis were significantly correlated with increased BMI in Jordanian women. With age adjustment, however, only hypertension was associated with obese level 3 with OR of 7.2 and 95% CI of 2.1-25.1 (p<0.01). CONCLUSION: There is a high prevalence of overweight/obesity among women in Jordan, which was related to high parity and low education level. This high prevalence of obesity increased the incidence of chronic diseases, such as hypertension. Therefore, community-based multiple strategies are required to combat obesity in Jordanian women.