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ID PMID Title PublicationDate abstract
34015366 Anti-inflammatory, and anti-arthritic effects by the twigs of Cinnamomum cassia on complet 2021 Oct 5 ETHNOPHARMACOLOGICAL RELEVANCE: The young branches of C. cassia Blume (Cinnamomi Ramulus; Guizhi; ; C. cassia twigs) have long been used as an anti-pyretic, anti-rheumatic, anti-spasmodic and stomachic in traditional medicine. AIM OF THE STUDY: The aim of this study was to test the anti-inflammatory, anti-nociceptive, and anti-arthritic effects of Cinnamomum cassia twigs in acute and chronic arthritis rats. MATERIALS AND METHODS: Subcutaneous injection of carrageenan for acute inflammation and complete Freund's adjuvant (CFA) for chronic arthritis was carried out in the hind paw of SD rats. The paw volume was measured by a plethysmometer; thermal hyperalgesia was tested using a thermal plantar tester; hyperalgesia was evaluated by ankle flexion evoked vocalizations. The c-Fos expression in the lumbar spinal cord was measured with the avidin-biotin-peroxidase technique. The nitric oxide (NO) generation in lipopolysaccharide (LPS)-induced RAW 264.7 cells was tested by Griess assay. RESULTS AND DISCUSSION: An 80% ethanoic extract of the C. cassia twigs exhibited chronic anti-inflammatory and anti-arthritic activities by reducing the edema volume in the paws of CFA-induced chronic arthritis in rats. In addition, it showed analgesic effects through the recovery of the paw withdrawal latency stimulated by thermal hyperalgesia, and suppressing the vocalization scores evoked by ankle flexion in the hind paws of the arthritis rats. It also controlled c-Fos expression in the lumbar spinal cord of the arthritis rats. Moreover, the addition its 80%-ethanoic extract, specifically, its ethyl acetate fraction, powerfully suppressed the paw swelling in carrageenan-stimulated arthritis and the NO production in LPS-induced murine immune cells. CONCLUSION: C. cassia twigs may act as a viably sufficient therapeutic or preventive candidate for osteoarthritis and rheumatoid arthritis; additionally, it could prevent gastrointestinal damage with its gastric protection.
34749331 INACTIVATED COVID-19 VACCINE CAN INDUCE REACTIVE POLYARTHRITIS IN OLDER PATIENTS: REPORT O 2021 Oct Reactive arthritis is an acute, sterile, non-suppurative and inflammatory arthropathy that usually follows infection process. Gastrointestinal, genitourinary and respiratory tract infections generally provoke reactive arthritis. Also, reactive arthritis can be seen after vaccination. Reactive arthritis cases have been reported after tetanus, combined diphteria-poliomyelitis-tetanus toxoid, hepatitis B or influenza vaccination. Although reactive arthritis is more common in youngs, healthcare workers should be aware of the development of post inactivated COVID-19 vaccine reactive arthritis in older patients. We present two cases with ReA induced by inactivated coronavirus 2019 (COVID-19) vaccination (CoronaVac, Sinovac). Both patients in our study were over 70 years old and presented with polyarthritis that developed after vaccination. Rheumatoid factor and anti-nucleer antibody were negative and patients responded well to short-term steroid therapy, arthritis were not resistant.
33596533 Tissue-specific activation of Myd88-dependent pathways governs disease severity in primary 2021 Mar Myd88 activation is an important driver of autoimmunity. Primary Sjögren's syndrome (pSS) is an autoimmune disease characterized by exocrine gland dysfunction in combination with serious systemic disease manifestations. Myd88-dependent signaling networks remain incompletely understood in the context of pSS. The objective of this study was to establish the contribution of tissue-specific Myd88 activation to local (exocrine) and systemic pSS manifestations. To this end, we generated two novel conditional knockout pSS mouse models; one lacking Myd88 in hematopoietic cells and a second strain in which Myd88 was deleted in the stromal compartment. Spontaneous production of inflammatory mediators was altered in salivary tissue, and nephritis was diminished in both conditional knockout strains. In contrast, pulmonary inflammation was increased in mice lacking Myd88 in hematopoietic cells and was reduced when Myd88 was ablated in stromal cells. Finally, anti-nuclear autoantibodies (ANAs) were attenuated in pSS mice lacking Myd88 in immune cells. Additionally, the ANA-specific B cell repertoire was skewed in the Myd88-deficient strains. Collectively, these data demonstrate that Myd88 activation in specific cell types is essential for distinct aspects of pSS pathology.
33288543 Integration of the Transcriptome and Genome-Wide Landscape of BRD2 and BRD4 Binding Motifs 2021 Jan 15 Fibroblast-like synoviocytes (FLS), one of the main cell types of the rheumatoid arthritis (RA) synovium, possess phenotypic and molecular characteristics of transformed cells. JQ1, an inhibitor of the bromodomain and extra terminal domain family that includes BRD2, BRD3, BRD4, and BRDt, has shown efficacy in models of arthritis. We demonstrate that the active isomer of JQ1 but not its inactive isomer inhibits IL-1β-induced RA-FLS activation and proliferation. To understand the mechanism of JQ1 action, we subjected JQ1-treated RA-FLS to transcriptional profiling and determined BRD2 and BRD4 cistromes by identifying their global chromatin binding sites. In addition, assay for transposable accessible chromatin by high throughput sequencing was employed to identify open and closed regions of chromatin in JQ1-treated RA-FLS. Through an integrated analysis of expression profiling, Brd2/Brd4 cistrome data, and changes in chromatin accessibility, we found that JQ1 inhibited key BRD2/BRD4 superenhancer genes, downregulated multiple crucial inflammatory pathways, and altered the genome-wide occupancy of critical transcription factors involved in inflammatory signaling. Our results suggest a pleiotropic effect of JQ1 on pathways that have shown to be individually efficacious in RA (in vitro, in vivo, and/or in humans) and provide a strong rationale for targeting BRD2/BRD4 for disease treatment and interception.
34570274 Variation of homocysteine levels in rheumatoid arthritis patients: relationship to inflamm 2021 Sep 27 BACKGROUND: The aim of this study was to evaluate the variation of homocysteine (Hcy) levels in patients with rheumatoid arthritis (RA) and to analyze the relationship to inflammatory parameters, cardiovascular risk, and methotrexate (MTX). METHODS: This cross-sectional study assessed disease activity and treatment in RA patients. The European League Against Rheumatism (EULAR) 2015 HeartSCORE was performed for cardiovascular (CV) risk estimation and levels of plasma Hcy, serum folate concentrations, vitamin B12, and erythrocyte sedimentation rate (ESR) were measured. RESULTS: A total of 103 participants with mean age 53 ± 10 years and mean disease duration 10.55 ± 7.34 years were included. Patients were treated with MTX in 69.9% of cases and corticosteroid in 80.5% of cases. Of all patients, 13% had a cardiovascular inheritance, 25% were hypertensive, and 18% had diabetes. The EULAR 2015 HeartSCORE was high and very high (≥5%) in 35% of cases. Mean Hcy level was 12.54 ± 4.2 µmol/L [6.89-32.92] and hyperhomocysteinemia was noted in 20.4% of patients. Analytic study demonstrated that hyperhomocysteinemia was associated with male gender (p = 0.01), MTX use (p = 0.01), smoking (p = 0.008), renal failure (p = 0.04), and high disease activity (p = 0.05), but there was no association with the HeartSCORE (p = 0.23). Hcy level was negatively correlated with folate (p = 0.009) and vitamin B12 level (p = 0.02) and positively with age (p = 0.01), C‑reactive protein (CRP; p = 0.05), and Simplified Disease Activity Index (SDAI; p = 0.03). In multivariate logistic regression analysis, current MTX use, levels of vitamin B12 and creatine, and Clinical Disease Activity Index (CDAI) appeared to be independent factors associated with hyperhomocysteinemia. CONCLUSION: MTX use, CDAI, and the levels of vitamin B12 and creatine are independent factors associated with hyperhomocysteinemia.
34235888 Increased frailty in people with osteoarthritis and rheumatoid arthritis and the influence 2021 Jul 7 OBJECTIVES: To determine the association between osteoarthritis (OA), rheumatoid arthritis (RA) and frailty and to determine whether co-morbidities interact with OA and RA to further increase the likelihood of frailty. METHODS: Participants of the UK Biobank aged 40-69 years at baseline were included. Demographic, lifestyle, and clinical data were collected at baseline, and follow-up in a subset. Frailty was assessed using a frailty index (FI) (continuous) and a modified frailty phenotype (robust, pre-frail, frail). The association between RA and OA and frailty at baseline and follow up, was assessed using multiple regression models. We looked at whether co-morbidities, including cardiovascular disease, diabetes, chronic obstructive pulmonary disease and depression, interacted additively with OA and RA to increase the likelihood of frailty. RESULTS: 457,561 participants contributed data. Those with (versus without) RA (n=4,894), and OA (n=35,884), respectively were more likely to be frail, adjusted relative risk ratio (95%CI) 10.7 (9.7, 11.7) and 3.4 (3.3, 3.6), and were more likely to have a higher FI at baseline. There was evidence of additive interaction, between RA, OA, and common co-morbidities increasing the occurrence of prevalent frailty. Among 25,163 participants included in longitudinal analysis, people with RA (n=202) and OA (n=1,811), at baseline had an increased adjusted frailty incidence rate ratio, 2.8 (1.7, 4.6) and 1.7 (1.3, 2.1) respectively and also a higher FI during follow up. CONCLUSION: People with RA and OA are more likely to have, or develop, frailty. Common comorbidities interact with OA and RA to further increase the likelihood of frailty.
32978937 Cardiovascular Risk Assessment and Impact of Medications on Cardiovascular Disease in Infl 2021 Jun 15 There is increased risk of cardiovascular disease in patients with chronic inflammatory disorders such as rheumatoid arthritis, psoriatic arthritis, and systemic lupus erythematosus. Studies have shown association between cardiovascular disease (eg, myocardial infarction, heart failure, stroke) and inflammatory bowel disease. Medications such as infliximab and adalimumab (monoclonal antibodies to tumor necrosis factor α) may help decrease the inflammatory burden and cardiovascular risk; however, there have been reports of hypertriglyceridemia and worsening of moderate to severe heart failure with these medications. Janus kinase inhibitors, such as tofacitinib, have been associated with hyperlipidemia and thromboembolism. We aim to discuss clinical and imaging modalities to assess cardiovascular risk in inflammatory bowel disease patients and review the role of various medications with respect to cardiovascular disease in this population.
35128335 Position Statement on Exercise Dosage in Rheumatic and Musculoskeletal Diseases: The Fole 2021 Dec There is convincing evidence to suggest that exercise interventions can significantly improve disease-related outcomes as well as comorbidities in rheumatic and musculoskeletal diseases (RMDs). All exercise interventions should be appropriately defined by their dose, which comprises of two components: a) the FITT (frequency, intensity, time and type) and b) the training (ie, specificity, overload, progression, initial values, reversibility, and diminishing returns) principles. In the published RMD literature, exercise dosage is often misreported, which in "pharmaceutical treatment terms", this would be the equivalent of receiving the wrong medication dosage. Lack of appropriately reporting exercise dosage in RMDs, therefore, results in limited clarity on the effects of exercise interventions on different outcomes while it also hinders reproducibility, generalisability and accuracy of research findings. Based on the collective but limited current knowledge, the main purpose of the present Position Statement is to provide specific guidance for RMD researchers to help improve the reporting of exercise dosage and help advance research into this important field of investigation. We also propose the use of the IMPACT-RMD toolkit, a tool that can be used in the design and reporting phase of every trial.
34987400 α-Mangostin Alleviated HIF-1α-Mediated Angiogenesis in Rats With Adjuvant-Induced Arthri 2021 A previously validated anti-rheumatic compound α-mangostin (MAN) shows significant metabolism regulatory effects. The current study aimed to clarify whether this property contributed to its inhibition on synovial angiogenesis. Male wistar rats with adjuvant-induced arthritis (AIA) were orally treated by MAN for 32 days. Afterwards, biochemical parameters and cytokines in plasma were determined by corresponding kits, and glycometabolism-related metabolites were further accurately quantified by LC-MS method. Anti-angiogenic effects of MAN were preliminarily assessed by joints based-immunohistochemical examination and matrigel plug assay. Obtained results were then validated by experiments in vitro. AIA-caused increase in circulating transforming growth factor beta, interleukin 6, hypoxia inducible factor-1 alpha (HIF-1α) and vascular endothelial growth factor (VEGF) in blood and local HIF-1α/VEGF expression in joints was abrogated by MAN treatment, and pannus formation within matrigel plugs implanted in AIA rats was inhibited too. Scratch and transwell assays revealed the inhibitory effects of MAN on human umbilical vein endothelial cells (HUVECs) migration. Furthermore, MAN inhibited tubule formation capability of HUVECs and growth potential of rat arterial ring-derived endothelial cells in vitro. Meanwhile, MAN eased oxidative stress, and altered glucose metabolism in vivo. Glycolysis-related metabolites including glucose 6-phosphate, fructose 6-phosphate, 3-phosphoglyceric acid and phosphoenolpyruvic acid in AIA rats were decreased by MAN, while the impaired pyruvate-synthesizing capability of lactate dehydrogenase (LDH) was recovered. Consistently, MAN restored lipopolysaccharide-elicited changes on levels of glucose and LDH in HUVECs culture system, and exerted similar effects with LDH inhibitor stiripentol on glycometabolism and VEGF production as well as tubule formation capability of HUVECs. These evidences show that MAN treatment inhibited aerobic glycolysis in AIA rats, which consequently eased inflammation-related hypoxia, and hampered pathological neovascularization.
34368202 Quality of a Supporting Mobile App for Rheumatic Patients: Patient-Based Assessment Using 2021 Introduction: Mobile applications promise to improve current health care. However, current mobile app quality ratings are mostly physician-based. The aim of this study was (1) to assess the quality of the self-management app Rheuma Auszeit using the validated uMARS (User Version of the Mobile App Rating Scale) app quality assessment tool and (2) to evaluate the association between uMARS scores and patients' characteristics. Materials and Methods: Consecutive patients with rheumatoid arthritis, psoriatic arthritis and spondyloarthritis were seen at the rheumatology clinic at university hospital Erlangen, Germany. They were asked to test Rheuma Auszeit, evaluate its quality using uMARS and complete a paper-based survey evaluating the individual preferences, attitudes and ehealth literacy. The association between uMARS scores and patients' characteristics was further explored. Results: Between December 2018 and January 2019, a total of 126 patients evaluated Rheuma Auszeit using uMARS and filled out the paper-based survey. The median uMARS score was 3.9, IQR 0.7. Functionality was the domain with the highest rating (median 4.8, IQR 0.8), followed by aesthetics (median 4.0, IQR 0.7), information (median 3.5, IQR 0.8), and engagement (median 3.2, IQR 1.0). Subjective quality was average (median 3.0, IQR 1.0). The lowest scoring individual item was customization with a median of 2.5/5. Lower functionality scores were reported among older female rheumatic patients (P < 0.004). Older male rheumatic patients reported a higher subjective quality score (P < 0.024). Perceived disease activity and disease duration did not significantly correlate with any uMARS subdomain scores. eHealth literacy significantly correlated with functionality uMARS subdomain ratings (Rho = 0.18; P < 0.042). Preferred time of app usage significantly correlated with engagement (Rho = 0.20; P < 0.024), functionality (Rho = 0.19; P < 0.029), total uMARS score (Rho = 0.21; P < 0.017) and subjective quality score (Rho = 0.21; P < 0.017). The vast majority of rheumatic patients would consider recommending Rheuma Auszeit to other patients (117/126; 92.9%). Conclusion: Rheuma Auszeit was well-accepted by German patients suffering from rheumatoid arthritis, psoriatic arthritis and ankylosing spondyloarthritis. Lacking customization could lead to low app compliance and should be improved. Lower functionality scores among older female rheumatic patients highlight the need for patient education. The study underlines the potential and feasibility of therapeutic complementary digital solutions in rheumatology.
33784247 [Health utility measurement by time trade-off method in Hungary]. 2021 Mar 30 Összefoglaló. Bevezetés: Az időalku (time trade-off) egy nemzetközileg széles körben alkalmazott életminőség- és egészséghasznosság-mérési módszer. Az időalkuval mért hasznosságértékek az egészségügyi technológiák költséghatékonysági vizsgálatakor az életminőséggel korrigált életév (quality-adjusted life year, QALY) mutatószám számítására használhatók. Kevés ismerettel rendelkezünk arról, hogy Magyarországon milyen betegségekben állnak rendelkezésre időalkuval mért hasznosságértékek. Célkitűzés: Célunk szisztematikus irodalmi áttekintés keretében összefoglalni és katalogizálni az időalku módszerrel mért hasznosságértékeket közlő publikációkat Magyarországon. Módszer: 2020 januárjában szisztematikus folyóirat-keresést végeztünk a PubMed, Web of Science és Matarka elektronikus adatbázisokban. Beválogatási kritériumaink a következők voltak: (1) eredeti közlemények, melyek (2) időalku módszerrel mértek hasznosságértéket, és (3) magyarországi mintán mért adatokat közöltek. Eredmények: 9 eredeti közleményt válogattunk be, amelyek összesen 7 krónikus betegségben (Crohn-betegség, időskori maculadegeneratio, krónikus migrén, pemphigus, psoriasis, primer dysmenorrhoea és rheumatoid arthritis) 23 egészségi állapot hasznosságát határozták meg. A kutatások mintanagysága 108 és 1996 fő között alakult. Két kutatás betegcsoportokat vizsgált, kettő az általános populációt, és három vizsgálatban szerepelt mindkettő. Hat kutatás használta a hagyományos időalku valamelyik formáját, egy pedig az összetett időalku módszert. Egy kutatásban szerepelt 'rosszabb a halálnál' válaszlehetőség. A leggyakrabban alkalmazott időtáv a standard 10 év volt (71%). Az egyes állapotok hasznosságának átlaga 0,34 (kezeletlen pemphigus vulgaris) és 0,94 (enyhe primer dysmenorrhoea) között változott. A 'non-traderek' aránya az egyes kutatásokban 0 és 29% között változott. Következtetések: Egyre több krónikus betegségben elérhetők a magyar társadalom vagy betegek preferenciáin alapuló egészséghasznosság-értékek. A hazai időalku-vizsgálatok többsége megfelel a nemzetközi minőségi követelményeknek. Az időalku módszer alkalmazása javasolt más krónikus állapotokban is, a felmért hasznosságértékek segíthetik az egészségügyi technológiákkal kapcsolatos finanszírozói döntéshozatalt. Orv Hetil. 2021; 162(14): 542-554. INTRODUCTION: Time trade-off (TTO) is a widely used method to assess health-related quality of life and health utilities for economic evaluations of health technologies. Little is known about the use of TTO in the Hungarian context. OBJECTIVE: To systematically summarize the existing literature on the method in Hungary. METHOD: In January 2020, we conducted a systematic literature search in three electronic databases (MEDLINE, Web of Science and the Hungarian Periodicals Table of Contents Database). Our inclusion criteria were: (1) original publications, which (2) measured utilities by using TTO, (3) from a Hungarian sample. RESULTS: Nine publications containing seven original studies were included that reported utilities for 23 different health states in seven chronic diseases (age-related macular degeneration, chronic migraine, Crohn's disease, pemphigus, primary dysmenorrhoea, psoriasis and rheumatoid arthritis). Sample sizes ranged from 108 to 1996 respondents. Two studies used general population samples, another two used patient groups and three studies used both. Six studies used a form of conventional TTO and one used composite TTO method. The most frequent timeframe was 10 years (71%). The lowest mean utility was 0.34 (uncontrolled pemphigus vulgaris), while the highest was 0.94 (mild primary dysmenorrhoea). The overall proportion of non-traders ranged between 0 and 29% across studies. CONCLUSIONS: A growing number of studies are using TTO to assess utilities for chronic conditions from the general population or patients in Hungary. The majority of Hungarian TTO studies have met international quality standards. The assessment of TTO utilities is recommended also in other chronic conditions to assist health technology assessment. Orv Hetil. 2021; 162(14): 542-554.
35024753 Staphylococcus aureus-induced septic arthritis of the ankle related to malum perforans in 2021 Apr Septic arthritis (SA) is a less common joint pathology with potentially fatal outcome. It is considered a medical emergency, in which prompt diagnosis and differentiation of bacterial etiology is essential for appropriate management. The knee is the most prevalent site for SA (~50% of cases), followed by hip, shoulder, and elbow. Early intervention requires an accurate diagnosis and imaging techniques enable both a positive diagnosis, as well as arthrocentesis and liquid analysis, the "gold standard" criteria. We report the case of a 70-year-old patient, with history of rheumatoid arthritis (RA), diabetes mellitus (DM) and persistent left malum perforans in the last year, with development of a severe and debilitating Staphylococcus aureus-related SA of the left ankle, which posed significant therapeutic challenges. He developed a plantar lesion at the ball of the left foot, in the past one year, which was labeled as malum perforans in the setting of DM. Musculoskeletal ultrasound was the primary imaging technique used to define the location and extent of the infectious process. Cultures drawn from the tissue were positive for S. aureus. After an antibiotic course, the apparent infectious features were remitted but the long-lasting open wound failed to improve. Antibiotic therapy was initiated in accordance with culture sensibility tests but short- and long-term outcome was unfavorable with both treatment unresponsiveness and comorbidity burden posing considerable difficulties. The association and interrelation between different comorbidities (such as hypertension, diabetes, or obesity), chronic systemic inflammation (e.g., C-reactive protein level, disease activity), and RA medication is sometimes difficult to understand and to address in daily practice, and this case report highlights multiple toils encountered in a SA patient with RA on immunosuppressive therapy and complicated DM.
34646534 Anti-arthritic effect of chicken embryo tissue hydrolyzate against adjuvant arthritis in r 2021 Oct Finding new, safe strategies to prevent and control rheumatoid arthritis is an urgent task. Bioactive peptides and peptide-rich protein hydrolyzate represent a new trend in the development of functional foods and nutraceuticals. The resulting tissue hydrolyzate of the chicken embryo (CETH) has been evaluated for acute toxicity and tested against chronic arthritis induced by Freund's full adjuvant (modified Mycobacterium butyricum) in rats. The antiarthritic effect of CETH was studied on the 28th day of the experiment after 2 weeks of oral administration of CETH at doses of 60 and 120 mg/kg body weight. Arthritis was evaluated on the last day of the experiment on the injected animal paw using X-ray computerized microtomography and histopathology analysis methods. The CETH effect was compared with the non-steroidal anti-inflammatory drug diclofenac sodium (5 mg/kg). Oral administration of CETH was accompanied by effective dose-dependent correction of morphological changes caused by the adjuvant injection. CETH had relatively high recovery effects in terms of parameters for reducing inflammation, inhibition of osteolysis, reduction in the inflammatory reaction of periarticular tissues, and cartilage degeneration. This study presents for the first time that CETH may be a powerful potential nutraceutical agent or bioactive component in the treatment of rheumatoid arthritis.
33710801 Illness Uncertainty in Parents of Children with Juvenile Idiopathic Arthritis. 2021 Apr OBJECTIVE: To gain a better understanding of uncertainty regarding the illness experienced by parents of children with juvenile idiopathic arthritis (JIA). METHODS: Parents/guardians of a child or young person (aged less than 18 years) diagnosed JIA were recruited in the United Kingdom via the National Rheumatoid Arthritis Society JIA group. Semistructured telephone interviews were conducted with the parents. RESULTS: Twenty parents took part, including 19 mothers and one father. Their children with JIA were mostly female (n = 15; 75%) with polyarticular arthritis (n = 12; 60%), averaged 8 years of age, and had been diagnosed for a mean of 3.7 (SD 2.3) years. Parents expressed uncertainty in the following five key domains: diagnosis, cause, symptoms, and prognosis; medical management; impact; parenting uncertainty; and awareness of JIA. All participants expressed uncertainty in at least four of the five domains. Although parents' uncertainty in the early stages of the disease related to lack of information and understanding of JIA, much uncertainty could not be resolved by receipt of information. These included concerns about their child's future and a lack of support with managing the emotional aspects of living with JIA. CONCLUSION: We found that parents' experiences of uncertainty went beyond dealing with the purely medical aspects of JIA. Provision of information about JIA, although essential, is not sufficient to help parents manage the considerable uncertainty they experience about many aspects of their child's JIA. Identifying ways to incorporate support for coping with uncertainty into routine care will be an important way of supporting parents to care for their child with JIA.
34729302 Recent developments in the medicinal chemistry of single boron atom-containing compounds. 2021 Oct Various boron-containing drugs have been approved for clinical use over the past two decades, and more are currently in clinical trials. The increasing interest in boron-containing compounds is due to their unique binding properties to biological targets; for example, boron substitution can be used to modulate biological activity, pharmacokinetic properties, and drug resistance. In this perspective, we aim to comprehensively review the current status of boron compounds in drug discovery, focusing especially on progress from 2015 to December 2020. We classify these compounds into groups showing anticancer, antibacterial, antiviral, antiparasitic and other activities, and discuss the biological targets associated with each activity, as well as potential future developments.
32929546 Clinical and radiological outcomes after arthrodesis of the first metatarsophalangeal join 2021 Mar PURPOSE: The main aim of this study was to investigate the correlation between radiographic findings and clinical outcomes following the first metatarsophalangeal (MTP) joint arthrodesis. METHODS: In a comparative retrospective study, on 46 patients (48 ft), the correlation between post-operative radiographic findings including hallux valgus angle (HVA) and first MTP dorsiflexion angle (MTPDA) and clinical outcomes including VAS pain, modified AOFAS hallux score, and FFI questionnaire were evaluated. Moreover, clinical outcomes were compared between cases with pre-operative diagnosis of first MTP inflammatory arthritis, hallux valgus, hallux varus, and grade 3 and 4 of hallux rigidus. The effect of first MTP arthrodesis on Meary's angle and intermetatarsal angle (IMA) were found out. RESULTS: The mean age of the patients was 56.3 ± 9.1 (range, 29-69) years, including 42 (91.3%) females and 4 (8.7%) males. We had fusion rate of 97.9%, one asymptomatic nonunion case (2.1%). Totally, mean scores of modified AOFAS hallux score, FFI percentage, and VAS pain were 88.9 ± 12.6, 9.4 ± 16.5, and 1.23 ± 2.24, respectively. Hallux varus was associated with the most favourable outcomes; whereas, patients with first MTP arthritis got the worst outcome. Regression analysis test between clinical outcomes and HVA > 15° and first MTPDA >15° showed correlation coefficient of almost zero. No statistically significant differences were found between the clinical outcomes of grade 3 and 4 of hallux rigidus (p value of modified AOFAS hallux score, FFI percentage, and VAS pain: 0.879, 0.906, and 0.298, respectively). Mean of HVA and IMA reduction in 15 hallux valgus underwent first MTP fusion were 34.4° and 8.4°, respectively. Meary's angle increased about 4° with statistically significant difference (p value 0.001). CONCLUSION: Patients with first MTP fusion > 15° in coronal and transverse plans could have acceptable clinical outcomes. The clinical outcome of first MTP arthrodesis for grade 3 hallux rigidus is comparable with grade 4. First MTP fusion would have positive effect on IMA and Meary's angle.
33859345 TNF-α impairs EP4 signaling through the association of TRAF2-GRK2 in primary fibroblast-l 2022 Feb Our previous study showed that chronic treatment with tumor necrosis factor-α (TNF-α) decreased cAMP concentration in fibroblast-like synoviocytes (FLSs) of collagen-induced arthritis (CIA) rats. In this study we investigated how TNF-α impairs cAMP homeostasis, particularly clarifying the potential downstream molecules of TNF-α and prostaglandin receptor 4 (EP4) signaling that would interact with each other. Using a cAMP FRET biosensor PM-ICUE3, we demonstrated that TNF-α (20 ng/mL) blocked ONO-4819-triggered EP4 signaling, but not Butaprost-triggered EP2 signaling in normal rat FLSs. We showed that TNF-α (0.02-20 ng/mL) dose-dependently reduced EP4 membrane distribution in normal rat FLS. TNF-α significantly increased TNF receptor 2 (TNFR2) expression and stimulated proliferation in human FLS (hFLS) via ecruiting TNF receptor-associated factor 2 (TRAF2) to cell membrane. More interestingly, we revealed that TRAF2 interacted with G protein-coupled receptor kinase (GRK2) in the cytoplasm of primary hFLS and helped to bring GRK2 to cell membrane in response of TNF-α stimulation, the complex of TRAF2 and GRK2 then separated on the membrane, and translocated GRK2 induced the desensitization and internalization of EP4, leading to reduced production of intracellular cAMP. Silencing of TRAF2 by siRNA substantially diminished TRAF2-GRK2 interaction, blocked the translocation of GRK2, and resulted in upregulated expression of membrane EP4 and intracellular cAMP. In CIA rats, administration of paroxetine to inhibit GRK2 effectively improved the symptoms and clinic parameters with significantly reduced joint synovium inflammation and bone destruction. These results elucidate a novel form of cross-talk between TNFR (a cytokine receptor) and EP4 (a typical G protein-coupled receptor) signaling pathways. The interaction between TRAF2 and GRK2 may become a potential new drug target for the treatment of inflammatory diseases.
34970731 Safety Profile of Upadacitinib up to 3 Years in Psoriatic Arthritis: An Integrated Analysi 2022 Apr INTRODUCTION: This integrated analysis describes the safety profile of upadacitinib, an oral Janus kinase inhibitor, at 15 and 30 mg once daily for up to 3 years of exposure in patients with active psoriatic arthritis (PsA) who had a prior inadequate response or intolerance to ≥ 1 non-biologic or biologic disease-modifying antirheumatic drug. METHODS: Safety data were pooled and analyzed from two randomized, placebo-controlled phase 3 trials. Both trials evaluated upadacitinib 15 mg and 30 mg once daily, and one trial also evaluated adalimumab 40 mg every other week. Treatment-emergent adverse events (TEAEs) and laboratory data were summarized for four groups: pooled placebo, pooled upadacitinib 15 mg, pooled upadacitinib 30 mg, and adalimumab. TEAEs were reported as exposure-adjusted event rates (events per 100 patient-years [E/100 PY]) up to a data cut-off of June 29, 2020. RESULTS: A total of 2257 patients received ≥ 1 dose of upadacitinib 15 mg (N = 907) or 30 mg (N = 921) for 2504.6 PY of exposure or adalimumab (N = 429) for 549.7 PY of exposure. Upper respiratory tract infection, nasopharyngitis, and increased creatine phosphokinase (CPK) were the most common TEAEs with upadacitinib. Rates of malignancies, adjudicated major adverse cardiovascular events (MACEs) and venous thromboembolic events (VTEs), and deaths were similar across treatment groups. Rates of herpes zoster (HZ) and opportunistic infections (OI; excluding tuberculosis, HZ, and oral candidiasis) were higher with upadacitinib versus adalimumab. Serious infection, anemia, and CPK elevations were most frequent with upadacitinib 30 mg. Potentially clinically significant laboratory abnormalities were uncommon. CONCLUSIONS: Upadacitinib 15 mg and adalimumab had similar safety profiles with the exception of HZ and OIs, consistent with what was observed in rheumatoid arthritis. Rates of malignancies, MACEs, VTEs, and deaths were comparable among patients receiving upadacitinib and adalimumab. No new safety risks emerged with longer-term exposure to upadacitinib. TRIAL REGISTRATION NUMBERS: SELECT-PsA 1: NCT03104400; SELECT-PsA 2: NCT03104374.
31643761 Abatacept. 2012 Abatacept is a recombinant fusion protein of the cell surface marker CTLA-4 and a fragment of immunoglobulin G that acts by interfering with T cell activation and is used to treat rheumatoid and psoriatic arthritis and juvenile idiopathic arthritis. Abatacept has been linked to a low rate of serum enzyme elevations during therapy, and to rare cases of idiosyncratic, clinically apparent liver injury with jaundice. Because abatacept is a potent inhibitor of lymphocyte function, it can cause reactivation of hepatitis B in susceptible patients.
34811543 Shortage of aspartate in mitochondria fuels arthritis. 2021 Dec In patients with rheumatoid arthritis, a short supply of aspartate in the mitochondria can force the endoplasmic reticulum of T cells to generate transmembrane TNF, which in turn contributes to synovial inflammation.