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ID PMID Title PublicationDate abstract
29146737 Rheumatic disorders associated with immune checkpoint inhibitors in patients with cancer-c 2018 Mar OBJECTIVES: To evaluate the prevalence and type of rheumatic immune-related adverse events (irAEs) in patients receiving immune checkpoint inhibitors (ICIs), as well as the correlation with tumour response. METHODS: This was a single-centre prospective observational study including all cancer patients receiving ICIs. The occurrence of irAEs and tumour response was assessed on a regular basis. Patients who experienced musculoskeletal symptoms were referred to the department of rheumatology for clinical evaluation and management. RESULTS: From September 2015 to May 2017, 524 patients received ICIs and 35 were referred to the department of rheumatology (6.6%). All but one of the rheumatic irAEs occurred with anti-programmed cell death protein 1(PD-1)/PD-1 ligand 1(PD-L1) antibodies, with a median exposure time of 70 days. There were two distinct clinical presentations: (1) inflammatory arthritis (3.8%) mimicking either rheumatoid arthritis (n=7), polymyalgia rheumatica (n=11) or psoriatic arthritis (n=2) and (2) non-inflammatory musculoskeletal conditions (2.8%; n=15). One patient with rheumatoid arthritis was anti-cyclic citrullinated peptide (anti-CCP) positive. Nineteen patients required glucocorticoids, and methotrexate was started in two patients. Non-inflammatory disorders were managed with non-steroidal anti-inflammatory drugs, analgesics and/or physiotherapy. ICI treatment was pursued in all but one patient. Patients with rheumatic irAEs had a higher tumour response rate compared with patients without irAEs (85.7% vs 35.3%; P<0.0001). CONCLUSION: Since ICIs are used with increasing frequency, knowledge of rheumatic irAEs and their management is of major interest. All patients were responsive either to low-to-moderate doses of prednisone or symptomatic therapies and did not require ICI discontinuation. Furthermore, tumour response was significantly higher in patients who experienced rheumatic irAEs.
29329035 Esterification of trans-aconitic acid improves its anti-inflammatory activity in LPS-induc 2018 Mar trans-Aconitic acid (TAA) is an abundant constituent in the leaves of Echinodorus grandiflorus, a medicinal plant used to treat rheumatoid arthritis in Brazil. Esterification was explored as a strategy to increase lipophilicity and biopharmaceutical properties of TAA, a highly polar tricarboxylic acid. We herein report the synthesis of TAA esters via Fischer esterification with ethanol, n-butanol and n-octanol. The reaction kinetics was investigated to produce mono-, di- and tri- derivatives. Mono- and diesters of TAA were obtained as a mixture of positional isomers, whereas the triesters were recovered as pure compounds. The obtained esters were screened in a model of acute arthritis induced by the injection of LPS in the knee joint of Swiss mice. The diesters were the most active compounds, regardless of the alcohol employed in the reaction, whereas bioactivity of the derivatives improved by increasing the length of the aliphatic chain of the alcohol employed in esterification. In general, the esters showed higher potency than TAA. When administered orally to mice at doses of 0.017-172.3 μmol/Kg, the diethyl, di-n-butyl and di-n-octyl esters of TAA reduced the cellular infiltration into the knee joint, especially of neutrophils. The study identified diesters of TAA as potential useful derivatives for the management of rheumatoid arthritis and other inflammatory diseases.
30547186 MicroRNA-124 inhibits TNF-α- and IL-6-induced osteoclastogenesis. 2019 Apr Receptor activator for nuclear factor κB ligand (RANKL)-independent osteoclastogenic pathway was reported recently. MicroRNA (miR)-124 has been known to suppress RANKL-dependent osteoclastogenesis by inhibiting NFATc1 expression. However, whether miR-124 regulates a RANKL-independent pathway has not been elucidated. In this study, we examined whether a RANKL-independent pathway is regulated by miR-124 in addition to the RANKL-dependent one. Using osteoclastogenic culture and pit-formation assay, we found that a miR-124 mimic inhibited osteoclastogenesis in mouse bone marrow-derived macrophages stimulated by TNF-α, IL-6, and M-CSF in the presence of osteoprotegerin. We also showed that the expression levels of osteoclast-specific genes and NFATc1 protein were suppressed in the miR-124 mimic-transfected cells by performing quantitative-polymerase chain reaction and western blotting. Our results indicate that miR-124 is important in inhibiting both RANKL-dependent and -independent osteoclast differentiation by suppressing NFATc1-mediated pathway.
29849731 Clinical Efficacy of Acupuncture on Rheumatoid Arthritis and Associated Mechanisms: A Syst 2018 OBJECTIVE: The objective of this review is to investigate the detailed existing scientific information about the clinical efficacy of acupuncture on rheumatoid arthritis (RA) conditions and to reveal the proposed mechanisms. METHODS: We searched the PubMed, EMBASE, Cochrane, AMED (Allied and Complementary Medicine), NCCAM (The National Center for Complementary and Alternative Medicine), and CNKI (China National Knowledge Infrastructure) databases to identify relevant monographs and related references from 1974 to 2018. Chinese journals and theses/dissertations were hand searched. RESULTS: 43 studies were recruited. Each research was analyzed for study design, subject characteristics, intervention, selected acupoints, assessment parameters, proposed mechanisms, and results/conclusions. CONCLUSIONS: In our review, we concluded that acupuncture alone or combined with other treatment modalities is beneficial to the clinical conditions of RA without adverse effects reported and can improve function and quality of life and is worth trying. Several important possible mechanisms were summarized including anti-inflammatory effect, antioxidative effect, and regulation of immune system function. However, there is still inconsistency regarding the clinical efficacy and lack of well-designed human/animal double-blinded RCTs. Future discussion for further agreement on taking traditional Chinese medicine (TCM) theory into consideration as much as possible is a top priority.
29544566 Ramosissimin, a new flavonol from Tararix ramosissima, induces apoptosis in rheumatoid art 2018 Mar 5 Tamarix ramosissima is a traditional Chinese herbal medicine used for rheumatoid arthritis (RA) treatment in Northwest China. Chemical investigation of EtOH/H2O extracts of T. ramosissima led to the discovery of a new flavonol, ramosissimin (1), together with the known flavonoids compounds quercetin (2), quercetin-3'4'-dimethylether (3) and kaempferol (4). By means of high resolution electrospray ionization mass spectroscopy (HRESIMS) and 1D and 2D-NMR experiments, and after comparison with literature data, the structures of the compounds were determined. The effect of compound 1 on the viability of RA fibroblast-like synoviocytes (RA-FLS) was evaluated by MTT assay. Apoptosis-inducing effect of compound 1 in RA-FLS was further investigated by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay and activated caspase-3/7 level assessment using luminescent assay. The results revealed that ramosissimin displayed remarkable proliferation inhibitory effect in RA-FLS. Furthermore, compound 1 could significantly induce cellular apoptosis of RA-FLS and increase activated caspase-3/7 levels. It is suggested that ramosissimin may inhibit the proliferation of RA-FLS by inducing apoptosis.
29531729 Severe pancytopenia and splenomegaly associated with felty's syndrome, both fully responsi 2018 Mar In severe cases of pancytopenia with subsequent infections due to long-term untreated Felty's syndrome, the initiation of immunosuppressive treatment with sole prednisone (1 mg/kg iv) should be considered, despite that, the low neutrocytes count would make one physician hesitant. A full resolution of whole blood count within 3 weeks and a 30% reduction in spleens sized was noted.
29334841 Tocilizumab in the treatment of myocardial infarction. 2018 Sep Tocilizumab (TCZ) is an important biologic response modifier that rheumatologists routinely employ in the treatment of several systemic autoimmune diseases. TCZ binds to interleukin (IL)-6 receptors, inhibits cellular activation, and mitigates inflammation by IL-6. In mid-2017, TCZ was approved by the US Food and Drug Administration for its first nonrheumatologic condition, the treatment of chimeric antigen receptor (CAR) T cell-induced severe or life-threatening cytokine release syndrome in patients 2 years of age or older. With this approval and with the increasing use of TCZ off-label for other non-rheumatologic conditions such as Castleman's Disease and its variant TAFRO syndrome, where else might TCZ be successfully utilized as treatment? Recently interesting data has been published regarding possible use of TCZ in the treatment of myocardial infarction. This review focuses on the role of IL-6 and its receptor in myocardial inflammation and association with adverse clinical outcomes. Discussed are one animal study and two human trials that have been published studying the effect of TCZ in patients with acute myocardial infarction. Finally, this review summarizes the current data and makes recommendations for future clinical trial development in what hopefully will be a promising application of TCZ for a serious nonrheumatologic condition.
31105982 Therapeutic Antibody-Like Immunoconjugates against Tissue Factor with the Potential to Tre 2018 Mar Accumulating evidence suggests that tissue factor (TF) is selectively expressed in pathological angiogenesis-dependent as well as macrophage-associated human diseases. Pathological angiogenesis, the formation of neovasculature, is involved in many clinically significant human diseases, notably cancer, age-related macular degeneration (AMD), endometriosis and rheumatoid arthritis (RA). Macrophage is involved in the progression of a variety of human diseases, such as atherosclerosis and viral infections (human immunodeficiency virus, HIV and Ebola). It is well documented that TF is selectively expressed on angiogenic vascular endothelial cells (VECs) in these pathological angiogenesis-dependent human diseases and on disease-associated macrophages. Under physiology condition, TF is not expressed by quiescent VECs and monocytes but is solely restricted on some cells (such as pericytes) that are located outside of blood circulation and the inner layer of blood vessel walls. Here, we summarize TF expression on angiogenic VECs, macrophages and other diseased cell types in these human diseases. In cancer, for example, the cancer cells also overexpress TF in solid cancers and leukemia. Moreover, our group recently reported that TF is also expressed by cancer-initiating stem cells (CSCs) and can serve as a novel oncotarget for eradication of CSCs without drug resistance. Furthermore, we review and discuss two generations of TF-targeting therapeutic antibody-like immunoconjugates (ICON and L-ICON1) and antibody-drug conjugates that are currently being tested in preclinical and clinical studies for the treatment of some of these human diseases. If efficacy and safety are proven in current and future clinical trials, TF-targeting immunoconjugates may provide novel therapeutic approaches with potential to broadly impact the treatment regimen of these significant angiogenesis-dependent, as well as macrophage-associated, human diseases.
29991946 Long-Term Dietary Changes after Diagnosis of Rheumatoid Arthritis in Swedish Women: Data f 2018 OBJECTIVE: To investigate long-term dietary changes after rheumatoid arthritis (RA) diagnosis in Swedish women, compared to women without RA. METHODS: This study included 21,602 women from the Swedish Mammography Cohort (SMC), who completed dietary questionnaires in 1997 and 2009. Between 1997 and 2009, 191 women were diagnosed with RA. Dietary changes after RA diagnosis were analyzed based on intake of 82 food items. Statistical analysis included linear mixed models. RESULTS: Women with RA, compared to women without RA, had significantly lower intake (mean servings per week) of animal products such as black pudding, egg, kidney, and liver paste (2.94±2.73 versus 2.45±1.82, p=0.010) and dairy products (35.14±20.02 versus 28.42±16.10, p=0.040) in 1997 and of cereals and grains (31.01±15.54 versus 28.00±14.98, p=0.009) in 2009. However, multivariable adjusted changes in dietary intake from 1997 to 2009 did not show any significant difference in intake. Nevertheless, women without RA increased their intake of whole wheat bread, wheat/oat bran, and rice more than women with RA. CONCLUSION: Women who had been diagnosed with RA had similar dietary patterns over time as the general population; these women did not remarkably change their diet over time due to their disease. Dietary recommendations for RA patients are needed.
29849651 AC-CUTE: An Open-Label Study to Evaluate Progression of Structural Joint Damage and Inflam 2018 AIM: Examine the efficacy of once-weekly subcutaneous tocilizumab (SC-TCZ) on joint damage at 24 weeks based on radiography of the hands and feet and magnetic resonance imaging (MRI) of the hand in subjects with moderate to severe rheumatoid arthritis (RA). METHODS: In this Australian open-label, multicentre, prospective, single-arm study, subjects received 162 mg SC-TCZ weekly. Primary endpoint was change in radiographic Genant-modified Total Sharp Score (TSS) between baseline and Week 24. Secondary endpoints included change from baseline to Week 24 in RA MRI scoring (RAMRIS) of erosions, synovitis, and osteitis and Cartilage Loss Score (CARLOS) in the dominant hand and disease activity score 28 (DAS28). RESULTS: 52 subjects were enrolled (80% female, mean (SD) age 57  (12) years). Radiography showed mild but not significant progression of joint damage (mean (SD) change in TSS 0.46 (1.29)). Synovitis reduced significantly on MRI; however, osteitis, erosion, and cartilage loss did not change significantly. DAS28 improved significantly by Week 24; 78% of subjects achieved DAS28 remission. SC-TCZ was generally well tolerated. CONCLUSION: Synovitis and DAS28 decreased significantly; however, no significant change in osteitis or joint damage was observed at Week 24. TRIAL REGISTRATION: This trial is registered with Clinicaltrials.gov registration number NCT01951170 (ML28703).
29697226 2018 Feb OBJECTIVES: This report details the research undertaken to understand registries listed on clinicaltrials.gov, as well the burden required to record some of the most intricate, necessary data so that it is available to all other registries and viewers. The published Outcome Measures Framework (OMF) was used to evaluate the completeness of entries. DATA SOURCES: We searched the records for patient registries posted in the ClinicalTrials.gov database. For both the quantitative and qualitative studies, all records on ClinicalTrials.gov on June 23, 2015 that were defined as Patient Registries in the ‘Study Type’ field were downloaded for inclusion in the analyses. REVIEW METHODS: A literature review, quantitative analysis, and qualitative analysis were undertaken to understand all facets of registration of patient registries. The report provides information on what fields within clinicaltrials.gov are populated most frequently, whether those fields were required or not, and explains how more complete data on the study population could be elicited and validated. It also describes how dominant definitions will be chosen as well as process measures such as treatments or procedures, and the associated outcome of the patients or participants involved. A qualitative analysis on four condition areas was conducted to measure the degree to which outcome data, as entered in clinicaltrials.gov, mapped to the framework developed in the OMF. The conditions examined were depression, asthma, rheumatoid arthritis, and cardiac surgery. Two of these conditions, cardiac surgery and rheumatoid arthritis, were considered “deeper dives” and examined more in-depth detail on the level of data available in clinicaltrials.gov or other registry-run Web sites, as applicable. RESULTS: These research approaches were conducted with the intent to inform researchers on the development of an Internet-based database intended to house a fully functional system to clearly define, and eventually harmonize, outcome measures. This system has been termed the Outcome Measures Repository (OMR). The information model and governance structure is described in this report. CONCLUSIONS: The intent of this report and the resulting OMR is to capture that data elements and sub-elements with the utmost attention to detail to ensure the optimal amount of information is captured while also avoiding undue burden on behalf of the registry steward responsible for entering the data into the OMR.
29189176 The Emerging Role of Complement C3 as A Biomarker of Insulin Resistance and Cardiometaboli 2018 Jan 31 BACKGROUND: An intricate network of reciprocal interactions between adipose tissue and immune system have been largely demonstrated, leading to the well-accepted concept of insulin resistance as a low grade inflammatory state and, conversely, chronic high-grade inflammation as a dysmetabolic condition. Immune homeostasis is regulated by several players including the complement system, a complex protein network at the crossroad between the innate and adaptive arms of the human defences against pathogens. OBJECTIVE: Complement C3 represents the nodal point of the complement cascade independently of the pathway recruited. Aim of this review is to collect the evidence supporting the role of complement C3 as a candidate biomarker of insulin resistance and other metabolic disorders. METHODS: We reviewed the available evidence pointing to a role of complement system, and in particular complement C3, in insulin resistance and other cardiometabolic diseases including diabetes (T2D), hypertension, non-alcoholic fatty liver disease (NAFLD) and atherosclerosis. RESULTS: Compelling preclinical evidence demonstrated a role of adipose-tissue C3 and its cleavage products C3a and acylation stimulating protein (ASP) in adipose tissue inflammation and insulin resistance. To further support this hypothesis, several clinical studies, both cross-sectional and longitudinal, confirmed this association in independent cohorts. Moreover, preliminary evidence support a role of complement C3 in other cardiometabolic diseases such as hypertension, NAFLD and atherosclerosis. CONCLUSION: Future studies are needed to fully confirm the usefulness of C3 as a clinical biomarker and to establish accurate cut-off values. Moreover, the therapeutic potential of C3 modulation in either cardiometabolic and inflammatory diseases need to be investigated.
30420888 The Effect of Prednisone on Tuberculin Skin Test Reaction in Patients with Rheumatoid Arth 2018 OBJECTIVES: To assess the correlation between prednisone and methotrexate (MTX) treatment duration and dosage with the TST induration diameter of the TST reaction among rheumatoid arthritis (RA) patients. METHOD: We retrospectively analyzed consecutive cases of RA patients who were TNF-i therapy candidates. TST measurements, prednisone and methotrexate dosages, and treatment durations were recorded. A control group was randomly selected from healthy subjects. We compared TST reaction size between the following three groups: RA patients with current prednisone treatment, RA prednisone naïve patients, and healthy individuals. RESULTS: Our study sample comprised 43 RA patients with prednisone treatment, 22 prednisone naïve patients, and 195 healthy subjects. There was no significant difference in mean TST between the groups (5.3±6.6, 7.8±6.2, and 7.6±7.0, respectively, p=0.149). No correlation was noted between TST size and prednisone u-y (r=0.229, p=0.140) or methotrexate u-y in patients with and without prednisone therapy (r=0.219, p=0.158; and r=-0.293, p=0.186, respectively). CONCLUSIONS: Our results show that the TST reaction size among RA patients may not be affected by prednisone therapy. In addition, the TST reaction of RA patients may present similarly to that of healthy individuals. Therefore, we suggest that the criterion of a TST reaction of 5 mm to define latent TB infection in our population should be reevaluated.
31308803 Ameliorative effects of ginseng and ginsenosides on rheumatic diseases. 2019 Jul BACKGROUND: Inflammation is a host-defensive innate immune response to protect the body from pathogenic agents and danger signals induced by cellular changes. Although inflammation is a host-defense mechanism, chronic inflammation is considered a major risk factor for the development of a variety of inflammatory autoimmune diseases, such as rheumatic diseases. Rheumatic diseases are systemic inflammatory and degenerative diseases that primarily affect connective tissues and are characterized by severe chronic inflammation and degeneration of connective tissues. Ginseng and its bioactive ingredients, genocides, have been demonstrated to have antiinflammatory activity and pharmacological effects on various rheumatic diseases by inhibiting the expression and production of inflammatory mediators. METHODS: Literature in this review was searched in a PubMed site of National Center for Biotechnology Information. RESULTS: The studies reporting the preventive and therapeutic effects of ginseng and ginsenosides on the pathogenesis of rheumatic diseases were discussed and summarized. CONCLUSION: Ginseng and ginsenosides play an ameliorative role on rheumatic diseases, and this review provides new insights into ginseng and ginsenosides as promising agents to prevent and treat rheumatic diseases.
30262960 Terminalia chebula Retz. Fruit Extracts Inhibit Bacterial Triggers of Some Autoimmune Dise 2018 Dec Terminalia chebula Retz. is a northern Indian plant species known for its anti-inflammatory and antimicrobial properties. T. chebula fruit powder was extracted with solvents of varying polarity and screened for bacterial growth inhibition by disc diffusion assay. The minimum inhibitory concentration (MIC) was quantified by both liquid dilution and disc diffusion techniques. To screen for combinatorial effects, the T. chebula fruit extracts were combined with a range of conventional antibiotics and tested against each bacteria using a liquid dilution assay. Where synergy was detected, the optimal ratios were determined using isobologram analysis. Toxicity was examined using Artemia nauplii and HDF bioassays. T. chebula fruit methanolic, aqueous and ethyl acetate extracts displayed strong antimicrobial activity against the bacterial triggers of all autoimmune inflammatory diseases except K. pneumoniae, for which only moderate inhibition was observed. Indeed, MIC values as low as 195 μg/mL were measured for the aqueous extract against a resistant strain of P. aeruginosa. Of further note, both the aqueous and ethyl acetate extracts interacted synergistically in combination with tetracycline against K. pneumoniae (Σ FIC 0.38 and 0.25 respectively). All extracts were nontoxic in the Artemia and HDF toxicity assays, further indicating their potential for medicinal use.
30254808 Adult-onset Still's Disease in a Female Patient with Schizophrenia: A Case Report and Lite 2018 Jul 21 Adult-onset Still's disease (AOSD) is a rare diagnosis. In small percentage of cases, AOSD is associated with other autoimmune diseases including schizophrenia. Despite the lack of sufficient studies, both conditions may share similar autoimmune pathogenic pathways. Herein we describe a 36-year-old woman with the past medical history of schizophrenia who presented with spiking fevers, arthralgia, evanescent rash and pleural chest pain. She reported developing these symptoms a while after poor compliance with her antipsychotic medication. On admission, physical examination was remarkable for high-grade fever, maculopapular rash, oligo arthralgia, hepatomegaly and lymphadenopathy. Laboratory investigation revealed leukocytosis with neutrophilia and markedly elevated ferritin. The patient met four out of four major, and three out of five minor Yamaguchi criteria for AOSD. The patient started on therapy with corticosteroid. Soon after, her symptoms resolved and most of her biochemical markers went back to normal. We review the literature on co-existence of AOSD with other autoimmune diseases, we also discuss that there may be a correlation between ceasing antipsychotic medication (with known immunomodulatory effect) in a schizophrenic patient and triggering an auto-inflammatory process such as AOSD in a susceptible host. In addition, we discussed the possible similar autoimmune pathway of schizophrenia to pathogenesis of AOSD.
30051403 Sex-Specific Cardiovascular Comorbidities with Associations in Dermatologic and Rheumatic 2018 Cardiology, dermatology, and rheumatology form a fascinating triad. Many skin and joint disorders are associated with cardiovascular comorbidities because they share etiologic elements. Female predominance is often remarkable and likely related to autoimmune pathology. Although studies have shown that X-encoded genes may be involved in the differences in immunity between males and females, other studies have also shown that sex chromosomes are irrelevant and that estrogens and androgens are responsible for the differences. The elevated immune activity in females provides a beneficial position in coping with a pathogenic stimulus but may also enhance their susceptibility to autoimmunity. The complexity of the immune system and its role as a defensive force against infection requires an armamentarium to precisely identify and selectively control inflammatory processes or cells which promote atherosclerosis. On the other hand, the inflammation in skin diseases seems to be an active source of diverse proinflammatory cytokines and chemokines which can predispose to cardiovascular comorbidities. Also, it has been shown that comorbidity disproportionately accelerates risk in women.The skin offers a readily available window to facilitate detection of risk factors or even to assist the diagnostic process regarding a variety of disorders, including those with cardiovascular involvement. Current imaging techniques provide exquisite capabilities for diagnosing and possibly even counteracting atherosclerotic plaque formation, before serious cardiovascular events occur. Combining imaging approaches (such as videocapillaroscopy, intravascular ultrasound, and FDG positron emission tomography) with insights based on immunology will likely accelerate advances in this area.We review major dermatologic manifestations and rheumatologic disorders which are associated with cardiac and vascular abnormalities. In particular we discuss sex-specific aspects concerning incidence and severity of cardiovascular disease associated with systemic sclerosis, rheumatoid arthritis, systemic lupus erythematosus, psoriasis, atopic dermatitis, and hidradenitis suppurativa.
29980576 Inequity in access to bDMARD care and how it influences disease outcomes across countries 2018 Oct OBJECTIVE: To establish in a global setting the relationships between countries' socioeconomic status (SES), measured biological disease modifying antirheumatic drug (bDMARD)-usage and disease outcomes. To assess if prescription and reimbursement rules and generic access to medication relates to a countries' bDMARD-usage. METHODS: Data on disease activity and drug use from countries that had contributed at least 100 patients were extracted from the METEOR database. Mean disease outcomes of all available patients at the final visit were calculated on a per-country basis. A questionnaire was sent to at least two rheumatologists per country inquiring about DMARD-prices, access to treatment and valid regulations for prescription and reimbursement. RESULTS: Data from 20 379 patients living in 12 different countries showed that countries' SES was positively associated with measured disease activity (meanDAS28), but not always with physical functioning (HAQ-score). A lower country's SES, stricter rules for prescription and reimbursement of bDMARDs as well as worse affordability of bDMARDs were associated with lower bDMARD-usage. bDMARD-usage was negatively associated with disease activity (although not with physical functioning), but the association was moderate at best. CONCLUSIONS: Disease activity in patients with rheumatoid arthritis as well as bDMARD-usage varies across countries worldwide. The (negative) relationship between countries' bDMARD-usage and level of disease activity is complex and under the influence of many factors, including-but not limited to-countries' SES, affordability of bDMARDs and valid prescription and reimbursement rules for bDMARDs.
30446926 Plantago squarrosa Murray extracts inhibit the growth of some bacterial triggers of autoim 2019 Apr Ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis and rheumatic fever are autoimmune inflammatory diseases that may be triggered in genetically susceptible individuals by specific bacterial pathogens. Inhibiting the growth of these bacteria with high antioxidant plant extracts may inhibit the aetiology of these diseases, as well as inhibiting the later phase symptoms. P. squarrosa extracts were analysed for antioxidant activity using a DPPH free radical scavenging assay. Bacterial growth inhibitory activity was evaluated using disc diffusion assays and the activity was quantified by MIC determination. The extracts were screened for toxicity by A. franciscana nauplii assays. The most potent antibacterial extract (ethyl acetate) was analysed by GC-MS headspace profile analysis and compounds were identified with reference to a phytochemical database. All extracts displayed strong DPPH radical scavenging activity. The ethyl acetate extract was particularly potent (IC(50) 1.4 µg/mL), whilst the other extracts also had significant radical scavenging activity (IC(50) values between 11 and 22 µg/mL). Notably, the bacterial growth inhibitory activity of the extracts correlated with their DPPH radical scavenging activity. The ethyl acetate extract, which had the greatest DPPH scavenging activity, generally displayed the most potent bacterial growth inhibitory activity. This extract was particularly potent against P. mirabilis, P. vulgaris and A. baylyi (MIC values of 484, 575 and 880 µg/mL, respectively). It also inhibited P. aeruginosa and S. pyogenes growth, albeit with higher MICs (1600-3700 µg/mL). All other extract-bacteria combinations were either inactive or resulted in mid-low potency inhibition. All extracts were non-toxic in the A. franciscana bioassay (LC(50) substantially > 1000 µg/mL). In total, 89 unique mass signals were identified in the P. squarrosa ethyl acetate extract by non-biased GC-MS headspace analysis. A number of compounds which may contribute to the antibacterial activity of this extract have been highlighted.
30113724 Safety, Pharmacokinetics, and Pharmacodynamics of Multiple Rising Doses of BI 655064, an 2018 Dec BI 655064 is a humanized antagonistic anti-cluster of differentiation (CD) 40 monoclonal antibody that selectively blocks the CD40-CD40L interaction. The CD40-CD40L pathway is a promising treatment target for autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and lupus nephritis. The safety, tolerability, pharmacokinetics, and pharmacodynamics of repeated once-weekly BI 655064 subcutaneous dosing over 4 weeks were evaluated in a multiple-dose study in healthy subjects. Subjects (N = 40) were randomized 4:1 to four sequential BI 655064 dose groups (80, 120, 180, 240 mg) or to placebo. Safety and tolerability, plasma exposure, CD40 receptor occupancy, and CD40L-induced CD54 upregulation were assessed over 64 and 78 days for the 80- to 180-mg and 240-mg dose groups, respectively. BI 655064 exposure increased in a supraproportional manner, due to target-mediated drug clearance, for doses between 80 mg and 120 mg, but was near proportional for doses greater than 120 mg. Terminal half-life ranged between 6 and 8 days. Dose-dependent accumulation of BI 655064 supports the use of a loading dose in future clinical studies. Following 4 weeks of dosing, >90% CD40 receptor occupancy and inhibition of CD54 upregulation were observed at all dose levels, lasting for 17 days after the last dose. BI 655064 was generally well tolerated. There were no serious adverse events and the frequency and intensity of adverse events were similar for BI 655064 and placebo; no dose relationship or relevant signs of an acute immune reaction were observed. These findings support further investigation of BI 655064 as a potential treatment for autoimmune diseases.