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Comparative Efficacy and Safety of Peficitinib 25, 50, 100, and 150 mg in Patients with Active Rheumatoid Arthritis: A Bayesian Network Meta-Analysis of Randomized Controlled Trials.
Lee, YH, Song, GG
Clinical drug investigation. 2020;(1):65-72
Abstract
BACKGROUND AND OBJECTIVE Peficitinib, a JAK3-selective inhibitor that blocks the signal transduction and then suppresses immune responses, has been developed for the treatment of patients with moderate to severe active rheumatoid arthritis (RA). We assessed the relative efficacy and safety of once-daily administration of peficitinib (a JAK3-selective inhibitor) 25 mg, 50 mg, 100 mg, and 150 mg in patients with active RA. METHODS A Bayesian network meta-analysis was conducted to combine direct and indirect evidence from eligible randomized controlled trials (RCTs). The literature search was performed up to May 2019 using MEDLINE, Embase, and the Cochrane Controlled Trials Register. RESULTS Three RCTs involving 948 patients met the inclusion criteria. There were ten pairwise comparisons, including five direct comparisons and five interventions. The American College of Rheumatology 20% (ACR20) response rate was significantly higher in the peficitinib 150-mg group than in the placebo group (odds ratio (OR): 3.61; 95% credible interval (CrI): 2.35-5.57). Similarly, the ACR20 response rate was significantly higher in the peficitinib 100-mg group than in the placebo group (OR: 2.33, 95% CrI: 1.51-3.56). The peficitinib 50-mg group had a significantly higher ACR20 response rate than the placebo group. However, the ACR20 response rate was not significantly higher in the peficitinib 25-mg group than in the placebo group. The ranking probability based on the surface under the cumulative ranking curve (SUCRA) indicated that peficitinib 150 mg was likely to achieve the best ACR20 response rate (SUCRA = 0.995), followed by peficitinib 100 mg (SUCRA = 0.696), peficitinib 50 mg (SUCRA = 0.558), peficitinib 25 mg (SUCRA = 0.153), and placebo (SUCRA = 0.098). The ACR50 and ACR70 response rates showed a similar distribution pattern to the ACR20 response rate. The difference in the number of patients with adverse events (AEs) among the intervention groups was not statistically significant. CONCLUSIONS Peficitinib 50, 100, and 150 mg once daily was effective in treating active RA, without causing a significant risk for AEs.
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The structure, specificity and function of anti-citrullinated protein antibodies.
Ge, C, Holmdahl, R
Nature reviews. Rheumatology. 2019;(8):503-508
Abstract
In this Perspectives article, we outline a proposed model for understanding the specificity and function of anti-citrullinated protein antibodies (ACPAs). We suggest that ACPAs vary in specificity between two extremes: some are 'promiscuous' in that they are highly specific for the citrulline side chain, but cross-react with a range of citrullinated peptides, whereas others are 'private' in that their recognition of citrulline as well as proximal amino acid side chains enables protein-specific interactions. Promiscuous ACPAs tend to dominate in the sera both before and after the onset of rheumatoid arthritis, but their functional role has not been clarified. No firm evidence exists that these ACPAs are pathogenic. By contrast, private ACPAs encompass antibodies that specifically recognize citrullinated epitopes on joint proteins or that cross-react with joint proteins, thereby opening up the possibility that these private ACPAs are arthritogenic. These joint-reactive antibodies are more likely to target joints by binding to joint tissues and to promote the formation of local immune complexes leading to bone erosions, pain and arthritis.
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Updated pharmacological management of rheumatoid arthritis for women before, during, and after pregnancy, reflecting recent guidelines.
Murray, KE, Moore, L, O'Brien, C, Clohessy, A, Brophy, C, Minnock, P, FitzGerald, O, Molloy, ES, Mongey, AB, Higgins, S, et al
Irish journal of medical science. 2019;(1):169-172
Abstract
BACKGROUND Rheumatoid arthritis (RA) is a chronic immune-mediated inflammatory disease which can cause significant disability, morbidity, mortality, and impaired fertility. It commonly affects women of childbearing age. Managing rheumatoid arthritis (RA) in the perinatal period poses challenges. There is concern about the teratogenic effects of many traditional disease-modifying anti-rheumatic drugs (DMARDs) and an ever-growing list of new therapeutic options with limited data in pregnancy and breastfeeding. AIMS We aimed to create a standardized approach to pharmacological management of RA patients seen in our newly established Rheumatology and Reproductive Health Service. METHODS We reviewed relevant publications on the use of anti-rheumatic drugs in pregnancy. These include recent guidelines from The British Society for Rheumatology (BSR) and British Health Professionals in Rheumatology (BHPR) and the European League Against Rheumatism (EULAR). RESULTS After considering relevant publications, we developed a Saint Vincent's University Hospital/National Maternity Hospital consensus protocol for evidence-based medication in pregnancy in RA. CONCLUSIONS RA tends to improve during pregnancy and flare postpartum. Several anti-rheumatic medication options during pregnancy and breastfeeding are now available including anti-tumor necrosis factor (anti-TNF) agents. Good disease control at all stages of reproduction is important to ensure best outcome for both mother and baby.
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Methotrexate an Old Drug with New Tricks.
Bedoui, Y, Guillot, X, Sélambarom, J, Guiraud, P, Giry, C, Jaffar-Bandjee, MC, Ralandison, S, Gasque, P
International journal of molecular sciences. 2019;(20)
Abstract
Methotrexate (MTX) is the first line drug for the treatment of a number of rheumatic and non-rheumatic disorders. It is currently used as an anchor disease, modifying anti-rheumatic drug in the treatment of rheumatoid arthritis (RA). Despite the development of numerous new targeted therapies, MTX remains the backbone of RA therapy due to its potent efficacy and tolerability. There has been also a growing interest in the use of MTX in the treatment of chronic viral mediated arthritis. Many viruses-including old world alphaviruses, Parvovirus B19, hepatitis B/C virus, and human immunodeficiency virus-have been associated with arthritogenic diseases and reminiscent of RA. MTX may provide benefits although with the potential risk of attenuating patients' immune surveillance capacities. In this review, we describe the emerging mechanisms of action of MTX as an anti-inflammatory drug and complementing its well-established immunomodulatory activity. The mechanisms involve adenosine signaling modulation, alteration of cytokine networks, generation of reactive oxygen species and HMGB1 alarmin suppression. We also provide a comprehensive understanding of the mechanisms of MTX toxic effects. Lastly, we discussed the efficacy, as well as the safety, of MTX used in the management of viral-related rheumatic syndromes.
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Combining Biologics in Inflammatory Bowel Disease and Other Immune Mediated Inflammatory Disorders.
Hirten, RP, Iacucci, M, Shah, S, Ghosh, S, Colombel, JF
Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2018;(9):1374-1384
Abstract
Current therapies used in the treatment of inflammatory bowel disease (IBD) are not effective in all patients. Biologic agents result in approximately 40% remission rates at 1 year in selected populations, prompting a growing interest in combining biologic therapy to improve outcomes. There are limited published data regarding the efficacy and safety of combination targeted therapy in IBD specifically, which include only 1 exploratory randomized control trial and 3 case reports or series. This review evaluates the published literature regarding this therapeutic paradigm in IBD and its extensive utilization in the treatment of other immune-mediated inflammatory disorders. The combination of biologic therapies demonstrates variable degrees of efficacy and highlights some safety concerns, depending upon the agents used and the disease state treated. A trial (Clinical Trials.gov Identifier: NCT02764762) combining vedolizumab and adalimumab is currently underway evaluating the effectiveness and safety of this approach in patients with Crohn's disease, which should provide further insight into this treatment concept. While combination biologic therapy is an attractive strategy, the lack of consistent superior efficacy as well as safety concerns militates the need for further trials prior to its general application in IBD.
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Tackling Pain Associated with Rheumatoid Arthritis: Proton-Sensing Receptors.
Sun, WH, Dai, SP
Advances in experimental medicine and biology. 2018;:49-64
Abstract
Rheumatoid arthritis (RA), characterized by chronic inflammation of synovial joints, is often associated with ongoing pain and increased pain sensitivity. Chronic pain that comes with RA turns independent, essentially becoming its own disease. It could partly explain that a significant number (50%) of RA patients fail to respond to current RA therapies that focus mainly on suppression of joint inflammation. The acute phase of pain seems to associate with joint inflammation in early RA. In established RA, the chronic phase of pain could be linked to inflammatory components of neuron-immune interactions and noninflammatory components. Accumulating evidence suggests that the initial inflammation and autoimmunity in RA (preclinical RA) begin outside of the joint and may originate at mucosal sites and alterations in the composition of microbiota located at mucosal sites could be essential for mucosal inflammation, triggering joint inflammation. Fibroblast-like synoviocytes in the inflamed joint respond to cytokines to release acidic components, lowering pH in synovial fluid. Extracellular proton binds to proton-sensing ion channels, and G-protein-coupled receptors in joint nociceptive fibers may contribute to sensory transduction and release of neurotransmitters, leading to pain and hyperalgesia. Activation of peripheral sensory neurons or nociceptors further modulates inflammation, resulting in neuroinflammation or neurogenic inflammation. Peripheral and central nerves work with non-neuronal cells (such as immune cells, glial cells) in concert to contribute to the chronic phase of RA-associated pain. This review will discuss actions of proton-sensing receptors on neurons or non-neuronal cells that modulate RA pathology and associated chronic pain, and it will be beneficial for the development of future therapeutic treatments.
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Review: Synovial Cell Metabolism and Chronic Inflammation in Rheumatoid Arthritis.
Falconer, J, Murphy, AN, Young, SP, Clark, AR, Tiziani, S, Guma, M, Buckley, CD
Arthritis & rheumatology (Hoboken, N.J.). 2018;(7):984-999
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Abstract
Metabolomic studies of body fluids show that immune-mediated inflammatory diseases such as rheumatoid arthritis (RA) are associated with metabolic disruption. This is likely to reflect the increased bioenergetic and biosynthetic demands of sustained inflammation and changes in nutrient and oxygen availability in damaged tissue. The synovial membrane lining layer is the principal site of inflammation in RA. Here, the resident cells are fibroblast-like synoviocytes (FLS) and synovial tissue macrophages, which are transformed toward overproduction of enzymes that degrade cartilage and bone and cytokines that promote immune cell infiltration. Recent studies have shown metabolic changes in both FLS and macrophages from RA patients, and these may be therapeutically targetable. However, because the origins and subset-specific functions of synoviocytes are poorly understood, and the signaling modules that control metabolic deviation in RA synovial cells are yet to be explored, significant additional research is needed to translate these findings to clinical application. Furthermore, in many inflamed tissues, different cell types can forge metabolic collaborations through solute carriers in their membranes to meet a high demand for energy or biomolecules. Such relationships are likely to exist in the synovium and have not been studied. Finally, it is not yet known whether metabolic change is a consequence of disease or whether primary changes to cellular metabolism might underlie or contribute to the pathogenesis of early-stage disease. In this review article, we collate what is known about metabolism in synovial tissue cells and highlight future directions of research in this area.
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The therapeutic effect of probiotics on rheumatoid arthritis: a systematic review and meta-analysis of randomized control trials.
Mohammed, AT, Khattab, M, Ahmed, AM, Turk, T, Sakr, N, M Khalil, A, Abdelhalim, M, Sawaf, B, Hirayama, K, Huy, NT
Clinical rheumatology. 2017;(12):2697-2707
Abstract
Rheumatoid arthritis is an autoimmune disease in which probiotics appears to have an immune modulating action along with decreased inflammatory process. Therefore, we aim to investigate the efficacy of probiotics as an adjuvant therapy for rheumatoid arthritis. A comprehensive literature search was performed using nine databases including PubMed and Web of Science. Interesting data was extracted and meta-analyzed. We assessed the risk of bias using Cochrane Collaboration's tool. The protocol was registered in PROSPERO (CRD 42016036769). We found nine studies involving 361 patients who met our eligibility criteria. Our meta-analysis indicated that pro-inflammatory cytokine IL-6 was significantly lower in the probiotics compared with the placebo group (standardized mean difference = - 0.708; 95% confidence interval (CI) - 1.370 to 0.047, P = 0.036). However, there was no difference between probiotics and placebo in disease activity score (mean difference 0.023; 95% CI - 0.584 to 0.631, P = 0.940). Probiotics lowered pro-inflammatory cytokines IL-6 in RA; however, its clinical effect is still unclear. Hence, many high-quality randomized controlled trials (RCTs) are still needed to prove this effect.
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Biomarkers for rheumatoid arthritis: From molecular processes to diagnostic applications-current concepts and future perspectives.
Nakken, B, Papp, G, Bosnes, V, Zeher, M, Nagy, G, Szodoray, P
Immunology letters. 2017;:13-18
Abstract
Early diagnosis and immediately started appropriate treatment are mandatory for the prevention of radiographic progression, functional disability and unfavourable disease outcome in rheumatoid arthritis (RA). The current classification criteria for RA include two different types of biomarkers representing inflammatory processes, such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) or immune processes including autoantibodies, such as rheumatoid factor (RF) and antibodies against citrullinated proteins (ACPA). After the discovery of RF, the recent recognition of various autoantibodies against post-translationally modified proteins opened new avenues to diagnosing RA and predicting the course of the disease. Citrullination and carbamylation of amino acids generate new epitopes that can potentially promote the production of novel autoantibodies. In spite of growing knowledge, the pathogenic role of these autoantibodies is still not fully elucidated in RA. In this paper, we review the currently available and novel promising immune biomarkers, which may help in early diagnosis and estimating prognosis in RA.