RA Drug Research Articles

Cardiometabolic outcomes in patients with overweight and obesity undergoing weight loss trials : a network meta-analysis

Abstract Objective Cardiometabolic outcomes are intrinsically linked with obesity. According to a study by Jayedi A et al. a 5kg weight gain could increase CVD mortality and MI risk by 11% and 18% respectively, with most overweight and obese patient also suffering from cardiometabolic derangements. This network meta-analysis evaluates cardiometabolic effects bought about by glucagon-like peptide 1 receptor agonists (GLP-1 RA) and other weight loss drugs in an overweight and obese population. Methods Cochrane CENTRAL, Embase and Medline were searched for randomised clinical trials (RCTs) on GLP-1 RA and United States Food and Drug administration weight loss drugs. A network meta-analysis was performed, using risk ratios(RR) to compare the efficacy of the interventions against one another. Network diagrams and surface under the cumulative ranking curve analysis were generated for the following cardiometabolic outcomes ( LDL, HDL, TC, TG, HbA1c, FPG, SBP and DBP). Results Among the cardiometabolic outcomes analysed, the GLP-1RA’s consistently ranked on top, with tirzepatide followed by semaglutide and then liraglutide. In terms of glycaemic control, tirzepatide 15, 10 and 5mg ranked first in a dose dependent manner(SUCRA = 0.8480, 0.8410, 0.6725) followed by semaglutide1.7mg(SUCRA= 0.6232). Tirzepatide 15mg did not achieve statistical significance compared to semaglutide 1.0mg (MD: -0.77, 95%CI: -2.04 to 0.50) or liraglutide1.8mg (MD: -0.64, 95%CI: -1.68 to 0.41). In reducing blood pressure, tirzepatide exhibiting a dose dependent reduction with Tirzepatide 15mg, (SUCRA =0.9457),10mg(SUCRA=0.9069)and 5mg(SUCRA=0.8419) followed by semaglutide 1.7mg (SUCRA =0.7415) then liraglutide 1.8mg(SUCRA = 0.5521).Tirzepatide 15mg demonstrated statistical significance compared to semaglutide 1.0mg (MD: -3.53, 95%CI: -6.78 to -0.27) and liraglutide 3.0mg (MD: -3.47, 95%CI: -5.59 to -1.36). The GLP-1RA’s also exhibited superiority in lipid reduction for TC and TG, with tirzepatide reducing TC (SUCRA = 0.7867) and TG(SUCRA = 0.9843) followed by semaglutide 1.7 mg (SUCRA = 0.7796) for TC and tirzepatide 10 mg (SUCRA = 0.9018) for TG. Orlistat 120mg(SUCRA =0.8789) and 60mg(SUCRA= 0.8458) were superior in reducing LDL, with tirzepatide 15mg(SUCRA =0.7806) and then semaglutide 2.4mg(SUCRA=0.7260) coming in behind. Naltrexone 32mg/Bupropion 360mg(SUCRA = 0.8757) ranked first followed by tirzepatide(SUCRA=0.8593) in increasing HDL, however the increase was not statistically significant (MD: 0.00, 95%CI: -0.04 to 0.05). Conclusion GLP-1 RAs’ superiority in addressing cardiometabolic parameters that are often deranged in patients with overweight and obesity highlights the need for weight lost medication transitioning from one that decreases and suppresses appetite or prevent the absorption of lipids to one that targets the altered metabolic mileu of patients with overweight and obesity, highlighting the multipronged approach needed to treat this metabolic disease.

Computational insights into rational design and virtual screening of pyrazolopyrimidine derivatives targeting Janus kinase 3 (JAK3).

The Janus kinase 3 (JAK3) family, particularly JAK3, is pivotal in initiating autoimmune diseases such as rheumatoid arthritis. Recent advancements have focused on developing antirheumatic drugs targeting JAK3, leading to the discovery of novel pyrazolopyrimidine-based compounds as potential inhibitors. This research employed covalent docking, ADMET (Absorption, Distribution, Metabolism, Excretion, Toxicity) analysis, molecular dynamics modeling, and MM/GBSA (Molecular Mechanics Generalized Born Surface Area) binding free energy techniques to screen 41 in silico-designed pyrazolopyrimidine derivatives. Initially, 3D structures of the JAK3 enzyme were generated using SWISS-MODEL, followed by virtual screening and covalent docking via AutoDock4 (AD4). The selection process involved the AMES test, binding affinity assessment, and ADMET analysis, narrowing down the candidates to 27 compounds that passed the toxicity test. Further covalent docking identified compounds 21 and 41 as the most promising due to their high affinity and favourable ADMET profiles. Subsequent development led to the creation of nine potent molecules, with derivatives 43 and 46 showing exceptional affinity upon evaluation through molecular dynamics simulation and MM/GBSA calculations over 300 nanoseconds, comparable to tofacitinib, an approved RA drug. However, compounds L21 and L46 demonstrated stable performance, suggesting their effectiveness in treating rheumatoid arthritis and other autoimmune conditions associated with JAK3 inhibition.

GLP-1 RAs and SGLT2-Is to Lower Glucose and Reduce the Risk of Cardiovascular and Diabetic Kidney Disease.

The landscape of diabetes management has changed, such that the goal of pharmacotherapy extends beyond glucose-lowering to prioritize risk reduction of cardiovascular disease and diabetic kidney disease. Two newer classes of medications, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2-Is), have become first line therapies for many patients with type 2 diabetes to reduce cardiovascular and renal complications of type 2 diabetes. This review article will describe the mechanism of action, evidence for cardiovascular and kidney outcomes, contraindications, adverse effects, and risk mitigation strategies for the GLP-1 RA and SGLT2-I drug classes. In addition, we will provide a practical approach for primary care clinicians to prescribe, adjust, and combine these medication classes, while considering patient preference, tolerability, comorbidities, cost, and availability.

Glucagon-Like Peptide-1 Receptor Agonist Use and Residual Gastric Content Before Anesthesia

Glucagon-like peptide-1 receptor agonist (GLP-1 RA) use is rapidly increasing in the US, driven by its expanded approval for weight management in addition to hyperglycemia management in patients with type 2 diabetes. The perioperative safety of these medications, particularly with aspiration risk under anesthesia, is uncertain. To assess the association between GLP-1 RA use and prevalence of increased residual gastric content (RGC), a major risk factor for aspiration under anesthesia, using gastric ultrasonography. This cross-sectional study prospectively enrolled patients from a large, tertiary, university-affiliated hospital from June 6 through July 12, 2023. Participants followed preprocedural fasting guidelines before an elective procedure under anesthesia. Patients with altered gastric anatomy (eg, from previous gastric surgery), pregnancy, recent trauma (<1 month), or an inability to lie in the right lateral decubitus position for gastric ultrasonography were excluded. Use of a once-weekly GLP-1 RA. The primary outcome was the presence of increased RGC, defined by the presence of solids, thick liquids, or more than 1.5 mL/kg of clear liquids on gastric ultrasonography. Analysis was adjusted for confounders using augmented inverse probability of treatment weighting, a propensity score-based technique. Secondarily, the association between the duration of drug interruption and the prevalence of increased RGC was explored. Among the 124 participants (median age, 56 years [IQR, 46-65 years]; 75 [60%] female), the prevalence of increased RGC was 56% (35 of 62) in patients with GLP-1 RA use (exposure group) compared with 19% (12 of 62) in patients who were not taking a GLP-1 RA drug (control group). After adjustment for confounding, GLP-1 RA use was associated with a 30.5% (95% CI, 9.9%-51.2%) higher prevalence of increased RGC (adjusted prevalence ratio, 2.48; 95% CI, 1.23-4.97). There was no association between the duration of GLP-1 RA interruption and the prevalence of increased RGC (adjusted odds ratio, 0.86; 95% CI, 0.65-1.14). Use of a GLP-1 RA was independently associated with increased RGC on preprocedural gastric ultrasonography. The findings suggest that the preprocedural fasting duration suggested by current guidelines may be inadequate in this group of patients at increased risk of aspiration under anesthesia.

Efficacy and safety of tirzepatide, GLP-1 receptor agonists, and other weight loss drugs in overweight and obesity: a network meta-analysis.

This network meta-analysis evaluates the efficacy and safety of tirzepatide compared to glucagon-like peptide-1 receptor agonists (GLP-1 RA) and other weight loss drugs in the treatment of overweight and obesity. MEDLINE, Embase, and Cochrane CENTRAL were searched for randomized controlled trials on tirzepatide, GLP-1 RA, and weight loss drugs approved by the US Food and Drug Administration. A network meta-analysis was performed, drawing direct and indirect comparisons between treatment groups. Network diagrams and surface under the cumulative ranking curve analysis were performed for primary (≥5%, ≥10%, ≥15%, absolute weight loss) and secondary outcomes and adverse effects. Thirty-one randomized controlled trials, involving more than 35,000 patients, were included in this study. Tirzepatide 15 mg ranked in the top three across weight-related parameters, glycemic profile (glycated hemoglobin), lipid parameters (total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides), and blood pressure. Tirzepatide 15 mg had the highest efficacy compared with placebo for achieving ≥15% weight loss (risk ratio 10.24, 95% CI: 6.42-16.34). As compared to placebo, tirzepatide and GLP-1 RA across all doses had significant increases in gastrointestinal adverse effects. The superiority of tirzepatide and GLP-1 RA in inducing weight loss and their ability to target multiple metabolic parameters render them promising candidates in the treatment of patients with overweight and obesity.

The therapeutic effect and mechanisms of ABP501, an adalimumab biosimilar, in rheumatoid arthritis

Adalimumab is one of the most widely used antibodies in the world. With the expiration of its patent rights, a large number of drugs with similar biological functions began to emerge. There are already three ADalimumab generic drugs in Europe and/or the United States: ABP501 (AMJEVITA/Solymbic) produced by Amgen, BI695501 (Cyltezo) produced by Boehringer-Ingelheim, and SB5 (Imraldi) produced by Samsung. All three agents meet the predetermined reciprocity criteria. Adalimumab inhibits the biological activity of TNF- α by inhibiting the binding of TNF- α to P55 and p75. The researchers point out that there are small differences in side effects and clinical reactions between reference drugs and similar drugs. In this study, the biological experimental results of RA were analyzed and evaluated. The launch of biological generics of adalizumab will provide us with an exciting opportunity to provide more choices for our patients in RA and other approved drugs. In order to better ensure its correctness and security, it is also necessary to use actual data.

Abstract 13263: Utilization of Proteomic Surrogates for Early Detection of Unexpected Drug Benefits

Introduction: Detection of benefits and adverse effects of therapies in early clinical trial phases could improve the safety, efficiency, and cost of clinical trials. For example, while SGLT2i and GLP-1 RA drugs are recognized success stories, earlier identification of their benefits beyond improved diabetic control may have had the potential to save loss of patients’ lives and years of sales. Hypothesis: Using the EXSCEL and SUGAR-DM-HF trials as examples to study GLP1-RA and SGLT2i responses, we hypothesized that previously validated proteomic surrogates of cardiovascular (CV) events, and kidney health could have enabled detection of these unexpected drug benefits earlier in development in a smaller number of participants over a shorter follow-up period. Methods: CV risk and kidney prognosis SomaSignal tests (each derived from ~5000 plasma proteins measurements using SomaScan® assay) were applied to paired plasma samples at baseline and 9-months (SUGAR-DM-HF) or 1-year (EXSCEL) in intervention (EXSCEL n=1840; SUGAR-DM-HF n=45) and control (EXSCEL n=1833; SUGAR-DM-HF n=52) participants. Power calculations were performed to determine the minimum number of samples needed to detect a significant change within the treatment period with alpha = 0.05, 80% power using a t-test comparing two-sample means. Results: We demonstrated that the cardiovascular benefits of exenatide were detectable with a proteomic surrogate within 1-year (p=0.002), with power analysis indicating a significant 1-year change is observable with group sizes of n=1368 compared with &gt;7000 participants for up to 6.8 years follow-up. Additionally, kidney protection (p=0.037) and CV protection (p=0.06) impacts of empagliflozin within 36 weeks were detectable using proteomic surrogates in small sample sizes (n ~ 50) compared to published outcomes studies requiring thousands of participants followed for &gt;2 years. Conclusions: SomaSignal tests were able to predict cardiometabolic benefits of GLP-1 RA and SGLT2i drugs within a significantly shortened interval and fewer participants than in the outcome trials. Proteomics may provide a powerful tool for improving the efficacy, and cost of drug development by predicting effects of novel therapeutics in smaller, shorter studies.

Use of a biomimetic hydrogel depot technology for sustained delivery of GLP-1 receptor agonists reduces burden of diabetes management

Glucagon-like peptide-1 (GLP-1) is an incretin hormone and neurotransmitter secreted from intestinal L cells in response to nutrients to stimulate insulin and block glucagon secretion in a glucose-dependent manner. Long-acting GLP-1 receptor agonists (GLP-1 RAs) have become central to treating type 2 diabetes (T2D); however, these therapies are burdensome, as they must be taken daily or weekly. Technological innovations that enable less frequent administrations would reduce patient burden and increase patient compliance. Herein, we leverage an injectable hydrogel depot technology to develop a GLP-1 RA drug product capable of months-long GLP-1 RA delivery. Using a rat model of T2D, we confirm that one injection of hydrogel-based therapy sustains exposure of GLP-1 RA over 42days, corresponding to a once-every-4-months therapy in humans. Hydrogel therapy maintains management of blood glucose and weight comparable to daily injections of a leading GLP-1 RA drug. This long-acting GLP-1 RA treatment is a promising therapy for more effective T2D management.

Patient perspectives on tapering biologic or targeted synthetic therapy in well-controlled rheumatoid arthritis and comparison with providers' perspectives.

We examined patient and providers' perspectives on tapering biologic or targeted synthetic disease modifying antirheumatic drugs (bDMARD or tsDMARD) in well-controlled RA to determine which factors influence their long-term treatment decisions. A standardized phone survey was administered to patients with well-controlled RA based on electronic health record review. Providers were also surveyed. Univariate and multivariable regression analysis was performed with odds ratios (OR) and 95% CI. Sixty-two patients and 11 providers completed the survey. In total, 39 (63%) patients would consider a bDMARD/tsDMARD taper. Patients were more likely to consider a taper if they thought their RA was well-controlled (OR 8.02, 95% CI 2.15-29.99, P = 0.002) and of shorter duration (OR 0.94, 95% CI 0.89-0.99, P = 0.02). Patients were less likely to consider a taper if older (OR 0.95, 95% CI 0.91-1.0, P = 0.05), if they were being treated with conventional synthetic DMARDs (OR 0.25, 95% CI 0.07-0.86, P = 0.0275) or daily glucocorticoids (OR 0.08, 95% CI 0.02-0.44, P = 0.0033). Patients' and providers' top concerns about long-term bDMARD/tsDMARD use were malignancy and infection. Their concerns about tapering were worsening pain, flare and loss of function. Patients were more likely to consider a bDMARD/tsDMARD taper than providers (63% vs 36%). Patients who have had well-controlled RA are more likely to consider tapering bDMARD/tsDMARD when not being treated with csDMARDs or glucocorticoids. Patients and providers shared similar concerns regarding long-term use and tapering of bDMARD/tsDMARD, but patients were more likely to consider a taper.

Identification of potential drug targets for rheumatoid arthritis from genetic insights: a Mendelian randomization study

IntroductionRheumatoid arthritis (RA) is a chronic inflammatory illness that mostly affects the joints of the hands and feet and can reduce life expectancy by an average of 3 to 10 years. Although tremendous progress has been achieved in the treatment of RA, a large minority of patients continue to respond poorly to existing medications, owing in part to a lack of appropriate therapeutic targets.MethodsTo find therapeutic targets for RA, a Mendelian randomization (MR) was performed. Cis-expression quantitative trait loci (cis-eQTL, exposure) data were obtained from the eQTLGen Consortium (sample size 31,684). Summary statistics for RA (outcome) were obtained from two largest independent cohorts: sample sizes of 97,173 (22,350 cases and 74,823 controls) and 269,377 (8279 cases and 261,098), respectively. Colocalisation analysis was used to test whether RA risk and gene expression were driven by common SNPs. Drug prediction and molecular docking was further used to validate the medicinal value of drug targets.ResultsSeven drug targets were significant in both cohorts in MR analysis and supported by localization. PheWAS at the gene level showed only ATP2A1 associated with other traits. These genes are strongly associated with immune function in terms of biological significance. Molecular docking showed excellent binding for drugs and proteins with available structural data.ConclusionThis study identifies seven potential drug targets for RA. Drugs designed to target these genes have a higher chance of success in clinical trials and is expected to help prioritise RA drug development and save on drug development costs.

Towards Better Sinomenine-Type Drugs to Treat Rheumatoid Arthritis: Molecular Mechanisms and Structural Modification.

Sinomenine is the main component of the vine Sinomenium acutum. It was first isolated in the early 1920s and has since attracted special interest as a potential anti-rheumatoid arthritis (RA) agent, owing to its successful application in traditional Chinese medicine for the treatment of neuralgia and rheumatoid diseases. In the past few decades, significant advances have broadened our understanding of the molecular mechanisms through which sinomenine treats RA, as well as the structural modifications necessary for improved pharmacological activity. In this review, we summarize up-to-date reports on the pharmacological properties of sinomenine in RA treatment, document their underlying mechanisms, and provide an overview of promising sinomenine derivatives as potential RA drug therapies.

Association between rheumatoid arthritis and thyroid dysfunction: A meta-analysis and systematic review.

ObjectiveRheumatoid arthritis (RA) is an autoimmune disorder. Multiple studies have investigated the risk of thyroid dysfunction in patients with RA but have reached conflicting conclusions. This systematic review aimed to determine whether patients with RA are at higher risk of thyroid dysfunction.MethodsWe comprehensively reviewed online literature databases, including PubMed, Scopus, Embase, and the Cochrane Library, from their respective inception dates to March 25, 2022. Studies that provided data on at least one case of thyroid dysfunction in RA patients and their controls were included. Based on these data, we calculated pooled odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) for thyroid dysfunction in RA and non-RA patients.ResultsTwenty-nine studies met the inclusion criteria, involving a total of 35,708 patients with RA. The meta-analysis showed that, compared with non-RA patients, RA patients had an increased risk of developing thyroid dysfunction, particularly hypothyroidism (OR 2.25, 95% CI 1.78–2.84). Subgroup analysis suggested that study type and sample source of control group were the source of heterogeneity.ConclusionsPatients with RA are at increased risk of developing thyroid dysfunction, especially hypothyroidism. Routine biochemical examination of thyroid function in RA patients should be strengthened. Larger prospective studies are needed to explore the causal relationship between RA and thyroid dysfunction, and to investigate the impact of thyroid dysfunction on RA disease activity, drug efficacy, and medication safety.Systematic review registration https://www.crd.york.ac.uk/prospero/, identifier CRD42022331142.

THE NECESSITY OF INTRODUCTION THE DRUG INSURANCE SYSTEM IN ARMENIA

The increase in the cost of the medicinal component of the treatment, the spread of chronic diseases, and the maintenance of socio-economic inequality in access to health services require the provision of adequate access to medicines. These issues create prerequisites for the improvement of the state health policy and, first, the drug supply system, which is an integral part of the treatment process. The financing of healthcare in Armenia is mainly formed from budget allocations and out of pocket expenditures of the population. Reducing the financial burden on the state and ensuring the rational use of drugs contributes to improving the health of the population. The implementation of a drug insurance scheme, which partially or fully cover the cost of drugs in RA, is one of the solutions for resolving the issue of access to medicines. This article studies the problems of financing healthcare system in Armenia and highlights the need of introduction a drug insurance system in Armenia

Association of Glucagon-Like Peptide-1 Receptor Agonist Use With Risk of Gallbladder and Biliary Diseases

ImportanceGlucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been widely recommended for glucose control and cardiovascular risk reduction in patients with type 2 diabetes, and more recently, for weight loss. However, the associations of GLP-1 RAs with gallbladder or biliary diseases are controversial.ObjectiveTo evaluate the association of GLP-1 RA treatment with gallbladder and biliary diseases and to explore risk factors for these associations.Data SourcesMEDLINE/PubMed, EMBASE, Web of Science, and Cochrane Library (inception to June 30, 2021), websites of clinical trial registries (July 10, 2021), and reference lists. There were no language restrictions.Study SelectionRandomized clinical trials (RCTs) comparing the use of GLP-1 RA drugs with placebo or with non−GLP-1 RA drugs in adults.Data Extraction and SynthesisTwo reviewers independently extracted data according to the PRISMA recommendations and assessed the quality of each study with the Cochrane Collaboration risk-of-bias tool. Pooled relative risks (RRs) were calculated using random or fixed-effects models, as appropriate. The quality of evidence for each outcome was assessed using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) framework.Main Outcomes and MeasuresThe primary outcome was the composite of gallbladder or biliary diseases. Secondary outcomes were biliary diseases, biliary cancer, cholecystectomy, cholecystitis, and cholelithiasis. Data analyses were performed from August 5, 2021, to September 3, 2021.ResultsA total of 76 RCTs involving 103 371 patients (mean [SD] age, 57.8 (6.2) years; 41 868 [40.5%] women) were included. Among all included trials, randomization to GLP-1 RA treatment was associated with increased risks of gallbladder or biliary diseases (RR, 1.37; 95% CI, 1.23-1.52); specifically, cholelithiasis (RR, 1.27; 95% CI, 1.10-1.47), cholecystitis (RR, 1.36; 95% CI, 1.14-1.62), and biliary disease (RR, 1.55; 95% CI, 1.08-2.22). Use of GLP-1 RAs was also associated with increased risk of gallbladder or biliary diseases in trials for weight loss (n = 13; RR, 2.29; 95% CI, 1.64-3.18) and for type 2 diabetes or other diseases (n = 63; RR, 1.27; 95% CI, 1.14-1.43; P <.001 for interaction). Among all included trials, GLP-1 RA use was associated with higher risks of gallbladder or biliary diseases at higher doses (RR, 1.56; 95% CI, 1.36-1.78) compared with lower doses (RR, 0.99; 95% CI, 0.73-1.33; P = .006 for interaction) and with longer duration of use (RR, 1.40; 95% CI, 1.26-1.56) compared with shorter duration (RR, 0.79; 95% CI, 0.48-1.31; P = .03 for interaction).Conclusions and RelevanceThis systematic review and meta-analysis of RCTs found that use of GLP-1 RAs was associated with increased risk of gallbladder or biliary diseases, especially when used at higher doses, for longer durations, and for weight loss.Trial RegistrationPROSPERO Identifier: CRD42021271599

Values, preferences and burden of treatment for the initiation of GLP-1 receptor agonists and SGLT-2 inhibitors in adult patients with type 2 diabetes: a systematic review

ObjectivesAssess values, preferences and burden of treatment that patients with type 2 diabetes consider when initiating glucagon-like peptide-1 receptor agonists (GLP-1 RA) or sodium-glucose cotransporter-2 inhibitors (SGLT-2i) compared with other...

Mathematical model for histogram analysis of dynamic contrast-enhanced MRI: A method to evaluate the drug treatment response in rheumatoid arthritis

PurposeTo evaluate the effectiveness of a mathematical model for histogram analysis of DCE-MRI in distinguishing responders from non-responders during RA drug treatment. MethodTwenty-three consecutive RA patients with clinically active inflammation prospectively underwent DCE-MRI at baseline and after treatment. Manual segmentation of the enhanced synovium was performed on the last phase of DCE-MRI. The voxel-based contrast enhancement was calculated in each phase to obtain 75th percentile values. Kinetic curves made from the 75th percentile values were fitted to mathematical model as follows, ΔS(t) = A(1 – e−αt)e-βt, where A is the upper limit of signal intensity (%), α (sec−1) is the rate of signal increase, and β (sec−1) is the rate of signal decrease during washout. AUC30 was calculated by integration of 30 s. SER was calculated as the signal intensity at the initial time point (t = 60) relative to the delayed time point (t = 300). The volumes of enhanced synovium (sum of the number of voxels) were also calculated. ResultsAfter treatment, α, Aα, AUC30 and SER were significantly lower in the responder group than in the non-responder group (p = 0.033, 0.024, 0.015, and 0.007). The p value of SER was lowest. Aα, AUC30, and the volume of enhanced synovium had significantly larger changes from baseline to after treatment in the responder group than in the non-responder group (p = 0.045, 0.017, and 0.008). The volume of enhanced synovium had the lowest p value. ConclusionsSER after treatment and change in the volume of enhanced synovium might be effective for distinguishing responders from non-responders.

JAK1: Number one in the family; number one in inflammation?

Several cytokines involved in inflammatory pathologies signal via the Janus kinase-signal transducer and activator of transcription pathway. Four JAKs are known: JAK1, JAK2, JAK3 and TYK2. The specific activation of JAKs and STATs determines the biological effects of each cytokine. JAK1 is involved in the signalling of 'γc' receptor cytokines (IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21), pro-inflammatory cytokines including IL-6, as well as IFN. The critical position of JAK1 downstream of these cytokines suggests that JAK1-selective inhibitors are comparable to non-selective ones, without the unwanted consequences of JAK2- or JAK3-blockade. JAK inhibition has led to a better understanding of the biology of synovial inflammation and bone homeostasis. Moreover, the efficacy of non-selective JAK inhibitors and novel JAK1-selective drugs in RA supports a role for JAK1 in its pathogenesis. JAK1-selective drugs are also showing promise in axial spondyloarthritis, suggesting that they may target additional regulatory pathways that impact cytokines such as TNF and IL-17A, which do not use JAKs. Additionally, evidence now supports a JAK1 predominance in the signalling of IL-6 and oncostatin M, and indirectly, of TNF in synovial fibroblasts, macrophages and endothelial cells. Notably, bone homeostasis is also dependent on cytokines relying on JAK1 signalling to promote receptor activator of NF-κB ligand expression in osteoblasts and T cells, contributing to osteoclastogenesis. Here, the contribution of JAK1 over other kinases is unclear. While beneficial effects of JAK inhibitors on bone erosion are supported by preclinical and clinical data, effects on new bone formation in axial spondyloarthritis requires additional study.

A Systematic Review of Discrete Choice Experiment Studies in Rheumatoid Arthritis Biological Medicines.

Objective:Rheumatoid arthritis is a chronic disease with various clinical characteristics. The introduction of biological drugs has enhanced the efficacy and increased diversity of treatment options. Considering the patients’ preferences in decision-making about treatment can improve their adherence. A discrete choice experiment is a type of conjoint method that can elicit preferences in more realistic scenarios. This article reviewed discrete choice experiment (DCE) studies to extract which attributes and levels were included in surveys. In addition, we focused on the process of designing surveys and the method that they used. Method: PubMed, EMBASE, Web of Science, Scopus, Ovid (Medline) and ProQuest were systematically searched in order to find studies that evaluated rheumatoid arthritis patients’ preferences about biological medicines. Studies published in peer-reviewed journals between 1/1/1990 and 12/31/2019 were included. The included studies were analyzed using a narrative synthesis method and descriptive statistics.Results:A total of 7124 studies were initially found. After deleting irrelevant and duplicate studies, 15 studies were included. The most common attributes that were used in surveys were efficacy, adverse effect, route of administration, frequency of administration, and cost. Most studies used a literature review for developing attributes and levels. The median number of included attributes and levels were seven and three, respectively. Eight studies explained their experimental design while seven studies did not. Conditional logit and mixed logit were the most common methods for modeling reciprocally.Conclusion:Several aspects of DCE studies investigating biological drugs in RA were assessed. Explaining the sample size, experimental design, and qualitative work for developing attributes can improve this type of study.

A Review on Rheumatoid Arthritis Interventions and Current Developments.

Rheumatoid arthritis is a chronic autoimmune disorder characterized by inflammation, swelling, and joint destruction primarily affecting the peripheral joints. In recent years, RA has become an alarming concern affecting more than 1.5% of the population worldwide. The majority of the drugs in clinical trials for rheumatoid arthritis are immunomodulatory. The development of novel drugs for RA is impending and scientists are exploring new strategies through various innovative approaches for RA drug development. Treat-to-target and window of opportunity hypothesis are the new approaches that are used to treat, improve outcomes, and prevent long-term use of ineffective therapy, respectively. Novel therapeutic agents (e.g. GM-CSF inhibitors, Matrix metalloproteinase inhibitors) and delivery systems (e.g., Liposomes, Superparamagnetic iron oxide nano particles (SPIONs)) are under investigation for more target based therapy with reduced side effects and toxicity. The new drug discovery and repositioning of previously FDA-approved drugs are also being considered for chronic inflammatory disorder. The review encompasses a vast array of information, including genetics, etiology, clinical symptoms, current treatment, and newer therapeutics approaches, focused on the development of RA interventions. The introduction of the bioinformatics-based approach in RA has also been significantly discussed in the review. This review provides a general understanding of the challenges and uncertainties in the treatment of RA and summarizes the evolving scenario as well as innovative approaches taken into consideration for drug development in rheumatoid arthritis.

In type 2 diabetes, GLP-1 RA plus SGLT2 inhibitor vs. either drug alone reduces HbA1c and SBP and may reduce body weight

Mantsiou C, Karagiannis T, Kakotrichi P, et al. Glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter-2 inhibitors as combination therapy for type 2 diabetes: a systematic review and meta-analysis. Diabetes Obes Metab. 2020;22:1857-68. 32476254.