Drugs In Arthritis Research Articles

Anti-inflammatory supramolecular hydrogel loaded chicoric acid based on graphene oxide modified hyaluronic acid and polyethylene glycol for rheumatoid arthritis treatment.

Chicoric acid (CA) as one of Chinese medicines had anti-inflammatory, less gastrointestinal irritation, less drug-resistance and low cost properties compared with chemical synthesized drug and biologics for rheumatoid arthritis (RA) treatment. To make CA preciously and effectly RA therapy, we firstly developed a supramolecular hydrogel (GHCAP) comprising β-cyclodextrin and graphene oxide (GO) modified hyaluronic acid (CD-HA-GO) as the "host" polymer and adamantane-modified four-arm polyethylene glycol (PEG-AD) as the "guest" polymer, and then the CA was loaded into the supramolecular hydrogel (DGHCAP). The results showed that DGHCAP exhibited injectable, high modulus, high CA loading rate (43.38 %) and slow CA releasing ratio (releasing 80 % in 80 h) compared with those of the supramolecular hydrogel without GO (DHCAP). Moreover, the DGHCAP demonstrated excellent compatibility and effect anti-inflammatory (down regulated proinflammatory cytokines such as IL-1β, IL-6, TNF-α and iNOs) in both in vitro and in vivo assays. The supramolecular hydrogels loaded Chinese medicine could provide another method to treat RA in clinical.

Understanding network meta-analysis.

Recently, in the World Journal of Clinical Cases, studied the different non-steroidal anti-inflammatory drugs (meloxicam, celecoxib, naproxen, and rofecoxib) for juvenile idiopathic arthritis with network meta-analysis (NMA). This manuscript aims to introduce to clinicians what NMA is. NMA represents a fundamental technique for simultaneously comparing three or more interventions within a single analysis, harnessing both direct and indirect evidence derived from a network of studies. It surpasses pair-wise meta-analysis which are confined to direct comparison of two items in clinical trials. This approach can estimate the relative effects between any pair of interventions within the network, often yielding more precise estimations than those generated from single direct or indirect analyses. NMA necessitates steps akin to those of conventional meta-analysis, involving a thorough literature search, assessment of potential trial biases, statistical analysis of reported pairwise comparisons for all relevant outcomes, and evaluation of overall certainty of evidence on an outcome-specific basis. However, NMA demands substantial resources, given its propensity to address broader inquiries, typically involving a larger number of studies at each phase of the systematic review, from screening to analysis, compared to traditional meta-analyses.

Trends in New Use of Disease-Modifying Antirheumatic Drugs for Juvenile Idiopathic Arthritis Among Commercially Insured Children in the United States from 2001 to 2022.

The objective of this study is to describe recent trends in disease-modifying antirheumatic drug (DMARD) use for children with juvenile idiopathic arthritis (JIA) in the United States. We used commercial claims data (2000-2022) to perform a serial cross-sectional utilization study of children aged 1 to 18 that were diagnosed with JIA. Initiations of conventional synthetic DMARDs (csDMARDs), biologic DMARDs (bDMARDs), or targeted synthetic DMARDs (tsDMARDs) were identified after a ≥12-month baseline and expressed as a percentage of all new DMARD initiations per year, by category, class, and individual agent. Trends were evaluated using linear regression. We also examined the first bDMARDs and tsDMARDs initiated after csDMARD monotherapy. We identified 20,258 new DMARD use episodes among 13,696 individuals (median age 14 years, 67.5% female). csDMARDs, although most used overall, declined from 89.5% of new use episodes to 43.2% (2001-2022, P < 0.001 for trend). In contrast, bDMARD use increased (10.5-50.0%, P < 0.001). For tumor necrosis factor inhibitors (TNFi), etanercept peaked at 28.3% in 2006 and declined to 4.2% in 2022 (P = 0.002). Meanwhile, adalimumab use doubled (7.0-14.0%, 2007-2008) after JIA approval, increasing further following a less painful formulation release (20.5% in 2022, P < 0.001). However, overall TNFi use has declined with increasing use of other bDMARDs and tsDMARDs, particularly ustekinumab, secukinumab, and tofacitinib. By 2022, adalimumab was the most common b/tsDMARD initiated first after csDMARDs (77.8%). Among commercially insured children with JIA in the United States, new b/tsDMARD use is rising and new csDMARD use is declining. For b/tsDMARDs, adalimumab is most used and is the predominant b/tsDMARD initiated first after csDMARDs. Patterns in DMARD use for JIA have evolved relative to multiple factors, including regulatory approvals and tolerability.

Preparation of combined colchicine with loxoprofen sodium loaded in dissolvable microneedles and its anti-gouty arthritis effect

Both colchicine (Col) and loxoprofen sodium (LS) are first-line drugs for gouty arthritis (GA). Dissolvable microneedles (DMNs) represent an innovative transdermal drug delivery system (TDDS) that maximizes the therapeutic effect of drugs. In this paper, a novel TDDS of combined Col with LS loaded in DMNs (Col-LS-DMNS) was prepared to treat GA. To assess the synergistic effects of Col and LS, cell viability assays were conducted using monosodium urate (MSU)-induced HaCaT cells. The optimization of the Col-LS-DMNs formulation was carried out through sealing membrane puncture tests, single-factor experiments, and Box-Behnken response surface methodology. The quality of Col-LS-DMNs was assessed using high-performance liquid chromatography (HPLC), scanning electron microscopy (SEM), sealing membrane puncture tests, in vitro mouse skin puncture experiments, and Franz diffusion cell assays. The therapeutic effect of Col-LS DMNs on GA through animal experiments. Results demonstrated that Col and LS exhibit a synergistic effect, with optimal mass ratio of 1:1. The optimal formulation included PVP K30 and CMC Na at a mass ratio of 10:1, with 63% water content and a mixed dosage of Col and LS of 42 mg. The drug content in Col-LS-DMNs was (19.11±0.65) μg of Col and (20.69±0.89) μg of LS per tablet. SEM imaging revealed that the needle tips were conical. Additionally, Col-LS-DMNs exhibited favorable mechanical properties and caused minimal skin damage. After 24 hours, the cumulative permeation amount was (21.55±19.49) μg/cm2. Col-LS-DMNs significantly reduced MSU-induced ankle swelling and decreased serum concentrations of TNF-α, IL-6, and IL-1β in rats. In conclusion, Col-LS-DMNs represent a promising new treatment modality for GA.

Factors predicting treatment response to biological and targeted synthetic disease-modifying antirheumatic drugs in psoriatic arthritis – a systematic review and meta-analysis

The therapeutic response of patients with psoriatic arthritis (PsA) varies greatly and is often unsatisfactory. Accordingly, it is essential to individualise treatment selection to minimise long-term complications. This study aimed to identify factors that might predict treatment response to biological and targeted synthetic disease-modifying antirheumatic drugs (bDMARDs and tsDMARDs) in patients with PsA and to outline their potential application using artificial intelligence (AI). Five electronic databases were screened to identify relevant studies. A random-effects meta-analysis was performed for factors that were investigated in at least four studies. Finally, 37 studies with a total of 17,042 patients were included. The most frequently investigated predictors in these studies were sex, age, C-reactive protein (CRP), the Health Assessment Questionnaire (HAQ), BMI, and disease duration. The meta-analysis revealed that male sex (odds ratio (OR) = 2.188, 95% confidence interval (CI) = 1.912–2.503) and higher baseline CRP (1.537, 1.111–2.125) were associated with greater treatment response. Older age (0.982, 0.975–0.99), higher baseline HAQ score (0.483, 0.336–0.696), higher baseline DAPSA score (0.789, 0.663–0.938), and higher baseline tender joint count (TJC) (0.97, 0.945–0.996) were negatively correlated with the response to therapy. The other factors were not statistically significant but might be of clinical importance in the context of a complex AI test battery. Further studies are needed to validate these findings and identify novel factors that could guide personalised treatment decisions for PsA patients, in particular in developing AI applications. In accordance with the latest medical developments, decision-support tools based on supervised learning algorithms have been proposed as a clinical application of these predictors.Key messages• Given the often unsatisfactory and unpredictable therapeutic response in patients with Psoriatic Arthritis (PsA), treatment selection must be highly individualized.• A systematic literature review was conducted to identify the most reliable predictors of treatment response to biologic and targeted synthetic disease-modifying antirheumatic drugs in PsA patients.• The potential integration of these predictors into AI tools for routine clinical practice is discussed.

Synthesis, XRD structural analysis and theoretical studies of a potential inhibitor against rheumatoid arthritis (RA).

This work focused on analyzing the properties of N-(5-nitrothiazol-2-yl)furan-2-carboxamide (C8H5N3O4S, NTFC) as a possible inhibitor of the rheumatoid arthritis process. The synthesis of NTFC was carried out and good-quality crystals were obtained and studied by NMR (1H and 13C), DEPT 135, UV-Vis, IR, MS and single-crystal X-ray diffraction. The structure of NTFC consists of two rings, thiazole and furan, and a central C-N-C(=O)-C segment, which appears to be planar. This central amide segment forms angles of 2.61 (10) and 7.97 (11)° with the planes of the thiazole and furan rings, respectively. The crystal structure of NTFC exhibits N-H...N, N-H...O and C-H...O hydrogen bonds, and C-H...π and π-π interactions that facilitate self-assembly and the formation of hydrogen-bonded dimers, which implies the appearance of R22(8) graph-set motifs in this interaction. The stability of the dimeric unit is complemented by the formation of strong intramolecular C-S...O interactions of chalcogen character, with an S...O distance of 2.6040 (18) Å. Hirshfeld surface (HS) analysis revealed that O...H/H...O interactions were dominant, accounting for 36.8% of the total HS, and that N-H...N interactions were fundamental to the formation of the dimeric structure. The molecular electrostatic potential (MEP) map showed a maximum energy of 46.73 kcal mol-1 and a minimum of -36.06 kcal mol-1. The interaction energies of molecular pairs around NTFC are highest for those interactions linked by N-H hydrogen bonds. The properties of the NTFC ligand as a potential inhibitor of the DHODH (dihydroorotate dehydrogenase) enzyme were evaluated by molecular docking, showing coupling energies very close to those obtained with the control drug for rheumatoid arthritis, i.e. leflunomide.

UBA1 dysfunction in VEXAS and cancer.

UBA1, an X-linked gene, encodes one of the only two ubiquitin E1 enzymes, playing a pivotal role in initiating one of the most essential post-translational modifications. In late 2020, partial loss-of-function mutations in UBA1 within hematopoietic stem and progenitor cells were found to be responsible for VEXAS Syndrome, a previously unidentified hematoinflammatory disorder predominantly affecting older males. The condition is characterized by severe inflammation, cytopenias, and an association to hematologic malignancies. In this research perspective, we comprehensively review the molecular significance of UBA1 loss of function as well as advancements in VEXAS research over the past four years for each of the VEXAS manifestations - inflammation, cytopenias, clonality, and possible oncogenicity. Special attention is given to contrasting the M41 and non-M41 mutations, aiming to elucidate their differential effects and to identify targetable mechanisms responsible for each of the symptoms. Finally, we explore the therapeutic landscape for VEXAS Syndrome, discussing the efficacy and potential of clone-targeting drugs based on the pathobiology of VEXAS. This includes azacitidine, currently approved for myelodysplastic neoplasms (MDS), novel UBA1 inhibitors being developed for a broad spectrum of cancers, Protein Kinase R-like Endoplasmic Reticulum Kinase (PERK) inhibitors, and auranofin, a long-established drug for rheumatoid arthritis. This perspective bridges basic research to clinical symptoms and therapeutics.

Identification of O-arylated huperzinines as novel cholinergic anti-inflammatory pathway agonists against gout arthritis

Lycodine alkaloids are important natural products with diverse biological effects. In this manuscript, we set out the first structural optimization of the 2-pyridone moiety of Lycodine alkaloid via selective O-arylation under metal-free conditions and obtained a series of potent bioactive molecules against monosodium urate (MSU)-induced IL-1β production. Further investigations demonstrated that these natural product derivatives could activate the neuro-immunomodulatory cholinergic anti-inflammatory pathway (CAP) to block the initial phase of NLRP3 inflammasome activation. Compared with the clinical drugs hydrocortisone and indomethacin, as well as commercially available CAP agonists GTS-21 and pnu282987, 3k and 3q possessed greater potency against MSU-induced IL-1β production. Meanwhile, these molecules possessed less cytotoxicity against promonocytic THP-1 macrophages when compared with colchicine. This work reports a concise strategy for direct modification of 2-pyridone moiety from natural Lycodine alkaloids, and provides novel frameworks for discovering CAP activators and drugs for gout arthritis.

Glucocorticoid sparing effect of Janus Kinase inhibitors compared to biological Disease Modifying Anti-Rheumatic Drugs in rheumatoid arthritis, a single-center retrospective analysis.

Glucocorticoid sparing in rheumatoid arthritis (RA) treatment is crucial to minimizing adverse effects associated with long-term use. Janus kinase inhibitors (JAKi) could potentially offer a more potent glucocorticoid-sparing effect than biological Disease-Modifying Antirheumatic Drugs (bDMARDs). This is a single-center retrospective analysis of RA patients treated with JAKi or bDMARDs. Glucocorticoid tapering, rescue therapy and discontinuation were analyzed through mixed-effects models, Poisson regression, and multivariable logistic regression, respectively, adjusting for baseline disease activity, demographic factors, and treatment line. A total of 716 RA patients treated with JAKi (n = 156) or bDMARDs (n = 560) were evaluated. JAKi treatment was associated with a more rapid reduction in glucocorticoid dose within the first 6 months and 60% higher odds of discontinuation compared with bDMARDs (adjusted odds ratio 1.63, 95% CI 1.02-2.60, p 0.039). Despite a higher baseline glucocorticoid dose, over 50% of JAKi-treated patients discontinued glucocorticoids after 12 months, vs ∼40% for bDMARDs. The need for glucocorticoid rescue therapy was significantly higher in the bDMARD group (rate ratio 2.66 (95% CI, 1.88-3.74)). Our findings indicate that JAK inhibitors facilitate more rapid glucocorticoid tapering compared with bDMARDs in RA patients. These results underscore the potential of JAK inhibitors to reduce long-term glucocorticoid exposure, highlighting their value in RA management strategies, including minimizing glucocorticoid-related adverse effects.

Decision Aid-Led Tapering of Biologic and Targeted Synthetic Disease-Modifying Antirheumatic Drugs in Rheumatoid Arthritis: A Qualitative Study.

To explore the experiences and perspectives of patients and rheumatologists on decision aid (DA)-led tapering of advanced therapy in rheumatoid arthritis (RA). Semistructured interviews were completed with patients and rheumatologists, embedded within a pilot study of DA-led tapering (ie, dose reduction) of biologic disease-modifying antirheumatic drugs (bDMARDs) and targeted synthetic DMARDs (tsDMARDs) in RA. All patients were in sustained (≥ 6 mos) remission and had chosen to reduce their therapy after a DA-led shared decision with their rheumatologist. The rheumatologists included those participating in the pilot (n = 4), and those who were not (n = 8). Reflexive thematic analysis of audiotaped and transcribed interviews identified themes in the group experiences. Patients (n = 10, 6 female) unanimously found the DA easy to understand and felt confident in shared decision making about treatment tapering and managing flares. Rheumatologists' (n = 12, 5 female) perspectives on tapering bDMARDs and tsDMARDs varied widely, from very supportive to completely opposed, and influenced their views on the DA. Rheumatologists expressed concerns about patient comprehension, destabilizing a stable situation, risks of flare, and extending appointment times. Despite their initial reservations about sending the DA to all eligible patients ahead of appointments, 3 of 4 participating rheumatologists adopted this approach during the pilot, which had the benefit of facilitating patient-led conversations. A DA-led strategy for tapering advanced therapy in RA was acceptable to patients and feasible in practice. Sending patients a DA ahead of their appointment facilitated patient-led conversations about tapering.

Childhood Arthritis and Rheumatology Research Alliance Biologic Disease-Modifying Antirheumatic Drug Consensus Treatment Plans for Refractory Moderately Severe Juvenile Dermatomyositis.

The objective was to develop consensus treatment plans (CTPs) for patients with refractory moderately severe juvenile dermatomyositis (JDM) treated with biologic disease-modifying antirheumatic drugs (bDMARDs). The Biologics Workgroup of the Childhood Arthritis and Rheumatology Research Alliance JDM Research Committee used case-based surveys, consensus framework, and nominal group technique to produce bDMARD CTPs for patients with refractory moderately severe JDM. Four bDMARD CTPs were proposed: tumor necrosis factor α (TNFα) inhibitor (adalimumab or infliximab), abatacept, rituximab, and tocilizumab. Each CTP has different options for dosing and/or route. Among 76 respondents, consensus was achieved for the proposed CTPs (93% [67 of 72]) as well as for patient characteristics, assessments, outcome measures, and follow-up. By weighted average, respondents indicated that they would most likely administer rituximab, followed by abatacept, TNFα inhibitor, and tocilizumab. CTPs for the administration of bDMARDs in refractory moderately severe JDM were developed using consensus methodology. The implementation of the bDMARD CTPs will lay the groundwork for registry-based prospective comparative effectiveness studies.

Development of a novel bacterial production system for recombinant bioactive proteins completely free from endotoxin contamination.

Endotoxins, or lipopolysaccharides (LPS), are potent immunostimulatory molecules of critical concern in bacterial recombinant protein expression systems. The gram-negative bacterium Acinetobacter baumannii exhibits an interesting and unique phenotype characterized by the complete loss of LPS. In this study, we developed a novel system for producing recombinant proteins completely devoid of endotoxin contamination using LPS-deficient A. baumannii. We purified endotoxin-free functional green fluorescent protein, which reduced endotoxin contamination by approximately three orders of magnitude, and also purified the functional cytokine tumor necrosis factor (TNF)-α. Additionally, utilization of the Omp38 signal peptide of A. baumannii enabled the extracellular production of variable domain of heavy chain of heavy chain (VHH) antibodies. With these advantages, mNb6-tri-20aa, a multivalent VHH that specifically binds to the spike protein of severe acute respiratory syndrome coronavirus 2, was purified from the culture supernatant, and endotoxin contamination was reduced by a factor of approximately 2 × 105 compared with that in conventional expression systems. A virus neutralization assay demonstrated the functionality of the purified antibody in suppressing viral infections. Moreover, we applied our system to produce ozoralizumab, a multispecific VHH that binds to human TNF-α and albumin and are marketed as a rheumatoid arthritis drug. We successfully purified a functional antibody from endotoxin contamination. This system establishes a new, completely endotoxin-free platform for the expression of recombinant proteins, which distinguishes it from other bacterial expression systems, and holds promise for future applications.

Integrated single-cell and bulk RNA sequencing identifies POSTN as a potential biomarker and therapeutic target for rheumatoid arthritis

BackgroundThis study aimed to integrate single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq data to identify potential biomarkers and therapeutic targets for rheumatoid arthritis (RA). MethodFirstly, we obtained the synovial scRNA-seq data from the Immport database and bulk RNA-seq data from the Gene Expression Omnibus (GEO) database. Then, we used weighted gene correlation network analysis (WGCNA) to screen for module genes most relevant to RA and intersected them with the differentially expressed genes (DEGs) obtained from scRNA-seq and bulk RNA-seq to obtain intersecting genes. Next, we constructed a protein–protein interaction (PPI) network of hub genes using the STRING database and Cytoscape software and validated its expression using external validation cohorts. Finally, we performed immune cell infiltration analysis using CIBERSORT and explored the expression and drug binding activity of key gene using clinical samples and molecular docking, respectively. ResultWe identified six cellular subgroups through dimensionality reduction and clustering, and fibroblasts may be the most important cell cluster in RA based on pseudotime and cell–cell communication analyses. Subsequently, we intersected module genes with DEGs obtained from scRNA-seq and bulk RNA-seq and constructed a PPI network of hub genes (BGN, COL11A1, COL1A1, GUCY1A1, POSTN). In external validation cohorts, POSTN was highly expressed and demonstrated the highest diagnostic performance (AUC = 0.716). In subsequent analyses, we defined POSTN as a key gene and found that its expression level was positively correlated with M2 macrophages in immune cell infiltration analysis. Additionally, POSTN was upregulated in clinical samples and exhibited favorable binding activity with nine anti-rheumatoid arthritis drugs (affinity ≤ −6.0 kcal/mol). ConclusionThrough bioinformatics analysis, clinical sample validation, and molecular docking, we found that POSTN was highly expressed in RA and stably bound to common anti-rheumatoid arthritis drugs, which will provide new insights into potential biomarkers and therapeutic targets for RA.

No difference in clinical parameters and drug retention in PsA patients receiving b/tsDMARD monotherapy versus combination with methotrexate: data from the RABBIT-SpA registry

BackgroundThe potential benefit of methotrexate (MTX) in combination with biologic (b) and targeted synthetic (ts) disease modifying anti-rheumatic drugs (DMARDs) in psoriatic arthritis (PsA) is still a matter of debate.ObjectivesTo...

Rational approach to the prescription of anti-rheumatic drugs in rheumatoid arthritis: a product leaflet-based strategy in Italy.

The treatment of patients with rheumatoid arthritis (RA) has dramatically changed in the past 30 years. Currently, numerous conventional, biologic, and targeted synthetic DMARDs have been licensed and used following recommendations provided by international and national scientific societies. However, the availability of biosimilars and the increasing necessity of savings impacted on the local/national prescription of these drugs. The information provided by data sheet of every single drug is a decisive factor on the choice of a certain treatment merged with the patient's profile. Thus, our purpose was to construct a rational algorithm for the treatment strategy in RA according to costs and the product leaflet of the biologic and targeted-synthetic DMARDs currently licensed in Italy. We used the most recent available recommendations and then we performed a review of the literature considering all the factors that are known to influence drug safety/effectiveness. All these factors were considered in the context of the data sheets of currently available originators and biosimilars.

Novel Approaches for Diagnosis and Herbal Treatment of Rheumatoid Arthritis - A Review

Background: Rheumatoid Arthritis is a chronic autoimmune disease that affects around 0.5% of the population. Limitations in movement may result from joint damage, which causes inflammation of the joint linings and the gradual deterioration of bone and cartilage. Objective: This article gives a summary of the current understanding of the potential pharmacological processes of herbal drugs, risk factors, and innovative experimental approaches in the management of rheumatoid arthritis. Methodology: A thorough literature search will be performed on five computerized databases, such as PubMed, Google Scholar, Science Direct, Elsevier, and Wiley Online Library (WOL), for review papers published between 1975 and 2023. Results: There are concerns about the current generation of potent synthetic rheumatoid arthritis drugs, including toxic side effects and relapses in symptoms upon withdrawal from therapy. Because of these constraints, RA patients are increasingly turning to herbal therapies. Due to the presence of naturally occurring active components in medicinal plants, herbal treatments are utilized to reduce arthritic pain and other symptoms. Conclusion: It emphasizes the growing significance of herbal medicines in the management of RA. Several plants are mentioned in the research as potential treatments for RA because of their antiinflammatory properties.

The rheumatoid arthritis drug auranofin exerts potent anti-lymphoma effect by stimulating TXNRD-mediated ROS generation and inhibition of energy metabolism

Since the survival of lymphoma patients who experience disease progression or relapse remains very poor, new therapeutic approaches and effective drugs are urgently needed. Here we show that auranofin (AF), an anti-rheumatoid drug thought to inhibit thioredoxin reductases (TXNRDs) as its mechanism of action, exhibited potent activity against multiple cancer types, especially effective against B cell lymphoma. Surprisingly, a knockdown of TXNRD1 and TXNRD2 did not cause significant cytotoxicity, suggesting that abrogation of TXNRD enzyme per se was insufficient to cause cancer cell death. Further mechanistic study showed that the interaction of AF with TXNRD could convert this antioxidant enzyme to a ROS-generating molecule via disrupting its electron transport, leading to a leak of electrons that interact with molecular oxygen to form superoxide. AF also suppressed energy metabolism by inhibiting both mitochondria complex II and the glycolytic enzyme GAPDH, leading to a significant depletion of ATP and inhibition of cancer growth in vitro and in vivo. Importantly, we found that the AF-mediated ROS stress could induce PD-L1 expression, revealing an unwanted effect of AF in causing immune suppression. We further showed that a combination of AF with anti-PD-1 antibody could enhance the anticancer activity in a syngeneic immune-competent mouse B-cell lymphoma model. Our study suggests that AF could be a potential drug for lymphoma treatment, and its combination with immune checkpoint inhibitors would be a logical strategy to increase the therapeutic activity.

An effective LC-MS method for the simultaneous determination of a potential anti-rheumatoid arthritis drug, carboxyamidotriazole, and its major metabolite in rat plasma.

Carboxyamidotriazole (CAI) was previously recognized as a well-tolerated anticancer drug. It has also demonstrated significant anti-inflammatory effects in various cell and animal model experiments, prompting its investigation as a potential treatment for rheumatoid arthritis. In this study, the potential biotransformation metabolites of CAI were identified both in vitro and in vivo. A sensitive, specific, and accurate LC-MS method was developed for the quantitative analysis of CAI and its major metabolite, CAI-OH, in rat plasma. CAI, CAI-OH, and telmisartan (used as an internal standard) were separated using a Zorbax SB C18 column. The mobile phase consisted of water (phase A, containing 0.1% formic acid) and acetonitrile (phase B, containing 0.1% formic acid) at a flow rate of 0.2 mL/min. The analytes were examined using a high-resolution mass spectrometer, with detected mass-to-charge ratios of m/z 424.01293 for CAI, m/z 440.00785 for CAI-OH, and m/z 515.24415 for telmisartan. Good linearity was observed within the range of 10-5000 ng/mL. Both inter- and intra-batch precision (relative standard deviation, %) were below 6%, and the accuracy ranged from 94.9% to 106.1%. The analytes remained stable throughout the entire experimental period. This method was successfully applied in a pharmacokinetic study of CAI following oral administration in rats.

Head-to-head trials in rheumatoid arthritis

Head-to-head studies are important to select the optimal treatment in terms of efficacy and side effect profiles when several drugs are available. This article describes all studies comparing the use of disease-modifying antirheumatic drugs (DMARD) in rheumatoid arthritis (RA) in head-to-head studies or in which aDMARD was at least included in an active comparison arm. A total of 23studies comparing DMARDs were identified. These included comparisons of Janus kinase (JAK) inhibitors with methotrexate and with adalimumab as well as the oral surveillance study. There are already an exceptionally large number of head-to-head studies in RA, both for comparisons of efficacy and safety of DMARDs. Nevertheless, more such comparative studies are needed, for example to clarify whether adverse events of tofacitinib observed in the oral surveillance study are specific to the JAK1/JAK3 inhibitor or are aclass effect of all JAK inhibitors.

A Machine Learning Approach for Prediction of CDAI Remission with TNF Inhibitors: A Concept of Precision Medicine from the FIRST Registry.

This study aimed to develop low-cost models using machine learning approaches predicting the achievement of Clinical Disease Activity Index (CDAI) remission 6months after initiation of tumor necrosis factor inhibitors (TNFi) as primary biologic/targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) for rheumatoid arthritis (RA). Data of patients with RA initiating TNFi as first b/tsDMARD after unsuccessful methotrexate treatment were collected from the FIRST registry (August 2003 to October 2022). Baseline characteristics and 6-month CDAI were collected. The analysis used various machine learning approaches including logistic regression with stepwise variable selection, decision tree, support vector machine, and lasso logistic regression (Lasso), with 48 factors accessible in routine clinical practice for the prediction model. Robustness was ensured by k-fold cross validation. Among the approaches tested, Lasso showed the advantages in predicting CDAI remission: with a mean area under the curve 0.704, sensitivity 61.7%, and specificity 69.9%. Predicted TNFi responders achieved CDAI remission at an average rate of 53.2%, while only 26.4% of predicted TNFi non-responders achieved remission. Encouragingly, the models generated relied solely on patient-reported outcomes and quantitative parameters, excluding subjective physician input. While external cohort validation is warranted for broader applicability, this study highlights the potential for a low-cost predictive model to predict CDAI remission following TNFi treatment. The approach of the study using only baseline data and 6-month CDAI measures, suggests the feasibility of establishing regional cohorts to generate low-cost models tailored to specific regions or institutions. This may facilitate the application of regional/in-house precision medicine strategies in RA management.