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Accumulated data implicate that long noncoding RNA (lncRNA) plays a pivotal role in rheumatoid arthritis (RA), potentially serving as a competitive endogenous RNA (ceRNA) for microRNAs (miRNAs). The lncRNA myocardial infarction-associated transcript (MIAT) has been demonstrated to regulate inflammation. However, the role of MIAT in the inflammation of RA remains inadequately explored. This study aims to elucidate MIAT's role in the inflammation of lipopolysaccharide (LPS)-induced macrophages and to uncover the underlying molecular mechanisms. We observed heightened MIAT expression in LPS-induced J774A.1 cells and collagen-induced arthritis mouse models, in contrast to the expression pattern of miR-30a-5p. Silencing MIAT resulted in increased expression of the inflammatory cytokines IL-1β and TNF-α. Simultaneously, MIAT interference significantly impeded macrophage autophagy, evidenced by decreased expression of autophagy-related markers LC3-II and Beclin-1, alongside increased levels of p62 in LPS-induced J774A.1 cells. Notably, MIAT functioned as a ceRNA, sponging miR-30a-5p and exerting a negative regulatory influence on its expression. SOCS1 emerged as a target of miR-30a-5p, modulated by MIAT. Mechanistically, inhibiting miR-30a-5p reversed the impact of MIAT deficiency in promoting LPS-induced inflammation, while SOCS1 knockdown countered the cytokine inhibitory effect induced by silencing miR-30a-5p. In summary, this study indicates that lncRNA MIAT suppresses inflammation in LPS-induced J774A.1 macrophages by stimulating autophagy through the miR-30a-5p/SOCS1 axis. This suggests that MIAT holds promise as a potential therapeutic target for RA inflammation., (© 2024. The Author(s).)

Background: Rheumatoid arthritis is an autoimmune inflammatory disorder that mainly affects bone and cartilage architecture. The continuous use of NSAIDs and DMARDs is associated with severe toxic effects. Therefore, the current study was designed to scrutinize herb-based therapy for the treatment of RA., Aim: To evaluate the anti-arthritic activity of ethanol extract of Ziziphus nummularia using formaldehyde-induced arthritic model in rats and elucidate the possible mechanism for anti-arthritic activity., Materials and Methods: Anti-arthritic activity of ETZN was studied at three oral doses, i.e., 200, 400, and 600 mg/kg. Selected doses were studied using various clinical parameters viz. paw volume, inflammatory index, motility test, stair test, anti-nociceptive efficacy, walking track analysis, and motor activity) from day 1 to day 10. On the last day, the animals were killed for the evaluation of hematological parameters, oxidative stress biomarkers, and histological and radiographic studies of the hind paw., Results: Treatment with ETZN 400 mg/kg and 600 mg/kg markedly elicited a significant reduction in paw volume, inflammatory index, and nociceptive action compared to diseased animals. Furthermore, the anti-inflammatory activity was confirmed by increased latency of pain threshold in thermal and mechanical algesia models. The anti-arthritic activity is mainly attributed to a reduction in oxidative stress biomarkers as well as restoration of haematological profile in treated animals when compared to diseased animals. Lastly, the anti-arthritic potential was confirmed by histological and radiological analysis which revealed a marked reduction in inflammatory cells and bone destruction as compared to diseased animals., Conclusion: The study revealed that ETZN exhibits significant anti-arthritic activity via modulation of oxidative stress biomarkers, restoration of hematological profile, and reduction in bone erosion., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Rheumatoid arthritis (RA) is the most common chronic inflammatory disease, primarily affecting the joints and with stromal tissue dysregulation causing chronic inflammation and joint destruction. Rutin is a natural flavonoid with potential therapeutic properties in chronic destructive conditions including rheumatoid diseases. In this study, the protective effects of rutin nanoformulation in an animal model of rheumatoid arthritis caused by Freund's complete adjuvant (FCA) were investigated. Sixty male rats were randomly divided into ten groups including normal, negative control, prednisolone 10 mg/kg (positive control), 3 doses of rutin (15, 30, 45mg/kg), rutin nanoparticles (15, 30, 45 mg/kg), and nanoparticle without rutin, for 28 days. Different behavioral parameters including the open field test, acetone drop test, hot plate test, Von Frey test, and inclined plane test were evaluated. Serum levels of glutathione (GSH), catalase, and nitric oxide as well as histopathological analyses were measured in different groups. Also, matrix metalloproteinase (MMP)-2 and MMP-9 activity were appraised by gelatin zymography. The injection of FCA prolonged the rats' immobility duration in comparison to the control group. Rheumatoid arthritis induction also increased nitric oxide and decreased GSH and catalase levels, while these effects were reversed in the groups that received nanoparticles containing rutin and prednisolone. Rutin nanoparticles suppressed MMP-9 and activated MMP-2. Also, this rutin drug delivery system plays a significant role in the improvement of histopathological symptoms. Considering the improvement of behavioral and tissue symptoms and the modulation of the level of inflammatory cytokines, nanoparticles containing rutin can be proposed as a suitable approach in the management of patients with rheumatoid arthritis., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Ethnopharmacological Relevance: Viscum coloratum (Kom.) Nakai has been traditionally used in China for nearly a thousand years to treat rheumatic diseases. However, its efficacy and mechanisms in treating rheumatoid arthritis (RA) have not been demonstrated., Aim of the Study: To investigate the anti-arthritic effects and molecular mechanisms of Viscum coloratum (Kom.) Nakai on collagen-induced arthritic mice through network pharmacology technology and experimental validation., Materials and Methods: First, the main ingredients of the extract of Viscum coloratum (Kom.) Nakai (EVC) were identified through chemical composition characterization using Ultra Performance Liquid Chromatography Tandem Mass Spectrometry (UPLC-MS). Then, the collagen-induced arthritis (CIA) model was established in DBA/1 J mice and the ameliorative effects of EVC on the progression of CIA mice were evaluated by oral treatment with different doses of the EVC for 28 days. After that, cytokine antibody microarray assay was used to detect the levels of multiple inflammation-related cytokines and chemokines in each group, and performed Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genome (KEGG) enrichment analysis. Subsequently, the potential target for the effective chemical components of EVC in treating RA was identified using various databases. Additionally, a drug-disease target protein-protein interaction network (PPI) was conducted using Cytoscape for visualization and clustering, while GO and KEGG enrichment analyses were performed with the Metascape database. Finally, identified phenotypes and targets by network pharmacology analysis were experimentally validated in vivo., Results: Treatment with EVC significantly suppressed the severity of CIA with a dramatic reduction of paw swelling, arthritis index, levels of IgGs (IgG, IgG1, IgG2a, and IgG2b), multi-inflammation-related cytokines and chemokines on the progression of CIA. Histopathological examinations showed EVC could markedly inhibit inflammatory cell infiltration, tartrate-resistant acid phosphatase (TRAP) activity of osteoclast, and bone destruction. Furthermore, GO and KEGG enrichment analyses revealed that EVC could ameliorate RA by inhibiting osteoclast differentiation and regulating multiple signaling pathways including Osteoclast differentiation, IL-17, and TNF. PPI network analysis demonstrated that AKT1, MMP9, MAPK3, and other genes were highly related to EVC in treating RA. Finally, we proved that EVC could inhibit the expression of NFTAc1, MMP9, Cathepsin K, and AKT which were closely related to osteoclast activity., Conclusions: EVC could treat RA through multiple components, multiple targets, and multiple pathways. The present study demonstrated the therapeutic efficacy of EVC and its molecular mechanisms in treating RA, indicating that it would be a potent candidate as a novel botanical drug for further investigation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Rheumatoid arthritis (RA) is a chronic autoimmune disease lacking a definitive cure. Although conventional treatments such as dexamethasone and methotrexate are prevalent, their usage is constrained by potential adverse effects. Melittin (MLT) has emerged as a promising natural anti-rheumatic drug; however, studies focusing on the role of MLT in modulating the expression and metabolism of RA-related genes are scarce., Method: Arthritis was induced in rats using Complete Freund's Adjuvant (CFA), followed by MLT injections for treatment. Post-treatment, the inflammatory status of each group was assessed, and the mechanistic underpinnings of MLT's ameliorative effects on RA were elucidated through transcriptomic and metabolomic analyses. Additionally, this study conducted qRT-PCR validation of key therapeutic genes and characterized the molecular docking interactions of MLT with key receptor proteins (TNF-α and IL-1β) using the AutoDock Vina software., Result: MLT significantly diminished redness and swelling in affected joints, ameliorated inflammatory cell infiltration, and mitigated joint damage. Integration of transcriptomic and metabolomic data revealed that MLT predominantly regulated the transcription levels of pathways and genes related to cytokines and immune responses, and the metabolic biomarkers of Sphingomyelin, fatty acid, and flavonoid. qRT-PCR confirmed MLT's downregulation of inflammation-related genes such as Il6, Jak2, Stat3, and Ptx3. Molecular docking simulations demonstrated the stable binding of MLT to TNF-α and IL-1β., Conclusion: MLT demonstrated significant efficacy in alleviating RA. This study provides a comprehensive summary of MLT's impact on gene expression and metabolic processes associated with RA., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Rheumatoid arthritis (RA) is a chronic and systemic autoimmune disease characterized by synovial inflammation and joint destruction. Despite progress in RA therapy, it remains difficult to achieve long-term remission in RA patients. Phosphodiesterase 3B (Pde3b) is a member of the phosphohydrolyase family that are involved in many signal transduction pathways. However, its role in RA is yet to be fully addressed., Methods: Studies were conducted in arthritic DBA/1 mice, a suitable mouse strain for collagen-induced rheumatoid arthritis (CIA), to dissect the role of Pde3b in RA pathogenesis. Next, RNAi-based therapy with Pde3b siRNA-loaded liposomes was assessed in a CIA model. To study the mechanism involved, we investigated the effect of Pde3b knockdown on macrophage polarization and related signaling pathway., Results: We demonstrated that mice with CIA exhibited upregulated Pde3b expression in macrophages. Notably, intravenous administration of liposomes loaded with Pde3b siRNA promoted the macrophage anti-inflammatory program and alleviated CIA in mice, as indicated by the reduced inflammatory response, synoviocyte infiltration, and bone and cartilage erosion. Mechanistic study revealed that depletion of Pde3b increased cAMP levels, by which it enhanced PKA-CREB-C/EBPβ pathway to transcribe the expression of anti-inflammatory program-related genes., Conclusion: Our results support that Pde3b is involved in the pathogenesis of RA, and Pde3b siRNA-loaded liposomes might serve as a promising therapeutic approach against RA., Competing Interests: The authors declare that they have no conflict of interest., (© 2024 Chen et al.)

Objective: The efficacy and safety of sarilumab (SARI) were investigated in real-world clinical practice in Japan., Method: Subjects were 121 rheumatoid arthritis (RA) patients in 23 medical institutions in Fukuoka Prefecture, Japan, who started treatment with SARI between May 2018 and November 2021. Data on the SARI starting dose, patients' baseline characteristics, disease activity, and blood test data at the start of treatment, as well as follow-up data on the SARI dose, disease activity, and adverse events until Week 52. Safety and the continuation rate calculated by the Kaplan-Meier method were evaluated, and the effectiveness of treatment at 1 year was assessed using the clinical disease activity index (CDAI). Patients' baseline characteristics for which significant differences were evident were adjusted with a propensity score by using the inverse probability of treatment-weighting (IPTW) method., Results: The continuation rate at Week 52 was 66.1%. The CDAI showed significant improvement from Week 4 that was maintained until Week 52. Comparisons conducted after IPTW adjustment for patients' baseline characteristics for which significant differences were evident revealed no significant differences at Week 52 between the groups classified by higher or lower body mass index (BMI) (p = 0.231), serious comorbidities (p = 0.973), MTX use (p = 0.321), or prior treatment with ≤ 1 or ≥ 2 biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) (p = 0.765)., Conclusions: The results showed that the efficacy of SARI is not affected by BMI, comorbidities, MTX use, or the number of prior b/tsDMARDs, and no new safety concerns were apparent. Key Points • This is the first real-world clinical study to report on the efficacy and safety of SARI in Japan. The results of this study indicate that the efficacy of SARI was not affected by BMI, comorbidities, MTX use, or number of previous b/tsDMARDs. • It was shown that SARI can be used in a Japanese population without any new side effects., (© 2024. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

There is no curative treatment for chronic auto-inflammatory diseases including rheumatoid arthritis, and current treatments can induce off-target side effects due to systemic immune suppression. This work has previously shown that dexamethasone-pulsed tolerogenic dendritic cells loaded with the arthritis-specific antigen human proteoglycan can suppress arthritis development in a proteoglycan-induced arthritis mouse model. To circumvent ex vivo dendritic cell culture, and enhance antigen-specific effects, drug delivery vehicles, such as liposomes, provide an interesting approach. Here, this work uses anionic 1,2-distearoyl-sn-glycero-3-phosphoglycerol liposomes with enhanced loading of human proteoglycan-dexamethasone conjugates by cationic lysine tetramer addition. Antigen-pulsed tolerogenic dendritic cells induced by liposomal dexamethasone in vitro enhanced antigen-specific regulatory T cells to a similar extent as dexamethasone-induced tolerogenic dendritic cells. In an inflammatory adoptive transfer model, mice injected with antigen-dexamethasone liposomes have significantly higher antigen-specific type 1 regulatory T cells than mice injected with antigen only. The liposomes significantly inhibit the progression of arthritis compared to controls in preventative and therapeutic proteoglycan-induced arthritis mouse models. This coincides with systemic tolerance induction and an increase in IL10 expression in the paws of mice. In conclusion, a single administration of autoantigen and dexamethasone-loaded liposomes seems to be a promising antigen-specific treatment strategy for arthritis in mice., (© 2024 The Authors. Advanced Healthcare Materials published by Wiley‐VCH GmbH.)

Rheumatoid arthritis (RA) is an autoimmune disease suffered by millions of people worldwide. It can significantly affect the patient's quality of life by damaging not only the joints but also organs such as the lungs and the heart. RA is normally treated using nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, disease-modifying antirheumatic drugs (DMARDs), and biologics. These active agents often cause side effects and offer low efficacy due to their lack of specificity and limited retention time. In an attempt to improve RA treatments, hydrogel-based systems have been proposed as drug delivery carriers. Due to their exceptional adaptability and biocompatibility, hydrogels have the potential of enhancing the delivery of RA therapy through different administration routes in an efficient and effective manner. In this review, we explore the application of hydrogel systems as potential carriers in RA treatment. Additionally, we discuss recent work in the field and highlight the required hydrogel properties, depending on the administration route. The outstanding potential of hydrogel systems as carriers for RA was demonstrated; however, there is extensive research yet to be done to improve available treatments for RA., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Mesenchymal stem cell exosome (MSCs-exo) is a class of products secreted by mesenchymal stem cells (MSCs) that contain various biologically active substances. MSCs-exo is a promising alternative to MSCs due to their lower immunogenicity and lack of ethical constraints. Ginsenoside Rh2 (Rh2) is a hydrolyzed component of the primary active substance of ginsenosides. Rh2 has a variety of pharmacological functions, including anti-inflammatory, anti-tumor, and antioxidant. Studies have demonstrated that gut microbiota and metabolites are critical in developing rheumatoid arthritis (RA). In this study, we constructed a collagen-induced arthritis (CIA) model in rats. We used MSCs-exo combined with Rh2 to treat CIA rats. To observe the effect of MSCs-exo combined with Rh2 on joint inflammation, rat feces were collected for 16 rRNA amplicon sequencing and untargeted metabolomics analysis. The results showed that the arthritis index score and joint swelling of CIA rats treated with MSCs-exo in combination with Rh2 were significantly lower than those of the model and MSCs-exo alone groups. MSCs-exo and Rh2 significantly ameliorated the disturbed gut microbiota in CIA rats. The regulation of Candidatus_Saccharibacteria and Clostridium_XlVb regulation may be the most critical. Rh2 enhanced the therapeutic effect of MSCs-exo compared with the MSCs-exo -alone group. Furthermore, significant changes in gut metabolites were observed in the CIA rat group, and these differentially altered metabolites may act as messengers for host-microbiota interactions. These differential metabolites were enriched into relevant critical metabolic pathways, revealing possible pathways for host-microbiota interactions., Competing Interests: Declaration of Competing Interest The authors declared no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Introduction: Rheumatoid arthritis (RA) is a systemic, inflammatory disease affecting multiple organs and causing physical disability over time., Objective: The primary objective was to evaluate treatment persistence to subcutaneous tocilizumab (TCZ-SC). Additionally, treatment effects on persistence and their associations with clinical and patient-reported outcomes were assessed., Method: We performed a multicenter, non-interventional, 52-week observational study on 222 patients with moderate or severe RA. Clinical outcomes were evaluated by using disease activity score for 28 joints (DAS28) and European League Against Rheumatism (EULAR) response, and patients' perceptions were evaluated by using Health Assessment Questionnaire (HAQ), Visual Analog Scale (VAS) for pain, and patient global assessment (PtGA) of disease activity. Safety was assessed throughout the study., Results: The mean age of the overall cohort was 62.2 ± 12.3 years, and 83.8% were females. Persistence to TCZ-SC was 89.6% at week 24 and 85.1% at week 52 in the overall cohort with slightly increased persistence in the combination group. At week 52, changes from the baseline were - 2.68 in DAS28, - 0.76 in HAQ, - 43.21 in VAS pain, and - 41.66 in PtGA (p < 0.0001 for all). Moderate and good EULAR response was achieved in 83.2% of patients. Non-serious and serious adverse events occurred in 18.5% and 3.2% of the participants, respectively., Conclusions: The current study confirms the favorable safety and effectiveness of TCZ-SC as well as its acceptability by RA patients in Greece, with sustained high persistence rates up to 52 weeks. TCZ-SC offers a sustainable treatment response in RA. Key Points • Based upon clinical and patient-reported outcomes, TCZ-SC is a highly effective and safe treatment modality in patients with moderate-to-severe RA. • Persistence to TCZ-SC was high throughout the study, both as monotherapy and in combination with csDMARDs. • TCZ-SC is effective both as monotherapy and when used in combination with other csDMARDs regardless of the line of treatment., (© 2024. The Author(s).)

Background: Per- and polyfluoroalkyl substances (PFAS) are known environmental contaminants with immunosuppressive properties. Their connection to rheumatoid arthritis (RA), a condition influenced by the immune system, is not well studied. This research explores the association between PFAS exposure and RA prevalence., Methods: This research utilized data from the NHANES, encompassing a sample of 10,496 adults from the 2003-2018 cycles, focusing on serum levels of several PFAS. The presence of RA was determined based on self-reports. This study used multivariable logistic regression to assess the relationship between individual PFAS and RA risk, adjusting for covariates to calculate odds ratios (ORs). The combined effects of PFAS mixtures were evaluated using BKMR, WQS regression, and quantile g-computation. Additionally, sex-specific associations were explored through stratified analysis., Results: Higher serum PFOA (OR = 0.88, 95% CI: 0.79, 0.98), PFHxS (OR = 0.91, 95% CI: 0.83, 1.00), PFNA (OR = 0.87, 95% CI: 0.77, 0.98), and PFDA (OR = 0.89, 95% CI: 0.81, 0.99) concentration was related to lower odds of RA. Sex-specific analysis in single chemical models indicated the significant inverse associations were only evident in females. BKMR did not show an obvious pattern of RA estimates across PFAS mixture. The outcomes of sex-stratified quantile g-computation demonstrated that an increase in PFAS mixture was associated with a decreased odds of RA in females (OR: 0.76, 95% CI: 0.62, 0.92). We identified a significant interaction term of the WQS*sex in the 100 repeated hold out WQS analysis. Notably, a higher concentration of the PFAS mixture was significantly associated with reduced odds of RA in females (mean OR = 0.93, 95% CI: 0.88, 0.98)., Conclusions: This study indicates potential sex-specific associations of exposure to various individual PFAS and their mixtures with RA. Notably, the observed inverse relationships were statistically significant in females but not in males. These findings contribute to the growing body of evidence indicating that PFAS may have immunosuppressive effects., (© 2024. The Author(s).)

Objectives: To investigate the impact of disease activity and treatment with disease-modifying antirheumatic drugs (DMARDs) on all-cause mortality in patients with rheumatoid arthritis and prevalent interstitial lung disease (RA-ILD)., Methods: Patients with RA-ILD were selected from the biologics register Rheumatoid Arthritis: Observation of Biologic Therapy (RABBIT). Using time-varying Cox regression, the association between clinical measures and mortality was investigated. The impact of DMARDs was analysed by (1) Cox regression considering cumulative exposure (ie, treatment months divided by total months) and (2) time-varying Cox regression as main approach (treatment exposures at monthly level)., Results: Out of 15 566 participants, 381 were identified as RA-ILD cases with 1258 person-years of observation and 2.6 years median length of follow-up. Ninety-seven patients (25.5%) died and 34 (35.1%) of these were not receiving DMARD therapy at the time of death. Higher inflammatory biomarkers but not swollen and tender joint count were significantly associated with mortality. Compared with tumour necrosis factor inhibitors (TNFi), non-TNFi biologic DMARDs (bDMARDs) exhibited adjusted HRs (aHRs) for mortality below 1, lacking statistical significance. This finding was stable in various sensitivity analyses. Joint aHR for non-TNFi biologics and JAKi versus TNFi was 0.56 (95% CI 0.33 to 0.97). Receiving no DMARD treatment was associated with a twofold higher mortality risk compared with receiving any DMARD treatment, aHR 2.03 (95% CI 1.23 to 3.35)., Conclusions: Inflammatory biomarkers and absence of DMARD treatment were associated with increased risk of mortality in patients with RA-ILD. Non-TNFi bDMARDs may confer enhanced therapeutic benefits in patients with RA-ILD., Competing Interests: Competing interests: AK: consulting fees: AbbVie, Gilead, Boehringer Ingelheim, Novartis, Janssen, UCB, Lilly and payment for lectures, presentations: AbbVie, Gilead, Boehringer Ingelheim, Roche, Novartis, Janssen, UCB, Lilly and support for attending meetings and/or travel: AbbVie, Boehringer Ingelheim and participation on a Data Safety Monitoring Board or Advisory Board: Pfizer and leadership or fiduciary role in other board, society, commitee or advocacy group, paid or unpaid: German Society for Rheumatology. CK: payment for lectures, presentations: AbbVie, AstraZeneca, BMS, Boehringer Ingelheim, Celltrion, Galapagos, GSK, Hexal, Janssen, Lilly, Medical School Hamburg, MSD, Novartis, Pfizer, Roche, Sanofi, UCB and participation on a Data Safety Monitoring Board or Advisory Board: Boehringer Ingelheim, Novartis. H-ML: grants or contracts from any entity: Pfizer, Novartis and consulting fees: AbbVie, AstraZeneca, Actelion, Amgen, Bayer Vital, Boehringer Ingelheim, BMS, Celgene, GSK, Gilead/Galapagos, Janssen, Lilly, Medac, MSD, Novartis, Pfizer, Roche/Chugai, Sanofi, UCB and payment for lectures, presentations: AbbVie, AstraZeneca, Actelion, Amgen, Bayer Vital, Boehringer Ingelheim, BMS, Celgene, GSK, Gilead/Galapagos, Janssen, Lilly, Medac, MSD, Novartis, Pfizer, Roche/Chugai, Sanofi, UCB and support for attending meetings and/or travel: AbbVie, AstraZeneca, Boehringer Ingelheim, BMS, Celgene, GSK, Gilead/Galapagos, Janssen, Lilly, MSD, Novartis, Pfizer, Roche/Chugai, Sanofi, USB and participation on a Data Safety Monitoring Board or Advisory Board: AbbVie, AstraZeneca, Amgen, Boehringer Ingelheim, BMS, Celgene, GSK, Gilead/Galapagos, Janssen, Lilly, Medac, MSD, Novartis, Pfizer, Roche/Chugai, Sanofi, UCB. AS: lecture honoraria from AbbVie, Amgen, BMS, Celltrion, MSD, Lilly, Pfizer, Roche, UCB., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Adalimumab (Humira) is a human monoclonal antibody that belongs to the tumor necrosis factor (TNF) alpha antagonist class of medications. Central Nervous System (CNS) demyelination is a rare side effect of adalimumab, and only a few cases have been reported in the literature of patients who developed multiple sclerosis or other demyelinating patterns after using adalimumab. In this report, we present a case of CNS demyelination in a patient with rheumatoid arthritis that developed a few months after using adalimumab. Performing brain MRI for asymptomatic individuals prior to initiating anti-TNF alpha agents to exclude a pre-existing demyelinating disease may be worthwhile. Routine brain MRI for monitoring and surveillance may facilitate detecting cases early and avoid the development of permanent neurological disability. Further studies are needed to clarify the neurological safety of anti-TNF alpha agents., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by progressive joint inflammation, resulting in cartilage destruction and bone erosion. It was reported that low-dose radiation modulates immune disease. Here, we investigated whether low-dose whole-body irradiation has preventive and therapeutic effects in collagen-induced RA (CIA) mouse models. Fractionated low-dose irradiation (0.05 Gy/fraction, total doses of 0.1, 0.5 or 0.8 Gy) was administered either concurrently with CIA induction by Type II collagen immunization (preventive) or after CIA development (therapeutic). The severity of CIA was monitored using two clinical parameters, paw swelling and redness. We also measured total Immunoglobulin G (IgG) and inflammatory cytokines (interleukine (IL)-6, IL-1β and tumor necrosis factor-alpha (TNF-α)) in the serum by enzyme-linked immunosorbent assay, and we evaluated histological changes in the ankle joints by immunohistochemistry and hematoxylin and eosin staining. Low-dose irradiation reduced CIA clinical scores by up to 41% in the preventive model and by 28% in the therapeutic model, while irradiation in the preventive model reduced the typical CIA incidence rate from 82 to 56%. In addition, low-dose irradiation in the preventive model decreased total IgG by up to 23% and decreased IL-1β and TNF-α by 69 and 67%, and in the therapeutic model, decreased total IgG by up to 35% and decreased IL-1β and IL-6 by 59 and 42% with statistical significance (P < 0.01, 0.05 and 0.001). Our findings demonstrate that low-dose radiation has preventive and therapeutic anti-inflammatory effects against CIA by controlling the immune response, suggesting that low-dose radiation may represent an alternative therapy for RA, a chronic degenerative immune disease., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

This case-control study investigated the link between dietary branched-chain amino acids (BCAAs) and the risk and severity of rheumatoid arthritis (RA). We assessed dietary BCAA intake in 95 RA patients and 190 matched controls using a food frequency questionnaire. We also assessed the disease severity using the disease activity score 28 (DAS-28), ESR, VAS, morning stiffness, and tender and swollen joints. Higher BCAA intake, expressed as a percentage of total protein, was significantly associated with increased risk of RA for total BCAAs (OR 2.14, 95% CI 1.53-3.00, P < 0.001), leucine (OR 2.40, 95% CI 1.70-3.38, P < 0.001), isoleucine (OR 2.04, 95% CI 1.46-2.85, P < 0.001), and valine (OR 1.87, 95% CI 1.35-2.59, P < 0.001). These associations remained significant even after adjusting for potential confounders (P < 0.001). However, BCAA intake did not show any significant association with RA severity in either crude or multivariate models (P > 0.05). Our findings suggest that higher dietary BCAA intake may contribute to the development of RA, but further research is needed to confirm these observations and explore the underlying mechanisms., (© 2024. The Author(s).)

Objectives: This observational study compares the effectiveness of baricitinib (BARI), a targeted synthetic disease-modifying antirheumatic drug (tsDMARD), with alternative biological DMARDs (bDMARDs) in patients with rheumatoid arthritis (RA), from a prospective, longitudinal cohort., Methods: We compared patients initiating a treatment course (TC) of BARI, tumour necrosis factor inhibitors (TNFi) or bDMARDs with other modes of action (OMA), during a period when all these DMARDs were available in Switzerland. The primary outcome was drug maintenance; secondary outcomes included discontinuation rates related specifically to ineffectiveness and adverse events. We further analysed rates of low disease activity (LDA) and remission (REM) at 12 months and drug maintenance in bDMARD-naïve and tsDMARD-naïve population., Results: A total of 1053 TCs were included: 273 on BARI, 473 on TNFi and 307 on OMA. BARI was prescribed to older patients with longer disease duration and more previous treatment failures than TNFi. Compared with BARI, the adjusted drug maintenance was significantly shorter for TNFi (HR for discontinuation: 1.76; 95% CI, 1.32 to 2.35) but not compared with OMA (HR 1.27; 95% CI, 0.93 to 1.72). These results were similar in the b/tsDMARD-naïve population. The higher discontinuation of TNFi was mostly due to increased discontinuation for ineffectiveness (HR 1.49; 95% CI, 1.03 to 2.15), with no significant differences in drug discontinuation for adverse events (HR 1.46; 95% CI, 0.83 to 2.57). The LDA and REM rates at 12 months did not differ significantly between the three groups., Conclusions: BARI demonstrated a significantly higher drug maintenance compared with TNFi, mainly due to lower drug discontinuations for ineffectiveness. We found no difference in drug maintenance between BARI and OMA. Clinical outcomes did not differ between the three groups. Our results suggest that BARI is an appropriate therapeutic alternative to bDMARDs in the management of RA., Competing Interests: Competing interests: BTPG has been once a paid speaker (Eli Lilly) and participated in the advisory board (Janssen). CP is employed by Eli Lilly and holds stock options (Eli Lilly and Company). CL is employed by Eli Lilly and holds stock options (Eli Lilly and Novartis). AF has received grants or contracts (Eli Lilly, Pfizer, AbbVie, Gilead and BMS), consulting fees (AstraZeneca, AbbVie, Pfizer and Gilead) and honorary payments (BMIS, AbbVie, Eli Lilly, Pfizer and MSD) and participated in advisory boards (Astra-Zeneca, Gilead, Novartis, AbbVie, Eli Lilly, Pfizer, J&J, Mylan and UCB). DM, RA, RM and DSC have no conflicts of interest to disclose., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The present study was conducted to scrutinize the pharmacological effect of Estragole (ESG) against CFA-induced arthritis in rats. The rats underwent induction of arthritis using the administration of CFA and after that, the rats were randomly divided into five different groups, where three groups correspond to diverse dosages of ESG, and the other two were control and CFA-arthritic control. Results of the study suggested that ESG in a dose-dependent manner, improves body weight and arthritis score of rats as evidenced by reduction of hind-paw volume. ESG also improved the antioxidant status of rats by reducing MDA levels and enhancing the concentration of endogenous antioxidants SOD and GPx. The level of pro-inflammatory cytokines was also found to be reduced in the case of ESG treated group as compared to CFA-group. In a western blot analysis, ESH showed downregulation of p-JAK-2/STAT-3. The study provided concrete evidence for the protective effect of ESG against rheumatoid arthritis in rats.

Background: There are currently no validated criteria that entirely explain or predict response to methotrexate (MTX) treatment in rheumatoid arthritis (RA). We tried to identify the connection between three variants (RFC1 G80A (rs1051266), TYMS 2R/3R (rs34743033), and ATIC C347G (rs2372536)) in the folate pathway of MTX metabolism and the response to MTX monotherapy in a cohort of RA cases., Methods: A prospective study on 100 RA patients on MTX monotherapy was performed. Disease activity was measured at the start of treatment and 6 months after treatment with MTX. The patients were then split into two groups: those who responded to the treatment and those who did not. The molecular genetic study for the RFC1 (G80A) variant was employed via the PCR-restriction fragment length polymorphism (PCR-RFLP) technique, the ATIC (C347G) variant was performed using TaqMan allelic discrimination real-time PCR, and the tandem repeat sequences of TYMS (2R/3R) were amplified by conventional PCR and detected by agarose gel electrophoresis., Results: The genotype distribution of RFC-1 (G80A) showed significant variations among non-responders and responders in the recessive genetic model. A significant difference was found in TYMS (2R/3R) in the dominant and heterozygous genetic models. However, ATIC (C347G) genotype frequency did not exhibit substantial link with drug response in all genetic models. Furthermore, the genotype and allele rates of the analyzed variants did not show any significant association with adverse events in all genetic models., Conclusion: The 80AA genotype of RFC-1 G80A and the 2R/3R or 3R/3R genotypes of TYMS 2R/3R are more vulnerable to the good consequences of MTX therapy. Key Points • Current recommendations support the gold standard role of MTX as a first-line monotherapy for RA patients. However, up to 40% of RA patients do not respond or exhibit partial response to MTX. • Persistent disease activity due to treatment unresponsiveness will affect the long-term outcomes in RA patients. • We aimed, through molecular genetic study, to identify the connection between three variants in the folate pathway of MTX metabolism and the response to methotrexate monotherapy in a cohort of RA patients., (© 2024. The Author(s).)

Ethnopharmacological Relevance: Iris Kashmiriana Baker, a traditional medicinal plant, is native to Asia, found in India, Nepal, Afghanistan, Pakistan, as name indicates majorly it's found in Kashmir region of India. Ethnopharmacologically this plant has been used there for the management of joint pain, but there was no scientific literature available. This species also comes under critically endangered species., Aim of the Study: The current study aims to evaluate the effect of Iris kashmiriana Baker against nociception and rheumatoid arthritis in experimental rats with In-silico model., Material and Methods: Various extracts of the plant were investigated for their in-vitro antioxidant activity. Acute inflammation and FCA induced in rat model, then acetic acid-induced writhing in mice were used. These anti-rheumatic results were justified by the computational method., Results: The total phenolic and flavonoid concentration of HE extracts were found to be 95.30 ± 2.80 mg/g and 18.18 ± 5.88 mg/g respectively. IC 50 and maximum inhibition of HE extracts against DPPH and H 2 O 2 were also effective. Among different doses, 400 mg/kg of HE extracts showed significant (p<0.001) reduction in acute inflammation (16.42 %), in analgesic activity, the HE extract was found statistically (p<0.001) reduced (60.15 %) and in arthritis model, maximum inflammation reduced (25.9%) was found with hydro ethanol extract and statistical significant (p<0.001). and the paw thickness was reduced (27.4 %). Antioxidant activity of HE extract was found to be optimum (37.01%, p<0.001), Superoxide dismutase concentration was found to be optimum (65.12%, p<0.001). In Histopathology, HE 400 mg/kg showed mild inflammation only. The weight of the thymus and spleen were also determined and the HE 400 mg/kg extract inhibited the increase in weight of these organs compared with positive group (28.26 %, and 25.11 %), respectively., Conclusion: Among all the different extracts and various doses, the iris kashmiriana Baker hydro-ethanolic (60:40) 400 mg/kg extract showed the best response among all different extracts., Competing Interests: Declaration of competing interest Authors show no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objective: To evaluate and compare the use of oral glucocorticoids with three classes of bDMARDs in patients with rheumatoid arthritis (RA)., Methods: We included patients from 13 observational registries treated with a TNF-inhibitor, abatacept or tocilizumab and with available information on the use of oral glucocorticoids. The main outcome was oral glucocorticoid withdrawal. A McNemar test was used to analyse the change in the use of glucocorticoids after 1 year. Kaplan-Meier estimates and Cox regressions, adjusted for patient, treatment, and disease characteristics, were used to evaluate glucocorticoid discontinuation in patients with glucocorticoids at baseline. Because of heterogeneity, analyses were done by registers and pooled using random-effects meta-analysis., Results: A total of 12,334 participants treated with TNF-inhibitors, 2100 with tocilizumab and 3229 with abatacept were included. At one-year, oral glucocorticoid use decreased in all treatment groups (odds ratio for stopping vs. starting of 2.19 [95% CI 1.58; 3.04] for TNF-inhibitors, 2.46 [1.39; 4.35] for tocilizumab; 1.73 [1.25; 2.21] for abatacept). Median time to glucocorticoid withdrawal was ≈2 years or more in most countries, with a gradual decrease over time. Compared to TNF-inhibitors, crude hazard ratios of glucocorticoid discontinuation were 0.65[0.48-0.87] for abatacept, and 1.04 [0.76-1.43] for tocilizumab, and adjusted hazard ratios were 1.1 [0.83-1.47] for abatacept, and 1.30 [0.96-1.78] for tocilizumab., Conclusion: After initiation of a bDMARD, glucocorticoid use decreased similarly in all treatment groups. However, glucocorticoid withdrawal was much slower than advocated by current international guidelines. More effort should be devoted to glucocorticoid tapering when low disease activity is achieved., (Copyright © 2023 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Objective: We investigated methotrexate safety and the influence of dose on efficacy outcomes in combination with three different biologic treatments and with active conventional treatment (ACT) in early rheumatoid arthritis (RA)., Methods: This post hoc analysis included 812 treatment-naïve patients with early RA who were randomized (1:1:1:1) in the NORD-STAR trial to receive methotrexate in combination with ACT, certolizumab-pegol, abatacept, or tocilizumab. Methotrexate safety, doses, and dose effects on Clinical Disease Activity Index (CDAI) remission were assessed after 24 weeks of treatment., Results: Compared with ACT, the prevalence of methotrexate-associated side effects was higher when methotrexate was combined with tocilizumab (hazard ratio [HR] 1.48, 95% confidence interval [CI] 1.20-1.84) but not with certolizumab-pegol (HR 0.99, 95% CI 0.79-1.23) or with abatacept (HR 0.93, 95% CI 0.75-1.16). With ACT as the reference, the methotrexate dose was significantly lower when used in combination with tocilizumab (β -4.65, 95% CI -5.83 to -3.46; P < 0.001) or abatacept (β -1.15, 95% CI -2.27 to -0.03; P = 0.04), and it was numerically lower in combination with certolizumab-pegol (β -1.07, 95% CI -2.21 to 0.07; P = 0.07). Methotrexate dose reductions were not associated with decreased CDAI remission rates within any of the treatment combinations., Conclusion: Methotrexate was generally well tolerated in combination therapies, but adverse events were a limiting factor in receiving the target dose of 25 mg/wk, and these were more frequent in combination with tocilizumab versus ACT. On the other hand, methotrexate dose reductions were not associated with decreased CDAI remission rates within any of the four treatment combinations at 24 weeks., (© 2023 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Introduction: There are conflicting findings on the link between liver fibrosis and cumulative methotrexate dosages. We aimed to determine the frequency of liver fibrosis in rheumatoid arthritis patients treated with methotrexate and to identify its associated factors., Methods: We conducted a cross-sectional study over 9 months (April-December 2021), including rheumatoid arthritis patients treated with methotrexate. Demographic and clinical data were collected. Liver stiffness was assessed by FibroScan. Fibrosis and significant liver fibrosis were defined as liver stiffness higher than 6 and 7.2 kPa, respectively. Liver tests, albuminemia, lipid profile, and blood glycemia were measured. Metabolic syndrome was also evaluated. Statistical analyses were performed using SPSS., Results: We included 21 men and 47 women. The mean age was 51.60 ± 1.82 years. The mean disease duration was 8.29 ± 6.48 years. The mean weekly intake of methotrexate was 13.76 ± 3.91 mg. The mean methotrexate duration was 4.67 ± 4.24 years. The mean cumulative dose was 3508.87 ± 3390.48 mg. Hypoalbuminemia and metabolic syndrome were found in 34% and 25% of cases. We noted increased alkaline phosphatase levels in four cases. The mean liver stiffness was 4.50 ± 1.53 kPa. Nine patients had liver fibrosis, and four had significant fibrosis. Associated factors with liver fibrosis were as follows: age ≥ 60 years (OR:22.703; 95% CI [1.238-416.487]; p = 0.035), cumulated dose of methotrexate ≥ 3 g (OR: 76.501; 95% CI [2.383-2456.070]; p = 0.014), metabolic syndrome (OR: 42.743; 95% CI [1.728-1057.273]; p = 0.022), elevated alkaline phosphatase levels (OR: 28.252; 95% CI [1.306-611.007]; p = 0.033), and hypoalbuminemia (OR: 59.302; 95% CI [2.361-1489.718]; p = 0.013)., Conclusion: Cumulating more than 3 g of methotrexate was associated with liver fibrosis in rheumatoid arthritis patients. Having a metabolic syndrome, higher age, hypoalbuminemia, and elevated alkaline phosphatase levels were also likely to be independently associated with liver fibrosis. Key points • Rheumatoid arthritis patients require monitoring hepatic fibrosis when the cumulated dose of methotrexate is above 3 g. • Metabolic syndrome is a risk factor for liver fibrosis, suggesting that its management is necessary to prevent this complication. • Hypoalbuminemia and elevated alkaline phosphatase levels (twice the upper limit) in rheumatoid arthritis patients treated with methotrexate were associated with liver fibrosis., (© 2023. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

Objectives: To investigate the relation between patient characteristics at rheumatoid arthritis (RA) diagnosis and subsequent initiation of treatment with biologic disease-modifying antirheumatic drugs (bDMARDs) or targeted synthetic DMARDs (tsDMARDs)., Design: A retrospective cohort study., Setting and Participants: Consecutive patients (N=330) with early RA (symptom duration <12 months) diagnosed at Skåne University Hospital, Malmö/Lund, Sweden, from 2012 to 2016, were included. Data on demographics, education, comorbidities and treatment were obtained from national registers., Outcome: The relation between patient characteristics at diagnosis and time to first bDMARD/tsDMARD initiation was analysed using Cox regression models. As a secondary outcome, the relation between characteristics at diagnosis and b/tsDMARD initiation within 3 years was analysed using logistic regression., Results: A total of 330 patients (mean age 59.2 years; SD 16.4) were included. During follow-up, 41% received a bDMARD (never preceded by a tsDMARD). Higher age at diagnosis was associated with a lower probability of starting bDMARD treatment (multivariable-adjusted HR 0.66 per SD; 95% CI 0.56 to 0.78). Anticitrullinated protein antibody (ACPA) positivity and higher tender joint count at diagnosis were also associated with subsequent bDMARD treatment initiation in multivariable analysis. A higher level of formal education and absence of comorbidities predicted start of a bDMARD in crude, but not in age-adjusted, analyses., Conclusions: Older patients with RA were less likely to start bDMARDs, whereas ACPA-positive patients, and those with extensive joint involvement at diagnosis, were more likely to receive early bDMARD treatment. The impact of age on the subsequent start of bDMARD therapy was not explained by level of education or comorbidities, suggesting that other aspects of age influence treatment decisions in early RA., Competing Interests: Competing interests: MH: Novartis; SE: AbbVie, Amgen, Janssen, Novartis, UCB Pharma; CT: AbbVie, BMS, Nordic Drugs, Pfizer, Roche, Consultant of: Roche, Grant/research support from: Bristol Myers-Squibb., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: RA patients are at higher risk of cardiovascular disease, influenced by therapies. Studying their cardiovascular and cardiometabolic proteome can unveil biomarkers and insights into related biological pathways., Methods: This study included two cohorts of RA patients: newly diagnosed individuals (n=25) and those with established RA (disease duration >25 years, n=25). Both cohorts were age and sex-matched with a control group (n=25). Additionally, a longitudinal investigation was conducted on a cohort of 25 RA patients treated with methotrexate and another cohort of 25 RA patients treated with tofacitinib for 6 months. Clinical and analytical variables were recorded, and serum profiling of 184 proteins was performed using the Olink technology platform., Results: RA patients exhibited elevated levels of 75 proteins that might be associated with cardiovascular disease. In addition, 24 proteins were increased in RA patients with established disease. Twenty proteins were commonly altered in both cohorts of RA patients. Among these, elevated levels of CTSL1, SORT1, SAA4, TNFRSF10A, ST6GAL1 and CCL18 discriminated RA patients and HDs with high specificity and sensitivity. Methotrexate treatment significantly reduced the levels of 13 proteins, while tofacitinib therapy modulated the expression of 10 proteins. These reductions were associated with a decrease in DAS28. Baseline levels of SAA4 and high levels of BNP were associated to the non-response to methotrexate. Changes in IL6 levels were specifically linked to the response to methotrexate. Regarding tofacitinib, differences in baseline levels of LOX1 and CNDP1 were noted between non-responder and responder RA patients. In addition, response to tofacitinib correlated with changes in SAA4 and TIMD4 levels., Conclusion: In summary, this study pinpoints molecular changes linked to cardiovascular disease in RA and proposes candidate protein biomarkers for distinguishing RA patients from healthy individuals. It also highlights how methotrexate and tofacitinib impact these proteins, with distinct alterations corresponding to each drug's response, identifying potential candidates, as SAA4, for the response to these therapies., Competing Interests: CP-S, NB, YH, and J-MM-M were co-founders of Cobiomic Biosciences S.L. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Cuesta-López, Escudero-Contreras, Hanaee, Pérez-Sánchez, Ruiz-Ponce, Martínez-Moreno, Pérez-Pampin, González, Plasencia-Rodriguez, Martínez-Feito, Balsa, López-Medina, Ladehesa-Pineda, Rojas-Giménez, Ortega-Castro, Calvo-Gutiérrez, López-Pedrera, Collantes-Estévez, Arias-de la Rosa and Barbarroja.)

Objectives: The effect of air pollution on the prognosis of rheumatoid arthritis-associated interstitial lung disease (RA-ILD) remains poorly understood. We aimed to evaluate the effect of long-term exposure to particulate matter with an aerodynamic diameter of ≤10 µm (PM 10 ) and nitrogen dioxide (NO 2 ) on mortality in patients with RA-ILD., Methods: We included 309 patients (mean age, 61.7 years; male, 44.3%) with RA-ILD. Individual-level long-term exposures to PM 10 and NO 2 at their residential addresses were estimated using a national-scale exposure prediction model. The effect of the two air pollutants on mortality was estimated using a Cox-proportional hazards model adjusted for individual-level and area-level characteristics., Results: The median follow-up period was 4.8 years, and 40.8% of patients died or underwent lung transplantation. The annual average concentrations of PM 10 and NO 2 were 56.3 μg/m 3 and 22.4 ppb, respectively. When air pollutant levels were stratified by quartiles, no association was observed between air pollutant concentration and mortality in patients with RA-ILD. However, when stratified by two groups (high exposure (top 25th percentile) vs low exposure (bottom 75th percentile)), we observed a significant association between high PM 10 exposure and mortality (HR 1.68; 95% CI 1.11 to 2.52; p=0.013) but no association between NO 2 exposure and mortality. In the subgroup analyses, the effect of high PM 10 exposure on mortality was significant in patients aged <65 years (HR 1.98; 95% CI 1.02 to 3.85; p=0.045)., Conclusions: Our results indicated that high PM 10 exposure may be associated with mortality in patients with RA-ILD., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: to investigate the occurrence and relative risk of incident malignancy in patients with rheumatic diseases and previous malignancies treated with biologic and targeted synthetic DMARDs (b/tsDMARDs)., Methods: Cohort study of patients included in BIOBADASER 3.0 up to 2021, treated with b/tsDMARDs and history of a previous malignancy. Incident cancer was defined as any cancer (new primary, local recurrence or metastases) during the drug exposure. Incidence rate ratios of cancer per 1,000 patients-year (PY) and 95 % confidence interval (CI) were estimated. Rates of incident cancer in tsDMARDs and other bDMARDs versus TNFi were compared., Results: A total of 352 patients from over 9,129 patients recorded in BIOBADASER 3.0 had a history of a previous malignancy. Overall, there were 47 incident malignancies (28 solid cancers, 18 non-melanoma skin cancers and 1 melanoma). The overall rate of incident malignancy was 47.4 (95 % CI 35.6-63.1) events/1,000 PY, ranging between 24.5 events/1000 PY in the anti-CD20 group to 93 events/1000 PY in the anti-CTLA-4 group. We did not find differences in the adjusted rate of incident cancer in patients exposed to JAKi [0.5 (95 % CI 0.2-1.7)], anti-CD20 [0.4(95 % CI 0.1-1)], or anti-IL6 [1.1(95 % CI 0.5-2.4)], anti-CTLA-4 [1.5 (95 % CI 0.7-3.1) or anti-IL17 [0.7 (95 % CI 0.2-2.4) versus TNFi therapy., Conclusions: We did not find differences in the risk of incident cancer in patients with rheumatic diseases and a previous malignancy between TNFi and other b/tsDMARDs. While incident cancers in our cohort were limited, our data is reassuring, awaiting validation in future studies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Methotrexate (MTX) is the cornerstone of rheumatoid arthritis (RA) treatment and is highly effective with low-dose intermittent administration. MTX is occasionally used in combination with non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen (APAP)/paracetamol for pain or inflammation control. With MTX treatment, the side effects, such as hepatotoxicity, renal failure, and myelosuppression should be considered. These are also seen with analgesics treatment., Methods: We used a large spontaneously reported adverse event database (FAERS [JAPIC AERS]) to analyze whether the reporting of adverse events increased upon MTX and analgesic therapy in patients with RA., Results: After identifying RA cases, the crude reporting odds ratios (cRORs) for hepatotoxicity, renal failure, and thrombocytopenia associated with the use of MTX, APAP, or NSAIDs were calculated by disproportionality analysis, which revealed significantly higher cRORs for these events. No analgesics showed consistent positive signals for drug-drug interaction (DDI) with concomitant low-dose MTX analyzed using four algorithms for DDI interaction (the Ω shrinkage measure, additive or multiplicative, and combination risk ratio models). However, in renal failure and thrombocytopenia, loxoprofen (Ω 025  = 0.08) and piroxicam (Ω 025  = 0.46), and ibuprofen (Ω 025  = 0.74) and ketorolac (Ω 025  = 3.52), respectively, showed positive signals in the Ω shrinkage measure model, and no consistency was found among adverse events or NSAIDs., Conclusions: Studies using spontaneous reporting systems have limitations such as reporting bias or lack of patient background; however, the results of our comprehensive analysis support the results of previous clinical or epidemiological studies. This study also demonstrated the usefulness of FAERS for DDI assessment., (© 2024. The Author(s).)

Objective: To evaluate the risk of malignancy (overall, breast, lung, and lymphoma) in patients with rheumatoid arthritis treated with abatacept, conventional synthetic (cs) disease-modifying antirheumatic drugs (DMARDs), and other biologic/targeted synthetic (b/ts)DMARDs in clinical practice., Methods: Four international observational data sources were included: ARTIS (Sweden), RABBIT (Germany), FORWARD (USA), and BC (Canada). Crude incidence rates (IRs) per 1000 patient-years of exposure with 95% confidence intervals (CIs) for a malignancy event were calculated; rate ratios (RRs) were estimated and adjusted for demographics, comorbidities, and other potential confounders. RRs were then pooled in a random-effects model., Results: Across data sources, mean follow-up for patients treated with abatacept (n = 5182), csDMARDs (n = 73,755), and other b/tsDMARDs (n = 37,195) was 3.0-3.7, 2.9-6.2, and 3.1-4.7 years, respectively. IRs per 1000 patient-years for overall malignancy ranged from 7.6-11.4 (abatacept), 8.6-13.2 (csDMARDs), and 5.0-11.8 (other b/tsDMARDs). IRs ranged from: 0-4.4, 0-3.3, and 0-2.5 (breast cancer); 0.1-2.8, 0-3.7, and 0.2-2.9 (lung cancer); and 0-1.1, 0-0.9, and 0-0.6 (lymphoma), respectively, for the three treatment groups. The numbers of individual cancers (breast, lung, and lymphoma) in some registries were low; RRs were not available. There were a few cases of lymphoma in some of the registries; ARTIS observed an RR of 2.8 (95% CI 1.1-6.8) with abatacept versus csDMARDs. The pooled RRs (95% CIs) for overall malignancy with abatacept were 1.1 (0.8-1.5) versus csDMARDs and 1.0 (0.8-1.3) versus b/tsDMARDs., Conclusions: This international, post-marketing observational safety study did not find any statistically significant increase in the risk of overall malignancies in pooled data in patients treated with abatacept compared with csDMARDs or with other b/tsDMARDs. Assessment of larger populations is needed to further evaluate the risks for individual cancers, especially lymphoma., Competing Interests: Declaration of Competing Interest TAS and AG were employees of (at the time of the analysis), and are shareholders in, Bristol Myers Squibb. SS has attended scientific advisory committee meetings for Atara, Boehringer Ingelheim, Merck, Pfizer, and Seqirus; received speaking fees from AstraZeneca, Boehringer Ingelheim, and Novartis; and received grant/research support from Boehringer Ingelheim. MB has received speaker fees from Novartis and Pfizer and provides expert testimony for Celltrion. MCH has received personal fees from Bristol Myers Squibb (advisory board member) and is Editor-in-Chief of Seminars in Arthritis and Rheumatism. MLS is an employee of, shareholder in, and consultant for Bristol Myers Squibb. JA has received grant/research support from and has served as a PI for AbbVie, AstraZeneca, Bristol Myers Squibb, Eli Lilly, Janssen, Merck, Pfizer, Roche, Samsung Bioepis, Sanofi, and UCB. AS has received grant/research support from a consortium of 14 companies (AbbVie, Bristol Myers Squibb, Celltrion, Fresenius Kabi, Gilead/Galapagos, Hexal, Lilly, Mylan/Viatris, Merck Sharp & Dohme, Pfizer, Roche, Samsung, Sanofi-Aventis, and UCB); and has received honoraria from AbbVie, Bristol Myers Squibb, Celltrion, Merck Sharp & Dohme, Pfizer, and Roche. YM (for the German RABBIT register) is supported by a joint, unconditional grant from AbbVie, Amgen, Bristol Myers Squibb, Celltrion, Fresenius Kabi, Hexal, Lilly, Merck Sharp & Dohme, Pfizer, Roche, Samsung Bioepis, Sanofi-Aventis, UCB, and Viatris; and has received honoraria from Pfizer. AD is an employee of, and shareholder in, Bristol Myers Squibb. No other disclosures relevant to this article were reported., (Copyright © 2023. Published by Elsevier Inc.)

Rheumatoid arthritis (RA) is an autoimmune disease characterized by aggressive cartilage and bone erosion. This work aimed to evaluate the metabolomic profile of Medicago sativa L. (MS) (alfalfa) seeds and explore its therapeutic impact against RA in rats. Arthritis was induced by complete Freund's adjuvant (CFA) and its severity was assessed by the arthritis index. Treatment with MS seeds butanol fraction and interlukin-1 receptor antagonist (IL-1RA) were evaluated through measuring interlukin-1 receptor (IL-1R) type 1 gene expression, interlukin-1 beta (IL-1β), oxidative stress markers, C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), prostaglandin E2 (PGE2), caspase-3 (Cas-3), intracellular adhesion molecule-1 (ICAM-1), DNA fragmentation, and chromosomal damage. Total phenolics/ flavonoids content in the ethyl acetate, butanol fraction and crude extract of MS seeds were estimated. The major identified compounds were Quercetin, Trans-taxifolin, Gallic acid, 7,4'-Dihydroxyflavone, Cinnamic acid, Kudzusaponin SA4, Isorhamnetin 3-O-beta-D-2'',3'',4''-triacetylglucopyranoside, Apigenin, 5,7,4'-Trihydroxy-3'-methoxyflavone, Desmethylxanthohumol, Pantothenic acid, Soyasapogenol E, Malvidin, Helilandin B, Stigmasterol, and Wairol. Treatment with MS seeds butanol fraction and IL-1RA enhanced all the biochemical parameters and the histopathological features of the ankle joint. In conclusion, Trans-taxifolin was isolated for the first time from the genus Medicago. MS butanol fraction seeds extract and IL-1 RA were considered as anti-rheumatic agents., (© 2023 Wiley-VHCA AG, Zurich, Switzerland.)

This study aimed to detect signals of adverse drug reactions (ADRs) associated with biological disease-modifying antirheumatic drugs (DMARDs) and targeted therapies in rheumatoid arthritis (RA) and ankylosing spondylitis (AS) patients. Utilizing the KOrean College of Rheumatology BIOlogics & Targeted Therapy Registry (KOBIO) data, we calculated relative risks, excluded previously reported drug-ADR pairs, and externally validated remaining pairs using US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) and single centre's electronic health records (EHR) data. Analyzing data from 2279 RA and 1940 AS patients, we identified 35 significant drug-ADR pairs in RA and 26 in AS, previously unreported in drug labels. Among the novel drug-ADR pairs from KOBIO, 15 were also significant in the FAERS data. Additionally, 2 significant drug-laboratory abnormality pairs were found in RA using CDM MetaLAB analysis. Our findings contribute to the identification of 14 novel drug-ADR signals, expanding our understanding of potential adverse effects related to biological DMARDs and targeted therapies in RA and AS. These results emphasize the importance of ongoing pharmacovigilance for patient safety and optimal therapeutic interventions., (© 2024. The Author(s).)

Introduction: Rheumatoid arthritis (RA) is a progressive inflammatory autoimmune disease characterised by chronic systemic inflammation, which can cause swelling, stiffening and destruction of articular cartilage and bone. Early diagnosis and treatment of RA can improve outcomes and slow the progression of joint damage. Preliminary exploratory research had hinted an expected effect of modified Zhiwang decoction (MZWD) in treating early RA. However, few randomised clinical trials have evaluated the effectiveness of MZWD in early RA. Therefore, a parallel-group randomised controlled trial was designed to evaluate the efficacy and safety of MZWD combined with methotrexate (MTX) on early RA., Methods and Analysis: This is a prospective, parallel-group, single-centre randomised controlled clinical study. A total of 150 patients will be randomly assigned to either the treatment (n=75) or control group (n=75). The treatment group will receive MZWD and MTX, and the control group will receive MTX for 12 weeks. The primary outcome of this study is Disease Activity Score-28, and the secondary outcomes are Fatigue Scale-14, Visual Analogue Scale pain scores and traditional Chinese medicine symptom scores. Safety outcomes, including adverse events and results of ECG and laboratory tests, will be monitored., Ethics and Dissemination: Ethics approval was obtained from the Clinical Research Ethics Committee of the China-Japan Friendship Hospital (no. 2022-KY-124) on 8 July 2022. The findings will be disseminated in peer-reviewed publications., Trial Registration Number: ClinicalTrials.gov Registry (NCT05508815)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: We aimed to investigate the risk of first primary cancer in patients with RA treated with janus kinase inhibitors (JAKi) compared with those who received biologic DMARDs (bDMARDs) in a real-world setting., Methods: We performed an observational cohort study using the nationwide registers in Denmark. Patients with RA aged 18+ years, without a previous cancer diagnosis, and who initiated treatment with JAKi or bDMARDs from 1 January 2017 to 31 December 2020 were followed for any cancer (except non-melanoma skin cancer). We applied inverse probability of treatment weighting (IPTW) to account for covariate differences between treatment groups. IPTW-generated weights were used with cause-specific Cox (CSC) models to calculate hazard ratios (HRs) for cancer incidence in JAKi-treated compared with bDMARD-treated patients with RA., Results: We identified 875 and 4247 RA patients treated with JAKi and bDMARDs, respectively. The JAKi group contributed 1315 person years (PYRS) and 19 cancers, the bDMARD group contributed 8597 PYRS and 111 cancers, with corresponding crude incidence rates per 1000 PYRS of 14.4 and 12.9. Comparing the two groups using weighted CSC models, a HR of 1.41 (95% CI 0.76, 2.37, 95% CIs) was seen for JAKi- vs bDMARD-treated patients with RA., Conclusion: JAKi treatment in real-world patients with RA was not associated with a statistically significant increased risk of first primary cancer compared with those who received bDMARDs. However, several numerically increased risk estimates were detected, and a clinically important excess risk of cancer among JAKi recipients cannot be dismissed., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

In real-world scenarios, Janus Kinase (JAK) inhibitors are often offered to "difficult-to-treat" rheumatoid arthritis patients, quite different from those included in randomized controlled trials. Our study aimed to evaluate the influence of patient-related factors on the effectiveness and safety of JAK inhibitors in real-world clinical practice. This observational retrospective study involved rheumatoid arthritis patients who received treatment with either tofacitinib, baricitinib, upadacitinib, or filgotinib. At 12 months of treatment, reasons for and rates of JAK inhibitor treatment discontinuation were examined. Treatment retentions were analyzed through Cox proportional hazard regression models and Kaplan-Meier estimates. Patient-related factors that could influence treatment retention were evaluated for the discontinuation reasons of lack of effectiveness and adverse events. At 12 months of treatment, discontinuation rates for 189 JAK inhibitor treatments were: lack of effectiveness (24.3%), adverse events (20.6%), and other reasons (3.7%). The remaining 51.4% represents the treatment continuation rate. No patient-related factors evaluated had an influence on treatment discontinuation due to lack of effectiveness. Ae significantly increased the risk of treatment discontinuation due to adverse events (p = 0.030). In terms of age, at 12 month of treatment, discontinuation rates due to adverse events were: < 65 years, 14.4% vs. 65 years or older, 26.3% (p = 0.019). Rheumatoid arthritis patients aged 65 years or older showed an increased risk of JAK inhibitor treatment discontinuation due to adverse events. Factors not related to treatment discontinuation were: sex, rheumatoid arthritis disease duration, rheumatoid arthritis disease activity, seropositivity for rheumatoid factor, seropositivity for anti-cyclic citrullinated peptides, number of prior biologic treatments, number of prior JAK inhibitor treatments, concomitant use of glucocorticoids, and concomitant use of conventional synthetic disease-modifying antirheumatic drugs., (© 2024. The Author(s).)

Objectives: To compare the use of glucocorticoids (GC) over time in patients with rheumatoid arthritis (RA) who were or were not treated initially with GC bridging therapy., Methods: Data from the BeSt, CareRA and COBRA trials were combined in an individual patient data (IPD) meta-analysis. We compared GC use between bridgers and non-bridgers at 12, 18 and 24 months from baseline with mixed-effects regression analysis. Secondary outcomes were mean cumulative GC dose until 24 months after baseline with and without the bridging period, Disease Activity Score based on 28 joints (DAS28) over time and number of disease-modifying antirheumatic drug (DMARD) changes., Results: 252/625 patients (40%) were randomised to GC bridging (bridgers). Excluding the period of bridging, later GC use was low in both groups and cumulative doses were similar. Mean DAS28 was similar between the groups, but bridgers improved more rapidly (p<0.001) in the first 6 months and the bridgers required significantly fewer changes in DMARDs (incidence rate ratio 0.59 (95% CI 0.38 to 0.94)). GC use was higher in the bridgers at t=12 months (OR 3.27 (95% CI 1.06 to 10.08)) and the bridging schedules resulted in a difference in cumulative GC dose of 2406 mg (95% CI 1403 to 3408) over 24 months., Conclusion: In randomised trials comparing GC bridging and no GC bridging, bridgers had a more rapid clinical improvement, fewer DMARD changes and similar late use of GC compared with non-bridgers. GC bridging per protocol resulted, as could be expected, in a higher cumulative GC dose over 2 years., Competing Interests: Competing interests: LvO, PHPdJ, RBML, JSS and TWJH declare no competing interests. MB: reports speaker fees from Novartis and Pfizer, and provided expert testimony for Celltrion. PV: holds the Pfizer Chair Early Rheumatoid Arthritis Management as well as the Galapagos Chair in RA at KU Leuven and received consultancy and/or speaker honoraria from AbbVie, Celltrion, Eli Lilly, Galapagos, Gilead, Nordic Pharma, Roularta and Sidekick Health within the last 24 months. SAB: received an ASPIRE grant from Pfizer. CFA: received study grants for BeSt and IMPROVED from Centocor (now Janssen) and AbbVie, respectively. PE: provided expert advice to AbbVie, AstraZeneca, BMS, Boehringer Ingelheim, Galapagos, Gilead, Janssen, MSD, Lilly, Novartis, Pfizer, Roche, Samsung. And clinical trials: AbbVie, BMS, Lilly, Novartis, Pfizer, Roche, Samsung. WL received study grants from Pfizer and consultancy speaker fees from Eli Lilly, Pfizer, Amgen, Galapagos and UCB., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To evaluate the efficacy and safety of adalimumab (ADA) combined with Tripterygium wilfordii Hook F (TwHF) in the treatment of methotrexate (MTX)-inadequate response patients with rheumatoid arthritis (RA)., Methods: In this multicenter, open-label, randomized controlled clinical trial, 64 RA patients with inadequate response to MTX were 1:1 randomly assigned into treatment or control groups. The treatment group was treated with ADA in combination with TwHF, and the control group was treated with ADA in combination with MTX for 24 weeks. The primary endpoint was the percentage of patients having low disease activity (2.6 ≤ DAS28-ESR < 3.2) and remission rates (DAS28-ESR < 2.6) at week 24., Results: In total, 53 of the 64 patients (82.8%) completed this 24-week clinical trial. By intent-to-treat (ITT) analysis, a comparable outcome was observed between the two groups. The percentage of patients achieving low disease activity in the treatment group and control group were 43.8% and 46.9% (95% CI, 21.28 to 27.48, p = .802). Percentage of patients achieving low disease activity rates were respectively 28.1% and 31.3% in the treatment group and control group (95% CI, 19.18 to 25.58, p = .784). In per-protocol (PP) analysis, the results were consistent with the ITT model. The incidence of adverse events was comparable between the two groups., Conclusions: There were no significant differences in efficacy and safety between ADA combined with TwHF versus ADA combined with MTX in the treatment of RA. TwHF might be an alternative treatment for RA patients who are intolerant to MTX., (© 2024 The Authors. International Journal of Rheumatic Diseases published by Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Toxicity associated with low doses of methotrexate (MTX) is low, but it may be fatal. Bone marrow suppression and mucositis are among the common side effects of low dose MTX toxicity. Different risk factors have been reported for toxicities associated with low doses of MTX, including accidental use of higher doses, renal dysfunction, hypoalbuminemia, and polypharmacy. In this paper, we present a female patient who had mistakenly used 7.5 mg of MTX daily instead of the same dose of MTX on Thursday and Friday. She was presented with mucositis and diarrhea to the emergency department. Moreover, we searched the databases Scopus and PubMed for available studies and case reports on toxicities associated with MTX dosing errors. The most frequently observed toxicities included gastrointestinal lesions, nausea, vomiting, skin lesions, and bone marrow suppression. Leucovorin, hydration, and urine alkalinization were among the most frequently used treatments. Finally, we summarize the data on the toxicities of low doses of MTX in different diseases., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

A series of 1-(2-oxocyclohexyl)butane-1, 3-dione derivatives were designed and synthesized as TLR4 inhibitors by modifying the core structure of the lead compound ((6, 8-dioxo-1, 2, 3, 4, 6, 7, 8, 8a-octahydronaphthalen-2-yl) carbamate)). In vitro, compound 3p significantly inhibited the proliferation of rat synovial cells, inhibited the proliferation of LPS-induced RAW264.7 cells, and inhibited TLR4 activity, with IC 50 values of 1.21 ± 0.09 μM, 0.73 ± 0.05 μM and 0.43 ± 0.03 μM, respectively, which was superior to the positive control methotrexate. In vivo anti-rheumatoid arthritis evaluation, compound 3p can significantly inhibit the inflammatory factors TNF-α, IL-1β and IL-6, so as to achieve the therapeutic purpose. In the preliminary mechanism study, compound 3p has obvious regulatory effects on the abnormal increase of TLR4, JAK2 and STAT3 protein and gene expression related to inflammatory signaling pathway in RAW264.7 cells. In summary, this study aims to develop more effective candidates for rheumatoid arthritis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Aim: The objective of this study was to assess the gastrointestinal side (GI) effects of oral methotrexate (MTX) in Japanese adult patients with rheumatoid arthritis (RA)., Methods: In this single-center retrospective study, 112 Japanese adult patients (over 18 years old) with RA were examined by Methotrexate Intolerance and Severity assessment in Adults (MISA) questionnaire., Results: Forty-five (40.2%) of patients were MTX intolerant (MISA score ≥1). Twelve patients (11.2%) were moderate-to-severe MTX intolerant (MISA cross-product score ≥4). The most common GI side effects of MTX were gastric discomfort (26.8%), followed by loss of appetite or dysgeusia (14.3%), fatigue and lethargy (12.5%), and nausea (10.7%)., Conclusions: Japanese adult patients with RA showed a high prevalence of MTX intolerance even in low-dose oral MTX. The MISA questionnaire was practical for finding patients with MTX intolerance., (© 2024 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Objectives: To analyse the changes in patient-reported outcomes after starting advanced antirheumatic treatment., Methods: The study included all patients who started self-administered biological or targeted synthetic treatments for rheumatoid arthritis between February and November 2020. The patients were given the RAID quality of life questionnaire to complete before starting the treatment and after 4 months. Univariate and multivariate analyses were performed to determine the association between patients' clinical and sociodemographic characteristics and quality of life improvement. The level of significance was set at 0.05., Results: Forty-six patients were included. Their ratings in the RAID questionnaire were improved after 4 months of treatment, both in the final overall total, which improved by 1.63±2.29 points, and in the different subtopics of the questionnaire (range 0-10). Pain was the domain that improved the most (2.33±2.82 points), followed by functional disability (2.15±2.51) and physical well-being (1.96±3.18). The improvement was statistically significant in all domains except the sleep score, which showed no statistically significant difference between the two time points analysed., Conclusions: Advanced antirheumatic treatment improves the quality of life of patients after 4 months of treatment., Competing Interests: Competing interests: None declared., (© European Association of Hospital Pharmacists 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: This study aims to examine whether comorbidities affect the likelihood of reaching primary remission on methotrexate monotherapy as the first disease-modifying antirheumatic drug (DMARD) in early rheumatoid arthritis (RA)., Methods: We used nationwide Swedish clinical and quality registers to collect RA disease activity measures and comorbidity data for patients diagnosed with RA 2007-2020 (n=11 001). The primary outcome was failure to reach 28-joint Disease Activity Score (DAS28) remission at 3 months. Secondary outcomes included Boolean, Simplified Disease Activity Index/Clinical Disease Activity Index remission, European Alliance of Associations for Rheumatology response and no swollen joint count at 3 and 6 months. For each comorbidity, and for combinations thereof, we calculated adjusted relative risks (RRs) of failure to reach remission, using modified Poisson regression., Results: In total, 53% (n=4019/7643) failed to reach DAS28 remission after 3 months of methotrexate monotherapy, ranging from 66% (n=25/38) among patients with chronic kidney disease to 48% (n=154/319) in patients with previous cancer. The risk of not reaching DAS28 remission at 3 months (RR adjusted for sex and age) was increased among patients with endocrine (RR 1.08, 95% CI 1.01 to 1.15), gastrointestinal (RR 1.16, 95% CI 1.03 to 1.30), infectious (RR 1.21, 95% CI 1.06 to 1.38), psychiatric (RR 1.24, 95% CI 1.15 to 1.35) and respiratory comorbidities (RR 1.16, 95% CI 1.01 to 1.32). Having three or more comorbidity categories was associated with a 27% higher risk of DAS28 remission failure at 3 months. A similar pattern was observed for the secondary outcomes., Conclusions: Comorbidities decrease the chance of reaching remission on methotrexate as DMARD monotherapy in patients with early RA and are important to consider when assessing treatment outcomes., Competing Interests: Competing interests: JA has received grants from Abbvie, AstraZeneca, BMS, Eli Lily, MSD, Pfizer, Roche, Samsung Bioepis, Sanofi and UCB; these entities have entered into agreements with Karolinska Institutet with JA as principal investigator mainly in the context of safety monitoring of biologics via ARTIS/Swedish Biologics Register. SS is a part-time employee of deCODE genetics, unrelated to this work. The other authors have declared no conflicts of interest., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Ethnopharmacological Relevance: Vetiver (Chrysopogon zizanioides) is indigenous to India where it is traditionally used to relief rheumatisms, lumbagos and sprains. Vetiver anti-inflammatory activity has not been previously investigated, and its specific interactions with body inflammation cascade remain largely unknown., Aim of the Study: The present work was performed to validate the ethnobotanical use of the plant and compare the anti-inflammatory activities of the ethanolic extracts of the most traditionally used part (aerial part) to that of the root. Furthermore, we attempt to reveal the molecular mechanism of this anti-inflammatory activity in correlation to the chemical composition of C. zizanioides aerial (CA) and root parts (CR)., Materials and Methods: Ultraperformance liquid chromatography coupled to high resolution mass spectrometry (UHPLC/HRMS) was used for comprehensive analysis of both CA and CR. The anti-inflammatory effect of both extracts was evaluated in complete Freund's adjuvant (CFA)-induced RA model in Wistar rats., Results: Phenolic metabolites were predominant in CA and 42 were identified for the first time, while only 13 were identified in CR. Meanwhile, triterpenes and sesquiterpenes were confined to the root extract. In CFA arthritis model, CA showed better anti-inflammatory activity than CR marked by an increase in serum level of IL-10 with simultaneous decrease in pro-inflammatory markers; IL-6, ACPA and TNF-α and was evident in histopathological examination. This anti-inflammatory effect was accompanied by down-regulation of JAK2/STAT3/SOCs3, ERK1/ERK2, TRAF6/c-FOS/NFATC1, TRAF6/NF-κB/NFATC1 and RANKL pathways which were all upregulated after CFA injection. These pathways were modulated to larger extent by CA, except for ERK1/ERK2 which was downregulated more effectively by CR. This differential effect between CA and CR can be explained by the variability in their phytoconstituents profile., Conclusion: In agreement with the ethnobotanical preference, CA extract was more effective than CR extract in reducing the symptoms of RA probably due to its enrichment with flavonoids, lignans, and flavolignans. Both CA and CR reduced the production of inflammatory cytokines through modulating various biological signaling pathways. These findings support the traditional use of vetiver leaves as a remedy for RA and suggest that the use of the whole plant may offer advantage by synergistically affecting more inflammatory pathways., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objectives: To investigate the efficacy and safety of otilimab, an anti-granulocyte-macrophage colony-stimulating factor antibody, in patients with active rheumatoid arthritis and an inadequate response to conventional synthetic (cs) and biologic disease-modifying antirheumatic drugs (DMARDs) and/or Janus kinase inhibitors., Methods: ContRAst 3 was a 24-week, phase III, multicentre, randomised controlled trial. Patients received subcutaneous otilimab (90/150 mg once weekly), subcutaneous sarilumab (200 mg every 2 weeks) or placebo for 12 weeks, in addition to csDMARDs. Patients receiving placebo were switched to active interventions at week 12 and treatment continued to week 24. The primary end point was the proportion of patients achieving an American College of Rheumatology ≥20% response (ACR20) at week 12., Results: Overall, 549 patients received treatment. At week 12, there was no significant difference in the proportion of ACR20 responders with otilimab 90 mg and 150 mg versus placebo (45% (p=0.2868) and 51% (p=0.0596) vs 38%, respectively). There were no significant differences in Clinical Disease Activity Index, Health Assessment Questionnaire-Disability Index, pain Visual Analogue Scale or Functional Assessment of Chronic Illness Therapy-Fatigue scores with otilimab versus placebo at week 12. Sarilumab demonstrated superiority to otilimab in ACR20 response and secondary end points. The incidence of adverse or serious adverse events was similar across treatment groups., Conclusions: Otilimab demonstrated an acceptable safety profile but failed to achieve the primary end point of ACR20 and improve secondary end points versus placebo or demonstrate non-inferiority to sarilumab in this patient population., Trial Registration Number: NCT04134728., Competing Interests: Competing interests: PCT has received consulting fees from AbbVie, Biogen, Bristol Myers Squibb, Fresenius, Galapagos, Gilead Sciences, GSK, Janssen, Lilly, Nordic Pharma, Pfizer, Roche, Sanofi and UCB, and research support from Galapagos. MEW receives research support from AbbVie, Aqtual, Bristol Myers Squibb and Lilly, and consultation fees from AbbVie, Aclaris, Amgen, Bayer, Bristol Myers Squibb, Corvitas, Genosco, Gilead Sciences, GSK, Horizon, Johnson & Johnson, Lilly, Novartis, Pfizer, Rami Therapeutics, R Pharma, Roche, Sanofi, Scipher, Sci Rhom, Set Point and Tremeau. He holds stock/stock options of CanFite, Inmedix and Scipher. IBMcI has received consultancy and research support from AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Causeway, Compugen, Gilead Sciences, GSK, Lilly, Novartis, Pfizer and UCB and holds a leadership role in Evelo, University of Glasgow, Versus Arthritis and is an NHS GGC Board Member and an Annals of the Rheumatic Diseases Editorial Board Member. TA has accepted research grants and/or honoraria for meetings from AbbVie, Alexion, Astellas Pharma, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eisai, Gilead Sciences, GSK, Lilly Japan, Mitsubishi Tanabe Pharma, Otsuka Pharmaceutical, Pfizer, Takeda Pharmaceutical and UCB Japan. VS has received consulting fees from AbbVie, Alpine, Alumis, Amgen, Aria, AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Celltrion, Ermium, Genentech/Roche, GSK, Horizon, Inmedix, Janssen, Kiniksa, Lilly, Merck, MiMedx, Novartis, Omeros, Pfizer, R-Pharm, RAPT, Regeneron, Samsung, Sandoz, Sanofi, Scipher, Setpoint, Sorrento, Spherix, Tonix and Urica. TT received payment or honoraria from AbbVie, Asahi Kasei, Astellas, AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eisai, Gilead Sciences, Janssen, Lilly Japan, Mitsubishi-Tanabe, Pfizer Japan and is an Annals of the Rheumatic Diseases Editorial Board Member. MB, DB, JD, CG, AG, SM, CO’S, DS, LAS, CS, JES, MW, RW and SW are employees of GSK and hold GSK stock/shares. RMF has received research support from AbbVie, Amgen, Arthrosi, AstraZeneca, Biogen, Bristol Myers Squibb, Boehringer Ingelheim, Galvani, Genentech/Roche, Gilead, GSK, Janssen, Lilly, Novartis, Pfizer, Priovant, Samsung, Sanofi-Genzyme, Selecta and UCB; consulting fees from AbbVie, Amgen, Arthrosi, Bristol Myers Squibb, Boehringer Ingelheim, Celltrion, Galapagos, Galvani, Gilead, GSK, Janssen, Lilly, Novartis, Pfizer, Priovant, Samsung and UCB and honoraria from AbbVie, GSK and Pfizer and is an Annals of the Rheumatic Diseases Editorial Board Member., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Synovial hypoxia-inducible factor 1α (HIF-1α) is a prospective therapeutic target for rheumatoid arthritis (RA). AMSP-30 m, a novel HIF-1α inhibitor, was reported to have notable anti-arthritic effects in rats with adjuvant-induced arthritis. However, its roles in inhibiting the pathogenic behaviors of fibroblast-like synoviocytes (FLS) and the involved mechanisms remain unknown. Here, AMSP-30 m inhibited proliferation and induced apoptosis in hypoxia-induced RA FLS (MH7A cell line), as evidenced by decreased cell viability, reduced Ki67-positive cells, G0/G1 phase arrest, lowered C-myc and Cyclin D1 protein levels, emergence of apoptotic nuclear fragmentation, raised apoptosis rates, and activation of caspase 3. Furthermore, AMSP-30 m prevented hypoxia-induced increases in pro-inflammatory factor production, MMP-2 activity, migration index, migrated/invasive cells, and actin cytoskeletal rearrangement. In vivo, AMSP-30 m alleviated the severity of rat collagen-induced arthritis (CIA). Mechanically, AMSP-30 m reduced HIF-1α expression and blocked sonic hedgehog (Shh) pathway activation in hypoxia-induced MH7A cells and CIA rat synovium, as shown by declines in pathway-related proteins (Shh, Smo, and Gli-1). Particularly, the combination of Shh pathway inhibitor cyclopamine enhanced AMSP-30 m's inhibitory effects on the pathogenic behaviors of hypoxia-stimulated MH7A cells, whereas the combination of Shh pathway activator SAG canceled AMSP-30 m's therapeutic effects in vitro and in CIA rats, implying a close involvement of Shh pathway inhibition in its anti-arthritic effects. We likewise confirmed AMSP-30 m's anti-proliferative role in hypoxia-induced primary CIA FLS. Totally, AMSP-30 m suppressed hypoxia-induced proliferation, inflammation, migration, and invasion of MH7A cells and ameliorated the severity of rat CIA via inhibiting Shh signaling., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: To investigate the efficacy and safety of otilimab, an antigranulocyte-macrophage colony-stimulating factor antibody, in patients with active rheumatoid arthritis., Methods: Two phase 3, double-blind randomised controlled trials including patients with inadequate responses to methotrexate (contRAst 1) or conventional synthetic/biologic disease-modifying antirheumatic drugs (cs/bDMARDs; contRAst 2). Patients received background csDMARDs. Through a testing hierarchy, subcutaneous otilimab (90/150 mg once weekly) was compared with placebo for week 12 endpoints (after which, patients receiving placebo switched to active interventions) or oral tofacitinib (5 mg two times per day) for week 24 endpoints., Primary Endpoint: proportion of patients achieving an American College of Rheumatology response ≥20% (ACR20) at week 12., Results: The intention-to-treat populations comprised 1537 (contRAst 1) and 1625 (contRAst 2) patients., Primary Endpoint: proportions of ACR20 responders were statistically significantly greater with otilimab 90 mg and 150 mg vs placebo in contRAst 1 (54.7% (p=0.0023) and 50.9% (p=0.0362) vs 41.7%) and contRAst 2 (54.9% (p<0.0001) and 54.5% (p<0.0001) vs 32.5%). Secondary endpoints: in both trials, compared with placebo, otilimab increased the proportion of Clinical Disease Activity Index (CDAI) low disease activity (LDA) responders (not significant for otilimab 150 mg in contRAst 1), and reduced Health Assessment Questionnaire-Disability Index (HAQ-DI) scores. Benefits with tofacitinib were consistently greater than with otilimab across multiple endpoints. Safety outcomes were similar across treatment groups., Conclusions: Although otilimab demonstrated superiority to placebo in ACR20, CDAI LDA and HAQ-DI, improved symptoms, and had an acceptable safety profile, it was inferior to tofacitinib., Trial Registration Numbers: NCT03980483, NCT03970837., Competing Interests: Competing interests: RMF has received research support from AbbVie, Amgen, Arthrosi, AstraZeneca, Biogen, Bristol Myers Squibb, Boehringer Ingelheim, Galvani, Genentech/Roche, Gilead, GSK, Janssen, Lilly, Novartis, Pfizer, Priovant, Samsung, Sanofi-Genzyme, Selecta and UCB; consulting fees from AbbVie, Amgen, Arthrosi, Bristol Myers Squibb, Boehringer Ingelheim, Celltrion, Galapagos, Galvani, Gilead, GSK, Janssen, Lilly, Novartis, Pfizer, Priovant, Samsung and UCB; has received honoraria from AbbVie, GSK and Pfizer and is an Annals of the Rheumatic Diseases Editorial Board Member. DvdH has received consulting fees from AbbVie, Bayer, Bristol Myers Squibb, Galapagos, Gilead, GSK, Janssen, Lilly, Novartis, Pfizer, UCB Pharma, is Director of Imaging Rheumatology BV and is an Annals of the Rheumatic Diseases Editorial Board Member. VS has received consulting fees from AbbVie, Alpine, Alumis, Amgen, Aria, AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Celltrion, Ermium, Genentech/Roche, GSK, Horizon, Inmedix, Janssen, Kiniksa, Lilly, Merck, MiMedx, Novartis, Omeros, Pfizer, R-Pharm, RAPT, Regeneron, Samsung, Sandoz, Sanofi, Scipher, Setpoint, Sorrento, Spherix, Tonix and Urica. TA has accepted research grants and/or honoraria for meetings from AbbVie, Alexion, Astellas Pharma, Bristol-Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eisai, Gilead Sciences, GSK, Lilly Japan, Mitsubishi Tanabe Pharma, Otsuka Pharmaceutical, Pfizer, Takeda Pharmaceutical, and UCB Japan. IBM has received consultancy and research support from AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Causeway, Compugen, Gilead Sciences, GSK, Lilly, Novartis, Pfizer, and UCB and holds a leadership role in Evelo, University of Glasgow, Versus Arthritis, and is an NHS GGC Board Member and an Annals of the Rheumatic Diseases Editorial Board Member. TT received payment or honoraria from AbbVie, Asahi Kasei, Astellas, AstraZeneca K.K., Bristol-Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eisai, Gilead Sciences, Janssen K.K, Lilly Japan, Mitsubishi-Tanabe, Pfizer Japan and is an Annals of the Rheumatic Diseases Editorial Board Member. PCT has received consulting fees from AbbVie, Biogen, Bristol Myers Squibb, Fresenius, Galapagos, Gilead Sciences, GSK, Janssen, Lilly, Nordic Pharma, Pfizer, Roche, Sanofi, and UCB, and research support from Galapagos. MB, DB, JD, CG, AG, SM, CO’S, DS, LAS, CS, JES, MW, RW and SW are employees of GSK and hold GSK stock/shares. MEW receives research support from AbbVie, Aqtual, Bristol Myers Squibb and Lilly, and consultation fees from AbbVie, Aclaris, Amgen, Bayer, Bristol Myers Squibb, Corvitas, Genosco, Gilead Sciences, GSK, Horizon, Johnson & Johnson, Lilly, Novartis, Pfizer, Rami Therapeutics, R Pharma, Roche, Sanofi, Scipher, Sci Rhom, Set Point and Tremeau. He holds stock/stock options of CanFite, Inmedix, and Scipher., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Etanercept biosimilars show comparable efficacy to their originators among biologic-naïve patients with RA in randomized controlled trials. Nationwide guidelines have obligated prescribing of etanercept biosimilars from 2016, resulting in significant cost savings. This analysis aimed to compare the effectiveness of etanercept originator vs etanercept biosimilar amongst biologic-naïve RA patients treated in routine clinical practice in the UK., Methods: Biologic-naïve RA patients starting etanercept in the British Society for Rheumatology Biologics Register in Rhematoid Arthritis (BSRBR-RA) cohort study from 2010 were included. Data collected at start of therapy includes patient demographics and disease activity. Follow-up data includes changes in disease activity and anti-rheumatic therapy. Six- and 12-month primary outcomes include DAS for 28-joints (DAS28) remission, EULAR response and minimal clinically important difference in function. Etanercept drug survival was assessed using Kaplan-Meier and Cox regression, including reasons for treatment withdrawal. Multiple imputation accounted for missing data. Propensity-decile adjustment was used to account for confounding by indication., Results: A total of 1806 biologic-naïve RA patients started etanercept: 1009 originator, 797 biosimilar. At 6 and 12 months, the proportion of patients achieving DAS28 remission and EULAR response were similar between treatments. During follow-up, 19% of originator patients switched onto etanercept biosimilar. Patients were censored at time of switch. Patients on originator were no more likely to stop therapy vs biosimilar; 71% of originator and 76% of biosimilar patients remained on therapy at 1 year., Conclusions: In one of the largest analyses of patients with RA, biologic-naïve RA patients treated with etanercept originator showed similar outcomes vs biosimilar using real-world data. Drug survival, and disease activity after 6 and 12 months of therapy, was similar between cohorts., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Background and Objectives: Methotrexate (MTX) is the first-line therapy for rheumatoid arthritis (RA). While therapeutic adherence is essential to successful management, no objective MTX assay is currently available. Using population pharmacokinetic modelling (PopPK), our objective was to describe the urinary MTX (MTXu) kinetics in treated patients and to evaluate its abilities to assess the MTX-adherence., Methods: The association between urinary methotrexate level and methotrexate administration was assessed using a generalized linear model. Then, a population pharmacokinetic model was developed based on data from 59 patients using with Monolix 2021. R2. Simulations were run to establish a reference kinetic profile and evaluate the proportion of samples predicted as true positives., Results: Compared to the control group, multivariate analysis showed that MTXu was independently associated with methotrexate administration (p < 0.0001) with a sensitivity and specificity greater than 99%. The final PopPK model selected was a two-compartment model with first-order absorption and elimination. Internal and external validation of the model met all predefined criteria. When using an analytical assay with a LOQ equal to 1 nM, the proportion of samples predicted as true positives is over 90%, as a function of MTX dose (7.5-25 mg/week) and post-administration sampling days (1-7 days)., Conclusion: We developed a pharmacokinetic model able to describe expected patterns of urinary methotrexate. This allowed us to propose a new objective test of MTX adherence, which could help in routine practice to differentiate patients who are truly unresponsive to methotrexate from those who are unresponsive because of non-adherence., Competing Interests: Declaration of Competing Interest All authors have no conflicts to disclose., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)