Rheumatoid arthritis (RA) is a chronic, inflammatory, autoimmune disease that primarily affects the joints. RA usually results in synovial hyperplasia, expansion of "pannus" and destruction of cartilage. The etiology and pathogenesis of RA are not fully understood, but immunity has been shown to play an important role in the development of autoimmune diseases such as RA. In addition, endogenous retroelements, the remnants of ancient retroviruses in the human genome, are involved in cancer and/or immune disorders. As evidenced by increasing evidences that the aberrant expression of retroelements induces innate immunity, despite the fact that the expression of most retroelements has been epigenetically suppressed over a long period of evolution. With the continuous development of disease-modifying anti-rheumatic drugs (DMARDs), RA disease activity has been alleviated and improved. Unfortunately, some patients have a limited response to DMARDs, and the drugs also have the disadvantages of some side effects and high economic costs. This review summarizes the pathogenic mechanisms of RA and endogenous retroelements in autoimmunity, and concludes with a summary of treatments for RA, along with new therapeutic recommendations.

To elucidate the therapeutic effect of orthopaedic surgical intervention (OSI) in difficult-to-treat rheumatoid arthritis (D2T RA) compared with non-D2T RA.

A total of 534 recent surgeries were analysed only in patients who had undergone OSI since 2016 and for whom a 12-month postoperative follow-up was available. D2T RA was determined according to the European League against Rheumatism definition, and patients with D2T RA were matched to patients with non-D2T RA using propensity scores calculated by a logistic regression analysis. The Health Assessment Questionnaire-Disability Index (HAQ-DI), Disease Activity Index 28 (DAS28), face scale, and patient's assessment of general health were measured repeatedly at baseline and 6 and 12 months and were compared using a two-way analysis of variance.

The HAQ-DI, DAS28, face scale, and general health showed significant postoperative improvements, and there were significant differences in the HAQ-DI and face scale scores between D2T RA and non-D2T RA. An additional analysis with DAS28 as a covariate showed no significant interaction for either, suggesting that these improvements in clinical assessment were due to OSI rather than improved disease activity.

In the absence of an effective pharmacological treatment strategy, OSI may be an effective treatment modality for the management of D2T RA.

Plain radiography continues to be a crucial imaging modality in the field of rheumatology. It provides a comprehensive view of bone-related changes and highlights soft tissue abnormalities. The significance of radiography extends to early disease detection, aiding in differentiating various conditions and monitoring the effectiveness of treatment. It remains the preferred imaging technique for evaluating disease progression, offering insights into cumulative damage over time.In the early stages of arthritis, magnetic resonance imaging and ultrasound are the preferred methods because they can identify subtle disease activity, such as synovitis, tenosynovitis, and dactylitis, osteitis or bone edema, and enthesitis. But they have a lower specificity in distinguishing among various rheumatic conditions.We evaluate the use of radiography in inflammatory arthropathies, highlighting its role in differential diagnoses. Advances in automated radiographic assessment for arthritis are addressed. The discussion encompasses rheumatoid arthritis, juvenile idiopathic arthritis, other connective tissue diseases, and spondyloarthritis.

Drug withdrawal in rheumatoid arthritis (RA) in remission can reduce toxicity, but with the risk of flare which requires close monitoring. We explored the potential of patient-reported outcomes (PROs) for flare detection among RA patients in sustained remission after conventional synthetic disease-modifying antirheumatic drug (csDMARD) cessation.

Four PROs (Factors that Limit sustAined Remission in rhEumatoid arthritis (FLARE-RA), EuroQol-5 Dimensions (EQ5D), Routine Assessment of Patient Index Data-3 (RAPID-3) and RA Flare Questionnaire (RA-FQ)) were captured at baseline and at sequential visits until time-of-flare or end of 6-month follow-up as part of the BIO-FLARE prospective cohort study. Flare was defined as any of (i) Disease Activity Score 28 (DAS28)-C reactive protein (CRP) ≥3.2 at any visit, (ii) DAS28-CRP≥2.4 on two visits within 2 weeks or (iii) resuming DMARD and/or steroid therapy despite DAS28-CRP<2.4. Cox regression models with time-varying covariates were fitted to evaluate associations between PRO changes and likelihood of flare. Receiver-operating characteristic (ROC) curves enabled discriminatory changes in each PRO to be compared as a means of identifying flare.

58/121 (47.9%) participants (70.1% females, mean age 64.8 years) experienced a flare. A 1-point change in each PRO score was strongly associated with flare development in the multivariate Cox regression model (p<0.001 in each case). ROC curve analysis confirmed that monitoring adverse changes in PROs from baseline offered robust discriminatory utility for identifying flare occurrence. This was most evident for RA-FQ and FLARE-RA (both areas under the curves 0.90, 95% CI 0.84 to 0.96; p=0.001); for example, an RA-FQ increment of ≥5.5 from baseline identified objective flare with positive and negative predictive values of 80% and 91%, respectively.

Our data support the potential value of remote PRO monitoring of RA patients in drug-free remission to identify flare occurrence.

Rheumatoid arthritis (RA) is one of the most prevalent autoimmune, chronic, inflammatory disease characterized by joint inflammation, synovial swelling, loss of articular structures, swelling, and pain. RA is a major cause of discomfort and disability worldwide, associated with infectious agents, genetic determinants, epigenetic factors, advancing age, obesity, and smoking. Although conventional therapies for RA alleviate the symptoms, but their long-term use is associated with significant side effects. This necessitates the urge to discover complementary and alternative medicine from natural products with minimum side effects.

In this review, natural product's potential mechanism of action against RA has been documented in the setting of in-vivo, in-vitro and pre-clinical trials, which provides new treatment opportunities for RA patients. The bioefficacy of these natural product's bioactive compounds must be further studied to discover novel natural medications for RA with high selectivity, improved effectiveness, and economic replacement with minimum side effects.

The current review article was designed systematically in chronological order. Plants and their phytochemicals are discussed in an order concerning their mode of action. All the mechanisms of action are depicted in diagrams which are thoroughly generated by the Chembiodraw to maintain the integrity of the work. Moreover, by incorporating the recent data with simple language which is not incorporated previously, we tried to provide a molecular insight to the readers of every level and ethnicity. Moreover, Google Scholar, PubMed, ResearchGate, and Science Direct databases were used to collect the data.

Traditionally, various plant extracts and bioactive compounds are effectively used against RA, but their comprehensive pharmacological mechanistic actions are rarely discussed. Therefore, the objective of this study is to systematically review the efficacy and proposed mechanisms of action of different plants and their bioactive compounds including Tripterygium wilfordii Hook F (celastrol and triptolide), Nigella sativa (thymoquinone), Zingiber officinale (shogaols, zingerone), Boswellia serrata (boswellic acids), Curcuma longa (curcumin), and Syzygium aromaticum (eugenol) against rheumatoid arthritis.

These plants have strong anti-inflammatory, anti-oxidant, and anti-arthritic effects in different study designs of rheumatoid arthritis with negligible side effects. Phytomedicines could revolutionize pharmacology as they act through alternative pathways hence seeming biocompatible.

Rheumatoid arthritis (RA) is an autoimmune disease of the joints with occasional involvement of extra-articular organs. Although rheumatoid factor (RF) is associated with more severe baseline disease severity and a higher incidence of extraarticular diseases, whether it predicts response to treatment in patients taking conventional disease-modifying antirheumatic drugs (DMARDs) is unclear as evidence has so far been conflicting.

A 3-year (January 2021 to December 2023) multicenter retrospective cohort study was done at 1 public and 4 private hospitals in Addis Ababa, Ethiopia. After categorizing eligible patients into RF-positive and RF-negative, they were retrospectively followed for 12 months. A disease activity score in 28 joints (DAS-28) score of less than 2.6 was used to define remission. The time-to-remission between the two groups was compared using the Kaplan-Meier survival function. In order to control for potential confounders, the Cox regression model was used to calculate adjusted hazard ratios (AHR).

After screening a total of 676 patients, 207 were found to be eligible for the study. The median (interquartile range (IQR)) age at diagnosis was 46 (36 - 58) years, and 171 (82.6%) were female. At 12 months of follow-up, remission occurred in 39.4% of RF-positive patients and 60.0% of RF-negative patients (AHR, 0.57; 95% confidence interval (CI), (0.368-0.88; P = 0.012). The overall remission rate was 47.3%.

In this study, among patients taking conventional DMARDs, RF-negative RA patients achieved better remission rates compared to RF-positive patients. The study provides insight into the association between RF status and treatment outcome among RA patients in a resource-limited setting. Key Points • Our work adds to the existing body of knowledge regarding the relationship between RF positivity and response to treatment in patients with RA. It is also the first study to examine this association in a previously understudied population of Sub-Saharan Africa.

A subset of human circulating FoxP3+ regulatory T cells expresses CD39 (cTreg39+) and hydrolyses pro-inflammatory adenine nucleotides released at inflammatory foci, releasing the anti-inflammatory agent adenosine. Methotrexate (MTX), inhibiting 5-aminoimidazole-4-carboxamide ribonucleotide transformylase, enhances the extrusion of adenine nucleotides and may help Treg39+ cells control inflammation. Therefore, we examined the relation of cTreg39+ cells with the effect of MTX in early rheumatoid arthritis (eRA).

Freshly isolated peripheral blood lymphocytes from 98 untreated eRA patients and 98 healthy controls (HC) were examined by cytometry. Twelve months (12 m) after initiating MTX, 82 patients were clinically re-evaluated and cytometry was repeated in 40 of them. The effect of MTX on Treg cell potency was assessed in Treg/Tresp cocultures.

The baseline (0 m) cTreg39+ cell frequency was elevated in eRA above HC levels. Patients who reached low disease activity at 12 months (12 m-LDA, DAS28-ESR ≤ 3.2, n = 51) had presented with a significantly higher 0 m cTreg39+ frequency vs those who did not (n = 31). The 0 m cTreg39+ cutoff for attaining 12 m-LDA was 42.0% (sensitivity = 90.4%, specificity = 96.8%). At 12 m, the cTreg39+ frequency was no longer elevated but its association with disease activity remained: it was still significantly higher in patients who had reached LDA vs those who had not. In vitro, MTX augmented the Treg39+ cell potency but had no effect on Treg39- cells.

MTX cooperates with Treg39+ cells and the baseline cTreg39+ frequency predicts the response to MTX in eRA. In addition, the transiently elevated baseline cTreg39+ frequency in eRA may provide a slot for prompt MTX initiation.

To provide recommendations on risk mitigation, diagnosis and treatment of infectious complications associated with the practice of regional anesthesia, acute and chronic pain management.

Following board approval, in 2020 the American Society of Regional Anesthesia and Pain Medicine (ASRA Pain Medicine) commissioned evidence-based guidelines for best practices for infection control. More than 80 research questions were developed and literature searches undertaken by assigned working groups comprising four to five members. Modified US Preventive Services Task Force criteria were used to determine levels of evidence and certainty. Using a modified Delphi method, >50% agreement was needed to accept a recommendation for author review, and >75% agreement for a recommendation to be accepted. The ASRA Pain Medicine Board of Directors reviewed and approved the final guidelines.

After documenting the incidence and infectious complications associated with regional anesthesia and interventional pain procedures including implanted devices, we made recommendations regarding the role of the anesthesiologist and pain physician in infection control, preoperative patient risk factors and management, sterile technique, equipment use and maintenance, healthcare setting (office, hospital, operating room), surgical technique, postoperative risk reduction, and infection symptoms, diagnosis, and treatment. Consensus recommendations were based on risks associated with different settings and procedures, and keeping in mind each patient's unique characteristics.

The recommendations are intended to be multidisciplinary guidelines for clinical care and clinical decision-making in the regional anesthesia and chronic interventional pain practice. The issues addressed are constantly evolving, therefore, consistent updating will be required.

To describe antibiotic use in patients with inflammatory arthritis (IA) and in the background population (BP) within one year before and after IA diagnosis.

Using data from Danish nationwide registries, we identified all adults with a first-time diagnosis of RA, PsA, or AS/spondyloarthritis (AS/SpA) from 2010 through 2018. For each IA patient, we randomly sampled 10 persons from the BP, matched on sex and birthdate. We calculated the prevalence (n [%]) of any antibiotic dispensing and the total antibiotic dispensing in the year before and after diagnosis.

We identified 28 504 new-onset IA patients (RA, n = 16 130; PsA, n = 5988; AS/SpA, n = 6386) and 285 040 BP individuals. Within one year before diagnosis, the total amount of dispensed antibiotics was higher in both RA, PsA and As/SpA compared with the BP (prevalence rate ratios [PRR], 1.48 [1.46; 1.51]; 1.67 [1.62; 1.72]; 1.52 [1.47; 1.56], respectively). The amount increased with 22% in IA patients three months before diagnosis compared with the preceding three-month period.  Although the prevalence of any antibiotic dispensing in IA patients decreased in the year following the diagnosis (IA; 40.6%), the total one-year antibiotic dispensing remained constant in RA (PRR 0.99 [0.97; 1.01]), decreased in PsA (0.91 [0.87; 0.94]) and increased in AS/SpA (1.08 [1.04; 1.12]) patients after diagnosis compared with before.

Antibiotics are more frequently dispensed to individuals developing IA compared with the BP. Antibiotic utilization patterns change after IA diagnosis with marked differences among IA subgroups.

The safety of antirheumatic drugs in pregnancy and their impact on maternal and neonatal outcomes are understudied. Despite pregnant individuals being excluded from clinical trials, their continued use of medications raises the importance of addressing knowledge gaps regarding safety and impact on outcomes. A scoping review was conducted following JBI methodology and PRISMA reporting guidelines to describe how antirheumatic drugs and associated adverse pregnancy outcomes have been investigated in observational studies using claims data. Electronic databases (MEDLINE (Ovid), Embase (Ovid), and CINAHL (EBSCO)) and grey literature were searched for observational studies using claims data to evaluate antirheumatic drug effects on pregnancy outcomes in individuals with rheumatic diseases. Of 4,325 articles identified, 38 eligible articles were included. The effects of conventional synthetic disease-modifying antirheumatic drugs (n =  37, 97.4%) and tumor necrosis factor inhibitor biological agents (n =  23, 60.5%) were extensively reported. Preterm birth (n =  25, 65.8%), preeclampsia (n =  17, 44.7%), stillbirth (n =  17, 44.7%), caesarean delivery (n =  16, 42.1%), and congenital anomalies (n =  14, 36.8%) were the most reported adverse pregnancy outcomes. Of 14 studies reporting congenital anomalies, 12 (85.7%) specified ICD codes and 4 (28.6%) specified validated definitions for identification in claims data, the most of any reported adverse pregnancy outcome. We found considerable ambiguity and heterogeneity in adverse pregnancy outcome definitions in claims data. There is a need for greater transparency and consistency in outcome reporting in observational studies using claims data. Protocol registration details: OSF, https://osf.io/5e6tp.

Rheumatoid arthritis (RA) is a systemic autoimmune disease involving activation of the immune system and the infiltration of immune cells. As the first immune cells to reach the site of inflammation, neutrophils perform their biological functions by releasing many active substances and forming neutrophil extracellular traps (NETs). The overactivated neutrophils in patients with RA not only directly damage tissues but also, more importantly, interact with various other immune cells and broadly activate innate and adaptive immunity, leading to irreversible joint damage. However, owing to the pivotal role and complex influence of neutrophils in maintaining homoeostasis, the treatment of RA by targeting neutrophils is very difficult. Therefore, a comprehensive understanding of the interaction pathways between neutrophils and various other immune cells is crucial for the development of neutrophils as a new therapeutic target for RA. In this study, the important role of neutrophils in the pathogenesis of RA through their crosstalk with various other immune cells and nonimmune cells is highlighted. The potential of epigenetic modification of neutrophils for exploring the pathogenesis of RA and developing therapeutic approaches is also discussed. In addition, several models for studying cell‒cell interactions are summarized to support further studies of neutrophils in the context of RA.

The diagnostic value of primary biliary cholangitis (PBC)-specific antibodies in patients with elevated alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) levels, and other identifiable causes, was unclear. Our study aimed to determine whether etiological treatments in PBC-specific antibody-positive patients could improve liver biochemical tests, thereby distinguishing them from individuals with PBC.

We enrolled patients who were positive for PBC-specific antibodies and elevated ALP and/or GGT levels but with other identifiable etiologies. Changes in liver biochemistry following non-ursodeoxycholic acid etiological treatments were monitored.

A total of 155 patients with positive PBC-specific antibodies and elevated ALP and/or GGT levels due to non-PBC diseases were enrolled. Among them, 100 patients were diagnosed with non-PBC liver diseases, mainly metabolic-associated fatty liver disease, drug-induced liver injury, and autoimmune hepatitis. Additionally, 55 patients had non-liver diseases, predominantly connective tissue diseases. The median follow-up duration was 15.9 (4.7-25.6) months. Among 141 patients who completed follow-up after receiving etiological treatments, 85.1% (120/141) showed improvement in ALP and/or GGT levels, with 51.8% (73/141) achieving normalization of both ALP and GGT. However, 68 patients continued to exhibit elevated ALP and/or GGT, with 55 patients displaying isolated GGT elevation and 11 patients showing liver histological changes not consistent with PBC.

PBC-specific antibodies, along with elevated ALP and GGT levels, may occur in various non-PBC diseases. Etiological treatments may improve or even resolve cholestatic biochemistry. For these patients, initiating etiological treatment rather than immediately starting ursodeoxycholic acid therapy would be justified.

Early diagnosis and modern treatment have changed everyday life of patients with rheumatoid arthritis (RA). However, symptoms are still pronounced several years after diagnosis. The aim of this study is therefore to synthesise the perception of everyday life in men and women with contemporary treated RA over the course of the first decade after diagnosis. This will be achieved by comparing subjective experiences with quantitative measures of disability and disease activity.

A longitudinal convergent mixed method was used. Thirty-one patients, clinically diagnosed with RA and ≥ 18 years of age, were recruited from the TIRA-2 project in southeast Sweden. Patients were followed over a decade regarding disease activity (DAS28), grip force (Grippit), pain intensity (VAS mm) and activity limitations (HAQ). Participation in valued life activities (VLA-swe) was assessed 10 years after diagnosis. The patients took part in individual interviews three- and ten-years post-diagnosis. Quantitative data were analysed through descriptive analyses and linear mixed models. The interviews were analysed using directed content analyses. The results from the quantitative and qualitative analyses were integrated in accordance with the chosen design.

Discrepancies between the quantitative and qualitative results were revealed, along with differences between sexes. Women expressed more problems related to disease activity and grip force, which did not coincide with the quantitative results. In fact, women experienced difficulties in activities despite decreased disease activity. Furthermore, their pain score changed quantitatively over time, which was not expressed in the interviews. These disconfirming results were not seen in men. Both women and men displayed confirming results regarding activity limitation. Some issues, such as with basic needs, were more visible quantitatively than through interviews.

Men and women with contemporary treated RA still experience disability a decade after diagnosis. Additionally, patients' experiences and quantitatively measured outcomes do not always coincide. The qualitative data adds information and thereby complements the quantitative data on disability. Our results confirm the importance of person-centred rehabilitation in optimising patients' possibilities for participation in everyday life.

Not applicable.

Rheumatoid arthritis (RA) is a chronic autoimmune disease and the integrity of CX3CR1+ synovial macrophage barrier significantly impacts its progression. However, the mechanisms driving the dynamic changes of this macrophage barrier remain unclear. Traditional drug therapies for RA have substantial limitations. Mesenchymal stem cells (MSCs)-based cell therapy, especially adipose-derived stem cells (ADSCs), hold therapeutic promise. Nevertheless, the underlying therapeutic mechanism of ADSCs, especially their interactions with CX3CR1+ macrophages, require further investigation.

To explore the interaction between ADSCs and CX3CR1+ synovial macrophages during barrier reconstruction, underlying the therapeutic mechanism of ADSCs and the mechanisms on the dynamic changes of the macrophage barrier, scRNA-seq analysis was conducted 4 days after ADSCs injection in serum transfer-induced arthritis model mice. The roles of mitochondria transfer and ADSCs transplantation were also explored. Bulk RNA-seq analysis was performed after the co-culture of ADSCs and CX3CR1+ synovial macrophages. To study the in vivo fate of ADSCs, bulk RNA-seq was performed on ADSCs retrieved at 0, 2, 4, and 7 days post-injection.

Intra-articular injection of ADSCs effectively attenuated the pathological progression of mice with serum transfer-induced arthritis. ADSCs gradually adhered to CX3CR1+ macrophages, facilitating the restore of the macrophage barrier, while the absence of this barrier greatly weakened the therapeutic effect of ADSCs. scRNA-seq analysis revealed an Atf3high Ccl3high subset of CX3CR1+ macrophages with impaired oxidative phosphorylation that increased during RA progression. ADSCs-mediated reduction of this subset appeared to be linked to mitochondrial transfer, and transplantation of isolated ADSCs-derived mitochondria also proved effective in treating RA. Both bulk RNA-seq and scRNA-seq analyses revealed multiple interaction mechanisms between ADSCs and CX3CR1+ macrophages, including Cd74/Mif axis and GAS6/MERTK axis, which contribute to barrier restoration and therapeutic effects. Furthermore, bulk RNA-seq analysis showed that ADSCs primarily contribute to tissue repair and immune regulation subsequently.

Our results suggest that ADSCs ameliorated the energy metabolism signature of CX3CR1+ lining macrophages and may promote barrier restoration through mitochondria transfer. In addition, we elucidated the fate of ADSCs and the therapeutic potential of mitochondria in RA treatment.

Rheumatic diseases encompass a wide range of autoimmune and inflammatory disorders, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), psoriatic arthritis (PsA), and systemic sclerosis (SSc). These conditions often result in chronic pain, disability, and reduced quality of life, with unpredictable disease courses that may lead to joint destruction, organ damage, or systemic complications. Biomarkers, defined as measurable indicators of biological processes or conditions, have the potential to transform clinical practice by improving disease diagnosis, monitoring, prognosis, and treatment decisions. While significant strides have been made in identifying and validating biomarkers in rheumatic diseases, challenges remain in their standardization, clinical utility, and integration into routine practice. This review provides an overview of the current state of biomarkers in rheumatic diseases, their roles in clinical settings, and the emerging advancements in the field.

Achieving clinical deep remission (CliDR) in rheumatoid arthritis (RA) is essential to prevent long-term joint damage, enhance patient quality of life, and possibly reduce and discontinue medication eventually. Recent research advances have raised the possibility of achieving deep remission and even drug-free remission. This comprehensive review examines current strategies of RA therapy, concept of deep remission, challenges, and the emerging prospects of drug-free remission. It also reviews the role of different treatments, including conventional disease-modifying antirheumatic drugs (DMARDs), biologic agents, and targeted synthetic drugs, in the journey from deep remission to drug-free remission. In addition, it emphasizes the importance of patient-centered care, early diagnosis, and individualized treatment approaches in optimizing outcomes for patients with RA.

Currently, expedited by the coronavirus disease 2019 pandemic, there is high demand for allocating patients in a state of low disease activity to telehealth, ideally based on remote measurements. This cross-sectional study assesses the discriminative accuracy of the Rheumatoid Arthritis Impact of Disease (RAID) questionnaire regarding high and low disease activity. Furthermore, we aimed to optimize this classification, developing a remote triage score based on RAID and other patient-reported outcome measures (PROMs).

Data were acquired from an outpatient clinic cohort of chronic rheumatoid arthritis patients at a large trainee hospital in the Netherlands. Patients were divided into high and low disease categories, based on 28-joint Disease Activity Score-C-reactive protein. Least absolute shrinkage and selection operator logistic regression were performed, including RAID item scores and other PROMs. Receiver operating characteristics curves and areas under the curve (AUCs) were obtained, and cut-off scores were based on predefined criteria of 90% and 95% sensitivity.

In total, 278 patients were analysed, of whom 77.2% were identified as having low disease activity. RAID results correlated with DAS28-CRP, showing good performance. The regression model included the RAID items pain and functional disability assessment, and the self-reported swollen joint count (SR-SJC). With an AUC of 0.88 (95% confidence interval 0.84-0.92), this model performed better than the RAID total score.

A remote triage score based on a composite score of pain, functional disability assessment, and SR-SJC can detect a sufficient proportion of patients with low disease activity who can be allocated to remote consultations.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that affects the joints and causes pain, swelling, and deformity. Current treatments, including nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and disease-modifying antirheumatic drugs, often have limited efficacy and adverse side effects. Nanostructured lipid carriers (NLCs) are promising drug delivery agents for treating RA. NLCs are comprised of solid and liquid lipids, forming a nanostructured matrix that enhances drug solubility, stability, and controlled release. They offer advantages over traditional carriers such as improved skin penetration, increased bioavailability, and reduced systemic side effects. Topical NLC formulations show improved stability and skin absorption, targeting drugs specifically to the affected joints, thus reducing the required dose and systemic exposure. Studies on NLCs for delivering anti-inflammatory and antirheumatic drugs, such as methotrexate, indomethacin, and curcumin, in RA animal models indicate the potential for improved therapeutic efficacy and safety. NLCs represent a promising approach for targeted RA drug delivery, offering better efficacy, fewer side effects, and higher patient compliance. However, further research is needed to optimize NLC formulations and evaluate their clinical efficacy and safety in RA patients. The development of NLC-based drug delivery systems for RA treatment may lead to more effective and well-tolerated therapies, thereby improving the quality of life of patients with this debilitating disease.

Dihydrofolate reductase activity is required in One Carbon Metabolism to ensure that the biologically active form of folate, tetrahydrofolate, is replenished and available as an enzyme cofactor for numerous cellular reactions, including purine and pyrimidine synthesis. Most cellular enzyme activity was thought to arise from the product of the DHFR gene on chromosome 5, with its paralogue DHFR2 (formerly known as DHFRL1; [chromosome 3]), believed to be responsible for mitochondrial dihydrofolate activity based on recombinant versions of the enzyme. In this paper, we confirm our earlier findings that dihydrofolate reductase activity in mitochondria is derived from the DHFR gene rather than DHFR2 and that endogenous DHFR2 protein is not detectable in most cells and tissues. Using HepG2 cell lines with modulated expression of either DHFR or DHFR2, we observed an impact of DHFR2 RNA on One Carbon Metabolism mediated through an influence on DHFR expression and activity. Knockout of DHFR2 results in a drop in dihydrofolate reductase activity, lowered 10-formyltetrahydrofolate abundance, downregulation of DHFR mRNA, and diminished DHFR protein abundance. We also observed downregulation of Serine Hydroxymethyltransferase and Thymidylate Synthase, two One Carbon Metabolism enzymes that work with DHFR to support de novo thymidylate synthesis. The expression of recombinant DHFR2 resulted in restoration of DHFR mRNA and protein levels while a DHFR knockdown cell line showed upregulation of DHFR2 RNA. We propose that the DHFR2 gene encodes an RNA molecule that regulates cellular dihydrofolate reductase activity through its impact on DHFR mRNA and protein.

The aim of this study was to investigate the prevalence of social frailty and associated factors.

A total of 655 consecutive patients who were able to complete the Kihon Checklist (KCL) and the Questionnaire on Social Frailty between June and August 2022 were enrolled. Social frailty was assessed using the Makizako Social Frailty Index. Patient characteristics were analysed by analysis of variance. Factors associated with social frailty were analysed using multivariate logistic analysis. Spearman's rank correlation coefficients were used to examine correlations between each KCL domain and social frailty.

The mean age was 68 years, and the disease duration was 12 years; 73% of patients were female. Social frailty was present in 30.8% of patients, with 36.5% classified as social prefrailty. Multivariate analysis revealed age and Health Assessment Questionnaire-Disability Index to be independent factors associated with social frailty. The proportion of social frailty increased with increasing age and worsening Health Assessment Questionnaire-Disability Index scores. The KCL domain 'Isolation' was the most strongly associated with social frailty (r = .601, P < .001), with higher scores associated with a higher proportion of social frailty.

Social frailty in patients with rheumatoid arthritis is associated with age and physical impairment (Health Assessment Questionnaire-Disability Index). Moreover, the KCL domain 'Isolation' was strongly associated with social frailty.

This study evaluated the effectiveness of Janus kinase inhibitors (JAKi) in patients with difficult-to-treat rheumatoid arthritis (D2T RA).

This study included 220 patients with RA who were treated with JAKi. Sixty-two patients were naïve to biological disease-modifying antirheumatic drugs (bDMARDs)/JAKi (1st group), 57 patients were failure to one bDMARDs/JAKi (2nd group), and 101 patients were failure to ≥ 2 bDMARDs/JAKi. Of these 101 patients, 25 did not meet the D2T RA criteria (non-D2T RA group) and 76 met the D2T RA criteria (D2T RA group).

: DAS28-ESR was improved in all groups at 24 weeks (1st: P < .01, 2nd: P < .01, non-D2T RA: P = .01, D2TRA: P = .02), and improvement ratio of DAS28-ESR was not different between DT2RA group and 2nd (P = .73) or non-D2T RA group (P = .68). Glucocorticoid use [odds ratios: 8.67; 95% confidence interval (CI): 1.23-60.90; P = .03] and number of past bDMARD/JAKi uses ≥ 3 (odds ratios: 10.55; 95% CI: 1.39-80.30; P = .02) were risk factors for DAS28-ESR ≥ 3.2 at 24 weeks in the D2T RA group.

Clinical efficacy of JAKi in D2T RA group did not differ from that in 2nd and non-D2T RA groups. Glucocorticoid use and multiple bDMARD/JAKi failure were poor prognostic factors for D2T RA.

Inflammatory arthritis affects approximately 2-3% of adults worldwide. For patients newly diagnosed with arthritis, effective self-management is crucial, as they often face several physiological, emotional, and social challenges. A self-management intervention called NISMA was thus developed to cater to this group. This study aimed to evaluate the feasibility and fidelity of this intervention before conducting a full-scale randomized controlled trial.

This feasibility study was conducted as a single-center randomized controlled trial. Twenty participants were expected to be sufficient for assessing the feasibility outcomes. The control group received only the usual care, while the intervention group received the NISMA intervention in addition, which involved individual and group sessions in a multidisciplinary setting. Feasibility was evaluated based on the recruitment, data collection, retention, and randomization processes. The patient-reported outcome measures and clinical measures were collected to review their potential for inclusion in a future randomized controlled trial. Fidelity was assessed by using documentation sheets filled in by the health professionals and audio recordings of the sessions to examine whether the intervention's principles and components were adequately addressed.

Among 47 eligible patients, we recruited 23 participants during a period of 4 months. The recruitment rate was 47% and the retention rate 91%. Randomization, although accepted, led to some disappointment in the control group. Data collection was effective, with only minimal missing data (< 1%). The fidelity was considered as high, as results indicated that nurses effectively engaged in collaborative partnerships with patients, utilizing planned questioning techniques and self-management strategies for problem-solving and resource utilization. However, action planning was inconsistently applied.

The study demonstrated the feasibility and the overall high fidelity of delivering the NISMA intervention to patients newly diagnosed with inflammatory arthritis. The insights from the study are useful for identifying the areas that require modifications before initiating a randomized controlled trial.

ClinicalTrials.gov ID: NCT06063252. Registered 02 October 2023 - retrospectively registered.

Macrophages are highly variable immune cells that are important in controlling inflammation and maintaining tissue balance. The ability to polarize into two major types-M1, promoting inflammation, and M2, resolving inflammation and contributing to tissue repair-determines their specific roles in health and disease. M2 macrophages are particularly important for reducing inflammation and promoting tissue regeneration, but their function is shaped mainly by surrounding cells. This is evident in obesity, diabetes, and chronic inflammation. Although many cytokines regulate macrophage polarization, interleukin-6 (IL-6) and interleukin-1β (IL-1β) are major players, but their effects on M2 macrophage behavior under metabolic stress remain unclear. This study describes the intricacies within M2 macrophages concerning IL-6 and IL-1β signaling when under metabolic stress. Though, more frequently than not, IL-6 is labelled as pro-inflammatory, it can also behave as an anti-inflammatory mediator. On the other hand, IL-1β is the main pro-inflammatory agent, particularly in metabolic disorders. The relationship between these cytokines and the macrophages is mediated through important pathways such as JAK/STAT and NFκB, which get perturbed by metabolic stress. Therefore, metabolic stress also alters the functional parameters of macrophages, including alterations in mitochondrial metabolism, glycolytic and oxidative metabolism. Phosphorylation alters the kinetics involved in energy consumption and affects their polarization and their function. However, it has been suggested that IL-6 and IL-1β may work in concert or competition when inducing M2 polarization and, importantly, implicate cytokine release, phagocytic activity, and tissue repair processes. In this review, we discuss the recent literature on the participation of IL-6 and IL-1β cytokines in macrophage polarization and how metabolic stress changes cytokine functions and synergistic relations. A better understanding of these cytokines would serve as an important step toward exploring alternative antiviral strategies directed against metabolic disturbance and, hence, approve further endeavors.

The prevalence of Pneumocystis jirovecii (PJ) pneumonia among rheumatic patients is rising. PJ colonization serves as a reservoir for transmission and precedes the development of PJ pneumonia. We aim to clarify the association of PJ colonization in patients of rheumatoid arthritis (RA) treated with biologics or Janus kinase inhibitors (JAKi).

A prospective cohort study was performed from March 2021 to July 2022 in the rheumatology outpatient department of National Cheng Kung University Hospital. We obtained oral-wash samples from asymptomatic RA patients treated with biologic disease-modifying antirheumatic drugs (bDMARDs) and JAKi. A real-time quantitative polymerase chain reaction assay focusing on the mitochondrial large subunit ribosomal ribonucleic acid gene of PJ was applied to detect colonization.

One hundred and ten RA patients were enrolled. Adjusted odds ratios (ORs) of PJ colonization were 6.40 (95% CI 1.34-30.57, p-value =0.02) in patients receiving bDMARDs or JAKi. Specifically, in patients treated with bDMARDs the adjusted OR was 8.08 (95% CI 1.57-41.51, p-value=0.012), and a trend toward developing PJ colonization was further identified in patients receiving JAKi (adjusted OR: 4.79, 95% CI 0.89-25.91, p=0.069). Among patients treated with bDMARDs or JAKi, medication duration >3 years and age >60 y/o are risk factors for PJ colonization.

RA patients on bDMARDs or JAK inhibitors have an approximately 6-fold higher risk of developing P. jirovecii colonization. Patients treated with bDMARDs had an 8-fold higher risk of P. jirovecii colonization. Risk factors of PJ colonization are medication duration >3 years and age > 60 y/o.

Interstitial lung disease (ILD) is a potential severe complication of various rheumatic diseases, typically connective tissue diseases (CTD), associated with significant morbidity and mortality. ILD may occur during the course of the disease but may also be its first manifestation. Several cell types are involved in ILD's pathogenesis, and if not controlled, pulmonary inflammation may lead to pulmonary fibrosis.

We searched PubMed, Medline, and the Cochrane Library for papers published between 1995 and February 2017 in the first version, and between 2017 and April 2023 using combinations of words. The most frequent systemic rheumatic diseases associated with ILD are systemic sclerosis (SSc), rheumatoid arthritis (RA), and idiopathic inflammatory myositis. Treatment and monitoring guidelines are still lacking, and current treatment strategies have been extrapolated from the literature on SSc and established treatments for non-pulmonary systemic rheumatic manifestations.

Given the complexity of diagnosis and the paucity of treatment trials, managing CTD patients with ILD is challenging. It requires the skills of multidisciplinary CTD-ILD clinics including at least rheumatologists and lung specialists.

CT-P47 is a candidate biosimilar of tocilizumab. This 12-week, randomized, double-blind, parallel-design, phase 1 study aimed to demonstrate pharmacokinetic (PK) equivalence of CT-P47 and reference tocilizumab. Participants were healthy Japanese adults aged 18-55 years. Participants were randomized (1:1:1) to receive a single intravenous dose (8 mg/kg) of CT-P47, EU-approved tocilizumab (EU-tocilizumab), or US-licensed tocilizumab (US-tocilizumab). Primary PK endpoints were area under the concentration-time curve (AUC) from time zero to infinity, AUC from time zero to the last quantifiable concentration, and maximum serum concentration. Additional PK variables, safety, and immunogenicity were evaluated. The study was conducted from January 20 to May 26, 2023, in three centers in Japan. In total, 133 male participants were randomized (n = 45 to CT-P47, n = 44 to EU-tocilizumab, and n = 44 to US-tocilizumab). For all primary PK variables, 90% confidence intervals of the ratio of geometric least squares means were within the predefined equivalence margin of 0.80-1.25. Secondary PK variables were similar across groups. The most common treatment-emergent adverse event (TEAE) was neutrophil count decreased, occurring in 15 (33.3%), 13 (30.2%), and 12 (27.3%) participants in the CT-P47, EU-tocilizumab, and US-tocilizumab groups, respectively. There were no serious TEAEs, deaths, or study drug discontinuations due to TEAEs. Few participants were anti-drug antibody (ADA)- or neutralizing antibody (NAb)-positive. At the end of study, four (8.9%), one (2.3%), and two (4.5%) participants in the CT-P47, EU-tocilizumab, and US-tocilizumab groups, respectively, were ADA-positive; two (4.4%), zero (0%), and one (2.3%) in the respective groups were NAb-positive. CT-P47 demonstrated PK equivalence and comparable safety to EU- and US-tocilizumab.

The incorporation of machine learning is becoming more prevalent in the clinical setting. By predicting clinical outcomes, machine learning can provide clinicians with a valuable tool for refining precision medicine approaches and improving treatment outcomes.

This was a post hoc analysis of pooled patient-level data from the global, real-world ACTION and ASCORE trials in patients with rheumatoid arthritis (RA) initiating abatacept. Patient demographic and disease characteristics were input across 10 machine learning models used to predict 12-month treatment retention. Retention was defined as treatment for > 365 days or ≤ 365 days in patients who achieved remission or major clinical response (based on European Alliance of Associations for Rheumatology response criteria). The pooled dataset was split into a training/validation cohort for model development and a test cohort for an unbiased evaluation of performance. SHapley Additive exPlanation (SHAP) values determined the level of importance and directionality for key patient features predicting abatacept retention.

The pooled ACTION and ASCORE dataset included 5320 patients with RA (mean [standard deviation] age 57.7 [12.7] years; 79% female). The 12-month abatacept retention rate was 61% (n = 3236) with a discontinuation rate of 39% (n = 2037). In the training set (n = 4218), the gradient-boosting classifier model demonstrated the best performance (testing accuracy: 62%). This model had an area under the receiver operating characteristic curve (95% confidence interval) of 0.620 (0.586, 0.653) and F1 score of 0.659 (0.625, 0.689) in the test set of patients (n = 1055). Using this model, the five most important variables predicting 12-month abatacept retention were low body mass index (BMI), low American College of Rheumatology functional status class, anti-citrullinated protein antibody (ACPA) positivity, low Patient Global Assessment, and younger age.

The gradient-boosting classifier model identified key patient features predictive of abatacept retention from this large, real-world study population. The SHAP values conveyed the directionality and importance of BMI, functional status, ACPA serostatus, Patient Global Assessment, and age for abatacept retention. Findings are consistent with previous observations and help validate the machine learning approach for predictive modelling in RA treatment, and may help inform clinical decision making.

NCT02109666 (ACTION), NCT02090556 (ASCORE).

To compare work loss after starting tumour necrosis factor inhibitors (TNFi), rituximab, abatacept or tocilizumab in patients with rheumatoid arthritis (RA).

We used data from the Swedish Rheumatology Quality Register to identify patients aged 19-62 years who were treated with TNFi (n=15 093), rituximab (n=2123), abatacept (n=1877) or tocilizumab (n=1720) between 2007 and 2020. Data on work loss (0-365 days per year) from sick leave and disability pension were retrieved from linkage to the Social Insurance Agency. Patients in the different treatment arms were balanced regarding baseline covariates using inverse probability weighting (IPTW).

Work loss increased for patients with RA until drug treatment initiation, reached a peak in the month after treatment initiation and then levelled off. Following IPTW, at 3 years before starting the treatment, there were no statistically significant differences in the mean annual adjusted work loss days between rituximab, abatacept or tocilizumab vs TNFi (mean difference vs TNFi: rituximab 1.1 days, 95% CI -4.5 to 6.7; abatacept 3.3, 95% CI -2.6 to 9.2; tocilizumab 1.2, 95% CI -4.9 to 7.3). At 3 years after starting the treatment (latest January 2021), there were also no statistically significant differences in the mean annual adjusted work loss days (mean difference: rituximab -4.8 days, 95% CI -11.3 to 1.7; abatacept 5.3, 95% CI -1.8 to 12.3; tocilizumab -0.6, 95% CI -7.7 to 6.5).

Taking channelling into account, patients with RA treated with TNFi, rituximab, abatacept or tocilizumab had similar trajectories of work loss from sick leave and disability pension until treatment initiation, and similar trend breaks and plateau 3 years thereafter.

Rheumatoid arthritis (RA) is a chronic inflammatory disease that leads to joint deformity and ultimately disability. The metabolite of quercetin, 4-Methylcatechol (4-MC), has been acknowledged for its anti-inflammatory and antioxidant properties; however, the protective effects of 4-MC on RA and its underlying mechanisms remain incompletely elucidated. In a collagen-induced arthritis (CIA) model, we observed that 4-MC effectively mitigated joint inflammation and bone destruction in CIA mice. Additionally, it significantly suppressed the upregulated expression of inflammatory cytokines in synovial tissues. Mechanistically, upon lipopolysaccharide (LPS) stimulation, 4-MC inhibited M1 polarization of macrophages and induced a phenotypic switch from M1 to M2 phenotype, thereby reducing the release of pro-inflammatory cytokines by M1 macrophages while increasing the release of anti-inflammatory cytokines by M2 macrophages. Furthermore, it attenuated LPS/adenosine triphosphate (ATP)-induced pyroptosis in macrophages by downregulating NLRP3 expression levels along with cleaved caspase-1, cleaved IL-1β, and GSDMD-NT expression levels. Notably, our findings revealed that 4-MC exerted inhibitory effects on the NF-κB signaling pathway through specific modulation of the NF-κB complex as well as phosphorylation of the upstream IKK kinase complex. Collectively, these results highlight significant therapeutic potential for utilizing 4-MC in RA treatment.

To evaluate the potential of clinical factors, ultrasound findings, serum autoantibodies, and serum cytokine and chemokine profiles as predictors of clinical outcomes in rheumatoid arthritis (RA).

We included 200 patients with RA treated with biological and targeted synthetic disease-modifying antirheumatic drugs in a prospective multicentre ultrasound cohort study. Their serum levels of multiple cytokines and chemokines, rheumatoid factors, and serum autoantibodies (anti-cyclic citrullinated peptide-2 (anti-CCP2) and anti-carbamylated protein antibodies) were measured at baseline, 3 months and 12 months.

Dimensionality reduction using 38 cytokines and chemokines demonstrated four distinct clusters that differed significantly regarding the frequencies of remission defined by clinical composite measures and ultrasound evaluations. Prominent differences in IL-1β, IL-5, IL-7, IL-10, IFNγ, GRO, IP-10, MCP-1 and MIP-1β characterised the between-cluster differences. Two distinct groups made of four clusters showed a significant difference in IgM-anti-CCP2 positivity. The least absolute shrinkage and selection operator regression of 38 cytokines and chemokines for Clinical Disease Activity Index (CDAI) remission at 12 months resulted in the selection of MIP-1β. Logistic regression using baseline levels of anti-citrullinated protein antibody, IgM-anti-CCP2 positivity, the CDAI, the total power Doppler score, the cluster by cytokines and chemokines, MIP-1β, methotrexate dose and mechanisms of action revealed that cluster by cytokines and chemokines was the sole significant factor for CDAI remission at 12 months.

Specific patterns of cytokines and chemokines-no other clinical factors and autoantibody profiles-were important to distinguish patients with RA achieving remission at 12 months.

UMIN000012524.

A lack of medication adherence among patients with rheumatoid arthritis (RA) has been reported. Inter-professional collaborations seem essential for an optimal therapeutic management of patients. The aim of this study was to analyse the barriers and facilitators of general practitioners (GPs) for the implementation of collaborative support programmes in RA.

A qualitative semi-structured study using face-to-face or telephone interviews was conducted. Eligible participants included French GPs referring patients with RA. Interviews were audio-recorded and then transcribed. Data were analysed using Braun and Clarke's thematic analysis framework with Nvivo®12 software.

Nineteen GPs were interviewed between August 2019 and February 2020. Five themes were identified in the care of their patients with RA. GPs reported being mainly involved in diagnosis and orientation, and frequently asked for pain management and explanation/reformulation of previously given information. They perceived their patients to be adherent to their treatments, although they frequently identified reasons for non-adherence. Regarding their perception of the community-hospital relationship, they sometimes considered it insufficient and expected more immediate interactions. Additionally, most interviewed GPs had no expectation regarding increased collaborations with community pharmacists (CPs) and several GPs were motivated to be more involved in a patient support programme. However, barriers were identified: lack of time and training, and insufficient payment.

The implementation of a collaborative patient support programme in RA should be developed taking into account the barriers and facilitators identified by GPs who appeared to be aware of the causes of potential non-adherence, and were particularly interested in receiving more information about the therapeutic monitoring of patients by hospital professionals.

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease characterized by synovial inflammation, cartilage damage, and bone loss. Although effective treatments are currently lacking, early interventions hold promise for alleviating RA symptoms. Inorganic nitrates and vitamin C (VC) are essential bioactive substances abundant in fruits and vegetables. Notably, nitrates and VC exhibit synergistic effects in a series of physiological and pathological conditions. In this study, we aim to examine the combination of nitrate and VC for preventing RA in a collagen-induced arthritis (CIA) rat model. Nitrate partly reduced foot swelling and arthritis scores and was more effective when combined with VC. Histopathological and radiological analyses revealed that nitrate + VC treatment alleviated synovial hyperplasia and bone loss. Additionally, nitrate + VC lowered the levels of TNF-α and IL-1β in serum as well as synovial tissue, decreased the expression of NF-κB and reduced the number of macrophages in synovial tissue. Compared to the CIA group, nitrate + VC decreased the levels of NLRP3 and GSDMD in macrophages, thus inhibiting pyroptosis. According to in vitro experiments, nitrate inhibited the activation of the NLRP3/caspase-1/GSDMD pathway in macrophages by conversion into nitrite. VC reduced the expression and phosphorylation of NF-κB in macrophages and thus reduced the expression levels of TNF-α and IL-1β. Therefore, nitrate/nitrite and VC may exert synergistic effects by blocking the interaction between NF-κB and NLRP3, further alleviating the inflammation and pyroptosis of macrophages, which provides a new strategy for RA prevention.

Objective. Telecontrol approaches for rheumatoid arthritis (RA) management aim to enhance patient outcomes. This pilot study assessed whether the Rheumatoid Arthritis Impact of Disease (RAID) approach could be used during teleconsultations to monitor RA disease activity through a web-based platform called iARPlus (Innovative Approach in Rheumatology). Methods. Forty RA patients participated in two in-person visits (baseline and 12 months) and seven teleconsultations over 12 months, collected via the iARPlus portal and accessible through an internet browser. Disease activity, at baseline and follow-up, was measured using the Clinical Disease Activity Index (CDAI) and self-reported RAID scores throughout the study. The RAID approach, developed by the European Alliance of Associations for Rheumatology (EULAR), combines key patient-reported outcomes (PROs). Results. Nineteen patients (mean age: 49.3 years) were treated with Janus kinase inhibitors (JAKis), and 21 patients (mean age: 48.1 years) received adalimumab. All patients had active disease (mean CDAI 27.9 ± 4.8). Strong correlations were found between CDAI and RAID scores at baseline (ρ = 0.809, p < 0.0001) and at follow-up (ρ = 0.789, p < 0.0001). JAKi-treated patients showed greater reductions in RAID scores, pain relief, and higher rates of disease remission compared to adalimumab-treated patients. Conclusions. RAID scores were effective in teleconsultations for assessing RA disease activity. JAKi treatment resulted in better pain control and disease activity improvement compared to adalimumab. Further studies are needed to confirm the clinical and economic benefits of telecontrol for RA management.

To explore the role of newly emerging autoantibodies (AAbs) - peptidyl-arginine deiminase 4 (aPAD4), carbamylated proteins (aCarP), and anti-RA33 (aRA33) - alongside the traditionally assessed rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA), in predicting the response to abatacept (ABT) and its retention rate in rheumatoid arthritis (RA) patients.

Data from 121 consecutive ABT-treated RA patients were recorded. The RF and ACPA status were retrospectively assessed by reviewing the patients' clinical records. Positivity for aPAD4, aCarP and aRA33 were determined by Enzyme-Linked Immunosorbent Assay (ELISA). The achievement of a moderate or good EULAR response at 6 months and the 3-years retention were analyzed as treatment outcomes. Multiple logistic regression models and Cox regression hazard analysis models were built to identify the association between such outcomes and the different AAbs, after adjustment for different confounders. The AAbs were assessed both individually and in different combinations to identify the most robust predictive model.

In the studied cohort, RF, ACPA, aPAD4, aCarP and aRA33-Ab tested positive in 74.4%, 69.4%, 43.8%, 23.9%, 14.9% patients, respectively. A moderate or good EULAR response at 6 months was achieved by 64.5% of subjects and the cumulative 3-years retention rate was 56.6%. A higher EULAR response rate was recorded in patient with positivity for RF (67% in subjects tested positive vs. 58% in negative), ACPA (68% vs. 57%), aPAD4 (68% vs. 62%), and aCarP (72% vs. 62%), although statistical significance was not reached likely due to sample size limitations. Similarly, ACPA, aPAD4, aCarP were associated with higher 3-year retention rates, though not statistically significant individually. The combined analysis revealed that positivity for ACPA and/or aPAD4 predicted a significantly higher EULAR response rate at 6 months compared with double negativity (adjusted OR 2.7, p 0.026). Furthermore, positivity for at least one of ACPA, aPAD4, or aCarP predicted a significantly higher 3-year ABT retention rate compared to triple negativity (62.1% single or double positive vs. 33.5% triple negative, adjusted HR 0.48, p 0.022).

This study highlights the potential benefits of using a combined assessment of ACPA aPAD4 and aCarP in predicting effectiveness of ABT in RA.