Tophi, inflammatory granulomas formed by intra-articular monosodium urate (MSU) crystal deposition, remain challenging due to limited drug efficacy. While arthroscopic surgery removes tophi rapidly, mechanical debridement risks injury, and intraoperative MSU release can trigger severe oxidative stress induced inflammatory storm. To overcome this, we developed a cascade nanozyme, Ce-MOF@Pt, enabling synergistic MSU clearance and ROS scavenging for MSU-induced gouty arthritis. Pt nanoparticles possess oxidase (OXD)-like activity, dissolving deeply embedded MSU crystals without mechanical injury and incidentally producing anti-inflammatory allantoin. The Ce-MOF matrix supports Pt and duplicates catalase (CAT)/superoxide dismutase (SOD)-like activities, cascading H2O2 decomposition and MSU-induced ROS elimination. As UA degradation elevates the local pH values, its dominant activity intelligently switches from OXD-like to SOD-like mode, while the CAT-like activity remains consistently high, ensuring continuous clearance of the H2O2 byproduct and offering integrated anti-oxidative therapy. In vitro, Ce-MOF@Pt reduced inflammation via ROS scavenging and macrophage reprogramming. In vivo, it alleviated pain symptoms and joint inflammation in MSU-induced gouty arthritis mice. Transcriptomics revealed Ce-MOF@Pt mitigated the inflammatory storm by alleviating endoplasmic reticulum stress. This novel Ce-MOF@Pt strategy offers minimally invasive tophi dissolution and prevents MSU-induced inflammation, providing a promising therapeutic approach for tophi.
Excess visceral adipose tissue (VAT) mass increases cardiovascular disease risk. Exercise supports overall health and VAT mass reduction in rheumatoid arthritis (RA). Unlike tumour necrosis factor (TNF), interleukin-6 (IL-6) is upregulated following exercise and is involved in free fatty acid mobilisation and might mediate the reduction in VAT mass. Given that treatment strategies for patients with RA include the inhibition of IL-6 (IL-6i) or TNF (TNFi), in this study we compared the effects of exercise on changes in VAT mass in patients with RA on stable IL-6i or TNFi treatment. In this secondary analysis of a randomised controlled trial, 69 patients with RA on stable TNFi (n = 40) or IL-6i (n = 29) therapy were stratified for treatment and assigned to a 12-week supervised high-intensity interval training (HIIT) intervention or no exercise (control). The primary objective was to investigate the effects of TNFi or IL-6i therapy on exercise-induced changes in VAT mass (in grams) from baseline to 12-week follow-up, assessed by abdominal MRI. Compared with the control group, HIIT did not change VAT mass in either TNFi {-34 g [95% confidence interval (CI), -206 to 139 g; P = 0.696]} or IL-6i [-16 g [95% CI, -228 to 197 g; P = 0.882)] treatment groups. There was no interaction between IL-6i and exercise on changes in VAT mass [18 g (95% CI, -256 to 292); interaction P = 0.895]. Exercise-induced changes to the subcutaneous adipose tissue and insulin sensitivity were negligible and not significantly different between treatment modalities. In conclusion, a 12-week HIIT intervention did not reduce VAT mass in patients with RA undergoing treatment with either TNFi or IL-6i.
Existing cost-of-illness studies on inflammatory arthritis (IA) and osteoarthritis (OA) often are cross-sectional, include patients with various disease durations, and rely primarily on claims data, which might not provide an accurate estimation of the associated costs. To address these limitations, we aimed to (1) quantify direct medical costs of an inception cohort of patients with IA and OA incurred from six months before to one year after diagnosis using hospital billing data and (2) identify cost drivers among these patients. All costs incurred in the hospital during the six months before diagnosis (Study Period 1), the 1st to 6th month after diagnosis (Study Period 2), and the 7th to 12th month after diagnosis (Study Period 3) were extracted from hospital billing records and assessed for inclusion in the cost estimation. A total of 85 rheumatoid arthritis (RA), 45 spondyloarthritis (SpA), 38 psoriatic arthritis (PsA), and 280 OA patients were included in this study. The highest direct medical costs were observed among patients with SpA in Study Period (1) and among patients with RA in Study Periods (2) and (3), while the lowest direct medical costs were observed among patients with OA in all three study periods. The largest cost drivers varied across study periods and among patients with different conditions. High direct medical costs were observed among patients with IA and OA both before and after diagnosis. The varying cost drivers over time and across different arthritis could provide a foundation for future healthcare resource planning.
A randomized, double-blind, placebo-controlled interventional pilot trial was conducted to evaluate the safety and efficacy of Exclzyme Pet in alleviating clinical symptoms associated with canine arthritis. A total of 26 client-owned dogs exhibiting clinical signs of arthritis were enrolled in a 30-day pilot trial, of which 23 completed the study. Subjects were randomly allocated to either the treatment group (N = 12), receiving Exclzyme Pet (2 g per dog, administered orally twice daily on an empty stomach with water), or the placebo group (N = 11), receiving maltodextrin at an equivalent dose. Exclzyme Pet resulted in a statistically significant reduction in scores for lameness, weight bearing, joint mobility, willingness to hold up contralateral limb, and pain by 51.96, 46.94, 48.94, 58.0, and 55.56%, respectively and demonstrated clear superiority over placebo. The overall quality of life, mood, and mobility improved significantly in the treatment group over the placebo. Serum C-reactive protein levels decreased markedly by 56.10% in dogs receiving Exclzyme Pet, whereas levels increased by 15.38% in the placebo group, indicating a strong anti-inflammatory effect (p < 0.001). No adverse hematological findings or clinical events were reported, and the supplement was well tolerated, without gastrointestinal or systemic complications. In conclusion, Exclzyme Pet demonstrated significant efficacy in reducing clinical signs of arthritis and improving functional outcomes in dogs, with no evident safety concerns during the entire study period. These results suggest that Exclzyme Pet may serve as a safe and effective adjunctive therapy for managing canine arthritis. Nevertheless, longer-duration clinical trials with large study population are needed to confirm these findings and further elucidate the mechanisms its therapeutic effects.
The concept of difficult-to-treat (D2T) disease is increasingly recognized across immune-mediated inflammatory diseases, and was recently introduced in spondyloarthritis (SpA). Several terms, including difficult-to-manage (D2M), complex-to-manage (C2M), and treatment-refractory (TR) describe disease states characterized by persistent symptoms and inadequate response to targeted therapies. This review aims to clarify the emerging constructs of D2M and TR disease in axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA), and their implications for emerging research in this area. Recent initiatives from ASAS, EULAR, and GRAPPA have proposed definitions to frame D2T clinical scenarios in axSpA and PsA. These converge on distinguishing treatment-refractory disease, characterized by persistent objective inflammation despite multiple targeted therapies, from broader D2M/C2M states driven by multifactorial contributors including non-inflammatory factors. Emerging data suggest that clinical and biological heterogeneity across disease domains may contribute to these phenotypes. Challenging phenotypic presentations often display overlapping features between axSpA and PsA, supporting the concept of a continuum across the SpA spectrum. Distinguishing TR disease from broader D2M/C2M states is essential for avoiding inappropriate treatment escalation, and supporting personalized multidisciplinary care. Further research is needed to validate these definitions, determine contributing factors and their prevalence, and clarify the molecular mechanisms underlying treatment refractory disease.
National oral health research strategies (NOHRSs) are increasingly recognized as critical mechanisms for aligning oral health research with public health needs, strengthening health systems, and advancing the World Health Organization's (WHO's) vision of "oral health for all." They are also pivotal for accelerating global progress toward Strategic Objective 6 of the WHO Global Oral Health Action Plan 2023-2030, which calls for the development of public health-oriented national research agendas. While global momentum for NOHRS development is growing, countries remain at markedly different stages of readiness and implementation. To support coordinated international progress, a satellite workshop was convened at the International Association for Dental, Oral, and Craniofacial Research (IADR) General Session and Pan European (PER) Congress in Barcelona, Spain, in June 2025. The workshop brought together invited participants, policymakers, and researchers representing diverse geographic, economic, and governance contexts. Drawing on a preworkshop survey, invited workshop presentations, and structured breakout discussions, this article synthesizes key insights and lessons learned.
Background/Objectives: Osteoporosis (OP) is a frequent complication of rheumatoid arthritis (RA), driven by chronic inflammation and subsequent bone destruction. While deer bone is recognized for its potential bone-health benefits, the therapeutic efficacy of its fermented products on RA-induced OP remains unclear. Methods: This study investigated the protective effects of Lactobacillus reuteri-fermented deer bone water extract (LR-DBW) against OP in an adjuvant arthritis (AA) rat model. Firstly, LC-MS/MS was employed to analyze the differential peptide profiles between LR-DBW and non-fermented deer bone water extract (DBW). Secondly, experiments such as Micro-CT, histological staining, and Western Blot were conducted to detect the improvement effect of LR-DBW on OP. Results:In vivo, LR-DBW administration significantly alleviated arthritis symptoms, increased bone mineral density (BMD), and improved bone microarchitecture in AA rats. In vitro, LR-DBW inhibited RANKL-induced osteoclastogenesis and actin ring formation in RAW264.7 cells. Mechanistically, LR-DBW inhibits the phosphorylation of ERK, JNK and p38 proteins. Conclusions: These research results indicate that one of the mechanisms by which inhibiting osteoclast differentiation into LR-DBW can alleviate osteoporosis caused by rheumatoid arthritis is through down-regulating the phosphorylation expression of ERK, JNK and p38 proteins. This highlights its potential as a functional food component for treating inflammatory bone diseases.
At the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) 2025 annual meeting in Bogotá, Columbia, Alexandra Khmelevskaya and Dr. Christopher Ritchlin presented a basic symposium on synovial immunopathology. They presented a comparative analysis between rheumatoid arthritis (RA) and psoriatic arthritis (PsA). Their multiomic studies revealed that RA is characterized by heightened intercellular signaling, particularly involving secreted phosphoprotein 1-positive (SPP1+) macrophages, chitinase-3-like protein 1-positive (CHI3L1+) fibroblasts, and fatty acid binding protein 5-positive inflammatory dendritic cell type 3 (FABP5+ iDC3]). Spatial transcriptomics confirmed direct, contact-dependent interactions between SPP1+ macrophages and iDC3 specifically in RA, whereas CHI3L1+ fibroblasts interacted with iDC3 through soluble mediators. Multiplex immunofluorescence validated the tissue localization of these subsets. In contrast, PsA was distinguished by transcriptionally activated CD8+ T cells in both synovium and peripheral blood, with open chromatin states indicating preactivation prior to tissue infiltration. These findings delineate RA-specific stromal-myeloid-dendritic cell networks and PsA-specific T-cell activation programs. Together, they underscore distinct immunopathogenic mechanisms and provide potential targets for precision therapeutics in inflammatory arthritis.
This study aimed to evaluate the anti-arthritic role of Garcinia cowa bark extract (GC) in a murine collagen-induced model of arthritis (CIA), as it mimics the clinical symptoms and pathological features of synovitis observed in human rheumatoid arthritis (RA). Rats were administered GC (1.25-5 mg/kg body weight, p.o.) from days 11 to 27, during which paw edema and arthritis score were regularly monitored. Following sacrifice on the 28th day, bone architecture was evaluated by radiography and histopathology, while the redox status was measured in the paw tissue in terms of myeloperoxidase (MPO) activity, protein carbonylation, lipid peroxidation, total antioxidant capacity by ferric ion reducing antioxidant power (FRAP) and 1,1-diphenyl-2-picrylhydrazyl (DPPH) assays, along with estimation of IL-6 and IL-10 by ELISA. In the CIA model, there was joint damage, enhanced oxidative stress, along with raised levels of IL-6 and IL-10. The pre-treatment with GC (5 mg/kg b.w.) prevented the progression of arthritis, evident from the reduction in paw edema, arthritic score, and attenuation of bony and cartilaginous damage. Additionally, GC improved the splenic and thymic indices, reduced levels of IL-6 and IL-10, and restored the redox balance as evidenced by reduction of MPO, protein carbonylation, and lipid peroxidation along with raised anti-oxidant capacity. Taken together, GC ameliorated oxidative stress and inflammation in an animal model of arthritis and therefore holds promise as an adjunct in the improved management of RA.
Psoriatic arthritis (PsA) often requires escalation from conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) to biologic therapy (bDMARDs), yet biomarkers guiding treatment decisions remain limited. Anti-CD74 autoantibodies have shown diagnostic potential in axial spondyloarthritis, but their relevance in PsA is insufficiently characterized. To evaluate whether IgA anti-CD74 levels are associated with treatment escalation in peripheral PsA (pPsA) and to characterize their relationships with clinical and immunological parameters. Serum samples from 171 PsA (127 pPsA, 44 axial PsA [axPsA]), 43 non-rheumatic disease controls (NRD), and 43 rheumatoid arthritis (RA) patients were analyzed. IgA anti-CD74 levels were measured by enzyme-linked immunosorbent assay (ELISA). Patients were stratified by disease duration and treatment exposure. Correlation analyses, receiver operating characteristic (ROC) curves, and logistic regression models were performed. A prospective subgroup of 53 early pPsA patients was followed to assess treatment initiation. IgA anti-CD74 levels were elevated in PsA compared with NRD controls (median 13 vs. 6 U/mL, p < 0.0001), with similar levels in pPsA and axPsA and comparable values in RA, indicating an association with inflammatory disease rather than disease specificity. Anti-CD74 positivity (>15 U/mL) was observed in 31.5% of pPsA and 43.2% of axPsA versus 2.3% of NRD, independent of disease duration. Anti-CD74 levels were associated with treatment escalation in pPsA, with higher levels in bDMARD-treated patients (median 13.0 vs. 11.0 U/mL, p = 0.04). In multivariate analyses, anti-CD74 was independently associated with csDMARD (OR 1.113, p = 0.022) and bDMARD use (OR 1.052, p = 0.02). After false discovery rate (FDR) correction, anti-CD74 remained associated with serum IgA (q = 0.0008) and weakly with IgG (q = 0.0250), but not with C-reactive protein (CRP) or age. Longitudinal associations were not significant after FDR correction (csDMARD initiation: p = 0.047, q = 0.094; bDMARD initiation: p = 0.19, q = 0.1866), indicating these findings are exploratory. IgA anti-CD74 levels are elevated in PsA and appear to reflect immunological activity not captured by CRP. Their independent association with treatment escalation in pPsA supports further evaluation as a biomarker candidate, although findings remain exploratory and require validation in larger longitudinal cohorts.
This review aims to provide a comprehensive and integrative evaluation of the therapeutic potential of curcumin in arthritis, focusing on its molecular mechanisms, preclinical evidence, and clinical applications. A systematic literature search was conducted across major databases, and a total of 165 studies were included in this review. Curcumin exerts multi-target effects on key pathogenic pathways involved in arthritis. At the molecular level, it inhibits inflammatory signaling pathways, particularly NF-κB, and reduces the production of pro-inflammatory mediators, including TNF-α, IL-1β, IL-6, COX-2, and PGE2. In parallel, curcumin modulates oxidative stress by enhancing antioxidant defenses, including superoxide dismutase (SOD) and glutathione (GSH), while reducing lipid peroxidation. It also regulates cell death pathways, including apoptosis, autophagy, and emerging mechanisms such as pyroptosis and ferroptosis, and preserves cartilage integrity by inhibiting matrix metalloproteinases and ADAMTS while promoting extracellular matrix components. Preclinical studies consistently demonstrate anti-inflammatory, antioxidant, and chondroprotective effects across in vitro and animal models. Clinical evidence, particularly in osteoarthritis, indicates improvements in pain and functional outcomes, with some studies suggesting efficacy comparable to nonsteroidal anti-inflammatory drugs. However, this evidence remains limited and should be interpreted with caution. However, variability in formulations and limited bioavailability remain key challenges influencing clinical outcomes. Overall, curcumin represents a promising multi-target therapeutic agent for arthritis. Further large-scale, well-designed randomized controlled trials using standardized and bioavailable formulations are required to confirm its efficacy and optimize its clinical application.
We investigated the effects of Helicobacter pylori (H. pylori) eradication on quality of life (QoL), pain, inflammation, and other symptoms in rheumatoid arthritis (RA) patients. In this study, patients with RA were divided into H.pylori-positive and H. pylorinegative groups. The positive group received a 5-day eradication treatment plus standard RA treatment. The negative group received only standard RA treatment. Arthritis severity, Disease Activity Score 28 (DAS28), VAS, the European Quality of Life Questionnaire (EQ-5D), Creactive protein (CRP), and erythrocyte sedimentation rate (ESR) were evaluated before treatment, at 4 and 8 weeks post-treatment. The H. pylori-positive group had significantly lower arthritis severity, painful joints, morning stiffness, disease activity, CRP, and ESR (p <0.05). The Health Assessment Questionnaire (HAQ) score at week 8 and pain at weeks 4 and 8 were significantly less than those of the H. pylori-positive (p <0.05). Only the HAQ score differed significantly between the groups, with greater improvement in the H. pylori-positive group. Moreover, the last component of the QoL improved significantly (all p <0.05). H. pylori eradication may confer additional benefits in RA, as greater improvements in inflammation, pain, functional status, and QoL were observed in the H. pylori-positive group. These results support a potential role of chronic infection in RA disease activity. More clinical trials with larger samples and longer follow-up are needed. Disease activity, pain, HAQ scores, and QoL improved for all patients, indicating the regimen's effectiveness. More pronounced improvements in the H. pylori-positive patients suggest a possible association between eradication therapy and symptom improvement.
Psoriatic arthritis (PsA) is a systemic chronic inflammatory disease characterized by arthritis and structural damage of joints associated with persistent inflammation. Radiographic progression (RP) is typically used to measure the development of structural damage using different semiquantitative scoring methods. An important therapeutic goal is to prevent structural damage. Visualizing such damage using RP seems to predict shorter survival in patients with PsA. Therapeutic agents that inhibit structural damage are considered disease-modifying in PsA. There are no validated and clinically useful biomarkers for stratifying patients and informing clinical treatment decisions to increase the likelihood of a response to any given therapy. This narrative review examines current approaches for assessing the extent of structural damage in PsA, monitoring of PsA disease activity, risk factors that contribute to the progression of RP in PsA, and discusses the efficacy (inhibition of RP) of the new approved therapies that have emerged over the last few years for use in PsA. While there are unmet needs to clarify and define RP, the extent of structural damage in the peripheral forms of PsA was most frequently determined using the PsA-modified Sharp and Sharp-van der Heijde Rheumatoid Arthritis scoring methods. Factors that lead to a more aggressive, faster, or more active RP are also related to the number of activity indicators (overweight, smoking, etc.). In patients with high psoriatic activity and thus greater disease progression, determining structural damage at 6 months of follow-up may be sufficiently sensitive to obtain RP information and evaluate the evolution of the disease.
Total hip arthroplasty (THA) is one of the most successful orthopaedic procedures and provides good functional outcomes in both rheumatoid arthritis (RA) and osteoarthritis (OA) patients. However, RA patients face higher risks of adverse post-operative outcomes. Despite recognising the unique risks of RA autoimmunity and drug therapy, there remains minimal RA-specific evidence to guide arthroplasty surgeons. This study analysed the rate of all cause revision, and revision for infection, dislocation, periprosthetic fracture, and aseptic loosening for 3657 RA and 446 428 OA patients who underwent primary THA recorded in the Australian Orthopaedic National Joint Replacement Registry (AOANJRR). Key findings of this study indicate that RA is associated with a younger age at THA, an increased risk of all-cause revision (HR 1.35; 95% CI 1.16-1.56; p = 0.001), and an increased risk of revision for infection (HR 1.48; 95% CI 1.12-1.98; p = 0.006), dislocation (HR 1.87; 95% CI 1.45-2.42; p < 0.001), and early aseptic loosening (0-3 month; HR 2.81; 95% CI 1.50-5.26; p = 0.001). There was no difference in all-cause revision for cemented, cementless, or hybrid THA fixation in RA patients. This study suggests that RA continues to be associated with worse post-THA outcomes compared to OA. Further research is needed to develop strategies that improve perioperative management of inflammation and immune suppression to reduce the risk of post-operative complications in RA patients undergoing THA.
Spondyloarthritis (SpA) is a set of immune-inflammatory conditions characterized by musculoskeletal and extra-articular manifestations. Increasing evidence indicates that alterations in the gut microbiota (dysbiosis) may influence both mucosal and systemic immune responses, potentially contributing to the loss of tolerance and the development of autoantibodies in SpA.This narrative review examines the current evidence linking gut dysbiosis to autoantibody development in SpA, with particular focus on ankylosing spondylitis (AS) and psoriatic arthritis (PsA).We summarized key mechanistic pathways, including Th17 axis activation, molecular mimicry, increased intestinal permeability ("leaky gut"), and altered microbial metabolite signaling. We discussed the potential relevance of these mechanisms to SpA-associated autoantibodies such as anti-CD74, anti-HSP65, and anti-Kaiso. Where direct evidence in SpA is limited, findings from other autoimmune diseases are considered as mechanistic analogies rather than definitive parallels.We further review microbiome-targeted therapeutic strategies, including probiotics, prebiotics, and bacterially based therapies, and highlight differences between preclinical findings and available clinical data. Although biologically plausible mechanisms, direct causal evidence linking gut dysbiosis to autoantibody production in SpA remains limited, and clear methodological heterogeneity persists across microbiome studies.Overall, while modulation of the gut-immune axis represents a promising research direction in SpA, further mechanistic and longitudinal human studies are required before microbiota-targeted interventions can be considered applicable for autoantibody modulation.
Health outcomes in children and young people are known to vary by ethnicity and socioeconomic position. In juvenile idiopathic arthritis (JIA), it is unclear whether this relates to differential changes following one of the most common treatments, TNF-inhibitors (TNFi). This study investigated these factors, disease activity and treatment persistence following initial TNFi therapy in patients with JIA in the UK. Patients with non-systemic JIA in the UK JIA Biologic Register starting their first TNFi biologic were included. Outcomes included change in disease activity between start of TNFi and 6 months, measured by JADAS-71.Multivariable linear regression was used to assess the association between ethnicity or socioeconomic position and change in JADAS. Treatment persistence was analysed using Kaplan-Meier estimates. Cox proportional hazards models compared TNFi drug persistence by ethnic group and by socioeconomic position. A total of 1,641 patients were included; 67% female, 90% White ethnic group (6% Asian, 2% Black, 2% Mixed), 25% in the most deprived socioeconomic group. JADAS-71 improved for all ethnic and socioeconomic groups by 6 months, with no difference in improvement by group.The proportion of patients remaining on TNFi at 12 months (67%) and the likelihood of stopping was similar between all ethnic and socioeconomic groups. Outcomes following TNFi initiation are similar between ethnic and socioeconomic groups. Based on the results of this study, ethnicity and socioeconomic position do not appear to be associated with differential change in disease activity, and there is no evidence that the effects of socioeconomic position are moderated by ethnicity or vice versa.
Glucocorticoid treatment for patients with rheumatoid arthritis (RA) is widely used as fast-acting bridging therapy to reduce disease activity. However, the safety is still discussed. This cohort study describes glucocorticoid dosage during the first year after treatment initiation in patients with RA and secondarily presents the one-year dosedependent infection risk. Hospital records were reviewed for 574 newly diagnosed RA cases treated at Department of Rheumatology Aalborg University Hospital between 2014 and 2022 to identify physician prescribed daily glucocorticoid dose and infections within the year following first visit. Daily glucocorticoid dose was presented. Secondary, the relative risk (RR) for one-year dose-dependent (non-exposed, low dose: 0-10 mg/day, high dose: >10 mg/day, from 21 days average) risk of first infection was calculated using modified Poisson regression. In total, 428 patients (75%) received glucocorticoid during the first year, with 313 (55%) initiated at first visit. Mean prescribed glucocorticoid dose was 9.3 mg/day, with 262 patients (46%) receiving tablets and 270 (47%) receiving intra-articular injection. Overall, 117 patients (20%) experienced an infection within the first year. The model was adjusted for asthma/chronic obstructive pulmonary disease, sex, and age, yielding a RR of 1.13 (95% confidence interval (CI): 0.77 to 1.67) for low-dose exposure versus non-exposure. Glucocorticoid dosages were highest early in disease course and declined substantially after the initial visit, suggesting that physicians in the Danish healthcare decrease dose within the first year after diagnosis. CI for dose-dependent infections risk were compatible with both benefit and harm.
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation, joint destruction, and systemic comorbidities, particularly cardiovascular disease (CVD) associated with severe dyslipidemia. The bidirectional crosstalk between immune-inflammatory processes and lipid metabolic disturbances is increasingly recognized as a key driver of RA pathogenesis, yet the molecular mechanisms integrating these domains remain poorly understood. This review synthesizes current evidence to propose the Sirtuin 1 (SIRT1)/signal transducer and activator of transcription 3 (STAT3) axis as a central regulator of immune, inflammatory, and lipid metabolic dysregulation in RA. SIRT1, an NAD+-dependent deacetylase, functions as a metabolic sensor with anti-inflammatory and lipid-regulating properties, whereas STAT3 acts as a proinflammatory transcription factor driving Th17 differentiation, synovial hyperplasia, and metabolic reprogramming. SIRT1 directly deacetylates and inactivates STAT3, establishing an antagonistic yin-yang relationship. In RA, chronic inflammation and metabolic stress suppress SIRT1 and hyperactivate STAT3, creating a positive feedback loop that perpetuates immune imbalance and lipid dysfunction. We further discuss therapeutic strategies targeting this axis, including SIRT1 activators, STAT3 inhibitors, and dietary interventions such as n-3 polyunsaturated fatty acids, which hold promise for simultaneously mitigating inflammation and correcting metabolic abnormalities in RA. This integrated perspective challenges the traditional siloed approach and opens new avenues for immunometabolic therapy in RA.
Outcomes in rheumatoid arthritis (RA) have improved considerably with the advent of new therapeutic modalities, improved therapeutic strategies and greater recognition of the need to manage comorbidities. Nevertheless, unmet needs remain. Sustained remission is achieved by only a minority of patients, in part owing to delays in diagnosis, imprecise risk stratification and suboptimal treatment selection. A pressing need therefore exists for robust diagnostic and prognostic tools to support clinical decision making. Advances in genetic, protein, imaging and multi-omics biomarkers offer opportunities to refine RA diagnosis, predict disease course and guide therapeutic choices. Parallel progress in biomarker discovery is also shaping understanding of major RA-associated comorbidities, including cardiovascular disease, interstitial lung disease, osteoporosis and malignancy. Together, clinical introduction of such biomarkers could enable earlier intervention, more precise therapy and improved outcomes for patients with RA.
We appreciate the interest of Joaquin et al in our recent study on the treatment persistence of ixekizumab in psoriatic arthritis. In response, we clarify that our study utilized prospectively collected real-world clinical data from a multicenter observational cohort, rather than administrative databases. We emphasize the importance of persistence, as assessed through the Drug Retention Rate (DRR), a validated measure in observational studies of biologic therapies. The DRR reflects a complex interplay of factors, including efficacy, safety, and patient choice, making it a valuable indicator of therapeutic performance. We agree that adherence is an interesting topic, but argue that its absence does not invalidate persistence data. Our study was designed to evaluate treatment persistence, not behavioural pharmacology. We believe that our methodological rigor, real-world design, and consistency with international literature make our data a reliable reference for understanding ixekizumab persistence in routine clinical pratice.