RMD Open

ObjectivesThe individual and socioeconomic burden of sarcopenia in rheumatoid arthritis (RA) is most relevant. However, longitudinal cohort data are scarce. MethodsProspective, single-center, controlled, observational cohort study of consecutive 124 postmenopausal women, 53 with RA, 71 healthy controls (HC). Low muscle mass and low muscle strengths was defined according to the European working group on sarcopenia in older people 2019 (appendicular lean mass index [ALMI] via dual-energy x-ray absorptiometry < 5.5 Kg/m2; handgrip strength via dynamometer < 16 Kg). Linear regression models were calculated including demographic and anthropometric data, comorbidities, and co-medication as confounders. ResultsMedian age was 63 (IQR 56, 70), follow-up 2.1 (IQR 2.0, 5.3) years. At baseline, median ALMI was 6.2 (IQR 6.0, 6.5) Kg/m2 in RA patients, 6.3 (IQR 5.6, 6.9) Kg/m2 in HC (p = 0.64) with no difference in rates of low muscle mass (RA 16.2 % vs. HC 15.1 %). In the fully adjusted model, mean change in ALMI per year was -0.05 (95%CI -0.10 to -0.01) Kg/m2 in RA patients and 0.00 (95%CI -0.02 to 0.03) Kg/m2 in HC resulting in a differential loss of -0.06 (95%CI -0.11 to -0.01) Kg/m2 per year (p = 0.027). For RA patients, the adjusted OR of experiencing any loss of muscle mass was 3.98 (95%CI 1.47 to 10.77) compared to HC (p = 0.007). On average, RA patients lost 0.78 % of muscle mass per year. At baseline, low grip strength was seen in 27.3 % of RA patients and in 2.9 % of HC (p = 0.002). In both groups, grip strength did not decline during study period. TNF inhibitors were associated with less, T-cell inhibition with greater loss of muscle mass. Low mass at baseline, disease duration and disease activity were not associated with loss of muscle mass. ConclusionPostmenopausal women with RA have a significant risk of accelerated loss of muscle mass over time.

BackgroundRadiographic signs of osteoarthritis (OA) are frequent in knees without symptoms. The long-term impact of these findings is not completely elucidated. We wanted to evaluate whether radiographic or clinical baseline findings are associated with the risk of total knee arthroplasty (TKA) in knees without symptomatic OA but with clinical OA of the other knee during a mean follow-up period of 15 years. MethodsA follow-up analysis was performed in 100 persons with unilateral, clinical knee OA according to the ACR (American College of Rheumatology) criteria, who participated in a clinical trial between 2000 and 2002. Baseline radiographs of the contralateral, non-symptomatic knee were available in 88 participants at follow-up. Data on TKA procedures were extracted from the Danish National Patient Register at follow-up. Radiographic and clinical findings were analyzed for associations with subsequent TKA. ResultsAt follow-up, 40% had received a TKA in their non-symptomatic knee. The risk of TKA was significantly associated with baseline joint space narrowing (risk ratio (RR) 1.6 (95% confidence interval (95% CI) 1.4 to 1.9)), osteophytes (RR 1.5 (95% CI 1.3 to 1.8)) and subchondral sclerosis (RR 2.4 (95% CI 1.6 to 3.7)). Among the clinical findings, only baseline body mass index (BMI) was significantly associated with the risk of TKA (RR 1.4 (95& CI 1.1 to 1.8)). ConclusionsRadiographic OA changes and BMI at baseline were significantly associated with the long-term risk of TKA in persons without symptomatic knee OA but with symptomatic OA in the contralateral knee, implying that radiographic OA findings are important prognostic factors regardless of symptoms.

BackgroundObesity is associated with lower treatment response in patients with rheumatoid arthritis (RA). Among obese patients, abatacept was suggested as a preferable option to tumour necrosis factor alpha (TNF) inhibitors. Sex and gender differences in RA were described. ObjectivesTo assess the comparative effectiveness of etanercept, infliximab, and abatacept, compared to adalimumab, in patients with RA stratified by body mass index (BMI) and sex. MethodsObservational cohort study in the Swiss Clinical Quality Management in Rheumatic Diseases (SCQM) registry (1997-2019). RA patients were classified in BMI-based cohorts: obese, overweight, and normal weight. Each BMI cohort was studied overall and stratified by sex. The study outcome was remission within 12-months, defined as a disease activity score (DAS28) <2.6. Missingness was addressed using confounder-adjusted response rate with attrition correction (CARRAC). Logistic regression compared the effectiveness of etanercept, infliximab, and abatacept versus adalimumab. ResultsThe study included 443 obese, 829 overweight, and 1243 normal weight RA patients. Across the BMI cohorts, there were no significant differences in the odds of remission at [&le;]12-months for the study drugs compared to adalimumab. However, among females, an inverse effect for infliximab was found, whereby overweight patients had higher odds of remission, while obese patients had lower odds of remission, compared to the respective adalimumab users. ConclusionsDespite the previous hypothesis, treatment with abatacept showed similar odds of remission compared to adalimumab in all BMI cohorts. Conversely, compared to adalimumab, infliximab performed better in overweight female patients but worse in female patients with obesity. However, further validation is needed.

ObjectiveCD3+CD8+CD28- cells are increased in the periphery and tissues of rheumatoid arthritis (RA) patients. The aim of this study was to characterise CD3+CD8+CD28- cells for the presence of cell surface receptors that regulate immune activation and function and to track their presence in a disease model of RA. Cell surface receptors expressed by CD3+CD8+CD28- cells were then related to serological and clinical disease parameters to establish whether these cells are prognostic of a clinical response to conventional DMARDs. MethodUsing healthy donor peripheral blood mononuclear (PBMC) cell surface expression of > 50 candidate markers were tested using flow cytometry and compared against CD28 expression. The prevalence of cells expressing the most suitable candidate was investigated in the collagen induced arthritis (CIA) and the antigen-induced arthritis (AIA) models. Fifty RA patients were recruited from University Hospital of Wales (UHW) rheumatology outpatient clinic. Clinical and serological markers of inflammation were noted, and PBMC were analysed using flow cytometry +/- in vitro stimulation. ResultsCD3+CD8+CD28- T cells express CD244, CD57, CX3CR1 and KLRG1. The strongest inverse correlate of CD28 expression was KLRG1. CD3+CD8+CD28-KLRG1+ cells were elevated in experimental models of RA. Notably, Il-10-deficiency was linked with exacerbated arthritis and an increase in the number of CD3+CD8+CD28-KLRG1+ cells, suggesting a regulatory role for Il-10 in their development or survival. In RA patients, CD3+CD8+CD28-KLRG1+ cells correlate with ACPA, RF and ESR, and produce more IL-10 than controls. Finally, these cells are higher in early arthritis patients that do not respond to treatment with synthetic DMARDs at six months. ConclusionKLRG1 is a marker for regulatory CD3+CD8+CD28- cells. The presence of CD3+CD8+CD28-KLRG1+ cells increases with certain measures of disease, and is indicative of poor treatment response to DMARDs in early arthritis. Key MessagesO_LIKLRG1 is a marker of CD28 negativity on CD8 T cells C_LIO_LICD3+CD8+CD28-KLRG1+ cells are increased in CIA mice and correlate with disease severity. C_LIO_LICD3+CD8+CD28-KLRG1+ cells positively correlate with ESR / ACPA and RF in patients. C_LIO_LICD3+CD8+CD28-KLRG1+ cells are increased in Il-10-deficient mice with inflammatory arthritis. C_LIO_LICD3+CD8+CD28-KLRG1+ cells produce more Il-10 than CD3+CD8+CD28+KLRG1-cells in RA patients. C_LIO_LICD3+CD8+CD28-KLRG1+ cells are higher in patients who do not respond to treatment with synthetic DMARDs after six months. C_LI

ObjectivesTo evaluate and compare the individual therapeutic efficacy of NICE-recommended physical activity (PA) and pharmacological interventions on pain amongst adults with rheumatoid arthritis (RA). MethodsA systematic-review and meta-analysis of studies published between March 1988 and April 2025 was conducted across seven databases; AMED, MEDLINE, CINAHL Plus, SPORTDiscus, EMBASE, Google Scholar, Web of Science, and reference lists. Included were monotherapeutic randomised controlled trials (RCTs) of DMARDs, NSAIDS, analgesics, aerobic and/or resistance training for managing pain perceptions; measured as change in pre-and-post-intervention scores using the visual analogue scale (VAS). Participants were aged [&ge;]18 years whose condition met American College of Rheumatology (ACR; 1987/2010) RA-criteria. Pooled meta-analyses results were presented as mean differences (MDs) and 95% confidence-intervals (95% CIs). Risk of bias (ROB) and certainty of evidence were assessed with the ROB 2 tool and Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. ResultsSearches identified 3286 articles. 25 trials were selected for inclusion (6468 participants); 14 RCTs of 11 aerobic-and/or-resistance-training programs (n=916), three yoga regimes, an individual joint-protection programme, a trial of Rocabado exercises, and 11 RCTs of 21 DMARD/NSAID monotherapies (n=5552); baricitinib, celecoxib, filgotinib, hydroxychloroquine, ketoprofen, leflunomide(n=2), methotrexate, naproxen (n=2), sarilumab, sulphasalazine, tofacitinib, and upadacitinib. Weighted mean differences in pain perceptions for behavioural and pharmacological interventions were -2.47mm (95% CI: -3.14 - -1.81, p<0.00001) and -11.20mm (95% CI: -11.35 - -11.05, p<0.00001) respectively. ConclusionDespite inconsistent control of medication histories and PA-prescription, adherence to behavioural and pharmacological interventions can successfully alleviate pain. First-line management using DMARDs or NSAIDs appears to be more effective than yoga, Rocabado exercises, or aerobic and/or resistance training alone. Systematic review registration numberCRD420251069339 Key MessagesO_LIBoth pharmacological and physical activity interventions can successfully reduce pain perceptions amongst patients with RA. C_LIO_LIIndependent use of DMARDs or NSAIDs appears to alleviate pain more than aerobic and/or resistance-training. C_LI

IntroductionThere is limited information on the effectiveness of COVID-19 vaccination in patients with autoimmune rheumatic diseases (AIRD). Methods136 consecutive patients with rheumatic diseases who never had a diagnosis of COVID-19 previously, and had completed vaccination with either the ChAdOx1 or BBV152 vaccines were recruited. Their IgG antibody titres to the Spike protein were estimated 1 month after the second dose. Results102 patients had AIRD while the 34 had non-AIRD. Lesser patients with AIRD (92/102) had positive antibodies titres than ones with non-AIRD(33/34) [p<0.001]. Amongst patients who received the ChAdOX1 vaccine, the AIRD group had lower antibody titres. Although the AIRD patients receiving BBV152 had similarly lower titres numerically, this did not attain statistical significance probably due to lesser numbers. Comparing the two vaccines, 114(95%) of those who received ChAdOx1 (n=120) and 11(68.7%) of those who received BBV152(n=16) had detectable antibodies [p=0.004]. Antibody titres also were higher in ChAdOx1 recipients when compared to BBV152. To validate the findings, we estimated antibody titres in 30 healthy people each who had received either vaccine. All 30 who had received ChAdOX1 and only 23/30 of those who had received BBV152 had positive antibodies (p=0.011). ConclusionIn this preliminary analysis, patients with AIRD had lower seroconversion rates as well as lower antibody titres as compared to patients with non-AIRD. Also,the humoral immunogenicity of the BBV152 vaccine appears to be less than that of the ChAdOX1 vaccine. Validation using larger numbers and testing of cellular immunity is urgently required.

Backgroundrheumatologists recognize the importance of rehabilitation in patients with rheumatoid arthritis (RA), but they are not confident if patients with significant disease activity would benefit from it. ObjectiveTo verify if rheumatoid arthritis patients with moderate to severe inflammatory activity (MHA) improve functional capacity (FC) after a comprehensive rehabilitation program. MethodsNested case-control study. RA patients who completed a rehabilitation program between June 2014 and December 2017 were included. The interventions were prescribed according to the rehabilitation teams discretion. FC was assessed with Health Assessment Questionnaire Disability Index (HAQ) and compared between before and after interventions. The group which improved at least 50% in CDAI was compared to the group which achieved <50%. ResultsWe included 46 patients with complete HAQ and baseline CDAI data, with a mean age of 53.6 years and mean disease duration of 11.8 years. HAQ and CDAI improved on average 0.481 ({+/-} 0.500) and 14.2 ({+/-} 16.7), respectively. Patients who improved CDAI tended to have a greater mean HAQ difference (0.6 vs. 0.3; p = 0.058). Conversely, patients who did not improve disease activity had a HAQ reduction of 0.3 ({+/-} 0.4). Post-hoc analysis was performed on the group of 9 patients with baseline CDAI [&le;]10. A mean baseline CDAI of 5.2 and a mean HAQ difference of 0.319 (0.079; 0.56; p = 0.016) were found. ConclusionsAfter rehabilitation, RA patients with sustained MHA improved FC similarly to patients with baseline mild activity or remission. Thus, patients with RA and MHA may benefit from rehabilitation concurrently with drug treatment. This study suggests that the range of improvement in FC with rehabilitation appears to have an additive effect to the drug therapy.

ObjectivesRheumatoid arthritis (RA) is associated with elevated risk of cardiovascular (CV) events that has been attributed to inflammation although this is not well supported by randomised controlled trial (RCT) data. This RCT evaluated the effect of adalimumab upon endothelial function and arterial stiffness in ACPA-positive RA. MethodsSixty subjects with active ACPA-positive RA stratified as Early (<12 months n=30) or Established (>12 months n=30) were enrolled and randomised 1:1 within each group to receive 40 mg adalimumab or placebo. They were assessed by DAS28-CRP, Reactive Hyperaemic Index (RHI) and Carotid-Femoral Pulse Wave Velocity (CF-PWV) twice prior to treatment and then at 1, 4, 12 and 24 weeks with one final open-label at 36 weeks. Secondary analysis evaluated the effects of disease duration, Shared Epitope (SE) and smoking status. ResultsThere were significant treatment effects upon DAS28-CRP at weeks 1, 4 and 12 in Early RA with transient effects upon RHI at week 1 in Established RA and CF-PWV in Early RA at week 4. Area-under-the-curve analysis found positive treatment effects in subjects expressing one SE (DAS28-CRP p 0.031, CF-PWV p 0.034) and in non-smokers (DAS28-CRP p 0.096, CF-PWV p 0.033). ConclusionsThis RCT appeared to show positive treatment effects upon CV risk. However, the effect of adalimumab upon RHI may be type 1 statistical error and the effect upon CF-PWV more likely represents physiologic pain-driven mechanisms rather than structural effects. This study highlights the challenges, the limitations, strengths of and opportunities for CV biomarker research in this complex field.

IntroductionChronic inflammation associated with ageing contributes to sarcopenia-related risk of falls and multimorbidity. The SARC-F questionnaire, based on strength, ambulation, rising from a chair, climbing stairs and falling, and MSRA (mini sarcopenia risk assessment) are validated tools to identify sarcopenia in elderly people. Here, we investigated the utility of SARC-F and MSRA in identifying the risk of sarcopenia and falls in young individuals living with juvenile idiopathic arthritis (JIA). MethodsJIA patients and healthy participants were invited to complete an online survey including the SARC-F, MSRA-5, and MSRA-7 questionnaires. Additional questions explored their nutrition and exercise habits. ResultsWe invited 101 healthy participants and 41 patients with JIA. Of the 41 JIA respondents, the median age was 23 years and 25 (61%) were female. According to the SARC-F, MSRA-5, and MSRA-7 questionnaires, 20%, 47%, and 33% were at risk of sarcopenia, respectively. Around 27% of JIA patients reported at least one fall in the past year compared to around 33% of healthy participants. However, 20% of JIA participants reported more than four falls in the past year in contrast to 4% of healthy participants. Furthermore, 44% of JIA participants reported difficulty climbing stairs and 17% reported limited ability to walk one kilometer. ConclusionsOur study has demonstrated the potential utility of SARC-F and MSRA in JIA for identifying patients at risk of falls. Whether SARC-F and MSRA have the potential to identify those with sarcopenia in young people with JIA warrants further validation. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=185 SRC="FIGDIR/small/25338687v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@cef147org.highwire.dtl.DTLVardef@4276fdorg.highwire.dtl.DTLVardef@191eb90org.highwire.dtl.DTLVardef@1004a1a_HPS_FORMAT_FIGEXP M_FIG C_FIG

ObjectivesTo compare the impact of COVID-19 on clinical status and psychological condition in patients with immune-mediated rheumatic diseases (IMRD) infected by SARS-CoV-2 with IMRD controls not infected, during a 6-month follow-up. MethodsThe ReumaCoV Brasil is a longitudinal study designed to follow-up IMRD patients for 6 months after COVID-19 (cases) compared with IMRD patients no COVID-19 (controls). Clinical data, disease activity measurements and current treatment regarding IMRD, and COVID-19 outcomes were evaluated in all patients. Disease activity was assessed through validated tools at inclusion and at 3 and 6 months post-COVID-19. The FACIT-F (Functional Assessment of Chronic Illness Therapy) and DASS 21 (Depression, Anxiety and Stress Scale - 21 Items) questionnaires were also applied at 6 months after COVID-19 in both groups before large-scale vaccination. The significance level was set as p<0.05, with a 95% confidence interval. ResultsA total of 601 patients were evaluated, being 321 cases (IMRD COVID-19+) and 280 controls (IMRD COVID-19 -), predominantly female with similar median age. No significant differences were noted in demographic data between the groups, including comorbidities, disease duration, and IMRD. Disease activity assessment over a 6-month follow-up showed no significant difference between cases and controls. While mean activity scores did not differ significantly, some patients reported worsened disease activity post-COVID-19, particularly in rheumatoid arthritis (RA) (32.2%) and systemic lupus erythematosus (SLE) (23.3%). Post-COVID-19 worsening in RA patients correlated with medical global assessment (MGA) and CDAI scores, with a moderate to large effect size. Diabetes mellitus showed a positive association (OR=7.15), while TNF inhibitors showed a protective effect (OR=0.51). Comparing SLEDAI pre- and post-COVID-19, a minority showed increased scores, with few requiring treatment changes. Fatigue, depression, anxiety, and stress were significantly higher in cases compared to controls. Worsening disease activity post-COVID correlated with worsened FACIT-F and DASS-21 stress scale in RA patients. No significant associations were found between COVID-19 outcomes and post-COVID-19 disease activity or psychological assessments. ConclusionsPost-COVID-19 IMRD patients show significant psychological well-being deterioration despite similar disease activity scores. The variability in reports on IMRD flares and the potential trigger of SARS-CoV-2 for autoimmune manifestations underline the need for detailed clinical assessment and a comprehensive approach to managing them.

ObjectivesSynovial monocytes in oligoarticular juvenile idiopathic arthritis (oJIA) are polarized, but little is known of how they contribute to disease and attain their pathogenic features. The aim of this study was to investigate the role of monocytes in the pathogenesis of oJIA. MethodsThe function of synovial monocytes was analysed by several assays believed to reflect key pathogenic events, such as T-cell activation-, efferocytosis- and cytokine production assays through flow cytometry in untreated oJIA patients (n=33). The effect of synovial fluid on healthy monocytes was investigated through mass spectrometry, broad-spectrum phosphorylation assays and functional assays. Additional effects on monocytes were studied through co-cultures with primary fibroblast-like synoviocytes. ResultsThe results demonstrate that synovial monocytes display functional alterations, e.g., increased ability to induce T-cell activation, increased efferocytosis and resistance to cytokine production following activation with LPS. In vitro, synovial fluid induced regulatory features in healthy monocytes through an IL-6/JAK/STAT mechanism. The magnitude of synovial IL-6 driven activation in monocytes was reflected in circulating cytokine levels. An increased ability to induce T-cell activation and markers of antigen presentation could be induced by co-culture with fibroblast-like synoviocytes. ConclusionsSynovial monocytes in oJIA are functionally affected, drive chronic inflammation, and promote adaptive immune responses. This phenotype can be replicated in vitro through a combination of synovial fluid (through IL-6/JAK/STAT) and cell-cell interactions. These data support a role of monocytes in the pathogenesis of oJIA and highlight a group of patients more likely to benefit from targeting the IL-6/JAK/STAT axis to restore synovial homeostasis. Key messagesO_ST_ABSWhat is already known on this topicC_ST_ABSO_LIMonocytes infiltrate the joint in oligoarticular juvenile idiopathic arthritis (JIA), where they display a pathogenic phenotype and signs of activation C_LI What this study addsO_LIThe results of this study demonstrate functional alterations of synovial monocytes in driving chronic inflammation in oligoarticular JIA C_LIO_LISynovial monocytes acquire their regulatory properties through the IL-6/JAK/STAT pathway in synovial fluid and their inflammatory properties through cell-cell interactions C_LIO_LIIn patients with high IL-6/JAK/STAT involvement, this is reflected in elevated circulating cytokine levels C_LI How this study might affect research, practice or policyO_LIThis study describes the mechanisms controlling the function of synovial monocytes in oligoarticular JIA and identifies patients likely to respond to IL-6/JAK/STAT inhibition, which should be further explored to facilitate personalized medicine. C_LI

BackgroundChondrocytes in osteoarthritic (OA) cartilage acquire a hypertrophic-like phenotype, where Hedgehog (Hh) signaling is pivotal. Hh overexpression causes OA-like cartilage lesions, whereas its downregulation prevents articular destruction in mouse models. Mutations in EVC and EVC2 genes disrupt Hh signaling, and are responsible for the Ellis-van Creveld syndrome skeletal dysplasia. Since Ellis-van Creveld syndrome protein (Evc) deletion is expected to hamper Hh target gene expression we hypothesized that it would also prevent OA progression avoiding chondrocyte hypertrophy. Our aim was to study Evc as a new therapeutic target in OA, and whether Evc deletion restrains chondrocyte hypertrophy and prevents joint damage in an Evc tamoxifen induced knockout (EvccKO) model of OA. MethodsOA was induced by surgical knee destabilization in wild-type (WT) and EvccKO adult mice, and healthy WT mice were used as controls (n=10 knees/group). Hypertrophic markers and Hh genes were measured by qRT-PCR, and metalloproteinases (MMP) levels assessed by western blot. Human OA chondrocytes and cartilage samples were obtained from patients undergoing knee joint replacement surgery. Cyclopamine (CPA) was used for Hh pharmacological inhibition and IL-1{beta} as an inflammatory insult. ResultsTamoxifen induced inactivation of Evc inhibited Hh overexpression and partially prevented chondrocyte hypertrophy during OA, although it did not ameliorate cartilage damage in DMM-EvccKO mice. Hh pathway inhibition did not modify the expression of proinflammatory mediators induced by IL-1 beta in human OA chondrocytes in culture. Hypertrophic - IHH - and inflammatory - COX-2 - markers co-localized in OA cartilage samples. ConclusionsTamoxifen induced inactivation of Evc partially prevented chondrocyte hypertrophy in DMM-EvccKO mice, but it did not ameliorate cartilage damage. Our results suggest that chondrocyte hypertrophy per se is not a pathogenic event in the progression of OA.

BackgroundRheumatoid arthritis (RA) is a chronic inflammatory disease characterized by metabolic dysregulation, including altered lipid metabolism. While polyunsaturated fatty acids have been studied, the plasma levels, endogenous synthesis, and relevance of monounsaturated fatty acids (MUFAs) in RA remain unclear. This study examined plasma MUFA levels in RA and their associations with disease activity, adiposity, and intake. MethodsIn this cross-sectional study, 59 individuals with rheumatoid arthritis (RA) and 33 non-RA controls frequency-matched on age, sex, and BMI were recruited between 2017 and 2022. Clinical assessments included disease activity (DAS28), body composition, and metabolic parameters. Dietary intake was assessed using a 4-day food journal, and plasma fatty acids were quantified by gas chromatography in 82 participants with available samples. The stearoyl-CoA desaturase-1 (SCD-1) index was used as a proxy for endogenous MUFA synthesis. Associations between MUFAs and clinical variables were evaluated using univariate and multivariable regression (p<0.05). ResultsRA participants had higher waist-to-hip ratio, fat mass, fasting triglycerides, and lower physical activity than controls. Plasma palmitoleic and oleic acids and the SCD-1 index were higher in RA, whereas linoleic and arachidonic acids were lower. Saturated and omega-3 fatty acids were similar. Higher oleic and gondoic acids were independently associated with greater disease activity; oleic acid was linked to central adiposity, and palmitoleic acid was higher in women, suggesting sex- and adiposity-specific regulation. ConclusionsHigher plasma MUFAs in RA are associated with disease activity, adiposity, and sex, highlighting altered MUFA metabolism as a feature of RA and a potential target for metabolic intervention. Key MessagesO_ST_ABSWhat is already known on this topicC_ST_ABSRheumatoid arthritis (RA) involves systemic inflammation and altered lipid metabolism. While polyunsaturated fatty acids have been studied extensively, the plasma levels, endogenous synthesis, and clinical relevance of monounsaturated fatty acids (MUFAs) in RA remain unclear. What this study addsPatients with RA have higher plasma MUFAs, including oleic and palmitoleic acids, and an elevated SCD-1 index, a marker of endogenous MUFA synthesis. Higher MUFAs are associated with disease activity, central adiposity, and sex-specific patterns, independent of dietary intake. How this study might affect research, practice or policyPlasma MUFAs could serve as potential biomarkers of RA disease activity and metabolic dysregulation. These findings suggest that altered MUFA metabolism contributes to inflammatory pathways, highlighting a potential target for future research, nutritional interventions, or therapeutic strategies.

Objectives: Juvenile systemic lupus erythematosus (JSLE) and juvenile dermatomyositis (JDM) are systemic autoimmune rheumatic diseases (RMDs) with childhood-onset associated with increased risk of damage accumulation and cardiovascular disease (CVD) over the life course. Methods: Damage associated with JSLE and JDM has been assessed using validated outcome measures in a longitudinal single-centre cohort study with long-term follow-up, involving data collected both retrospectively and prospectively. Descriptive statistics, sensitivity and regression analyses have been used to evaluate predictors of damage and CVD-risk. Results: We assessed comparatively a JSLE cohort (n=76), with a mean age of 24.3 +/- 4.2 years and a JDM cohort (n=79) with a mean 20.1 +/-5.0 years (p<0.001), with matched duration of follow-up (10.0 +/- 4.2 vs. 11.0 +/- 5.1, respectively, p=0.68). Traditional CVD-risk factors, including hypertension (p=0.02), dyslipidaemia (p=0.0005), and higher total cholesterol (p=0.01) and LDL-cholesterol (p=0.02) levels at the last assessment were higher in JSLE vs. JDM. Over the disease course, 39 (51.3%) AYA with JSLE vs. 47 (59.4%) AYA with JDM accumulated damage (p=0.307), which was independently predicted by the body mass index in both cohorts (p=0.038 and p=0.026, respectively). The PDAY score was the only tool able to stratify AYA based on CVD-risk (median = 5 (4-13) points in JSLE vs. 0 (0-3) points in JDM, p=0.0001), as all the adult CVD-risk scores were very low in both cohorts. Conclusions: This is the first comparative evaluation of JSLE vs. JDM in adulthood, which highlighted increased damage burden and CVD-risk in JSLE that warrants further investigation.

Objectiveimmune dysregulation may play a role in cardiovascular (CV) risk excess in rheumatoid arthritis (RA). However, exact mediators are unknown. Age-associated B cells (ABCs) have emerged as multi-faceted pro-inflammatory mediators, also in the atherosclerosis microenvironment, but their role in autoimmunity is ill-defined. Our aim was to evaluate ABCs levels in the earliest stages of inflammatory arthritis and their potential role as biomarkers of atherosclerosis. MethodsABCs were quantified by flow cytometry in 58 early RA patients, 11 individuals with clinical-suspect arthralgia (CSA) and 33 healthy controls (HC). Atherosclerosis occurrence was measured by Doppler-ultrasound. Cytokines were measured by multiplex immunoassays. Cardiometabolic-related proteins were evaluated using high-throughput targeted proteomics. ResultsCirculating ABCs were increased in RA patients compared with HC within the CD19+ and PBMCs pools (p=0.013 and p<0.001, respectively). Numerically higher ABCs levels were found in CSA. ABCs frequency was unrelated to disease features and traditional CV risk factors but negatively associated with good therapeutic outcomes upon csDMARD at 6 and 12 months. ABCs frequency was positively correlated with proinflammatory cytokines (IFNg, TNF, IL-6 and IL-21) and proteomic signatures related to B- and T-cell responses as well as cellular pathways linked to atherosclerosis. ABCs were independently associated with atherosclerosis occurrence and extent in RA patients. Furthermore, adding ABCs levels significantly improved risk stratification over conventional instruments. ConclusionsABCs expansion is an early event along arthritis course, linked to therapeutic outcomes, inflammatory milieu and atherosclerosis burden. ABCs may be a missing link between humoral responses and atherosclerosis in autoimmunity.

IntroductionPain in patients with rheumatoid arthritis (RA) is an unmet clinical need. Targeting joint inflammation with disease modifying antirheumatic drugs (DMARDs) has not resulted in the anticipated reduction in pain for many patients. This can partly be explained by the concept of central sensitisation whereby spinal and supraspinal pathways have a lower threshold of activation leading to increased perception of pain. Synovial stromal cells such as fibroblasts are also thought to play a role through peripheral sensitisation of nerves in the joint. Synovial fibroblasts are known to produce pro-algesic mediators such as interleukin 6 (IL-6) and nerve growth factor (NGF) at the mRNA level. These pro-algesic mediators could activate sensory nerve fibres that send signals from the joint to the spinal cord, thereby driving persistent pain in RA. The purpose of this study is to evaluate which pro-algesic mediators are produced by lining versus sublining fibroblasts and whether the level of these mediators correlates with clinical measures of pain in patients with RA. Methods and analysisFiND-Pain RA is a multi-centre observational study which will recruit 50 patients with seropositive RA who attend the rheumatology department of Guys and St Thomas Hospital, London and the Nuffield Orthopaedic Centre, Oxford. Clinical examination, pain-focused patient reported outcome measures (PROMs), ultrasound examination and ultrasound guided synovial biopsy of the knee will be performed. The levels of known and putative pro-algesic mediators will be measured in fibroblasts from the lining and sublining layer of the synovium. The location and spatial morphology of sensory nerve fibres and their proximity to lining and sub-lining fibroblasts will be characterized. The primary outcome will be to determine whether the knee pain scores of participants correlate with the level of LIF, a novel putative pain-mediator expressed in sub-lining fibroblasts. The secondary outcomes will be to determine whether other pro-algesic mediators produced by lining or sub-lining fibroblasts correlate with clinical measures of pain and to assess the location and proximity of sensory nerve fibres to lining versus sub-lining fibroblasts. Ethics and disseminationThe study has been approved by the Bromley Research Ethics Committee (REC: 21/LO/0712). The findings of this study will be disseminated through open-access publications, as well as scientific and clinical conferences.

This study assessed the evidence on the efficacy of tapering anti-TNF, JAK inhibitors, and tocilizumab in rheumatoid arthritis patients. In February 2024, a systematic review was conducted by searching Medline, Embase, Web of Sciences, and the Cochrane Library for randomized controlled trials comparing the efficacy of tapering vs standard treatment. The outcomes evaluated were the maintenance of low disease activity (LDA), remission, and flare-ups. A meta-analysis was conducted when data were available. The risk of bias was assessed using RoB 2. The study was registered on PROSPERO. A total of 2861 records were identified, with 1638 records screened after removing duplicates. Finally, fifteen studies involving 2782 patients were included. Follow-up ranged from 6 months to 3.5 years. Tapering anti-TNF did not affect LDA maintenance while showing a lower probability of maintaining remission (RR 0.69, 95% CI 0.57-0.84) and a higher risk of flare-ups (RR 1.96, 95% CI 1.57-2.45). Tapering JAK inhibitors showed a decreased probability of maintaining LDA (RR 0.83, 95% CI 0.76-0.91) and remission (RR 0.86, 95% CI 0.75-0.99), and more frequent and earlier flares. Tapering tocilizumab also resulted in a lower probability of maintaining LDA or remission and a higher risk of flares. Although tapering anti-TNF did not affect LDA maintenance, due to the increased risk of flare-ups and reduced remission probability, routine dose tapering of anti-TNF, JAK inhibitors, and tocilizumab for all patients is not recommended. Identifying patients who may benefit from tapering is crucial.

BackgroundOsteoarthritis (OA) is the most common joint disease and is characterized by bone remodeling, cartilage degradation and synovial inflammation. To date, no effective treatment is available for this debilitating condition. Recent evidence suggests that mitochondrial dysfunction, including oxidative phosphorylation (OxPhos) failure, accumulates within OA chondrocytes and may contribute to pathogenesis. In this context, mitochondrial dysfunction may be associated with observable changes in mitochondrial number, size and shape. However, a comprehensive characterization of mitochondria-related features during OA, from tissue-to-cell level, is still lacking. Addressing these gaps could inform therapeutic strategies, such as the partial restoration of OxPhos, which has been proposed as a therapeutic approach. MethodsHere, we employed a multimodal approach that included Fourier-transform infrared spectroscopy (FTIR), scanning transmission electron microscopy (STEM) and real-time cellular metabolic assays (Seahorse technology) to better characterize mitochondrial parameters in cartilage during OA. Two types of experimental models were used using human cartilage: (1) undamaged versus damaged OA zones, and (2) non-OA versus OA samples. In addition, we investigated the potential of repurposing bezafibrate, an approved peroxisome proliferator-activated receptor (PPAR) agonist, as a mitochondria-based therapy to restore OxPhos in OA chondrocytes. ResultsWe identified that OA chondrocytes exhibit a decrease in glycogen deposits surface, and an increased number of mitochondria alongside an OxPhos dysfunction compared to non-OA chondrocytes. A similar trend toward glycogen storage deficiency and increased mitochondria number was observed in OA chondrocytes from damaged cartilage areas. Furthermore, multivariate analyses revealed that the clinical profiles of OA patients allowed OA chondrocytes to be separated into responders and non-responders to bezafibrate. ConclusionWe provide evidence that OA chondrocytes display decreased glycogen deposits surface, increased mitochondrial number and OxPhos dysfunction. Additionally, we identified that bezafibrate, a PPAR agonist, improved OxPhos function in a subgroup of OA chondrocytes derived from patients.

ObjectiveTemporomandibular joint (TMJ) osteoarthritis (OA) is a degenerative disease affecting the whole synovial joint, with a higher prevalence in women. While obesity is recognised as a risk factor for knee OA, its association with TMJ degeneration remains controversial. Recently, metabolic endotoxemia, characterised by a subclinical elevation of circulating lipopolysaccharide (LPS), has been proposed as a key mediator of obesity. It was thought to accelerate OA progression in knee joints by triggering low-grade systemic inflammation. However, the contribution of endotoxemia to TMJ OA is unclear. This study investigated whether chronic LPS exposure induces TMJ OA and whether its interplay with adipose tissue is involved in this process, particularly in a sex-specific context. MethodsMetabolic endotoxemia was induced in 6-month-old female and male Wistar rats by continuous subcutaneous infusion of LPS for 4 - 6 weeks using osmotic pumps. Ten weeks after the start of LPS infusion, peripheral blood, subcutaneous and visceral white adipose tissue, and TMJs were harvested for biochemical, histological, micro-computed tomography and gene expression analyses. Primary TMJ chondrocytes isolated from healthy female and male rats were further used to assess sex-specific responses to leptin and LPS in vitro. ResultsChronic LPS exposure induced pronounced OA-like changes in female TMJs, including cartilage matrix loss, subchondral bone resorption and mild synovial inflammation, whereas male joints were minimally affected. In female cartilage, immunofluorescence analyses showed an increased proportion of cells co-expressing leptin, leptin receptor and inducible nitric oxide synthase, supporting local activation of leptin-associated inflammatory pathways. In contrast, LPS immunosignal was not detected in cartilage. Systemically, LPS-treated female rats exhibited elevated circulating LPS and leptin concentrations, together with adipocyte hypertrophy and inflammatory changes in subcutaneous adipose tissue, whereas these changes were not evident in males. In vitro, leptin induced stronger metabolic and inflammatory responses in female chondrocytes, including reduced intracellular lipid content and metabolic activity, increased nitric oxide production, and upregulated catabolic gene expressions following LPS priming. ConclusionChronic systemic LPS exposure induced sex-specific TMJ OA associated with adipose tissue dysfunction and altered leptin signalling. These findings support a potential female-biased systemic-to-local adipose-cartilage link between endotoxemia and TMJ OA pathogenesis.

IntroductionPotassium inadequacy (diet and body storage) may adversely affect rheumatoid arthritis (RA) and is sparsely reported. We evaluated the therapeutic benefits (RA) of food-based potassium intake, recommended daily allowance (RDA), and higher. ObjectiveTo evaluate pain reduction by oral potassium in chronic RA Methods172 consenting and eligible symptomatic patients (median duration 6.5 years) on ongoing standard care were randomized in a single-center study (80% power, significant p < 0.05) - Arm A (vegetarian diet as per the India RDA for potassium), Arm B (Arm A diet plus novel potassium food supplement) and Arm C (regular diet, control). Efficacy and safety, and diet intake (three-day recall, Food Composition tables) were assessed (blinded) at monthly intervals till 16-week of study completion and statistically analyzed using standard methods. Study groups were found matched and showed inadequate baseline dietary potassium (RDA). On study completion, the median daily potassium intake was 2959 mg in Arm A, 6063 mg in Arm B, and 2553 mg in Arm C. Study subjects remained normokalemic at all evaluations. Overall, the background medication remained stable. Results155 patients (90.1%) completed the study. Adverse events were mild. On comparison, the improvement in pain (primary efficacy) on study completion was significant in Arm B as per protocol analysis; the mean change in pain visual analog scale from baseline was -2.23 (95% confidence interval -2.99 to -1.48). Arm B showed impressive improvement in joint function. High potassium intake predicted low pain (Likelihood ratio 2.9, logistic regression). Compliance (intervention), diet recall, medication, complex nature of dietary intervention/other nutrients, and lack of placebo were potential confounders to ascertain the effectiveness of potassium. ConclusionA planned vegetarian diet and food supplement intervention with a predominantly increased potassium intake significantly reduced chronic RA pain. This adjunct treatment was found safe and well tolerated. However, it requires further validation. Trial RegistrationClinical Trial Registry of India- CTRI/2022/03/040726 KEY MESSAGE What is already known on the topic?O_LIRA is predominantly managed with drug therapy and diet is often neglected C_LIO_LIRA is complicated by hypertension and other cardiovascular disorders, and osteoporosis which may benefit from potassium intervention. C_LIO_LIPotassium and potassium ion channels are important the pathophysiology of pain (and probably inflammation) C_LIO_LIPatients of RA may be deficient in potassium due to inadequate diet or sarcopenia C_LI What does this study add?O_LIPotassium-rich vegetarian diet and a novel high-potassium food supplement significantly reduced pain in chronic RA on supervised standard drug care. C_LIO_LISeveral participants showed improved joint function and better blood pressure status C_LIO_LIHigher potassium intake based on food and diet was safe and well tolerated C_LI How this study might affect research, practice, or policy?O_LIPotassium rich predominantly vegetarian diet should be advocated in the management of RA as an adjuvant C_LIO_LIA judicious use of high potassium food supplement along with suitable diet may benefit difficult and chronic RA C_LIO_LIThe current guidelines on oral potassium intake in RA and other medical disorders need to be revised and call for more research C_LI