Onset Of Rheumatoid Arthritis Research Articles

Targeting Therapeutic Windows for Rheumatoid Arthritis Prevention.

Rheumatoid arthritis (RA) is a worldwide public health problem. Interventions to delay or prevent the onset of RA have attracted much attention in recent years, and researchers are now exploring various prevention strategies. At present, there is still no unified consensus for RA prevention, but targeting therapeutic windows and implementing interventions for at-risk individuals are extremely important. Due to the limited number of clinical trials on pharmacologic interventions, further studies are needed to explore and establish optimal intervention regimens and effective measures to prevent progression to RA. In this review, we introduce the RA disease process and risk factors, and present research on the use of both Western and Chinese medicine from clinical perspectives regarding RA prevention. Furthermore, we describe several complete and ongoing clinical studies on the use of Chinese herbal formulae for the prevention of RA.

LncRNA SNHG3 discriminates rheumatoid arthritis from healthy individuals and regulates inflammatory response and oxidative stress via modulating miR-128-3p.

This study evaluated the expression and significance of SNHG3 in Rheumatoid arthritis (RA) aiming to explore a biomarker and regulator for RA. The expression of SNHG3 in serum and synovial tissue was compared between RA patients and healthy individuals using PCR. The RA animal models were induced by the porcine type II collagen with Wistar rats and validated by the foot volume and AI score. The human fibroblast-like synoviocytes (H-FLS) were treated with LPS to mimic the injury during RA onset and the cell growth was assessed by CCK8 assay. SNHG3 was significantly downregulated in the serum and synovial tissue of RA patients compared with healthy individuals. Downregulated SNHG3 could discriminate RA patients from healthy individuals with high sensitivity (0.875) and specificity (0.844). Porcine type II collagen induced increasing foot volume and AI scores of rats and SNHG3 was downregulated in RA rats. In LPS-induced H-FLS, SNHG3 negatively regulated miR-128-3p, and the alleviated effect of SNHG3 overexpression on cellular inflammation and oxidative stress was reversed by miR-128-3p upregulation. Serum SNHG3 was considered a potential diagnostic biomarker for RA from healthy individuals. SNHG3 regulated inflammatory response and oxidative stress via negatively modulating miR-128-3p.

Rheumatoid arthritis epidemiology: a nationwide study in Poland.

To assess the incidence and prevalence of rheumatoid arthritis (RA) in Poland for the period 2013-2021, total and dependent on gender, age, region and serological status. Information on reported National Health Fund (NHF) health services and reimbursed prescriptions were used, defining an RA patient as a person who had at least two visits in different quarters with ICD-10 code M05 or M06 and at the same time filled at least one reimbursed prescription for a drug whose active substance is methotrexate, sulfasalazine, leflunomide or was treated with biologic disease-modifying anti-rheumatic drugs (bDMRDs) or targeted synthetic DMARDs (tsDMARDs) as part of a drug program financed by the National Health Fund. The nationwide standardised incidence rate of RA in 2021 was 29 persons per 100,000 population (18 per 100,000 population of seropositive vs. 11 per 100,000 population of seronegative RA). The prevalence of RA in Poland in 2021 was 689.0 people per 100,000 population, a total of 0.7% (1.1% in women and 0.3% in men). The incidence of seronegative RA was approximately 38%. The majority of new RA diagnoses were in the sixth and seventh decades of life, irrespective of patients' gender. The results allow RA to be classified as a disease with a significant social impact. A trend of later onset of RA has been observed, which requires special consideration of the needs of patients over 55years of age.

Sexual and reproductive health while living with rheumatoid arthritis: The impact of the disease stage on patient perspectives.

Rheumatoid arthritis (RA) is one of the most prevalent rheumatic diseases that harms all aspects of patients' lives, including sexual and reproductive health (SRH), often neglected in patients' care. The study aimed to explore the sexual and reproductive experiences of Mexican outpatients with RA from a narrative perspective. From July 2020 to October 2021, 30 adult patients with RA from the Department of Immunology and Rheumatology outpatient clinic of a national referral center for rheumatic diseases had in-depth interviews audiotaped, transcribed, and analyzed using a thematic analysis approach. Results are presented in a descriptive and interpretative manner and integrated into a theoretical model for the topic understanding. Five intertwined major themes emerged: I) RA onset: Absence of SRH contents, II) Healthcare for RA: Emerging SRH contents, III) RA's impact: Proliferation of SRH contents, IV) Coping with the process of living with RA: SRH-related strategies, and V) The impact of the COVID-19 pandemic on patients' experiences: Increased SRH burden. SRH contents emerged through these major themes (but at RA onset), mostly when inquired and mainly when narrating the RA impact and coping. Patients identified that RA affected their couple dynamics, sexual function, and reproductive project. The SRH care was considered relevant but limited and focused on reproductive contents. It worsened during the COVID-19 pandemic. We proposed a theoretical model where patients' SRH experiences are embedded across their RA biography and integrated with the RA impact and the copy with the disease process. These intertwined experiences were also evident during the COVID-19 pandemic, which challenged participants' biopsychosocial resources. The sexual and reproductive experiences narrated by the RA outpatients concerning their disease-related biography showed that even when the SRH appeared as not prioritized at the disease onset, it was widely expressed during the process of living and coping with the disease and was additionally affected by the COVID-19 pandemic.

OA20 Serious infections hospital admissions and mortality in patients with early inflammatory arthritis: results from the National Early Inflammatory Arthritis Audit

Abstract Background/Aims To identify the risk of serious infections (SI) according to initial treatment strategy, using conventional synthetic disease modifying anti-rheumatic drugs (csDMARD) and corticosteroids, in patients recruited to the National Early Inflammatory Arthritis Audit (NEIAA). Methods An observational cohort study design was used. The population included adults in England with a new onset rheumatoid arthritis (RA), fulfilling ACR/EULAR 2010 criteria, between April 2018-March 2021. Outcomes studied were SI, defined by infections requiring hospitalisation (primary admission diagnosis/nosocomial acquisition) or death (SI stated on death certificate), identified using NHS Digital linkage. Patients' characteristics were tabulated by treatment strategies. Hazard ratios (HR) were calculated using single failure Cox proportional-hazards models, with confounders-adjusted models (age, gender, smoking status, comorbidities, social deprivation) and fully-adjusted models including disease factors (seropositivity, DAS28). Individuals were considered at risk from the date of RA diagnosis, and censored at SI event, death, or March 2021 (whichever was earliest). Results 20,060 patients with RA were included. Initial DMARD therapy was known for 19,572 patients, of whom 11,966 were on methotrexate/MTX based strategies (mono or combo), 5,059 on csDMARD combination strategies (other than MTX) and 2,547 on no DMARD strategy. 15,319 patients were on corticosteroids at baseline. Mean age 59.5 years (+/-15); 63% female; smoking status (20% current; 30% ex-smokers); comorbidities (21% hypertension; 10% diabetes; and 12% lung disease). Rheumatoid Factor/CCP antibodies were positive in 68%. At presentation, median disease scores were 5.1 (interquartile range [IQR]: 4.0-5.9) for DAS28, 1.1 (IQR: 0.6-1.7) for health assessment questionnaire (HAQ) and 24 (IQR: 16.0-33.0) for musculoskeletal health questionnaire (MSKHQ).There were 519 SI admissions and 17 SI deaths, corresponding to incidence rates per 100 person-years for admissions: 3.19 (95% CI: 2.93-3.48) and deaths: 0.10 (95% CI: 0.06-0.16). In fully-adjusted models, increasing age predicted both SI admissions and deaths. Being a smoker, having a comorbidity, higher disease activity (DAS28), symptom burden (MSKHQ) and disability (HAQ) at presentation associated with more SI admissions. For each 1 unit increase in DAS28, the risk of SI increased by 8% (HR 1.08 [95% CI:1.01-1.16]). Seropositivity did not associate with SI. MTX-based strategies 0.75 (95% CI:0.62-0.91) and csDMARD combination therapy 0.70 (95% CI:0.53-0.94) associated with fewer SI admissions compared to no DMARD. In unadjusted models, corticosteroid associated with more SI admissions 1.29 (95% CI:1.10 -1.62); however, in fully-adjusted models this association was no longer statistically significant. csDMARD strategies did not associated with SI deaths in any of the models. Conclusion Patient and disease factors at diagnosis appear to be important predictors of admissions and mortality for serious infections. Infection risk appears to be greatest in those with higher RA disease activity. An important limitation is that NEIAA does not capture data on treatment changes over time and steroid use beyond baseline. Disclosure M. Adas: None. K. Bechman: None. M. Russell: Honoraria; Lilly and Menarini. Other; upport for attending conferences from Lilly, Pfizer, Janssen, and UCB, and advisory board fees from Biogen.. I. Karafotias: None. D. Nagra: None. S. Patel: None. S. Gallagher: None. E. Price: None. M. Garton: None. A. Rutherford: None. A. Cope: None. S. Norton: None. J. Galloway: Honoraria; from Abbvie, Biovitrum, Bristol Myers Squib (BMS), Celgene, Chugai, Gilead, Janssen, Lilly, Novartis, Pfizer, Roche, Sanofi, Sobi, and UCB.

OA06 Regional differences in work productivity in patients with early rheumatoid arthritis in England and Wales

Abstract Background/Aims Inflammatory arthritis including rheumatoid arthritis (RA) causes significant work disability. Rapid diagnosis and early intervention can reduce the impact of disease. We have previously shown significant regional variation in care delivery. In this study we aim to study regional variation in work outcomes in early RA in England and Wales. Methods We used data from the UK National Early Inflammatory Arthritis Audit between April 2018 and March 2023 to identify patients with early-onset RA in England and Wales. At diagnosis, clinicians collected information on demographics and disease activity. Participants were invited to complete work outcome questionnaires at baseline and 3 months. Our analysis was restricted to patients with work data available at 3 months. The primary outcome was discontinuation of work due to arthritis. Patient characteristics were tabulated by region. Regression models (adjusted for age and gender) examined the associations between work discontinuation and region. Clustered standard errors were estimated to account for within-Trust correlations. Sensitivity models further explored the effects of deprivation and treatment delay. Results A total of 3,730 patients with confirmed RA provided work data. Mean age was 67, 62.3% were female and 7.8% from minority ethnic backgrounds. 14% were current smokers and 55.6% had one or more comorbidities. Median baseline DAS28 was 5.2 (IQR: 4.2-6.1). 363/3730 (10%) had stopped work due to RA by 3 months. 534/3,730 (14%) stopped work for any reason. In regression analysis, significant regional differences were seen in the odds of stopping work due to RA. The Midlands was the largest regional contributor of data and was used as the reference group. Patients from Northwest England were most likely to stop work by 3 months (age- and gender-adjusted OR 1.59, [95% CI 1.13-2.25]) with Midlands patients least likely. Sensitivity analysis showed that deprivation and treatment delay only partially attenuate the association between region and work outcome (OR for Northwest 1.57 [1.06-2.33]). Conclusion There is evidence of regional variation in the impact of new onset RA on work participation. Our analyses suggest that the associations are only partly explained by regional differences in care delivery or deprivation. Other factors such as job type and access to occupational health support warrant further investigation. Disclosure E. Alveyn: Other; Educational support from UCB. M. Adas: None. I. Sahbudin: None. A. Boonen: None. K. Bechman: Honoraria; UCB, Vifor Pharma. M.D. Russell: Honoraria; Abbvie, BioGen, Lilly, Galapagos, Menarini. Other; Educational grants from Lilly, Janssen, Pfizer, UCB. D. Nagra: Honoraria; Abbvie, Galapagos, Lilly. Other; Educational support from UCB. S. Gallagher: None. E. Price: None. K. Walker-Bone: None. S. Norton: None. J. Galloway: Honoraria; AbbVie, Celgene, Chugai, Gilead, Janssen, Eli Lilly, Pfizer, Roche and UCB.

OA03 Developing a multivariable prediction model to identify anti-CCP positive individuals among those with non-specific musculoskeletal symptoms in primary care

Abstract Background/Aims A phase of immunologically imminent rheumatoid arthritis (RA) precedes the onset of clinical RA, characterised by increased circulating anti-cyclic citrullinated peptide (anti-CCP) antibodies. Early identification in the pre-clinical phase of RA in primary care (PC), through targeted anti-CCP testing, could prompt secondary care referral for earlier diagnosis, achieving better long-term outcomes. This study aimed to develop a model identifying those likely to be anti-CCP positive amongst people presenting to PC with non-specific musculoskeletal symptoms. Methods Participants were recruited across the UK between 2014 and 2020 to the Leeds ‘Co-ordinated Programme to Prevent Arthritis’, a prospective, observational cohort study. Participants were aged ≥18 years who presented to PC with non-specific musculoskeletal symptoms and no history of clinical synovitis. Fifteen baseline predictors were considered: age; gender; smoking status; first degree relative (FDR) with RA; and patient reported pain in: neck; back; shoulders; elbows; hips; wrists; thumbs; hand and/or fingers; knees; ankles; foot and/or toes. Participants were followed up at 12 months to determine if they had developed RA. Analysis was performed in R. Variable selection was carried out via LASSO logistic regression. Model performance was assessed using area under the receiver operating characteristic curve (ROC AUC); decision curve analysis was utilised to assess clinical utility. Internal validation was carried out via 200 bootstrap re-samples with replacement to estimate corrected model fit estimates. Results Analysis included 6,879 participants; 203 (2.95%) anti-CCP positive. Thirteen predictors were retained (age and ankles omitted); scores for each predictor were: sex (male) [+3], FDR with RA [+3], smoking (ever) [+2], pain in back [-3], neck [-2], knee [-1], wrist [+4], foot/toes [+3], hand/fingers [+3], shoulder [+3], thumb [+1]. With a score of ≥ 11 (≥4% risk) for anti-CCP testing, the ROC AUC was 0.65 (95% CI [0.61-0.69], corrected AUC=0.49). Choosing a threshold of 4% suggested that the benefit of testing one anti-CCP positive patient is 24 times larger than the harm of testing one anti-CCP negative patient. Sensitivity and specificity were 38.42 and 81.88 and positive- and negative-predicted values were 6.06 and 97.76. The net benefit was 0.0040 (corrected=0.0026). This threshold resulted in 19% being tested, corresponding to 39% of all anti-CCP positive participants. 12 month follow-up data were available for 2,480 participants. Out of those who would be tested using our model, 6.68% developed RA, compared with 1.94% if everyone was tested. Out of those tested who were anti-CCP positive, 56.85% developed RA (amongst those tested who were anti-CCP negative, 1.23% developed RA). Conclusion Targeted use of anti-CCP testing in PC may prompt earlier identification of people at risk of RA. Interviews with PC clinicians are currently being undertaken to understand the key behaviours required to support clinicians using this prediction model, alongside heath economic modelling to explore potential cost-effectiveness. Disclosure H.J. Siddle: Grants/research support; HJS has received funding from HEE/NIHR for this research [ICA-SCL-2018-04-ST2-004]. M. Wilson: None. J.L. Nam: None. L. Garcia-Montoya: None. L. Duquenne: None. K. Mankia: Consultancies; Serac Lifesciences. Honoraria; Galapagos, Lilly, Abbvie. Grants/research support; Eli Lilly, Gilead. Other; Attending meetings/travel: Abbvie. P. Emery: Consultancies; Lilly, Galapagos. Honoraria; Novartis, Lilly, Abbvie, Gilead, Galapagos. Grants/research support; Lilly, Samsung. Other; Advisory Board: Lilly, Astra Zeneca, BMS. E.M.A. Hensor: Grants/research support; Institution level grant for the NIHR Leeds Biomedical Research Centre.

OA02 Longitudinal high throughput proteomics identifies novel proteins associated with inflammation and future response in new-onset, treatment-naïve rheumatoid arthritis

Abstract Background/Aims Despite the availability of effective targeted therapies, only 20-30% achieve low disease activity and even fewer attain remission. There remains a pressing need to identify meaningful biomarkers and disease endotypes to enable precision medicine. We aimed to identify serum protein biomarkers that associate with RA inflammation and future remission in a treatment-naïve, new-onset RA trial cohort. Methods Serum from 105 patients from the ‘VEDERA’ trial (first-line tumour necrosis factor inhibitor + methotrexate [TNFi + MTX] versus methotrexate treat-to-target [MTX-TT]) at baseline, week 24 and 48 were analysed for 92 proteins using the Olink Target 96 Inflammation panel. Clinical and MSUS assessments completed at baseline, weeks 24 and 48 were used for the analyses. Clinical remission was defined as DAS28-ESR ≤ 2.6 and joint-level remission as absence of power Doppler ultrasound synovitis (PDUS). After adjusting for age, gender and seropositive status, Bayesian mixed effects regression (posterior estimates and 95% credible intervals reported) was used to identify association of (i) proteins with clinical disease activity (DAS28-ESR) and joint-level inflammation (total power Doppler ultrasound synovitis (PDUS) scores] and (ii) baseline proteins with future (week 24 or 48) clinical and joint-level remission. Results Longitudinally, out of 92 proteins, 10 and 14 were significantly associated with DAS28-ESR and total PDUS scores respectively, with 3 proteins in common: leukaemia inhibitory factor receptor (LIF-R); fractalkine (CX3CL1); interleukin-10 receptor alpha (IL-10RA). Baseline levels of 9 proteins were associated with future clinical remission (week 24 = 6 proteins; week 48 = 3 proteins) while 6 were associated with future PDUS status (week 24 = 4 proteins; week 48 = 3 proteins). Proteins that were associated with inflammation longitudinally and whose baseline levels associated with future remission included IL-17C, fibroblast growth factor 5 (FGF-5), lymphotoxin alpha and TNF. Posterior estimates and 95% credible intervals for above proteins are reported in Table 1. Conclusion Using longitudinal high-throughput proteomics in a treatment-naïve early onset RA cohort, this study sheds new light on known and novel protein associates of inflammation and future remission. With future validation, these biomarkers could provide mechanistic understanding and allow for individualised treatment strategies to improve outcomes. Disclosure R. Shukla: None. R. Wakefield: None. A. Tan: None. P. Emery: Consultancies; BristolMyersSquibb, AbbVie, Gilead, Galapagos, Eli Lilly, MSD, Pfizer, Novartis, Roche and Samsung. Grants/research support; AbbVie, Eli Lilly, Novartis, BristolMyersSquibb, Pfizer and Roche, outside the submitted work. D. Plant: None. M.H. Buch: Consultancies; AbbVie, Arxx Therapeutics, Boehringer Ingelheim, Galapagos, Gilead, and Pfizer; and speaker fees from AbbVie, CESAS Medical, Galapagos, Gilead, Medistream, and Pfizer. Grants/research support; grant support from Gilead.

The prevalence and risk factors of rheumatoid arthritis-associated interstitial lung disease: a systematic review and meta-analysis

Background Interstitial lung disease (ILD) is the most widespread and fatal pulmonary complication of rheumatoid arthritis (RA). Existing knowledge on the prevalence and risk factors of rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is inconclusive. Therefore, we designed this review to address this gap. Materials and Methods To find relevant observational studies discussing the prevalence and/or risk factors of RA-ILD, EMBASE, Web of Science, PubMed, and the Cochrane Library were explored. The pooled odds ratios (ORs) / hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated with a fixed/ random effects model. While subgroup analysis, meta-regression analysis and sensitivity analysis were carried out to determine the sources of heterogeneity, the I2 statistic was utilized to assess between-studies heterogeneity. Funnel plots and Egger’s test were employed to assess publication bias. Following the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines, our review was conducted. Results A total of 56 studies with 11,851 RA-ILD patients were included in this meta-analysis. The pooled prevalence of RA-ILD was 18.7% (95% CI 15.8–21.6) with significant heterogeneity (I2 = 96.4%). The prevalence of RA-ILD was found to be more likely as a result of several identified factors, including male sex (ORs = 1.92 95% CI 1.70–2.16), older age (WMDs = 6.89, 95% CI 3.10–10.67), having a smoking history (ORs =1.91, 95% CI 1.48–2.47), pulmonary comorbidities predicted (HRs = 2.08, 95% CI 1.89–2.30), longer RA duration (ORs = 1.03, 95% CI 1.01–1.05), older age of RA onset (WMDs =4.46, 95% CI 0.63–8.29), positive RF (HRs = 1.15, 95%CI 0.75-1.77; ORs = 2.11, 95%CI 1.65–2.68), positive ACPA (ORs = 2.11, 95%CI 1.65–2.68), higher ESR (ORs = 1.008, 95%CI 1.002–1.014), moderate and high DAS28 (≥3.2) (ORs = 1.87, 95%CI 1.36–2.58), rheumatoid nodules (ORs = 1.87, 95% CI 1.18-2.98), LEF use (ORs = 1.42, 95%CI 1.08–1.87) and steroid use (HRs= 1.70, 1.13–2.55). The use of biological agents was a protective factor (HRs = 0.77, 95% CI 0.69–0.87). Conclusion(s) The pooled prevalence of RA-ILD in our study was approximately 18.7%. Furthermore, we identified 13 risk factors for RA-ILD, including male sex, older age, having a smoking history, pulmonary comorbidities, older age of RA onset, longer RA duration, positive RF, positive ACPA, higher ESR, moderate and high DAS28 (≥3.2), rheumatoid nodules, LEF use and steroid use. Additionally, biological agents use was a protective factor.

The changes of intestinal flora and its relevance with memory Tfh and B cells in rheumatoid arthritis patients treated with csDMARDs and csDMARDs + bDMARDs

BackgroundA growing body of experimental and clinical evidence has implicated gut microbiota in the onset and course of rheumatoid arthritis (RA). The imbalance of intestinal flora in RA patients may lead to abnormal expression of immune cells and related cytokines. PurposeConventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and conventional synthetic disease-modifying antirheumatic drugs combined with biological disease-modifying antirheumatic drugs (csDMARDs + bDMARDs) are widely used to treat RA, but the characteristics of gut microbiota before and after treatment and their relationship with memory Tfh/B cells and cytokines remain unclear. MethodsStool samples were collected from 50 RA patients and 25 healthy controls (HCs) for 16SrRNA gene sequencing. We examined the proportion of lymphocyte subsets in healthy controls and RA patients. Enzyme linked immunosorbent assay (ELISA) was used to detect the levels of related cytokines in serum. The α and β diversity of intestinal flora, and the correlation between intestinal flora and clinical indicators, lymphocyte subsets, cytokines were analyzed. ResultAt the genus level, Ruminococcaceae_Ruminococcus was decreased in the csDMARDs and csDMARDs + bDMARDs treatment group, whereas Faecalibacterium was reduced in the csDMARDs treatment group, compared to untreated group. CD4+CD45RO+CCR7+CXCR5+central memory Tfh cells and CD4+CD45RO+CCR7-CXCR5+effector memory Tfh cells were significantly lower in the csDMARDs + bDMARDs treatment group than in untreated group. CD19+CD27+IgD+pre-switched memory B cells were higher in the csDMARDs and csDMARDs + bDMARDs treatment groups, whereas CD19+CD27+IgD-switched memory B cells were significantly lower than in untreated group. Ruminococcaceae_Ruminococcus was negatively correlated with CD19+CD27+IgD+ pre-switched memory B cells but positively correlated with CD4+CD45RO+CCR7-CXCR5+effector memory Tfh and CD19+CD27+IgD-switched memory B cells in patients with RA treated with DMARDs. ConclusionThe gut microbiota, memory Tfh cells, memory B cells, and cytokines of patients with RA changed significantly under different treatment regimens and had certain correlations with the clinical indicators of RA.

MicroRNA-150 Deletion Reduces the Occurrence and Severity of Rheumatoid Arthritis by Inhibiting IL-17.

Understanding the effects of epigenetic factors on the pathogenesis of rheumatoid arthritis (RA) is important for the early diagnosis and therapeutic intervention of this disease. MicroRNA-150 (miR-150) exerts an important influence on the development and function of lymphocytes. However, the role of miR-150 in the pathogenesis of RA remains unclear. To explore the role of miR-150 in the pathogenesis of RA and the related immune mechanism. In this study, we used miR-150 knock-out (miR-150KO) and created animal models of RA. Flow cytometry, immunohistochemistry, and real-time RT-PCR were employed to assess the frequency of T cell subsets and cytokines expression. Compared to wild-type (WT) mice, the onset of RA was postponed and the incidence of RA was reduced in miR-150KO mice. The expression of IL-4 and IFN-γ significantly increased while the expression of IL-17 decreased significantly in NKT and CD4+ T cells of KO mice compared to that of WT mice after RA induction. In addition, the expression of IL-4 and IFN-γ increased while the expression of IL-17 decreased significantly in the joint tissues of KO mice compared to that of WT mice. Furthermore, the mRNA expression of TNF-α and IL-17 decreased significantly in the synovial fluid cells of KO mice compared to that of the WT mice after RA induction. MiR-150 deficiency decreases the expression of IL-17 in T cells and joint tissues, and alleviates the occurrence and progression of RA in mice.

Retention rate of biologic and targeted synthetic anti-rheumatic drugs in elderly rheumatoid arthritis patients: data from GISEA registry.

An increased number of elderly individuals affected by rheumatoid arthritis (RA) has been reported, including both patients with RA onset in advanced age and patients aged with the disease. In this registry-based study, we aimed to analyze the retention rate and cause of discontinuation of biologic (b) and targeted synthetic (ts)-disease-modifying anti-rheumatic drugs (DMARDs) in RA patients over 65 year old. RA patients enrolled in the Italian GISEA registry and starting a b- or a ts-DMARD over 65 years of age were included. Demographic, clinical, serologic, and therapeutic features were collected. A total of 1,221 elderly RA patients were analyzed (mean age 71.6 ± 5.2 years). RA was diagnosed before 65 years in 72.5% of cases, a 60.6% of patients experienced a previous b- or ts-DMARD. In patients older than 65 initiating a new b- or ts-DMARDS, tumor necrosis factor alpha inhibitors (TNFi) were prescribed in 29.6% of patients, abatacept in 24.8%, anti-interleukin 6 receptor antagonists (anti-IL6R) in 16.3%, Janus kinases inhibitors (JAKi) in 24.9%, and rituximab in 4.4%. The main causes of discontinuation were primary or secondary inadequate responses (66.1%). The median retention rate for all treatments was 181.3 weeks. A statistically higher retention rate was observed for abatacept when compared to TNFi (p = 0.02), JAKi (p < 0.001), and anti-IL6R (p < 0.001), and for TNFi vs. JAKi (p = 0.013). We described, in a real-life setting, elderly RA patients treated with a biologic or a ts-DMARD in Italy. Loss of efficacy was the main cause of discontinuation, and the DMARD safety profile suggests that age does not contraindicate their use. Our study reinforced that the control of disease activity is mandatory.

Exploring the Link between Head and Neck Cancer and Elevated Risk of Rheumatoid Arthritis: A National Population-Based Cohort Study.

An increased risk of cancer among patients with rheumatoid arthritis (RA) has been reported. However, the risk of RA events among patients with head and neck cancer (HNC) is unknown. Therefore, we investigated the incidence and risk of RA among patients with HNC. This study was based on a cohort dataset. Overall, 2824 individuals without HNC and 706 patients with HNC were selected using propensity score matching. The overall RA event rate was 12.19 for patients with HNC and 7.60 for those without HNC. A significantly increased risk of developing RA was also observed among patients with HNC. The risk of developing RA over time was relatively high within the first year after HNC diagnosis; further, it increased significantly during the follow-up period. Moreover, middle-aged male patients with HNC exhibited an increased risk of developing RA compared with the controls; however, no significant difference was noted among female patients or other age groups. Notably, subgroup analysis according to cancer subtype revealed that only oral cancer survivors had an increased risk of developing RA. These results underscore the importance of vigilant monitoring by clinicians to promptly identify the onset of RA in patients with HNC.

Rheumatoid arthritis and the intestinal microbiome: probiotics as a potential therapy.

Rheumatoid arthritis (RA) is a systemic autoimmune disorder characterized by swollen joints, discomfort, stiffness, osteoporosis, and reduced functionality. Genetics, smoking, dust inhalation, high BMI, and hormonal and gut microbiota dysbiosis are all likely causes of the onset or development of RA, but the underlying mechanism remains unknown. Compared to healthy controls, patients with RA have a significantly different composition of gut microbiota. It is well known that the human gut microbiota plays a key role in the initiation, maintenance, and operation of the host immune system. Gut microbiota dysbiosis has local or systematic adverse effects on the host immune system, resulting in host susceptibility to various diseases, including RA. Studies on the intestinal microbiota modulation and immunomodulatory properties of probiotics have been reported, in order to identify their potential possibility in prevention and disease activity control of RA. This review summarized current studies on the role and potential mechanisms of gut microbiota in the development and progression of RA, as well as the preventative and therapeutic effects and potential mechanisms of probiotics on RA. Additionally, we proposed the challenges and difficulties in the application of probiotics in RA, providing the direction for the research and application of probiotics in the prevention of RA.

Role of the CXCR4-Gnαq-Plcβ signaling pathway in the pathogenesis of collagen-induced arthritis in rats

Rheumatoid arthritis (RA) is a chronic autoimmune disease in which immune cells and inflammatory cytokines are abnormally activated, leading to immunoregulatory dysfunction in the body and triggering systemic inflammatory responses. The interaction between CXC chemokine receptor 4 (CXCR4) and heterotrimeric G-protein α-subunit Gαq (Gnαq) activates phospholipase Cβ (PLCβ), which influences the expression of downstream effectors and participates widely in the onset and development of various diseases, thus suggesting the potential involvement of these molecules in RA pathogenesis. Therefore, the present study aimed to determine whether the CXCR4-Gnαq-PLCβ signaling pathway participates in the onset and development of RA. Using a collagen-induced arthritis (CIA) rat model, we found that compared with the control (healthy) rat group, CIA rats exhibited highly time-dependent arthritis, with the maximum arthritis score occurring in week 3. In contrast to the splenic and joint tissue of control rats, CIA rats showed obvious hyperplasia in the lymphoid white pulp and main germination centers of the spleen, narrowing of joint cavities, and inflammatory cellular infiltration on articular surfaces. The serum levels of expression of IL-1β, IL-4, IL-6, and TNF-α were significantly elevated (P < 0.05, P < 0.01). Core genes of the CXCR4-Gnαq-PLCβ pathway, namely CXCR4, Gnαq, PLCβ1, MMP1, and MMP3, also showed a significant increase in mRNA and protein expression levels (P < 0.05, P < 0.01). Proteins related to the CXCR4-Gnαq-PLCβ pathway were mainly localized to the red and white pulp regions in the spleen as well as in stromal, endothelial, and subdifferentiated synovial cells in the joints. These results indicated that CXCR4 is dependent on Gnαq for inducing the expression of PLCβ1 and stimulation of secretion of inflammatory cytokines by inflammatory cells. This consequently affects the expression of matrix metalloproteinases (MMPs), which serve as downstream effectors, thereby promoting RA pathogenesis. Our findings play an important role in elucidating the mechanisms of the onset and development of RA.

The role of microbiota on rheumatoid arthritis onset.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that causes inflammation and pain, which can lead to the loss of normal joint function. Although the exact cause of the disease is not yet fully understood, both environmental factors and genetics may play a role in its development. Moreover, research suggests microbiota contributes to the onset and progression of RA. People with RA show higher quantities of bacteria such as Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, Prevotella copri, Proteus mirabilis, and Lactobacillus salivarius compared to healthy individuals. Conversely, studies propose that Lactobacillus casei, a probiotic bacterium with immunomodulatory properties, has beneficial effects for RA in murine and human models. Therefore, this work reviews the potential role of the gut microbiota in the development of RA and explores the feasibility of using probiotic bacteria as a supplementary treatment for this disease.

Peculiarities of pharmacotherapy of patients with rheumatoid arthritis associated with interstitial lung disease

Objective: a comparative study of the peculiarities of pharmacotherapy of rheumatoid arthritis (RA) in presence and in absence of interstitial lung disease (ILD).Material and methods. The study included 1034 patients with active RA who met the 2010 ACR/EULAR criteria. Patients were divided into two groups: with ILD according to high-resolution computed tomography of the lungs (n=82) and without ILD or other types of chronic obstructive pulmonary diseases, including bronchial asthma (52 patients excluded; n=900). Based on medical documentation, archived medical records and medical history, a “drug card” was created for all stages of pharmacotherapy of patients with active RA. The Cumulative Illness Index Score (CIRS) was used to assess the profile and severity of comorbidities.Results and discussion. The main indicators of RA activity in the patients of the two groups were comparable, but a greater number of comorbidities (p˂0.0001) and a higher value of the CIRS multimorbidity index (p˂0.0001) were found in the group with ILD. The presence of ILD had no influence on the frequency of prescription, the total duration of use and the maximum dose of glucocorticoids (GC) (p˂0.05). The average dose of GC was statistically significantly higher in the group with ILD (p=0.008). These patients were taking disease-modifying antirheumatic drugs (DMARDs): methotrexate (p=0.04), leflunomide (p=0.02) and sulfasalazine (p=0.03), less frequently, but they took hydroxychloroquine significantly more frequently (p=0.02) with a comparable total duration of use of each medication. RA patients with ILD and without ILD received biologic DMARDs (bDMARDs) and targeted synthetic DMARDs (tsDMARDs) in 62.2 and 59.6% of cases, respectively (p˂0.05). At the same time, patients without ILD had experience of taking a greater number of different bDMARDs/tsDMARDs (p=0.03). In the group with ILD, patients more frequently received anti-B-cell therapy (p˂0.0001) and significantly less frequently drugs of other classes: tumour necrosis factor α inhibitors (p˂0.0001) and interleukin 6 inhibitors (p=0.01), T-cell costimulation blocker (p=0.04) and Janus kinase inhibitors (p=0.001). Patients with ILD were statistically significantly older at the start of bDMARD/tsDMARD therapy (p˂0.0001), and the period from the onset of RA to the start of bDMARD/tsDMARD therapy was comparable in both groups (p˂0.05).Conclusion. The observed peculiarities of pharmacotherapy in the group with ILD (frequency of use, choice and dose of GC, DMARDs, biologics and tsDMARDs) are probably related to the presence of ILD on the one hand and to the characteristics of concomitant pathology and older age on the other, as the activity of RA was comparable in our patients with and without ILD.

The first presentation of a case of nail-patella syndrome newly diagnosed at the onset of rheumatoid arthritis: a case report

/SummaryBackgroundNail-patella syndrome (NPS) is a rare autosomal dominant disorder that is characterized by dysplasia of the nails, hypoplasia and/or dislocation of the patella and the presence of iliac horns. Using the CARE guidelines, we present the first reported case of NPS that was newly diagnosed at the onset of rheumatoid arthritis (RA).Case presentationA 74-year-old man was admitted to our hospital due to an 8-month history of arthralgia in bilateral wrists, elbows and fingers. He had a past history of glaucoma and left patella dislocation that had been operatively recentered at the age of 15 years. Laboratory data showed elevated levels of serum C-reactive protein and rheumatoid factor and an elevated titer of anti-SS-A antibodies, while estimated glomerular filtration rate (eGFR), titers of other antibodies and the results of a urinary test were normal. An X-ray showed deformity of bilateral radial heads and the right elbow, and magnetic resonance imaging (MRI) of his hands showed synovitis and erosion in the multiple swollen joints of the wrists and fingers. In addition to these typical features of RA, he had bilateral thumb nail dysplasia with mild hypoplasia of bilateral patellae and iliac horns as shown by the X-ray. He was diagnosed as having autosomal dominant disorder NPS co-existing with RA and he was treated with methotrexate in combination with an oral Janus kinase (JAK) inhibitor, leading to induction of remission.ConclusionsWe have presented a rare case of NPS that was newly diagnosed at the onset of RA. Clinical and radiographic findings of NPS are highlighted in this case report for diagnosing NPS on the basis of typical manifestations.

Abatacept inhibits inflammation and onset of rheumatoid arthritis in individuals at high risk (ARIAA): a randomised, international, multicentre, double-blind, placebo-controlled trial

Individuals with anti-citrullinated protein antibodies (ACPAs) and subclinical inflammatory changes in joints are at high risk of developing rheumatoid arthritis. Treatment strategies to intercept this pre-stage clinical disease remain to be developed. We aimed to assess whether 6-month treatment with abatacept improves inflammation in preclinical rheumatoid arthritis. The abatacept reversing subclinical inflammation as measured by MRI in ACPA positive arthralgia (ARIAA) study is a randomised, international, multicentre, double-blind, placebo-controlled trial done in 14 hospitals and community centres across Europe (11 in Germany, two in Spain, and one in the Czech Republic). Adults (aged ≥18 years) with ACPA positivity, joint pain (but no swelling), and signs of osteitis, synovitis, or tenosynovitis in hand MRI were randomly assigned (1:1) to weekly subcutaneous abatacept 125 mg or placebo for 6 months followed by a double-blind, drug-free, observation phase for 12 months. The primary outcome was the proportion of participants with any reduction in inflammatory MRI lesions at 6 months. The primary efficacy analysis was done in the modified intention-to-treat population, which included participants who were randomly assigned and received study medication. Safety analyses were conducted in participants who received the study medication and had at least one post-baseline observation. The study was registered with the EUDRA-CT (2014-000555-93). Between Nov 6, 2014, and June 15, 2021, 139 participants were screened. Of 100 participants, 50 were randomly assigned to abatacept 125 mg and 50 to placebo. Two participants (one from each group) were excluded due to administration failure or refusing treatment; thus, 98 were included in the modified intention-to-treat population. 70 (71%) of 98 participants were female and 28 (29%) of 98 were male. At 6 months, 28 (57%) of 49 participants in the abatacept group and 15 (31%) of 49 participants in the placebo group showed improvement in MRI subclinical inflammation (absolute difference 26·5%, 95% CI 5·9-45·6; p=0·014). Four (8%) of 49 participants in the abatacept group and 17 (35%) of 49 participants in the placebo group developed rheumatoid arthritis (hazard ratio [HR] 0·14 [0·04-0·47]; p=0·0016). Improvement of MRI inflammation (25 [51%] of 49 participants in the abatacept group, 12 [24%] of 49 in the placebo group; p=0·012) and progression to rheumatoid arthritis (17 [35%] of 49, 28 [57%] of 49; HR 0·14 [0·04-0·47]; p=0·018) remained significantly different between the two groups after 18 months, 12 months after the end of the intervention. There were 12 serious adverse events in 11 participants (four [8%] of 48 in the abatacept group and 7 [14%] of 49 in the placebo group). No deaths occurred during the study. 6-month treatment with abatacept decreases MRI inflammation, clinical symptoms, and risk of rheumatoid arthritis development in participants at high risk. The effects of the intervention persist through a 1-year drug-free observation phase. Innovative Medicine Initiative.

Search for predictors of methotrexate toxicity in rheumatoid arthritis

Aim. To determine prognostic markers of methotrexate (MT) toxicity in rheumatoid arthritis (RA).Materials and methods. The study included 294 patients with RA who were prescribed MT at a dose of 10 to 25 mg per week for the first time as basic anti-inflammatory therapy (BPVT). The following adverse events (AEs) were recorded: hepatotoxicity, toxicity from the gastrointestinal tract, blood system. Qualitative parameters were considered as possible predictors of MT intolerance: gender, obesity, smoking, systemic manifestations, as well as rheumatoid factor (RF), antibodies to cyclic citrullinated peptide (ACCP), intake of glucocorticosteroids (GCS), form of administration of MT; and quantitative: age of RA onset, baseline disease activity according to DAS28 (Disease Activity Score 28) and HAQ (Health Assessment Questionnaire), MT dose. Statistical processing was performed by one-factor methods using Pearson’s χ2 test with Yates correction, Fisher’s exact two-tailed test, Mann–Whitney U-test, and Student’s t-test. Multivariate analysis was carried out by binary logistic regression.Results. In a univariate analysis, significant results were obtained for hepatotoxicity: a direct correlation with the use of corticosteroids at the onset (odds ratio (OR) 2.0; 95 % confidence interval (CI) 1.1–3.8, p = 0.03), inversely correlated with MT tablet intake (OR 0.5, 95 % CI 0.2–0.95, p = 0.03). According to the results of multivariate analysis, hepatotoxicity was recorded more often when taking GCS in the debut 2.01 times (95 % CI 1.02–3.96, p = 0.043), and in the presence of ACCP – 3.16 times (95 % CI 1.06–9.45, p = 0.039); and less frequently when taking tableted MT by 2.62 times (95 % CI 0.17–0.84, p = 0.017). Gastrointestinal toxicity tends to be associated with a younger age of RA onset (p = 0.06) and greater RA HAQ activity at onset (p = 0.07).Conclusions. Hepatotoxicity is more expected in patients seropositive for ACCP and GCS treatment in the onset of RA, but is less common when taking MT tablets. AEs from the gastrointestinal tract are associated with a younger age of onset of the disease and a greater degree of activity according to the HAQ index.