Associations of per- and polyfluoroalkyl substances (PFAS) and their mixture with risk of rheumatoid arthritis in the U.S. adult population.

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

Impact of DMARD treatment and systemic inflammation on all-cause mortality in patients with rheumatoid arthritis and interstitial lung disease: a cohort study from the German RABBIT register.

OBJECTIVES: To investigate the impact of disease activity and treatment with disease-modifying antirheumatic drugs (DMARDs) on all-cause mortality in patients with rheumatoid arthritis and prevalent interstitial lung disease (RA-ILD). METHODS: Patients with RA-ILD were selected from the biologics register Rheumatoid Arthritis: Observation of Biologic Therapy (RABBIT). Using time-varying Cox regression, the association between clinical measures and mortality was investigated. The impact of DMARDs was analysed by (1) Cox regression considering cumulative exposure (ie, treatment months divided by total months) and (2) time-varying Cox regression as main approach (treatment exposures at monthly level). RESULTS: Out of 15 566 participants, 381 were identified as RA-ILD cases with 1258 person-years of observation and 2.6 years median length of follow-up. Ninety-seven patients (25.5%) died and 34 (35.1%) of these were not receiving DMARD therapy at the time of death. Higher inflammatory biomarkers but not swollen and tender joint count were significantly associated with mortality. Compared with tumour necrosis factor inhibitors (TNFi), non-TNFi biologic DMARDs (bDMARDs) exhibited adjusted HRs (aHRs) for mortality below 1, lacking statistical significance. This finding was stable in various sensitivity analyses. Joint aHR for non-TNFi biologics and JAKi versus TNFi was 0.56 (95% CI 0.33 to 0.97). Receiving no DMARD treatment was associated with a twofold higher mortality risk compared with receiving any DMARD treatment, aHR 2.03 (95% CI 1.23 to 3.35). CONCLUSIONS: Inflammatory biomarkers and absence of DMARD treatment were associated with increased risk of mortality in patients with RA-ILD. Non-TNFi bDMARDs may confer enhanced therapeutic benefits in patients with RA-ILD.

Host-microbiota interactions in collagen-induced arthritis rats treated with human umbilical cord mesenchymal stem cell exosome and ginsenoside Rh2.

Mesenchymal stem cell exosome (MSCs-exo) is a class of products secreted by mesenchymal stem cells (MSCs) that contain various biologically active substances. MSCs-exo is a promising alternative to MSCs due to their lower immunogenicity and lack of ethical constraints. Ginsenoside Rh2 (Rh2) is a hydrolyzed component of the primary active substance of ginsenosides. Rh2 has a variety of pharmacological functions, including anti-inflammatory, anti-tumor, and antioxidant. Studies have demonstrated that gut microbiota and metabolites are critical in developing rheumatoid arthritis (RA). In this study, we constructed a collagen-induced arthritis (CIA) model in rats. We used MSCs-exo combined with Rh2 to treat CIA rats. To observe the effect of MSCs-exo combined with Rh2 on joint inflammation, rat feces were collected for 16 rRNA amplicon sequencing and untargeted metabolomics analysis. The results showed that the arthritis index score and joint swelling of CIA rats treated with MSCs-exo in combination with Rh2 were significantly lower than those of the model and MSCs-exo alone groups. MSCs-exo and Rh2 significantly ameliorated the disturbed gut microbiota in CIA rats. The regulation of Candidatus_Saccharibacteria and Clostridium_XlVb regulation may be the most critical. Rh2 enhanced the therapeutic effect of MSCs-exo compared with the MSCs-exo -alone group. Furthermore, significant changes in gut metabolites were observed in the CIA rat group, and these differentially altered metabolites may act as messengers for host-microbiota interactions. These differential metabolites were enriched into relevant critical metabolic pathways, revealing possible pathways for host-microbiota interactions.

Persistence on subcutaneous tocilizumab as monotherapy or in combination with synthetic disease-modifying anti-rheumatic drugs in rheumatoid arthritis patients in Greece (EMBRACE study): a multicenter, post-marketing, non-interventional, observational trial.

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

Effects of Viscum coloratum (Kom.) Nakai on collagen-induced rheumatoid arthritis.

ETHNOPHARMACOLOGICAL RELEVANCE: Viscum coloratum (Kom.) Nakai has been traditionally used in China for nearly a thousand years to treat rheumatic diseases. However, its efficacy and mechanisms in treating rheumatoid arthritis (RA) have not been demonstrated. AIM OF THE STUDY: To investigate the anti-arthritic effects and molecular mechanisms of Viscum coloratum (Kom.) Nakai on collagen-induced arthritic mice through network pharmacology technology and experimental validation. MATERIALS AND METHODS: First, the main ingredients of the extract of Viscum coloratum (Kom.) Nakai (EVC) were identified through chemical composition characterization using Ultra Performance Liquid Chromatography Tandem Mass Spectrometry (UPLC-MS). Then, the collagen-induced arthritis (CIA) model was established in DBA/1 J mice and the ameliorative effects of EVC on the progression of CIA mice were evaluated by oral treatment with different doses of the EVC for 28 days. After that, cytokine antibody microarray assay was used to detect the levels of multiple inflammation-related cytokines and chemokines in each group, and performed Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genome (KEGG) enrichment analysis. Subsequently, the potential target for the effective chemical components of EVC in treating RA was identified using various databases. Additionally, a drug-disease target protein-protein interaction network (PPI) was conducted using Cytoscape for visualization and clustering, while GO and KEGG enrichment analyses were performed with the Metascape database. Finally, identified phenotypes and targets by network pharmacology analysis were experimentally validated in vivo. RESULTS: Treatment with EVC significantly suppressed the severity of CIA with a dramatic reduction of paw swelling, arthritis index, levels of IgGs (IgG, IgG1, IgG2a, and IgG2b), multi-inflammation-related cytokines and chemokines on the progression of CIA. Histopathological examinations showed EVC could markedly inhibit inflammatory cell infiltration, tartrate-resistant acid phosphatase (TRAP) activity of osteoclast, and bone destruction. Furthermore, GO and KEGG enrichment analyses revealed that EVC could ameliorate RA by inhibiting osteoclast differentiation and regulating multiple signaling pathways including Osteoclast differentiation, IL-17, and TNF. PPI network analysis demonstrated that AKT1, MMP9, MAPK3, and other genes were highly related to EVC in treating RA. Finally, we proved that EVC could inhibit the expression of NFTAc1, MMP9, Cathepsin K, and AKT which were closely related to osteoclast activity. CONCLUSIONS: EVC could treat RA through multiple components, multiple targets, and multiple pathways. The present study demonstrated the therapeutic efficacy of EVC and its molecular mechanisms in treating RA, indicating that it would be a potent candidate as a novel botanical drug for further investigation.

Therapeutic delivery systems for rheumatoid arthritis based on hydrogel carriers.

Rheumatoid arthritis (RA) is an autoimmune disease suffered by millions of people worldwide. It can significantly affect the patient's quality of life by damaging not only the joints but also organs such as the lungs and the heart. RA is normally treated using nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, disease-modifying antirheumatic drugs (DMARDs), and biologics. These active agents often cause side effects and offer low efficacy due to their lack of specificity and limited retention time. In an attempt to improve RA treatments, hydrogel-based systems have been proposed as drug delivery carriers. Due to their exceptional adaptability and biocompatibility, hydrogels have the potential of enhancing the delivery of RA therapy through different administration routes in an efficient and effective manner. In this review, we explore the application of hydrogel systems as potential carriers in RA treatment. Additionally, we discuss recent work in the field and highlight the required hydrogel properties, depending on the administration route. The outstanding potential of hydrogel systems as carriers for RA was demonstrated; however, there is extensive research yet to be done to improve available treatments for RA.

Estragole Ameliorates CFA Induced Rheumatoid Arthritis Symptoms in Wistar Rats by Inhibiting JAK-2/STAT-3 Pathway.

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

The association between dietary intake of branched-chain amino acids and odds and severity of rheumatoid arthritis.

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

Comparative effectiveness of baricitinib and alternative biological DMARDs in a Swiss cohort study of patients with RA.

OBJECTIVES: This observational study compares the effectiveness of baricitinib (BARI), a targeted synthetic disease-modifying antirheumatic drug (tsDMARD), with alternative biological DMARDs (bDMARDs) in patients with rheumatoid arthritis (RA), from a prospective, longitudinal cohort. METHODS: We compared patients initiating a treatment course (TC) of BARI, tumour necrosis factor inhibitors (TNFi) or bDMARDs with other modes of action (OMA), during a period when all these DMARDs were available in Switzerland. The primary outcome was drug maintenance; secondary outcomes included discontinuation rates related specifically to ineffectiveness and adverse events. We further analysed rates of low disease activity (LDA) and remission (REM) at 12 months and drug maintenance in bDMARD-naïve and tsDMARD-naïve population. RESULTS: A total of 1053 TCs were included: 273 on BARI, 473 on TNFi and 307 on OMA. BARI was prescribed to older patients with longer disease duration and more previous treatment failures than TNFi. Compared with BARI, the adjusted drug maintenance was significantly shorter for TNFi (HR for discontinuation: 1.76; 95% CI, 1.32 to 2.35) but not compared with OMA (HR 1.27; 95% CI, 0.93 to 1.72). These results were similar in the b/tsDMARD-naïve population. The higher discontinuation of TNFi was mostly due to increased discontinuation for ineffectiveness (HR 1.49; 95% CI, 1.03 to 2.15), with no significant differences in drug discontinuation for adverse events (HR 1.46; 95% CI, 0.83 to 2.57). The LDA and REM rates at 12 months did not differ significantly between the three groups. CONCLUSIONS: BARI demonstrated a significantly higher drug maintenance compared with TNFi, mainly due to lower drug discontinuations for ineffectiveness. We found no difference in drug maintenance between BARI and OMA. Clinical outcomes did not differ between the three groups. Our results suggest that BARI is an appropriate therapeutic alternative to bDMARDs in the management of RA.

Drug-drug interaction assessment based on a large-scale spontaneous reporting system for hepato- and renal-toxicity, and thrombocytopenia with concomitant low-dose methotrexate and analgesics use.

BACKGROUND: Methotrexate (MTX) is the cornerstone of rheumatoid arthritis (RA) treatment and is highly effective with low-dose intermittent administration. MTX is occasionally used in combination with non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen (APAP)/paracetamol for pain or inflammation control. With MTX treatment, the side effects, such as hepatotoxicity, renal failure, and myelosuppression should be considered. These are also seen with analgesics treatment. METHODS: We used a large spontaneously reported adverse event database (FAERS [JAPIC AERS]) to analyze whether the reporting of adverse events increased upon MTX and analgesic therapy in patients with RA. RESULTS: After identifying RA cases, the crude reporting odds ratios (cRORs) for hepatotoxicity, renal failure, and thrombocytopenia associated with the use of MTX, APAP, or NSAIDs were calculated by disproportionality analysis, which revealed significantly higher cRORs for these events. No analgesics showed consistent positive signals for drug-drug interaction (DDI) with concomitant low-dose MTX analyzed using four algorithms for DDI interaction (the Ω shrinkage measure, additive or multiplicative, and combination risk ratio models). However, in renal failure and thrombocytopenia, loxoprofen (Ω025 = 0.08) and piroxicam (Ω025 = 0.46), and ibuprofen (Ω025 = 0.74) and ketorolac (Ω025 = 3.52), respectively, showed positive signals in the Ω shrinkage measure model, and no consistency was found among adverse events or NSAIDs. CONCLUSIONS: Studies using spontaneous reporting systems have limitations such as reporting bias or lack of patient background; however, the results of our comprehensive analysis support the results of previous clinical or epidemiological studies. This study also demonstrated the usefulness of FAERS for DDI assessment.

Predictors at diagnosis for start of biologic disease-modifying antirheumatic drugs in patients with early rheumatoid arthritis: a cohort study.

OBJECTIVES: To investigate the relation between patient characteristics at rheumatoid arthritis (RA) diagnosis and subsequent initiation of treatment with biologic disease-modifying antirheumatic drugs (bDMARDs) or targeted synthetic DMARDs (tsDMARDs). DESIGN: A retrospective cohort study. SETTING AND PARTICIPANTS: Consecutive patients (N=330) with early RA (symptom duration <12 months) diagnosed at Skåne University Hospital, Malmö/Lund, Sweden, from 2012 to 2016, were included. Data on demographics, education, comorbidities and treatment were obtained from national registers. OUTCOME: The relation between patient characteristics at diagnosis and time to first bDMARD/tsDMARD initiation was analysed using Cox regression models. As a secondary outcome, the relation between characteristics at diagnosis and b/tsDMARD initiation within 3 years was analysed using logistic regression. RESULTS: A total of 330 patients (mean age 59.2 years; SD 16.4) were included. During follow-up, 41% received a bDMARD (never preceded by a tsDMARD). Higher age at diagnosis was associated with a lower probability of starting bDMARD treatment (multivariable-adjusted HR 0.66 per SD; 95% CI 0.56 to 0.78). Anticitrullinated protein antibody (ACPA) positivity and higher tender joint count at diagnosis were also associated with subsequent bDMARD treatment initiation in multivariable analysis. A higher level of formal education and absence of comorbidities predicted start of a bDMARD in crude, but not in age-adjusted, analyses. CONCLUSIONS: Older patients with RA were less likely to start bDMARDs, whereas ACPA-positive patients, and those with extensive joint involvement at diagnosis, were more likely to receive early bDMARD treatment. The impact of age on the subsequent start of bDMARD therapy was not explained by level of education or comorbidities, suggesting that other aspects of age influence treatment decisions in early RA.

Exploring candidate biomarkers for rheumatoid arthritis through cardiovascular and cardiometabolic serum proteome profiling.

Introduction: RA patients are at higher risk of cardiovascular disease, influenced by therapies. Studying their cardiovascular and cardiometabolic proteome can unveil biomarkers and insights into related biological pathways. Methods: This study included two cohorts of RA patients: newly diagnosed individuals (n=25) and those with established RA (disease duration >25 years, n=25). Both cohorts were age and sex-matched with a control group (n=25). Additionally, a longitudinal investigation was conducted on a cohort of 25 RA patients treated with methotrexate and another cohort of 25 RA patients treated with tofacitinib for 6 months. Clinical and analytical variables were recorded, and serum profiling of 184 proteins was performed using the Olink technology platform. Results: RA patients exhibited elevated levels of 75 proteins that might be associated with cardiovascular disease. In addition, 24 proteins were increased in RA patients with established disease. Twenty proteins were commonly altered in both cohorts of RA patients. Among these, elevated levels of CTSL1, SORT1, SAA4, TNFRSF10A, ST6GAL1 and CCL18 discriminated RA patients and HDs with high specificity and sensitivity. Methotrexate treatment significantly reduced the levels of 13 proteins, while tofacitinib therapy modulated the expression of 10 proteins. These reductions were associated with a decrease in DAS28. Baseline levels of SAA4 and high levels of BNP were associated to the non-response to methotrexate. Changes in IL6 levels were specifically linked to the response to methotrexate. Regarding tofacitinib, differences in baseline levels of LOX1 and CNDP1 were noted between non-responder and responder RA patients. In addition, response to tofacitinib correlated with changes in SAA4 and TIMD4 levels. Conclusion: In summary, this study pinpoints molecular changes linked to cardiovascular disease in RA and proposes candidate protein biomarkers for distinguishing RA patients from healthy individuals. It also highlights how methotrexate and tofacitinib impact these proteins, with distinct alterations corresponding to each drug's response, identifying potential candidates, as SAA4, for the response to these therapies.

The impact of folate pathway variants on the outcome of methotrexate therapy in rheumatoid arthritis patients.

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

PM10 increases mortality risk in rheumatoid arthritis-associated interstitial lung disease.

OBJECTIVES: The effect of air pollution on the prognosis of rheumatoid arthritis-associated interstitial lung disease (RA-ILD) remains poorly understood. We aimed to evaluate the effect of long-term exposure to particulate matter with an aerodynamic diameter of ≤10 µm (PM10) and nitrogen dioxide (NO2) on mortality in patients with RA-ILD. METHODS: We included 309 patients (mean age, 61.7 years; male, 44.3%) with RA-ILD. Individual-level long-term exposures to PM10 and NO2 at their residential addresses were estimated using a national-scale exposure prediction model. The effect of the two air pollutants on mortality was estimated using a Cox-proportional hazards model adjusted for individual-level and area-level characteristics. RESULTS: The median follow-up period was 4.8 years, and 40.8% of patients died or underwent lung transplantation. The annual average concentrations of PM10 and NO2 were 56.3 µg/m3 and 22.4 ppb, respectively. When air pollutant levels were stratified by quartiles, no association was observed between air pollutant concentration and mortality in patients with RA-ILD. However, when stratified by two groups (high exposure (top 25th percentile) vs low exposure (bottom 75th percentile)), we observed a significant association between high PM10 exposure and mortality (HR 1.68; 95% CI 1.11 to 2.52; p=0.013) but no association between NO2 exposure and mortality. In the subgroup analyses, the effect of high PM10 exposure on mortality was significant in patients aged <65 years (HR 1.98; 95% CI 1.02 to 3.85; p=0.045). CONCLUSIONS: Our results indicated that high PM10 exposure may be associated with mortality in patients with RA-ILD.

Detection of novel drug-adverse drug reaction signals in rheumatoid arthritis and ankylosing spondylitis: analysis of Korean real-world biologics registry data.

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

Effectiveness and safety of sarilumab in patients with rheumatoid arthritis: A multicenter, retrospective, inverse probability of treatment-weighted analysis based on the FRAB-registry.

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

Autoantigen-Dexamethasone Conjugate-Loaded Liposomes Halt Arthritis Development in Mice.

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

Patient-related factors influencing the effectiveness and safety of Janus Kinase inhibitors in rheumatoid arthritis: a real-world study.

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