Systemic inflammatory biomarkers are novel predictors of all-cause and cardiovascular mortality in individuals with osteoarthritis: a prospective cohort study using data from the NHANES.

BACKGROUND: Chronic inflammation may contribute to increased mortality risk in individuals with osteoarthritis (OA), but research on the prognostic value of inflammatory biomarkers is limited. We aimed to evaluate the associations of the systemic immune-inflammation index (SII) and systemic inflammation response index (SIRI) with all-cause and cardiovascular mortality among US adults with OA. METHODS: This cohort study included 3545 adults with OA aged ≥ 20 years from the National Health and Nutrition Examination Survey 1999-2020. The SII and SIRI were calculated using complete blood cell count data. Participants were categorized as having a higher or lower SII and SIRI using cutoff points derived by the maximally selected rank statistics method. Cox proportional hazards models, Fine-Gray competing risk regression models and time-dependent receiver operating characteristic (ROC) analysis were used to evaluate the associations between the SII/SIRI and mortality in OA patients. RESULTS: Over a median follow-up of 5.08 (3.42-9.92) years, 636 (17.94%) deaths occurred, including 149 (4.20%) cardiovascular deaths. According to multivariable-adjusted models involving demographic, socioeconomic, and health factors, OA patients with a higher SII had a twofold greater risk of all-cause mortality than patients with a lower SII (HR 2.01; 95% CI: 1.50-2.68). Similarly, a higher SIRI was associated with an 86% increased risk of all-cause mortality relative to a lower SIRI (HR 1.86; 95% CI: 1.46-2.38). Similar to the trend found with all-cause mortality, patients with an elevated SII and SIRI had a 88% and 67% increased risk of cardiovascular mortality, respectively, compared to patients with a lower SII (HR 1.88; 95% CI: 1.16-3.03) and SIRI (HR 1.67; 95% CI: 1.14-2.44). Time-dependent ROC curves showed that both the SII and SIRI have moderate and valid performance in predicting short- and long-term mortality in patients with OA. CONCLUSIONS: Higher SII and SIRI values were associated with greater all-cause and cardiovascular mortality among US adults with OA.

Clinical use of macitentan in the treatment of connective tissue disease-associated pulmonary arterial hypertension.

Background: Connective tissue disease (CTD) is the second most common cause of the pulmonary arterial hypertension (PAH). Currently, clinical data concerning CTD-PAH is scarce. Our study aimed to assess the efficacy and safety of macitentan in the treatment of CTD-PAH. Methods: In this retrospective study, patients diagnosed with CTD-PAH at The First Affiliated Hospital of Soochow University from April 2020 to November 2021 were included. Of the patients, 9 were switched to macitentan monotherapy whereas 23 received initial combination therapy. The mean follow-up time was 24 weeks. Six-minute walking distance (6MWD), World Health Organization functional class (WHO-FC), serum N-terminal pro-brain natriuretic peptide (NT-proBNP), and echocardiography parameters before and after medication were assessed. Adverse reactions were also recorded and compared. Results: After 24 weeks of treatment, 6MWD, NT-proBNP, systolic pulmonary artery pressure (sPAP) estimated by ultrasound, tricuspid regurgitation pressure gradient (TRPG) and tricuspid annular plane systolic excursion (TAPSE) in the macitentan monotherapy group revealed significant differences (Z=-2.67, Z=-2.67, t=6.20, t=5.60, t=-3.04, P<0.05). There were no statistically significant differences in right ventricular diameter (RVD), right atrial diameter (RAD), ascending aortic root inner diameter (AAO) and left ventricular end-diastolic diameter (LVEDd) (P>0.05). After 24 weeks of medication, the number of patients with WHO-FC grade III/IV symptoms decreased from 6 to 3, 1 to 0 respectively (P<0.05), and that of patients with WHO-FC grade I/II symptoms increased from 0 to 2, 2 to 4 respectively(P<0.05). After 24 weeks of treatment, 6MWD, NT-proBNP, LVEDd, sPAP and TRPG in the macitentan combined with sildenafil treatment group revealed statistically significant differences (Z=-4.11, Z=-3.74, Z=-3.83, t=6.88, t=6.54, P<0.001). Significant differences in RVD, RAD, and TAPSE were found (t=3.46, t=3.69, t=-3.12, P<0.05). There were no statistically significant variances in AAO between the groups (P>0.05). The number of patients with WHO-FC grade III/IV symptoms decreased from 16 to 8, 5 to 0 respectively (P<0.05), and that of patients with WHO-FC grade I/II symptoms increased from 0 to 1, 2 to 14 respectively (P<0.001). There were no statistically significant differences before and after treatment in 6MWD, NT-proBNP, RVD, RAD, AAO, LVEDd, sPAP, TRPG and TAPSE between the two groups (P>0.05). There were no statistically significant differences in alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum creatinine (Scr) and hemoglobin (Hb) between 0 and 24 weeks (P>0.05). Conclusions: Exercise tolerance and cardiac function in patients with CTD-PAH were significantly improved after treatment with macitentan, which was well tolerated. Therefore, macitentan may be an effective and safe targeted drug for CTD-PAH.

Association between hyperuricemia and long-term mortality in patients with hypertension: results from the NHANES 2001-2018.

Objective: The prevalence of hyperuricemia and hypertension is steadily increasing, and these conditions often share common risk factors. This study aimed to investigate the association among hyperuricemia, hypertension, and all-cause mortality in a nationally representative U.S. population. Methods: Data for 38,644 participants were obtained from the National Health and Nutrition Examination Survey (NHANES) 2001-2018. Hyperuricemia was defined as a serum urate concentration >420 µmol/L in men and >360 µmol/L in women. Information regarding death outcomes was obtained through the National Death Index (NDI). Multivariate logistic regression, Cox proportional hazards models, and restricted cubic spline (RCS) analyses were used to evaluate the association between hyperuricemia and hypertension in all included participants, as well as long-term mortality in patients with hypertension. Results: Among all participants, 6,956 (18.0%) had hyperuricemia, while 31,688 (82.0%) had nonhyperuricemia. According to the adjusted models, hyperuricemia was more strongly associated with hypertension (OR 2.04) than was non-hyperuricemia. During the median follow-up period of 78 months, both hyperuricemia (HR 1.48, 1.95) and hypertension (HR 1.42, 1.69) independently associated with the increased risk of all-cause mortality and cardiovascular mortality, respectively, with the highest risk observed in those with both conditions (HR 1.87, 2.82). RCS analyses revealed nonlinear J-shaped (for hypertension) and U-shaped (for both all-cause and cardiovascular mortality) relationships with serum urate levels. Conclusions: Hyperuricemia is associated with an elevated risk of developing hypertension compared to non-hyperuricemia. Among patients with hypertension, those with hyperuricemia are more likely to experience all-cause and cardiovascular mortality during long-term follow-up.

The neutrophil-lymphocyte ratio predicts all-cause and cardiovascular mortality among U.S. adults with rheumatoid arthritis: results from NHANES 1999-2020.

Background: The neutrophil-to-lymphocyte ratio (NLR) is recognized as a biomarker for systemic inflammation and immune activation. However, its connection with the mortality risk in individuals with rheumatoid arthritis (RA) is not well understood. This study aimed to investigate the association between NLR and all-cause and cardiovascular mortality risk in U.S. adults with RA. Methods: Data were gathered from the National Health and Nutrition Examination Survey (NHANES) cycles spanning 1999 to March 2020. We included adults aged ≥20 years. The NLR was computed by dividing the neutrophil count by the lymphocyte count from complete blood counts. The maximally selected rank statistics method helped identify the optimal NLR cutoff value associated with significant survival outcomes. Multivariable logistic regression models were performed to investigate the relationship between the NLR and the all-cause and cardiovascular mortality of RA. Restricted cubic spline (RCS) analyses were utilized to detect whether there were linear or non-linear relationships between NLR and mortality. Results: In this study, 2002 adults with RA were included, with 339 having a higher NLR (≥3.28) and 1663 having a lower NLR (<3.28). During a median follow-up of 84 months, 79 RA individuals died. Participants with higher NLR had a 2-fold increased risk of all-cause (HR = 2.02, 95% CI: 1.53-2.66) and cardiovascular mortality (HR = 2.48, 95% CI: 1.34-4.57) versus lower NLR, after adjusting for demographics, socioeconomic status, and lifestyle factors. Kaplan-Meier analysis revealed that the survival rate for the higher NLR group was significantly lower than the lower NLR group, in terms of both all-cause and cardiovascular mortality (both P<0.0001). The RCS curve demonstrated a positive linear association between the NLR and all-cause and cardiovascular mortality. Conclusion: A higher NLR was independently predictive of elevated long-term mortality risk in U.S. adults with RA. The NLR may serve as an inexpensive, widely available prognostic marker in RA.

Comparison of biologics and small-molecule drugs in axial spondyloarthritis: a systematic review and network meta-analysis.

Background: Biologics and small-molecule drugs have become increasingly accepted worldwide in the treatment of axial spondyloarthritis (axSpA), including ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (nr-axSpA). However, a quantitative multiple comparison of their efficacy and safety is lacking. This study aims to provide an integrated assessment of the relative benefits and safety profiles of these drugs in axSpA treatment. Methods: We included randomized clinical trials that compared biologics and small-molecule drugs in the treatment of axSpA patients. The primary outcomes assessed were efficacy, including the Assessment of SpondyloArthritis International Society (ASAS) improvement of 20% (ASAS20) and 40% (ASAS40). Safety outcomes included treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs). We used the surface under the cumulative ranking (SUCRA) curve value and ranking plot to evaluate and rank clinical outcomes and safety profiles of different treatments. The two-dimensional graphs were illustrated to visually assess both the efficacy (horizontal axis) and safety (vertical axis) of each intervention. Results: Our analysis included 57 randomized clinical trials involving a total of 11,787 axSpA patients. We found that seven drugs (TNFRFc, TNFmAb, IL17Ai, IL17A/Fi, IL17RAi, JAK1/3i, and JAK1i) were significantly more effective in achieving ASAS20 response compared to the placebo (PLA). Except for IL17RAi, these drugs were also associated with higher ASAS40 responses. TNFmAb demonstrated the highest clinical response efficacy among all the drugs. Subgroup analyses for AS and nr-axSpA patients yielded similar results. IL17A/Fi emerged as a promising choice, effectively balancing efficacy and safety, as indicated by its position in the upper right corner of the two-dimensional graphs. Conclusion: Our findings highlight TNFmAb as the most effective biologic across all evaluated efficacy outcomes in this network meta-analysis. Meanwhile, IL17A/Fi stands out for its lower risk and superior performance in achieving a balance between efficacy and safety in the treatment of axSpA patients.

Efficacy and safety of jakinibs in rheumatoid arthritis: a systematic review and meta-analysis.

OBJECTIVES: To assess the efficacy and safety of jakinibs for the treatment of active rheumatoid arthritis (RA) in patients with an inadequate response or intolerance to conventional synthetic or biologic disease-modifying antirheumatic drugs (DMARDs). METHODS: A systematic search was conducted in PubMed, Embase, and the Cochrane Library. Randomized placebo-controlled trials (RCTs) of jakinibs in RA patients were eligible. The effective outcome was RA improvement to reach an American College of Rheumatology 20%/50%/70% (ACR20/50/70) response rate at weeks 12 and 24 after treatment. The safety outcomes included treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and discontinuations due to adverse events, infections, and serious infections. RESULTS: Twenty-eight randomized, double-blind, controlled trials including 14,500 patients were included. At both weeks 12 and 24, the pooled analysis suggested effective treatment with jakinibs, represented as an increased clinical response of ACR20, ACR50, and ACR70. Subgroup analysis based on different types of jakinibs demonstrated that only peficitinib treatment had no impact on the clinical response of ACR50 or ACR70 at week 12. Jakinibs were associated with an increased incidence of infections at week 12 and TEAEs and infections at week 24. No increase in the risk of SAEs, discontinuations due to adverse events, or serious infections was observed in comparisons between treatment with jakinibs and treatment with placebo in these patients. CONCLUSIONS: Jakinibs are efficacious and well tolerated in RA patients up to 24 weeks, although they are associated with an increased risk of infectious complications. Key Points • ACR20/50/70 in patients treated with jakinibs was significantly higher than those in patients treated with placebo. • No difference in ACR50/70 was observed in patients with RA treated with peficitinib and placebo. • Jakinibs are beneficial and well tolerated in RA treatment.

Efficacy and safety of IL-17 inhibitors for the treatment of ankylosing spondylitis: a systematic review and meta-analysis.

OBJECTIVES: To systematically assess the efficacy and safety of IL-17 inhibitors in patients with active ankylosing spondylitis. METHODS: A systematic review of the literature was performed for randomized controlled trials (RCTs) concerning IL-17 inhibitors in patients with ankylosing spondylitis. Meta-analyses were used to determine the efficacy and safety of the IL-17 inhibitors in the treatment of these patients. The primary endpoint was predefined as the proportion of patients with at least 20% improvement in the Assessment of Spondyloarthritis International Society (ASAS20) response criteria at week 16, and the secondary endpoint was defined as ASAS40 at week 16. RESULTS: Six phase III randomized, double-blind, placebo-controlled trials including 1733 patients (1153 patients received IL-17 inhibitors, including secukinumab or ixekizumab, whereas 580 patients received a placebo as comparators) were included. At week 16, the IL-17 inhibitor regimen produced a significant increase in the ASAS20 response rate (RR = 1.63, 95% CI 1.45 to 1.84, p = 0.00) and the secondary endpoint ASAS40 response rate (RR = 2.12, 95% CI 1.75 to 2.56, p = 0.00) versus those for the placebo. With respect to the safety profile, more treatment-emergent adverse events (RR = 1.11, 95% CI 1.01 to 1.22, p = 0.03) and non-severe infections (RR = 1.82, 95% CI 1.40 to 2.37, p < 0.001) were described after treatment with IL-17 inhibitors than after treatment with placebo, while no increased risk of other adverse events was indicated after IL-17 inhibitor therapy, including death, discontinuation due to adverse events, or serious adverse events. CONCLUSIONS: IL-17 inhibitors produced favorable response rates but an increased risk of non-severe infections in the treatment of active ankylosing spondylitis.

Forkhead box o3a suppresses lipopolysaccharide-stimulated proliferation and inflammation in fibroblast-like synoviocytes through regulating tripartite motif-containing protein 3.

Fibroblast-like synoviocytes (FLS), synovial tissue-specific cells, are key effector cells during the pathogenesis of rheumatoid arthritis (RA). Our previous study has shown that tripartite motif-containing protein 3 (TRIM3) overexpression inhibits the proliferation and cytokine secretion of RA FLS. Experiments with gene knockout mice have suggested the important roles of forkhead box o3a (Foxo3a) in RA pathogenesis. The present study aimed to investigate the correlation between Foxo3a and TRIM3 during RA pathogenesis. The expression of Foxo3a and TRIM3 was reduced in RA synovial tissues in comparison to healthy controls, and Foxo3a messenger RNA (mRNA) expression in RA synovial tissues correlated positively with TRIM3 mRNA expression. We found that stimulation with lipopolysaccharide (LPS) caused the downregulation of Foxo3a and TRIM3 in FLS. Foxo3a or TRIM3 overexpression significantly attenuated the promoting effects of LPS on cell proliferation and the release of tumor necrosis factor-α, interleukin-6 (IL-6), and IL-1ß. In addition, Foxo3a suppressed the inhibitory effects of LPS on the mRNA and protein levels of TRIM3, as well as the activity of TRIM3 promoter. Foxo3a or TRIM3 overexpression attenuated collagen-induced arthritis in rats. Furthermore, knockdown of TRIM3 significantly suppressed the effects of Foxo3a overexpression on LPS-activated FLS. In summary, our findings suggested that Foxo3a exerted inhibitory effects on LPS-induced proliferation and inflammation through increasing TRIM3 transcription. The decreased expression of Foxo3a may contribute to the RA pathogenesis.