Rheumatology and Therapy最新文献

Introduction: Ixekizumab, an interleukin 17A (IL-17A) inhibitor, has demonstrated rapid and sustained improvement in the signs and symptoms in patients with active radiographic axial spondyloarthritis (r-axSpA) in global and Chinese populations. We studied the effect of ixekizumab on patient-reported outcomes (PROs) (including patient global, spinal pain, stiffness, and fatigue) and overall health-related quality of life (HRQoL) of ixekizumab in the phase 3 study in China.

Methods: In this Chinese phase 3, randomized, double-blind, placebo-controlled study, patients with r-axSpA were randomized (1:1) to receive ixekizumab 80 mg every 4 weeks (IXEQ4W; starting dose 160 mg) or placebo for 16 weeks. At week 16, patients receiving placebo were switched to IXEQ4W, and those receiving IXEQ4W continued, until week 52. Data for patient global, spinal pain, spinal pain at night, stiffness, and fatigue were collected through week 52. Minimally clinical important differences (MCIDs) were determined for spinal pain and spinal pain at night. The subgroup analyses by baseline disease duration since diagnosis and baseline C-reactive protein (CRP) level were conducted post hoc.

Results: Compared with placebo, patients treated with IXEQ4W reported significantly greater improvement with a rapid onset in changes from baseline of PROs (patient global, spinal pain, spinal pain at night, stiffness, and fatigue) through week 16. Improvements were maintained through week 52. A similar trend of improvement was also observed in MCID response in spinal pain and spinal pain at night. The improvement in overall HRQoL was supported by EQ-5D-5L assessment. Subgroup analyses demonstrated that IXEQ4W provided significantly greater efficacy at week 16 compared with placebo, irrespective of baseline disease duration or baseline CRP level.

Conclusion: IXEQ4W provided rapid and sustained improvement in clinically relevant PROs and overall HRQoL through 1-year treatment in Chinese patients with r-axSpA. Regardless of the baseline disease duration or baseline CRP level, consistent efficacy was observed.

Trial registration: ClinicalTrials.gov identifier NCT04285229.

Introduction: Biologic therapies are licensed for both psoriasis (PsO) and psoriatic arthritis (PsA) with some electronic medical record data suggest that IL (Interleukin)-23 blockers might be more protective in PsA prevention than TNF blockers; however, the findings have been inconsistent. Higher Psoriasis Area and Severity Index (PASI) scores have also been linked to an increased PsA risk. To clarify these unresolved issues we investigated biologic agents, methotrexate, phototherapy, and topical therapy for PsA prevention in patients with psoriasis.

Methods: This retrospective cohort study analyzed data from 58,671 patients with psoriasis from the Israeli Meuhedet Health Services Organization database was evaluated for incident PsA. Patients were categorized on the basis of treatment: group 1, topical therapy; group 2, phototherapy; group 3, conventional disease-modifying antirheumatic drugs (cDMARDs; methotrexate); group 4, biologic DMARDs which was also stratified according to biologic class.

Results: The PsA incidence rate was lower in the biologic agents' group versus the methotrexate group (HR 0.46 [95% CI 0.35-0.62]). The incidence rates per 100 person-years varied across biologic treatment groups, with the anti‑IL‑12/23 or anti‑IL‑23p19 group at 4.57, the anti-IL-17 group at 4.35, and the TNF inhibitor group at 2.55. No differences were found between various biological agents in terms of preventing PsA. The phototherapy group exhibited a higher PsA development rate than the topical therapy group (HR 1.85 [95% CI 1.65-2.07]).

Conclusion: Biological agents are more effective than methotrexate in reducing incident PsA in patients with psoriasis. This lower rate of PsA on topical therapy compared to phototherapy supports the importance of psoriasis severity as a risk factor.

Introduction: Drug persistence may be a surrogate marker that reflects both long-term efficacy and safety in clinical settings, and tuberculosis (TB) is considered as one of the most important opportunistic infections after the biological treatment in rheumatoid arthritis (RA). We aimed to compare drug persistence and incidence of TB between tumor necrosis factor alpha (TNFα) inhibitors and tocilizumab in patients with RA using data from the Korean Health Insurance Review and Assessment Service database.

Methods: In this analysis, 5449 patients with RA who started TNFα inhibitors, such as adalimumab, etanercept, infliximab, and golimumab or tocilizumab, as the first-line biological therapy between January 2014 and December 2017 were analyzed and followed up until December 2019. Drug persistence was defined as the duration from initiation to first discontinuation, and TB was defined as the prescription of > 2 anti-TB medications after the initiation of biologics.

Results: TNFα inhibitors and tocilizumab were prescribed in 4202 (adalimumab, 1413; etanercept, 1100; infliximab, 769; golimumab 920) and 1247 patients with RA, respectively. During the analysis period, 2090 (49.7%) and 477 (38.3%) patients with RA discontinued TNFα inhibitors and tocilizumab, respectively, and 42 patients with RA developed TB (TNFα inhibitors, 33; tocilizumab, 9). After adjustment for confounding factors, TNFα inhibitors were significantly associated with a higher risk of discontinuation compared with tocilizumab (hazard ratio (HR) 1.63, p < 0.001). In subgroup analysis, all types of TNFα inhibitors, except for infliximab, demonstrated a significantly lower persistence rate compared with tocilizumab. There was no significant difference in TB incidence between tocilizumab and TNFα inhibitors. In subgroup analysis, infliximab has a significantly higher risk of TB compared with tocilizumab (HR 2.84, p = 0.02).

Conclusion: In this analysis, tocilizumab had longer persistence than TNFα inhibitors with a similar incidence of TB. Our analysis has limitations: (1) The HIRA database lacks clinical details like disease activity and joint damage extent, potentially influencing the analysis results. (2) Reasons for discontinuing biological agents were not available. (3) TB diagnoses may be inaccurate because of missing microbiological results. (4) We did not analyze the impact of treating latent TB infection on TB development post-biological treatment, despite mandatory screening in Korea.

Introduction: Psoriatic arthritis (PsA) is associated with increased cardiovascular (CV) risk and mortality. Aortic stiffness measured by carotid-femoral pulse wave velocity (cfPWV) has been shown to predict CV risk in the general population. The present study aimed to examine cfPWV values of patients with PsA compared to healthy controls and to evaluate associations of cfPWV with patient- and disease-associated characteristics, as well as with an established traditional CV prediction score of the European Society of Cardiology (Systemic Coronary Risk Evaluation; SCORE), for the first time.

Methods: cfPWV and SCORE were evaluated in patients with PsA and healthy controls, along with clinical and laboratory disease parameters. Differences in cfPWV measurements between the two groups and associations of cfPWV with patient- and disease-associated characteristics were statistically evaluated.

Results: A total of 150 patients with PsA (PSOCARD cohort) and 88 control subjects were recruited. cfPWV was significantly higher in the PsA group compared to controls, even after adjustment for confounders (p_adj = 0.034). Moreover, cfPWV was independently associated with disease duration (r = 0.304, p = 0.001), age (rho = 0.688, p < 0.001), systolic arterial pressure (rho = 0.351, p < 0.001), glomerular filtration rate (inverse: rho = - 0.264, p = 0.001), and red cell distribution width, a marker of major adverse CV events (MACE) (rho = 0.190, p = 0.02). SCORE revealed an elevated CV risk in 8.73% of the patients, whereas cfPWV showed increased aortic stiffness and end-organ disease in 16.00% of the same cohort.

Conclusions: In the largest cfPWV/PsA cohort examined to date, patients with PsA exhibited increased aortic stiffness compared to healthy controls. PsA duration was the most important independent disease-associated predictor of increased aortic stiffness, next to traditional CV risk factors. cfPWV measurements may help identify subclinical end-organ disease and abnormal aortic stiffness and thus assist CV risk classification in PsA.

Introduction: Gout, a common comorbidity of chronic kidney disease (CKD), is associated with high morbidity and healthcare utilization. However, a large proportion of gout remains undermanaged or untreated which may lead to worse patient outcomes and greater healthcare costs. This study estimates the present and future health and economic burden of controlled and uncontrolled gout in a virtual United States (US) CKD population.

Methods: A validated microsimulation model was used to project the burden of gout in patients with CKD in the USA through 2035. Databases were utilized to build a virtual CKD population of "individuals" with controlled or uncontrolled gout. Modelling assumptions were made on the basis of the literature, which was sparse in some cases. Health and economic outcomes with the current care (baseline) scenario were evaluated, along with potential benefits of urate-lowering intervention scenarios.

Results: The prevalence of comorbid gout and CKD in the USA was projected to increase by 29%, from 7.9 million in 2023 to 9.6 million in 2035 in the baseline scenario. Gout flares, tophi, and comorbidity development were also projected to increase markedly through 2035, with the economic burden of gout in the CKD population subsequently increasing from $38.9 billion in 2023 to $47.3 billion in 2035. An increased use of oral urate-lowering therapies in undermanaged patients, and pegloticase use in patients refractory to oral urate-lowering therapies were also project to result in 744,000 and 353,000 fewer uncontrolled gout cases, respectively, by 2035. Marked reductions in complications and costs ensued.

Conclusions: This study projected a substantial increase in comorbid gout and CKD. However, improved use of urate-lowering interventions could mitigate this growth and reduce the health and economic burdens of gout.

Introduction: Patients with systemic lupus erythematosus (SLE) have variable treatment pathways, including antimalarials, glucocorticoids, immunosuppressants, and/or biologics. This study describes differences in clinical outcomes when initiating belimumab (BEL) before and after immunosuppressant use.

Methods: This real-world, retrospective cohort study (GSK Study 217536) used de-identified administrative claims data from January 2015 to December 2022 in the Komodo Health Database. Adults with moderate/severe SLE initiating BEL (index date) were identified from January 2017 to May 2022, allowing a ≥ 24-month baseline period. Patients were stratified into those initiating BEL before immunosuppressant use (no immunosuppressant use within 24 months before index) and those initiating BEL after immunosuppressant use (one immunosuppressant used within 24 months before index). Oral glucocorticoid (OGC) use, SLE flares, new organ damage, and all-cause healthcare resource utilization (HCRU) were analyzed descriptively over a 24-month follow-up.

Results: Baseline SLE severity was similar for patients initiating BEL before (n = 2295) versus after (n = 4114) immunosuppressant use (moderate, 83.1% vs 79.0%; severe, 16.8% vs 21.0%). Patients initiating BEL before versus after immunosuppressant use had lower SLE flare rates and OGC use. Post-index, patients initiating BEL before versus after immunosuppressant use discontinued their OGC sooner (moderate baseline SLE, 4.5 vs 8.9 months; severe baseline SLE, 6.2 vs 11.6 months). Patients initiating BEL before versus after immunosuppressant use had lower SLE flare rates per person-year at all time points (especially severe flare rates in patients with severe baseline SLE, 0.70 vs 1.48 through 24 months post-index). Median time to new organ damage occurrence was longer in patients initiating BEL before versus after immunosuppressant use (moderate baseline SLE, 32.1 vs 26.7 months; severe baseline SLE, 22.7 vs 21.6 months). All-cause HCRU was similar between cohorts.

Conclusions: These results suggest that patients initiating BEL before versus after immunosuppressant use had more favorable outcomes.

Introduction: Research has highlighted the role of runt-related transcription factor 2 (Runx2) in the development of osteoarthritis (OA); however, its causal association remains unclear. This study aimed to explore whether Runx2 expression is causally associated with OA and assess its therapeutic potential for OA.

Methods: Genetic proxy instruments for Runx2 expression were obtained from gene expression quantitative trait locus (eQTLs) study of eQTLGen Consortium (n = 31,684). Aggregated genome-wide association study (GWAS) data for OA (including all OA [177,517 cases and 649,173 controls], knee OA (KOA) [62,497 cases and 333,557 controls], and hip OA (HOA) [36,445 cases and 316,943 controls]) were extracted from the Genetics of Osteoarthritis Consortium. We integrated eQTLs data with OA GWAS data to estimate their causal association and to estimate the potential of Runx2 as a drug target in the treatment of OA using summary data-based Mendelian randomization (SMR) analysis. Furthermore, different OA GWAS data (including all OA [77,052 cases and 378,169 controls], KOA [24,955 cases and 378,169 controls], and HOA [15,704 cases and 378,169 controls]) derived from the GWAS Catalog database were used for replication study.

Results: SMR analysis showed that high expression levels of Runx2 were associated with an increased risk of all OA [odds ratio (OR) 1.044, 95% confidence interval (CI) 1.023-1.067; P = 5.03 × 10^-5], KOA (OR 1.040, 95% CI 1.006-1.075; P = 0.021), and HOA (OR 1.067, 95% CI 1.022-1.113; P = 0.003). This suggests that Runx2 inhibitors may have promising potential for the treatment of OA. Notably, the causal effects of Runx2 with all OA (OR 1.053, 95% CI 1.027-1.079; P = 3.95 × 10^-5) and KOA (OR 1.043, 95% CI 1.001-1.087; P = 0.045) were repeated in the replication study, but limited evidence supported the association of Runx2 expression levels with HOA (OR 1.045, 95% CI 0.993-1.101; P = 0.094).

Conclusions: Our analyses indicate a positive correlation between Runx2 expression and OA risk across all three phenotypes, suggesting the potential of Runx2 inhibitors in the treatment of OA and providing evidence from a genetic perspective.

Introduction: Juvenile dermatomyositis (JDM) is characterized by persistent non-purulent inflammation in the muscle and skin. The underlying mechanisms still remain uncertain. This study aims to elucidate the mechanism of interleukin-6 (IL-6) activation of Janus kinase/signal transducer and activator of transcription 3 pathway (JAK/STAT3), contributing to the pathogenesis of JDM.

Methods: Serum IL-6 levels were compared between 72 newly diagnosed patients with JDM and the same patient cohort in treatment remission. Single-cell RNA sequencing (scRNA-seq) was employed to identify differential signaling pathway expression in muscle biopsy samples from two patients with JDM and healthy controls. Immunohistochemistry was used to examine differences in STAT3 phosphorylation between JDM and control muscle tissues. In vitro, skeletal muscle cell lines were stimulated with IL-6, and the transcription levels of genes related to mitochondrial calcium channels were quantified via reverse transcription-polymerase chain reaction (RT-PCR). Reactive oxygen species (ROS) production was measured in both IL-6 treated and untreated groups. ROS levels were then compared between IL-6 receptor antagonist pre-treated skeletal muscle cells and untreated cells.

Results: IL-6 levels in newly onset patients with JDM were significantly higher compared to the same patient cohort in remission states (p < 0.0001). Serum IL-6 was significantly increased in patients with negative myositis specific antibody (MSA), positive melanoma differentiation associated protein 5 (MDA5) and positive nuclear matrix protein 2 (NXP2), yet not for JDM with positive transcriptional intermediary factor γ (TIF1γ), based on subgroup analysis. ScRNA-seq analysis of muscle biopsies from patients with MDA5-positive JDM and patients with MSA negative JDM revealed abnormal activation of the JAK/STAT3 pathway in skeletal myocytes, macrophages, and vascular endothelial cells. The phosphorylation levels of STAT3 were elevated in active JDM cases. Transcription of the calcium channel modulation gene sarcolipin (SLN) was significantly higher in JDM primary skeletal muscle cells compared to normal cells. In vitro, IL-6 enhanced SLN transcription and induced ROS production, and blocking the IL-6 receptor resulted in decreased ROS generation in skeletal muscle cells.

Conclusions: IL-6/JAK/STAT3 signaling pathway was abnormally activated in patients with JDM. IL-6 may be involved in the pathogenesis of muscle damage by triggering the development of calcium overload and production of ROS. Blockade of the IL-6/JAK/STAT3 pathway can be a potential treatment option for JDM, especially MDA5-positive patients and those who are negative for MSA.

Introduction

The evolution of disease-modifying antirheumatic drugs (DMARDs) for the treatment of rheumatoid arthritis (RA) has improved patient prognosis. However, more real-world safety/effectiveness data comparing methotrexate (MTX), tofacitinib, tumor necrosis factor inhibitors (TNFi), and non-TNFi biologic DMARDs (bDMARDs) are warranted.

Methods

The CorEvitas RA Japan registry was used to identify patients with rheumatologist-diagnosed RA who initiated MTX/tofacitinib/TNFi/non-TNFi bDMARDs. Safety outcomes included incidence of major adverse cardiovascular events (MACE), total cardiovascular disease, total serious infections, total herpes zoster, and total malignancies (excluding non-melanoma skin cancer). Effectiveness outcomes included change from baseline (Δ) in Clinical Disease Activity Index (CDAI) and proportion of patients achieving a minimum clinically important difference (MCID) in CDAI at month 6. Adjusted regression models were fit; marginal means were estimated.

Results

Overall, 1972 patients were included in the safety cohort: MTX (N = 298); tofacitinib (N = 253); TNFi (N = 663); non-TNFi (N = 758). Mean follow-up time was 3.8, 2.9, 3.0, and 2.9 years for MTX, tofacitinib, TNFi, and non-TNFi, respectively. Adjusted incidence rates (IRs, patients with events/100 patient-years [95% confidence intervals]) for MACE and total cardiovascular disease, respectively, were numerically lower for MTX (0.34 [0, 0.83]; 0.42 [0, 0.92]) and TNFi (0.09 [0, 0.27]; 0.61 [0.15, 1.07]) versus tofacitinib (0.48 [0, 1.20]; 2.30 [0.38, 4.22]) and non-TNFi (0.77 [0.35, 1.19]; 1.28 [0.73, 1.82]). Serious infections were numerically higher for non-TNFi (4.47 [3.38, 5.56]); herpes zoster was higher for tofacitinib (7.41 [4.52, 10.29]), versus other groups. IRs for malignancies were comparable between groups. Mean ΔCDAI and rates of achieving MCID in CDAI at month 6 were generally greater with tofacitinib versus other groups.

Conclusion

Some variations in incidence of safety outcomes were observed between treatments, while certain effectiveness outcomes favored tofacitinib. Sample size variation between groups and low number of safety events limited the analysis. Further studies are warranted to investigate observed differences.

ClinicalTrials.gov

NCT05572567.

Introduction: In ORAL Surveillance, incidence rates (IRs) of major adverse cardiovascular events (MACE) and malignancies (excluding non-melanoma skin cancer [NMSC]) in cardiovascular (CV)-risk-enriched patients with rheumatoid arthritis (RA) were numerically greater with tofacitinib in North America versus the rest of the world, due to underlying risk factors. Here, we evaluated the safety and efficacy of tofacitinib versus tumor necrosis factor inhibitors (TNFi) among patients with RA across geographical regions.

Methods: Patients with RA in ORAL Surveillance (NCT02092467), who were aged ≥ 50 years with ≥ 1 additional CV risk factor, received tofacitinib 5 or 10 mg twice daily or TNFi; 45.9% were from either Poland or North America. This post hoc analysis stratified patients by region (Poland, North America, Other countries). Efficacy endpoints included Clinical Disease Activity Index, Disease Activity Score in 28 joints, with C-reactive protein (DAS28-4[CRP]), and Health Assessment Questionnaire-Disability Index (HAQ-DI). IRs and hazard ratios for adverse events were reported.

Results: Of 4362 patients (Poland, N = 759; North America, N = 1243; Other countries, N = 2360), more patients from North America versus Poland/Other countries had CV risk factors such as body mass index ≥ 30 kg/m² and history of diabetes/hypertension; however, more patients from Poland versus other regions were ever smokers and more patients from Poland/North America versus Other countries had history of coronary artery disease. MACE IRs were similar in North America and Poland, and numerically higher versus Other countries. IRs for malignancies (excluding NMSC) were numerically higher in North America versus Poland/Other countries with tofacitinib. Serious infections IRs were numerically higher in North America versus Poland across treatments. Venous thromboembolism/all-cause mortality IRs were generally comparable across regions. DAS28-4(CRP)/HAQ-DI improvements were generally lowest in North America.

Conclusions: Differences in safety outcomes were driven by the presence of baseline risk factors; North America and Poland demonstrated a higher proportion of patients with some baseline CV risk factors/comorbidities versus Other countries.

Trial registration: NCT02092467 (ClinicalTrials.gov).