Arthritis Care & Research最新文献

Objective: We evaluated the role of 25-hydroxyvitamin D (25[OH]D), prednisone, and other risk factors for bone mineral density (BMD) loss and osteoporosis in systemic lupus erythematosus (SLE).

Methods: We calculated the association between 25(OH)D levels and other potential risk factors and BMD measures (spine T scores) and osteoporosis (defined as a T score ≤ -2.5) in a lupus cohort of 1,003 patients. Generalized estimating equations were used to assess the statistical significance of observed differences, accounting for patients with multiple BMD measures.

Results: Univariate analysis showed that older age, lower body mass index (BMI), mean past SLE activity (Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index > 2), mean daily prednisone dose at any level, and a history of low C3 or C4 were associated with osteoporosis. Older age, lower BMI, mean 25(OH)D levels, mean daily prednisone dose (again at any dose), and prior low C3 were associated with lower spine T scores. In the multivariate analysis for osteoporosis, older age, lower BMI, low mean 25(OH)D levels, and prednisone dose >5 mg/day remained predictors. Discontinuation of prednisone within one year before the next BMD measurement led to higher mean spine T scores.

Conclusion: Prednisone dose, even at 5 mg/day, and low mean 25(OH)D levels were found to be modifiable predictors of osteoporosis. Mean (reflecting supplementation), rather than initial, 25(OH)D levels were significantly associated with BMD. Some of the bone loss from prior prednisone use appears to be reversible.

Objective: Low preoperative cardiorespiratory fitness is associated with poorer functional and subjective recovery following hip or knee arthroplasty. The objective of this study was to evaluate the ability of simple, indirect assessment tools (the Duke Activity Status Index, daily step count, and timed up and go test) to estimate directly measured cardiorespiratory fitness and identify patients with low preoperative fitness (<15 mL/kg/min) among those with severe hip or knee osteoarthritis.

Methods: Ninety-one patients with severe hip or knee osteoarthritis who were scheduled for total joint arthroplasty were recruited. Within 1 week before surgery, participants performed symptom-limited maximal cardiopulmonary exercise testing, the Duke Activity Status Index questionnaire, accelerometry to determine daily step count, and the timed up and go test.

Results: All three indirect tools provided strong estimates of peak oxygen consumption ( $\dot{V}$ O₂) (r² ≥ 0.61). The Duke Activity Status Index slightly underestimated peak $\dot{V}$ O₂ by 0.9 mL/kg/min. All three metrics performed strongly in their ability to accurately identify patients without a peak $\dot{V}$ O₂ < 15 mL/kg/min; however, their accuracy to positively predict peak $\dot{V}$ O₂ > 15 mL/kg/min was only fair.

Conclusion: These simple, practical, cost-effective tools have utility for estimating preoperative fitness to rule out low fitness. These tools could be used by perioperative clinicians for identifying patients who may not require preoperative cardiopulmonary exercise testing, thereby optimizing resource allocation.

Objective: This study aimed to characterize the pharmacokinetics, pharmacodynamics, safety, and exploratory efficacy of subcutaneous belimumab in pediatric patients with active systemic lupus erythematosus (SLE) receiving standard therapy.

Methods: This single-arm, multicenter, open-label trial (GSK study 200908; ClinicalTrials.gov identifier: NCT04179032) used three-weight-band subcutaneous dosing of belimumab 200 mg every week (qw) for pediatric patients weighing ≥50 kg, every 10 days for pediatric patients weighing 30 to <50 kg, and every 2 weeks (q2w) for pediatric patients weighing 15 to <30 kg. The pharmacokinetic profile was characterized by observed concentration at week 12 and population pharmacokinetics (popPK) estimates derived from concentrations over 52 weeks. Pharmacodynamics, safety, and exploratory efficacy (≥4-point reduction from the baseline Safety of Estrogens in Lupus Erythematosus National Assessment - Systemic Lupus Erythematosus Disease Activity Index [SELENA-SLEDAI] score) were descriptively evaluated. Alternative two-weight-band subcutaneous dosing (≥40 kg: 200 mg qw; 15 to <40 kg: 200 mg q2w) was simulated to predict pharmacokinetics for this regimen.

Results: Patients weighing 30 to <50 kg had lower observed belimumab concentrations than those weighing ≥50 kg (week 12 geometric mean 82.8 vs 134 μg/mL), but popPK analyses predicted the three weight bands to be generally consistent and in alignment with established adult subcutaneous and pediatric intravenous exposures. The pharmacodynamic and safety profile was consistent with known belimumab effects. By week 52, 18 of 22 patients (81.8%) had a ≥4-point reduction from baseline SELENA-SLEDAI scores. Hypothetical two-weight-band dosing simulations predicted consistent exposure across weight bands and in line with established exposures in SLE.

Conclusion: Exposure following subcutaneous belimumab administration in pediatric patients is consistent with approved usage; these findings, along with consistent safety and efficacy data, support subcutaneous belimumab use for pediatric patients with SLE.

Objective: This study assessed sarilumab in treating patients with polyarticular-course juvenile idiopathic arthritis (pcJIA).

Methods: This phase 2b, open-label study (NCT02776735) consisted of three sequential parts (each with a core-treatment and extension-phase). During part 1, three doses were assessed in two weight groups (Group A/B: ≥30-60 kg/≥10-<30 kg) to select the optimal dose with regards to pharmacokinetics, safety and efficacy to evaluate in latter parts. During the extension-phase of part 1, patients initially assigned to the selected optimal dose continued on this dose; the remaining patients were switched to this selected dose. Patients in parts 2 and 3 received the selected dose from baseline. The primary endpoint was pharmacokinetic exposure (AUC_{0- Շ}, C_max, C_trough). Safety and efficacy were assessed.

Results: Mean age of treated patients (n=101; 76.2% female) was 9.4 years. Of the evaluated doses in part 1, dose 2 (Group A/B: 3.0/4.0 mg/kg every 2 weeks [q2w]) was selected. In patients receiving selected dose from baseline (n=73), C_max, AUC_0-14days and C_trough at steady-state in Group A/B were 27.1/40.4 mg/L, 276/395 day*mg/L, and 9.57/14.4 mg/L respectively. At Week 48, JIA-ACR 30/50/70/90 rates were 100%/100%/93.8%/76.6%. Adverse events were reported in 70/73 (95.9%) patients. Twenty-seven (37%) patients experienced grade 3/4 neutropenia; with no associated infections. No death occurred.

Conclusion: In pcJIA patients receiving the selected dose from baseline, pharmacokinetic exposure was comparable to a dose of 200mg q2w for adults with rheumatoid arthritis. Clinically relevant improvements were observed in disease activity, with safety being consistent with the known profile of sarilumab.

Objective: Pulmonary fibrosis (PF) is a severe extra-articular manifestation of rheumatoid arthritis (RA). This study aimed to externally validate a genetic risk score (GRS) and a combined risk score (CRS) for predicting the risk of RA-associated PF in an independent cohort of patients with early RA.

Methods: This study used an inception cohort of 1,118 patients diagnosed with RA from northern Sweden between 1996 and 2016. Clinical data were systematically collected, and genotyping was performed for 12 single-nucleotide polymorphisms (SNPs) associated with idiopathic PF. Statistical analyses, including logistic regression and area under the curve (AUC) assessments, were conducted to evaluate the performance of the GRS and in combination with clinical data as the CRS in predicting RA-PF development.

Results: Of the 1,115 patients with complete data, 60 (5.6%) were diagnosed with PF. PF was significantly associated with age, rheumatoid factor positivity, disease activity, and MUC5B (rs35705950) and FAM13A(rs2609255) SNPs. The GRS demonstrated a significant association with RA-PF (odds ratio 2.6, 95% confidence interval 1.6-4.5), whereas the CRS exhibited superior performance (AUC 0.75, P < 0.001) compared to the GRS alone (AUC 0.62). The combined risk score outperformed the GRS in discriminating RA-PF, indicating its potential utility in clinical practice.

Conclusion: This study provides external validation of the Veterans Affairs Rheumatoid Arthritis Registry interstitial lung disease GRS (VARA-ILD-GRS) and the VARA-ILD-CRS in an RA cohort, demonstrating their generalizability and effectiveness in identifying individuals at high risk for RA-ILD. The findings support the integration of genetic and clinical data in risk stratification models, which could significantly improve screening strategies for patients with RA at risk of developing PF.

Persistent pain remains a major challenge in inflammatory arthritis, even when joint inflammation is well controlled. Pain and associated symptoms such as fatigue cannot be explained by peripheral inflammation alone but reflect altered central pain processing. These changes may arise through “top-down” mechanisms, reflecting pre-existing dysfunction in pain perception, or “bottom-up” pathways, driven by peripheral inflammation acting on the brain. Neuroimaging has transformed understanding of these processes by providing in vivo markers of how brain function and structure are related to pain. Functional magnetic resonance imaging (MRI) demonstrates that both task-evoked and resting-state activity are altered in inflammatory arthritis. Connectivity changes involving the thalamus, insula, medial prefrontal cortex, and default mode and salience networks correlate with pain, fatigue, and affective symptoms. Notably, tumor necrosis factor α (TNF-α) inhibitors rapidly normalize pain-related activation, preceding improvements in joint swelling, strongly supporting a bottom-up role for peripheral inflammation. Recent randomized controlled trial data show that baseline central nervous system pain activation predicts analgesic response to TNF-α blockade, positioning neuroimaging as a potential tool for treatment stratification. Complementary modalities provide further insights. Proton electron tomography studies suggest altered pain responses, and novel tracers may clarify contributions of neuroinflammation. Magnetic resonance spectroscopy reveals neurochemical correlates such as increased choline and myo-inositol linked to fatigue, although group-level evidence for overt neuroinflammation remains limited. Structural MRI highlights gray matter changes in regions mediating sensory, cognitive, and affective processing. Together, this supports a dual top-down and bottom-up model of persistent pain in inflammatory arthritis, with important implications for mechanism-based therapies targeting both immune and brain pathways.

Objective: Relapsing polychondritis (RP) is a rare disease defined by recurrent cartilaginous inflammation. Anti-collagen II (Col2) antibodies have been proposed as a diagnostic biomarker for RP, but their performance characteristics are not well defined.

Methods: In an observational cohort, anti-Col2 antibody levels were measured in patients with RP compared to other inflammatory diseases that mimic RP. In parallel, a systematic review and meta-analysis was performed to assess anti-Col2 antibody prevalence across a broad spectrum of diseases. Individual study risk ratios (RRs) and pooled disease category RRs, study bias, and interstudy heterogeneity were assessed.

Results: In the observational cohort, anti-Col2 antibody prevalence did not differ between RP and comparators. The performance characteristics of anti-Col2 to diagnose RP were poor (sensitivity = 18%; specificity = 72%). Anti-Col2 antibody titers did not correlate with disease activity in RP (r = 0.08, P = 0.44). In the systematic review, 71 of 2,443 reviewed articles were included. Anti-Col2 antibodies were not associated with RP across five pooled studies (RR: 2.09; 95% confidence interval [CI]: 0.05-81.80; P = 0.69). Anti-Col2 antibodies were significantly associated with a composite group of inflammatory diseases with cartilaginous involvement (RR: 2.99; 95% CI: 1.29-6.91; P = 0.01). Studies using healthy controls reported increased effect sizes compared to studies that used disease controls (β-estimate = 1.14, I² = 17.08%; P = 0.0004).

Conclusion: Anti-Col2 antibodies are neither sensitive nor specific for RP, are detected in the minority of patients with RP, and are detected at similar prevalences across a spectrum of inflammatory diseases with cartilage inflammation. Use of these antibodies to diagnose or monitor RP is not advisable.

Objective: Body mass index (BMI), glomerular filtration rate (GFR), and pretreatment urate levels have been reported to influence the urate-lowering response to allopurinol. We investigated whether the fractional excretion of uric acid (FEUA) also modulates this response and relates to oxypurinol concentrations. We further evaluated its potential influence on febuxostat, not as a direct comparison, but to determine whether the effect of FEUA was specific to allopurinol.

Methods: The data are from n = 1,547 and n = 296 patients starting allopurinol and febuxostat, respectively. The relationship between FEUA (≤5.5% or >5.5%) and the dose response to allopurinol or febuxostat was assessed by linear mixed-effects regression models on serum urate levels and adjusted for BMI, estimated GFR (eGFR), and treatment doses. Concentrations of oxypurinol were measured in a subgroup of patients (n = 181). A multiple linear regression model was used to assess the association between FEUA and oxypurinol concentrations, adjusted for BMI, eGFR, allopurinol dosage, and serum urate levels.

Results: The median FEUA in the whole population was 4.0% (quartile 1-3: 3%-5.1%). The changes in serum urate levels for each 150-mg increase in allopurinol in patients with FEUA ≤5.5% or >5.5% were -72.37 (confidence interval [CI] -74.81 to -69.94) μM and -65.96 (CI -71.29 to -60.62) μM, respectively (P = 0.032). We found higher oxypurinol concentrations in patients with the lowest FEUA (P = 0.032). However, we did not observe any interaction between the febuxostat response and FEUA (P = 0.13).

Conclusion: Allopurinol is more effective in patients with low FEUA, probably because of the reduced renal excretion of oxypurinol. These data highlight the similarity between the renal handling of oxypurinol and urate.

Objective: This investigation compared all-cause and cause-specific mortality in patients with and without rheumatoid arthritis (RA) in the Veterans Health Administration (VHA) following immune checkpoint inhibitor (ICI) cancer treatment.

Methods: Veterans with RA and a control set of Veterans without RA who were matched on age, sex, and year of Veterans Affairs enrollment and had received an ICI were identified. All-cause and cause-specific mortality were obtained. Survival from the time of ICI initiation was evaluated using Cox models, Kaplan-Meier curves, and log rank testing.

Results: There were 301 patients with RA and 2,114 controls without RA treated with an ICI. The majority of the participants were white, male, and current/former smokers. Lung cancer was the most common malignancy (51.2%), pembrolizumab was the most frequently used ICI (43.9%), and most patients received ICI monotherapy (97.1%). Cox proportional hazard ratio comparison of all-cause mortality in patients with RA to controls without RA was 1.08 (95% confidence interval [CI] 0.94-1.25) for the crude analysis and 1.09 (95% CI 0.94-1.25) for the adjusted analysis. Cause of death was similar in the two groups, most frequently neoplasm in 93.0% and 90.9% for RA and non-RA groups, respectively (P = 0.737). Deaths due to infection were rare in both groups (<1.0%).

Conclusion: Patients with RA who received ICIs for the treatment of malignancy did not experience increased mortality or differences in cause of death compared with patients without RA receiving ICIs. These preliminary data suggest ICI therapy may be considered as part of cancer treatment in RA patients based on individual patient circumstances.