Association of the different types of radiographic damage with physical function in patients with rheumatoid arthritis: analysis of the RAPID trials.
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ABSTRACT:
SUBMITTER: Gherghe AM
PROVIDER: S-EPMC4800803 | biostudies-other | 2016
REPOSITORIES: biostudies-other
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Project description:Recent reports have suggested that increasing adiposity may protect against radiographic damage in rheumatoid arthritis (RA). We explored the role of serum adipokines (adiponectin, resistin, and leptin) in mediating this association.Patients with RA underwent total-body dual x-ray absorptiometry for measurement of total and regional body fat and lean mass, abdominal computed tomography for measurement of visceral fat area, and radiographs of the hands and feet scored according to the modified Sharp/van der Heijde (SHS) method. Serum levels of adipokines were measured and cross-sectional associations with radiographic damage were explored, adjusting for pertinent confounders. The associations of measures of adiposity with radiographic damage were explored with the introduction of adipokines into multivariable modeling as potential mediators.Among the 197 patients studied, adiponectin demonstrated a strong association with radiographic damage, with the log SHS score increasing by 0.40 units for each log unit increase in adiponectin (P = 0.001) after adjusting for pertinent predictors of radiographic damage. Adiponectin independently accounted for 6.1% of the explainable variability in SHS score, a proportion comparable with rheumatoid factor, and greater than HLA-DRB1 shared epitope alleles or C-reactive protein levels. Resistin and leptin were not associated with radiographic damage in adjusted models. An inverse association between visceral fat area and radiographic damage was attenuated when adiponectin was modeled as a mediator. The association of adiponectin with radiographic damage was stronger in patients with longer disease duration.Adiponectin may represent a mechanistic link between low adiposity and increased radiographic damage in RA. Adiponectin modulation may represent a novel strategy for attenuating articular damage.
| S-EPMC2759038 | biostudies-literature
Project description:IntroductionThe western population is ageing. It is unknown whether age at diagnosis affects the severity of Rheumatoid Arthritis (RA), we therefore performed the present study.Method1,875 RA-patients (7,219 radiographs) included in five European and North-American cohorts (Leiden-EAC, Wichita, Umeå, Groningen and Lund) were studied on associations between age at diagnosis and joint damage severity. In 698 Leiden RA-patients with 7-years follow-up it was explored if symptom duration, anti-citrullinated-peptide-antibodies (ACPA), swollen joint count (SJC) and C-reactive-protein (CRP) mediated the association of age with joint damage. Fifty-six other RA-patients of the EAC-cohort underwent baseline MRIs of wrist, MCP and MTP-joints; MRI-inflammation (RAMRIS-synovitis plus bone marrow edema) was also evaluated in mediation analyses. Linear regression and multivariate normal regression models were used.ResultsAnalysis on the five cohorts and the Leiden-EAC separately revealed 1.026-fold and 1.034-fold increase of radiographic joint damage per year increase in age (β=1.026, 1.034, both p<0.001); this effect was present at baseline and persisted over time. Age correlated stronger with baseline erosion-scores compared to joint space narrowing (JSN)-scores (r=0.38 versus 0.29). Symptom duration, ACPA, SJC and CRP did not mediate the association of age with joint damage severity. Age was significantly associated with the MRI-inflammation-score after adjusting for CRP and SJC (β=1.018, p=0.027). The association of age with joint damage (β=1.032, p=0.004) decreased after also including the MRI-inflammation-score (β=1.025, p=0.021), suggesting partial mediation.ConclusionRA-patients presenting at higher age have more severe joint damage; this might be partially explained by more severe MRI-detected inflammation at higher age.
| S-EPMC4547419 | biostudies-literature
Project description:ObjectiveRecent evidence has highlighted a major genetic contribution to radiographic damage in rheumatoid arthritis (RA). The objective of this study was to determine whether genetic variants in the loci for interleukin-1 (IL-1), IL-6, IL-10, protein tyrosine phosphatase N22 (PTPN22), and selenoprotein S are associated with radiographic damage.MethodsModified Larsen scores of radiographic damage were determined in a cross-sectional population of patients with RA (n = 964). Rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) were also assayed. The Kruskal-Wallis nonparametric test was used to compare median radiographic damage scores across genotype groups, followed by the Cuzick nonparametric test for trend to assess gene-dose effects.ResultsAn allele-dose association of IL-6 -174G with increasing radiographic damage was present (P = 0.005), but only in patients who were RF positive (P = 0.004) or anti-CCP positive (P = 0.01). Patients with the IL-10 -592CC genotype had more extensive radiographic damage than did those with the AC or AA genotype (P = 0.006), but this was observed only among patients who were RF negative (P = 0.002) or anti-CCP negative (P = 0.002). However, RF status and anti-CCP status were not associated with the IL-6 or IL-10 genotype. No other genetic associations were detected, apart from a marginal association of PTPN22 +1858T with increased radiographic damage.ConclusionThe reported associations of IL-6 -174G with high IL-6 production and IL-10 -592 with low IL-10 production and our own results support a role of genetically determined dysregulated cytokine production in disease severity. The lack of association of these genotypes with RF and anti-CCP antibody status suggests that they act downstream of autoantibody production. We conclude that IL-6 and IL-10 genotypes may be useful in predicting disease severity in autoantibody-positive and autoantibody-negative patients, respectively.
| S-EPMC2435416 | biostudies-literature
Project description:To examine the association between sonographic enthesitis and the severity of radiographic features of damage in the peripheral and axial joints in psoriatic arthritis (PsA).A cross-sectional analysis was conducted in patients with PsA. The MAdrid Sonography Enthesitis Index (MASEI) scoring system was used to quantify the extent of sonographic entheseal abnormalities. Radiographic damage in the peripheral joints and spine was assessed by the modified Steinbrocker score (mSS), Modified New York Criteria for sacroiliitis, and the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). The association between MASEI and the extent of radiographic damage was assessed using negative binomial and logistic regression. The results were expressed in terms of the regression coefficient estimates and their exponentiated values (eβ) or odds ratios (OR), and 95% confidence intervals (CI).Two hundred and twenty three patients were analyzed; 58% were males, with mean ± SD age of 55.9 ± 12.9 years and PsA duration of 16.7 ± 12.4 years. Regression analyses yielded an association between higher MASEI scores (10 units increase) and peripheral joint damage including mSS (eβ = 1.42, 95% CI: 1.15, 1.72), joint ankylosis (OR = 1.93, 95% CI: 1.37, 2.72), arthritis mutilans (OR = 1.77, 95% CI: 1.23, 2.54), and periostitis (OR = 1.41, 95% CI: 1.08, 1.84). Similarly, an association was found between higher MASEI scores and axial damage as measured by mSASSS (eβ = 2.18, 95% CI: 1.16, 4.09) and sacroiliitis (OR = 1.33, 95% CI: 1.03, 1.72).The severity of sonographic enthesitis is a potential marker of radiographic peripheral and axial joint damage in PsA.
| S-EPMC5558768 | biostudies-other
Project description:BackgroundThe detection of statistically significant reductions in radiographic progression during clinical studies in patients with rheumatoid arthritis (RA) has become increasingly difficult over the past decade due to early-escape study designs and declining rates of progression in control-group patients. We investigated the impact of extremes of radiographic data (outliers) and baseline prognostic factors on detection of treatment effects, to provide guidance on future analysis of joint structural data in RA clinical trials.MethodsData were from two, phase 3, randomized, double-blind, placebo-controlled trials of tofacitinib in adult patients with moderate to severe RA: ORAL Scan (NCT00847613) and ORAL Start (NCT01039688). These studies detected significant reductions in radiographic progression with tofacitinib 10 mg twice daily (BID) plus background methotrexate (ORAL Scan), and with tofacitinib 5 or 10 mg BID as monotherapy (ORAL Start). We evaluated mean changes from baseline in van der Heijde modified total Sharp score (mTSS) at month 6 and month 12, using analysis of covariance (ANCOVA). A trimmed analysis was used to deal with extremes of data. The impact of baseline prognostic factors on radiographic progression was evaluated using ANCOVA to analyze the mean change from baseline in mTSS for each factor in turn.ResultsThe analysis included data from 720 patients from ORAL Scan and 880 patients from ORAL Start. Trimmed analyses were unbiased for the true mean estimate and enabled us to remove the effect of influential extreme observations in the data set. Almost all patients had at least one poor prognostic factor at baseline (e.g., high level of disease activity, or positive for rheumatoid factor). The strongest predictor of treatment effect was the severity of radiographic damage at baseline.ConclusionsA trimmed analysis can establish whether any significant inhibition of structural damage is being driven by extremes of data, and should be one of the sensitivity analyses of choice for structural data in RA clinical trials. Furthermore, analysis of radiographic data based on baseline prognostic factors may reveal increased treatment effects. Application of these methods to analysis of radiographic data from clinical trials in patients with RA, allows a more complete interpretation of data.Trial registrationClinicaltrials.gov NCT00847613 (registered 17 February 2009) and NCT01039688 (registered 23 December 2009).
| S-EPMC5034418 | biostudies-literature
Project description:IntroductionWe conducted a post hoc analysis of efficacy and safety of filgotinib stratified by estimated radiographic progression rate before baseline (BL) in patients with rheumatoid arthritis (RA) who had inadequate response to methotrexate (MTX; FINCH 1; NCT02889796) or were naïve to it (FINCH 3; NCT02886728).MethodsRadiographic progression rate was BL-Modified Total Sharp Score (mTSS) divided by RA duration (BL mTSS/year); estimated rapid radiographic progression (e-RRP) was BL change in mTSS/year ≥ 5; and estimated nonrapid radiographic progression (e-NRRP) was BL mTSS/year < 5. Efficacy and safety were compared between subgroups. All p-values are nominal.ResultsIn FINCH 1 and FINCH 3, 558/1755 (31.8%) and 787/1249 (63.0%) patients, respectively, had BL e-RRP. BL characteristics were generally similar between subgroups within each trial. At week (W) 24, in FINCH 1, proportions achieving a Disease Activity Score 28 for rheumatoid arthritis with C-reactive protein < 2.6 were significantly greater with filgotinib 200 (FIL200) and 100 mg (FIL100) versus placebo among e-RRP and e-NRRP subgroups. In each study, proportions of FIL-treated patients achieving Clinical Disease Activity Index ≤ 2.8 and Simple Disease Activity Index ≤ 3.3 were similar between subgroups. In FINCH 3, disease activity measures were at least numerically improved among patients receiving FIL versus MTX monotherapy. At W24, mTSS changes from BL (CFB) were greater among patients with e-RRP in FINCH 1 and FINCH 3 versus e-NRRP (0.81 versus 0.19, p = 0.001; 0.67 versus 0.25, p = 0.31, respectively). At W52, in FINCH 1, mTSS CFBs were smaller among e-RRP patients treated with FIL200 (0.40; p < 0.001) and FIL100 (0.77; p = 0.024) versus adalimumab (ADA; 1.46). In FINCH 3 at W52, mTSS CFBs were significantly smaller with FIL200 versus MTX among e-RRP patients. Rates of treatment-emergent adverse events (AEs) were comparable between subgroups and across treatment arms.ConclusionsPatients with previous e-RRP who received standard care tended to progress radiographically. FIL200 demonstrated persistent, consistent benefit for disease activity control among e-RRP and e-NRRP subgroups, and AE profiles were similar between subgroups. Although filgotinib efficacy was somewhat reduced among patients with e-RRP, filgotinib treatment slowed radiographic progression in both subgroups.Trial registrationClinicaltrials.gov NCT02889796, NCT02886728.
| S-EPMC9931963 | biostudies-literature
Project description:IntroductionThis article aims to describe malignancies in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), or non-radiographic axial spondyloarthritis (nr-axSpA) treated with upadacitinib (UPA) or active comparators.MethodsThis integrated safety analysis includes data from 11 phase 3 UPA trials across RA (6 trials), PsA (2 trials), AS (2 trials; one phase 2b/3), and nr-axSpA (1 trial). Treatment-emergent adverse events (TEAEs) were summarized for RA (pooled UPA 15 mg [UPA15], pooled UPA 30 mg [UPA30], adalimumab 40 mg [ADA], methotrexate monotherapy [MTX]), PsA (pooled UPA15, pooled UPA30, ADA), AS (pooled UPA15), and nr-axSpA (UPA15). TEAEs were reported as exposure-adjusted event rates (events/100 patient-years).ResultsMedian treatment duration ranged from 1.0 to 4.0 years (with a maximum of 6.6 years in RA). Across treatments and indications, rates of malignancy excluding nonmelanoma skin cancer (NMSC) ranged from 0.2 to 1.1, while NMSC ranged from 0.0 to 1.4. In RA, rates of malignancy excluding NMSC were generally similar between UPA15, UPA30, ADA, and MTX (breast and lung cancer were the most common). In RA and PsA, Kaplan-Meier analyses revealed no differences in event onset of malignancy excluding NMSC with UPA15 versus UPA30 over time. In RA, NMSC rates were higher with UPA30 than UPA15; both UPA15 and UPA30 were higher than ADA and MTX. In PsA, rates of malignancy excluding NMSC and NMSC were generally similar between UPA15, UPA30, and ADA. In AS and nr-axSpA, malignancies were reported infrequently. Few events of lymphoma were reported across the clinical programs.ConclusionRates of malignancy excluding NMSC were generally similar between UPA15, UPA30, ADA, and MTX and were consistent across RA, PsA, AS, and nr-axSpA. A dose-dependent increased rate of NMSC was observed with UPA in RA.Trial registrationClinicaTrials.gov identifier: NCT02706873, NCT02675426, NCT02629159, NCT02706951, NCT02706847, NCT03086343, NCT03104400, NCT03104374, NCT03178487, and NCT04169373.
| S-EPMC10796874 | biostudies-literature
Project description:BackgroundAdipokines have inflammatory and immunomodulatory properties that may contribute to erosive joint damage. The association of serum adipokine levels with progression of radiographic joint damage in patients with rheumatoid arthritis (RA) was prospectively explored.MethodsPatients with RA underwent serum adipokine assessment (adiponectin, resistin, leptin) at three timepoints and hand/feet x-rays, scored using the Sharp-van der Heijde Score (SHS), at baseline and the third study visit, separated by an average of 39±4 months. The associations of baseline and average adipokine levels with change in SHS were explored, adjusting for pertinent confounders.ResultsOf the 152 patients studied, 85 (56%) showed an increase in SHS (defined as >0 SHS units). Among the adipokines studied, only adiponectin was significantly associated with radiographic progression, with average adiponectin levels more strongly associated than baseline levels. After adjusting for average C reactive protein and baseline SHS, patients in the highest quartile of average adiponectin had a SHS progression rate more than double the lowest quartile (1.00 vs 0.48 units/year; p=0.008). Similarly, those in the highest quartile of adiponectin had a more than fivefold greater odds of any radiographic progression compared with the lowest quartile (OR 5.75; p=0.002). The magnitude of the association of average adiponectin levels with radiographic progression was greater in women, those with body mass index <30 kg/m(2) and those receiving baseline biological disease-modifying antirheumatic drugs.ConclusionsThese prospective data provide evidence of temporality and dose-response in the relationship between circulating adiponectin and erosive joint destruction in RA, and highlight subgroups of patients at highest risk for adiponectin-associated radiographic progression.
| S-EPMC3543946 | biostudies-literature
Project description:Demonstrating inhibition of the structural damage to joints as a statistically significant difference in radiographic progression as measured by the van der Heijde modified Total Sharp Score (mTSS) is a common objective in trials for rheumatoid arthritis treatments. The frequently used analysis of the covariance model with missing data imputed using linear extrapolation (analyses of covariance, ANCOVA+LE) may not be ideal for long-term extension studies or for paediatric studies. The random coefficient (RC) model may represent a better alternative.A two-arm (active treatment and placebo) setting with a week 44 study period was considered. RC model, ANCOVA+LE and ANCOVA with last observation carried forward imputation were compared under different scenarios in bias, root mean square error (RMSE), power and type I error rate.The RC model outperformed ANCOVA+LE in metrics measuring bias, RMSE, power and type I error rate under the evaluated scenarios. ANCOVA and RC provide similar performance when there are no missing data. With missing data, RC+observed (OBS) provides similar or better results than ANCOVA+LE in power and bias.Our simulations support that RC is both a more sensitive and a more precise alternative to the commonly used ANCOVA+LE as a primary method for analysing mTSS in long-term extension and paediatric studies with a higher likelihood of missing data. The RC model can provide a reference at time points with missing data by estimating a slope; mTSS change by one unit change in time. ANCOVA+LE is recommended as a sensitivity analysis.
| S-EPMC10083852 | biostudies-literature
Project description:Nationwide lockdowns during SARS-CoV-2 (COVID-19) can compromise mental health and psychological wellbeing and limit opportunities for physical activity (PA), particularly in clinical populations, such as people with rheumatoid arthritis (RA), who are considered at risk for COVID-19 complications. This study aimed to investigate associations between PA and sedentary time (ST) with indicators of mental health and wellbeing in RA during COVID-19 lockdown, and examine the moderation effects of self-isolating. 345 RA patients completed an online questionnaire measuring PA (NIH-AARP Diet and Health Study Questionnaire), ST (International Physical Activity Questionnaire-Short Form), pain (McGill Pain Questionnaire and Visual Analogue Scale), fatigue (Multidimensional Fatigue Inventory), depressive and anxious symptoms (Hospital Anxiety and Depression Scale), and vitality (Subjective Vitality Scale) during the United Kingdom COVID-19 lockdown. Associations between PA and ST with mental health and wellbeing were examined using hierarchical multiple linear regressions. Light PA (LPA) was significantly negatively associated with mental fatigue (??=?- .11), depressive symptoms (??=?- .14), and positively with vitality (??=?.13). Walking was negatively related to physical fatigue (??=?- .11) and depressive symptoms (??=?- .12) and positively with vitality (??=?.15). Exercise was negatively associated with physical (??=?- .19) and general (??=?- .12) fatigue and depressive symptoms (??=?- .09). ST was positively associated with physical fatigue (??=?.19). Moderation analyses showed that LPA was related to lower mental fatigue and better vitality in people not self-isolating, and walking with lower physical fatigue in people self-isolating. These findings show the importance of encouraging PA for people with RA during a lockdown period for mental health and wellbeing.
| S-EPMC7703721 | biostudies-literature