Effect of intravenous tiludronate disodium administration on the radiographic progression of osteoarthritis of the fetlock joint in Standardbred racehorses

2021 ◽  
Vol 259 (6) ◽  
pp. 651-661
Author(s):  
Andrea Bertuglia ◽  
Ilaria Basano ◽  
Eleonora Pagliara ◽  
Nika Brkljaca Bottegaro ◽  
Giuseppe Spinella ◽  
...  
2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Jeffrey R. Curtis ◽  
Michael E. Weinblatt ◽  
Nancy A. Shadick ◽  
Cecilie H. Brahe ◽  
Mikkel Østergaard ◽  
...  

Abstract Background The multi-biomarker disease activity (MBDA) test measures 12 serum protein biomarkers to quantify disease activity in RA patients. A newer version of the MBDA score, adjusted for age, sex, and adiposity, has been validated in two cohorts (OPERA and BRASS) for predicting risk for radiographic progression. We now extend these findings with additional cohorts to further validate the adjusted MBDA score as a predictor of radiographic progression risk and compare its performance with that of other risk factors. Methods Four cohorts were analyzed: the BRASS and Leiden registries and the OPERA and SWEFOT studies (total N = 953). Treatments included conventional DMARDs and anti-TNFs. Associations of radiographic progression (ΔTSS) per year with the adjusted MBDA score, seropositivity, and clinical measures were evaluated using linear and logistic regression. The adjusted MBDA score was (1) validated in Leiden and SWEFOT, (2) compared with other measures in all four cohorts, and (3) used to generate curves for predicting risk of radiographic progression. Results Univariable and bivariable analyses validated the adjusted MBDA score and found it to be the strongest, independent predicator of radiographic progression (ΔTSS > 5) compared with seropositivity (rheumatoid factor and/or anti-CCP), baseline TSS, DAS28-CRP, CRP SJC, or CDAI. Neither DAS28-CRP, CDAI, SJC, nor CRP added significant information to the adjusted MBDA score as a predictor, and the frequency of radiographic progression agreed with the adjusted MBDA score when it was discordant with these measures. The rate of progression (ΔTSS > 5) increased from < 2% in the low (1–29) adjusted MBDA category to 16% in the high (45–100) category. A modeled risk curve indicated that risk increased continuously, exceeding 40% for the highest adjusted MBDA scores. Conclusion The adjusted MBDA score was validated as an RA disease activity measure that is prognostic for radiographic progression. The adjusted MBDA score was a stronger predictor of radiographic progression than conventional risk factors, including seropositivity, and its prognostic ability was not significantly improved by the addition of DAS28-CRP, CRP, SJC, or CDAI.


2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1252.2-1253
Author(s):  
R. Garofoli ◽  
M. Resche-Rigon ◽  
M. Dougados ◽  
D. Van der Heijde ◽  
C. Roux ◽  
...  

Background:Axial spondyloarthritis (axSpA) is a chronic rheumatic disease that encompasses various clinical presentations: inflammatory chronic back pain, peripheral manifestations and extra-articular manifestations. The current nomenclature divides axSpA in radiographic (in the presence of radiographic sacroiliitis) and non-radiographic (in the absence of radiographic sacroiliitis, with or without MRI sacroiliitis. Given that the functional burden of the disease appears to be greater in patients with radiographic forms, it seems crucial to be able to predict which patients will be more likely to develop structural damage over time. Predictive factors for radiographic progression in axSpA have been identified through use of traditional statistical models like logistic regression. However, these models present some limitations. In order to overcome these limitations and to improve the predictive performance, machine learning (ML) methods have been developed.Objectives:To compare ML models to traditional models to predict radiographic progression in patients with early axSpA.Methods:Study design: prospective French multicentric cohort study (DESIR cohort) with 5years of follow-up. Patients: all patients included in the cohort, i.e. 708 patients with inflammatory back pain for >3 months but <3 years, highly suggestive of axSpA. Data on the first 5 years of follow-up was used. Statistical analyses: radiographic progression was defined as progression either at the spine (increase of at least 1 point per 2 years of mSASSS scores) or at the sacroiliac joint (worsening of at least one grade of the mNY score between 2 visits). Traditional modelling: we first performed a bivariate analysis between our outcome (radiographic progression) and explanatory variables at baseline to select the variables to be included in our models and then built a logistic regression model (M1). Variable selection for traditional models was performed with 2 different methods: stepwise selection based on Akaike Information Criterion (stepAIC) method (M2), and the Least Absolute Shrinkage and Selection Operator (LASSO) method (M3). We also performed sensitivity analysis on all patients with manual backward method (M4) after multiple imputation of missing data. Machine learning modelling: using the “SuperLearner” package on R, we modelled radiographic progression with stepAIC, LASSO, random forest, Discrete Bayesian Additive Regression Trees Samplers (DBARTS), Generalized Additive Models (GAM), multivariate adaptive polynomial spline regression (polymars), Recursive Partitioning And Regression Trees (RPART) and Super Learner. Finally, the accuracy of traditional and ML models was compared based on their 10-foldcross-validated AUC (cv-AUC).Results:10-fold cv-AUC for traditional models were 0.79 and 0.78 for M2 and M3, respectively. The 3 best models in the ML algorithm were the GAM, the DBARTS and the Super Learner models, with 10-fold cv-AUC of: 0.77, 0.76 and 0.74, respectively (Table 1).Table 1.Comparison of 10-fold cross-validated AUC between best traditional and machine learning models.Best modelsCross-validated AUCTraditional models M2 (step AIC method)0.79 M3 (LASSO method)0.78Machine learning approach SL Discrete Bayesian Additive Regression Trees Samplers (DBARTS)0.76 SL Generalized Additive Models (GAM)0.77 Super Learner0.74AUC: Area Under the Curve; AIC: Akaike Information Criterion; LASSO: Least Absolute Shrinkage and Selection Operator; SL: SuperLearner. N = 295.Conclusion:Traditional models predicted better radiographic progression than ML models in this early axSpA population. Further ML algorithms image-based or with other artificial intelligence methods (e.g. deep learning) might perform better than traditional models in this setting.Acknowledgments:Thanks to the French National Society of Rheumatology and the DESIR cohort.Disclosure of Interests:Romain Garofoli: None declared, Matthieu resche-rigon: None declared, Maxime Dougados Grant/research support from: AbbVie, Eli Lilly, Merck, Novartis, Pfizer and UCB Pharma, Consultant of: AbbVie, Eli Lilly, Merck, Novartis, Pfizer and UCB Pharma, Speakers bureau: AbbVie, Eli Lilly, Merck, Novartis, Pfizer and UCB Pharma, Désirée van der Heijde Consultant of: AbbVie, Amgen, Astellas, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Cyxone, Daiichi, Eisai, Eli-Lilly, Galapagos, Gilead Sciences, Inc., Glaxo-Smith-Kline, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, UCB Pharma; Director of Imaging Rheumatology BV, Christian Roux: None declared, Anna Moltó Grant/research support from: Pfizer, UCB, Consultant of: Abbvie, BMS, MSD, Novartis, Pfizer, UCB


Author(s):  
Andrew X. Zhu ◽  
Richard S. Finn ◽  
Yoon-Koo Kang ◽  
Chia-Jui Yen ◽  
Peter R. Galle ◽  
...  

Abstract Background Post hoc analyses assessed the prognostic and predictive value of baseline alpha-fetoprotein (AFP), as well as clinical outcomes by AFP response or progression, during treatment in two placebo-controlled trials (REACH, REACH-2). Methods Serum AFP was measured at baseline and every three cycles. The prognostic and predictive value of baseline AFP was assessed by Cox regression models and Subpopulation Treatment Effect Pattern Plot method. Associations between AFP (≥ 20% increase) and radiographic progression and efficacy were assessed. Results Baseline AFP was confirmed as a continuous (REACH, REACH-2; p < 0.0001) and dichotomous (≥400 vs. <400 ng/ml; REACH, p < 0.01) prognostic factor, and was predictive for ramucirumab survival benefit in REACH (p = 0.0042 continuous; p < 0.0001 dichotomous). Time to AFP (hazard ratio [HR] 0.513; p < 0.0001) and radiographic (HR 0.549; p < 0.0001) progression favoured ramucirumab. Association between AFP and radiographic progression was shown for up to 6 (odds ratio [OR] 5.1; p < 0.0001) and 6–12 weeks (OR 1.8; p = 0.0065). AFP response was higher with ramucirumab vs. placebo (p < 0.0001). Survival was longer in patients with an AFP response than patients without (13.6 vs. 5.6 months, HR 0.451; 95% confidence interval, 0.354–0.574; p < 0.0001). Conclusions AFP is an important prognostic factor and a predictive biomarker for ramucirumab survival benefit. AFP ≥ 400 ng/ml is an appropriate selection criterion for ramucirumab. Clinical Trial Registration ClinicalTrials.gov, REACH (NCT01140347) and REACH-2 (NCT02435433).


2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 769.2-770
Author(s):  
J. Rademacher ◽  
M. Siderius ◽  
L. Gellert ◽  
F. Wink ◽  
M. Verba ◽  
...  

Background:Radiographic spinal progression determinates functional status and mobility in ankylosing spondylitis (AS)1.Objectives:To analyse whether biomarker of inflammation, bone turnover and adipokines at baseline or their change after 3 months or 2 years can predict spinal radiographic progression after 2 years in AS patients treated with TNF-α inhibitors (TNFi).Methods:Consecutive AS patients from the Groningen Leeuwarden Axial Spondyloarthritis (GLAS) cohort2 starting TNFi between 2004 and 2012 were included. The following serum biomarkers were measured at baseline, 3 months and 2 years of follow-up with ELISA: - Markers of inflammation: calprotectin, matrix metalloproteinase-3 (MMP-3), vascular endothelial growth factor (VEGF) - Markers of bone turnover: bone-specific alkaline phosphatase (BALP), serum C-terminal telopeptide (sCTX), osteocalcin (OC), osteoprotegerin (OPG), procollagen typ I and II N-terminal propeptide (PINP; PIINP), sclerostin. - Adipokines: high molecular weight (HMW) adiponectin, leptin, visfatinTwo independent readers assessed spinal radiographs at baseline and 2 years of follow-up according to the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). Radiographic spinal progression was defined as mSASSS change ≥2 units or the formation of ≥1 new syndesmophyte over 2 years. Logistic regression was performed to examine the association between biomarker values at baseline, their change after 3 months and 2 years and radiographic spinal progression. Multivariable models for each biomarker were adjusted for mSASSS or syndesmophytes at baseline, elevated CRP (≥5mg/l), smoking status, male gender, symptom duration, BMI, and baseline biomarker level (the latter only in models with biomarker change).Results:Of the 137 included AS patients, 72% were male, 79% HLAB27+; mean age at baseline was 42 years (SD 10.8), ASDAScrp 3.8 (0.8) and mSASSS 10.6 (16.1). After 2 years of follow-up, 33% showed mSASSS change ≥2 units and 24% had developed ≥1 new syndesmophyte. Serum levels of biomarkers of inflammation and bone formation showed significant changes under TNFi therapy, whereas adipokine levels were not altered from baseline (Figure 1).Univariable logistic regression revealed a significant association of baseline visfatin (odds ratio OR [95% confidence interval] 1.106 [1.007-1.215]) and sclerostin serum levels (OR 1.006 [1.001-1.011]) with mSASSS progression after 2 years. Baseline sclerostin levels were also associated with syndesmophyte progression (OR 1.007 [1.001-1.013]). In multivariable logistic analysis, only baseline visfatin level remained significantly associated (OR 1.465 [1.137-1.889]) with mSASSS progression. Furthermore, baseline calprotectin showed a positive association with both, mSASSS (OR 1.195 [1.055-1.355]) and syndesmophyte progression (OR 1.107 [1.001-1.225]) when adjusting for known risk factors for radiographic progression.Univariable logistic regression showed that change of sclerostin after 3 months was associated with syndesmophytes progression (OR 1.007 [1.000-1.015), change of PINP level after 2 years was associated with mSASSS progression (OR 1.027 [1.003-1.052]) and change of visfatin after 2 years was associated with both measures of radiographic progression – mSASSS (OR 1.108 [1.004-1.224]) and syndesmophyte formation (OR 1.115; [1.002-1.24]). However, those associations were lost in multivariable analysis.Conclusion:Independent of known risk factors, baseline calprotectin and visfatin levels were associated with radiographic spinal progression after 2 years of TNFi. Although biomarkers of inflammation and bone formation showed significant changes under TNFi therapy, these changes were not significantly related to radiographic spinal progression in our cohort of AS patients.References:[1]Poddubnyy et al 2018[2]Maas et al 2019Acknowledgements:Dr. Judith Rademacher is participant in the BIH-Charité Clinician Scientist Program funded by the Charité –Universitätsmedizin Berlin and the Berlin Institute of Health.Disclosure of Interests:Judith Rademacher: None declared, Mark Siderius: None declared, Laura Gellert: None declared, Freke Wink Consultant of: AbbVie, Maryna Verba: None declared, Fiona Maas: None declared, Lorraine M Tietz: None declared, Denis Poddubnyy: None declared, Anneke Spoorenberg Consultant of: Abbvie, Pfizer, MSD, UCB, Lilly and Novartis, Grant/research support from: Abbvie, Pfizer, UCB, Novartis, Suzanne Arends Grant/research support from: Pfizer.


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