Evaluation of the non-steroidal anti-inflammatory drug-sparing effect of etanercept in axial spondyloarthritis: results of the multicenter, randomized, double-blind, placebo-controlled SPARSE study

International audienceIntroductionIn clinical practice, nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly discontinued after response to biologic therapy is achieved in patients with axial spondyloarthritis (axSpA), but the impact of NSAID discontinuation has not been assessed in prospective controlled trials. The aim of the SPARSE study was to evaluate the effects of the anti-tumor necrosis factor agent etanercept on NSAID intake and conventional clinical outcomes in axSpA patients.MethodsIn the double-blind, placebo-controlled period, patients with active (mini Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ≥4) axSpA despite optimal NSAID intake were randomized to receive etanercept 50 mg or placebo once weekly for 8 weeks. All patients were advised to taper/discontinue their NSAID intake during the treatment period. NSAID intake was self-reported by diary and Assessment of SpondyloArthritis International Society (ASAS)-NSAID scores calculated based on ASAS recommendations. The primary endpoint was change from baseline to week 8 in ASAS-NSAID score (analysis of covariance).ResultsIn 90 randomized patients at baseline, mean age (standard deviation) was 38.9 (11.8) years; disease duration, 5.7 (8.1) years; 59/90 (66%) were human leukocyte antigen-B27 positive; 51/90 (57%) had radiographic sacroiliitis; and 45/90 (50%) were magnetic resonance imaging sacroiliitis-positive. Mean ASAS-NSAID scores were similar between etanercept and placebo groups at baseline (98.2 (39.0) versus 93.0 (23.4)), as were BASDAI (6.0 (1.7) versus 5.9 (1.5)), and Bath Ankylosing Spondylitis Functional Index (5.2 (2.1) versus 5.1 (2.2)). Mean changes (SE) in ASAS-NSAID score from baseline to week 8 were –63.9 (6.1) and –36.6 (5.9) in the etanercept and placebo groups (between-group difference, –27.3; P = 0.002). Significantly higher proportions of patients receiving etanercept versus placebo had an ASAS-NSAID score <10 (46% versus 17%; P = 0.008) and ASAS-NSAID score of 0 (41% versus 14%; P = 0.013) at this time point. Significantly more patients in the etanercept versus placebo group achieved BASDAI50 (39% versus 18%; P = 0.032) and ASAS40 (44% versus 21%; P = 0.028) at week 8.ConclusionsIn patients with axSpA, etanercept was associated with clinically relevant NSAID-sparing effects in addition to significant improvements in conventional clinical outcomes

Validation in the ESPOIR cohort of vitamin K-dependent protein S (PROS) as a potential biomarker capable of predicting response to the methotrexate/etanercept combination

Abstract Background To validate the ability of PROS (vitamin K-dependent protein S) and CO7 (complement component C7) to predict response to the methotrexate (MTX)/etanercept (ETA) combination in rheumatoid arthritis (RA) patients who received this therapeutic combination in a well-documented cohort. Method From the ESPOIR cohort, RA patients having received the MTX/ETA or MTX/adalimumab (ADA) combination as a first-line biologic treatment were included. Serum concentrations of PROS and CO7 were measured by ELISA prior to the initiation of ETA or ADA, at a time where the disease was active (DAS28 ESR > 3.2). The clinical efficacy (response/non-response) of both combinations has been evaluated after at least 6 months of treatment, according to the EULAR response criteria with some modifications. Results Thirty-two were treated by MTX/ETA; the numbers of responders and non-responders were 24 and 8, respectively. Thirty-three patients received the MTX/ADA combination; 27 and 5 patients were respectively responders and non-responders. While there were no differences for demographic, clinical, biological, and X-rays data, as well as for CO7, serum levels of PROS tended to be significantly higher in responders to the MTX/ETA combination ( p = 0.08) while no difference was observed in the group receiving MTX/ADA. For PROS, the best concentration threshold to differentiate both groups was calculated at 40 μg/ml using ROC curve. The theranostic performances of PROS appeared better for the ETA/MTX combination. When considering the response to this combination, analysis of pooled data from ESPOIR and SATRAPE (initially used to validate PROS and CO7 as potential theranostic biomarkers) cohorts led to a higher theranostic value of PROS that became significant ( p = 0.009). Conclusion PROS might be one candidate of a combination of biomarkers capable of predicting the response to MTX/ETA combination in RA patients refractory to MTX. Trial registration ClinicalTrials.gov identifiers: NCT03666091 and NCT00234234

114-3-3E, a new alarmin candidate, elicits a catabolic and proinflammatory effect involving innate immunity through TLR signaling in osteoarthritis

Article soumis en juillet 2019, actuellement en major revisionInternational audienc

99mTc-NTP 15-5 is a companion radiotracer for assessing joint functional response to sprifermin (rhFGF-18) in a murine osteoarthritis model

International audienceAbstract With the emergence of disease modifying osteoarthritis drugs (DMOAD), imaging methods to quantitatively demonstrate their efficacy and to monitor osteoarthritis progression at the functional level are urgently needed. Our group showed that articular cartilage can be quantitatively assessed in nuclear medicine imaging by our radiotracer 99m Tc-NTP 15-5 targeting cartilage proteoglycans. In this work, surgically induced DMM mice were treated with sprifermin or saline. We investigated cartilage remodelling in the mice knees by 99m Tc-NTP 15-5 SPECT-CT imaging over 24 weeks after surgery, as wells as proteoglycan biochemical assays. OA alterations were scored by histology according to OARSI guidelines. A specific accumulation of 99m Tc-NTP 15-5 in cartilage joints was evidenced in vivo by SPECT-CT imaging as early as 30 min post-iv injection. In DMM, 99m Tc-NTP 15-5 accumulation in cartilage within the operated joints, relative to contralateral ones, was observed to initially increase then decrease as pathology progressed. Under sprifermin, 99m Tc-NTP 15-5 uptake in pathological knees was significantly increased compared to controls, at 7-, 12- and 24-weeks, and consistent with proteoglycan increase measured 5 weeks post-surgery, as a sign of cartilage matrix remodelling. Our work highlights the potential of 99m Tc-NTP 15-5 as an imaging-based companion to monitor cartilage remodelling in OA and DMOAD response

Ultra-low-dose in brain 18F-FDG PET/MRI in clinical settings

International audienceAbstract We previously showed that the injected activity could be reduced to 1 MBq/kg without significantly degrading image quality for the exploration of neurocognitive disorders in 18F-FDG-PET/MRI. We now hypothesized that injected activity could be reduced ten-fold. We simulated a 18F-FDG-PET/MRI ultra-low-dose protocol (0.2 MBq/Kg, PET ULD ) and compared it to our reference protocol (2 MBq/Kg, PET STD ) in 50 patients with cognitive impairment. We tested the reproducibility between PET ULD and PET STD using SUVratios measurements. We also assessed the impact of PET ULD for between-group comparisons and for visual analysis performed by three physicians. The intra-operator agreement between visual assessment of PET STD and PET ULD in patients with severe anomalies was substantial to almost perfect (kappa > 0.79). For patients with normal metabolism or moderate hypometabolism however, it was only moderate to substantial (kappa > 0.53). SUV ratios were strongly reproducible (SUVratio difference ± SD = 0.09 ± 0.08). Between-group comparisons yielded very similar results using either PET ULD or PET STD . 18F-FDG activity may be reduced to 0.2 MBq/Kg without compromising quantitative measurements. The visual interpretation was reproducible between ultra-low-dose and standard protocol for patients with severe hypometabolism, but less so for those with moderate hypometabolism. These results suggest that a low-dose protocol (1 MBq/Kg) should be preferred in the context of neurodegenerative disease diagnosis

Effect of age at rheumatoid arthritis onset on clinical, radiographic, and functional outcomes: The ESPOIR cohort

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18F]FDG PET/CT for predicting triple-negative breast cancer outcomes after neoadjuvant chemotherapy with or without pembrolizuma

International audiencePurpose: To determine if pretreatment [18F]FDG PET/CT could contribute to predicting complete pathological complete response (pCR) in patients with early-stage triple-negative breast cancer (TNBC) undergoing neoadjuvant chemotherapy with or without pembrolizumab. Methods: In this retrospective bicentric study, we included TNBC patients who underwent [18F]FDG PET/CT before neoadjuvant chemotherapy (NAC) or chemo-immunotherapy (NACI) between March 2017 and August 2022. Clinical, biological, and pathological data were collected. Tumor SUVmax and total metabolic tumor volume (TMTV) were measured from the PET images. Cut-off values were determined using ROC curves and a multivariable model was developed using logistic regression to predict pCR. Results: N = 191 patients were included. pCR rates were 53 and 70% in patients treated with NAC (N = 91) and NACI (N = 100), respectively (p 12.3), and low TMTV (≤ 3.0 cm3) were predictors of pCR in the NAC cohort while tumor staging classification ( 17.2), and low TMTV (≤ 7.3 cm3) correlated with pCR in the NACI cohort. In multivariable analysis, only high tumor SUVmax (NAC: OR 8.8, p < 0.01; NACI: OR 3.7, p = 0.02) and low TMTV (NAC: OR 6.6, p < 0.01; NACI: OR 3.5, p = 0.03) were independent factors for pCR in both cohorts, albeit at different thresholds. Conclusion: High tumor metabolism (SUVmax) and low tumor burden (TMTV) could predict pCR after NAC regardless of the addition of pembrolizumab. Further studies are warranted to validate such findings and determine how these biomarkers could be used to guide neoadjuvant therapy in TNBC patients

Performance of AI-Based Automated Classifications of Whole-Body FDG PET in Clinical Practice: The CLARITI Project

Purpose: To assess the feasibility of a three-dimensional deep convolutional neural network (3D-CNN) for the general triage of whole-body FDG PET in daily clinical practice. Methods: An institutional clinical data warehouse working environment was devoted to this PET imaging purpose. Dedicated request procedures and data processing workflows were specifically developed within this infrastructure and applied retrospectively to a monocentric dataset as a proof of concept. A custom-made 3D-CNN was first trained and tested on an “unambiguous” well-balanced data sample, which included strictly normal and highly pathological scans. For the training phase, 90% of the data sample was used (learning set: 80%; validation set: 20%, 5-fold cross validation) and the remaining 10% constituted the test set. Finally, the model was applied to a “real-life” test set which included any scans taken. Text mining of the PET reports systematically combined with visual rechecking by an experienced reader served as the standard-of-truth for PET labeling. Results: From 8125 scans, 4963 PETs had processable cross-matched medical reports. For the “unambiguous” dataset (1084 PETs), the 3D-CNN’s overall results for sensitivity, specificity, positive and negative predictive values and likelihood ratios were 84%, 98%, 98%, 85%, 42.0 and 0.16, respectively (F1 score of 90%). When applied to the “real-life” dataset (4963 PETs), the sensitivity, NPV, LR+, LR− and F1 score substantially decreased (61%, 40%, 2.97, 0.49 and 73%, respectively), whereas the specificity and PPV remained high (79% and 90%). Conclusion: An AI-based triage of whole-body FDG PET is promising. Further studies are needed to overcome the challenges presented by the imperfection of real-life PET data

Clinical significance of a self-reported familial occurrence of rheumatoid arthritis among patients with recent-onset arthritis: data from the ESPOIR cohort

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Hybrid [18F]-F-DOPA PET/MRI Interpretation Criteria and Scores for Glioma Follow-up After Radiotherapy

International audienceObjective18F‑fluoro-L‑3,4‑dihydroxyphenylalanine positron emission tomography (F‑DOPA PET) is used in glioma follow-up after radiotherapy to discriminate treatment-related changes (TRC) from tumor progression (TP). We compared the performances of a combined PET and MRI analysis with F‑DOPA current standard of interpretation.MethodsWe included 76 consecutive patients showing at least one gadolinium-enhanced lesion on the T1‑w MRI sequence (T1G). Two nuclear medicine physicians blindly analyzed PET/MRI images. In addition to the conventional PET analysis, they looked for F‑DOPA uptake(s) outside T1G-enhanced areas (T1G/PET), in the white matter (WM/PET), for T1G-enhanced lesion(s) without sufficiently concordant F‑DOPA uptake (T1G+/PET), and F‑DOPA uptake(s) away from hemorrhagic changes as shown with a susceptibility weighted imaging sequence (SWI/PET). We measured lesions’ F‑DOPA uptake ratio using healthy brain background (TBR) and striatum (T/S) as references, and lesions’ perfusion with arterial spin labelling cerebral blood flow maps (rCBF). Scores were determined by logistic regression.Results53 and 23 patients were diagnosed with TP and TRC, respectively. The accuracies were 74% for T/S, 76% for TBR, and 84% for rCBF, with best cut-off values of 1.3, 3.7 and 1.25, respectively. For hybrid variables, best accuracies were obtained with conventional analysis (82%), T1G+/PET (82%) and SWI/PET (81%). T1G+/PET, SWI/PET and rCBF ≥ 1.25 were selected to construct a 3-point score. It outperformed conventional analysis and rCBF with an AUC of 0.94 and an accuracy of 87%.ConclusionsOur scoring approach combining F‑DOPA PET and MRI provided better accuracy than conventional PET analyses for distinguishing TP from TRC in our patients after radiation therapy