Guy Cavet

University of Occupational and Environmental Health, Kitakyūshū, Fukuoka, Japan

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Publications (48)605.2 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Objectives. To assess the ability of a multi-biomarker disease activity (MBDA) score to track clinical response in patients with rheumatoid arthritis (RA) treated with different TNF inhibitors. Methods. The study included 147 patients who had received adalimumab, etanercept, or infliximab for a year or more, during routine clinical care at the University Hospital of Occupational and Environmental Health, Japan. MBDA scores and clinical measures of disease activity were evaluated at baseline and, after 24 weeks (N = 84) and 52 weeks of treatment. Relationships between the changes (∆) in MBDA score and changes in clinical measures or EULAR response categories were evaluated. Results. The median disease activity was 5.7 by DAS28-ESR and 64 by MBDA score at baseline, and decreased significantly with treatment. ∆MBDA scores over 1 year correlated with ∆DAS28-ESR (r = 0.48) and ∆DAS28-CRP (r = 0.46). Linear relationships between ∆MBDA scores and ∆DAS28-ESR or ∆DAS28-CRP were not significantly different between TNF inhibitors. The MBDA scores declined significantly more in good responders (median change: –29) than moderate (–21), and more in moderate than in non-responders (+ 2), by the EULAR criteria. Conclusions. MBDA scores tracked disease activity and treatment response in patients with RA treated with three TNF inhibitors. The relationships between ∆MBDA scores and ∆DAS28-ESR or ∆DAS28-CRP were consistent across the three TNF inhibitor groups.
    Modern Rheumatology 10/2014; DOI:10.3109/14397595.2014.958893 · 2.21 Impact Factor
  • Annals of the Rheumatic Diseases 06/2014; 73(Suppl 2):393-394. DOI:10.1136/annrheumdis-2014-eular.2057 · 9.27 Impact Factor
  • Annals of the Rheumatic Diseases 01/2014; 71(Suppl 3):355-355. DOI:10.1136/annrheumdis-2012-eular.2589 · 9.27 Impact Factor
  • Annals of the Rheumatic Diseases 01/2014; 72(Suppl 3):A395-A396. DOI:10.1136/annrheumdis-2013-eular.1206 · 9.27 Impact Factor
  • Annals of the Rheumatic Diseases 01/2014; 72(Suppl 3):A388-A388. DOI:10.1136/annrheumdis-2013-eular.1187 · 9.27 Impact Factor
  • Annals of the Rheumatic Diseases 01/2014; 71(Suppl 3):371-371. DOI:10.1136/annrheumdis-2012-eular.2631 · 9.27 Impact Factor
  • Annals of the Rheumatic Diseases 01/2014; 71(Suppl 3):126-126. DOI:10.1136/annrheumdis-2012-eular.1892 · 9.27 Impact Factor
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    ABSTRACT: OBJECTIVE: Previous studies indicated that pyridinoline, a collagen crosslink in cartilage and bone, might be a good marker to predict joint destruction in patients with rheumatoid arthritis (RA), although large prospective studies are lacking. We evaluated the predictive value of serum pyridinoline levels for joint destruction, both at baseline for longterm prediction and during the disease course for near-term prediction. METHODS: Patients with early RA from the Leiden Early Arthritis Clinic were studied. Radiographs at baseline and yearly during 7 years of followup were scored according to the Sharp-van der Heijde Scoring (SHS) method. Pyridinoline serum levels at baseline and during followup were measured by ELISA. The association between baseline pyridinoline levels and difference in SHS over 7 years was tested, with a multivariate normal regression model. Second, the association between pyridinoline levels determined during the disease course and progression of SHS over the next year was tested with a multivariable linear regression analysis. RESULTS: Studying baseline pyridinoline serum levels in 437 patients revealed that the mean SHS over 7 years was 6% higher for every higher pyridinoline level (nmol/l) at baseline (p = 0.001). Subsequently, during followup (n = 184 patients) the progression in SHS in the upcoming year was 17% higher for every higher nmol/l pyridinoline level (p = 0.001). The area under the receiver-operation characteristic curve for rapid radiological progression was 0.59. CONCLUSION: Increased pyridinoline serum levels, both at baseline and during the disease course, are associated with more severe joint destruction during the coming year(s), although the predictive accuracy as a sole predictor was moderate.
    The Journal of Rheumatology 06/2013; DOI:10.3899/jrheum.121392 · 3.17 Impact Factor
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    ABSTRACT: Disease activity measurement is a key component of rheumatoid arthritis (RA) management. Biomarkers that capture the complex and heterogeneous biology of RA have the potential to complement clinical disease activity assessment. To develop a multi-biomarker disease activity (MBDA) test for rheumatoid arthritis. Candidate serum protein biomarkers were selected from extensive literature screens, bioinformatics databases, mRNA expression and protein microarray data. Quantitative assays were identified and optimized for measuring candidate biomarkers in RA patient sera. Biomarkers with qualifying assays were prioritized in a series of studies based on their correlations to RA clinical disease activity (e.g. the Disease Activity Score 28-C-Reactive Protein [DAS28-CRP], a validated metric commonly used in clinical trials) and their contributions to multivariate models. Prioritized biomarkers were used to train an algorithm to measure disease activity, assessed by correlation to DAS and area under the receiver operating characteristic curve for classification of low vs. moderate/high disease activity. The effect of comorbidities on the MBDA score was evaluated using linear models with adjustment for multiple hypothesis testing. 130 candidate biomarkers were tested in feasibility studies and 25 were selected for algorithm training. Multi-biomarker statistical models outperformed individual biomarkers at estimating disease activity. Biomarker-based scores were significantly correlated with DAS28-CRP and could discriminate patients with low vs. moderate/high clinical disease activity. Such scores were also able to track changes in DAS28-CRP and were significantly associated with both joint inflammation measured by ultrasound and damage progression measured by radiography. The final MBDA algorithm uses 12 biomarkers to generate an MBDA score between 1 and 100. No significant effects on the MBDA score were found for common comorbidities. We followed a stepwise approach to develop a quantitative serum-based measure of RA disease activity, based on 12-biomarkers, which was consistently associated with clinical disease activity levels.
    PLoS ONE 04/2013; 8(4):e60635. DOI:10.1371/journal.pone.0060635 · 3.53 Impact Factor
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    ABSTRACT: BACKGROUND: Heritability studies have suggested an important role of genetic predisposition ito progression of joint destruction in Rheumatoid Arthritis (RA); the heritability is estimated at 45-58%. Several SNPs have been identified to associate with RA susceptibility. We studied the association of several of these loci with progression of joint destruction. METHOD: In total 1,750 RA-patients with 4,732 Sharp-van der Heijde scored X-rays of four independent data-sets were studied. Thirteen susceptibility SNPs that were not associated with joint destruction before were tested in 596 Dutch RA-patients. Subsequently, significant SNPs were studied in RA data-sets from North-America and Iceland. Data were summarized in inverse weighted variance meta-analyses. Further, the association with circulating protein levels was studied and the associated region was fine-mapped. RESULTS: In stage-1, three loci (AFF3, IL2RA and BLK) were significantly associated with rate of joint destruction and were further analyzed in the additional data-sets. In the combined meta-analyses, the minor allele of IL2RA-rs2104286(C) was associated with less progression of joint destruction (P=7.2x10(-4) ). Furthermore, the IL2RA-rs2104286 protective genotype was associated with lower circulating levels of soluble IL-2RA (0.85 95%CI 0.77-0.93, P=1.4x10(-3) ). Additionally, lower sIL-2RA levels were associated with a lower rate of joint destruction (P=4.2x10(-3) ). The association of IL2RA with rate of joint destruction was further focused to a region of 40kb encompassing the IL2RA intron 1 and the 5' region of IL2RA and RBM17. CONCLUSION: Present genetic and serologic data suggest that inherited altered genetic constitution at IL2RA locus may predispose to a less destructive course of RA. © 2013 American College of Rheumatology.
    Arthritis & Rheumatology 03/2013; DOI:10.1002/art.37938 · 7.87 Impact Factor
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    ABSTRACT: Objective. To evaluate a multi-biomarker disease activity (MBDA) score, a novel index based on 12 serum proteins, as a tool to guide management of RA patients. Methods. A total of 125 patients with RA from the Behandel Strategieën study were studied. Clinical data and serum samples were available from 179 visits, 91 at baseline and 88 at year 1. In each serum sample, 12 biomarkers were measured by quantitative multiplex immunoassays and the concentrations were used as input to a pre-specified algorithm to calculate MBDA scores. Results. MBDA scores had significant correlation with DAS28-ESR (Spearman’s ρ = 0.66, P < 0.0001) and also correlated with simplified disease activity index, clinical disease activity index and HAQ Disability Index (all P < 0.0001). Changes in MBDA between baseline and year 1 were also correlated with changes in DAS28-ESR (ρ = 0.55, P < 0.0001). Groups stratified by European League Against Rheumatism disease activity (DAS28-ESR ≤ 3.2, 3.2–5.1 and > 5.1) had significantly different MBDA scores (P < 0.0001) and MBDA score could discriminate ACR/EULAR Boolean remission with an area under the receiver operating characteristic curve of 0.83 (P < 0.0001). Conclusion: The MBDA score reflects current clinical disease activity and can track changes in disease activity over time.
    Rheumatology (Oxford, England) 02/2013; 52(7). DOI:10.1093/rheumatology/kes362 · 4.44 Impact Factor
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    ABSTRACT: Objectives. To determine whether molecular remission defined by a multi-biomarker disease activity (MBDA) score predicts a reduced risk of joint damage progression, and whether the MBDA score can augment existing classifications of remission. Methods. The study examined 271 visits for 163 RA patients in the Leiden Early Arthritis Cohort. The MBDA score and other variables from each visit were evaluated for prediction of progression [change in Sharp–van der Heijde Score (ΔSHS) >3] over the ensuing 12 months. Positive likelihood ratios (PLRs) for non-progression were calculated for remission based upon DAS based on 28-joint counts and CRP (DAS28-CRP <2.32), EULAR/ACR Boolean criteria and MBDA score (≤25). Results. Ninety-three per cent of patients in MBDA-defined remission did not experience progression, compared with 70% of patients not in MBDA remission (P = 0.001). There were no significant differences in the fraction of non-progressers between patients in remission and those not in remission using either DAS28-CRP or EULAR/ACR criteria. The PLR for non-progression over 12 months for MBDA remission was 4.73 (95% CI 1.67, 15.0). Among patients in DAS28-CRP remission, those with a high MBDA score were 2.3 times as likely (95% CI 1.1, 3.7) to have joint damage progression during the next year. Conclusion. MBDA-defined remission was an indicator of limited radiographic progression over the following 12 months. For patients in DAS28-CRP remission, high MBDA scores were a significant indicator of elevated risk of progression. MBDA results may provide a useful adjunct to clinical assessment to identify progression-free remission and assess subclinical disease.
    Rheumatology (Oxford, England) 01/2013; 52(5). DOI:10.1093/rheumatology/kes378 · 4.44 Impact Factor
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    ABSTRACT: Objectives Mavrilimumab, a human monoclonal antibody targeting the alpha subunit of the granulocyte-macrophage colony-stimulating factor receptor, was evaluated in a phase 2 randomised, double-blind, placebo-controlled study to investigate efficacy and safety in subjects with rheumatoid arthritis (RA). Methods Subcutaneous mavrilimumab (10 mg, 30 mg, 50 mg, or 100 mg) or placebo was administered every other week for 12 weeks in subjects on stable background methotrexate therapy. The primary endpoint was the proportion of subjects achieving a ≥1.2 decrease from baseline in Disease Activity Score (DAS28-CRP) at week 12. Results 55.7% of mavrilimumab-treated subjects met the primary endpoint versus 34.7% placebo (p=0.003) at week 12; for the 10 mg, 30 mg, 50 mg, and 100 mg groups, responses were 41.0% (p=0.543), 61.0% (p=0.011), 53.8% (p=0.071), and 66.7% (p=0.001) respectively. Response rate differences from placebo were observed at week 2 and increased throughout the treatment period. The 100 mg dose demonstrated a significant effect versus placebo on DAS28-CRP<2.6 (23.1% vs 6.7%, p=0.016), all categories of the American College of Rheumatology (ACR) criteria (ACR20: 69.2% vs 40.0%, p=0.005; ACR50: 30.8% vs 12.0%, p=0.021; ACR70: 17.9% vs 4.0%, p=0.030), and the Health Assessment Questionnaire Disability Index (−0.48 vs −0.25, p=0.005). A biomarker-based disease activity score showed a dose-dependent decrease at week 12, indicating suppression of disease-related biological pathways. Adverse events were generally mild or moderate in intensity. No significant hypersensitivity reactions, serious or opportunistic infections, or changes in pulmonary parameters were observed. Conclusions Mavrilimumab induced rapid clinically significant responses in RA subjects, suggesting that inhibiting the mononuclear phagocyte pathway may provide a novel therapeutic approach for RA.
    Annals of the rheumatic diseases 12/2012; 72(9). DOI:10.1136/annrheumdis-2012-202450 · 9.27 Impact Factor
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    ABSTRACT: Abstract Objective: To assess how use of a multi-biomarker disease activity (MBDA) test for rheumatoid arthritis (RA) affects treatment decisions made by health care providers (HCPs) in clinical practice. Research Design and Methods: At routine office visits, 101 patients with RA were assessed by their HCPs (N=6), and they provided samples for MBDA testing. HCPs completed surveys before and after viewing the MBDA test result, recording dosage and frequency for all planned RA medications and physician global assessment of disease activity. Frequency and types of change in treatment plan that resulted from viewing the MBDA test result were determined. Main Outcome Measure: Percentage of cases in which the HCP changed the planned treatment after viewing the MBDA test result. Results: Prior to HCP review of the MBDA test, disease modifying anti-rheumatic drug (DMARD) use by the 101 patients included methotrexate in 62% of patients; hydroxychloroquine 29%; TNF-inhibitor 42%; non-TNF-inhibitor biologic agent 19%; and other drugs at lower frequencies. Review of MBDA test results changed HCP treatment decisions in 38 cases (38%), of which 18 involved starting, discontinuing or switching a biologic or non-biologic DMARD. Other changes involved drug dosage, frequency or route of administration. The total frequency of use of the major classes of drug therapy changed by <5%. Treatment plans changed 63% of the time when the MBDA test result was perceived as being not consistent or somewhat consistent with the HCP assessment of disease activity. Study Limitations: Limited sample size; lack of control group; no longitudinal follow-up. Conclusions: The addition of the MBDA test to clinical assessment led to meaningful changes in the treatment plans of 38% of RA patients being cared for by HCPs in office practice. Even though treatment was potentially improved, the overall quantity of drug use was minimally affected.
    Current Medical Research and Opinion 11/2012; DOI:10.1185/03007995.2012.753042 · 2.37 Impact Factor
  • Rheumatoid arthritis – Non-biologic treatment and small molecules; 09/2012
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    ABSTRACT: Objective Quantitative assessment of disease activity in rheumatoid arthritis (RA) is important for patient management, and additional objective information may aid rheumatologists in clinical decision making. We validated a recently developed multibiomarker disease activity (MBDA) test relative to clinical disease activity in diverse RA cohorts. Methods Serum samples were obtained from the Index for Rheumatoid Arthritis Measurement, Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study, and Leiden Early Arthritis Clinic cohorts. Levels of 12 biomarkers were measured and combined according to a prespecified algorithm to generate the composite MBDA score. The relationship of the MBDA score to clinical disease activity was characterized separately in seropositive and seronegative patients using Pearson's correlations and the area under the receiver operating characteristic curve (AUROC) to discriminate between patients with low and moderate/high disease activity. Associations between changes in MBDA score and clinical responses 6–12 weeks after initiation of anti–tumor necrosis factor or methotrexate treatment were evaluated by the AUROC. Results The MBDA score was significantly associated with the Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP) in both seropositive (AUROC 0.77, P < 0.001) and seronegative (AUROC 0.70, P < 0.001) patients. In subgroups based on age, sex, body mass index, and treatment, the MBDA score was associated with the DAS28-CRP (P < 0.05) in all seropositive and most seronegative subgroups. Changes in the MBDA score at 6–12 weeks could discriminate both American College of Rheumatology criteria for 50% improvement responses (P = 0.03) and DAS28-CRP improvement (P = 0.002). Changes in the MBDA score at 2 weeks were also associated with subsequent DAS28-CRP response (P = 0.02). Conclusion Our findings establish the criterion and discriminant validity of a novel multibiomarker test as an objective measure of RA disease activity to aid in the management of RA in patients with this condition.
    06/2012; 64(12). DOI:10.1002/acr.21767
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    ABSTRACT: Rheumatoid arthritis (RA) is a chronic inflammatory disorder that primarily involves the joints. Accurate and frequent assessment of RA disease activity is critical to optimal treatment planning. A novel algorithm has been developed to determine a multi-biomarker disease activity (MBDA) score based upon measurement of the concentrations of 12 serum biomarkers in multiplex format. Biomarker assays from several different platforms were used in feasibility studies to identify biomarkers of potential significance. These assays were adapted to a multiplex platform for training and validation of the algorithm. In this study, the analytical performance of the underlying biomarker assays and the MBDA score was evaluated. Quantification of 12 biomarkers was performed with multiplexed sandwich immunoassays in three panels. Biomarker-specific capture antibodies were bound to specific locations in each well; detection antibodies were labeled with electrochemiluminescent tags. Data were acquired with a Sector Imager 6000, and analyte concentrations were determined. Parallelism, dynamic range, cross-reactivity, and precision were established for each biomarker as well as for the MBDA score. Interference by serum proteins, heterophilic antibodies, and common RA therapies was also assessed. The individual biomarker assays had 3-4 orders of magnitude dynamic ranges, with good reproducibility across time, operators, and reagent lots; the MBDA score had a median coefficient of variation of <2% across the score range. Cross-reactivity as well as interference by serum rheumatoid factor (RF), human anti-mouse antibodies (HAMA), or common RA therapies, including disease-modifying antirheumatic drugs and biologics, was minimal. The same MBDA score was observed in different subjects despite having different biomarker profiles, supporting prior literature reports that multiple pathways contribute to RA.
    Journal of pharmaceutical and biomedical analysis 06/2012; 70:415-24. DOI:10.1016/j.jpba.2012.06.003 · 2.83 Impact Factor
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    ABSTRACT: To evaluate the performance of individual biomarkers and a multi-biomarker disease activity (MBDA) score in the early rheumatoid arthritis (RA) patient population from the computer assisted management in early rheumatoid arthritis (CAMERA) study. Twenty biomarkers were measured in the CAMERA cohort, in which patients were treated with either intensive or conventional methotrexate-based treatment strategies. The MBDA score was calculated using the concentrations of 12 biomarkers (SAA, IL-6, TNF-RI, VEGF-A, MMP-1, YKL-40, MMP-3, EGF, VCAM-1, leptin, resistin and CRP) according to a previously trained algorithm. The performance of the scores was evaluated relative to clinical disease activity assessments. Change in MBDA score over time was assessed by paired Wilcoxon rank sum test. Logistic regression was used to evaluate the ability of disease activity measures to predict radiographic progression. The MBDA score had a significant correlation with the disease activity score based on 28 joints-C reactive protein (DAS28-CRP) (r=0.72; p<0.001) and an area under the receiver operating characteristic curve for distinguishing remission/low from moderate/high disease activity of 0.86 (p<0.001) using a DAS28-CRP cut-off of 2.7. In multivariate analysis the MBDA score, but not CRP, was an independent predictor of disease activity measures. Additionally, mean (SD) MBDA score decreased from 53 (18) at baseline to 39 (16) at 6 months in response to study therapy (p<0.0001). Neither MBDA score nor clinical variables were predictive of radiographic progression. This multi-biomarker test performed well in the assessment of disease activity in RA patients in the CAMERA study. Upon further validation, this test could be used to complement currently available disease activity measures and improve patient care and outcomes.
    Annals of the rheumatic diseases 05/2012; 71(10):1692-7. DOI:10.1136/annrheumdis-2011-200963 · 9.27 Impact Factor
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    ABSTRACT: Inferring functional consequences is a bottleneck in high-throughput cancer mutation discovery and genetic association studies. Most polymorphisms and germline mutations are unlikely to have functionally significant consequences. Most cancer somatic mutations do not contribute to tumorigenesis and are not under selective pressure. Identifying and understanding functionally important mutations can clarify disease biology and lead to new therapeutic and diagnostic opportunities. We investigated the extent to which protein mutations with functional consequences are enriched in clusters at conserved positions across related proteins. We found that disease-causing mutations form clusters more than random mutations or single nucleotide polymorphisms, confirming that mutation hotspots occur at the domain level. In addition to helping to identify functionally significant mutations, analysis of clustered mutations can indicate the mechanism and consequences for protein function. Our analysis focused on somatic cancer mutations suggests functional impact for many, including singleton mutations in FGFR1, FGFR3, GFI1B, PIK3CG, RALB, RAP2B, and STK11. This provides evidence and generates mechanistic hypotheses for the contribution of such mutations to cancer. The same approach can be applied to mutations suspected of involvement in other diseases. An interactive Web application for browsing mutation clusters is available at http://www.mcluster.org.
    Human Mutation 03/2010; 31(3):264-71. DOI:10.1002/humu.21194 · 5.05 Impact Factor
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    ABSTRACT: The insulin-like growth factor-I receptor (IGF-IR) pathway is required for the maintenance of the transformed phenotype in neoplastic cells and hence has been the subject of intensive drug discovery efforts. A key aspect of successful clinical development of targeted therapies directed against IGF-IR will be identification of responsive patient populations. Toward that end, we have endeavored to identify predictive biomarkers of response to an anti-IGF-IR-targeting monoclonal antibody in preclinical models of breast and colorectal cancer. We find that levels of the IGF-IR itself may have predictive value in these tumor types and identify other gene expression predictors of in vitro response. Studies in breast cancer models suggest that IGF-IR expression is both correlated and functionally linked with estrogen receptor signaling and provide a basis for both patient stratification and rational combination therapy with antiestrogen-targeting agents. In addition, we find that levels of other components of the signaling pathway such as the adaptor proteins IRS1 and IRS2, as well as the ligand IGF-II, have predictive value and report on the development of a pathway-focused panel of diagnostic biomarkers that could be used to test these hypotheses during clinical development of IGF-IR-targeting therapies.
    Molecular Cancer Therapeutics 09/2009; 8(8):2110-21. DOI:10.1158/1535-7163.MCT-09-0381 · 6.11 Impact Factor

Publication Stats

8k Citations
605.20 Total Impact Points

Institutions

  • 2013
    • University of Occupational and Environmental Health
      Kitakyūshū, Fukuoka, Japan
  • 2012–2013
    • Crescendo Bioscience
      San Francisco, California, United States
    • University of California, San Francisco
      San Francisco, California, United States
  • 2002
    • InPharmatics
      San Diego, California, United States
    • Stanford Medicine
      • Department of Biochemistry
      Stanford, California, United States
  • 2001
    • University of Cambridge
      Cambridge, England, United Kingdom
  • 1998
    • Stanford University
      • Department of Biochemistry
      Palo Alto, California, United States