Publications by authors named "Denis Mulleman"

67 Publications

Poor assessment of bone mineral density after a forearm fracture in women aged 50 years or older: Data from a French health insurance database.

Joint Bone Spine 2021 03 20;88(2):105121. Epub 2021 Jan 20.

Université de Tours, 37000 Tours, France; Service de rhumatologie, CHRU de Tours, 37044 Tours cedex 9, France. Electronic address:

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http://dx.doi.org/10.1016/j.jbspin.2020.105121DOI Listing
March 2021

Increased high molecular weight adiponectin and lean mass during tocilizumab treatment in patients with rheumatoid arthritis: a 12-month multicentre study.

Arthritis Res Ther 2020 09 29;22(1):224. Epub 2020 Sep 29.

Laboratoire de Biochimie Médicale, UF de Biochimie Endocrinienne et Métabolique, CHU de Besançon; EA 3920 Marqueurs pronostiques et facteurs de régulation des pathologies cardiaques et vasculaires, Université de Bourgogne Franche Comté, Besançon, France.

Background: Patients with rheumatoid arthritis (RA) have an increased risk of cardiovascular (CV) disease. Adiponectin is involved in the metabolism of glucose and lipids with favourable effects on CV disease, especially its high molecular weight (HMW) isoform. Body composition changes are described in RA with various phenotypes including obesity. The effects of tocilizumab on serum adiponectin and body composition, especially fat mass, in patients with RA are not well determined.

Methods: Patients with active RA despite previous csDMARDs and/or bDMARDs and who were tocilizumab naïve were enrolled in a multicentre open-label study. They were evaluated at baseline, 1, 3, 6 and 12 months. Clinical assessment included body mass index (BMI) and anthropometric measurements. Lipid and metabolic parameters, serum adiponectin (total and HMW), leptin, resistin and ghrelin were measured at each time point. Body composition (lean mass, fat mass, % fat, fat in the android and gynoid regions) was evaluated at baseline, 6 and 12 months.

Results: One hundred seven patients were included. Both total and HMW adiponectin significantly increased from baseline to month 3, peaking respectively at month 3 (p = 0.0105) and month 1 (p < 0.0001), then declining progressively until month 6 to 12 and returning to baseline values. Significant elevation in HMW adiponectin persisted at month 6 (p = 0.001). BMI and waist circumference significantly increased at month 6 and 12, as well as lean mass at month 6 (p = 0.0097). Fat mass, percentage fat and android fat did not change over the study period. Lipid parameters (total cholesterol and LDL cholesterol) increased while glycaemia, insulin and HOMA-IR remained stable. Serum leptin, resistin and ghrelin did not change during follow-up.

Conclusions: Tocilizumab treatment in RA patients was associated with a significant increase in total and HMW adiponectin, especially at the onset of the treatment. Tocilizumab also induced a significant gain in lean mass, while fat mass did not change. These variations in adiponectin levels during tocilizumab treatment could have positive effects on the CV risk of RA patients. In addition, tocilizumab may have an anabolic impact on lean mass/skeletal muscle.

Trial Registration: The ADIPRAT study was a phase IV open-label multicentre study retrospectively registered on ClinicalTrials.gov under the number NCT02843789 (date of registration: July 26, 2016).
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http://dx.doi.org/10.1186/s13075-020-02297-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523335PMC
September 2020

2020 French recommendations on the management of septic arthritis in an adult native joint.

Joint Bone Spine 2020 Dec 3;87(6):538-547. Epub 2020 Aug 3.

Rheumatology Department, South Hospital, Rennes University Hospital, Rennes, France; Western France Reference Centre for Complex Bone and Joint Infections (CRIOGO), Rennes, France.

Septic arthritis (SA) in an adult native joint is a rare condition but a diagnostic emergency due to the morbidity and mortality and the functional risk related to structural damage. Current management varies and the recommendations available are dated. The French Rheumatology Society (SFR) Bone and Joint Infection Working Group, together with the French Language Infectious Diseases Society (SPILF) and the French Orthopaedic and Trauma Surgery Society (SOFCOT) have worked according to the HAS methodology to devise clinical practice recommendations to diagnose and treat SA in an adult native joint. One new focus is on the importance of microbiological documentation (blood cultures and joint aspiration) before starting antibiotic treatment, looking for differential diagnoses (microcrystal detection), the relevance of a joint ultrasound to guide aspiration, and the indication to perform a reference X-ray. A cardiac ultrasound is indicated only in cases of SA involving Staphylococcus aureus, oral streptococci, Streptococcus gallolyticus or Enterococcus faecalis, or when infective endocarditis is clinically suspected. Regarding treatment, we stress the importance of medical and surgical collaboration. Antibiotic therapies (drugs and durations) are presented in the form of didactic tables according to the main bacteria in question (staphylococci, streptococci and gram-negative rods). Probabilistic antibiotic therapy should only be used for patients with serious symptoms. Lastly, non-drug treatments such as joint drainage and early physical therapy are the subject of specific recommendations.
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http://dx.doi.org/10.1016/j.jbspin.2020.07.012DOI Listing
December 2020

Exposure-Response Relationship of Certolizumab Pegol and Achievement of Low Disease Activity and Remission in Patients With Rheumatoid Arthritis.

Clin Transl Sci 2020 07 1;13(4):743-751. Epub 2020 Apr 1.

Department of Medicine, University of California San Diego, La Jolla, California, USA.

Anti-tumor necrosis factor (anti-TNF) drugs are often prescribed for the treatment of rheumatoid arthritis (RA) and other immune-mediated inflammatory diseases. Although this treatment has been shown to be effective in many patients, up to 40% of patients do not achieve disease control. Drug concentration in plasma may be a factor affecting the observed variability in therapeutic response. In this study, we aimed to identify the plasma concentrations of the anti-TNF certolizumab pegol (CZP), associated with improvement in disease activity in patients with RA. Data were pooled from three randomized, controlled clinical trials with a combined total of 1,935 patients analyzed. Clinical outcomes of low disease activity (LDA) and remission were defined as Disease Activity Score in 28 joints with C-reactive protein (DAS28(CRP)) ≤ 2.7 and < 2.3, respectively. Quartile analysis results indicated that there may be an exposure-response relationship between CZP concentration and LDA/remission outcomes at weeks 12 and 24; the association was strongest for LDA (P < 0.05). Receiver operating characteristic (ROC) analysis showed that CZP concentrations ≥ 28.0 μg/ml at week 12, and ≥ 17.6 μg/ml at week 24, were associated with a greater likelihood of achieving LDA/remission outcomes. Although confirmatory studies are warranted to define the optimal CZP therapeutic range at weeks 12 and 24, these data indicate that CZP concentrations may be associated with improvement of disease activity.
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http://dx.doi.org/10.1111/cts.12760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359948PMC
July 2020

Methotrexate effect on immunogenicity and long-term maintenance of adalimumab in axial spondyloarthritis: a multicentric randomised trial.

RMD Open 2020 01 9;6(1). Epub 2020 Jan 9.

Department of Rheumatology, University of Tours, EA 7501 GICC, CHRU de Tours, Tours, France

Objectives: Anti-drug antibodies (ADA) are responsible for decreased adalimumab efficacy in axial spondyloarthritis (SpA). We aimed to evaluate the ability of methotrexate (MTX) to decrease adalimumab immunisation.

Methods: A total of 110 patients eligible to receive adalimumab 40 mg subcutaneously (s.c.) every other week were randomised (1:1 ratio) to receive, 2 weeks before adalimumab (W-2) and weekly, MTX 10 mg s.c. (MTX+) or not (MTX-). ADA detection and adalimumab serum concentration were assessed at weeks 4 (W4), 8 (W8), 12 (W12) and 26 (W26) after starting adalimumab (W0). The primary outcome was the proportion of patients with ADA at W26. Four years after the study completion, we retrospectively analysed adalimumab maintenance in relation with MTX co-treatment duration.

Results: We analysed data for 107 patients (MTX+; n=52; MTX-; n=55). ADA were detected at W26 in 39/107 (36.4%) patients: 13/52 (25%) in the MTX+ group and 26/55 (47.3%) in the MTX- group (p=0.03). Adalimumab concentration was significantly higher in the MTX+ than MTX- group at W4, W8, W12 and W26. The two groups did not differ in adverse events or efficacy. In the follow-up study, MTX co-treatment >W26 versus no MTX or ≤W26 was significantly associated with adalimumab long-term maintenance (p=0.04).

Conclusion: MTX reduces the immunogenicity and ameliorate the pharmacokinetics of adalimumab in axial SpA. A prolonged co-treatment of MTX>W26 seems to increase adalimumab long-term maintenance.
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http://dx.doi.org/10.1136/rmdopen-2019-001047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046954PMC
January 2020

[Rheumatology, the multitude of options].

Med Sci (Paris) 2019 Dec 6;35(12):1029-1033. Epub 2020 Jan 6.

Université de Tours, EA 7501, Groupe insuffisance cardiaque et cardiomyopathie (GICC), CHRU de Tours, Service de rhumatologie, Tours, France.

The number of therapeutic antibodies available in rheumatology increases every year, mainly indicated in chronic inflammatory rheumatisms and other immune-mediated inflammatory diseases. The choice between all these monoclonal antibodies depends on their specificities, patients and diseases characteristics. Until now, there is no reliable biomarker, predictive of response for specialized medicine purpose. Today, therapeutic drug monitoring and anti-drug antibodies testing can help to better adapt the dose of the drug and to help in the decision to switch to another biological drug according to the activity of the inflammatory disease.
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http://dx.doi.org/10.1051/medsci/2019204DOI Listing
December 2019

A Comparative Study of Fibromyalgia, Rheumatoid Arthritis, Spondyloarthritis, and Sjögren's Syndrome; Impact of the Disease on Quality of Life, Psychological Adjustment, and Use of Coping Strategies.

Pain Med 2021 Feb;22(2):372-381

Département de Psychologie, Université de Tours, EE 1901 Qualipsy 'Qualité de Vie et Santé Psychologique,' Tours Cedex, France.

Background: Fibromyalgia, rheumatoid arthritis, spondyloarthritis, and Sjögren's syndrome are chronic rheumatic diseases with very different clinical characteristics, but which share symptoms such as pain and fatigue. The aim of the study was to examine the impact of the disease on psychological adaptation in fibromyalgia compared with other rheumatic diseases (rheumatoid arthritis, spondyloarthritis, and Sjögren's syndrome).

Methods: In a multicenter study, 165 women with rheumatic diseases (48 with fibromyalgia, 47 with rheumatoid arthritis, 47 with spondyloarthritis, 23 with Sjögren's syndrome) completed the General Health Questionnaire-28 (emotional distress), Fatigue Severity Scale (fatigue), Fibromyalgia Impact Questionnaire (impact of the disease), Coping Strategies Questionnaire (coping), and Mini International Neuropsychiatric Interview (comorbidity with DSM IV axis-I disorders). We used the Kruskal-Wallis test, Mann-Whitney U test, and chi2 test to compare comorbid anxiety and depressive disorders and to compare the impact of the disease on patients' mental well-being and daily life and adjustment (coping strategies).

Results: Anxiety and depressive disorders were more common in fibromyalgia patients; they had higher scores on impact of the disease, physical symptoms, pain, and fatigue than rheumatoid arthritis patients and reported more fatigue than patients with spondyloarthritis. Overall, they used more maladaptive coping strategies (less use of distancing from pain than patients with rheumatoid arthritis and spondyloarthritis, less use of ignoring pain sensations, and more use of catastrophizing than those with rheumatoid arthritis). No differences were found between fibromyalgia and Sjögren's syndrome on impact and adjustment.

Conclusions: Compared with other rheumatic diseases, fibromyalgia has a greater impact on daily life; patients have more difficulty adjusting to the disease and generally use poorer strategies to cope with pain.
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http://dx.doi.org/10.1093/pm/pnz255DOI Listing
February 2021

Non-Linear Rituximab Pharmacokinetics and Complex Relationship between Rituximab Concentrations and Anti-Neutrophil Cytoplasmic Antibodies (ANCA) in ANCA-Associated Vasculitis: The RAVE Trial Revisited.

Clin Pharmacokinet 2020 04;59(4):519-530

Université de Tours, EA 7501 GICC, Tours, France.

Background And Objectives: Rituximab is approved in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and leads to a decrease of ANCA levels. The objectives of this study were to investigate the non-linear pharmacokinetics of rituximab and the relationship between its concentrations and ANCA levels in AAV patients.

Methods: Ninety-two AAV patients from the RAVE (Rituximab in ANCA-Associated Vasculitis) trial were assessed. Both ANCA anti-myeloperoxidase (MPO-ANCA) and anti-proteinase 3 (PR3-ANCA) levels were used as biomarkers. The pharmacokinetics of rituximab were described using a semi-mechanistic two-compartment model that included a latent target antigen turnover and allowed the estimation of specific target-mediated elimination in addition to its non-specific elimination of rituximab. The effect of rituximab on the ANCA level was described using a semi-mechanistic compartment model with a negative feedback (Friberg) model with no transit compartment. A population modeling approach was used.

Results: Our pharmacokinetic and pharmacokinetic-pharmacodynamic (PK-PD) models satisfactorily described both concentration-time and concentration-effect relationship data. The mean (inter-individual standard deviation) estimated non-specific clearance was 0.15 L/day (0.30%) and the target-mediated elimination rate constant was 2.4 × 10 nmol/day. The elimination half-lives for MPO-ANCA and PR3-ANCA were 24 and 18 days, respectively.

Conclusions: A non-linear target-mediated elimination of rituximab was detected in AAV patients. Our PK-PD model allowed quantification of the association between rituximab concentrations and ANCA levels. This decrease was deep but delayed, and more sustained in patients with MPO-ANCA than in those with PR3-ANCA. Our results suggest that repeating courses of rituximab might improve the clinical response to rituximab.
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http://dx.doi.org/10.1007/s40262-019-00826-5DOI Listing
April 2020

CD4+ count-dependent concentration-effect relationship of rituximab in rheumatoid arthritis.

Br J Clin Pharmacol 2019 12 22;85(12):2747-2758. Epub 2019 Nov 22.

EA 7501 GICC, Université de Tours, Tours, France.

Aims: Rituximab is approved in rheumatoid arthritis (RA). A substantial decrease in CD4+ count was observed in responders after a single cycle of treatment. This study aimed to describe and quantifying the influence of CD4+ count depletion on the concentration-response relationship of rituximab in RA patients.

Methods: In this retrospective monocentric observational study, 52 patients were assessed. Repeated measurements of rituximab concentrations (pharmacokinetics), CD4+ counts (biomarker) and disease activity score in 28 joints (DAS28, clinical response) were made. Rituximab pharmacokinetics was described using a 2-compartment model, and CD4+ cell counts and DAS28 measurements were described using indirect turnover and direct Emax pharmacokinetic-pharmacodynamic models, respectively. Delay between rituximab concentrations and responses was accounted for by including biophase compartments.

Results: Elimination half-life of rituximab was 18 days. The pharmacokinetic-pharmacodynamic model showed that DAS28 response to rituximab was partly associated with CD4+ cell depletion. At 6 months, a deeper DAS28 decrease was observed in patients when CD4+ cell count is decreased: median [interquartile range] of DAS28 was 3.7 [2.9-4.4] and 4.5 [3.7-5.3] in patients with and without CD4+ decrease, respectively.

Conclusions: This is the first study to quantify the relationship between rituximab concentrations, CD4+ count and DAS28 in RA patients. This model showed that approximately 75% of patients had CD4+ count decrease, and that the clinical improvement is 2-fold higher in patients with CD4+ cells decrease than in others.
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http://dx.doi.org/10.1111/bcp.14102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6955400PMC
December 2019

Adalimumab concentration-based tapering strategy: as good as the recommended dosage.

Ann Rheum Dis 2018 04 6;77(4):473-475. Epub 2018 Jan 6.

Department of Rheumatology, Health Research Institute (IdiPAZ), Hospital Universitario La Paz, Madrid, Spain.

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http://dx.doi.org/10.1136/annrheumdis-2017-212376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5890625PMC
April 2018

Model-Based Therapeutic Drug Monitoring of Infliximab Using a Single Serum Trough Concentration.

Clin Pharmacokinet 2018 09;57(9):1173-1184

Laboratory of Pharmacology-Toxicology, Université François-Rabelais de Tours, CNRS, UMR 7292, CHRU de Tours, 2 Boulevard Tonnellé, 37044, Tours Cedex, France.

Background And Objectives: The pharmacokinetics of infliximab are highly variable and influence clinical response in chronic inflammatory diseases. The goal of this study was to build a Bayesian model allowing predictions of upcoming infliximab concentrations and dosing regimen adjustment, using only one concentration measurement and information regarding the last infliximab infusion.

Methods: This retrospective study was based on data from 218 patients treated with infliximab in Tours University Hospital who were randomly assigned to learning (two-thirds) or validation (one-third) data subsets. One-compartment pharmacokinetic and time since last dose (TLD) models were built and compared using learning and validation subsets. From these models, Bayesian pharmacokinetic and TLD models using one concentration measurement (1C-PK and 1C-TLD) were designed. The predictive performances of the 1C-TLD model were tested on two external validation cohorts.

Results: Pharmacokinetic and TLD models described the data satisfactorily and provided accurate parameter estimations. Comparable predictions of infliximab concentrations were obtained from pharmacokinetic versus TLD models, as well as from Bayesian 1C-PK versus 1C-TLD models. The 1C-TLD model showed satisfactory prediction of future infliximab concentrations and provided satisfactory predictions of infliximab steady-state concentration for up to three upcoming visits after a blood sample.

Conclusions: Accurate individual concentration predictions can be obtained using a single infliximab concentration measurement and information regarding only the last infusion. The 1C-TLD model may help to optimize the dosing regimen of infliximab in routine therapeutic drug monitoring.
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http://dx.doi.org/10.1007/s40262-017-0621-6DOI Listing
September 2018

Practical recommendations for the use of therapeutic drug monitoring of biopharmaceuticals in inflammatory diseases.

Clin Pharmacol 2017 3;9:101-111. Epub 2017 Oct 3.

Institute for Research IdiPAZ, University Hospital La Paz, Madrid, Spain.

Biopharmaceuticals directed against tumor necrosis factor-alpha, integrins, interleukins, interferons and their receptors have become key agents for the management of inflammatory diseases in the fields of gastroenterology, rheumatology, dermatology and neurology. However, response to these treatments is far from optimal. Therapeutic failure has been attributed in part to inadequate serum concentrations of the drug and the formation of antidrug antibodies (ADA). Therapeutic drug monitoring (TDM) based on drug concentrations and ADA represents a pharmacologically sound tool for guiding dosage adjustments to optimize exposure. Although becoming standard practice in tertiary care centers, the widespread accessibility and recognition of TDM is hindered by several hurdles, including a lack of education of health care providers on TDM. In this paper, the Monitoring of monoclonal Antibodies Group in Europe (MAGE) provides an introduction on the fundamental principles of the concept of TDM, aiming to educate clinicians and assist them in the process of implementing TDM of anti-inflammatory biopharmaceuticals.
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http://dx.doi.org/10.2147/CPAA.S138414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5633318PMC
October 2017

Current Practices for Therapeutic Drug Monitoring of Biopharmaceuticals in Pediatrics.

Ther Drug Monit 2017 08;39(4):370-378

Departments of *Pediatric Rheumatology,†Pediatric Gastroenterology,‡Pediatric Dermatology, and§Immunology, University Hospital La Paz, Madrid, Spain;¶Laboratory for Therapeutic and Diagnostic Antibodies, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium; and‖Department of Rheumatology, Université François-Rabelais de Tours, Tours, France.

Biopharmaceuticals have recently emerged as effective treatments for refractory pediatric autoimmune conditions. Several reports have shown a relationship between drug concentration, antidrug antibodies, and clinical response in these patients, strongly suggesting the potential interest, usefulness, and reliability of therapeutic drug monitoring (TDM) in children. This article reviews the current state of research in juvenile idiopathic arthritis, pediatric inflammatory bowel disease, and pediatric psoriasis from a TDM point of view. There is a remarkable lack of evidence-based data in pediatric patients, which is reflected throughout the article. Most investigations of TDM are focused on research of tumor necrosis factor alpha antagonists in inflammatory bowel disease, albeit preliminary publications are emerging from pediatric rheumatologists and dermatologists. To date, immunogenicity has been a primary concern, particularly regarding infliximab and adalimumab therapy in children, as it may lead to a loss of therapeutic response. Preliminary investigations show that adjusting the dose according to blood drug concentrations improves disease outcomes by overcoming antidrug antibodies, suggesting a crucial role for TDM. Patients who receive other drugs, such as etanercept, abatacept, or tocilizumab, could benefit from TDM because dosage can be optimized by adjusting it to the minimum effective dose.
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http://dx.doi.org/10.1097/FTD.0000000000000423DOI Listing
August 2017

Therapeutic Drug Monitoring of Biopharmaceuticals May Benefit From Pharmacokinetic and Pharmacokinetic-Pharmacodynamic Modeling.

Ther Drug Monit 2017 08;39(4):322-326

*Université François-Rabelais de Tours, faculté de Médecine, France;†CNRS UMR 7292 GICC, Tours, France;‡Amsterdam Rheumatology Immunology Center, Reade;§Sanquin Research, Department of Immunopathology, Amsterdam, the Netherlands; and¶Laboratory for Therapeutic and Diagnostic Antibodies, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium.

Biopharmaceuticals, especially monoclonal antibodies, have been increasingly used to treat several chronic inflammatory diseases. Due to the complexity of their pharmacokinetics and concentration-effect relationship, therapeutic drug monitoring (TDM) has been used to optimize their dosing regimen. Up to date, several decisional algorithms have been developed to provide tools for monoclonal antibodies' therapeutic drug monitoring. However, these algorithms are unable to determine the individual optimal dosing scheme. The aim of this article is to deal with population pharmacokinetic (PK) and pharmacokinetic-pharmacodynamic (PK-PD) modeling. Allowing the quantification of the variability of the dose-concentration-response relationship, population pharmacokinetic-pharmacodynamic modeling may be a valuable tool to determine the optimal dosing scheme. Based on population modeling, Bayesian estimators may be developed to optimize dosing schemes for each patient using limited sampling strategies. These estimators may allow accurate dosing adjustment for each patient individually.
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http://dx.doi.org/10.1097/FTD.0000000000000389DOI Listing
August 2017

Current Practice for Therapeutic Drug Monitoring of Biopharmaceuticals in Rheumatoid Arthritis.

Ther Drug Monit 2017 08;39(4):364-369

*Department of Rheumatology and Laboratory of Pharmacology-Toxicology, Université François-Rabelais de Tours, Tours, France; and †Rheumatology Department and Health Research Institute (Idipaz), Hospital Universitario de La Paz, Madrid, Spain.

The treatment of rheumatoid arthritis (RA) has largely improved in the biopharmaceutical era. These compounds, primarily tumor necrosis factor (TNF) inhibitors, are effective, but some patients may show poor response, sometimes because of the presence of antidrug antibodies (ADAs). In some instances, clinicians may increase or taper the dose depending on the clinical response. Besides the current clinical-based practice, a tailored strategy based on drug monitoring has emerged as a way to improve the use of these drugs. However, the relevance of this therapeutic drug monitoring (TDM) of biopharmaceuticals in RA is still unknown. In this literature review, we examine the most relevant articles dealing with the concentration-response relationship, ADA detection and pharmacokinetics in RA patients receiving biopharmaceuticals. A concentration-response relationship was clearly established for TNF inhibitors. Moreover, ADA positivity was associated with low drug concentrations, poor clinical outcome, and reduced drug survival for TNF-inhibitor monoclonal antibodies. Concomitant use of disease-modifying antirheumatic drugs, especially methotrexate, is associated with good clinical outcome, increased drug concentrations, and reduced immunogenicity. Strategies based on TDM of TNF inhibitors seem promising for RA, but randomized controlled trials are required to support this. A concentration-response relationship may exist with tocilizumab, and immunogenicity seems rare. Finally, the relevance of TDM for RA patients receiving rituximab and abatacept remains unclear.
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http://dx.doi.org/10.1097/FTD.0000000000000421DOI Listing
August 2017

High incidence of vertebral osteoporotic fracture within the first year after liver transplantation.

Clin Exp Rheumatol 2017 Nov-Dec;35(6):913-918. Epub 2017 Apr 29.

Department of Rheumatology, CHRU de Tours; and Université François-Rabelais de Tours, France.

Objectives: Bone loss is a complication for patients with liver diseases and after transplantation, which results in increased fracture risk. The aim of this study was to determine the incidence of osteoporotic vertebral fractures following liver transplantation.

Methods: We performed a prospective study of patients who were awaiting liver transplantation. Patients were seen at baseline (visit 1) and one year after transplantation (visit 2). At each visit, risk factors of osteoporosis were collected, biochemical tests were performed and bone mineral density with Vertebral Fracture Assessment was assessed.

Results: One hundred and fifteen patients were in the pre-transplant group and 33 patients were in the post-transplant group. In the pre-transplant group, the prevalence of vertebral fractures was 23.5%. The prevalence of densitometric osteoporosis was higher at the lumbar spine than at the femoral neck. In the post-transplant group, the prevalence of vertebral fractures at visit 1 and visit 2 was 33.3% and 60.6% respectively with an incidence of 23.1 fractures per 100 patient-years.

Conclusions: Bone fragility was highly prevalent before transplantation and worsens one year after transplantation. Bone status should be evaluated in patients with liver diseases before transplantation to identify patients at high risk of fracture and help clinicians to prescribe appropriate preventive care.
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March 2018

Rationale for Therapeutic Drug Monitoring of Biopharmaceuticals in Inflammatory Diseases.

Ther Drug Monit 2017 08;39(4):339-343

*Université François-Rabelais de Tours, CNRS UMR 7292, Tours, France; †Unit of Pharmacology-Toxicology, University Hospital, Tours, France; ‡Neurologia 2, Centro Riferimento Regionale Sclerosi Multipla (CReSM), Orbassano, Turin, Italy; §Neuroscience Institute Cavalieri Ottolenghi (NICO), San Luigi Hospital, Orbassano, Turin, Italy; ¶Department of Clinical Pharmacology, Tours University Hospital, Tours, France; ∥Unit of Immunology, La Paz University Hospital, Madrid, Spain; and ††Department of Rheumatology, Tours University Hospital, Tours, France.

Biopharmaceuticals bring together a number of specific characteristics as compared with other drugs. However, as it is done for most drugs, an individual adjustment of their dose may be necessary. Similar to "chemical" drugs, biopharmaceuticals used in immunoinflammatory diseases have a rather narrow therapeutic range, lack good early clinical or biological marker of response, have variable pharmacokinetics, and their serum concentrations are most often related with response. Monoclonal antibodies have additional specific sources of pharmacokinetic variability. Low concentrations may increase the risks of immunization, plasmapheresis may increase their elimination, and subcutaneous formulations may be associated with decreased adherence. For all these reasons, pharmacokinetic therapeutic drug monitoring may be useful. However, few randomized controlled therapeutic drug monitoring studies have been published. For monoclonal antibodies, a precise definition of the therapeutic concentrations is challenging because of the interindividual variability in their concentration-effect relationship.
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http://dx.doi.org/10.1097/FTD.0000000000000410DOI Listing
August 2017

International and multidisciplinary expert recommendations for the use of biologics in systemic lupus erythematosus.

Autoimmun Rev 2017 Jun 18;16(6):650-657. Epub 2017 Apr 18.

Rheumatology Department, Strasbourg University Hospital, Strasbourg, France; IBMC, CNRS, UPR3572, Strasbourg, France; Université de Strasbourg, Strasbourg, France. Electronic address:

Background/purpose: Despite conventional immunosuppressants, active and steroid-dependent systemic lupus erythematosus (SLE) represents a therapeutic challenge. Only one biologic, belimumab, has been approved, but other biologics are sometimes used off-label. Given the lack of evidence-based data in some clinical situations encountered in real life, we developed expert recommendations for the use of biologics for SLE.

Methods: The recommendations were developed by a formal consensus method. This method aims to formalize the degree of agreement among experts by identifying, through iterative ratings with feedback, the points on which experts agree, disagree or are undecided. Hence, the recommendations are based on the agreed-upon points. We gathered the opinion of 59 French-speaking SLE experts from 3 clinical networks dedicated to systemic autoimmune diseases (FLEUR, IMIDIATE, FAI2R) from Algeria, Belgium, France, Italy, Morocco, Switzerland and Tunisia. Represented medical specialities were internal medicine (49%), rheumatology (34%), nephrology (7%), dermatology (5%), pediatrics (3%) and cardiology (2%). Two methodologists and 3 strictly independent SLE expert groups contributed to developing these recommendations: a steering group (SG) (n=9), an evaluation group (EG) (n=28) and a reading group (RG) (n=22). Preliminary recommendations were drafted by the SG, then proposed to the EG. Each EG member rated the degree of agreement from 1 to 9 (1: lowest; 9: strongest) for each recommendation. After 2 rating rounds, the SG submitted a new version of the recommendations to the RG. With comments from the RG, the SG finalised the recommendations.

Results: A total of 17 final recommendations were formulated by the SG, considering all agreement scores and comments by the EG and RG members and the two methodologists. These recommendations define the subset of patients who require a biologic; the type of biologics to use (belimumab, rituximab, etc.) depending on the organ involvement and associated co-treatments; what information should be given to patients; and how to evaluate treatment efficacy and when to consider discontinuation.

Conclusion: Overall, 17 recommendations for the good use of biologics in SLE were formulated by a large panel of SLE experts to provide guidance for clinicians in daily practice. These recommendations will be regularly updated according to the results of new randomized trials and increasing real life experience.
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http://dx.doi.org/10.1016/j.autrev.2017.04.011DOI Listing
June 2017

Current Practice for Therapeutic Drug Monitoring of Biopharmaceuticals in Spondyloarthritis.

Ther Drug Monit 2017 08;39(4):360-363

*Rheumatology Department and Pharmacology-Toxicology Laboratory, Université François-Rabelais de Tours, CNRS, UMR 7292, Tours, France; and †Rheumatology Department and Health Research Institute (Idipaz), Hospital Universitario de La Paz, Madrid, Spain.

Treatment of spondyloarthritis (SpA) has greatly improved in the biopharmaceutical era. These compounds, primarily tumor necrosis factor inhibitors, are effective, but some patients may show poor response, sometimes due to the presence of antidrug antibodies (ADAs). In some instances, clinicians may increase or taper the dose, depending on the clinical response. Besides the current clinical practice, a tailored strategy based on drug monitoring is emerging as a way to improve the use of these drugs. However, the relevance of this therapeutic drug monitoring of biopharmaceuticals for SpA is still unknown. In this literature review, we examined the most relevant articles dealing with the concentration-response relation, ADA detection, and pharmacokinetics in SpA treated with biopharmaceuticals. ADAs were associated with low or undetectable concentration of monoclonal antibodies. The relation between drug concentration and clinical response in SpA is debated, some studies showing an association and others not. Therefore, therapeutic drug monitoring of biopharmaceuticals for SpA requires a better understanding of the association among the pharmacokinetics, pharmacodynamics, and immunogenicity of these drugs.
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http://dx.doi.org/10.1097/FTD.0000000000000400DOI Listing
August 2017

Biopharmaceuticals: Reference Products and Biosimilars to Treat Inflammatory Diseases.

Ther Drug Monit 2017 08;39(4):308-315

*Department of Pharmaceutical and Pharmacological Sciences, Laboratory for Therapeutic and Diagnostic Antibodies, KU Leuven, Leuven, Belgium; †Division of Neurology and Multiple Sclerosis Regional Center, AOU San Luigi, Orbassano, Turin, Italy; and Departments of ‡Rheumatology and §Pharmacovigilance, Université François-Rabelais de Tours, Tours, France.

Biopharmaceuticals are primarily therapeutic proteins developed to perform specific functions by acting on the disease pathophysiology. Compared with low-molecular chemically synthesized drugs, production of biopharmaceuticals is much more complex and routes of administration and pharmacokinetics differ. Biopharmaceuticals are blockbusters in the treatment of inflammatory diseases, such as psoriasis, multiple sclerosis, rheumatic diseases, and inflammatory bowel diseases, and the introduction of these drugs has revolutionized treatment. Disadvantages include their high costs and the fact that they can evoke antidrug antibodies leading to decreased efficacy. Treatment can be optimized through the development of dosing algorithms and cost can be reduced by biosimilars, after a comparable biological activity, safety, and efficacy have been demonstrated.
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http://dx.doi.org/10.1097/FTD.0000000000000385DOI Listing
August 2017

Antigenic burden and serum IgG concentrations influence rituximab pharmacokinetics in rheumatoid arthritis patients.

Br J Clin Pharmacol 2017 08 12;83(8):1773-1781. Epub 2017 Apr 12.

CNRS, GICC UMR 7292, Université François-Rabelais de Tours, Tours, France.

Aims: Rituximab is a monoclonal antibody directed against CD20, which is approved in rheumatoid arthritis (RA). This study aimed at assessing the influence of CD19+ cell counts as target-antigen amount, and of immunoglobulin G (IgG) serum concentrations on rituximab pharmacokinetics in RA patients.

Methods: In a cohort of 64 RA patients who had received repetitive courses of rituximab, the influence of CD19+ cell count, IgG serum concentration, body surface area, sex and disease activity score in 28 joints on rituximab pharmacokinetic parameters was assessed using a population pharmacokinetic analysis.

Results: A two-compartment model, with first-order distribution and elimination best described the data. The volume of distribution of central compartment and clearance of rituximab were estimated at 4.7 l and 0.56 l day , respectively. Distribution and elimination half-lives were 0.9 days and 17.3 days, respectively. As expected, the central volume of distribution increased with body surface area (P = 0.012) and was higher in male than in female (P = 0.004). We found that the elimination rate constant (k ) increased with CD19+ count (P = 0.00022) and IgG concentration (P = 7.4 × 10 ), and that k decreased with time (P = 0.00015), partly explained by a change in target-antigen amount.

Conclusions: The association between CD19+ count and k may be explained by target-mediated drug disposition, while the association between IgG serum concentration and k may be explained by a saturation of the neonatal Fc receptor at high IgG concentrations, resulting in decreased recycling of rituximab.
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http://dx.doi.org/10.1111/bcp.13270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5510084PMC
August 2017

Brief Report: Relationship Between Serum Infliximab Concentrations and Risk of Infections in Patients Treated for Spondyloarthritis.

Arthritis Rheumatol 2017 01 28;69(1):108-113. Epub 2016 Nov 28.

Université François-Rabelais, CNRS, Genetics, Immunotherapy, Chemistry and Cancer UMR 7292 and CHRU de Tours, Service de Rhumatologie, Hôpital Trousseau, Tours, France.

Objective: Tumor necrosis factor inhibitors are effective in reducing inflammation in rheumatic diseases but increase the risk of infections. This study was undertaken to investigate the relationship between the trough serum concentration of infliximab (IFX) and the risk of a first infection episode.

Methods: We retrospectively included all patients who started IFX treatment for an approved indication in our department. Patients were followed up based on recommended IFX infusion schedules. We studied the relationship between the occurrence of a first infection episode requiring hospitalization, anti-infection treatment, or IFX infusion deferral, and the last trough IFX concentration and mean of the last 3 trough IFX concentrations measured before the infection episode.

Results: Of the 201 patients included in the analysis, 173 had spondyloarthritis (SpA). The SpA patients had a mean ± SD age of 46 ± 12 years and a disease duration of 6.2 ± 6.1 years. During a median follow-up of 1.1 year, 87 SpA patients had at least 1 infection episode. Using Cox models, we found that the probability of survival without infection was significantly higher in patients with a mean of the last 3 trough IFX concentrations lower than the median (<11.3 mg/liter) than in patients with a mean concentration greater than the median (P = 0.048 by log-rank test). Glucocorticoid use and IFX concentration were significantly associated with the risk of a first infection episode in the multivariable analysis (P = 0.004 for both). The risk of infection episode was significantly increased in the highest quartile of the mean of the last 3 trough IFX concentrations (>20.3 mg/liter) (hazard ratio 2.65 [95% confidence interval 1.14-6.14], P = 0.023).

Conclusion: Our findings indicate that a high IFX concentration is correlated with a higher risk of a first infection episode, but these findings need to be replicated in further prospective studies.
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http://dx.doi.org/10.1002/art.39841DOI Listing
January 2017

Impact of Anti-Inflammatory Drugs on Pyogenic Vertebral Osteomyelitis: A Prospective Cohort Study.

Int J Rheumatol 2016 19;2016:9345467. Epub 2016 Oct 19.

Infectious Diseases Unit, University Hospital of Bretonneau, Denis Diderot University, Tours, France.

. Pyogenic vertebral osteomyelitis (PVO) are frequently misdiagnosed and patients often receive anti-inflammatory drugs for their back pain. We studied the impact of these medications. . We performed a prospective study enrolling patients with PVO and categorized them depending on their drugs intake. Then, we compared diagnosis delay, clinical presentation at hospitalization, incidence of complications, and cure rate. . In total, 79 patients were included. Multivariate analysis found no correlation between anti-inflammatory drug intake and diagnosis delay, clinical presentation, complications, or outcome. . Anti-inflammatory drugs intake does not affect diagnostic delay, severity at diagnosis, or complications of PVO.
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http://dx.doi.org/10.1155/2016/9345467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5090101PMC
October 2016

Repeated decrease of CD4+ T-cell counts in patients with rheumatoid arthritis over multiple cycles of rituximab treatment.

Arthritis Res Ther 2016 10 28;18(1):253. Epub 2016 Oct 28.

Université François-Rabelais de Tours, CNRS, UMR 7292, Tours, France.

Background: Significant peripheral blood CD4+ T-cell depletion has been observed after a first cycle of rituximab, a monoclonal antibody directed against the CD20 antigen, which is currently used in rheumatoid arthritis. Of note, an absence of CD4+ T-cell decrease has been observed in non-responders. Herein, we describe CD4+ T-cell changes over repeated cycles of rituximab and their relationship with clinical outcomes.

Methods: Patients with rheumatoid arthritis who started rituximab between July 2007 and July 2013 were analyzed up to November 2014. Lymphocyte phenotyping and clinical assessments were performed before, and 3 and 6 months after each cycle. Lymphocytes counts and disease activity were compared at each time point, using nonparametric tests.

Results: Patients received up to seven cycles of treatment during the study period. Mean CD4+ T-cell counts were above the upper limit of the reference range before each rituximab infusion and repeatedly reached the reference range at 6 months (and/or 3 months) post infusion. CD4+ T cells decreased concurrently with disease activity score.

Conclusions: CD4+ T-cell counts could be a relevant biomarker of response to rituximab in rheumatoid arthritis and could be considered in making decisions about the timing of retreatment.
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http://dx.doi.org/10.1186/s13075-016-1152-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5086062PMC
October 2016

The underlying inflammatory chronic disease influences infliximab pharmacokinetics.

MAbs 2016 10 9;8(7):1407-1416. Epub 2016 Aug 9.

a Université François Rabelais de Tours, CNRS, UMR, "Genetics, Immunotherapy, Chemistry and Cancer ," Tours , France.

Infliximab is an anti-tumor necrosis factor monoclonal antibody approved in chronic inflammatory diseases such as rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), Crohn's disease (CD) and ulcerative colitis (UC). Infliximab pharmacokinetics is variable between patients, but influence of the underlying disease was never assessed. This study aimed at assessing this influence using a cohort of patients monitored in a single center and with the same assay. Infliximab trough concentrations were determined on samples collected between weeks 0 and 22 after treatment initiation in 218 patients treated for RA, PsA, AS, CD or UC. Infliximab pharmacokinetics was analyzed by a one-compartment population model with first-order elimination rate constant. In AS patients, volume of distribution (V) and elimination clearance (CL) were 5.4 L and 0.24 L/day, respectively. In CD and UC patients, V was 49% and 52% higher than in AS, respectively, and CL was 47% and 60% higher than in AS, respectively. In RA patients, CL was 49% higher than in AS patients. Simulations showed that without methotrexate, a 3 mg/kg dosing regimen would lead only 16% of RA patients to reach the target concentration (2.5 mg/L) at week 22, whereas target concentrations would be reached in approximately half of RA patients cotreated with methotrexate, as well as half of CD (3.5 mg/L) and UC (3.7 mg/L) patients. The suboptimality of approved dosing regimens supports the development of dosing optimization based on concentration measurements.
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http://dx.doi.org/10.1080/19420862.2016.1216741DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5058621PMC
October 2016

Comparison of the Big Five personality traits in fibromyalgia and other rheumatic diseases.

Joint Bone Spine 2017 Mar 3;84(2):203-207. Epub 2016 Jun 3.

EA 2114 « Psychologie des âges de la vie et adaptation », département de psychologie, université François-Rabelais de Tours, 3, rue des Tanneurs, BP 4103, 37041 Tours cedex 1, France; Clinique psychiatrique universitaire, CHRU de Tours, 37044 Tours cedex 09, France. Electronic address:

Introduction: The personality of patients with fibromyalgia is still under debate. Some studies found high neuroticism associated with low extraversion, while others found that these traits do not differ from the normal population. Personality factors intervene in the emotional regulation and modulation of pain. The aim of the study was to determine the personality traits of patients with fibromyalgia compared to other rheumatic diseases.

Methods: In a multicentric study, women with fibromyalgia, rheumatoid arthritis, spondyloarthritis or Sjögren's syndrome were asked to complete the Big Five Inventory, which encompasses five main personality dimensions, namely (1) extraversion vs. introversion, (2) agreeableness vs. antagonism, (3) conscientiousness vs. impulsivity, (4) neuroticism vs. emotional stability, and (5) openness vs. closed-mindedness. Variance analysis (Student's t-test and ANOVA with post-hoc comparisons or Bonferroni correction) was performed. We also conducted hierarchical and non-hierarchical cluster analyses.

Results And Discussion: Participants were 163 women with fibromyalgia (n=48), rheumatoid arthritis (n=46), spondyloarthritis (n=46) and Sjögren's syndrome (n=23). The mean age was 47.18years (±10.81years, range 21 to 65). Patients with fibromyalgia had higher scores on agreeableness (F(3, 159)=3.39, P<0.05), neuroticism (F(3, 159)=3.79, P<0.05) and openness (F(3, 159)=4.32, P<0.01) than those with other rheumatic diseases. This study highlights the specificity of personality in fibromyalgia. It also underlines the protective role of personality traits: in the fibromyalgia group, high neuroticism and low conscientiousness (high impulsivity) were associated with a high level of chronic pain.
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http://dx.doi.org/10.1016/j.jbspin.2016.03.006DOI Listing
March 2017

IgG1 Allotypes Influence the Pharmacokinetics of Therapeutic Monoclonal Antibodies through FcRn Binding.

J Immunol 2016 Jan 18;196(2):607-13. Epub 2015 Dec 18.

Université François Rabelais de Tours, CNRS UMR7292, Tours F-37032, France; Laboratoire d'Immunologie, Centre Hospitalier Régional Universitaire de Tours, Tours F-37032, France; and

Because IgG1 allotypes might have different half-lives, their influence on infliximab (G1m17,1 allotype) pharmacokinetics was investigated in a group of spondyloarthritis patients. Infliximab was found to have a shorter half-life in patients homozygous for the G1m17,1 allotypes than in those carrying the G1m3 with no G1m1 (G1m3,-1) allotype. Because the neonatal FcR (FcRn) is involved in the pharmacokinetics of mAbs, the interaction of different IgG1 allotypes with FcRn was examined using cellular assays and surface plasmon resonance. G1m17,1 mAbs, such as infliximab and rituximab, were shown to bind more efficiently to FcRn and to be transcytosed better than the G1m3,-1 mAb cetuximab, which explains why infliximab is a better competitor for endogenous IgG1 in G1m3,-1 allotype-bearing patients. A set of four allotype variants of adalimumab (G1m17,1; G1m17,-1; G1m3,1; and G1m3,-1) was also tested for its binding to FcRn, revealing that the G1m3,1 variant, not present in commercial mAbs, binds more efficiently to FcRn and is transcytosed better than the other three variants, all of which are found in therapeutic mAbs.
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http://dx.doi.org/10.4049/jimmunol.1501780DOI Listing
January 2016

Clinical Pharmacokinetics and Pharmacodynamics of Monoclonal Antibodies Approved to Treat Rheumatoid Arthritis.

Clin Pharmacokinet 2015 Nov;54(11):1107-23

Laboratory of Pharmacology-Toxicology, Université François-Rabelais de Tours, CNRS, GICC UMR 7292, CHRU de Tours, 2 Boulevard Tonnellé, 37044, Tours Cedex, France.

Monoclonal antibodies (mAbs) are increasingly used to treat rheumatoid arthritis (RA). At present, anti-tumor necrosis factor-α drugs (infliximab, adalimumab, certolizumab pegol, and golimumab), rituximab, and tocilizumab are approved for RA treatment. This review focuses on the pharmacokinetics and pharmacodynamics of mAbs approved in RA. Being large proteins, mAbs exhibit complex pharmacokinetic and pharmacodynamic properties. In particular, owing to the interactions of mAbs with their antigenic targets, the pharmacokinetics of mAbs depends on target turnover and exhibits non-specific (linear) and target-mediated (often nonlinear) clearances. Their volume of distribution is low (3-4 L) and their elimination half-life usually ranges from 2 to 3 weeks. The inter-individual pharmacokinetic variability of mAbs is usually large and is partly explained by differences in antigenic burden or by anti-drug antibodies, which accelerate mAb elimination. The inter-individual variability of clinical response is large and influenced by the pharmacokinetics. The analysis of mAbs concentration-effect relationship relies more and more often on pharmacokinetic-pharmacodynamic modeling; these models being suitable for dosing optimization. Even if adverse effects of mAbs used in RA are well known, the relationship between mAb concentration and adverse effects is poorly documented, especially for anti-tumor necrosis factor-α mAbs. Overall, RA patients treated with mAbs should benefit from individualized dosing strategies. Because of the complexity of their pharmacokinetics and mechanisms of action, the current dosing strategy of mAbs is not based on sound knowledge. New studies are needed to assess individual dosing regimen, adjusted notably to disease activity.
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http://dx.doi.org/10.1007/s40262-015-0296-9DOI Listing
November 2015

Development and validation of an enzyme-linked immunosorbent assay to measure adalimumab concentration.

Bioanalysis 2015 ;7(10):1253-60

1Université François Rabelais de Tours, CNRS UMR 7292, Tours, France.

Background: Adalimumab is a therapeutic antibody used for treating inflammatory diseases. To understand interindividual PK variability, there is a need to develop and validate an assay to measure serum adalimumab concentrations.

Methods: An ELISA was developed on microtiter plates coated with TNF-α. Seven nonzero adalimumab standards ranging from 0.05 to 50 mg/l and three quality controls (0.2, 2.5 and 7 mg/l) were tested for their intra and interday precision on six occasions.

Results: The LOD, LLOQ and ULOQ of the assay were 0.022, 0.073 and 9 mg/l, respectively.

Conclusion: This method is accurate, reproducible and may be useful for PK studies and for therapeutic drug monitoring of adalimumab.
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http://dx.doi.org/10.4155/bio.15.30DOI Listing
February 2016

F-18 fluorodeoxyglucose positron emission tomography can detect early response to adalimumab, a tumor necrosis factor-α antagonist, in rheumatoid arthritis: A prospective pilot study.

Joint Bone Spine 2015 Oct 13;82(5):381-3. Epub 2015 Mar 13.

Université François-Rabelais de Tours, 3, rue des Tanneurs, 37041 Tours cedex 1, France; CNRS UMR 7292, 2, boulevard Tonnellé, 37044 Tours cedex 9, France; Service de rhumatologie, CHRU de Tours, avenue de la République, 37044 Tours cedex 9, France. Electronic address:

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http://dx.doi.org/10.1016/j.jbspin.2015.01.014DOI Listing
October 2015