Is interleukin-1 a good target for therapeutic intervention in intervertebral disc degeneration: lessons from the osteoarthritic experience

IL-1 plays a key role in disc degeneration and could be a valid target for inhibiting this process. IL-1 receptor antagonist (IL-1ra) might be a good candidate to inhibit IL-1 activity. However, many questions need to be addressed before contemplating therapy in humans. IL-1 blockade is also a great challenge in osteoarthritis and results from animal models suggest that IL-1ra may have beneficial effects. The clinical benefit of a local injection of IL-1ra in knee osteoarthritis may be limited by the antagonist's short half-life. Further studies with longer-lasting antagonists are needed to explore this new therapeutic approach

Therapeutic drug monitoring of monoclonal antibodies in chronic inflammatory diseases: A snapshot of laboratories and applications across Europe

The European Cooperation in Science and Technology (COST) action ENOTTA (The European Network on Optimising Treatment with Therapeutic Antibodies in chronic inflammatory diseases) was launched in 2022. To pave the way for harmonization of analytical methods for quantitation of serum levels of therapeutic antibodies in research and clinical settings, ENOTTA recently performed an online survey mapping laboratories in the field. The survey, which contained 30 questions surrounding therapeutic drug monitoring of relevant drugs and anti-drug antibodies, was distributed via the ENOTTA and European Federation of Clinical Chemistry and Laboratory networks. Among 63 respondents across Europe, 45 reported analytical activity, with a range of utilized methods. Future engagement of as many sites as possible will enable comparison of methodologies and facilitate progress in the field

Infliximab in ankylosing spondylitis: alone or in combination with methotrexate? A pharmacokinetic comparative study.

International audienceINTRODUCTION: Methotrexate (MTX) has been shown to modify infliximab pharmacokinetics in rheumatoid arthritis. However, its combination with infliximab in the treatment of ankylosing spondylitis (AS) is not recommended. The objective of this study was to examine the influence of MTX on infliximab exposure in patients with AS. METHODS: Patients with AS patients who had predominantly axial symptoms were randomised to receive infliximab alone (infusions of 5 mg/kg at weeks 0, 2, 6, 12 and 18) or infliximab combined with MTX (10 mg/week). Infliximab concentrations were measured before and 2 hours after each infusion and at 1, 3, 4, 5, 8, 10, 14 and 18 weeks. We estimated individual cumulative area under the concentration versus time curves (AUC) for infliximab concentration between baseline and week 18 (AUC(0-18)). Clinical and laboratory evaluations were performed at each visit. The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score was the primary end point for clinical response. RESULTS: Twenty-six patients were included (infliximab group: n = 12, infliximab + MTX group: n = 14), and 507 serum samples were available for measurement of infliximab concentration. The two groups did not differ with regard to AUC(0-18) or evolution of BASDAI scores and biomarkers of inflammation. CONCLUSIONS: The combination of MTX and infliximab does not increase the exposure to infliximab over infliximab alone in patients with AS. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00507403

Antibodies toward infliximab are associated with low infliximab concentration at treatment initiation and poor infliximab maintenance in rheumatic diseases

International audienceINTRODUCTION: A proportion of patients receiving infliximab have antibodies toward infliximab (ATI), which are associated with increased risk of infusion reaction and reduced response to treatment. We studied the association of infliximab concentration at treatment initiation and development of ATI as well as the association of the presence of ATI and maintenance of infliximab. METHODS: All patients with rheumatoid arthritis (RA) or spondyloarthritis (SpA) receiving infliximab beginning in December 2005 were retrospectively followed until January 2009 or until infliximab discontinuation. Trough serum infliximab and ATI concentrations were measured at each visit. The patients were separated into two groups: ATI(pos) if ATI were detected at least once during the follow-up period and ATI(neg) otherwise. Repeated measures analysis of variance was used to study the association of infliximab concentration at treatment initiation and the development of ATI. Maintenance of infliximab in the two groups was studied by using Kaplan-Meier curves. RESULTS: We included 108 patients: 17 with RA and 91 with SpA. ATI were detected in 21 patients (19%). The median time to ATI detection after initiation of infliximab was 3.7 months (1.7 to 26.0 months). For both RA and SpA patients, trough infliximab concentration during the initiation period was significantly lower for ATI(pos) than ATI(neg) patients. RA patients showed maintenance of infliximab at a median of 19.5 months (5.0 to 31.0 months) and 12.0 months (2.0 to 24.0 months) for ATI(neg) and ATI(pos) groups, respectively (P = 0.08). SpA patients showed infliximab maintenance at a median of 16.0 months (3.0 to 34.0 months) and 9.5 months (3.0 to 39.0 months) for ATI(neg) and ATI(pos) groups, respectively (P = 0.20). Among SpA patients, those who were being treated concomitantly with methotrexate had a lower risk of developing ATI than patients not taking methotrexate (0 of 14 patients (0%) vs. 25 of 77 patients (32%); P = 0.03). CONCLUSIONS: High concentrations of infliximab during treatment initiation reduce the development of ATI, and the absence of ATI may be associated with prolonged maintenance of infliximab. Thus, trough serum infliximab concentration should be monitored early in patients with rheumatic diseases

European Network on Optimising Treatment with Therapeutic Antibodies in chronic inflammatory diseases (ENOTTA)

Although treatment of chronic inflammatory diseases has been revolutionised with the introduction of targeted therapies with therapeutic antibodies, a large portion of patients do not respond to treatment or they lose response over time. This is mainly attributed to suboptimal dosing, immunogenicity and interpatient variability in pharmacokinetics. To overcome the problems of suboptimal treatment, researchers have started to focus on individualised treatment optimisation strategies based on development of patient stratification tools and therapeutic drug monitoring (TDM)-guided dose adaptations based on serum drug concentrations. A substantial improvement in patient care will be realised by implementing individualised (TDM-guided) dosing schemes of therapeutic antibodies in daily clinical practice for treatment of chronic inflammatory diseases, which will ultimately result in a more cost-effective use of these expensive drugs (“the right drug at the right dose for the right patient”). However, expertise on individualised (TDM-guided) treatment optimisation is highly fragmented in Europe, and largely limited to a few pioneering centres. Transferring knowledge and techniques to other (peripheral) centres is challenging, especially due to the need for inhouse expertise and a lack of standardisation in TDM assays. Therefore, this Action will create an interdisciplinary, pan-European Network in order to defragment and structure the scientific research in this field and to facilitate the implementation of individualised (TDM-guided) cost-effective dose optimisation of therapeutic antibodies in daily clinical practice for treatment of chronic inflammatory diseases

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

Objective. 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. Methods. 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. Results. In total, 79 patients were included. Multivariate analysis found no correlation between anti-inflammatory drug intake and diagnosis delay, clinical presentation, complications, or outcome. Conclusion. Anti-inflammatory drugs intake does not affect diagnostic delay, severity at diagnosis, or complications of PVO

Variability of response to anti-TNF alpha in inflammatory rheumatisms : contribution of biological markers and imaging

Il existe une variabilité interindividuelle de la relation dose - effet chez les patients atteints de maladies inflammatoires rhumatismales traités par les inhibiteurs du Tumor Necrosis Factor-alpha (TNF-a). Dans la première partie de cette thèse, la physiopathologie du TNF-a dans le processus inflammatoire est présentée. Ensuite, le travail se concentre sur la relation concentration-effet en utilisant la modélisation pharmacocinétique-pharmacodynamique (PK-PD) modèles. À la fin, après une discussion sur les biomarqueurs d'imagerie, la thèse traite de l'utilité d'une nouvelle technique permettant de détecter la réponse précoce au traitement, à savoir la tomographie par émission de positons (TEP). En résumé, ce travail décrit la relation PK-PD dans les maladies inflammatoires rhumatismales traitées par anticorps monoclonaux en utilisant les marqueurs cliniques et biologiques, et démontre également l'influence de fortes concentrations d'anticorps monoclonaux pour la maintenance au traitement. La TEP est une technique prometteuse pour identifier la réponse précoce aux antagoistes du TNF-a.There is an interindividual variability of the dose - response relationship in patients with inflammatory rheumatic diseases treated by Tumor Necrosis Factor-alpha (TNF-a) inhibitors. In the first part of this thesis, the pathophysiology of TNF-a in inflammatory processes is presented. Then, the work focuses on the concentration-effect relationship using pharmacokinetic-pharmacodynamic (PK-PD) models. At the end, after discussion on imaging biomarkers, the thesis discusses the usefulness of a new technique to detect the early response to treatment, namely the positron emission tomography (PET). In summary, this work describes the PK-PD relationship in rheumatic inflammatory diseases treated by monoclonal antibodies using clinical and biological markers and demonstrates also the influence of high concentrations of monoclonal antibodies on maintenance to treatment. PET is a promising technique to identify early response to TNF-a antagonists

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Le phénomène du vide intra-vertébral et spondylodiscites infectieuses

LILLE2-BU Santé-Recherche (593502101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Variabilité pharmacocinétique de l'infliximab dans la polyarthrite rhumatoïde

TOURS-BU Médecine (372612103) / SudocSudocFranceF