A new pharmacokinetic model of urinary methotrexate to assess adherence in rheumatoid arthritis.

BACKGROUND AND OBJECTIVES: Methotrexate (MTX) is the first-line therapy for rheumatoid arthritis (RA). While therapeutic adherence is essential to successful management, no objective MTX assay is currently available. Using population pharmacokinetic modelling (PopPK), our objective was to describe the urinary MTX (MTXu) kinetics in treated patients and to evaluate its abilities to assess the MTX-adherence. METHODS: The association between urinary methotrexate level and methotrexate administration was assessed using a generalized linear model. Then, a population pharmacokinetic model was developed based on data from 59 patients using with Monolix 2021. R2. Simulations were run to establish a reference kinetic profile and evaluate the proportion of samples predicted as true positives. RESULTS: Compared to the control group, multivariate analysis showed that MTXu was independently associated with methotrexate administration (p < 0.0001) with a sensitivity and specificity greater than 99%. The final PopPK model selected was a two-compartment model with first-order absorption and elimination. Internal and external validation of the model met all predefined criteria. When using an analytical assay with a LOQ equal to 1 nM, the proportion of samples predicted as true positives is over 90%, as a function of MTX dose (7.5-25 mg/week) and post-administration sampling days (1-7 days). CONCLUSION: We developed a pharmacokinetic model able to describe expected patterns of urinary methotrexate. This allowed us to propose a new objective test of MTX adherence, which could help in routine practice to differentiate patients who are truly unresponsive to methotrexate from those who are unresponsive because of non-adherence.

Management and outcome of native joint septic arthritis: a nationwide survey in French rheumatology departments, 2016-2017.

OBJECTIVES: To describe current management and outcome of native joint septic arthritis (NJSA) in French rheumatology departments. METHODS: For this retrospective, nationwide multicentric study, 127 French rheumatology departments were contacted to report up to 12 cases of NJSA that occurred between 1 January 2016 and 31 December 2017. Characteristics, diagnosis procedures, therapeutic management and outcome were recorded. RESULTS: Overall, 362 patients were included (mean age 64.0±18.6 years, median Charlson comorbidity index 3.5 (0-14)). Knee was the most frequent site (n=160 (38.9%)), and Staphylococcus sp (n=185 (51.4%)), the most frequent pathogen. All patients received antibiotics for a mean duration of 46.8 (±22.0) days, including intravenous route for a mean of 17.2 (±15.4) days. Management was heterogeneous. Surgical procedure was performed in 171 (48.3%), joint immobilisation in 128 (43.8%). During follow-up, 91 (28.3%) patients have had serious complications and 28 (9.2%) of them died. Factors associated with 1-year mortality were age (OR 1.08, 95% CI 1.04 to 1.13; p<0.001), Charlson's index (OR 1.30, 95% CI 1.06 to 1.58; p=0.012), presence of bacteraemia (OR 4.02, 95% CI 1.35 to 11.99; p=0.008), antibiotic use in the previous 3 months (OR 3.32, 95% CI 1.11 to 9.87; p=0.029) and Staphylococcus aureus NJSA compared with Streptococcus sp. NJSA (OR 7.24, 95% CI 1.26 to 41.68, p=0.027). The complete recovery with no adverse joint outcome at 1 year was observed in n=125/278 patients (55.0%). CONCLUSION: Prognosis of NJSA remained severe with a high rate of morbimortality. Its management was very heterogeneous. This study highlights the importance of the new French recommendations, published after the completion of the study, in order to facilitate NJSA management.

[Effectiveness, therapeutic maintenance and reasons for stopping tocilizumab (TCZ): A retrospective and monocentric study in 88 patients followed for rheumatoid arthritis (RA) at the Reims university hospital]. / Efficacité, maintien thérapeutique et motifs d'arrêt du tocilizumab (TCZ) : étude monocentrique et rétrospective chez 88 patients suivis pour une polyarthrite rhumatoïde (PR) au CHU de Reims.

OBJECTIVE: Study the therapeutic maintenance, efficacy and reasons for tocilizumab stop in daily practice. PATIENTS AND METHODS: A monocentric, retrospective study of patients treated for rheumatoid arthritis who received at least one TCZ infusion between January 2009 and December 2015. Therapeutic maintenance was evaluated using the Kaplan-Meier method. The efficacy of TCZ was measured by DAS28 and the EULAR response. Reasons for stopping and new treatment lines were also collected. RESULTS: Of the 88 patients (83% women and 17% men) who were included, the mean age was 54±12.5 years. There were 75% positive rheumatoid factors and 76% positive anti-CCP. The mean duration of the follow-up was 31 months. TCZ was used as monotherapy in 24 patients (27%). Before the introduction of TCZ, the mean DAS28 was 5.07±1.32. The EULAR response at 1 year in patients still under treatment (n=63) was obtained in 59 (93.7%) patients, 46 good responders and 13 moderate responders. Therapeutic maintenance was 82.9%, 72.5%, 68.7% and 57.2%, respectively, at 12, 24, 36 and 54 months. Twenty-eight patients (32%) followed TCZ, 10 for adverse events and 14 for ineffectiveness. Abatacept was the main new therapeutic line. CONCLUSION: The therapeutic maintenance of TCZ in common practice over a long period of follow-up is similar to pivotal studies. Efficacy data are reassuring in the long-term.