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A semiphysiologically based pharmacokinetic (semi-PBPK) population model was used to evaluate the influence of enterohepatic recycling and protein binding, as well as the effect of genetic variability in CYP1A2, CYP2C19, and ABCG2, on the large interindividual variability of teriflunomide (active metabolite) concentrations following leflunomide administration in rheumatoid arthritis (RA) patients. The model was developed with total and free teriflunomide concentrations determined in RA patients taking leflunomide, as well as mean teriflunomide concentrations following the administration of leflunomide or teriflunomide extracted from the literature. Once developed, the 15-compartment model was able to predict total and free teriflunomide concentrations and was used to screen demographic and genotypic covariates, of which only fat-free mass and liver function (ALT) improved prediction. This approach effectively evaluated the effects of multiple covariates on both total and free teriflunomide concentrations, which have only been explored previously through simplistic one-compartment models for total teriflunomide. [ABSTRACT FROM AUTHOR]

Summary A system has been established to assess the recruitment of 99mTc-hexamethylpropylene amine oxamine (99mTc-HMPAO)-labelled PBMC and [125I]iododeoxyuridine-labelled Con A stimulated lymphoblasts to allogeneic human synovial xenografts in the ears of SCID mice. Successful engraftment of osteoarthritic synovium was achieved in approximately 90% of cases and a connection between the human microvasculature of the xenograft and the circulation of the mouse was shown. Cells were delivered to the xenograft by a system of regional vascular perfusion, thus avoiding the major murine vascular beds. The accumulation of 99mTc-HMPAO-labelled PBMC in mouse ears was monitored in real time. Direct injection of xenograft-bearing ears with recombinant human TNF-α, 7 h prior to perfusion, increased the accumulation of both PBMC and lymphoblasts in cytokine-injected ears compared to contralateral control-injected ears. Autoradiography revealed the presence of [125I]iododeoxyuridine-labelled lymphoblasts associated with human microvasculature within the xenograft. However, the increased accumulation of lymphoblasts in cytokine-injected ears occurred in the tissues surrounding the xenograft, where lymphoblasts were associated more often with murine than human vessels. Although the system described offers advantages over similar models, the propensity for mouse endothelium to interact with human leucocytes is likely to be a generic disadvantage for models of human leucocyte recruitment to xenografts in immunodeficient mice. [ABSTRACT FROM AUTHOR]

Aims: To develop a non-linear mixed-effects population pharmacokinetic and pharmacodynamic (PK-PD) model describing the change in the concentration of methotrexate polyglutamates in erythrocytes (ery-MTX-PG n with "n" number of glutamate, representing PK component) and how this relates to modified 28-joint Disease Activity Score incorporating erythrocyte sedimentation rate (DAS-28-3) for rheumatoid arthritis (RA), representing PD component., Methods: An existing PK model was fitted to data from a study consisting of 117 RA patients. The estimation of population PK-PD parameters was performed using stochastic approximation expectation maximisation algorithm in Monolix 2021R2. The model was used to perform Monte Carlo simulations of a loading dose regimen (50mg subcutaneous methotrexate as loading doses, then 20mg weekly oral methotrexate) compared to a standard dosing regimen (10mg weekly oral methotrexate for 2 weeks, then 20mg weekly oral methotrexate)., Results: Every 40 nmol/L increase in ery-MTX-PG 3-5 total concentration correlated with 1-unit reduction in DAS-28-3. Significant covariate effects on the therapeutic response of methotrexate included the use of prednisolone in the first 4 weeks (positive use correlated with 25% reduction in DAS-28-3 when other variables were constant) and patient age (every 10-year increase in age correlated with 3.4% increase in DAS-28-3 when other variables were constant). 4 methotrexate loading doses led to a higher percentage of patients achieving a good/moderate response compared to the standard regimen (Week 4: 87.6% vs. 39.8%; Week 10: 64.7% vs. 57.0%)., Conclusions: A loading dose regimen was more likely to achieve higher ery-MTX-PG concentration and better therapeutic response after 4 weeks of methotrexate treatment., (© 2024 The Author(s). British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Aims: Composite indices for quantifying rheumatoid arthritis (RA) disease activity such as the 28-joint disease activity score (DAS28) are comprised of single parameters ('metrics') in various combinations. Population modelling methods were used to evaluate single metrics for their ability to reflect changes in disease activity with a view to understanding and improving composite indices., Methods: A total of 11 single metrics of RA disease activity (tender and swollen joint counts, acute phase reactants and global health, pain and physical function assessments) were obtained from 203 patients with recent onset RA. Participants received combination disease-modifying anti-rheumatic drugs (DMARDs) according to a treat-to-target approach with a pre-defined protocol for treatment intensification. Models describing each metric's magnitude and variability of change from baseline to a single 'treated' state in the population were developed using nonmem(®) . Measures that displayed uniformly large changes between states across the population were ranked higher in terms of discriminatory capacity., Results: Joint counts demonstrated a greater ability to discriminate changes in RA disease activity than others. Correlations between metrics demonstrated that erythrocyte sedimentation rate (ESR) had limited relationships with others for baseline scores and changes in RA disease activity (r generally < 0.2). However it appeared to be important in describing changes for those individuals where ESR levels were initially elevated., Conclusion: It appears unlikely that a single group of metrics may be suitable to capture disease activity changes across all RA patients and defining the most appropriate metric(s) for individual patients will be an important area of future research., (© 2016 The British Pharmacological Society.)

Aim: Leflunomide, via its active metabolite teriflunomide, is used in rheumatoid arthritis (RA) treatment, yet approximately 20 to 40% of patients cease due to toxicity. The aim was to develop a time-to-event model describing leflunomide cessation due to toxicity within a clinical cohort and to investigate potential predictors of cessation such as total and free teriflunomide exposure and pharmacogenetic influences., Methods: This study included individuals enrolled in the Early Arthritis inception cohort at the Royal Adelaide Hospital between 2000 and 2013 who received leflunomide. A time-to-event model in nonmem was used to describe the time until leflunomide cessation and the influence of teriflunomide exposure and pharmacogenetic variants. Random censoring of individuals was simultaneously described. The clinical relevance of significant covariates was visualized via simulation., Results: Data from 105 patients were analyzed, with 34 ceasing due to toxicity. The baseline dropout hazard and baseline random censoring hazard were best described by step functions changing over discrete time intervals. No statistically significant associations with teriflunomide exposure metrics were identified. Of the screened covariates, carriers of the C allele of CYP1A2 rs762551 had a 2.29 fold increase in cessation hazard compared with non-carriers (95% CI 2.24, 2.34, P = 0.016)., Conclusions: A time-to-event model described the time between leflunomide initiation and cessation due to side effects. The C allele of CYP1A2 rs762551 was linked to increased leflunomide toxicity, while no association with teriflunomide exposure was identified. Future research should continue to investigate exposure-toxicity relationships, as well as potentially toxic metabolites., (© 2015 The British Pharmacological Society.)

Aims: To develop a population model describing the disease activity (DAS28) time course in patients with early rheumatoid arthritis (RA) treated with triple disease-modifying anti-rheumatic drug (DMARD) therapy (methotrexate, sulfasalazine and hydroxychloroquine)., Methods: DAS28 was obtained in 263 patients with early RA from initiation of therapy until 60 weeks. Using NONMEM(®), base models (DAS28 vs. time) and covariate influences were investigated for the population., Results: The best model was an exponential model of DAS28 vs. time that was additive to baseline DAS28, with covariance between parameters, and a combined residual error model. Age and patient smoking history were covariates significantly affecting response to therapy. Population estimates were baseline DAS28 (5.7), extent of change in DAS28 (-2.8) and the half-life of disease activity (6.2 weeks; time to steady disease state achieved within approximately 30 weeks). Older individuals exhibited more severe baseline DAS28, described by a power function centred around 57 years (baseline DAS28 for 40- and 70-year-old patients were 5.4 vs. 5.8, respectively) and current smokers took longer to achieve a steady disease state (approximately 50 weeks). There was considerable within-patient random variability in DAS28 over time (empirical 90% CI for DAS28 in a population typical patient at 60 weeks: 1.8, 4.2 with median value of 2.8)., Conclusions: This is the first report of a disease activity model for early RA treated with triple DMARD therapy. Smoking and age were identified as covariates., (© 2014 The British Pharmacological Society.)

Objective: To determine whether application of criteria for remission in rheumatoid arthritis (RA) may result in underestimation of foot joint involvement among patients in a clinic setting., Methods: RA patients (n = 123) were assessed at baseline and 6 months after commencement of a response-driven combination disease-modifying antirheumatic drug (DMARD) protocol. Remission was assessed using disease activity measures (the 28-joint Disease Activity Score using the erythrocyte sedimentation rate [DAS28-ESR], Simplified Disease Activity Index [SDAI], and Clinical Disease Activity Index [CDAI]) as well as Boolean-based criteria for remission (the 1981 American College of Rheumatology [ACR] preliminary criteria and the 2011 ACR/European League Against Rheumatism [EULAR] provisional criteria). The prevalence of foot synovitis and the mean swollen/tender foot joint count in RA patients meeting any of these remission criteria were estimated by hurdle (mixed distribution) regression., Results: In patients who received 6 months of combination DMARD treatment, application of the 1981 ACR criteria and the newly proposed 2011 ACR/EULAR criteria, each utilizing full joint counts (which includes assessment of the feet), classified the least number of patients as being in remission (8-10%), and evidence of foot synovitis was minimal among these patients. In contrast, ongoing foot synovitis was present in a substantial proportion of patients (>20%) meeting the 28-joint count criteria for remission, including the DAS28-ESR, SDAI, CDAI, and 2011 ACR/EULAR criteria (clinical practice setting or clinical trials). Furthermore, applying the 2011 ACR/EULAR composite remission criterion of a SDAI score ≤3.3 to define remission did not adequately capture the resolution of foot synovitis (i.e., residual foot involvement was still detected in a substantial proportion of patients classified as being in remission by this definition)., Conclusion: Although the DAS28-ESR, CDAI, and SDAI have been validated for assessment of remission in RA, this study shows that the performance of these 3 disease activity measures, which do not provide a direct assessment of the foot, in detecting foot synovitis is poor, in contrast to that of the 1981 ACR and 2011 ACR/EULAR remission criteria utilizing full joint counts. Thus, patients may be at risk of ongoing damage if treatment decisions are made solely on the basis of criteria that omit foot joint assessment., (Copyright © 2012 by the American College of Rheumatology.)

Objective: To determine whether a regimen of methotrexate, cyclosporin A, and corticosteroids introduced at onset in poor-prognosis rheumatoid arthritis (RA) can produce a significant improvement in outcome compared with standard monotherapy with sulfasalazine (SSZ)., Methods: Eighty-two consecutive patients presenting with new, untreated RA of less than 12 months' duration who fulfilled criteria for poor long-term outcome were randomized to receive either combination therapy (n = 40) or SSZ alone (n = 42). The primary outcome measures were remission and American College of Rheumatology (ACR) criteria for 20% improvement at 48 weeks., Results: After 48 weeks, the numbers of patients who met the ACR criteria for 20% improvement were not significantly different between the two groups (combination 58% versus SSZ 45%), and similar numbers of patients had persisting clinical remission (approximately 10% both groups). During the first 3 months, there were significantly greater reductions in parameters of disease activity in the combination group. By 24 weeks, the swollen and tender joint counts, C-reactive protein levels, and erythrocyte sedimentation rates had fallen significantly in both groups, with a greater improvement in the swollen and tender joint count in the combination group. At 48 weeks, the radiographic damage score had increased by a median of 1 (range 0-42.5) in the combination group and 1.25 (range 0-72.5) in the SSZ group (P = 0.28; although there were significant differences in the scores for the right hand). There were significantly fewer withdrawals due to lack of efficacy in the combination group than in the SSZ group (1 of 40 versus 10 of 42; P = 0.007). In the combination group, dose reduction was needed in 22.5% because of hypertension and in 22.5% because of elevated creatinine levels. Over 48 weeks, serum creatinine increased in both groups, but particularly in the combination arm., Conclusion: In poor-prognosis RA patients, "aggressive" combination therapy led to more rapid disease suppression but did not result in significantly better ACR response or remission rates. This suggests that in poor-prognosis disease, an approach based on identifying patients with poor treatment responses before extra therapy is added ("step-up" approach) may be more appropriate than the use of combination therapy in all patients from the outset.

Vasomotor reactions after administration of gold sodium thiomalate (GST) are well recognized, but such reactions have not been reported to occur in association with oral gold treatment. We describe a woman with rheumatoid arthritis who experienced typical nitritoid reactions after treatment with GST, and later, with auranofin.