A population model of early rheumatoid arthritis disease activity during treatment with methotrexate, sulfasalazine and hydroxychloroquine.
OBJECTIVE
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.
Australian Centre for Pharmacometrics, University of South Australia, Adelaide, Australia.
Jessica
J
Wojciechowski
Michael D
MD
Wiese
Susanna M
SM
Proudman
David J R
DJ
Foster
Richard N
RN
Upton
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018501:Antirheumatic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000473:pathology; D001499:Bayes Theorem; D003627:Data Interpretation, Statistical; D018450:Disease Progression; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D006886:Hydroxychloroquine / Q000008:administration & dosage / Q000627:therapeutic use*; D007596:Joints / Q000473:pathology; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000627:therapeutic use*; D008875:Middle Aged; D008954:Models, Biological; D011237:Predictive Value of Tests; D012720:Severity of Illness Index; D012460:Sulfasalazine / Q000008:administration & dosage / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
D018501:Antirheumatic Agents; D012460:Sulfasalazine; D006886:Hydroxychloroquine; D008727:Methotrexate
28 Joint Disease Activity Score; disease activity; disease modifying anti-rheumatic drugs; population modelling; rheumatoid arthritis