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Objectives Hydroxychloroquine (HCQ) is recommended for the management of systemic lupus erythematosus (SLE). However, substantial interindividual pharmacokinetic variability, suboptimal adherence, and the lack of standardized therapeutic drug monitoring (TDM) may limit its efficacy.The aim of our study was to quantify serum HCQ concentrations in a cohort of SLE patients followed at the Rheumatology Unit of the University Hospital of Padua, estimate the prevalence of underexposure as an indirect indicator of non-adherence, evaluate the association between serum concentrations and disease activity/status, and assess the clinical relevance of literature-proposed cut-offs.Methods SLE patients receiving HCQ for more than 6 months were enrolled at routine follow-up visits (December 5, 2024 – June 21, 2025). Venous blood samples were performed aiming to measure HCQ serum levels. HCQ concentrations were evaluated by high-performance liquid chromatography coupled with tandem mass spectrometry. An average conversion factor of serum of 0.53 was used compared to whole blood. Based on published thresholds, three serum ranges were used to infer adherence: <106 microg/L, 106–265 microg/L, and >265 microg/L. Disease remission was defined according to Zen et al., and low disease activity (LLDAS) according to Franklyn et al. Associations between remission/LLDAS and clinical-therapeutic variables were investigated using descriptive statistics, bivariate tests, and multivariable linear/logistic regression models adjusted for covariates, with robust standard errorsResults Among 209 patients, 82.3% were in remission/LLDAS and 17.7% had active disease. Overall, HCQ levels were <106 microg/L in 30 patients (14,4%), 106–265 microg/L in 46 patients (22,0%) and >265 microg/L in 133 patients (63,6%), suggesting that a considerable proportion may be non-adherent. Mean concentrations were higher in remission/LLDAS compared to active disease (333.4 ± 211.6 vs. 270.5 ± 157.9 microg/L; p=0.044). In adjusted models, higher serum concentrations were independently associated with remission/LLDAS (OR 1.26 per +100 microg/L; p=0.049).Conclusions Serum HCQ concentrations are independently associated with remission/LLDAS. Continuous evaluation of serum levels appears more informative than applying fixed cut-offs derived from whole blood. These findings support the role of TDM primarily to assess adherence and to guide clinical decisions in cases of discordant disease activity, rather than as a prognostic tool based on predefined thresholds.