title: The importance of assessing medication exposure to the definition of refractory disease in systemic lupus erythematosus.
abstract: Treatment of patients with Systemic Lupus Erythematosus (SLE) who have active disease refractory to current therapeutic strategies continues to be a real challenge. Here, we propose that the classic definition of refractory SLE patients - failure to achieve adequate response to the standard of care - should be further refined to incorporate the dimension of adequate drug exposure. Inter-individual pharmacokinetic variability may induce insufficient exposure to many drugs used in SLE, leading to both apparent inefficacy of treatments and inappropriate therapeutic escalation. Among others, we have shown that individual assessment of exposure to mycophenolic acid, the active metabolite of mycophenolate mofetil (MMF) could be used to determine whether a given patient received adequate doses of MMF. We have also shown that measuring blood concentrations of hydroxychloroquine could be used as an efficient way to assess observance, which is a critical issue since a significant proportion of refractory SLE patients is likely to have poor observance as the primary source of treatment failure. Finally, we have underlined the importance of assessing drug interactions as SLE patients often require, in addition to immunosuppressants, several other drugs to prevent or treat associated conditions, which may result in decreased exposure to immunosuppressants. Considering these data, we believe that refractory SLE patients should not only be defined as the failure to achieve adequate therapeutic response to the standard of care, but should also incorporate the dimension of inadequate pharmacokinetic exposure and include drug blood level, interaction and observance monitoring.
authors.affiliation: Service de médecine interne 2, Centre National de Référence Lupus Systémique et Syndrome des Anticorps anti-phospholipides, Hôpital Pitié-Salpêtrière, Paris, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Arnaud
authors.forename: Noël
authors.initials: N
authors.lastname: Zahr
authors.forename: Nathalie
authors.initials: N
authors.lastname: Costedoat-Chalumeau
authors.forename: Zahir
authors.initials: Z
authors.lastname: Amoura
mesh_terms: D054316:Biomarkers, Pharmacological / Q000378:metabolism; D018450:Disease Progression; D004347:Drug Interactions; D005602:France; D006801:Humans; D006886:Hydroxychloroquine / Q000097:blood; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008180:Lupus Erythematosus, Systemic / Q000175:diagnosis* / Q000188:drug therapy* / Q000453:epidemiology; D008991:Monitoring, Physiologic / Q000706:statistics & numerical data; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D015588:Observer Variation; D017211:Treatment Failure
chemical_list: D054316:Biomarkers, Pharmacological; D007166:Immunosuppressive Agents; D006886:Hydroxychloroquine; D009173:Mycophenolic Acid