| dc.description.abstract | This thesis investigates immunological, genetic, metabolic and clinical factors thought to influence the risk of cutaneous adverse drug reactions (cADRs) from antiepileptic drugs (AEDs). These reactions span from simple maculopapular exanthemas (MPEs) to serious bullous manifestations, and their frequency decreases with increasing severity. The present studies focus on MPEs, which, although mild, usually cause an abrupt withdrawal of AEDs that may precipitate seizure breakthrough and limit optimal treatment. The overall aim of the thesis was to gain more knowledge on the roles of selected predisposing factors to cADRs.
Studies I-III have a case-control design, whereas study IV is a retrospective cohort study.
Paper I compares the occurrence of cADRs from carbamazepine (CBZ) used in multiple sclerosis (MS) for neuropathic pain and in epilepsy. The assumption of an overall enhanced risk of cADRs in patients with the autoimmune disorder MS was not confirmed when adjusted for sex and age. A slightly increased frequency of cADRs in patients with MS (17 %) compared to patients with epilepsy (13 %) was explained by the fact that females of fertile age are overrepresented both among those who have MS and those who develop cADRs to AEDs in general.
The aim of Paper II was to assess the clinical usefulness of HLA-A markers as a predictor of cADRs from AEDs. The expression of the suggested predisposing factor, HLA-A* 31:01, was not significantly higher among subjects with cADRs from CBZ, thus questioning the usefulness of this marker as a predictor for CBZ rash in the Norwegian population. However, the frequency of HLA-A* 24:02 was significantly higher in patients with cADRs from any aromatic AED (p = 0.022 when compared to controls). The association was present for lamotrigine (LTG) alone, a finding which later has been confirmed in a meta-analysis published by others. HLA-A* 24:02 may thus have a potential role as a biomarker for cADRs from aromatic AEDs.
In Paper III, we investigated the possible association between cADRs from LTG and heterozygosity of the genetic variants *2 (P24T) and *3 (L48V) of LTG´s main metabolizing enzyme, UGT1A4. Although these variants may alter the metabolism of LTG to some degree, no association with the occurrence of cADRs could be identified, possibly as serum level changes are too small to affect the risk.
The aim of Paper IV was to throw light on LTG-related cADRs with focus on incidence, classification and differential diagnoses in pediatric and adult patients. Although a higher incidence of cADRs from LTG in children has previously been suggested, we found a lower incidence in children (3.6 %) than in adults (5.9 %). Other emergent skin reactions than immunologically mediated cADRs from LTG were more common in children (4.2 %). Thorough analysis of potential cADRs and the circumstances under which they occur, play an important role for the appropriate assessment and management of AED-related skin reactions in clinical practice. Viral infection may mimic cADRs, and cADRs may mimic viral infection. Thus, alternative causes of emerging skin eruptions should receive adequate attention to avoid unjustified discontinuation of the AED.
The present studies add clinically relevant knowledge on various issues related to cADRs from AEDs. Further research will hopefully develop additional biomarkers and promote clinical guidelines which may reduce these obstacles of AED treatment. A greater understanding of the complex mechanisms and the individual biological factors underlying cADRs facilitates the development of the personalized medicine approach to the management of epilepsy. | en_US |
