Optimizing thiopurine therapy in autoimmune hepatitis: A multi-center study on monitoring metabolite profiles and co-therapy with allopurinol.
Journal
Hepatology (Baltimore, Md.)
ISSN: 1527-3350
Titre abrégé: Hepatology
Pays: United States
ID NLM: 8302946
Informations de publication
Date de publication:
29 May 2024
29 May 2024
Historique:
received:
09
02
2024
accepted:
09
04
2024
medline:
20
8
2024
pubmed:
20
8
2024
entrez:
20
8
2024
Statut:
aheadofprint
Résumé
In autoimmune hepatitis (AIH), achieving complete biochemical remission (CBR) with current weight-based thiopurine dosing is challenging. We investigated whether patients could be stratified regarding CBR according to a target range of thiopurine metabolites. Moreover, we explored the effects of azathioprine dosage increases and co-therapy of allopurinol with low-dose thiopurines on metabolite profiles and treatment response. The relation between metabolites and treatment response was assessed in 337 individuals from four European centers. In a global, cross-sectional analysis, active metabolites 6-thioguanin nucleotides (6TGN) were similar in those with and without CBR. However, analyzing patients with sequential measurements over 4 years (N=146) revealed higher average 6TGN levels in those with stable CBR (260 pmol/0.2 ml) compared to those failing to maintain CBR (181 pmol/0.2 ml;p=0.0014) or never achieving CBR (153 pmol/0.2 ml;p<0.0001), with an optimal 6TGN-cutoff of ≥223 pmol/0.2 ml (sensitivity: 76%, specificity: 78%). Only 42% exhibited 6TGN ≥223 pmol/0.2 ml following weight-based dosing, as doses weakly correlated with 6TGN but with 6-methylmercaptopurine (6MMP), a metabolite associated with toxicity. Azathioprine dose increases led to preferential 6MMP formation (+127% vs. 6TGN +34%;p<0.0001). Conversely, adding allopurinol to thiopurines in difficult-to-treat patients (N=36) raised 6TGN (168→321 pmol/0.2 ml;p<0.0001) and lowered 6MMP (2125→184 pmol/0.2 ml;p<0.0001), resulting in improved transaminases in all patients and long-term CBR in 75%. Maintaining CBR in AIH was associated with 6TGN ≥223 pmol/0.2 ml. For patients who fail to achieve CBR and therapeutic 6TGN levels despite thiopurine dose increase due to preferential 6MMP formation, co-medication of allopurinol alongside low-dose thiopurines represents an efficient alternative.
Sections du résumé
BACKGROUND AIMS
UNASSIGNED
In autoimmune hepatitis (AIH), achieving complete biochemical remission (CBR) with current weight-based thiopurine dosing is challenging. We investigated whether patients could be stratified regarding CBR according to a target range of thiopurine metabolites. Moreover, we explored the effects of azathioprine dosage increases and co-therapy of allopurinol with low-dose thiopurines on metabolite profiles and treatment response.
APPROACH RESULTS
UNASSIGNED
The relation between metabolites and treatment response was assessed in 337 individuals from four European centers. In a global, cross-sectional analysis, active metabolites 6-thioguanin nucleotides (6TGN) were similar in those with and without CBR. However, analyzing patients with sequential measurements over 4 years (N=146) revealed higher average 6TGN levels in those with stable CBR (260 pmol/0.2 ml) compared to those failing to maintain CBR (181 pmol/0.2 ml;p=0.0014) or never achieving CBR (153 pmol/0.2 ml;p<0.0001), with an optimal 6TGN-cutoff of ≥223 pmol/0.2 ml (sensitivity: 76%, specificity: 78%). Only 42% exhibited 6TGN ≥223 pmol/0.2 ml following weight-based dosing, as doses weakly correlated with 6TGN but with 6-methylmercaptopurine (6MMP), a metabolite associated with toxicity. Azathioprine dose increases led to preferential 6MMP formation (+127% vs. 6TGN +34%;p<0.0001). Conversely, adding allopurinol to thiopurines in difficult-to-treat patients (N=36) raised 6TGN (168→321 pmol/0.2 ml;p<0.0001) and lowered 6MMP (2125→184 pmol/0.2 ml;p<0.0001), resulting in improved transaminases in all patients and long-term CBR in 75%.
CONCLUSIONS
CONCLUSIONS
Maintaining CBR in AIH was associated with 6TGN ≥223 pmol/0.2 ml. For patients who fail to achieve CBR and therapeutic 6TGN levels despite thiopurine dose increase due to preferential 6MMP formation, co-medication of allopurinol alongside low-dose thiopurines represents an efficient alternative.
Identifiants
pubmed: 39162583
doi: 10.1097/HEP.0000000000000940
pii: 01515467-990000000-00895
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
Copyright © 2024 American Association for the Study of Liver Diseases.