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. 2022 Aug;67(8):4008-4019.
doi: 10.1007/s10620-021-07273-y. Epub 2021 Nov 2.

Azathioprine with Allopurinol Is a Promising First-Line Therapy for Inflammatory Bowel Diseases

Elsa L S A van Liere  1   2 , Ahmed B Bayoumy  3 , Chris J J Mulder  4 , Ben Warner  5 , Bu Hayee  6 , Bilal A Mateen  6 , Jonathan D Nolan  7 , Nanne K H de Boer  4 , Simon H C Anderson  5 , Azhar R Ansari  7
Affiliations

Azathioprine with Allopurinol Is a Promising First-Line Therapy for Inflammatory Bowel Diseases

Elsa L S A van Liere et al. Dig Dis Sci. 2022 Aug.

Abstract

Background: Beneficial response to first-line immunosuppressive azathioprine in patients with inflammatory bowel disease (IBD) is low due to high rates of adverse events. Co-administrating allopurinol has been shown to improve tolerability. However, data on this co-therapy as first-line treatment are scarce.

Aim: Retrospective comparison of long-term effectiveness and safety of first-line low-dose azathioprine-allopurinol co-therapy (LDAA) with first-line azathioprine monotherapy (AZAm) in patients with IBD without metabolite monitoring.

Methods: Clinical benefit was defined as ongoing therapy without initiation of steroids, biologics or surgery. Secondary outcomes included CRP, HBI/SCCAI, steroid withdrawal and adverse events.

Results: In total, 166 LDAA and 118 AZAm patients (median follow-up 25 and 27 months) were evaluated. Clinical benefit was more frequently observed in LDAA patients at 6 months (74% vs. 53%, p = 0.0003), 12 months (54% vs. 37%, p = 0.01) and in the long-term (median 36 months; 37% vs. 24%, p = 0.04). Throughout follow-up, AZAm patients were 60% more likely to fail therapy, due to a higher intolerance rate (45% vs. 26%, p = 0.001). Only 73% of the effective AZA dose was tolerated in AZAm patients, while LDAA could be initiated and maintained at its target dose. Incidence of myelotoxicity and elevated liver enzymes was similar in both cohorts, and both conditions led to LDAA withdrawal in only 2%. Increasing allopurinol from 100 to 200-300 mg/day significantly lowered liver enzymes in 5/6 LDAA patients with hepatotoxicity.

Conclusions: Our poor AZAm outcomes emphasize that optimization of azathioprine is needed. We demonstrated a long-term safe and more effective profile of first-line LDAA. This co-therapy may therefore be considered standard first-line immunosuppressive.

Keywords: Allopurinol; Azathioprine; Drug repositioning; Inflammatory bowel disease; Thiopurines.

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Conflict of interest statement

ELSA van Liere and AB Bayoumy received unrestricted travel grants from Thimotheus Consult. CJJ Mulder has served as consultant for HLW Pharma BV, Douglas Pharma, Arega and TEVA Pharma BV. NKH de Boer has served as consultant and principal investigator for TEVA Pharma BV and Takeda. He has served as a speaker for AbbVie and MSD and has received unrestricted research grants from Dr. Falk, TEVA Pharma BV and Takeda. AR Ansari has served as consultant and speaker for Dr. Falk. He has received unrestricted research grants from Janssen Cilag and MSD. SHC Anderson, B Warner, B Hayee, BA Mateen and JD Nolan declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Flowchart showing the selection of the study population
Fig. 2
Fig. 2
Clinical benefit (CB) in patients receiving low-dose azathioprine with allopurinol (LDAA)
Fig. 3
Fig. 3
Clinical benefit (CB) in patients receiving azathioprine monotherapy (AZAm)
Fig. 4
Fig. 4
Kaplan Meier survival curve of clinical benefit (CB) in patients treated with azathioprine monotherapy (AZAm) and low-dose azathioprine with allopurinol (LDAA). A statistical difference between the curves was found (p = 0.003)
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