Clinical and Translational Gastroenterology · 10 authors, 3 centres
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This retrospective study compared split-dose thiopurine (SDT) versus low-dose thiopurine-allopurinol cotherapy (LDTA) in 62 children with IBD who had impaired thiopurine metabolism. LDTA showed higher efficacy in normalizing metabolites on intention-to-treat analysis (95% vs 69%, P < 0.05), but also a higher side effect rate (20% vs 3%, P < 0.05). The authors suggest SDT as the first-line approach due to its favorable safety profile, with LDTA reserved for SDT failures.
**Background:** Thiopurines (azathioprine and 6-mercaptopurine) are mainstays for maintaining remission in pediatric inflammatory bowel disease (IBD), but up to 40–60% of patients discontinue due to lack of efficacy or adverse events. A subset of patients, termed 'hypermetabolizers,' preferentially produce 6-methyl mercaptopurine (6-MeMP) over the active 6-thioguanine nucleotide (6-TGN), leading to subtherapeutic 6-TGN levels and increased hepatotoxicity risk. Two strategies to overcome this shunting are split-dose thiopurine (SDT) and low-dose thiopurine-allopurinol cotherapy (LDTA), but comparative data in children are lacking.
**Methods:** This retrospective study at Great Ormond Street Hospital (2010–2021) included 62 children with IBD (58% Crohn's disease, 19% ulcerative colitis, 23% IBD-unclassified; median age 12 years; 52% male) who switched from conventional once-daily thiopurine to either SDT (n=42 initially, group A) or LDTA (n=20 initially, group B) due to preferential 6-MeMP metabolism or side effects. Twelve patients crossed from SDT to LDTA due to persistent shunting, and 1 was lost to follow-up, yielding final per-protocol groups of 29 (SDT, group C) and 31 (LDTA, group D). Efficacy was defined as normalization of metabolite profile at 6 months (6-TGN 230–450 pmol/8×10^8, 6-MeMP <5,700 pmol/8×10^8, ratio <11) or resolution of adverse effects.
**Key Results:** On intention-to-treat analysis, LDTA was significantly more effective than SDT (95% vs 69%, P < 0.05). However, per-protocol analysis showed no difference (97% vs 100%, P = NS). At 1–3 months post-intervention, LDTA produced significantly lower 6-TGN/6-MeMP ratio (0.67 vs 6.80, P < 0.001), higher 6-TGN (334.5 vs 233 pmol/8×10^8, P < 0.05), and lower 6-MeMP (192 vs 1,298 pmol/8×10^8, P < 0.001) compared to SDT. At 6 months per-protocol, LDTA maintained lower 6-MeMP (262.5 vs 1,153.0, P < 0.05) and ratio (1.00 vs 5.00, P < 0.05), with significantly higher ALT (21.00 vs 15.50 U/L, P < 0.05) and lower platelet count (295.50 vs 352.50 ×10^9/L, P < 0.05), though all values remained within normal range. At 12 months, only 6-MeMP (187.00 vs 854.50, P < 0.05) and ratio (0.50 vs 3.50, P < 0.001) remained significantly different. Side effects were more frequent with LDTA (20% vs 3%, P < 0.05), including allergic reaction, low neutrophils, abnormal pancreatic enzymes, abnormal liver function, vomiting, and high 6-TGN. Two patients (6%) discontinued LDTA due to adverse events (headache, allergic reaction); none discontinued SDT.
**Clinical Implications:** Both SDT and LDTA are effective strategies for normalizing thiopurine metabolism in children with IBD who have failed conventional therapy. LDTA demonstrates superior biochemical efficacy but carries a higher side effect profile. The authors recommend SDT as the first-line approach due to its favorable safety profile, reserving LDTA for patients who fail SDT. These findings support a stepwise approach to managing thiopurine shunting in pediatric IBD. Limitations include the retrospective design, lack of standardized clinical care, and subjective outcome measures (PGA). Prospective randomized studies are needed to confirm these observations and identify predictors of SDT failure.