Efficacy, safety and drug survival of thioguanine as maintenance treatment for inflammatory bowel disease: a retrospective multi-centre study in the United Kingdom

Abstract

Background Thioguanine (TG) is a thiopurine which has been used for patients with inflammatory bowel disease (IBD), who have failed azathioprine (AZA) or mercaptopurine (MP) due to adverse events or suboptimal response. Its widespread use has been hampered due to concerns about nodular regenerative hyperplasia (NRH) of the liver. The aim of this study was to investigate the long-term efficacy and safety of low-dose TG therapy in IBD patients failing AZA and MP. Methods A retrospective multicentre study was performed in IBD patients who failed prior treatment with conventional thiopurines with or without following immunomodulation (thiopurine-allopurinol, biologicals, methotrexate, tacrolimus) and were subsequently treated with TG as rescue monotherapy between 2003 and 2019 at three hospitals in the United Kingdom. Clinical response, adverse events, laboratory results, imaging and liver biopsies were retrospectively collected. Results A total of 193 patients (57% female and 64% Crohn’s disease) were included, with a median daily TG dose of 20 mg (range: 20–40 mg), a median treatment duration of 23 months (IQR 10–47) and a median follow-up of 36 months (IQR 22–53). The clinical response rate at 12 months was 65 and 54% remained on TG until the end of follow-up. Adverse events consisted primarily of elevated liver tests (6%), myelotoxicity (7%) and rash (5%). NRH was histologically diagnosed in two patients and two other patients (1%) developed non-cirrhotic portal hypertension. The median 6-TGN and TPMT levels were 953 pmol/8 × 105 RBC (IQR 145–1761) and 47 mu/L (IQR 34.5–96). Conclusions Long-term follow-up suggests that TG can be an effective and well-tolerated therapy in more than half of difficult-to-treat and multi-therapy failing IBD patients. Findings of this study indicate that TG can be used safely and the occurrence of hepatotoxicity was low. The incidence rate of NRH was within the background incidence.

Case Report: Azathioprine: An Old and Wronged Immunosuppressant

“…A study from United Kingdom evaluated the use of thioguanine in 193 IBD patients along a median follow-up treatment of 23 months. The 12-month clinical response rate was 65% and elevated liver tests, myelotoxicity and rash were observed in 6%, 7% and 5% of the patients, respectively, emphasizing the safety and efficacy of this therapy (37). This may become a new thiopurine therapy for transplantation.…”

Relationship Between Thiopurine S-Methyltransferase Genotype/Phenotype and 6-Thioguanine Nucleotide Levels in 316 Patients With Inflammatory Bowel Disease on 6-Thioguanine

“…In the normal and slow metabolism groups, all patients were administered 20 mg/d or lower, indicating that dose adjustments might be justifiable in daily practice. In a recent study 17 evaluating 193 patients with IBD treated with TG as rescue therapy, it was reported that in all 12 patients with primary nonresponse, fast TPMT metabolism was observed (mean TPMT level of 91.6 6 26.9 mU/L). Combined with the findings observed in this study that fast metabolism (TPMT level .65 mU/L) was associated with lower 6-TGN levels, this indicates that dose adjustments might be beneficial in these patients.…”

“… 14 , 15 This has been achieved by administering a lower daily clinical dose of TG in IBD (20 mg/d) than those in initial reports for IBD and leukemia. Similar to other immunosuppressives, adverse events remain an important reason for patients to cease TG treatment in IBD, observed in 11%–20% 16 , 17 of cases; however, these adverse events are reversible with no reported deaths. To further improve safety, TDM and TPMT geno/phenotyping might add value to reduce adverse events if the facility is available at the treatment center.…”

Correction to: Efficacy, safety and drug survival of thioguanine as maintenance treatment for inflammatory bowel disease: a retrospective multi-centre study in the United Kingdom

“…After publication of this article [ 1 ], the authors reported three adjustments: Competing interests: the travel grants were paid by HLW Pharma instead of TEVA Pharma. TGN-units all over the manuscript have to be adjusted from pmol/8 × 10 5 RBC to pmol/8 × 10 8 RBC.…”