BACKGROUND:Data about the safety of allopurinol in pregnant women are sparsely reported. AIMS:To investigate the risk of adverse pregnancy outcome and congenital abnormalities after in utero exposure to allopurinol in inflammatory bowel disease (IBD) pregnancies and in general. METHODS:We collected safety data of patients with IBD who were treated with allopurinol during pregnancy between January 2013 and March 2022. Additionally, we performed a systematic review about the teratogenic potential of allopurinol. RESULTS:We collected data from 42 allopurinol-exposed pregnancies, including one twin pregnancy; in all women, allopurinol was combined with a thiopurine. Six pregnancies (14.3%) resulted in miscarriage and one in stillbirth at 32 weeks. A congenital anomaly was observed in one newborn (coarctation of the aorta discovered postpartum). Three pregnancies, including the twin pregnancy, ended in moderate preterm delivery and one in very preterm delivery. Five neonates (15.2%) were small for gestational age. From our literature search, we identified an additional 102 allopurinol-exposed pregnancies resulting in 129 live births, including 36 infants from our cohort. Ten infants (7.8%) were born with a congenital anomaly. Two (1.6%) had a comparable pattern of multiple anomalies. The systematic review sub-analysis including only infants born to mothers with IBD (n = 76) revealed that 2.6% of infants had congenital anomalies after in utero exposure to a low dose of allopurinol. CONCLUSIONS:Overall, the teratogenicity of allopurinol remains inconclusive. Children conceived by mothers treated for IBD with allopurinol/thiopurine co-therapy do not seem to have an increased risk of congenital anomalies.

Background Home use of a buffer-containing extraction device for fecal calprotectin determination can bypass the labor-intensive extraction procedure and potentially prevent degradation at room temperature. Methods In this prospective cross-sectional observational study, 2 CALiaGold tubes (extraction device) and one native tube were filled from the same bowel movement by patients with inflammatory bowel disease. Afterwards patients completed a questionnaire including whether they preferred the extraction device or the normal sampling method. All tubes were sent to the laboratory and when they arrived, 2 more CALiaGold tubes were filled at the laboratory from the native sample. The fecal calprotectin concentrations in all tubes were measured by a particle-enhanced turbidimetric immunoassay. Results Fifty-three patients were included in the study. Fecal calprotectin levels were significantly higher in samples extracted by the patient compared to the analyst-performed extractions. When patients were divided into 3 groups (i.e., fecal calprotectin levels <50 ug/g, 50 to 200 µg/g, and >200 µg/g) a substantial concordance was found (Cohen kappa 0.654). Patients sampling imprecision was higher (P < 0.018, median CV 16%) compared to the analyst. Most patients preferred this extraction device. Conclusions Patient-performed fecal calprotectin extraction seems a realistic alternative sampling method and is preferred by most patients.

Background Safety of thioguanine in pregnant patients with inflammatory bowel disease [IBD] is sparsely recorded. This study was aimed to document the safety of thioguanine during pregnancy and birth. Methods In this multicentre case series, IBD patients treated with thioguanine during pregnancy were included. Data regarding disease and medication history, pregnancy course, obstetric complications, and neonatal outcomes were collected. Results Data on 117 thioguanine-exposed pregnancies in 99 women were collected. Most [78%] had Crohn's disease and the mean age at delivery was 31 years. In 18 pregnancies [15%], IBD flared. Obstetric and infectious complications were seen in 15% [n = 17] and 7% [n = 8] of pregnancies, respectively. Ten pregnancies [8.5%] resulted in a first trimester miscarriage, one in a stillbirth at 22 weeks of gestational age and one in an induced abortion due to trisomy 21. In total, 109 neonates were born from 101 singleton pregnancies and four twin pregnancies. One child was born with a congenital abnormality [cleft palate]. In the singleton pregnancies, 10 children were born prematurely and 10 were born small for gestational age. Screening for myelosuppresion was performed in 16 neonates [14.7%]; two had anaemia in umbilical cord blood. All outcomes were comparable to either the general Dutch population or to data from three Dutch cohort studies on the use of conventional thiopurines in pregnant IBD patients. Conclusion In this large case series, the use of thioguanine during pregnancy is not associated in excess with adverse maternal or neonatal outcomes.

Background Currently thioguanine is solely used as treatment for inflammatory bowel disease after azathioprine and/or mercaptopurine failure. This study aimed to determine the safety, effectiveness, and 12-month drug survival of thioguanine in thiopurine-naïve patients with inflammatory bowel disease. Methods A retrospective cohort study was performed in thiopurine-naïve patients with inflammatory bowel disease treated with thioguanine as first thiopurine derivate. Clinical effectiveness was defined as the continuation of thioguanine without the (re)initiation of concurrent biological therapy, systemic corticosteroids, or a surgical intervention. All adverse events were categorized by the Common Terminology Criteria for Adverse Events. Results A total of 114 patients (male 39%, Crohn’s disease 53%) were included with a median treatment duration of 25 months and a median thioguanine dosage of 20 mg/d. Clinical effectiveness at 12 months was observed in 53% of patients, and 78% of these responding patients remained responsive until the end of follow-up. During the entire follow-up period, 26 patients were primary nonresponders, 8 had a secondary loss of response, and 11 patients were unable to cease therapy with systemic corticosteroids within 6 months and were therefore classified as nonresponders. After 12 months, thioguanine was still used by 86% of patients. Fifty (44%) patients developed adverse events (grade 1 or 2) and 9 (8%) patients ceased therapy due to the occurrence of adverse events. An infection was documented in 3 patients, none of them requiring hospitalization and pancytopenia occurred in 2 other patients. No signs of nodular regenerative hyperplasia or portal hypertension were observed. Conclusions At 12 months, first-line thioguanine therapy was clinically effective in 53% of thiopurine-naïve inflammatory bowel disease patients with an acceptable safety profile.

From the *Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism Research Institute, Amsterdam University Medical Centre, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands †Department of Radiology and Nuclear Medicine, Amsterdam University Medical Centre, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands ‡Departments of Gastroenterology & Clinical Pharmacology, Christchurch Hospital, Canterbury District Health Board and University of Otago, Christchurch, New Zealand §Inflammatory Bowel Diseases Group, Mater Research Institute, University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia Address correspondence to: Femke Crouwel, De Boelelaan 1117, 1081 HV Amsterdam, the Netherlands (f.crouwel@amsterdamumc.nl.nl).

Background and Aims: Non-invasive biomarkers are gaining interest for monitoring disease activity in patients with inflammatory bowel diseases (IBD). Fecal calprotectin is a reliable biomarker but patients often report the collection of feces being unpleasant and cumbersome. In this study, we aimed to assess if salivary calprotectin could be used as a non-invasive biomarker to determine disease activity instead of fecal calprotectin. Methods: In this cross-sectional explorative cohort study, stimulated saliva was collected from patients with an established IBD diagnosis and healthy controls. The concentration of calprotectin in saliva was determined by a particle-enhanced turbidimetric immunoassay. Intestinal disease activity was assessed with fecal calprotectin levels and the Harvey-Bradshaw Index (HBI) or Simple Clinical Colitis Activity Index (SCCAI). Missing data were handled using multiple imputation. Results: Sixty-three patients (41 Crohn’s disease and 22 ulcerative colitis) and 11 controls were included. Patients had a mean fecal calprotectin of 138.78 µg/g and a median salivary calprotectin of 1.87 mg/L. No significant correlation was found between salivary calprotectin and fecal calprotectin levels (p=0.495). When patients were stratified in two subgroups based on a fecal calprotectin cut-off value of 250 µg/g, there were no significant differences in salivary calprotectin levels between both patient groups (p=0.641) and between patients and healthy controls (p=0.248). Also, salivary, and fecal calprotectin levels were not significantly different when stratifying patients in two subgroups, active disease and remission, using HBI/SCCAI scores. Conclusions: Salivary calprotectin does not correlate to fecal calprotectin and disease activity scores in patients, making it unreliable for assessing IBD activity.

Abstract Background Currently thioguanine is considered as off-label rescue therapy for Inflammatory Bowel Disease (IBD) after conventional thiopurine failure. This study aimed to determine the safety, effectiveness and 12-month drug tolerability of thioguanine in thiopurine-naïve IBD patients. Methods We performed an analysis of our multicenter, retrospective cohort study including thiopurine-naïve IBD patients treated with thioguanine as first-line maintenance therapy without concomitant biological therapy. Clinical effectiveness was defined as a sustained clinical response (based on physician’s global assessment) without the (re-)initiation of concurrent biological therapy, corticosteroids or a IBD-related surgical intervention. All adverse events that occurred during follow-up were categorized by the Common Terminology Criteria for Adverse Events. Elevation of two concurrent liver tests were categorized as drug-induced liver injury. Results A total of 103 IBD patients (female 61%, Crohn’s disease 52%) were included with a median daily thioguanine dose of 20mg and median 6-thioguanine nucleotide (6-TGN) levels of 635 pmol/8x108 RBC (IQR 425–1100). Clinical effectiveness at 12 months was observed in 60 out of 99 patients (61%) and 80% of patients were still using thioguanine 12 months after initiation. Four patients did not reach the 12-month follow-up period but were in remission at time of data collection. Of the responding patients at 12 months 88% (N=53) remained responsive until the end of follow-up (median follow-up period 28 months, IQR 17–40 months). Forty-nine patients (48%) developed adverse events (grade 1 or 2), of which 24% graded as moderate (grade 2) and none as severe. Seven patients ceased therapy due to the occurrence of adverse events. Adverse events consisted mainly of elevated liver tests (26%) and gastrointestinal complaints (17%). An infection was documented in three patients, none of them requiring hospitalization. Pancytopenia occurred in two other patients with 6-TGN levels of respectively 2900 and 140 pmol/8x108 RBC. None of the included patients had signs of (noncirrhotic) portal hypertension or underwent a liver biopsy during follow-up. Conclusion This is the first cohort study that reports on the safety and effectiveness of first-line thioguanine maintenance therapy in IBD. Thioguanine therapy was, 12 months after initiation, still used by 80% and clinically effective in 61% of thiopurine-naive patients. Adverse events were relatively common but mainly mild (grade 1) and the discontinuation rate related to adverse events was lower than observed during conventional thiopurine therapy. No signs of (noncirrhotic) portal hypertension were reported

Exactly 70 years ago [1951] mercaptopurine was discovered by Gertrude Elion as a novel treatment option for acute leukaemia. A total of three thiopurines (also thioguanine [1950] and azathioprine [1957]) were developed over time. These immunosuppressive drugs were also successfully introduced a few decades later to prevent rejection of transplanted organs and to treat several autoimmune diseases. For her discovery of thiopurines and other antimetabolite drugs, in 1988 Elion was rewarded, together with George Hitchings and James Black, with the Nobel Prize in Physiology or Medicine. Important steps have been made in recent years to unravel its metabolism, mode of action and pharmacogenetics. Today thiopurine [based] therapy remains an essential immunosuppressive approach in treating patients with inflammatory bowel disease.

Background and Aims: The gut microbiota plays an important role in the metabolization and modulation of several types of drugs. With this study we aimed to review the literature relating to microbial drug metabolism of medication prescribed in inflammatory bowel disease [IBD] practice. Methods: A systematic literature search was performed in Embase and PubMed from inception to October 2019. The search was conducted with predefined MeSH/Emtree and text terms. All studies regarding drug metabolism by microbiota of medication prescribed in IBD practice were eligible. A total of 1018 records were encountered and 89 articles were selected for full text reading. Results: Intestinal bacterial metabolism or modulation is of influence in four specific drugs used in IBD (mesalazines, methotrexate, glucocorticoids and thioguanine). The gut microbiota cleaves the azo-bond of sulfasalazine, balsalazide and olsalazine and releases the active moiety 5-aminosalicylic acid. It has an impact on the metabolization and potentially on the response of methotrexate therapy. In particular, thioguanine can be converted by intestinal bacteria into the pharmacologically active 6-thioguanine nucleotides without the requirement of host metabolism. Glucocorticoid compounds can be prone to bacterial degradation. Conclusion: The human intestinal microbiota can have a major impact on drug metabolism and efficacy of medication prescribed in IBD practice. A better understanding of these interactions between microbiota and drugs is needed and should be an integral part of the drug development pathway of new IBD medication.

With great interest, we have read the letter by Verstockt et al 1 considering the response rate and outcome of thiopurine monotherapy in patients with Crohn’s disease (CD). The title, however, stating that thiopurine monotherapy has a limited place in treatment of patients with mild-to-moderate CD raised some questions. Almost all patients in this retrospective cohort were treated with azathioprine (AZA) and nowhere is mentioned if patients who experience intolerance were switched to another thiopurine or received a rechallenge. A retrospective study among 1327 patients exposed both to AZA or mercaptopurine (MP) demonstrated, however, that almost half of patients intolerant to the first thiopurine were able to tolerate the second.2 In addition, another study demonstrated that almost 65% had clinical improvement during thioguanine (TG) treatment after AZA or MP failure, so switching could potentially lead to a higher response rate.3 Moreover, the discussed lack of therapeutic drug …

In the recent era of growing availability of biological agents, the role of thiopurines needs to be reassessed with the focus on toxicity. We assessed the incidence and predictive factors of thiopurine-induced adverse events (AE) resulting in therapy cessation in pediatric inflammatory bowel disease (IBD), related to thiopurine metabolites and biochemical abnormalities, and determined overall drug survival. We performed a retrospective, single-center study of children diagnosed with IBD between 2000 and 2019 and treated with thiopurine therapy. The incidence of AE and overall drug survival of thiopurines were evaluated using the Kaplan–Meier method. Correlations between thiopurine metabolites and biochemical tests were computed using Spearman’s correlation coefficient. Of 391 patients with IBD, 233 patients (162 Crohn’s disease, 62 ulcerative colitis, and 9 IBD-unclassified) were prescribed thiopurines (230 azathioprine and 3 mercaptopurine), of whom 50 patients (22%) discontinued treatment, at least temporary, due to thiopurine-induced AE (median follow-up 20.7 months). Twenty-six patients (52%) were rechallenged and 18 of them (70%) tolerated this. Sixteen patients (6%) switched to a second thiopurine agent after azathioprine intolerance and 10 of them (63%) tolerated this. No predictive factors for development of AE could be identified. Concentrations of 6-thioguanine nucleotides (6-TGN) were significantly correlated with white blood cell and neutrophil count, 6-methylmercaptopurine (6-MMP) concentrations with alanine aminotransferase and gamma-glutamyltranspeptidase. Approximately 20% of pediatric patients with IBD discontinued thiopurine treatment due to AE. A rechallenge or switch to mercaptopurine is an effective strategy after development of AE. Concentrations of 6-TGN and 6-MMP are associated with biochemical abnormalities.

Abstract Background For measurement of fecal calprotectin (FC) a stool sample is sent to the laboratory, where calprotectin is extracted and determined. With the CALiaGold (CG) tube, especially designed for home sampling, this labor-intensive extraction procedure in the laboratory can be bypassed. Furthermore, the home-use of this buffer containing extraction device can potentially prevent FC degradation. We aimed to determine the reliability of patient performed FC extraction, to assess whether degradation during transport can be prevented and to determine its usability by patients. Methods In this prospective cross-sectional observational study, 4 CG tubes and 2 regular tubes were filled from the same bowel movement by patients with inflammatory bowel disease. Half of the tubes were directly frozen, others were sent to the laboratory by mail. Four more CG tubes were filled at the laboratory; 2 from the native sample sent by mail and 2 from the directly frozen native sample. The FC levels were measured by a particle enhanced turbidimetric immunoassay. The directly frozen tubes were used for the comparison between patient and analyst performed extractions, while the tubes sent by regular mail were used to determine FC stability during transport. The usability was assessed with a questionnaire. Results Fifty-three patients were included. No significant difference was found in patient performed extractions compared to analyst performed extractions in samples with FC levels <200 µg/g. However, in samples with FC levels ≥200 µg/g patient performed extractions were significantly lower (p=0.014). When patients were divided in 3 groups (i.e. FC levels <50ug/g, 50–200 µg/g and >200 µg/g), the resulting Cohen’s kappa coefficient was 0.787 (95% CI: 0.646–0.928), reflecting a substantial agreement between patient and analyst performed extraction. A median FC increase of 28.6% was found in the native samples after one freeze-thaw cycle, potentially explaining the higher FC levels in the analyst performed extractions from the directly frozen native sample. Patients sampling imprecision was higher (p<0.01, median CV 17%) compared to the analyst (median CV 8%). Higher FC levels were found in the CG tubes sent by mail compared to native samples, reflecting less FC degradation. The questionnaire revealed that 62% of patients preferred the CG tube and 8% the conventional tube. Conclusion Patient performed FC extraction is a realistic alternative sampling method, especially since the freeze-thaw process in the native samples may have led to higher values in the analyst performed extractions. Moreover, usage may prevent FC degradation during transport and patients prefer the use of the extraction device.

Thiopurines (mercaptopurine, azathioprine and thioguanine) are well-established maintenance treatments for a wide range of diseases such as leukemia, inflammatory bowel disease (IBD), systemic lupus erythematosus (SLE) and other inflammatory and autoimmune diseases in general. Worldwide, millions of patients are treated with thiopurines. The use of thiopurines has been limited because of off-target effects such as myelotoxicity and hepatotoxicity. Therefore, seeking methods to enhance target-based thiopurine-based treatment is relevant, combined with pharmacogenetic testing. Controlled-release formulations for thiopurines have been clinically tested and have shown promising outcomes in inflammatory bowel disease. Latest developments in nano-formulations for thiopurines have shown encouraging pre-clinical results, but further research and development are needed. This review provides an overview of novel drug delivery strategies for thiopurines, reviewing modified release formulations and with a focus on nano-based formulations.

Azathioprine and mercaptopurine exposure during conception and pregnancy has been considered safe in patients with inflammatory bowel disease (IBD). Its use is not associated with a higher risk of preterm birth or low birthweight. Data on the safety of tioguanine, an alternative thiopurine-derivate, in pregnant IBD patients is limited. In a small case series, tioguanine appeared safe for both mother and fetus. In this study, we describe the teratogenicity and safety of tioguanine during pregnancy in a large group of IBD patients. We performed a preliminary analysis of our ongoing multicenter descriptive case series of female IBD patients who were treated with tioguanine at some point during their pregnancy. Data regarding disease and medication history, pregnancy course and neonatal outcomes, such as preterm birth, miscarriage, birthweight, Apgar scores and congenital abnormalities were collected by the treating physician. Seventy-three pregnancies, including three twin pregnancies were collected. Most women (80%) had Crohn’s disease and the mean age during delivery was 31 years (range 21-42). Tioguanine was used throughout the entire pregnancy in 89% with a median daily dose of 20 mg. Five (6.8%) of these pregnancies resulted in a miscarriage, all within the first 13 weeks. No congenital abnormalities were reported in all seventy-one live born children. In the singleton pregnancies the median birthweight was 3375 gram (IQR 3075-3739, N=61, 4 missing values) with a median gestational age of 39.0 weeks (IQR 38.3-40.0, N=61). Four children (6.5%) were born prematurely (<37 weeks). Two of them were born after a spontaneous onset of labor with respectively 33 + 6 and 35 + 6 weeks, while in the other two labor was induced due to a placental abruption (32 + 1 weeks) or HELLP syndrome (31 + 4 weeks). Three children (4.9%) had a low birthweight (<2500 gram), all of them born prematurely, and five patients (8.3%, N=60, 5 missing values) were born small for gestational age (<10th percentile). The median Apgar score after 1 and 5 minutes was respectively 9 (IQR 8-9, N=58) and 10 (IQR 9-10, N=59). Two neonates (3.4%), one born pre-and dysmature and the other a premature second-born twin, had an Apgar score (<7) after 5 minutes. In this large case-series, tioguanine exposure during pregnancy was not associated with an increased risk of congenital abnormalities, low birthweight or preterm birth in IBD patients. These data support the safe use of tioguanine during pregnancy in IBD.

Liver InternationalVolume 40, Issue 12 p. 3141-3141 LETTER TO THE EDITOR Discontinuation rate of azathioprine Femke Crouwel, Corresponding Author f.crouwel@amsterdamumc.nl orcid.org/0000-0001-8755-9146 Department of Gastroenterology and Hepatology, AG&M Research Institute, Amsterdam University Medical Centre, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands Correspondence Femke Crouwel MD, Department of Gastroenterology and Hepatology, Amsterdam University Medical Centre, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands. Email: f.crouwel@amsterdamumc.nlSearch for more papers by this authorHans J. C. Buiter, Department of Clinical Pharmacology and Pharmacy, Amsterdam University Medical Centre, Vrije Universiteit Amsterdam, Amsterdam, the NetherlandsSearch for more papers by this authorNanne K. de Boer, Department of Gastroenterology and Hepatology, AG&M Research Institute, Amsterdam University Medical Centre, Vrije Universiteit Amsterdam, Amsterdam, the NetherlandsSearch for more papers by this author Femke Crouwel, Corresponding Author f.crouwel@amsterdamumc.nl orcid.org/0000-0001-8755-9146 Department of Gastroenterology and Hepatology, AG&M Research Institute, Amsterdam University Medical Centre, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands Correspondence Femke Crouwel MD, Department of Gastroenterology and Hepatology, Amsterdam University Medical Centre, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands. Email: f.crouwel@amsterdamumc.nlSearch for more papers by this authorHans J. C. Buiter, Department of Clinical Pharmacology and Pharmacy, Amsterdam University Medical Centre, Vrije Universiteit Amsterdam, Amsterdam, the NetherlandsSearch for more papers by this authorNanne K. de Boer, Department of Gastroenterology and Hepatology, AG&M Research Institute, Amsterdam University Medical Centre, Vrije Universiteit Amsterdam, Amsterdam, the NetherlandsSearch for more papers by this author First published: 05 July 2020 https://doi.org/10.1111/liv.14574Citations: 1Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume40, Issue12December 2020Pages 3141-3141 RelatedInformation

Thiopurine-derivates azathioprine and mercaptopurine are frequently used to maintain remission in inflammatory bowel diseases (IBD). Despite their efficacy, more than 50% of patients discontinue therapy, mainly due to the development of adverse events. Thioguanine is an alternative thiopurine and has been conditionally licensed in The Netherlands as I BD treatment for patients after conventional thiopurine therapy failure. In this review we will provide practical information on initiating and maintaining thioguanine therapy in IBD and provide information concerning safety issues and future perspectives. The thioguanine toxicity profile is relatively mild and the reported incidence of nodular regenerative hyperplasia related to thioguanine use seems comparable to conventional thiopurines and the background incidence in IBD patients. Routine monitoring of laboratory parameters and adverse events is recommended, comparable to the monitoring of patients on conventional thiopurine therapy.

Cladribine (CdA), a purine nucleoside analogue (PNA) that targets anti-CD4 and 8 T-cells, has recently been repositioned by Merck as an oral disease-modifying therapy for of highly active relaspe-remitting Multiple Sclerosis (RRMS), available as oral cladribine tablets (Mavenclad 10 mg). Its surplus value in the existing panel of disease-modifying therapy (DMT) for MS like the anti-CD20 B-cell targeting monoclonal antibodies, that is, rituximab (mouse chimeric), ocrelizumab (humanised) and ofatumumab (fully human) of which present data suggest that these are very effective in multiple sclerosis, is curious.1 In this personal viewpoint, we would like to highlight the potentially usefulness of PNA’s available and their limitations. PNAs are active in chronic lymphocytic leukaemia, hairy cell leukaemia (HCL) and off-label in low-grade lymphomas. Cladribine has been used for HCL since the early 1980s as intravenous therapy.2 Cladribine delivered subcutaneously (SC) appeared to be most convenient in HCL and is considered to have equal efficacy compared with intravenous administration. Oral CdA use has been suggested since the early 1990s by Carson et al 3 were it not that being unstable at acidic pH and is degraded by bacterial nucleoside phosphorylases. Other available PNAs are fludarabine (F-Ara) and clofarabine (CAFdA), which all are deoxyadenosine derivatives that act as antimetabolites that compete with natural deoxynucleosides used for DNA synthesis (figure 1). Figure 1 Chemical structures of purine analogues cladribine, fludarabine and clofarabine, compared with their natural deoxynucleoside, deoxyadenosine. All of these PNAs need to be metabolised to exert their cytotoxic … Correspondence to Dr Hans J C Buiter, Clinical Pharmacology and Pharmacy, Amsterdam University Medical Centres, Amsterdam 1081 HV, The Netherlands; hjc.buiter{at}amsterdamumc.nl

SummaryBackgroundTioguanine (or thioguanine) is an alternative drug for IBD patients who fail prior conventional immunomodulating therapy.AimTo report effectiveness, safety and therapeutic drug monitoring in a cohort of patients with prolonged tioguanine maintenance therapy.MethodsIn this nationwide, multicentre study, medical records of tioguanine‐ using IBD patients were retrospectively reviewed. Response to therapy was defined as clinical effectiveness without (re)initiation of corticosteroids, concurrent biological therapy or surgical intervention. All adverse events that occurred during the follow‐up were listed and graded according to the common terminology criteria (CTC).ResultsTwo hundred and seventy‐four patients (female 63%, Crohn's disease in 68%) were included with median treatment duration of 51 months, 1567 patient‐years of follow‐up and median 20 mg/d tioguanine dosage. Tioguanine was tolerated in 79%, clinical effectiveness at 6 months was documented in 66% and sustained clinical effectiveness during 12 months in 51% of patients. Forty‐one per cent of patients developed adverse events: 5% were graded as severe. Adverse events comprised infection requiring hospitalisation in three and skin cancer in eight patients (two melanomas). Asymptomatic nodular regenerative hyperplasia of the liver occurred in two out of 52 patients with liver biopsies (3.8%) and portal hypertension in three whereof one potentially associated with tioguanine (0.4%). Clinical effectiveness was correlated with 6‐thioguanine nucleotide threshold concentrations >682 pmol/8×108 RBC (P < 0.05).ConclusionsLong‐term tioguanine therapy for at least 12 months was effective in 51% and well tolerated as a maintenance treatment for IBD in about 70% of patients. Adverse events were common, but mainly mild or moderate. 6‐Thioguanine nucleotide threshold concentration ≥ 700 pmol/8×108 RBC is proposed as target level with higher odds for clinical effectiveness.