Abdominal pain in patients with inflammatory bowel disease in remission: A prospective study on contributing factors.

BACKGROUND: Abdominal pain is highly prevalent in patients with inflammatory bowel disease (IBD) in remission, but the aetiology is incompletely understood. AIM: To investigate the association of clinical, lifestyle and psychosocial factors with abdominal pain in patients with IBD in remission. METHODS: We performed a prospective multicentre study enrolling consecutive patients with IBD. Data were collected between 1 January 2020 and 1 July 2021, using myIBDcoach, an established remote monitoring platform for IBD. Chronic abdominal pain in IBD in remission (IBDremissionPain+) was defined as abdominal pain score ≥3 (0-10 NRS) on ≥1/3 of all assessments, combined with faecal calprotectin <150 µg/g in 90 days around periodic assessments. Disease activity, lifestyle and psychosocial factors were assessed every 1-3 months during 18 months. Using linear mixed models, the association of these factors with abdominal pain over time was analysed. RESULTS: We included 559 patients, of whom 429 (76.7%) remained in biochemical remission. Of these, 198 (46.2%) fulfilled the criteria for chronic abdominal pain. IBDremissionPain+ patients were characterised by female sex, younger age, higher BMI, and shorter disease duration. They reported more often or higher levels of stress, fatigue, depressive and anxiety symptoms, and life events (all p < 0.001). In the multivariable analysis, sex, disease entity, fatigue, depressive symptoms and life events were associated with abdominal pain over time (all p < 0.05). CONCLUSION: In this cohort of patients with IBD in remission, abdominal pain was common and associated with psychosocial factors. A more holistic treatment approach for patients with IBD suffering from abdominal pain may improve quality of care and subjective wellbeing.

Perspective on skeletal health in inflammatory bowel disease.

Osteopenia and osteoporosis are common features in inflammatory bowel disease (IBD), comprising both Crohn's disease and ulcerative colitis. Moreover, Crohn's disease is associated with increased fracture risk. The etiology of bone loss in IBD is multifactorial. It includes insufficient intake or absorption of calcium, vitamin D, and potassium; smoking; a low peak bone mass; a low body mass index; and decreased physical activity. In several studies, it has been shown that elevated concentrations of systemic and local pro-inflammatory cytokines, including tumor necrosis factor alpha (TNF-α), interferon-γ (IFNγ), interleukin (IL)-1ß, IL-4, IL-5, IL-6, IL-13, and IL-17, present in IBD patients are potentially detrimental for bone metabolism and may be responsible for bone loss and increased fracture risk. This perspective aims to review the current literature on the role of inflammatory factors in the pathophysiology of skeletal problems in IBD and to suggest potential treatment to improve bone health, based on a combination of evidence and clinical and pathophysiological reasoning.

Exocrine pancreatic and enterocyte function in patients with advanced pancreatic cancer.

BACKGROUND & AIMS: Exocrine pancreatic function is affected in patients with locally advanced pancreatic cancer (LAPC), clinically leading to steatorrhea. It is unknown whether maldigestion and malabsorption can also be attributed to impaired intestinal enterocyte function. In this exploratory study enterocyte function was assessed in patients with locally advanced pancreatic cancer, treated with Irreversible Electroporation (IRE). METHODS: Enterocyte function was studied by Citrulline Generation Test (CGT). Intestinal absorption capacity of energy and fat was calculated from the differences between nutritional intake (four-days diary) and quantified fecal losses energy and fat in three-days feces collection. RESULTS: Twelve patients were included before IRE, and 5 patients had follow-up measurements. Fasted citrulline [CIT] and glutamine [GLU] levels were below reference levels of healthy subjects ([CIT] 38 ± 8 µmol/L; [GLU] 561 ± 77 µmol/L) both before ([CIT] 25 ± 9 µmol/L; [GLU] 65 ± 35 µmol/L) and after IRE ([CIT] 19 ± 9 µmol/L; [GLU] 53 ± 26 µmol/L) whereas CGT curves were normal, indicating normal enterocyte function (slope 0.21 ± 0.12 and 0.17 ± 0.07 µmol/L/min; [CIT] increment 63 ± 39 and 80 ± 44% respectively). Severe energy/fat malabsorption was present in 6 out of 12 patients with LAPC (mean loss 349 kcal/d, 13 g fat/d) before and in 4 out of 5 patients (mean loss 509 kcal/d, 32 g fat/d) after IRE respectively. CONCLUSIONS: Enterocyte function was generally within reference limits in patients with advanced pancreatic cancer. Severe malabsorption may be explained by exocrine pancreatic insufficiency.

Variability of core microbiota in newly diagnosed treatment-naïve paediatric inflammatory bowel disease patients.

BACKGROUND & AIMS: Intestinal microbiota is considered to play a crucial role in the aetiology of inflammatory bowel disease (IBD). We aimed to describe faecal microbiota composition and dynamics in a large cohort of children with de novo (naïve) IBD, in comparison to healthy paediatric controls (HC). METHODS: In this prospective study, performed at two tertiary centres, faecal samples from newly diagnosed, treatment-naïve paediatric IBD patients were collected prior to bowel cleansing for colonoscopy (t0) and 1, 3 and 6 weeks and 3 months after initiation of therapy. The microbial profiles of Crohn's disease (CD) and Ulcerative colitis (UC) patients were compared with HC and linked to therapeutic response. Microbiota composition was analysed by IS-pro technology. RESULTS: Microbial profiles of 104 new IBD-patients (63 CD, 41 UC, median age 14.0 years) were compared to 61 HC (median 7.8 years). IBD was mainly characterised by decreased abundance of Alistipes finegoldii and Alistipes putredinis, which characterize a healthy state microbial core. The classifier including these core species as predictors achieved an AUC of the ROC curve of .87. Core bacteria tended to regain abundance during treatment, but did not reach healthy levels. CONCLUSION: Faecal microbiota profiles of children with de novo CD and UC can be discriminated from HC with high accuracy, mainly driven by a decreased abundance of species shaping the microbial core in the healthy state. Paediatric IBD can therefore be characterized by decreased abundance of certain bacterial species reflecting the healthy state rather than by the introduction of pathogens.

Impacts of perianal disease and faecal incontinence on quality of life and employment in 1092 patients with inflammatory bowel disease.

BACKGROUND: Patient reported outcomes regarding perianal disease and faecal incontinence in the community-based inflammatory bowel disease population are poorly described. AIMS: To determine the impacts of perianal disease and faecal incontinence on quality of life and employment in inflammatory bowel disease patients. METHODS: For this cross-sectional study, a comprehensive survey was sent out to members of the Dutch National Crohn's and Colitis patient organisation. Validated questionnaires regarding faecal incontinence and active perianal disease were used to estimate its prevalence's. The effect on the quality of life (36-Item Short Form Survey) and on employment status (multivariate binary regression analysis) was assessed in this inflammatory bowel disease population. RESULTS: A total number of 1092 returned questionnaires (58% responders) were used for analysis; 750 respondents (69%) were female; mean age was 47 years (IQR 35-59). In 621 patients (57%) Crohn's disease, in 422 (39%) ulcerative colitis and in 49 (4%) patients unclassifiable inflammatory bowel disease was self-reported. The 114 patients (10%) with a stoma were excluded for continence related analyses. Faecal incontinence was reported in 555 patients (57%), was comparable between the different inflammatory bowel disease diagnoses and affected all 36-Item Short Form Survey subscales adversely (incontinence vs continence: Physical functioning 75 vs 84, P < 0.0001; Limitations due to physical health 49 vs 63, P < 0.0001; Limitations due to emotional problems 49 vs 64, P < 0.0001; Energy/fatigue 47 vs 53, P < 0.0001; Emotional well-being 71 vs 74, P = 0.005; Social functioning 63 vs 73, P < 0.0001; Pain 66 vs 75, P < 0.0001; General health 41 vs 48, P < 0.0001). Active perianal disease was reported in 39% Crohn's disease, 16% ulcerative colitis (84% fissures) and 20% unclassifiable inflammatory bowel disease patients. Faecal incontinence was more common in patients with perianal disease (67% vs 53%, P = 0.003). When correcting for age, disease duration, inflammatory bowel disease-related surgery and faecal incontinence, active perianal disease was independently affecting employment (OR 0.67; 95% CI 0.50-0.91; P = 0.01). CONCLUSIONS: Faecal incontinence and perianal disease are quality of life determining factors. Faecal incontinence needs more attention among clinicians, and development of new (drug) therapies needs to be focussed on perianal disease.

The nocebo effect challenges the non-medical infliximab switch in practice.

BACKGROUND: In clinical practice, non-medical switching of biological medication may provoke nocebo effects due to unexplained deterioration of therapeutic benefits. Indication extrapolation, idiosyncratic reactions, and interchangeability remain challenged in clinical practice after biosimilar approval by the European Medicines Agency. The principle of "first do no harm" may be challenged in a patient when switching from originator to biosimilar biological. AIM: To describe the 1-year results of a pragmatic study on infliximab biosimilar implementation in immune-mediated inflammatory disease patients on the basis of shared decision-making under effectiveness and safety monitoring. METHODS: Inflammatory bowel disease and rheumatology patients on infliximab originator were converted to infliximab biosimilar after providing informed consent. Nocebo response patients were monitored after switch back to originator. Linear mixed models were used to analyze continuous endpoints on effectiveness and laboratory outcomes to determine significance (P ≤ 0.05) of change over time after switching. RESULTS: After inviting 146 patients, a group of 125 patients enrolled in the project over time, respectively, 73 Crohn's disease, 28 ulcerative colitis, nine rheumatoid arthritis, ten psoriatic arthritis, and five ankylosing spondylitis patients. No statistically significant changes in effectiveness and safety were observed in any of the indications after a median of 4 infusions in 9 months of study. An overall nocebo response of 12.8% was found among the patients during a minimal observation period of 6 months after the transition to biosimilar infliximab. The overall nocebo response rate did not differ between the studied indications. CONCLUSIONS: In inflammatory bowel disease and rheumatological patients, similar effectiveness and safety were demonstrated on the transition into infliximab biosimilar. In our series, patient empowerment and registration of treatment outcomes delineated biosimilar transition, an approach that hypothetically could reduce nocebo response rates which are relevant to account for regarding biosimilar implementation.

Smoking is Associated with Higher Disease-related Costs and Lower Health-related Quality of Life in Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Smoking affects the course of inflammatory bowel disease [IBD]. We aimed to study the impact of smoking on IBD-specific costs and health-related quality-of-life [HrQoL] among adults with Crohn's disease [CD] and ulcerative colitis [UC]. METHODS: A large cohort of IBD patients was prospectively followed during 1 year using 3-monthly questionnaires on smoking status, health resources, disease activity and HrQoL. Costs were calculated by multiplying used resources with corresponding unit prices. Healthcare costs, patient costs, productivity losses, disease course items and HrQoL were compared between smokers, never-smokers and ex-smokers, adjusted for potential confounders. RESULTS: In total, 3030 patients [1558 CD, 1054 UC, 418 IBD-unknown] were enrolled; 16% smoked at baseline. In CD, disease course was more severe among smokers. Smoking was associated with > 30% higher annual societal costs in IBD (€7,905 [95% confidence interval €6,234 - €9,864] vs €6,017 [€5,186 - €6,946] in never-smokers and €5,710 [€4,687 - €6,878] in ex-smokers, p = 0.06 and p = 0.04, respectively). In CD, smoking patients generated the highest societal costs, primarily driven by the use of anti-tumour necrosis factor compounds. In UC, societal costs of smoking patients were comparable to those of non-smokers. Societal costs of IBD patients who quitted smoking > 5 years before inclusion were lower than in patients who quitted within the past 5 years (€ 5,135 [95% CI €4,122 - €6,303] vs €9,342 [€6,010 - €12,788], p = 0.01). In both CD and UC, smoking was associated with a lower HrQoL. CONCLUSIONS: Smoking is associated with higher societal costs and lower HrQoL in IBD patients. Smoking cessation may result in considerably lower societal costs.

The Economic Impact of the Introduction of Biosimilars in Inflammatory Bowel Disease.

OBJECTIVE: Inflammatory bowel disease [IBD] entails a high economic burden to society. We aimed to estimate the current and future impact of the introduction of biosimilars for infliximab on IBD-related health care costs. METHODS: We designed a stochastic economic model to simulate the introduction of biosimilars in IBD, using a 5-year time horizon, based on the Dutch situation. Prevalence data on ulcerative colitis [UC] and Crohn's disease [CD] and IBD-related health care costs data were used as input. Assumptions were made on price reductions of anti-tumour necrosis factor [TNF] therapy, increase of anti-TNF prescription rate, and development of hospitalization costs. The base case scenario included a gradual decrease in prices of biosimilars up to 60%, a gradual decrease in prices of original anti-TNF compounds up to 50%, and an annual increase of anti-TNF prescription rate of 1%, and this was compared with no introduction of biosimilars. Sensitivity analyses were performed. RESULTS: For the base case, cost savings over the total of 5 years were on average €9,850 per CD patient and €2,250 per UC patient, yielding in €493 million total cost savings [a reduction of 28%] for The Netherlands. Results were predominantly determined by price reduction of anti-TNF therapy, threshold price reduction at which physicians switch patients towards biosimilars and the extent to which switching will take place. CONCLUSIONS: The introduction of biosimilars for infliximab can be expected to have a major impact on the cost profile of IBD. The economic impact will depend on local pricing, procurement policies and the physician's willingness to switch patients to biosimilars.

Smoking is Associated With Extra-intestinal Manifestations in Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Smoking affects the course of disease in patients with ulcerative colitis (UC) and Crohn's disease (CD). We aimed to study the association between smoking and extra-intestinal manifestations (EIMs) in inflammatory bowel disease (IBD). METHODS: We cross-sectionally explored the association between smoking and EIMs in IBD in three cohort studies: (1) the COIN study, designed to estimate healthcare expenditures in IBD; (2) the Groningen study, focused on cigarette smoke exposure and disease behaviour in IBD; and (3) the JOINT study, evaluating joint and back manifestations in IBD. RESULTS: In the COIN, Groningen and JOINT cohorts, 3030, 797 and 225 patients were enrolled, of whom 16, 24 and 23.5% were current smokers, respectively. Chronic skin disorders and joint manifestations were more prevalent in smoking IBD patients than in non-smokers (COIN, 39.1 vs 29.8%, p <0.01; Groningen, 41.7 vs 30.0%, p <0.01) in both CD and UC. In the JOINT cohort, smoking was more prevalent in IBD patients with joint manifestations than in those without (30.3 vs 13.0%, p <0.01). EIMs appeared to be more prevalent in high- than in low-exposure smokers (56.0 vs 37.1%, p = 0.10). After smoking cessation, the prevalence of EIMs in IBD patients rapidly decreased towards levels found in never smokers (lag time: COIN cohort, 1-2 years; Groningen cohort, within 1 year). CONCLUSIONS: There is a robust dose-dependent association between active smoking and EIMs in both CD and UC patients. Smoking cessation was found to result in a rapid reduction of EIM prevalence to levels encountered in never smokers.

Refractory diversion neovaginitis in a sigmoid-colon-derived neovagina: clinical and histopathological considerations.

Colonic segments are being used as pedicled grafts in neovaginoplasty, a surgical procedure to (re)construct a (neo)vagina. A disadvantage of using colonic grafts is the potential occurrence of neovaginal complications due to diversion from the faecal stream. Here, we report a case of severe, refractory diversion colitis of the sigmoid neovagina, so-called 'diversion neovaginitis', in a 42-year-old woman with complete androgen insensitivity syndrome. Neovaginal biopsy specimens showed colonic-type mucosa with strong increase of lymphoplasmacellular infiltrate in the lamina propria, ulceration with fibrinoid deposition and some crypt irregularity. Endoscopy showed erythematous mucosa, superficial ulceration, mucus discharge and multiple pseudopolyp-like lesions. Local application of mesalazine foam enemas and sodium butyrate enemas initially gave symptom relief. However, this was a temporary effect, ultimately necessitating removal of the neovaginal construct. It is important that all patients are informed about neovaginal bowel complications, for example, diversion neovaginitis. Regular medical and endoscopic follow-up appears recommendable.

Tropheryma whipplei, a Potential Commensal Detected in Individuals Undergoing Routine Colonoscopy.

Mucosal biopsy samples from individuals not suspected of having Whipple's disease were tested for the presence of Tropheryma whipplei. A sensitive and specific real-time PCR assay targeting a sequence present seven times in the T. whipplei genome was used. T. whipplei DNA was detected in 2.0 and 3.8% of the patients undergoing gastroduodenoscopy and colonoscopy, respectively, who were tested.

The pharmacokinetic effect of adalimumab on thiopurine metabolism in Crohn's disease patients.

BACKGROUND AND AIMS: A drug interaction between infliximab and azathioprine has previously been reported in Crohn's disease patients: the concentration of the main active thiopurine metabolites, the 6-thioguanine nucleotides (6-TGN), increased 1-3 weeks after the first infliximab infusion by 50% compared to baseline. The aim of this prospective study was to determine the effect of adalimumab on thiopurine metabolism in Crohn's disease patients, evaluated by 6-TGN and 6-methylmercaptopurine ribonucleotides (6-MMPR) concentration measurement. METHODS: Crohn's disease patients on azathioprine or mercaptopurine maintenance therapy starting with concomitant adalimumab treatment were included. 6-TGN and 6-MMPR concentrations were determined before initiation of adalimumab and after 2, 4, 6 and 12 weeks of combination therapy. The activity of three essential enzymes involving thiopurine metabolism, thiopurine S-methyltransferase (TPMT), hypoxanthine-guanine phosphoribosyl transferase (HGPRT) and inosine-triphosphate pyrophosphatase (ITPase), was evaluated at baseline and week 4. Clinical outcome was evaluated by the Crohn's disease activity index and C-reactive protein concentrations at baseline, week 4 and week 12. RESULTS: Twelve Crohn's disease patients were analyzed. During the follow-up period of 12 weeks the median 6-TGN and 6-MMPR concentrations did not significantly change compared to baseline. TPMT, ITPase and HGPRT enzyme activity did not change either after 4 weeks. In two patients (17%) myelotoxicity was observed within 2-4 weeks, in whom both low therapeutic 6-TGN and 6-MMPR concentrations were found. CONCLUSIONS: In this study in Crohn's disease patients no pharmacokinetic interaction was shown between adalimumab and the conventional thiopurines, azathioprine and mercaptopurine.

Bomb calorimetry, the gold standard for assessment of intestinal absorption capacity: normative values in healthy ambulant adults.

BACKGROUND: Intestinal absorption capacity is considered to be the best method for assessing overall digestive intestinal function. Earlier reference values for intestinal function in healthy Dutch adults were based on a study that was conducted in an inpatient metabolic unit setting in a relatively small series. The present study aimed to readdress and describe the intestinal absorption capacity of healthy adults, who were consuming their usual (Western European) food and beverage diet, in a standard ambulatory setting. METHODS: Twenty-three healthy subjects (aged 22-60 years) were included in the analyses. Nutritional intake (energy and macronutrients) was determined with a 4-day nutritional diary. Subsequently, mean faecal losses of energy (by bomb calorimetry), fat, protein and carbohydrate were determined following a 3-day faecal collection. Finally, intestinal absorption capacity was calculated from the differences between intake and losses. RESULTS: Mean (SD) daily faeces production was 141 (49) g (29% dry weight), containing 891 (276) kJ [10.7 (1.3) kJ g(-1) wet faeces; 22.6 (2.5) kJ g(-1) dry faeces], 5.2 (2.2) g fat, 10.0 (3.8) g protein and 29.7 (11.7) g carbohydrates. Mean (SD) intestinal absorption capacity of healthy subjects was 89.4% (3.8%) for energy, 92.5% (3.7%) for fat, 86.9% (6.4%) for protein and 87.3% (6.6%) for carbohydrates. CONCLUSIONS: The present study provides normative values for both stool nutrient composition and intestinal energy and macronutrient absorption in healthy adults on a regular Dutch diet in an ambulatory setting. Intestinal energy absorption was found to be approximately 90%.

Long-term follow-up of children exposed intrauterine to maternal thiopurine therapy during pregnancy in females with inflammatory bowel disease.

BACKGROUND: Inflammatory bowel disease (IBD) affects a substantial number of female patients in their reproductive years. Therefore, many physicians face the dilemma whether thiopurines, prescribed to maintain remission, can be taken safely during pregnancy. Data on long-term development outcome of children exposed to maternal thiopurine therapy are very limited. AIM: To assess the long-term effects of in utero exposure to thiopurines during pregnancy on infant health status. METHODS: A prospective multicentre follow-up study was performed in children exposed intrauterine to maternal thiopurine therapy. Physical, cognitive and social aspects of infant health status were assessed with the 43-item TNO-AZL Preschool Children Quality of Life Questionnaire (TAPQOL). Furthermore, information on visits to general practitioner and medical specialists, and physician's advice regarding lactation was evaluated. Data were compared with normative data from a control group consisting of 340 children. RESULTS: Thirty children were included in this study [median 3.8 years (IQR 2.9-4.7)]. No differences on global medical and psychosocial health status were found between children exposed to intrauterine thiopurines and the reference group. Exposure to intrauterine thiopurines was not associated with increased susceptibility to infection or immunodeficiency in childhood. Twenty-one of 30 children were exclusively formula-fed based on a negative advice of medical specialists directed at thiopurine use during lactation. CONCLUSIONS: Thiopurine use during pregnancy did not affect long-term development or immune function of children up to 6 years of age. Our results underscore the present notion that mothers, even those using thiopurines, should be encouraged to breastfeed their infants.

Thiopurine treatment in patients with Crohn's disease leads to a selective reduction of an effector cytotoxic gene expression signature revealed by whole-genome expression profiling.

Crohn's disease (CD) is characterized by chronic inflammation of the gastrointestinal tract, as a result of aberrant activation of the innate immune system through TLR stimulation by bacterial products. The conventional immunosuppressive thiopurine derivatives (azathioprine and mercaptopurine) are used to treat CD. The effects of thiopurines on circulating immune cells and TLR responsiveness are unknown. To obtain a global view of affected gene expression of the immune system in CD patients and the treatment effect of thiopurine derivatives, we performed genome-wide transcriptome analysis on whole blood samples from 20 CD patients in remission, of which 10 patients received thiopurine treatment, compared to 16 healthy controls, before and after TLR4 stimulation with LPS. Several immune abnormalities were observed, including increased baseline interferon activity, while baseline expression of ribosomal genes was reduced. After LPS stimulation, CD patients showed reduced cytokine and chemokine expression. None of these effects were related to treatment. Strikingly, only one highly correlated set of 69 genes was affected by treatment, not influenced by LPS stimulation and consisted of genes reminiscent of effector cytotoxic NK cells. The most reduced cytotoxicity-related gene in CD was the cell surface marker CD160. Concordantly, we could demonstrate an in vivo reduction of circulating CD160(+)CD3(-)CD8(-) cells in CD patients after treatment with thiopurine derivatives in an independent cohort. In conclusion, using genome-wide profiling, we identified a disturbed immune activation status in peripheral blood cells from CD patients and a clear treatment effect of thiopurine derivatives selectively affecting effector cytotoxic CD160-positive cells.

The effect of allopurinol and low-dose thiopurine combination therapy on the activity of three pivotal thiopurine metabolizing enzymes: results from a prospective pharmacological study.

INTRODUCTION: Thiopurine therapy is often discontinued in inflammatory bowel disease (IBD) patients. The xanthine oxidase (XO) inhibitor allopurinol has previously shown to enhance thiopurine efficacy and to prevent adverse reactions, the mechanism of this beneficial interaction is not completely clarified. The aim of this study is to observe possible effects of allopurinol and low-dose thiopurine combination therapy on the activity of three pivotal thiopurine metabolizing enzymes. METHODS: A prospective study of IBD patients failing thiopurine therapy due to a skewed thiopurine metabolism was performed. Patients were treated with allopurinol and azathioprine or mercaptopurine. Xanthine oxidase, hypoxanthine-guanine phosphoribosyl transferase (HGPRT) and thiopurine S-methyl transferase (TPMT) activities, and thiopurine metabolites concentrations were measured during thiopurine monotherapy, and after 4 and 12 weeks of combination therapy. RESULTS: Of fifteen IBD patients, XO activity decreased from 0.18 (IQR 0.08-0.3) during thiopurine monotherapy to 0.14 (IQR 0.06-0.2) and 0.11 (IQR 0.06-0.2; p=0.008) mU/hour/ml at 4 and 12 weeks, respectively. HGPRT activity increased from 150 (IQR 114-176) to 180 (IQR 135-213) and 204 nmol/(h×mg protein) (IQR 173-213; p=0.013). TPMT activity seemed not to be affected. 6-Thioguanine nucleotide concentrations increased from 138 (IQR 119-188) to 235 (223-304) and to 265 pmol/8×10^8 (IQR 188-344), whereas 6-methyl mercaptopurine ribonucleotides concentrations decreased from 13230 (IQR 7130-17420) to 690 (IQR 378-1325) and 540 (IQR 240-790) pmol/8×10^8 at 4 and 12 weeks of combination therapy (both p<0.001). CONCLUSION: Allopurinol and thiopurine combination-therapy seems to increase HGPRT and decrease XO activity in IBD patients, which at least in part may explain the observed changes in thiopurine metabolite concentrations.