Abstract Background Crohn’s disease (CD) is a chronic, relapsing–remitting gastrointestinal inflammatory condition with a multifactorial etiology. At present, drug therapy is the most important treatment option. However, a substantial number of CD patients experience side effects and/or nonresponse to medical drugs. In part, this might be attributed to the interaction of the intestinal microbiome with xenobiotics, such as medical drugs. The aim of this study was to explore the effect of the common CD drugs budesonide, 6-mercaptopurine (6-MP), as well as tofacitinib on the CD patient’s microbiome in vitro. Results We performed 16S rRNA gene-based bacterial community profiling and metaproteomic analyses on anaerobic ex vivo incubations of CD patient-derived fecal microbiota (FM) that were exposed to CD drugs or control conditions. Both bacterial community profiling and metaproteomics revealed larger differences in 24-h FM incubations between the five donor-derived FM samples than between the various drug incubations. Incubation of the FM of one of the donors with 6-MP or tofacitinib resulted in a significant alteration in the metaproteome when compared to the control condition, whereas no effect could be observed upon incubation with budesonide. Considering only bacterial proteins detected in at least 80% of either the drug or control FM incubations, 33 proteins were consistently more abundant and 93 less abundant in all five donor-derived samples with 6-MP incubation, distinguishing 6-MP from control conditions. In contrast to metaproteomic analyses, bacterial community profiling only detected a significantly lower relative abundance of Colidextribacter in 15 µg/ml tofacitinib FM incubations. No alterations were detected in overall bacterial richness, diversity, or community structure in response to incubation with any of the drugs. Conclusions Tofacitinib and especially 6-MP significantly affect microbial function, but barely microbial composition in vitro. These drug-induced functional changes may subsequently influence host physiology and potentially inflammation in CD. Our findings emphasize the relevance to include functional microbial studies when investigating drug–microbiota interactions. Further research is needed to elucidate the impact of 6-MP-induced microbial alterations on intestinal physiology and inflammation in CD.

INTRODUCTION:An increasing number of patients in clinical practice are transitioning from intravenous (IV) to subcutaneous (SC) dosing of infliximab. In this simulation study, we evaluated hypothetical dosing scenarios both for typical adults and adults with obesity and for children switching from steady-state IV to SC infliximab, as well as those initiating SC infliximab therapy. METHODS:By combining two previous published infliximab models, we were able to simulate both IV and SC dosing in adults and children. Various dosing regimens were simulated using a large virtual population. In each scenario, the distribution of trough concentrations and area under the plasma concentration-time curve (AUC) was calculated. RESULTS:Peak levels were higher after IV dosing compared with SC dosing, while trough levels were higher after SC dosing, leading to more stable infliximab levels over time. Overall exposure remained largely similar when switching from a standard IV to SC dosing regimen. Patients with a high body mass index and those on high-frequency IV dosing regimens of infliximab demonstrated reduced exposure when transitioned to the fixed SC dose. Paediatric patients exhibited higher exposure on the fixed SC dose. Simulation of SC induction schemes demonstrated early achievement of steady-state plasma levels. CONCLUSION:Infliximab exposure (AUC) remains largely similar when transitioning from standard IV to SC dosing. Current dosing regimens may not be optimal for patients with severe obesity, paediatric patients and patients on high-frequency infliximab regimens. These findings provide a foundation for future clinical research to refine SC infliximab dosing in these populations.

Abstract Background Thiopurines, such as azathioprine (AZA), mercaptopurine (MP) and thioguanine (TG), are commonly used to maintain disease remission in inflammatory bowel disease (IBD). AZA and MP are metabolized to form the active 6-thioguanine nucleotides (6-TGN) and the 6-methylmercaptopurine ribonucleotides (6-MMPR), associated with intolerable adverse drug reactions. Previous studies report a shift in thiopurine metabolism during pregnancy, characterized by a decrease in 6-TGN and an increase in 6-MMPR levels 1,2. The influence of these changes on clinical outcomes remains unclear. This study aims to explore the association of changes in 6-TGN and 6-MMPR levels during pregnancy with disease activity and toxicity markers in women with IBD. Methods A retrospective cohort study was conducted recruiting patients with IBD from six Dutch medical centers. Adult women who were pregnant between 2017 and 2022, using thiopurines for IBD, and with at least one thiopurine metabolite measurement during pregnancy were included. Linear mixed effects models assessed 6-TGN and 6-MMPR levels during pregnancy (categorized to half trimesters) and within 6 months postpartum, compared to preconceptional levels, adjusting for dosage and repeated measurements. The influence of percentual changes in 6-TGN and 6-MMPR on disease activity (calprotectin >250μg/g), hepatotoxicity (alanine aminotransferase (ALT) >2xULN) and myelotoxicity (leukocytes <4.0x109/L) were analyzed, adjusting for dosage and trimester. Results A total of 87 women with 100 pregnancies were included, of whom 64.4% were diagnosed with Crohn’s disease and 32.2% with ulcerative colitis. An adverse pregnancy outcome occurred in 13 pregnancies (13%), with rates comparable to the healthy Dutch population. Subtherapeutic levels of 6-TGN were measured in 32 pregnancies (32%). There were no instances of leukopenia; transient hepatotoxicity occurred thrice (3%). There was active disease in 30 pregnancies, corresponding to 37 metabolite measurements. Analysis showed a significant reduction in 6-TGN levels in the second trimester (Figure 1), with non-significant increases in 6-MMPR. Though disease activity coincided with subtherapeutic 6-TGN-levels 21 times (56.8%), the reduction in 6-TGN was not associated with changes in calprotectin (Estimated marginal mean difference (EMM) =5.435, p=0.104), ALT (EMM=-0.025, p=0.858) or leukocytes (EMM=0.068, p=0.536, Table 1). Conclusion Our study results indicate that despite that 6-TGN levels decrease and 6-MMP may increase during pregnancy, these fluctuations do not seem to associate with markers of disease activity, hepatotoxicity and myelotoxicity. Larger, prospective studies are needed to re-evaluate the postulated need for thiopurine monitoring in the third trimester. References 1.Flanagan E, Wright EK, Hardikar W, et al. Maternal thiopurine metabolism during pregnancy in inflammatory bowel disease and clearance of thiopurine metabolites and outcomes in exposed neonates. Aliment Pharmacol Ther. 2021;53:810-820. 2.Jharap B, De Boer NKH, Stokkers P, et al. Intrauterine exposure and pharmacology of conventional thiopurine therapy in pregnant patients with inflammatory bowel disease. Gut. 2014;63(3):451-457. doi:10.1136/gutjnl-2012-303615

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract that encompasses two major conditions: Crohn’s disease (CD) and ulcerative colitis (UC). Historically, IBD has been primarily reported in western countries, but over the past decades, its prevalence is rapidly increasing, especially in lower and middle-income countries (LMICs) such as India and China and also in Sub-Saharan Africa. The prevalence of IBD in LMICs has been the subject of growing concern due to the impact of access to public healthcare and the burden it places on healthcare resources. The classical thiopurines face significant challenges due to cessation of therapy in approximately half of patients within one year due to side effects or ineffectiveness. In this article, we highlight innovating thiopurine treatment for IBD patients in downregulating side effects and improving efficacy.

Abstract Background OPTIC was a prospective placebo-controlled trial investigating therapeutic drug monitoring (TDM)-based mercaptopurine (MP) therapy in ulcerative colitis (UC). Although the primary endpoint (corticosteroid-free clinical remission and endoscopic improvement at week 52) favoured patients with TDM-based MP therapy over placebo, drug-related adverse events were frequent and drop-out rates high. This post-hoc analysis was carried out to show the therapeutic implications of proactive TDM of MP. Methods UC patients with active disease, despite ≥2 g/day mesalamine, underwent remission induction treatment with corticosteroids and initiated weight-based MP therapy (1-1.5 mg/kg). TDM based optimisations were performed at week 6, 12, 18, 24, 36 and 52 using the Dervieux method, unblinded non-including thiopurine expert physicians (DA, MD and AB) provided dosing advice according to a predefined algorithm, aiming for 6-TGN levels of 600-1200 pmol/8×108 RBC and 6-MMP of <5700 pmol/8×108 RBC. Associations between 6-TGN and 6-MMP levels, MP dose and thiopurine S-methyltransferase (TPMT) polymorphisms were explored. Results In total, 29 patients initiated MP treatment (41% female, median age 46 yrs [IQR 26-58], median disease duration 6 yrs [IQR 1-14]). TPMT heterozygosity was found in 4/29 patients (3/4 TPMT*3A, 1/4 TPMT*3C). TDM dose adjustments were required in 22/29 patients: 14/29 started allopurinol and decreased MP dose, 5/29 discontinued MP before the first TDM assessment, 2/29 continued MP at the initial dose up until week 52 and the remaining underwent MP dose adjustments. Most adjustments (71%) were made at week 6, thereafter 6-MMP levels stabilised, while 6-TGN concentrations remained stable (Figure 1). TPMT variant carriers had a higher median 6-TGN concentration compared to non-carriers (1700 [IQR 1625-1850] vs 539 pmol/8×108 RBC [IQR 355-953], P<0.001) and more likely to have leukopenia (P=0.025). Two TPMT heterozygous patients achieved the primary endpoint with dose reductions, two discontinued due to myelotoxicity or hepatotoxicity. Until week 52, 16/29 patients completed the trial, 14/29 reached the endpoint with a median 6-TGN of 585 pmol/8×108 RBC (IQR 428-745) and 6-MMP of 268 pmol/8×108 RBC (IQR 110-1257). MP dose correlated with 6-MMP but not with 6-TGN levels. Independently of allopurinol co-prescription, the initial median weight-based MP dose of 100 mg (IQR 75-125) decreased significantly to 50 mg (IQR 25-100, P=0.041). Conclusion Most patients underwent TDM optimisation of MP, half of the patients initiated allopurinol with decreased MP dose. TPMT heterozygosity led to supratherapeutic 6-TGN concentrations and adverse events. Weight-based initial MP dose may need reconsideration.

Therapeutic drug monitoring (TDM) of tumor necrosis factor-α (TNFα)-inhibitors adalimumab and infliximab is important to establish optimal drug dose and maximize treatment efficacy. Currently, TDM is primarily performed with ELISA techniques in clinical laboratories, resulting in a long sample-to-result workflow. Point-of-care (POC) detection of these therapeutic antibodies could significantly decrease turnaround times and allow for user-friendly home-testing. Here, we adapted the recently developed bioluminescent dRAPPID (dimeric Ratiometric Plug-and-Play Immunodiagnostics) sensor platform to allow POC TDM of infliximab and adalimumab. We applied the two best performing dRAPPID sensors, with limit-of-detections of 1 pM and 17 pM, to measure the infliximab and adalimumab levels in 49 and 40 patient serum samples, respectively. The analytical performance of dRAPPID was benchmarked with commercial ELISAs and yielded Pearson's correlation coefficients of 0.93 and 0.94 for infliximab and adalimumab, respectively. Furthermore, a dedicated bioluminescence reader was fabricated and used as a readout device for the TDM dRAPPID sensors. Subsequently, infliximab and adalimumab patient serum samples were measured with the TDM dRAPPID sensors and bioluminescence reader, yielding Pearson's correlation coefficients of 0.97 and 0.86 for infliximab and adalimumab, respectively, and small proportional differences with ELISA (slope was 0.97 ± 0.09 and 0.96 ± 0.20, respectively). The adalimumab and infliximab dRAPPID sensors, in combination with the dedicated bioluminescence reader, allow for ease-of-use TDM with a fast turnaround time and show potential for POC TDM outside of clinical laboratories.

Underdosing of adalimumab can result in non-response and poor disease control in patients with rheumatic disease or inflammatory bowel disease. In this pilot study we aimed to predict adalimumab concentrations with population pharmacokinetic model-based Bayesian forecasting early in therapy. Adalimumab pharmacokinetic models were identified with a literature search. A fit-for-purpose evaluation of the model was performed for rheumatologic and inflammatory bowel disease (IBD) patients with adalimumab peak (first dose) and trough samples (first and seventh dose) obtained by a volumetric absorptive microsampling technique. Steady state adalimumab concentrations were predicted after the first adalimumab administration. Predictive performance was calculated with mean prediction error (MPE) and normalised root mean square error (RMSE). Thirty-six patients (22 rheumatologic and 14 IBD) were analysed in our study. After stratification for absence of anti-adalimumab antibodies, the calculated MPE was −2.6 www.trialregister.nl ).

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.

Introduction A substantial number of Crohn’s disease (CD) patients experience side-effects and/or non-response to medical drugs. In part, this might be attributed to the interaction of the intestinal microbiome with xenobiotics. The aim of this study was to explore the effect of common CD drugs on the patient’s microbiome in vitro . Methods The fecal microbiome of each of 5 CD patients was exposed to 42 μg/ml budesonide, 55 μg/ml 6-mercaptopurine (6-MP), 5 or 15 μg/ml tofacitinib, or DMSO-control in defined culture medium in an anaerobic chamber at 37°C for 24 hours. Subsequently, DNA and proteins were isolated and subjected to 16 rRNA gene amplicon sequencing and LC-MS proteomic analysis, respectively. Results Metagenomic and metaproteomic analyses revealed larger differences between donors than between drug exposures. Exposure to 6-MP and tofacitinib resulted in a significant alteration in the metaproteome when compared to the control condition, whereas no effect could be observed for budesonide. Applying a stringent selection, 33 proteins were more abundant and 93 less abundant in all 6-MP cultures and could thereby discriminate clearly between 6-MP and control. In contrast to metaproteomic analyses, metagenomic analyses only detected a lower relative abundance of Colidextribacter in 15 μg/ml tofacitinib cultures, but not in overall richness, diversity or community structure. Conclusion Tofacitinib and especially 6-MP clearly affect microbial function, but barely microbial composition in vitro . These drug-induced functional changes may subsequently influence host physiology and potentially inflammation in CD. Our findings emphasize the relevance to include functional microbial studies when investigating drug-microbiota interactions. Further research needs to elucidate the impact of 6-MP-induced microbial alterations on intestinal physiology and inflammation in CD.

Tioguanine is metabolised by fewer enzymatic steps compared to azathioprine and mercaptopurine, without generating 6-methylmercaptopurine ribonucleotides. However, thiopurine S-methyl transferase (TPMT) plays a role in early toxicity in all thiopurines. We aimed to describe the hazards and opportunities of tioguanine use in inflammatory bowel disease (IBD) patients with aberrant TPMT metabolism and propose preventative measures to safely prescribe tioguanine in these patients. In this retrospective cohort study, all determined TPMT genotypes (2016–2021) were evaluated for aberrant metabolism (i.e., intermediate and poor TPMT metabolisers). Subsequently, all IBD patients on tioguanine with aberrant TPMT genotypes were evaluated for tioguanine dosages, adverse drug events, lab abnormalities, treatment duration and effectiveness. TPMT genotypes were determined in 485 patients, of whom, 50 (10.3%) and 4 patients (0.8%) were intermediate and poor metabolisers, respectively. Of these patients, 12 intermediate and 4 poor TPMT metabolisers had been prescribed tioguanine in varying doses. In one poor TPMT metaboliser, tioguanine 10 mg/day induced delayed pancytopenia. In general, reduced tioguanine dosages of 5 mg/day for intermediate TPMT metabolisers, and 10 mg two-weekly for poor TPMT metabolisers, resulted in a safe, long-term treatment strategy. Diminished or absent TPMT enzyme activity was related with a pharmacokinetic shift of tioguanine metabolism which is associated with relatively late-occurring myelotoxicity in patients on standard tioguanine dose. However, in strongly reduced dose regimens with strict therapeutic drug and safety monitoring, tioguanine treatment remained a safe and effective option in IBD patients with dysfunctional TPMT.

There are limited data on therapeutic drug monitoring (TDM) in inflammatory bowel disease (IBD) patients treated with vedolizumab (VDZ). Although an exposure–response relation has been demonstrated in the post-induction phase, this relationship is more uncertain in the maintenance phase of treatment. The aim of our study was to determine whether there is an association between VDZ trough concentration and clinical and biochemical remission in the maintenance phase. A prospective, observational multicenter study has been performed on patients with IBD on VDZ in the maintenance treatment (≥14 weeks). Patient demographics, biomarkers, and VDZ serum trough concentrations were collected. Clinical disease activity was scored by the Harvey Bradshaw Index (HBI) for Crohn’s disease (CD) and the Simple Clinical Colitis Activity Index (SCCAI) for ulcerative colitis (UC). Clinical remission was determined as HBI < 5 and SCCAI < 3. Biochemical remission was defined as fecal calprotectin <250 mg/kg and serum CRP <5 mg/L. A total of 159 patients (59 CD, 100 UC) were included. In none of the patient groups, a statistically significant correlation between trough VDZ concentration and clinical remission was observed. Patients in biochemical remission had higher VDZ trough concentrations (p = 0.019). In this population, higher trough VDZ concentrations were associated with biochemical remission but not with clinical remission.

Background:Inflammatory bowel disease (IBD) is a chronic relapsing-remitting disease. An adverse immune reaction toward the intestinal microbiota is involved in the pathophysiology and microbial perturbations are associated with IBD in general and with flares specifically. Although medical drugs are the cornerstone of current treatment, responses vary widely between patients and drugs. The intestinal microbiota can metabolize medical drugs, which may influence IBD drug (non-)response and side effects. Conversely, several drugs can impact the intestinal microbiota and thereby host effects. This review provides a comprehensive overview of current evidence on bidirectional interactions between the microbiota and relevant IBD drugs (pharmacomicrobiomics). Methods:Electronic literature searches were conducted in PubMed, Web of Science and Cochrane databases to identify relevant publications. Studies reporting on microbiota composition and/or drug metabolism were included. Results:The intestinal microbiota can both enzymatically activate IBD pro-drugs (e.g., in case of thiopurines), but also inactivate certain drugs (e.g., mesalazine by acetylation via N-acetyltransferase 1 and infliximab via IgG-degrading enzymes). Aminosalicylates, corticosteroids, thiopurines, calcineurin inhibitors, anti-tumor necrosis factor biologicals and tofacitinib were all reported to alter the intestinal microbiota composition, including changes in microbial diversity and/or relative abundances of various microbial taxa. Conclusion:Various lines of evidence have shown the ability of the intestinal microbiota to interfere with IBD drugs and vice versa. These interactions can influence treatment response, but well-designed clinical studies and combined in vivo and ex vivo models are needed to achieve consistent findings and evaluate clinical relevance.

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

Background: In inflammatory bowel disease (IBD), conventional thiopurine users cease treatment in 60% of cases within 5 years, mostly because of adverse events or nonresponse. In this study, the authors aimed to investigate the role of 6-thioguanine nucleotide (TGN) measurements, geno/phenotyping of thiopurine S-methyltransferase (TPMT), and their mutual relationship with TG therapy in IBD. Methods: An international retrospective, multicenter cohort study was performed at 4 centers in the Netherlands (Máxima Medical Centre) and the United Kingdom (Guy's and St. Thomas' Hospital, Queen Elizabeth Hospital, and East Surrey Hospital). Results: Overall, 526 6-TGN measurements were performed in 316 patients with IBD. The median daily dosage of TG was 20 mg/d (range 10–40 mg/d), and the median duration of TG use was 21.1 months (SD, 28.0). In total, 129 patients (40.8%) had a known TPMT status. In the variant-type and wild-type TPMT genotype metabolism groups, median 6-TGN values were 1126 [interquartile range (IQR) 948–1562] and 467.5 pmol/8 × 10E8 red blood cells (RBCs) (IQR 334–593). A significant difference was observed between the 2 groups (P = 0.0001, t test). For TPMT phenotypes, in the slow, fast, and normal metabolism groups, the median 6-TGN values were 772.0 (IQR 459–1724), 296.0 (IQR 200–705), and 774.5 pmol/8 × 10E8 RBCs (IQR 500.5–981.5), with a significant difference observed between groups (P < 0.001, analysis of variance). Conclusions: Our findings indicated that TPMT measurements at TG initiation can be useful but are not necessary for daily practice. TPMT genotypes and phenotypes are both associated with significant differences in 6-TGN levels between metabolic groups. However, the advantage of TG remains that RBC 6-TGN measurements are not crucial to monitor treatments in patients with IBD because these measurements did not correlate with laboratory result abnormalities. This presents as a major advantage in countries where patients cannot access these diagnostic tests.

Leflunomide is a prodrug for teruflunomide and used for rheumatic diseases. Teriflunomide is considered to be teratogenic and should be avoided in pregnancy. We describe a case of teriflunomide exposure up to the third trimester of pregnancy. A healthy baby was delivered, despite substantial drug exposure. Multiple washout procedures were required to reduce teriflunomide concentrations below the safe target concentration 0.02 mg/L.

Pharmacogenetics is a discipline that investigates how genetic variation relates to the drug efficacy and safety. The goal of pharmacogenetics is a personalized treatment, where according to genotype we would be able to prescribe the most effective drug at the most appropriate dose for an individual patient. The aim of this review is to summarize pharmacogenetics as a specialization with its own background, research, methods, including barriers and promises for the future.

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

OBJECTIVE: Adalimumab (ADA) trough levels correlate with clinical remission. Despite suggestions that therapeutic drug monitoring of ADA can optimize treatment in this population, it is not yet implemented in clinical practice. This study was conducted to provide more insight in ADA trough levels and antibodies to adalimumab (ATA) in an inflammatory bowel disease (IBD) population already treated with adalimumab. DESIGN: We carried out a prospective cohort study in IBD outpatients already treated with adalimumab. METHODS: Patient demographics were collected from the electronic hospital information system. Blood was drawn for determination of ADA trough levels and ATAs. Disease activity indices for Crohn's disease and ulcerative colitis and quality of life scores were obtained by a questionnaire. RESULTS: A total of 92 patients was included. ADA levels varied from < 0.1 to 20.2 mg/L. Mean ADA level was 7.7 mg/L (SD = 4.5), 4 patients developed ATAs. ADA levels ≤ 5 mg/L were demonstrated in 27 patients (29%). The ADA level was not significantly associated with remission [P = 0.391). Quality of life score correlated with ADA level (P = 0.031). CONCLUSION: Therapeutic drug monitoring in inflammatory bowel disease outpatients revealed large interindividual differences in adalimumab trough levels. These levels were subtherapeutic in nearly a third of patients. We think, despite no significant correlation was found between adalimumab trough level and disease activity, therapeutic drug monitoring has the potential to individualize treatment in inflammatory bowel disease patients using adalimumab.