Mark G. Ward

Review article: consensus statements on therapeutic drug monitoring of anti-tumour necrosis factor therapy in inflammatory bowel diseases

Therapeutic drug monitoring (TDM) in inflammatory bowel disease (IBD) patients receiving anti‐tumour necrosis factor (TNF) agents can help optimise outcomes. Consensus statements based on current evidence will help the development of treatment guidelines.

Infliximab and adalimumab drug levels in Crohn's disease: contrasting associations with disease activity and influencing factors

Discriminative drug level thresholds for disease activity endpoints in patients with Crohns disease. have been consistently demonstrated with infliximab, but not adalimumab.

Intra‐patient variability in adalimumab drug levels within and between cycles in Crohn's disease

Whether therapeutic drug monitoring for adalimumab needs to be performed at trough has not been defined.

The potential value of faecal lactoferrin as a screening test in hospitalized patients with diarrhoea.

Background:  Nosocomial diarrhoea is common and its investigation carries a significant healthcare cost. This study aimed to determine the utility of faecal lactoferrin (FL), a readily measurable marker of intestinal inflammation, in hospitalized patients with diarrhoea.

343 Azathioprine Decreases the Risk of Adalimumab Primary Non-Response and Secondary Loss of Response but Only if Adequately Dosed

regimens. Secondary endpoint was clinical remission at week 8 (Harvey-Bradshaw Index ≤4 in Crohns disease (CD) or partial Mayo score ≤2 in Ulcerative Colitis (UC)). Results: Fifty-seven IBD patients (11 UC, 46 CD) were included in the study (group 0 n=29, group 1 n=17, group 2 n=11). Median time of infliximab drug-holiday before retreatment was 13 months (IQR 6-37.5). Median number of re-infusions was 6 (IQR 3.8-12.3). No significant differences were found among baseline characteristics of groups, with the exception of extraintestinal manifestations that were more frequent in the group 0 (p=0.03) and time of wash-out from the first infliximab treatment that was shorter in the group 2 (p=0.001). Fourteen patients (24%) presented an infusion reaction during infliximab retreatment; among them 11 subjects (19%) had a reaction during the second or the third re-infusion, and 10 patients (17%) discontinued infliximab due to severe re-infusion reaction. Group 1 presented significantly fewer re-infusion reactions in comparison with both groups 0 and 2 (1 versus 13, p=0.04). Also patients who maintained immunomodulators during infliximab drugholiday had significantly fewer re-infusion reactions in comparison with those without immunomodulators (1 versus 13, p=0.02). At multivariate analysis, only the maintenance with immunosuppressive agents during infliximab drug-holiday was independently associated with fewer re-infusion reactions (p=0.04). Thirty patients (53%) achieved clinical remission at week 8 with no significant differences among groups. Conclusion: Retreatment with infliximab may be effective in IBD patients; the induction regimen with 5 mg/kg at week 0-4-8 seems to be better tolerated, although only maintenance therapywith immunomodulators after discontinuation of the first course of infliximab therapy significantly reduced the occurrence of infusion reactions during retreatment.

Is there a role for thioguanine therapy in IBD in 2017 and beyond

ABSTRACT Introduction: Conventional thiopurines are effective for the maintenance of remission of Crohn’s disease and ulcerative colitis, however, up to half of patients are intolerant or unresponsive to these medications. Thioguanine is an alternative thiopurine that has shown efficacy in inflammatory bowel disease, and is particularly useful to circumvent certain side effects associated with conventional thiopurines, for example, pancreatitis. Its association with nodular regenerative hyperplasia of the liver has hindered its widespread use. Areas covered: We aim to outline the rational use of thioguanine, including safety monitoring, with particular regard to hepatotoxicity. A literature search was performed: PubMed was searched for full papers and abstracts published in English since January 2000 using the following terms, alone and in combination: ‘azathioprine’, ‘thiopurine’, ‘Crohn’s disease’, ‘inflammatory bowel disease’, ‘nodular regenerative hyperplasia’, ‘mercaptopurine’, ‘thioguanine’, ‘ulcerative colitis’. Further relevant papers were identified from the reference lists of selected papers. Expert commentary: Despite optimisation strategies such as metabolite measurements and the use of allopurinol, a significant proportion of patients will remain intolerant to thiopurines, especially those with allergic reactions, including pancreatitis. For this subgroup of patients we suggest that low dose thioguanine is an alternative to other therapies that are either parenteral or expensive.

How should immunomodulators be optimized when used as combination therapy with anti-tumor necrosis factor agents in the management of inflammatory bowel disease?

In the last 15 years the management of inflammatory bowel disease has evolved greatly, largely through the increased use of immunomodulators and, especially, anti-tumor necrosis factor (anti-TNF) biologic agents. Within this time period, confidence in the use of anti-TNFs has increased, whilst, especially in recent years, the efficacy and safety of thiopurines has been questioned. Yet despite recent concerns regarding the risk: benefit profile of thiopurines, combination therapy with an immunomodulator and an anti-TNF has emerged as the recommended treatment strategy for the majority of patients with moderate-severe disease, especially those who are recently diagnosed. Concurrently, therapeutic drug monitoring has emerged as a means of optimizing the dosage of both immunomodulators and anti-TNFs. However the recommended therapeutic target levels for both drug classes were largely derived from studies of monotherapy with either agent, or studies underpowered to analyze outcomes in combination therapy patients. It has been assumed that these target levels are applicable to patients on combination therapy also, however there are few data to support this. Similarly, the timing and duration of treatment with immunomodulators when used in combination therapy remains unknown. Recent attention, including post hoc analyses of the pivotal registration trials, has focused on the optimization of anti-TNF agents, when used as either monotherapy or combination therapy. This review will instead focus on how best to optimize immunomodulators when used in combination therapy, including an evaluation of recent data addressing unanswered questions regarding the optimal timing, dosage and duration of immunomodulator therapy in combination therapy patients.

PTH-074 The Presence of Total Anti-Drug Antibodies to Biologic Drugs Does not Adversely Affect Long-Term Outcomes in Crohn’s Disease Patients with Adequate Drugs Levels and Absent Free Anti-Drug Antibodies

Introduction The use of therapeutic drug monitoring (TDM) for anti-TNF drugs has become increasingly widespread over recent years. It is now used in many centres to guide clinical decisions regarding dose optimisation, the use of concomitant immunomodulators as well as switching or withdrawal of treatment.1 TDM usually includes the measurement of serum trough levels of infliximab (IFX) or adalimumab (ADA) as well as anti-drug antibodies (ADAb). There are two different approaches to measuring ADAb; some techniques measure total ADAb (drug-ADAb complexes as well as free ADAb), whilst other measure only free ADAb. However, the clinical relevance of the differing data generated by these techniques is not yet fully understood. Methods A prospective evaluation of trough drug levels and ADAb was performed using our standard ELISA assay (LISA TRACKER, Theradiag) in 145 IBD patients on anti-TNF agents between January and May 2014. This technique measures only free ADAb. The samples were also anaylsed using an ELISA assay that measures total ADAb (IDKmonitor, Immundiagnostik). Long term outcomes were evaluated for 21 (17 IFX, 4 ADA) patients with Crohn’s disease (CD) who were found to have negative free ADAb but positive total ADAb. Outcome assessments were made by review of a prospectively maintained database, with a mean follow-up period of 22 months. Clinical outcome measures included; the need to escalate/switch/withdraw biologic treatment, infusion/injection-site reactions, documented clinical flare (HBI > 5) and need for steroid treatment. Biochemical outcome measures included; CRP > 5 mg/L and faecal calprotectin >150 ug/g. The subsequent development of positive free ADAb and subtherapeutic/undetectable drug levels were also collected as outcome measures. Results Anti-drug antibody (ADAb) detection: Of the 21 CD patients with positive total ADAb and negative free ADAb at the time of initial sampling, 3 (14%) went on to subsequently develop positive free ADAb during the follow-up period. Sixteen patients (75%) were taking concomitant immunomodulators, including all 3 patients who subsequently developed free ADAb. The mean IFX trough level in patients who went on to develop free ADAb was 1.05 ug/ml, compared to 4.04 ug/ml in those who did not. Outcomes: All 3 (100%) of the patients who developed positive free ADAb subsequently went on to have subtherapeutic or undetectable drug levels and required a switch in anti-TNF therapy. Two of the 3 (67%) had a flare in disease activity with an elevated faecal calprotectin. Two (67%) also developed significant infusion reactions. Of the remaining 18 patients who did not subsequently developed free ADAb, only one patient (6%) required a switch in anti-TNF, 4 (22%) developed clinical flares and 3 (17%) required steroid treatment. None of the 18 patients who remained free ADAb negative had undetectable drug levels during the follow-up period. Conclusion Long-term outcomes were not shown to be adversely affected by the presence of total ADAb, in the absence of free ADAb and adequate drug levels. However, patients who subsequently developed free ADAb and subtherapeutic or undetectable drug levels had unfavourable long-term outcomes. The presence of total ADAb does not appear to accurately predict the development of free ADAb. This data supports the use of ELISA techniques which measure free ADAb as well as drug levels. Our study and other similar work,2 suggests that quantification of drug-ADAb complexes (total ADAb) appears to be less relevant to long-term clinical outcomes and therefore, less informative to clinical decision making. References 1 Ben-Horin S, Chowers Y. Tailoring anti-TNF therapy in IBD: drug levels and disease activity. Nature Reviews Gastroenterology & Hepatology 2014;11:243–255. 2 van schouwenburg, et al. Long-term measurement of anti-adalimumab using pH-shift-anti-idiotype antigen binding tests shows predictive value and transient antibody formation.Ann Rheum Dis. 2013;72:1680–6. Disclosure of Interest None Declared

Su1206 Association Between Crohn's Disease Activity and Therapeutic Drug Monitoring of Thiopurines and Infliximab Comparing Free and Total Antidrug Antibody Measurement

Introduction Therapeutic drug monitoring (TDM) of infliximab (IFX) is useful in patients with Crohn’s disease (CD). Therapeutic cut-offs to predict active disease and the influence of thiopurines on drug levels (DL) according to 6-thioguanine nucleotide (TGN) are not defined. There is limited data on the utility of free anti-drug antibodies (ADAb) against total ADAb. We assessed the utility of TDM of IFX in CD using a commercially available ELISA and investigated the influence of TGNs on DL and free/total ADAb. Method Prospective evaluation of trough DL and ADAb using Lisa-Tracker, ((LT), Theradiag, France) and Immundiagnostik ELISA, ((IM), Germany) in 79 CD patients (male = 40) between January and May 2014. Only free ADAb is detected with LT assay, whereas IM assay measures total ADAb (semiquantitative). Total ADAb results were calculated using the cut off control. Results of TDM were assessed with respect to faecal calprotectin (FC), C-reactive protein (CRP) and clinical activity (Harvey Bradshaw Index, (HBI) Results Higher DL were observed amongst patients in remission (HBI 245 pmol/8 × 10 8 ) was not associated with ADAb (p = 0.5). TGN quartile analysis did not identify a value associated with DL (p > 0.5), nor was a therapeutic TGN associated with higher DL (p = 0.7). Conclusion IFX DL were inversely related to disease activity. A cut-off of 3.0–5.7 μg/mL was associated with active disease depending on the definition used. The presence of free ADAb was associated with active inflammation, whereas the presence of total ADAb was not. There was no relationship between TGN and DL or ADAb, although most patients were adequately dosed. This study highlights the limitations and utility of TDM in IBD. Disclosure of interest B. Warner: None Declared, M. Ward: None Declared, E. Johnston: None Declared, P. Irving Speaker Bureau of: AbbVie, MSD, Takeda, Warner Chilcott, Shire, Ferring and Tillotts Pharma.

Therapeutic drug monitoring of vedolizumab in inflammatory bowel disease: current data and future directions:

The introduction of vedolizumab, a lymphocyte adhesion inhibitor, has expanded the relatively limited therapeutic armamentarium available for Crohn’s disease and ulcerative colitis. Despite its effectiveness, both primary nonresponse and secondary loss of response to vedolizumab do occur, as is observed with the use of anti-tumour necrosis factor (TNF) therapy. Further, in a proportion, onset of efficacy may be relatively slow. A large body of data support an exposure–response relationship with anti-TNF drug levels, which has led to therapeutic drug monitoring becoming incorporated into everyday clinical management. The influence of patient and disease factors on the pharmacokinetics of anti-TNF levels, including immunogenicity, has also been examined. The role of therapeutic drug monitoring with vedolizumab is less clear. This review summarizes the available evidence on the pharmacokinetics and pharmacodynamics of vedolizumab in inflammatory bowel disease and how drug levels, immunogenicity and other factors influence clinical outcomes. Vedolizumab clearance is increased with very high body weight and hypoalbuminaemia, but is not influenced by the addition of an immunomodulator. Immunogenicity is uncommon. α4β7 receptor saturation occurs at low serum vedolizumab drug levels, and measuring it alone is insufficient to predict clinical outcomes. Using quartile analysis of vedolizumab drug levels, there appears to be a modest exposure–response relationship during induction. Drug levels at week 6 of approximately >20 μg/ml have been shown to be associated with improved clinical outcomes, including subsequent mucosal healing rates during maintenance and avoiding the need to dose escalate due to lack of response. There are currently insufficient data to support the routine use of therapeutic drug monitoring during maintenance therapy. Further studies to elucidate the role of therapeutic drug monitoring of vedolizumab are needed.