A randomised, crossover trial exploring the patient perspective and effectiveness of biosimilar adalimumab transition: IBD reference and biosimilar adalimumab cross over study (iBaSS).

BACKGROUND: Patient satisfaction has been positively associated with adherence which is expected to impact outcomes. Although vital for successful implementation of biosimilar medicines, little is known about the patient perspective of transition. AIM: The aim of this study was to investigate clinical outcomes and patient experience of transitioning between reference adalimumab and a biosimilar (SB5). METHOD: iBaSS is a phase IV single-centre, prospective, randomised, single-blind, cross-over study in adult subjects with Crohn's disease. Participants, stable on adalimumab before consent, received 24 weeks of treatment with both reference adalimumab and SB5. The primary outcome was the proportion of patients maintaining baseline clinical status throughout each treatment period, with patients' perspective of disease control and treatment satisfaction assessed as secondary outcomes. RESULTS: A total of 112 participants, representative of the heterogeneous patient populations encountered in routine clinical practice, were enrolled. A similar proportion of participants maintained baseline clinical status through each treatment period: 81.8% with reference adalimumab and 79.5% with SB5. Patient reported outcomes (IBD-Control questionnaire (SB5: 15.5; reference adalimumab 15) and TSQM), adverse events and therapeutic drug monitoring remained consistent through both treatment periods, although a higher median injection pain VAS score was noted with SB5 (53/100 versus 6/100 with reference adalimumab). The number of switches undertaken in the study did not impact serum drug concentration or immunogenicity. CONCLUSION: This study, mimicking real world adalimumab transition, demonstrates that patients undertaking brand transition can be expected to have consistent clinical and satisfaction outcomes. CLINICAL TRIAL REGISTERED WITH EUDRACT: Number 2018-004967-30.

Switching from intravenous to subcutaneous infliximab maintenance therapy in inflammatory bowel disease: Post hoc longitudinal analysis of a randomized trial.

BACKGROUND: Pharmacokinetic non-inferiority of subcutaneous (SC) to intravenous (IV) CT-P13 maintenance therapy was demonstrated in a randomized trial (NCT02883452). This post hoc analysis evaluated longitudinal clinical outcomes with the two infliximab treatment strategies. METHODS: Patients with Crohn's disease or ulcerative colitis received CT­P13 IV loading doses (5 mg/kg; Week [W] 0 and W2) before randomization (1:1) to receive CT-P13 SC (body weight-based dosing every 2 weeks [Q2W]; W6-54; 'SC maintenance group') or CT­P13 IV (5 mg/kg Q8W; W6-22) then CT-P13 SC (Q2W; W30-54; 'IV-to-SC switch group'). Paired W30/W54 patient-level data were analyzed. RESULTS: Fifty-three (IV-to-SC switch) and fifty-nine (SC maintenance) patients were analyzed. Median trough serum CT-P13 concentrations were significantly higher at W54 versus W30 in the IV-to-SC switch group (20.4 versus 2.3 µg/mL; p < 0.00001), while remaining consistent in the SC maintenance group. Statistically significant improvements in pharmacokinetics, efficacy, fecal calprotectin levels, and quality of life were seen following switch to SC administration at W30 in the IV-to-SC switch group; safety findings were similar pre- and post-switch. CONCLUSION: Formulation switching from IV to SC infliximab maintenance therapy was well tolerated and may provide additional clinical improvements. Findings require confirmation in larger prospective studies.

Establishing key performance indicators for inflammatory bowel disease in the UK.

Background and aims: Healthcare quality improvement (QI) is the systematic process to continuously improve the quality of care and outcomes for patients. The landmark Inflammatory Bowel Disease (IBD) UK National Audits provided a means to measure the variation in care, highlighting the need to define the standards of excellence in IBD care. Through a consensus approach, we aimed to establish key performance indicators (KPIs), providing reliable benchmarks for IBD care delivery in UK. Methods: KPIs that measure critical aspects of a patient journey within an IBD service were identified though stakeholder meetings. A two-stage Delphi consensus was then conducted. The first involved a multidisciplinary team of IBD clinicians and patients to refine definitions and methodology. The second stage assessed feasibility and utility of the proposed QI process by surveying gastroenterology services across UK. Results: First, the four proposed KPIs were refined and included time from primary care referral to diagnosis in secondary care, time to treatment recommendation following a diagnosis, appropriate use of steroids and advanced therapies prescreening and assessment. Second, the Delphi consensus reported >85% agreement on the feasibility of local adoption of the QI process and >75% agreement on the utility of benchmarking of the KPIs. Conclusions: Through a structured approach, we propose quantifiable KPIs for benchmarking to improve and reduce the individual variation in IBD care across the UK.

Subcutaneous Infliximab Monotherapy Versus Combination Therapy with Immunosuppressants in Inflammatory Bowel Disease: A Post Hoc Analysis of a Randomised Clinical Trial.

BACKGROUND AND OBJECTIVE: Whether benefits and risks of intravenous (IV) infliximab combotherapy with immunosuppressants versus infliximab monotherapy apply to subcutaneous (SC) infliximab is unknown. This post hoc analysis of a pivotal randomised CT-P13 SC 1.6 trial aimed to compare SC infliximab monotherapy with combotherapy in inflammatory bowel disease (IBD). METHODS: Biologic-naïve patients with active Crohn's disease or ulcerative colitis received CT-P13 IV 5 mg/kg at Week (W) 0 and 2 (dose-loading phase). At W6, patients were randomised (1:1) to receive CT-P13 SC 120 or 240 mg (patients < 80 or ≥ 80 kg) every 2 weeks until W54 (maintenance phase), or to continue CT-P13 IV every 8 weeks until switching to CT-P13 SC from W30. The primary endpoint-non-inferiority of trough serum concentrations-was assessed at W22. We report a post hoc analysis comparing pharmacokinetic, efficacy, safety and immunogenicity outcomes up to W54 for patients randomised to CT-P13 SC, stratified by concomitant immunosuppressant use. RESULTS: Sixty-six patients were randomised to CT-P13 SC (37 monotherapy, 29 combotherapy). At W54, there were no significant differences in the proportions of patients achieving target exposure (5 µg/mL; 96.6% monotherapy vs 95.8% combotherapy; p > 0.999) or meeting efficacy or biomarker outcomes including clinical remission (62.9% vs 74.1%; p = 0.418). Monotherapy and combotherapy groups had comparable immunogenicity (anti-drug antibodies [ADAs]: 65.5% vs 48.0% [p = 0.271], neutralising antibodies [in ADA-positive patients]: 10.5% vs 16.7% [p = 0.630], respectively). CONCLUSIONS: Pharmacokinetics, efficacy and immunogenicity were potentially comparable between SC infliximab monotherapy and combotherapy in biologic-naïve IBD patients. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02883452.

Impact of direct-access IBD physician delivered endoscopy on clinical outcomes: a pre-implementation and post-implementation study.

Introduction: Patients with suspected inflammatory bowel disease (IBD) referred from primary care often face diagnostic and treatment delays. This study aimed to compare a novel direct-access IBD endoscopy pathway with the traditional care model. Method: Single centre real-world study analysing primary care referrals with suspected IBD. Group A: patients triaged to direct-access IBD endoscopy. Group B: patients undergoing traditional outpatient appointments before the availability of direct-access IBD endoscopy. Demographics, fecal calprotectin (FCP), C-reactive protein (CRP), disease activity score, endoscopy findings, treatment and follow-up were collected and statistically analysed. Ranked semantic analysis of IBD symptoms contained within referral letters was performed. Results: Referral letters did not differ significantly in Groups A and B. Demographic data, FCP and CRP values were similar. Referral to treatment time (RTT) at the time of IBD endoscopy was reduced from 177 days (Group B) to 24 days (Group A) (p<0.0001). Diagnostic yield of IBD was 35.6% (Group B) versus 62.0% (Group A) (p=0.0003). 89.2% of patients underwent colonoscopy in Group B versus 46.4% in Group A. DNA rates were similar in both groups. The direct to IBD endoscopy pathway saved 100% of initial IBD consultant clinics with a 2.5-fold increase in IBD nurse-led follow-up. Conclusion: Our novel pathway resulted in an 86% reduction in RTT with associated increased diagnostic yield while saving 100% of initial IBD consultant outpatient appointments. Replication in other trusts may improve patient experience and accelerate time to diagnosis/treatment while optimising the use of healthcare resources.

Patient perspectives of successful adalimumab biosimilar transitioning in Crohn's disease: an interview study.

OBJECTIVES: Transition from originator biological medicines to their biosimilar equivalents is now part of routine clinical practice, but there is little understanding of patient experiences, which influence adherence and overall satisfaction with care. Understanding this will help ensure future switches adequately address patients' concerns and expectations leading to better outcomes for all stakeholders. METHOD: 35 patients participating in a clinical trial including an open-label transition event from originator to biosimilar adalimumab, mimicking what would be encountered in a real-world setting, took part in semi-structured interviews exploring their experience of biosimilar transition. RESULTS: Opinions expressed were often heterogeneous, but common experiences and themes were identified. Five themes were identified following thematic analysis. (1) Understanding and awareness of biosimilars: prior awareness of biosimilars and knowledge of the biosimilar concept was low, indicating a disparity between healthcare professionals and patients. (2) Motivation to undertake transition: patients accept a biosimilar transition to minimise drug expenditure. (3) Initial concerns: before undertaking biosimilar transition away from the brand they had experienced, anticipated loss of efficacy and adverse effects from the biosimilar were common concerns for patients. (4) Reassuring factors: trust in the healthcare team is critical to patient acceptance of biosimilars. Important reassurances include a point of contact, education about biosimilars and monitoring. (5) Experiences during the transition: on reflection, participants described consistent efficacy and tolerability (although 22 participants specifically mentioned injection pain) following brand transition. CONCLUSION: The majority of patients felt comfortable with future transition to another adalimumab biosimilar. Injection experience was an important component of patient satisfaction.

Food-related quality of life is impaired in inflammatory bowel disease and associated with reduced intake of key nutrients.

BACKGROUND: Inflammatory bowel disease (IBD) may impact the extent to which food, eating, and drinking bring satisfaction and enjoyment to peoples' lives, and this may impact dietary intake. The prevalence of an impaired food-related quality of life (FR-QoL), its associated factors, and its impact on diet have not been explored. OBJECTIVES: To measure the prevalence and nature of the burden of impaired FR-QoL in people with IBD, the factors associated with these, and their associations with nutrient intake. METHODS: We recruited 1576 outpatients with IBD (≥16 years old) in person from 7 IBD centers across the United Kingdom. Patients completed validated questionnaires to measure their FR-QoL, quality of life (QoL), distress, fatigue, anxiety, and depression. Dietary intake was recorded using the European Prospective Investigation into Cancer FFQ. A health professional recorded disease activity, Montreal classification, blood results, BMI, and malnutrition risk. FR-QoL was regressed onto explanatory variables using univariable and multivariable analyses. RESULTS: Data from 1221 patients were available (77.4% response; Crohn's disease, 65%; ulcerative colitis, 35%). The FR-QoL mean (± SD) score was 80.8 ± 26.9, with wide ranges (minimum, 29; maximum, 145). Following multivariable regression, the strongest associations with FR-QoL were the number of recent disease flares (5 flares ß = -12.7; P < 0.001), the IBD-specific QoL (ß = 0.33; P < 0.001), and IBD-related distress (ß = -0.26; P < 0.001). Patients with poorer FR-QoL had lower intakes of fiber (nonstarch polysaccharide; Q1 to Q5 difference = 2.1 g/d; 95% CI: 0.4-3.8; P = 0.048), calcium (192.6 mg/d; 95% CI: 112.5-272.6; P < 0.001), phosphorus (167 mg/d; 95% CI: 58-276; P = 0.041), and magnesium (34.4 mg/d; 95% CI: 9.3-59.4; P = 0.041). CONCLUSIONS: Impaired FR-QoL is prevalent in IBD and is associated with recurrent disease flares, a reduced IBD-specific QoL, and greater IBD-related distress. A poorer FR-QoL was associated with lower intakes of key nutrients of importance to IBD, including those relating to gut health and bone mineralization.

Innovative approaches to biologic development on the trail of CT-P13: biosimilars, value-added medicines, and biobetters.

The biosimilar concept is now well established. Clinical data accumulated pre- and post-approval have supported biosimilar uptake, in turn stimulating competition in the biologics market and increasing patient access to biologics. Following technological advances, other innovative biologics, such as "biobetters" or "value-added medicines," are now reaching the market. These innovative biologics differ from the reference product by offering additional clinical or non-clinical benefits. We discuss these innovative biologics with reference to CT-P13, initially available as an intravenous (IV) biosimilar of reference infliximab. A subcutaneous (SC) formulation, CT-P13 SC, has now been developed. Relative to CT-P13 IV, CT-P13 SC offers clinical benefits in terms of pharmacokinetics, with comparable efficacy, safety, and immunogenicity, as well as increased convenience for patients and reduced demands on healthcare system resources. As was once the case for biosimilars, nomenclature and regulatory pathways for innovative biologics require clarification to support their uptake and ultimately benefit patients.

Prevalence and long-term outcome of sub-clinical primary sclerosing cholangitis in patients with ulcerative colitis.

BACKGROUND: Primary sclerosing cholangitis (PSC) is closely associated with inflammatory bowel disease, particularly ulcerative colitis (UC), with an increased risk of biliary and colorectal malignancy. We sought to clarify the prevalence, characteristics and long-term outcome of sub-clinical PSC diagnosed by magnetic resonance cholangiogram (MRC) in patients with UC and normal liver biochemistry, with or without colorectal dysplasia (CRD). METHODS: In this prospective case-control study, 70 patients with UC and normal liver function (51 extensive UC, 19 CRD), 28 healthy volunteers (negative controls) and 28 patients with PSC and cholestasis (positive controls) underwent MRC and blood evaluation. MRC scans were interpreted blindly by two radiologists who graded individually, the scans as definitive for PSC, possible for PSC or normal. Clinical outcome was assessed by blood monitoring, abdominal imaging and endoscopic surveillance. RESULTS: 7/51 (14%) with extensive UC and 4/19 (21%) with CRD had biliary abnormalities on MRC consistent with PSC. 7/11 (64%) with sub-clinical PSC had isolated intrahepatic duct involvement. Sub-clinical PSC was associated with advanced age (P = .04), non-smoking (P = .03), pANCA (P = .04), quiescent colitis (P = .02), absence of azathioprine (P = .04) and high-grade CRD (P = .03). Inter-observer (kappa = 0.88) and intra-observer (kappa = 0.96) agreement for MRC interpretation was high. No negative controls were assessed as definite PSC, 4/28 were considered on blinding as possible PSC. During follow-up of sub-clinical PSC (median 10.1(3.1-11.9) years), four patients developed abnormal liver biochemistry, two had radiological progression of PSC and seven developed malignancy, including two biliary and one colorectal carcinoma. CONCLUSIONS: Prevalence of sub-clinical PSC appears high in patients with extensive UC and normal liver biochemistry, with or without CRD. Disease progression and malignancy were identified on long-term follow-up. MRC should be considered for all patients with extensive UC or CRD to stratify surveillance.

Enhancing treatment success in inflammatory bowel disease: Optimising the use of anti-TNF agents and utilising their biosimilars in clinical practice.

Anti-tumour necrosis factor (TNF) agents such as infliximab and adalimumab have greatly altered the treatment landscape in inflammatory bowel disease (IBD). However, there are remaining unmet needs and opportunities to optimise their use. Recent data suggest that proactive therapeutic drug monitoring may lead to more efficient usage of these agents, with potential for higher rates of corticosteroid-free clinical remission than with reactive monitoring. Expanded application of faecal calprotectin measurements may also be valuable, given the ease of use of the assay and its proven effectiveness as a diagnostic tool and predictor of relapse risk. From a practical viewpoint, improved multidisciplinary working may be essential to optimise patient care, with IBD nurse specialists playing an increasingly central role within this model. Finally, the availability of biosimilars of the anti-TNF agents allow drug costs to be reduced without compromising safety or efficacy - thereby providing opportunities to improve accessibility. Alongside extensive data on originator to biosimilar infliximab switch, new studies are beginning to demonstrate the safety of biosimilar to biosimilar switch, as well as adalimumab biosimilar transitions. The risk of a nocebo effect when switching to a biosimilar can be reduced through improved patient education and preparation.

Anti-TNF biosimilars in Crohn's Disease: a patient-centric interdisciplinary approach.

Introduction: The purpose of this review is to highlight the role of biosimilars in early treatment in IBD and introduce ways to facilitate a patient-centric switching process through multidisciplinary approach. Areas covered: We summarize existing scientific literature related to the role of biosimilars in inflammatory bowel disease in terms of early treatment and cost-saving and implementing switching process. Expert opinion: Use of anti-TNF biosimilars in patients has the potential for large drug-acquisition cost-saving, which can be reinvested into early treatment. Managed switched programs for adalimumab can add further benefits in the future.

Nationwide improvement in outcomes of emergency admission for ulcerative colitis in England, 2005-2013.

BACKGROUND: The UK IBD Audit Programme reported improved inpatient care processes for ulcerative colitis (UC) between 2005 and 2013. There are no independent data describing national or institutional trends in patient outcomes over this period. AIM: To assess the association between the outcome of emergency admission for UC and year of treatment. METHODS: Retrospective analysis of hospital administrative data, focused on all emergency admissions to English public hospitals with a discharge diagnosis of UC. We extracted case mix factors (age, sex, co-morbidity, emergency bed days in last year, deprivation status), outcomes of index admission (death and first surgery), 30-day emergency readmissions (all-cause, and selected causes) and outcome of readmission. RESULTS: There were 765 deaths and 3837 unplanned first operations in 44 882 emergency admissions, with 5311 emergency readmissions (with a further 171 deaths and 517 first operations). Case mix adjusted odds of death for any given year were 9% lower (OR 0.91, 95% CI: 0.89-0.94), and that for emergency surgery 3% lower (OR 0.97, 95% CI: 0.95-0.98) than the preceding year. Results were robust to sensitivity analysis (admissions lasting ≥4 days). There was no reduction in odds for all-cause readmission, but rates for venous thromboembolism declined significantly. Analysis of institutional-level metrics across 136 providers showed a stepwise reduction in outliers for mortality and unplanned surgery. CONCLUSIONS: Risk of death and unplanned surgery for UC patients admitted as emergencies declined consistently, as did unexplained variation between hospitals. Risk of readmission was unchanged (over 1 in 10). Multiple factors are likely to explain these nationwide trends.

A retrospective observational study of early experiences of vedolizumab treatment for inflammatory bowel disease in the UK: The REVIVE study.

Results from clinical trials show that vedolizumab is an efficacious treatment for inflammatory bowel disease, namely Crohn's disease (CD) and ulcerative colitis (UC). However, there is limited evidence from real-world clinical practice, especially on early clinical experiences in the UK.To describe real-world early experiences of vedolizumab to treat CD and UC in the UK.A retrospective, chart review study of patients with CD or UC treated with vedolizumab across 5 UK hospitals. All eligible adults (≥18 years at initiation) with a diagnosis of CD and ≥14 weeks of data or UC and ≥10 weeks of data available following vedolizumab initiation were included.Data were analyzed for 112 patients (CD: 66; UC: 46). Patients with CD had a median of 7.4 (interquartile range 5.7-9.4) months follow-up and patients with UC had a median of 7.4 (5.6-10.2) months follow-up post-vedolizumab initiation. Most patients, 80% (53/66) with CD and 89% (41/46) with UC, remained on vedolizumab treatment at the time of data collection. No new safety signals were identified during the study.These results add to the body of evidence supporting vedolizumab as an effective and well-tolerated treatment for CD and UC in real-world clinical practice.

Association of Genetic Variants in NUDT15 With Thiopurine-Induced Myelosuppression in Patients With Inflammatory Bowel Disease.

Importance: Use of thiopurines may be limited by myelosuppression. TPMT pharmacogenetic testing identifies only 25% of at-risk patients of European ancestry. Among patients of East Asian ancestry, NUDT15 variants are associated with thiopurine-induced myelosuppression (TIM). Objective: To identify genetic variants associated with TIM among patients of European ancestry with inflammatory bowel disease (IBD). Design, Setting, and Participants: Case-control study of 491 patients affected by TIM and 679 thiopurine-tolerant unaffected patients who were recruited from 89 international sites between March 2012 and November 2015. Genome-wide association studies (GWAS) and exome-wide association studies (EWAS) were conducted in patients of European ancestry. The replication cohort comprised 73 patients affected by TIM and 840 thiopurine-tolerant unaffected patients. Exposures: Genetic variants associated with TIM. Main Outcomes and Measures: Thiopurine-induced myelosuppression, defined as a decline in absolute white blood cell count to 2.5 × 109/L or less or a decline in absolute neutrophil cell count to 1.0 × 109/L or less leading to a dose reduction or drug withdrawal. Results: Among 1077 patients (398 affected and 679 unaffected; median age at IBD diagnosis, 31.0 years [interquartile range, 21.2 to 44.1 years]; 540 [50%] women; 602 [56%] diagnosed as having Crohn disease), 919 (311 affected and 608 unaffected) were included in the GWAS analysis and 961 (328 affected and 633 unaffected) in the EWAS analysis. The GWAS analysis confirmed association of TPMT (chromosome 6, rs11969064) with TIM (30.5% [95/311] affected vs 16.4% [100/608] unaffected patients; odds ratio [OR], 2.3 [95% CI, 1.7 to 3.1], P = 5.2 × 10-9). The EWAS analysis demonstrated an association with an in-frame deletion in NUDT15 (chromosome 13, rs746071566) and TIM (5.8% [19/328] affected vs 0.2% [1/633] unaffected patients; OR, 38.2 [95% CI, 5.1 to 286.1], P = 1.3 × 10-8), which was replicated in a different cohort (2.7% [2/73] affected vs 0.2% [2/840] unaffected patients; OR, 11.8 [95% CI, 1.6 to 85.0], P = .03). Carriage of any of 3 coding NUDT15 variants was associated with an increased risk (OR, 27.3 [95% CI, 9.3 to 116.7], P = 1.1 × 10-7) of TIM, independent of TPMT genotype and thiopurine dose. Conclusions and Relevance: Among patients of European ancestry with IBD, variants in NUDT15 were associated with increased risk of TIM. These findings suggest that NUDT15 genotyping may be considered prior to initiation of thiopurine therapy; however, further study including additional validation in independent cohorts is required.

Inflammatory bowel disease registries for collection of patient iron parameters in Europe.

Iron deficiency without anemia and iron deficiency anemia are common and frequently overlooked complications of inflammatory bowel disease. Despite the frequency and impact of iron deficiency in inflammatory bowel disease, there are gaps in our understanding about its incidence, prevalence and natural history and, consequently, patients may be undertreated. Medical registries have a key role in collecting data on the disease's natural history, the safety and effectiveness of drugs in routine clinical practice, and the quality of care delivered by healthcare services. Even though iron deficiency impacts inflammatory bowel disease patients and healthcare systems substantially, none of the established European inflammatory bowel disease registries systematically collects information on iron parameters and related outcomes. Collection of robust iron parameter data from patient registries is one way to heighten awareness about the importance of iron deficiency in this disease and to generate data to improve the quality of patient care, patient outcomes, and thus quality of life. This objective could be achieved through collection of specific laboratory, clinical, and patient-reported measurements that could be incorporated into existing registries. This review describes the status of current European inflammatory bowel disease registries and the data they generate, in order to highlight their potential role in collecting iron data, to discuss how such information gathering could contribute to our understanding of iron deficiency anemia, and to provide practical information in regard to the incorporation of accumulated iron parameter data into registries.

Biosimilar Infliximab in Inflammatory Bowel Disease: Outcomes of a Managed Switching Programme.

BACKGROUND AND AIMS: Biosimilar infliximab CT-P13 offers the potential for large drug acquisition cost savings. However, there are limited published data regarding its efficacy, safety, and immunogenicity in inflammatory bowel disease [IBD], particularly in switching IBD patients from originator to biosimilar infliximab. We present the outcomes of a service evaluation of switching IBD patients established on originator infliximab to biosimilar, using a managed switching programme funded via a gain share agreement in a UK teaching hospital. METHODS: Evaluation outcomes included drug persistence, changes in drug acquisition costs, patient-reported side effects, adverse events, patient outcomes assessed using the IBD-control Patient-Reported Outcome Measures [PROM] questionnaire, serum drug and antibody levels, and routinely collected biochemical markers. RESULTS: A total of 143 patients with IBD [118 Crohn's disease, 23 ulcerative colitis, 2 IBD unclassified] were switched from originator infliximab to CT-P13. Patients reported a similar incidence of side effects before and after switch. No clinically significant differences were observed in mean C-reactive protein [CRP], albumin, haemoglobin levels, or platelet and white cell counts after the switch to CT-P13, whereas mean IBD-control-8 score improved from 10.4 to 11.2 [p = 0.041]. There was no significant difference in drug persistence between biosimilar and originator infliximab [p = 0.94] and no increase in immunogenicity was found. Drug acquisition costs decreased by £40,000-60,000 per month. CONCLUSIONS: A managed switching programme from originator infliximab to biosimilar CT-P13 in IBD, using a gain-share agreement, delivers significant cost savings and investment in clinical services while maintaining similar patient-reported outcomes, biochemical response, drug persistence, and adverse event profile.

Mercaptopurine versus placebo to prevent recurrence of Crohn's disease after surgical resection (TOPPIC): a multicentre, double-blind, randomised controlled trial.

BACKGROUND: Up to 60% of patients with Crohn's disease need intestinal resection within the first 10 years of diagnosis, and postoperative recurrence is common. We investigated whether mercaptopurine can prevent or delay postoperative clinical recurrence of Crohn's disease. METHODS: We did a randomised, placebo-controlled, double-blind trial at 29 UK secondary and tertiary hospitals of patients (aged >16 years in Scotland or >18 years in England and Wales) who had a confirmed diagnosis of Crohn's disease and had undergone intestinal resection. Patients were randomly assigned (1:1) by a computer-generated web-based randomisation system to oral daily mercaptopurine at a dose of 1 mg/kg bodyweight rounded to the nearest 25 mg or placebo; patients with low thiopurine methyltransferase activity received half the normal dose. Patients and their carers and physicians were masked to the treatment allocation. Patients were followed up for 3 years. The primary endpoint was clinical recurrence of Crohn's disease (Crohn's Disease Activity Index >150 plus 100-point increase in score) and the need for anti-inflammatory rescue treatment or primary surgical intervention. Primary and safety analyses were by intention to treat. Subgroup analyses by smoking status, previous thiopurines, previous infliximab or methotrexate, previous surgery, duration of disease, or age at diagnosis were also done. This trial is registered with the International Standard Randomised Controlled Trial Register (ISRCTN89489788) and the European Clinical Trials Database (EudraCT number 2006-005800-15). FINDINGS: Between June 6, 2008, and April 23, 2012, 240 patients with Crohn's disease were randomly assigned: 128 to mercaptopurine and 112 to placebo. All patients received at least one dose of study drug, and no randomly assigned patients were excluded from the analysis. 16 (13%) of patients in the mercaptopurine group versus 26 (23%) patients in the placebo group had a clinical recurrence of Crohn's disease and needed anti-inflammatory rescue treatment or primary surgical intervention (adjusted hazard ratio [HR] 0·54, 95% CI 0·27-1·06; p=0·07; unadjusted HR 0·53, 95% CI 0·28-0·99; p=0·046). In a subgroup analysis, three (10%) of 29 smokers in the mercaptopurine group and 12 (46%) of 26 in the placebo group had a clinical recurrence that needed treatment (HR 0·13, 95% CI 0·04-0·46), compared with 13 (13%) of 99 non-smokers in the mercaptopurine group and 14 (16%) of 86 in the placebo group (0·90, 0·42-1·94; pinteraction=0·018). The effect of mercaptopurine did not significantly differ from placebo for any of the other planned subgroup analyses (previous thiopurines, previous infliximab or methotrexate, previous surgery, duration of disease, or age at diagnosis). The incidence and types of adverse events were similar in the mercaptopurine and placebo groups. One patient on placebo died of ischaemic heart disease. Adverse events caused discontinuation of treatment in 39 (30%) of 128 patients in the mercaptopurine group versus 41 (37%) of 112 in the placebo group. INTERPRETATION: Mercaptopurine is effective in preventing postoperative clinical recurrence of Crohn's disease, but only in patients who are smokers. Thus, in smokers, thiopurine treatment seems to be justified in the postoperative period, although smoking cessation should be strongly encouraged given that smoking increases the risk of recurrence. FUNDING: Medical Research Council.

Clinical Features and HLA Association of 5-Aminosalicylate (5-ASA)-induced Nephrotoxicity in Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Nephrotoxicity is a rare idiosyncratic reaction to 5-aminosalicylate (5-ASA) therapies. The aims of this study were to describe the clinical features of this complication and identify clinically useful genetic markers so that these drugs can be avoided or so that monitoring can be intensified in high-risk patients. METHODS: Inflammatory bowel disease patients were recruited from 89 sites around the world. Inclusion criteria included normal renal function prior to commencing 5-ASA, ≥50% rise in creatinine any time after starting 5-ASA, and physician opinion implicating 5-ASA strong enough to justify drug withdrawal. An adjudication panel identified definite and probable cases from structured case report forms. A genome-wide association study was then undertaken with these cases and 4109 disease controls. RESULTS: After adjudication, 151 cases of 5-ASA-induced nephrotoxicity were identified. Sixty-eight percent of cases were males, with nephrotoxicity occurring at a median age of 39.4 years (range 6-79 years). The median time for development of renal injury after commencing 5-ASA was 3.0 years (95% confidence interval [CI] 2.3-3.7). Only 30% of cases recovered completely after drug withdrawal, with 15 patients requiring permanent renal replacement therapy. A genome-wide association study identified a suggestive association in the HLA region (p = 1×10(-7)) with 5-ASA-induced nephrotoxicity. A sub-group analysis of patients who had a renal biopsy demonstrating interstitial nephritis (n = 55) significantly strengthened this association (p = 4×10(-9), odds ratio 3.1). CONCLUSIONS: This is the largest and most detailed study of 5-ASA-induced nephrotoxicity to date. It highlights the morbidity associated with this condition and identifies for the first time a significant genetic predisposition to drug-induced renal injury.

HLA-DQA1-HLA-DRB1 variants confer susceptibility to pancreatitis induced by thiopurine immunosuppressants.

Pancreatitis occurs in approximately 4% of patients treated with the thiopurines azathioprine or mercaptopurine. Its development is unpredictable and almost always leads to drug withdrawal. We identified patients with inflammatory bowel disease (IBD) who had developed pancreatitis within 3 months of starting these drugs from 168 sites around the world. After detailed case adjudication, we performed a genome-wide association study on 172 cases and 2,035 controls with IBD. We identified strong evidence of association within the class II HLA region, with the most significant association identified at rs2647087 (odds ratio 2.59, 95% confidence interval 2.07-3.26, P = 2 × 10(-16)). We replicated these findings in an independent set of 78 cases and 472 controls with IBD matched for drug exposure. Fine mapping of the HLA region identified association with the HLA-DQA1*02:01-HLA-DRB1*07:01 haplotype. Patients heterozygous at rs2647087 have a 9% risk of developing pancreatitis after administration of a thiopurine, whereas homozygotes have a 17% risk.

Tuberculosis and TNF-inhibitors: history of exposure should outweigh investigations.

A 39-year-old Indian man was diagnosed with ulcerative colitis on colonic biopsy and started on mesalazine, prednisolone and azathioprine. However, the colitis remained active and required antitumour necrosis factor (TNF) treatment with infliximab. Prior to starting infliximab, his chest X-ray was normal and QuantiFERON interferon γ release assay for tuberculosis (TB) was negative. However, his wife had been treated for pulmonary TB 11 years previously when they were cohabiting. On attending for his third dose of infliximab, he was feverish and tachycardic, and was admitted for investigation. Chest X-ray on admission showed changes consistent with miliary TB, and thoracic CT confirmed extensive miliary nodules with supraclavicular and mediastinal lymphadenopathy. Abdominal CT showed multiple mesenteric lymph nodes. Subsequent bronchoalveolar lavage, neck lymph node aspirate and colonic biopsies all cultured Mycobacterium tuberculosis. In retrospect, a clear history of close household TB exposure should have precipitated consideration of TB chemoprophylaxis prior to anti-TNF treatment.