Reena Khanna

The relationship between infliximab concentrations, antibodies to infliximab and disease activity in Crohn's disease

Objective Although low infliximab trough concentrations and antibodies to infliximab (ATI) are associated with poor outcomes in patients with Crohns disease (CD), the clinical relevance of ATI in patients with adequate infliximab concentrations is uncertain. We evaluated this question using an assay sensitive for identification of ATI in the presence of infliximab. Design In an observational study, 1487 trough serum samples from 483 patients with CD who participated in four clinical studies of maintenance infliximab therapy were analysed using a fluid phase mobility shift assay. Infliximab and ATI concentrations most discriminant for remission, defined as a C-reactive protein concentration of ≤5 mg/L, were determined by receiver operating characteristic curves. A multivariable regression model evaluated these factors as independent predictors of remission. Results Based upon analysis of 1487 samples, 77.1% of patients had detectable and 22.9% had undetectable infliximab concentrations, of which 9.5% and 71.8%, respectively, were positive for ATI. An infliximab concentration of >2.79 μg/mL (area under the curve (AUC)=0.681; 95% CI 0.632 to 0.731) and ATI concentration of <3.15 U/mL (AUC=0.632; 95% CI 0.589 to 0.676) were associated with remission. Multivariable analysis showed that concentrations of both infliximab trough (OR 1.8; 95% CI 1.3 to 2.5; p<0.001) and ATI (OR 0.57; 95% CI 0.39 to 0.81; p=0.002) were independent predictors of remission. Conclusions The development of ATI increases the probability of active disease even at low concentrations and in the presence of a therapeutic concentration of drug during infliximab maintenance therapy. Evaluation of strategies to prevent ATI formation, including therapeutic drug monitoring with selective infliximab dose intensification, is needed.

A global consensus on the classification, diagnosis and multidisciplinary treatment of perianal fistulising Crohn's disease

Objective To develop a consensus on the classification, diagnosis and multidisciplinary treatment of perianal fistulising Crohns disease (pCD), based on best available evidence. Methods Based on a systematic literature review, statements were formed, discussed and approved in multiple rounds by the 20 working group participants. Consensus was defined as at least 80% agreement among voters. Evidence was assessed using the modified GRADE (Grading of Recommendations Assessment, Development, and Evaluation) criteria. Results Highest diagnostic accuracy can only be established if a combination of modalities is used. Drainage of sepsis is always first line therapy before initiating immunosuppressive treatment. Mucosal healing is the goal in the presence of proctitis. Whereas antibiotics and thiopurines have a role as adjunctive treatments in pCD, anti-tumour necrosis factor (anti-TNF) is the current gold standard. The efficacy of infliximab is best documented although adalimumab and certolizumab pegol are moderately effective. Oral tacrolimus could be used in patients failing anti-TNF therapy. Definite surgical repair is only of consideration in the absence of luminal inflammation. Conclusions Based on a multidisciplinary approach, items relevant for fistula management were identified and algorithms on diagnosis and treatment of pCD were developed.

Early combined immunosuppression for the management of Crohn's disease (REACT): a cluster randomised controlled trial

BACKGROUND Conventional management of Crohns disease features incremental use of therapies. However, early combined immunosuppression (ECI), with a TNF antagonist and antimetabolite might be a more effective strategy. We compared the efficacy of ECI with that of conventional management for treatment of Crohns disease. METHODS In this open-label cluster randomised controlled trial (Randomised Evaluation of an Algorithm for Crohns Treatment, REACT), we included community gastroenterology practices from Belgium and Canada that were willing to be assigned to either of the study groups, participate in all aspects of the study, and provide data on up to 60 patients with Crohns disease. These practices were randomly assigned (1:1) to either ECI or conventional management. The computer-generated randomisation was minimised by country and practice size. Up to 60 consecutive adult patients were assessed within practices. Patients who were aged 18 years or older; documented to have Crohns disease; able to speak or understand English, French, or Dutch; able to access a telephone; and able to provide written informed consent were followed up for 2 years. The primary outcome was the proportion of patients in corticosteroid-free remission (Harvey-Bradshaw Index score ≤ 4) at 12 months at the practice level. This trial is registered with ClinicalTrials.gov, number NCT01030809. FINDINGS This study took place between March 15, 2010, and Oct 1, 2013. Of the 60 practices screened, 41 were randomly assigned to either ECI (n=22) or conventional management (n=19). Two practices (one in each group) discontinued because of insufficient resources. 921 (85%) of the 1084 patients at ECI practices and 806 (90%) of 898 patients at conventional management practices completed 12 months follow-up and were included in an intention-to-treat analysis. The 12 month practice-level remission rates were similar at ECI and conventional management practices (66·0% [SD 14·0] and 61·9% [16·9]; adjusted difference 2·5%, 95% CI -5·2% to 10·2%, p=0·5169). The 24 month patient-level composite rate of major adverse outcomes defined as occurrence of surgery, hospital admission, or serious disease-related complications was lower at ECI practices than at conventional management practices (27·7% and 35·1%, absolute difference [AD] 7·3%, hazard ratio [HR]: 0·73, 95% CI 0·62 to 0·86, p=0·0003). There were no differences in serious drug-related adverse events. INTERPRETATION Although ECI was not more effective than conventional management for controlling Crohns disease symptoms, the risk of major adverse outcomes was lower. The latter finding should be considered hypothesis-generating for future trials. ECI was not associated with an increased risk of serious drug-related adverse events or mortality. FUNDING AbbVie Pharmaceuticals.

Peppermint oil for the treatment of irritable bowel syndrome: a systematic review and meta-analysis.

Goals: The aim of this study was to assess the efficacy and safety of enteric-coated peppermint oil capsules compared with placebo for the treatment of active irritable bowel syndrome (IBS). Background: IBS is a common disorder that is often encountered in clinical practice. Medical interventions are limited and the focus is on symptom control. Study: Randomized placebo-controlled trials with a minimum treatment duration of 2 weeks were considered for inclusion. Cross-over studies that provided outcome data before the first cross-over were included. A literature search upto February 2013 identified all applicable randomized-controlled trials. Study quality was evaluated using the Cochrane risk of bias tool. Outcomes included global improvement of IBS symptoms, improvement in abdominal pain, and adverse events. Outcomes were analyzed using an intention-to-treat approach. Results: Nine studies that evaluated 726 patients were identified. The risk of bias was low for most of the factors assessed. Peppermint oil was found to be significantly superior to placebo for global improvement of IBS symptoms (5 studies, 392 patients, relative risk 2.23; 95% confidence interval, 1.78-2.81) and improvement in abdominal pain (5 studies, 357 patients, relative risk 2.14; 95% confidence interval, 1.64-2.79). Although peppermint oil patients were significantly more likely to experience an adverse event, such events were mild and transient in nature. The most commonly reported adverse event was heartburn. Conclusions: Peppermint oil is a safe and effective short-term treatment for IBS. Future studies should assess the long-term efficacy and safety of peppermint oil and its efficacy relative to other IBS treatments including antidepressants and antispasmodic drugs.

Review article: a clinician's guide for therapeutic drug monitoring of infliximab in inflammatory bowel disease

Tumour necrosis factor (TNF)‐antagonists have an established role in the treatment of inflammatory bowel diseases (IBDs), however, subtherapeutic drug levels and the formation of anti‐drug antibodies (ADAs) may decrease their efficacy.

Therapeutic drug monitoring in inflammatory bowel disease: current state and future perspectives.

Current available anti-inflammatory drugs, in particular monoclonal antibodies directed against the cytokine tumor necrosis factor α (TNF), have greatly enhanced the treatment of inflammatory bowel diseases (IBD). Although many patients respond to ant-TNF therapy, a proportion of patients will not respond (primary non-response) or will lose response to the drug over time (secondary non-response). This loss of response can be caused by patient, TNF-inhibitor, or disease-related factors influencing the pharmacokinetics and pharmacodynamics of the drug. Therefore, monitoring pharmacological parameters (i.e. therapeutic drug monitoring) may help guide therapeutic decisions. This review emphasizes interesting and important new findings, and provides an updated overview, on the subject of therapeutic drug monitoring. While exploring the hypothesis that “one size does not fit all”, we focused on the first prospective studies investigating the novel approach in IBD of ‘target concentration adjusted dosing’ and personalized medicine.

A retrospective analysis: the development of patient reported outcome measures for the assessment of Crohn's disease activity.

The Crohns Disease Activity Index (CDAI) is a measure of disease activity based on symptoms, signs and a laboratory test. The US Food and Drug Administration has indicated that patient reported outcomes (PROs) should be the primary outcome in randomised controlled trials for Crohns disease (CD).

Development and validation of a histological index for UC

Objective Although the Geboes score (GS) and modified Riley score (MRS) are commonly used to evaluate histological disease activity in UC, their operating properties are unknown. Accordingly, we developed an alternative instrument. Design Four pathologists scored 48 UC colon biopsies using the GS, MRS and a visual analogue scale global rating. Intra-rater and inter-rater reliability for each index and individual index items were measured using intraclass correlation coefficients (ICCs). Items with high reliability were used to develop the Robarts histopathology index (RHI). The responsiveness/validity of the RHI and multiple histological, endoscopic and clinical outcome measures were evaluated by analyses of change scores, standardised effect size (SES) and Guyatts responsiveness statistic (GRS) using data from a clinical trial of an effective therapy. Results Inter-rater ICCs (95% CIs) for the total GS and MRS scores were 0.79 (0.63 to 0.87) and 0.80 (0.69 to 0.87). The correlation estimates between change scores in RHI and change score in GS and MRS were 0.75 (0.67 to 0.82) and 0.84 (0.79 to 0.88), respectively. The SES and GRS estimates for GS, MRS and RHI were: 1.87 (1.54 to 2.20) and 1.23 (0.97 to 1.50), 1.29 (1.02 to 1.56) and 0.88 (0.65 to 1.12), and 1.05 (0.79 to 1.30) and 0.88 (0.64 to 1.12), respectively. Conclusions The RHI is a new histopathological index with favourable operating properties.

Biosimilars in IBD: hope or expectation?

A biosimilar is a biological medicine that enters the market subsequent to expiration of the patent of an original reference product and its similarity to the reference medicine exhibits ‘no clinically meaningful differences in terms of quality, safety and efficacy’.1 In practice, patents protect a reference product for 10 years after its approval before registration for a similar biological medicine can be applied for.1 The term ‘biosimilar’ is recognised by all regulators, but synonyms include ‘similar biotherapeutic product’ (WHO) and ‘subsequent-entry biologic’ (Canada).2 Biopharmaceutical agents are derived from living cells or organisms and are usually complex proteins. Therefore, regulators are establishing novel specific approval pathways for biosimilars that differ from those for chemical generics. Since the first approval in 2005, several biosimilars of somatropin (human growth hormone), filgrastim (granulocyte colony-stimulating factor, G-CSF) and epoetin (erythropoietin) have become available in Europe. Currently, 12 biosimilars are authorised in the European market, and numerous others, including monoclonal antibodies (mAbs), have applied for authorisation.3 ,4 This subject has received increasing attention in gastroenterology, because the patent on infliximab is due to expire and regulatory approval for two biosimilar infliximabs have already been filed for to the European Medicines Agency (EMA). One of these molecules is already available for patient care in South Korea.4 ,5 Biological agents are currently in widespread use for the treatment of chronic inflammatory diseases. As recently as in 2000, only two of the worlds top 10 grossing drugs were biological agents. In 2012, estimates are that seven are biological agents, of which adalimumab and infliximab lead the list.6 The long duration of development and high manufacturing costs are cited as the main contributors to the high cost of biological agents. For example, the average yearly cost of infliximab treatment for Crohns disease in …

IOIBD technical review on endoscopic indices for Crohn's disease clinical trials

Background Crohns disease (CD) is a chronic disabling and progressive IBD. Only strategies looking beyond symptoms and based on tight monitoring of objective signs of inflammation such as mucosal lesions may have the potential for disease modification. Endoscopic evaluation is currently the gold standard to assess mucosal lesions and has become a major therapeutic endpoint in clinical trials. Several endoscopic indices have been proposed to evaluate disease activity; unvalidated and arbitrary definitions have been used in clinical trials for defining endoscopic response and endoscopic remission in CD. Methods In these recommendations from the International Organization for the Study of Inflammatory Bowel Disease, we first reviewed all technical aspects of available endoscopic scoring systems in the literature. Second, in order to achieve consensus on endoscopic definitions of remission and response in trials, a two-round vote based on a Delphi method was performed among 14 specialists in the field of IBDs. Results At the end of the voting process, the investigators ranked first a >50% decrease in Simple Endoscopic Score for Crohns Disease (SES-CD) or Crohns Disease Endoscopic Index of Severity for the definition of endoscopic response, and an SES-CD 0–2 for the definition of endoscopic remission in CD. All experts agreed on a Rutgeerts’ score i0–i1 for the definition of endoscopic remission after surgery.