Canadian association of gastroenterology clinical practice guideline for the management of Luminal Crohn's Disease

Crohn's disease (CD) is a lifelong illness with substantial morbidity, although new therapies and treatment paradigms have been developed. We provide guidance for treatment of ambulatory patients with mild to severe active luminal CD. We performed a systematic review to identify published studies of the management of CD. The quality of evidence and strength of recommendations were rated according to the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach. Statements were developed through an iterative online platform and then finalized and voted on by a group of specialists. The consensus includes 41 statements focused on 6 main drug classes: antibiotics, 5-aminosalicylate, corticosteroids, immunosuppressants, biologic therapies, and other therapies. The group suggested against the use of antibiotics or 5-aminosalicylate as induction or maintenance therapies. Corticosteroid therapies (including budesonide) can be used as induction, but not maintenance therapies. Among immunosuppressants, thiopurines should not be used for induction, but can be used for maintenance therapy for selected low-risk patients. Parenteral methotrexate was proposed for induction and maintenance therapy in patients with corticosteroid-dependent CD. Biologic agents, including tumor necrosis factor antagonists, vedolizumab, and ustekinumab, were recommended for patients failed by conventional induction therapies and as maintenance therapy. The consensus group was unable to clearly define the role of concomitant immunosuppressant therapies in initiation of treatment with a biologic agent. Optimal management of CD requires careful patient assessment, acknowledgement of patient preferences, evidence-based use of existing therapies, and thorough assessment to define treatment success.

Reduction in surgical stoma rates in Crohn's disease: a population-based time trend analysis.

AIM: Trends in surgical rates for Crohn's disease (CD) in the biological era are controversial. We aim to assess modern trends in the formation rates of surgical stomas. METHOD: Population-based surveillance in the Calgary Health Zone (CHZ), Canada, was conducted between 1 April 2002 and 31 March 2011, using the Discharge Abstract Database to identify adult patients with CD admitted to hospital and treated with surgical stoma formation (n = 545). Annual stoma incidence was calculated by dividing the number of incident stomas by the prevalence of CD in the CHZ. Time trend analysis of the stoma-formation rate was performed, expressed as annual percentage change (APC) with 95% CI. Stoma-formation rates were stratified according to procedure (emergency vs elective) and duration of stoma [temporary (reversed within 2 years of formation) vs permanent]. RESULTS: The overall rate of stoma formation between 2002 and 2011 showed a downwards trend, of a mean of 5.2% (95% CI: -8.5 to -1.8) per year, from a rate of 2.30 stomas/100 person-years (PY) in 2002 to 1.51 stomas/100 PY in 2011. The rate of emergency stoma formation decreased significantly from 2002 to 2011 (mean APC = -9.4%; 95% CI: -15.6 to -2.8), while the rate of elective ostomies essentially showed no change (mean APC = -0.9%; 95% CI: -5.3 to 3.8). The rate of temporary stoma formation decreased significantly, by 4.6% (95% CI: -7.3 to -1.8) per year, while permanent stoma formation was stable (APC = 1.0%; 95% CI: -4.0 to +6.3). CONCLUSION: A reduction in the overall rate of stoma formation in CD has been driven by fewer emergency stomas, although rates of permanent stoma have remained stable.

Systematic review with meta-analysis: endoscopic and histologic placebo rates in induction and maintenance trials of ulcerative colitis.

BACKGROUND: Regulatory requirements for claims of mucosal healing in ulcerative colitis (UC) will require demonstration of both endoscopic and histologic healing. Quantifying these rates is essential for future drug development. AIMS: To meta-analyse endoscopic and histologic placebo response and remission rates in UC randomised controlled trials (RCTs) and identify factors influencing these rates. METHODS: MEDLINE, EMBASE and the Cochrane Library were searched from inception to March 2017 for placebo-controlled trials of pharmacological interventions for UC. Endoscopic and histologic placebo rates were pooled by random effects. Mixed effects univariable and multivariable meta-regression was used to evaluate the influence of patient, intervention and trial-related study-level covariates on these rates. RESULTS: Fifty-six induction (placebo n = 4171) and 8 maintenance trials (placebo n = 1011) were included. Pooled placebo endoscopic remission and response rates for induction trials were 23% [95 confidence interval (CI) 19-28%] and 35% [95% CI 27-42%] respectively, and 20% [95% CI 16-24%] for maintenance of remission. The pooled histologic placebo remission rate was 14% [95% CI 8-22%] for induction trials. High heterogeneity was observed for all outcomes (I2 56.2%-88.3%). On multivariable meta-regression, central endoscopy reading was associated with significantly lower endoscopic placebo remission rates (16% vs 25%; OR = 0.52, [95% CI 0.29-0.92], P = 0.03). On univariable meta-regression, higher histologic placebo remission was associated with concomitant corticosteroids (OR = 1.17 [95% CI 1.08-1.26], P < 0.0001, per 10% increase in corticosteroid use). CONCLUSIONS: Placebo endoscopic and histologic rates range from 14% to 35% in UC RCTs but are highly heterogeneous. Outcome standardisation may reduce heterogeneity and is needed in this field.

Long-term safety of adalimumab in clinical trials in adult patients with Crohn's disease or ulcerative colitis.

BACKGROUND: Adalimumab is used to treat moderate to severe Crohn's disease (CD) and ulcerative colitis (UC) when conventional therapies fail. AIM: To update long-term adalimumab safety from CD and UC trials; the previous report was CD only, 3160 patients/3402 patient-years (PYs). METHODS: Treatment-emergent adverse events (AEs; first dose to 70 days after last dose/December 31, 2015) in adults in phase 2/3 and 3/3b trials and open-label extensions were coded using Medical Dictionary for Regulatory Activities (MedDRA-v18.1). Rates were assessed as events/100 (E/100 PYs). RESULTS: The database (16 trials; CD, N = 3606; UC, N = 1739) represented 4145 and 3397 PYs of exposure, respectively. For CD, incidences of any AEs with adalimumab were 60.8%-65.1%, depending on dose, and 71.5% with placebo; for UC, the incidences were 53.5%-54.8% and 56.1%, respectively. Rates of any AEs (CD, 605 E/100 PYs; UC, 361 E/100 PYs), serious AEs (CD, 36.1 E/100 PYs; UC, 18.9 E/100 PYs), and malignancies (CD, 1.2 E/100 PYs; UC, 1.0 E/100 PYs) were similar between current and prior analyses. Apparent rate of opportunistic infections was lowered to 0.3 and 0.2 E/100 PYs for CD and UC, respectively, by recent MedDRA changes excluding oral candidiasis and tuberculosis. Standardised incidence ratios for malignancies were similar to the general population (CD, 1.45 [95% CI, 0.90-2.22]; UC, 1.36 [95% CI, 0.84-2.07]). Demyelinating disorders were uncommon (CD, 0.1 E/100 PYs; UC, <0.1 E/100 PYs). CONCLUSIONS: Patients with moderately to severely active Crohn's disease or ulcerative colitis continued to experience acceptable safety with adalimumab, without new safety signals.

Clinical, endoscopic and radiographic outcomes with ustekinumab in medically-refractory Crohn's disease: real world experience from a multicentre cohort.

BACKGROUND: Ustekinumab is a monoclonal antibody targeting interleukins-12 and -23, with efficacy in Crohn's disease (CD) demonstrated in clinical trials. AIM: To assess the real-world clinical, endoscopic and radiographic response and remission outcomes achieved with ustekinumab in medically-refractory CD. METHODS: A retrospective multicentre cohort study was performed on CD patients receiving ustekinumab between 2011 and 2016. The primary outcome was achievement of clinical and objective steroid-free response and remission at 3, 6 and 12 months. Clinical response and remission were defined by reduction in Harvey Bradshaw Index (HBI) of ≥3 points and an HBI ≤4 points respectively. Objective response was defined by improvement in endoscopic or radiographic CD, as assessed by ileocolonoscopy, contrast-enhanced ultrasound or CT/MR enterography. Objective remission was defined by endoscopic mucosal healing or complete resolution of inflammatory parameters on radiographic assessment. RESULTS: A total of 167 CD patients were treated with ustekinumab. 95.2% (159/167) previously failed anti-TNF therapy. Median follow-up was 45.6 weeks (IQR: 24.4-88.9). At 3 months, clinical response was achieved in 38.9% (65/167) and remission in 15.0% (25/167) of patients. At 6 months, clinical response was achieved in 60.3% (91/151) and remission in 25.2% (38/151) of patients. At 12 months, clinical response was achieved in 59.5% (66/111) and remission in 27.9% (31/111) of patients. Endoscopic or radiographic response was demonstrated in 54.5% (67/123) at 6 months and 55.8% (48/86) of patients at 12 months. CONCLUSIONS: Ustekinumab is an effective therapeutic option for inducing and maintaining clinical, endoscopic and radiographic response in patients with Crohn's disease failing anti-TNF therapy.

The effects of pregnancy on the pharmacokinetics of infliximab and adalimumab in inflammatory bowel disease.

BACKGROUND: Transplacental transfer of infliximab and adalimumab results in detectable drug levels in the cord blood and infant. AIM: To determine if pregnancy influenced the pharmacokinetics of anti-TNF agents in women with inflammatory bowel disease. METHODS: Twenty-five women from the University of Calgary inflammatory bowel disease(IBD) pregnancy clinic on maintenance infliximab or adalimumab were recruited prospectively with serum bio-banking performed each trimester. Infliximab trough and adalimumab steady-state levels were the outcomes of interest and were analysed using the ANSER infliximab and adalimumab assays. Multivariate linear mixed-effects models were constructed to assess infliximab and adalimumab drug levels during pregnancy adjusting for the clinical covariates of albumin, BMI and CRP. RESULTS: Fifteen women (eight Crohn's disease, seven ulcerative colitis) received infliximab and 10 women with 11 pregnancies were treated with adalimumab. Median age was 29.6 years (IQR: 27.6-31.2 years). Median disease duration was 9.2 years (IQR: 3.16-15.0 years). Median trough infliximab concentrations were 8.50 µg/mL (IQR: 7.23-10.07 µg/mL), 10.31 µg/mL (IQR: 7.66-15.63 µg/mL) and 21.02 µg/mL (IQR: 16.01-26.70 µg/mL) at trimesters 1, 2 and 3 respectively. Significant changes in albumin and BMI (P < 0.05) but not CRP (P > 0.05) were documented throughout pregnancy. After adjusting for albumin, BMI and CRP, infliximab trough levels increased during pregnancy, by 4.2 µg/mL per trimester (P = 0.02), while adalimumab drug levels remained stable (P > 0.05). CONCLUSIONS: Infliximab levels rise during pregnancy, whereas adalimumab levels remain stable after accounting for changes in albumin, BMI and CRP. Therapeutic drug monitoring in the second trimester may be useful in guiding dosing in the third trimester.

RETRACTED: Efficacy and Safety of Induction Dosing of Vedolizumab for Reducing Biliary Inflammation in Primary Sclerosing Cholangitis (Psc) in Individuals with Inflammatory Bowel Disease.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). The abstract authors and presenters of PS124 - EFFICACY AND SAFETY OF INDUCTION DOSING OF VEDOLIZUMAB FOR REDUCING BILIARY INFLAMMATION IN PRIMARY SCLEROSING CHOLANGITIS (PSC) IN INDIVIDUALS WITH INFLAMMATORY BOWEL DISEASE submitted and presented at ILC 2016 have raised concerns that the source data in some cases are inconsistent and requires further evaluation to determine the true magnitude of effect. Hence given the potential impact of this study in PSC at the authors request this abstract, until such time the data can be more completely presented in manuscript form, is being retracted.

Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE): Determining Therapeutic Goals for Treat-to-Target.

OBJECTIVES: The Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) program was initiated by the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD). It examined potential treatment targets for inflammatory bowel disease (IBD) to be used for a "treat-to-target" clinical management strategy using an evidence-based expert consensus process. METHODS: A Steering Committee of 28 IBD specialists developed recommendations based on a systematic literature review and expert opinion. Consensus was gained if ≥75% of participants scored the recommendation as 7-10 on a 10-point rating scale (where 10=agree completely). RESULTS: The group agreed upon 12 recommendations for ulcerative colitis (UC) and Crohn's disease (CD). The agreed target for UC was clinical/patient-reported outcome (PRO) remission (defined as resolution of rectal bleeding and diarrhea/altered bowel habit) and endoscopic remission (defined as a Mayo endoscopic subscore of 0-1). Histological remission was considered as an adjunctive goal. Clinical/PRO remission was also agreed upon as a target for CD and defined as resolution of abdominal pain and diarrhea/altered bowel habit; and endoscopic remission, defined as resolution of ulceration at ileocolonoscopy, or resolution of findings of inflammation on cross-sectional imaging in patients who cannot be adequately assessed with ileocolonoscopy. Biomarker remission (normal C-reactive protein (CRP) and calprotectin) was considered as an adjunctive target. CONCLUSIONS: Evidence- and consensus-based recommendations for selecting the goals for treat-to-target strategies in patients with IBD are made available. Prospective studies are needed to determine how these targets will change disease course and patients' quality of life.

Clinical practice guidelines for the medical management of nonhospitalized ulcerative colitis: the Toronto consensus

BACKGROUND & AIMS:: The medical management of ulcerative colitis (UC) has improved through the development of new therapies and novel approaches that optimize existing drugs. Previous Canadian consensus guidelines addressed the management of severe UC in the hospitalized patient. We now present consensus guidelines for the treatment of ambulatory patients with mild to severe active UC. METHODS: A systematic literature search identified studies on the management of UC. The quality of evidence and strength of recommendations were rated according to the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach. Statements were developed through an iterative online platform and then finalized and voted on by a working group of specialists. RESULTS: The participants concluded that the goal of therapy is complete remission, defined as both symptomatic and endoscopic remission without corticosteroid therapy. The consensus includes 34 statements focused on 5 main drug classes: 5-aminosalicylate (5-ASA), corticosteroids, immunosuppressants, anti-tumor necrosis factor (TNF) therapies, and other therapies. Oral and rectal 5-ASA are recommended first-line therapy for mild to moderate UC, with corticosteroid therapy for those who fail to achieve remission. Patients with moderate to severe UC should undergo a course of oral corticosteroid therapy, with transition to 5-ASA, thiopurine, anti-TNF (with or without thiopurine or methotrexate), or vedolizumab maintenance therapy in those who successfully achieve symptomatic remission. For patients with corticosteroid-resistant/dependent UC, anti-TNF or vedolizumab therapy is recommended. Timely assessments of response and remission are critical to ensuring optimal outcomes. CONCLUSIONS: Optimal management of UC requires careful patient assessment, evidence-based use of existing therapies, and thorough assessment to define treatment success.(AU)

Novel concepts in inflammatory bowel disease.

INTRODUCTION: Clinical management in inflammatory bowel disease (IBD) is constantly changing. Although improvement in symptoms is of paramount importance, using this as the only surrogate marker of disease activity might underestimate disease burden. SOURCES OF DATA: New data from randomized clinical trials are now available. Treatment paradigms are constantly changing leading to an evolution in the therapeutic approach in routine IBD practice. AREAS OF AGREEMENT: Patients with an aggressive disease phenotype should be identified at the onset and treated more intensely in order to achieve long-lasting mucosal remission. AREAS OF CONTROVERSY: Patients who have mild and indolent disease need to be identified and not over treated. GROWING POINTS: The primary endpoint in IBD management should ideally be mucosal healing. Ample data are now available that correlates mucosal healing with surgical-free outcomes with minimal intestinal damage and patient disability. However, the exact degree of mucosal healing that will lead to improved long-term remission, decreased hospital and surgical rates remains unknown. AREAS TIMELY FOR DEVELOPING RESEARCH: Clinical translational work is needed to identify novel pathways in IBD pathogenesis that sub-select patients who would benefit by specific-cytokine pathway modulation.

Adalimumab maintains remission of Crohn's disease after up to 4 years of treatment: data from CHARM and ADHERE.

BACKGROUND: Therapies that maintain remission for patients with Crohn's disease are essential. Stable remission rates have been demonstrated for up to 2 years in adalimumab-treated patients with moderately to severely active Crohn's disease enrolled in the CHARM and ADHERE clinical trials. AIM: To present the long-term efficacy and safety of adalimumab therapy through 4 years of treatment. METHODS: Remission (CDAI <150), response (CR-100) and corticosteroid-free remission over 4 years, and maintenance of these endpoints beyond 1 year were assessed in CHARM early responders randomised to adalimumab. Corticosteroid-free remission was also assessed in all adalimumab-randomised patients using corticosteroids at baseline. Fistula healing was assessed in adalimumab-randomised patients with fistula at baseline. As observed, last observation carried forward and a hybrid nonresponder imputation analysis for year 4 (hNRI) were used to report efficacy. Adverse events were reported for any patient receiving at least one dose of adalimumab. RESULTS: Of 329 early responders randomised to adalimumab induction therapy, at least 30% achieved remission (99/329) or CR-100 (116/329) at year 4 of treatment (hNRI). The majority of patients (54%) with remission at year 1 maintained this endpoint at year 4 (hNRI). At year 4, 16% of patients taking corticosteroids at baseline were in corticosteroid-free remission and 24% of patients with fistulae at baseline had healed fistulae. The incidence rates of adverse events remained stable over time. CONCLUSIONS: Prolonged adalimumab therapy maintained clinical remission and response in patients with moderately to severely active Crohn's disease for up to 4 years. No increased risk of adverse events or new safety signals were identified with long-term maintenance therapy. (clinicaltrials.gov number: NCT00077779).

Review article: dermatological complications of immunosuppressive and anti-TNF therapy in inflammatory bowel disease.

BACKGROUND: With the expanding list of medications available to treat patients with inflammatory bowel disease (IBD), it is important to recognise adverse events, including those involving the skin. Dermatological adverse events may be confused with extra-intestinal manifestations of IBD. AIM: To review drug-related dermatological manifestations associated with immunosuppressive and anti-tumour necrosis factor (anti-TNF) therapy. METHODS: The literature was searched on PubMed for dermatological adverse events in IBD. RESULTS: Present thiopurine exposure was associated with a 5.9-fold [95% confidence interval (CI), 2.1-16.4] increased risk of developing non-melanoma skin cancer (NMSC). The peak incidence is highest in Caucasians over the age of 65 years with crude incidence rates of 4.0 and 5.7/1000 patient-years for present and previous use. In anti-TNF-exposed subjects, drug-induced lupus was reported in 1% of the cases and a psoriatic rash in up to 3% of the cases. Anti-TNF monotherapy increases the risk of NMSC ~2-fold to a rate of 0.5 cases per 1000 person-years. Cutaneous lymphomas have been rarely reported in subjects on thiopurine or anti-TNF drug monotherapy. Combination therapy seems to have an additive effect on the risk of developing NMSC and lymphoma. CONCLUSIONS: Physicians need to be aware of the wide spectrum of dermatological complications of immunosuppressive and anti-TNF therapy in IBD, especially psoriasis and non-melanoma skin cancer. Vigilance and regular screening for non-melanoma skin cancer is recommended. Case discussions between gastroenterologists and dermatologists should be undertaken to best manage dermatological adverse events.

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

BACKGROUND: 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. AIM: The evidence supporting the use of therapeutic drug monitoring (TDM) based clinical algorithms for infliximab (IFX) and their role in clinical practice will be discussed. METHODS: The literature was reviewed to identify relevant articles on the measurement of IFX levels and antibodies-to-infliximab. RESULTS: Treatment algorithms for IBD have evolved from episodic monotherapy used in patients refractory to all other treatments, to long-term combination therapy initiated early in the disease course. Improved remission rates have been observed with this paradigm shift, nevertheless many patients ultimately lose response to therapy. Although empiric dose optimization or switching agents constitute the current standard of care for secondary failure, these interventions have not been applied in an evidence-based manner and are probably not cost-effective. Multiple TDM-based algorithms have been developed to identify patients that may benefit from measurement of IFX and ADA levels to guide adjustments to therapy. CONCLUSIONS: Therapeutic drug monitoring offers a rational approach to the management of secondary failure to IFX. This concept has gained momentum based on evidence from case series, cohort studies and post-hoc analyses of randomised controlled trials.

Medical management of inflammatory bowel disease among Canadian gastroenterologists.

BACKGROUND: Little is known about physician perceptions of and practices in using infliximab - a biological agent that was approved in Canada for the treatment of Crohn's disease in 2001, and for ulcerative colitis in 2006. OBJECTIVES: To describe Canadian gastroenterologists' use and perceptions of infliximab in the treatment of refractory inflammatory bowel disease (IBD), and to identify factors that may influence a gastroenterologist's decision to initiate infliximab therapy. METHODS: A postal questionnaire was distributed to all practicing clinicians captured in the 2007 membership of the Canadian Association of Gastroenterology. Each physician was contacted up to a maximum of three times. RESULTS: Of 466 questionnaires mailed out, responses were received from 336 (72%), with 292 respondents (63%) returning fully completed surveys. For 80% of respondents, IBD patients comprised less than 30% of their clinical practice. Most prescribed infliximab at an initial dose of 5 mg/kg (97%), prescribed loading doses at 0, 2 and 6 weeks (88%), premedicated with corticosteroids (74%), administered maintenance infusions at eight-week intervals (89%), co-administered immunosuppressive agents (81%) and continued infliximab 'indefinitely' as long as it was effective and well tolerated (76%). Most gastroenterologists (>70%) identified lack of drug insurance coverage and provincial funding criteria as important barriers to prescribing infliximab. CONCLUSIONS: Most Canadian gastroenterologists exhibited similar practice patterns with respect to the use of infliximab for induction and maintenance therapy of IBD. Common barriers to the initiation of infliximab therapy were identified.

Adalimumab sustains steroid-free remission after 3 years of therapy for Crohn's disease.

BACKGROUND: Treatments that achieve sustainable steroid-free clinical remission in Crohn's disease are needed; however, long-term steroid-sparing efficacy data are limited. AIM: To evaluate steroid-sparing efficacy and the impact of steroid discontinuation on adverse events during treatment of Crohn's disease with adalimumab in the phase III randomised, double-blind 1-year CHARM trial and for an additional 2 years in its open-label extension ADHERE. METHODS: Steroid-free remission and response and steroid-sparing (≥50% steroid dose reduction) remission rates were evaluated over 3 years in patients who were taking corticosteroids at CHARM baseline. RESULTS: Of 778 patients randomised in CHARM (including those who did not achieve clinical response to open-label induction therapy), 313 patients (40%) were on corticosteroids at baseline. In the 206 patients randomised to adalimumab, rates of steroid-free remission at 1 year and 3 years were 26% and 23% respectively; corresponding rates were 29% and 25% for steroid-sparing remission and 32% and 28% for steroid-free response. Although the incidence of serious infections with adalimumab treatment during CHARM was higher in patients taking steroids at baseline than those who were not, the rates of overall adverse events, serious infections and opportunistic infections were lower in patients who were able to discontinue corticosteroids than those who remained on steroids. CONCLUSION: Adalimumab therapy resulted in modest but clinically meaningful rates of steroid-free remission, sustained over 3 years of treatment, in a heavily pretreated population of patients with Crohn's disease receiving steroids at the start of therapy (http://www.clinicaltrials.gov number: NCT00077779).

Review article: defining remission in ulcerative colitis.

BACKGROUND: There is no international agreement on scoring systems used to measure disease activity in ulcerative colitis, nor is there a validated definition for disease remission. AIM: To review the principles and components for defining remission in ulcerative colitis and propose a definition that will help improve patient outcomes. METHODS: A review of current standards of remission from the perspective of clinical trials, guidelines, clinical practice and patients was conducted by the authors. Selected literature focused on the components of a definition of remission, the utility of a definition and treatment strategies, based on current definitions. RESULTS: Different definitions of remission affect the assessment of outcome and make it difficult to compare trials. In the clinic, endoscopy is rarely used to confirm remission, because mucosal healing has only recently begun to be related to the duration of subsequent remission in a way that will affect clinical practice. Histopathology may be the ultimate arbiter of mucosal healing. There is no agreement on the definition of remission in current guidelines. Patient-defined remission may predict endoscopic remission, but has yet to be shown to predict duration of remission. CONCLUSIONS: A standard based on clinical symptoms and endoscopy is proposed. Histopathology is a third dimension of remission that may have prognostic value. The definition of remission should help predict long-term outcome. The expectations of patients and their physicians need to be raised, as the goal of treatment of active ulcerative colitis should be to induce remission.

Adalimumab sustains clinical remission and overall clinical benefit after 2 years of therapy for Crohn's disease.

BACKGROUND: In the randomized, double-blind, placebo-controlled CHARM trial, adalimumab was more effective than placebo in maintaining clinical remission for patients with moderate-to-severe Crohn's disease (CD) through 56 weeks. AIM: To substantiate the long-term safety and clinical benefits of adalimumab through 2 years of therapy in CHARM and its open-label extension (ADHERE). METHODS: Patients entering ADHERE on blinded therapy received adalimumab 40 mg every other week (eow). Patients who had already moved to open-label adalimumab eow or weekly in CHARM continued their regimens. Data were analysed by originally randomized treatment group at CHARM baseline (adalimumab 40 mg eow, adalimumab 40 mg weekly, or placebo), regardless of whether patients entered ADHERE or received open-label adalimumab (eow or weekly). RESULTS: After up to 2 years of therapy, 37.6%, 41.9% and 49.8% of patients originally randomized to placebo, adalimumab eow and adalimumab weekly, respectively, were in clinical remission. All groups experienced sustained improvements on the Inflammatory Bowel Disease Questionnaire. Decreasing hazard rates for both all-cause and CD-related hospitalizations were observed over time. Over a 2-year period, the rates of serious adverse events and malignancies (33.3 and 1.1 events/100-patient-years respectively) were similar to those observed during the overall adalimumab CD clinical development programme. CONCLUSIONS: Adalimumab demonstrated sustained maintenance of clinical remission, improvements in quality of life and reductions in hospitalization during long-term treatment for CD, with no new safety concerns identified.