Royal London Hospital

BACKGROUND: Methods of classifying chronic obstructive pulmonary disease (COPD) depend largely upon spirometric measurements but disability is only weakly related to measurements of lung function. With the increased use of pulmonary rehabilitation, a need has been identified for a simple and standardised method of categorising disability in COPD. This study examined the validity of the Medical Research Council (MRC) dyspnoea scale for this purpose. METHODS: One hundred patients with COPD were recruited from an outpatient pulmonary rehabilitation programme. Assessments included the MRC dyspnoea scale, spirometric tests, blood gas tensions, a shuttle walking test, and Borg scores for perceived breathlessness before and after exercise. Health status was assessed using the St George's Respiratory Questionnaire (SGRQ) and Chronic Respiratory Questionnaire (CRQ). The Nottingham Extended Activities of Daily Living (EADL) score and Hospital Anxiety and Depression (HAD) score were also measured. RESULTS: Of the patients studied, 32 were classified as having MRC grade 3 dyspnoea, 34 MRC grade 4 dyspnoea, and 34 MRC grade 5 dyspnoea. Patients with MRC grades 1 and 2 dyspnoea were not included in the study. There was a significant association between MRC grade and shuttle distance, SGRQ and CRQ scores, mood state and EADL. Forced expiratory volume in one second (FEV1) was not associated with MRC grade. Multiple logistic regression showed that the determinants of disability appeared to vary with the level of disability. Between MRC grades 3 and 4 the significant covariates were exercise performance, SGRQ and depression score, whilst between grades 4 and 5 exercise performance and age were the major determinants. CONCLUSIONS: The MRC dyspnoea scale is a simple and valid method of categorising patients with COPD in terms of their disability that could be used to complement FEV1 in the classification of COPD severity.

Alphaxalone-alphadolone (Althesin), diluted and administered as a controlled infusion, was used as a sedative for 30 patients in an intensive therapy unit. This technique allowed rapid and accurate control of the level of sedation. It had three particularly useful applications: it provided "light sleep," allowed rapid variation in the level of sedation, and enabled repeated assessment of the central nervous system.Sedation was satisfactory for 86% of the total time, and no serious complications were attributed to the use of the drug. Furthermore, though alphaxalone-alphadolone was given for periods up to 20 days there was no evidence of tachyphylaxis or delay in recovery time.

Importance Cancer and other noncommunicable diseases (NCDs) are now widely recognized as a threat to global development. The latest United Nations high-level meeting on NCDs reaffirmed this observation and also highlighted the slow progress in meeting the 2011 Political Declaration on the Prevention and Control of Noncommunicable Diseases and the third Sustainable Development Goal. Lack of situational analyses, priority setting, and budgeting have been identified as major obstacles in achieving these goals. All of these have in common that they require information on the local cancer epidemiology. The Global Burden of Disease (GBD) study is uniquely poised to provide these crucial data. Objective To describe cancer burden for 29 cancer groups in 195 countries from 1990 through 2017 to provide data needed for cancer control planning. Evidence Review We used the GBD study estimation methods to describe cancer incidence, mortality, years lived with disability, years of life lost, and disability-adjusted life-years (DALYs). Results are presented at the national level as well as by Socio-demographic Index (SDI), a composite indicator of income, educational attainment, and total fertility rate. We also analyzed the influence of the epidemiological vs the demographic transition on cancer incidence. Findings In 2017, there were 24.5 million incident cancer cases worldwide (16.8 million without nonmelanoma skin cancer [NMSC]) and 9.6 million cancer deaths. The majority of cancer DALYs came from years of life lost (97%), and only 3% came from years lived with disability. The odds of developing cancer were the lowest in the low SDI quintile (1 in 7) and the highest in the high SDI quintile (1 in 2) for both sexes. In 2017, the most common incident cancers in men were NMSC (4.3 million incident cases); tracheal, bronchus, and lung (TBL) cancer (1.5 million incident cases); and prostate cancer (1.3 million incident cases). The most common causes of cancer deaths and DALYs for men were TBL cancer (1.3 million deaths and 28.4 million DALYs), liver cancer (572 000 deaths and 15.2 million DALYs), and stomach cancer (542 000 deaths and 12.2 million DALYs). For women in 2017, the most common incident cancers were NMSC (3.3 million incident cases), breast cancer (1.9 million incident cases), and colorectal cancer (819 000 incident cases). The leading causes of cancer deaths and DALYs for women were breast cancer (601 000 deaths and 17.4 million DALYs), TBL cancer (596 000 deaths and 12.6 million DALYs), and colorectal cancer (414 000 deaths and 8.3 million DALYs). Conclusions and Relevance The national epidemiological profiles of cancer burden in the GBD study show large heterogeneities, which are a reflection of different exposures to risk factors, economic settings, lifestyles, and access to care and screening. The GBD study can be used by policy makers and other stakeholders to develop and improve national and local cancer control in order to achieve the global targets and improve equity in cancer care.

INTRODUCTION: The SCARE Guidelines were published in 2016 to provide a structure for reporting surgical case reports. Since their publication, SCARE guidelines have been widely endorsed by authors, journal editors, and reviewers, and have helped to improve reporting transparency of case reports across a range of surgical specialties. In order to encourage further progress in reporting quality, the SCARE guidelines must themselves be kept up to date. We completed a Delphi consensus exercise to update the SCARE guidelines. METHODS: A Delphi consensus exercise was undertaken. All members of the previous Delphi group were invited to participate, in addition to researchers who have previously studied case reports, and editors from the International Journal of Surgery Case Reports. The expert group was sent an online questionnaire where they were asked to rate their agreement with proposed changes to each of the 24 items. RESULTS: 56 people agreed to participate and 45 (80%) invitees completed the survey which put forward modifications to the original guideline. The collated responses resulted in modifications. There was high agreement amongst the expert group. CONCLUSION: A modified and improved SCARE checklist is presented, after a Delphi consensus exercise was completed. The SCARE 2018 Statement: Updating Consensus Surgical CAse REport (SCARE) Guidelines.

The molecular mechanisms involved in the development of type 2 diabetes are poorly understood. Starting from genome-wide genotype data for 1924 diabetic cases and 2938 population controls generated by the Wellcome Trust Case Control Consortium, we set out to detect replicated diabetes association signals through analysis of 3757 additional cases and 5346 controls and by integration of our findings with equivalent data from other international consortia. We detected diabetes susceptibility loci in and around the genes CDKAL1, CDKN2A/CDKN2B, and IGF2BP2 and confirmed the recently described associations at HHEX/IDE and SLC30A8. Our findings provide insight into the genetic architecture of type 2 diabetes, emphasizing the contribution of multiple variants of modest effect. The regions identified underscore the importance of pathways influencing pancreatic beta cell development and function in the etiology of type 2 diabetes.

Multiple sclerosis (MS) is the commonest non-traumatic disabling disease to affect young adults. The incidence of MS is increasing worldwide, together with the socioeconomic impact of the disease. The underlying cause of MS and mechanisms behind this increase remain opaque, although complex gene-environment interactions almost certainly play a significant role. The epidemiology of MS indicates that low serum levels of vitamin D, smoking, childhood obesity and infection with the Epstein-Barr virus are likely to play a role in disease development. Changes in diagnostic methods and criteria mean that people with MS can be diagnosed increasingly early in their disease trajectory. Alongside this, treatments for MS have increased exponentially in number, efficacy and risk. There is now the possibility of a diagnosis of 'pre-symptomatic MS' being made; as a result potentially preventive strategies could be studied. In this comprehensive review, MS epidemiology, potential aetiological factors and pathology are discussed, before moving on to clinical aspects of MS diagnosis and management.

This paper is the first in a series of two publications relating to the European Crohn's and Colitis Organisation [ECCO] evidence-based consensus on the diagnosis and management of Crohn's disease and concerns the methodology of the consensus process, and the classification, diagnosis and medical management of active and quiescent Crohn's disease. Surgical management as well as special situations including management of perianal Crohn's disease of this ECCO Consensus are covered in a subsequent second paper [Gionchetti et al JCC 2016].

Diagnostic karyotype provides the framework for risk-stratification schemes in acute myeloid leukemia (AML); however, the prognostic significance of many rare recurring cytogenetic abnormalities remains uncertain. We studied the outcomes of 5876 patients (16-59 years of age) who were classified into 54 cytogenetic subgroups and treated in the Medical Research Council trials. In multivariable analysis, t(15;17)(q22;q21), t(8;21)(q22;q22), and inv(16)(p13q22)/t(16;16)(p13;q22) were the only abnormalities found to predict a relatively favorable prognosis (P < .001). In patients with t(15;17) treated with extended all-trans retinoic acid and anthracycline-based chemotherapy, additional cytogenetic changes did not have an impact on prognosis. Similarly, additional abnormalities did not have a significant adverse effect in t(8;21) AML; whereas in patients with inv(16), the presence of additional changes, particularly +22, predicted a better outcome (P = .004). In multivariable analyses, various abnormalities predicted a significantly poorer outcome, namely abn(3q) (excluding t(3;5)(q25;q34)), inv(3)(q21q26)/t(3;3)(q21;q26), add(5q)/del(5q), -5, -7, add(7q)/del(7q), t(6;11)(q27;q23), t(10;11)(p11 approximately 13;q23), other t(11q23) (excluding t(9;11)(p21 approximately 22;q23) and t(11;19)(q23;p13)), t(9;22)(q34;q11), -17, and abn(17p). Patients lacking the aforementioned favorable or adverse aberrations but with 4 or more unrelated abnormalities also exhibited a significantly poorer prognosis (designated "complex" karyotype group). These data allow more reliable prediction of outcome for patients with rarer abnormalities and may facilitate the development of consensus in reporting of karyotypic information in clinical trials involving younger adults with AML. This study is registered at http://www.isrctn.org as ISRCTN55678797 and ISRCTN17161961.

This new diagnostic consensus guideline is a joint project of the European Crohn’s and Colitis Organisation [ECCO] and the European Society of Gastrointestinal and Abdominal Radiology [ESGAR] that now merges the former ECCO-ESGAR Imaging Guideline and the former ECCO Endoscopy Guideline, also including laboratory parameters. It has been drafted by 30 ECCO and ESGAR members from 17 European countries. All the authors recognize th e work of and are grateful to previous ECCO and ESGAR members who contributed tocreating the earlier consensus guidelines on imaging and endoscopy. The former guidelines have been condensed into this new diagnostic consensus guideline which consists of two papers: the first detailing assessment at initial diagnosis, to monitor treat ment and for the detection of complications; the second dealing with the available scoring systems and general considerations regarding the different diagnostic tools. The strategy to define consensus was similar to that previously described in other ECCO consensus guidelines [available at www.ecco-ibd.eu]. Briefly, an open call for participants was made, with ECCO participants selected by the Guidelines’ Committee of ECCO [known as GuiCom] on the basis of their publication record and a personal statement and ESGAR participants nominated by ESGAR. The following working parties were established: diagnostics at initial diagnosis, diagnostics for monitoring treatment in patients with known IBD, diagnostics for the detect ion of complications, scores for IBD, and general principles and technical aspects. Provisional guideline statements and supporting text were written following a comprehensive literature review, then refined following two voting rounds. The first voting round introduced a more comprehensive voting procedure, in which each Guidelines participants voted on all statements by explicitly reviewing those statements together with their respective supporting text and references. The second voting round included optional national representative participation of ECCO’s 36 member countries and ESGAR’s 28 member countries. The level of evidence was graded according to the Oxford Centre for Evidence-Based Medicine [www.cebm.net]. The ECCO statements were finalized by the authors at a face-to-face meeting in Barcelona in October 2017 and represent consensus with agreement of at least 80% of the present participants. Consensus statements are intended to be read in context with their qualifying comments and not in isolation. The supporting text was then finalised under the direction of each working group leader [SV, TK, GF, VA, EC], before being integrated by the consensus leaders [CM, JS, AS].

HENRY HEAD, M.D., F.R.S., GORDON HOLMES, M.D.; SENSORY DISTURBANCES FROM CEREBRAL LESIONS1, Brain, Volume 34, Issue 2-3, 1 November 1911, Pages 102–254, ht

beta-Lactamases are the commonest single cause of bacterial resistance to beta-lactam antibiotics. Numerous chromosomal and plasmid-mediated types are known and may be classified by their sequences or phenotypic properties. The ability of a beta-lactamase to cause resistance varies with its activity, quantity, and cellular location and, for gram-negative organisms, the permeability of the producer strain. beta-Lactamases sometimes cause obvious resistance to substrate drugs in routine tests; often, however, these enzymes reduce susceptibility without causing resistance at current, pharmacologically chosen breakpoints. This review considers the ability of the prevalent beta-lactamases to cause resistance to widely used beta-lactams, whether resistance is accurately reflected in routine tests, and the extent to which the antibiogram for an organism can be used to predict the type of beta-lactamase that it produces.

BACKGROUND: Traumatic coagulopathy is thought to be caused primarily by fluid administration and hypothermia. METHODS: A retrospective study was performed to determine whether coagulopathy resulting from the injury itself is a clinically important entity in severely injured patients. RESULTS: One thousand eight hundred sixty-seven consecutive trauma patients were reviewed, of whom 1,088 had full data sets. Median Injury Severity Score was 20, and 57.7% had an Injury Severity Score > 15; 24.4% of patients had a significant coagulopathy. Patients with an acute coagulopathy had significantly higher mortality (46.0% vs. 10.9%; chi2, p < 0.001). The incidence of coagulopathy increased with severity of injury, but was not related to the volume of intravenous fluid administered (r2 = 0.25, p < 0.001). CONCLUSION: There is a common and clinically important acute traumatic coagulopathy that is not related to fluid administration. This is a marker of injury severity and is related to mortality. A coagulation screen is an important early test in severely injured patients.

A classification of anal fistulas is presented, which is the result of an analysis of 400 cases treated over the past 15 years, based on the pathogenesis of the disease and the normal muscular anatomy of the pelvic floor. Four main types were found but numerous variations of each occur, which are described. It is hoped that this will alert the surgeon to the various complex situations that he may encounter.

BACKGROUND: Psilocybin is a serotonin receptor agonist that occurs naturally in some mushroom species. Recent studies have assessed the therapeutic potential of psilocybin for various conditions, including end-of-life anxiety, obsessive-compulsive disorder, and smoking and alcohol dependence, with promising preliminary results. Here, we aimed to investigate the feasibility, safety, and efficacy of psilocybin in patients with unipolar treatment-resistant depression. METHODS: In this open-label feasibility trial, 12 patients (six men, six women) with moderate-to-severe, unipolar, treatment-resistant major depression received two oral doses of psilocybin (10 mg and 25 mg, 7 days apart) in a supportive setting. There was no control group. Psychological support was provided before, during, and after each session. The primary outcome measure for feasibility was patient-reported intensity of psilocybin's effects. Patients were monitored for adverse reactions during the dosing sessions and subsequent clinic and remote follow-up. Depressive symptoms were assessed with standard assessments from 1 week to 3 months after treatment, with the 16-item Quick Inventory of Depressive Symptoms (QIDS) serving as the primary efficacy outcome. This trial is registered with ISRCTN, number ISRCTN14426797. FINDINGS: Psilocybin's acute psychedelic effects typically became detectable 30-60 min after dosing, peaked 2-3 h after dosing, and subsided to negligible levels at least 6 h after dosing. Mean self-rated intensity (on a 0-1 scale) was 0·51 (SD 0·36) for the low-dose session and 0·75 (SD 0·27) for the high-dose session. Psilocybin was well tolerated by all of the patients, and no serious or unexpected adverse events occurred. The adverse reactions we noted were transient anxiety during drug onset (all patients), transient confusion or thought disorder (nine patients), mild and transient nausea (four patients), and transient headache (four patients). Relative to baseline, depressive symptoms were markedly reduced 1 week (mean QIDS difference -11·8, 95% CI -9·15 to -14·35, p=0·002, Hedges' g=3·1) and 3 months (-9·2, 95% CI -5·69 to -12·71, p=0·003, Hedges' g=2) after high-dose treatment. Marked and sustained improvements in anxiety and anhedonia were also noted. INTERPRETATION: This study provides preliminary support for the safety and efficacy of psilocybin for treatment-resistant depression and motivates further trials, with more rigorous designs, to better examine the therapeutic potential of this approach. FUNDING: Medical Research Council.

BACKGROUND: Fabry's disease, lysosomal alpha-galactosidase A deficiency, results from the progressive accumulation of globotriaosylceramide and related glycosphingolipids. Affected patients have microvascular disease of the kidneys, heart, and brain. METHODS: We evaluated the safety and effectiveness of recombinant alpha-galactosidase A in a multicenter, randomized, placebo-controlled, double-blind study of 58 patients who were treated every 2 weeks for 20 weeks. Thereafter, all patients received recombinant alpha-galactosidase A in an open-label extension study. The primary efficacy end point was the percentage of patients in whom renal microvascular endothelial deposits of globotriaosylceramide were cleared (reduced to normal or near-normal levels). We also evaluated the histologic clearance of microvascular endothelial deposits of globotriaosylceramide in the endomyocardium and skin, as well as changes in the level of pain and the quality of life. RESULTS: In the double-blind study, 20 of the 29 patients in the recombinant alpha-galactosidase A group (69 percent) had no microvascular endothelial deposits of globotriaosylceramide after 20 weeks, as compared with none of the 29 patients in the placebo group (P<0.001). Patients in the recombinant alpha-galactosidase A group also had decreased microvascular endothelial deposits of globotriaosylceramide in the skin (P<0.001) and heart (P<0.001). Plasma levels of globotriaosylceramide were directly correlated with clearance of the microvascular deposits. After six months of open-label therapy, all patients in the former placebo group and 98 percent of patients in the former recombinant alpha-galactosidase A group who had biopsies had clearance of microvascular endothelial deposits of globotriaosylceramide. The incidence of most treatment-related adverse events was similar in the two groups, with the exception of mild-to-moderate infusion reactions (i.e., rigors and fever), which were more common in the recombinant alpha-galactosidase A group. IgG seroconversion occurred in 88 percent of patients who received recombinant alpha-galactosidase A. CONCLUSIONS: Recombinant alpha-galactosidase A replacement therapy cleared microvascular endothelial deposits of globotriaosylceramide from the kidneys, heart, and skin in patients with Fabry's disease, reversing the pathogenesis of the chief clinical manifestations of this disease.

Importance: The increasing burden due to cancer and other noncommunicable diseases poses a threat to human development, which has resulted in global political commitments reflected in the Sustainable Development Goals as well as the World Health Organization (WHO) Global Action Plan on Non-Communicable Diseases. To determine if these commitments have resulted in improved cancer control, quantitative assessments of the cancer burden are required. Objective: To assess the burden for 29 cancer groups over time to provide a framework for policy discussion, resource allocation, and research focus. Evidence Review: Cancer incidence, mortality, years lived with disability, years of life lost, and disability-adjusted life-years (DALYs) were evaluated for 195 countries and territories by age and sex using the Global Burden of Disease study estimation methods. Levels and trends were analyzed over time, as well as by the Sociodemographic Index (SDI). Changes in incident cases were categorized by changes due to epidemiological vs demographic transition. Findings: In 2016, there were 17.2 million cancer cases worldwide and 8.9 million deaths. Cancer cases increased by 28% between 2006 and 2016. The smallest increase was seen in high SDI countries. Globally, population aging contributed 17%; population growth, 12%; and changes in age-specific rates, -1% to this change. The most common incident cancer globally for men was prostate cancer (1.4 million cases). The leading cause of cancer deaths and DALYs was tracheal, bronchus, and lung cancer (1.2 million deaths and 25.4 million DALYs). For women, the most common incident cancer and the leading cause of cancer deaths and DALYs was breast cancer (1.7 million incident cases, 535 000 deaths, and 14.9 million DALYs). In 2016, cancer caused 213.2 million DALYs globally for both sexes combined. Between 2006 and 2016, the average annual age-standardized incidence rates for all cancers combined increased in 130 of 195 countries or territories, and the average annual age-standardized death rates decreased within that timeframe in 143 of 195 countries or territories. Conclusions and Relevance: Large disparities exist between countries in cancer incidence, deaths, and associated disability. Scaling up cancer prevention and ensuring universal access to cancer care are required for health equity and to fulfill the global commitments for noncommunicable disease and cancer control.

Importance: Clinical outcomes for glioblastoma remain poor. Treatment with immune checkpoint blockade has shown benefits in many cancer types. To our knowledge, data from a randomized phase 3 clinical trial evaluating a programmed death-1 (PD-1) inhibitor therapy for glioblastoma have not been reported. Objective: To determine whether single-agent PD-1 blockade with nivolumab improves survival in patients with recurrent glioblastoma compared with bevacizumab. Design, Setting, and Participants: In this open-label, randomized, phase 3 clinical trial, 439 patients with glioblastoma at first recurrence following standard radiation and temozolomide therapy were enrolled, and 369 were randomized. Patients were enrolled between September 2014 and May 2015. The median follow-up was 9.5 months at data cutoff of January 20, 2017. The study included 57 multicenter, multinational clinical sites. Interventions: Patients were randomized 1:1 to nivolumab 3 mg/kg or bevacizumab 10 mg/kg every 2 weeks until confirmed disease progression, unacceptable toxic effects, or death. Main Outcomes and Measures: The primary end point was overall survival (OS). Results: A total of 369 patients were randomized to nivolumab (n = 184) or bevacizumab (n = 185). The MGMT promoter was methylated in 23.4% (43/184; nivolumab) and 22.7% (42/185; bevacizumab), unmethylated in 32.1% (59/184; nivolumab) and 36.2% (67/185; bevacizumab), and not reported in remaining patients. At median follow-up of 9.5 months, median OS (mOS) was comparable between groups: nivolumab, 9.8 months (95% CI, 8.2-11.8); bevacizumab, 10.0 months (95% CI, 9.0-11.8); HR, 1.04 (95% CI, 0.83-1.30); P = .76. The 12-month OS was 42% in both groups. The objective response rate was higher with bevacizumab (23.1%; 95% CI, 16.7%-30.5%) vs nivolumab (7.8%; 95% CI, 4.1%-13.3%). Grade 3/4 treatment-related adverse events (TRAEs) were similar between groups (nivolumab, 33/182 [18.1%]; bevacizumab, 25/165 [15.2%]), with no unexpected neurological TRAEs or deaths due to TRAEs. Conclusions and Relevance: Although the primary end point was not met in this randomized clinical trial, mOS was comparable between nivolumab and bevacizumab in the overall patient population with recurrent glioblastoma. The safety profile of nivolumab in patients with glioblastoma was consistent with that in other tumor types. Trial Registration: ClinicalTrials.gov Identifier: NCT02017717.

The management of inflammatory bowel disease represents a key component of clinical practice for members of the British Society of Gastroenterology (BSG). There has been considerable progress in management strategies affecting all aspects of clinical care since the publication of previous BSG guidelines in 2004, necessitating the present revision. Key components of the present document worthy of attention as having been subject to re-assessment, and revision, and having direct impact on practice include: The data generated by the nationwide audits of inflammatory bowel disease (IBD) management in the UK in 2006, and 2008. The publication of 'Quality Care: service standards for the healthcare of people with IBD' in 2009. The introduction of the Montreal classification for Crohn's disease and ulcerative colitis. The revision of recommendations for the use of immunosuppressive therapy. The detailed analysis, guidelines and recommendations for the safe and appropriate use of biological therapies in Crohn's disease and ulcerative colitis. The reassessment of the role of surgery in disease management, with emphasis on the importance of multi-disciplinary decision-making in complex cases. The availablity of new data on the role of reconstructive surgery in ulcerative colitis. The cross-referencing to revised guidelines for colonoscopic surveillance, for the management of metabolic bone disease, and for the care of children with inflammatory bowel disease. Use of the BSG discussion forum available on the BSG website to enable ongoing feedback on the published document http://www.bsg.org.uk/forum (accessed Oct 2010). The present document is intended primarily for the use of clinicians in the United Kingdom, and serves to replace the previous BSG guidelines in IBD, while complementing recent consensus statements published by the European Crohn's and Colitis Organisation (ECCO) https://www.ecco-ibd.eu/index.php (accessed Oct 2010).

Many common variants have been associated with hematological traits, but identification of causal genes and pathways has proven challenging. We performed a genome-wide association analysis in the UK Biobank and INTERVAL studies, testing 29.5 million genetic variants for association with 36 red cell, white cell, and platelet properties in 173,480 European-ancestry participants. This effort yielded hundreds of low frequency (<5%) and rare (<1%) variants with a strong impact on blood cell phenotypes. Our data highlight general properties of the allelic architecture of complex traits, including the proportion of the heritable component of each blood trait explained by the polygenic signal across different genome regulatory domains. Finally, through Mendelian randomization, we provide evidence of shared genetic pathways linking blood cell indices with complex pathologies, including autoimmune diseases, schizophrenia, and coronary heart disease and evidence suggesting previously reported population associations between blood cell indices and cardiovascular disease may be non-causal.

Crohn’s disease [CD] is a chronic inflammatory bowel disease [IBD] that can result in progressive bowel damage and disability.1 CD can affect individuals of any age, from children to the elderly,2,3 and may cause significant morbidity and impact on quality of life. Up to one-third of patients present with complicated behaviour [strictures, fistula, or abscesses] at diagnosis.4 Most patients over time will develop a complication, with roughly 50% of patients requiring surgery within 10 years of diagnosis.5–7 As the precise aetiology of CD remains unknown, a curative therapy is not yet available.8 Several agents are available for the medical treatment of CD. Medical agents include mesalazine [5-ASA], locally active steroids [such as budesonide], systemic steroids, thiopurines such as azathioprine [AZA] and mercaptopurine [MP], methotrexate [MTX], and biologic therapies (such as anti-tumour necrosis factor [TNF], anti-integrins, and anti-interleukin [IL] 12/23]. The European Crohn’s and Colitis Organisation [ECCO] produces and regularly updates several guidelines aimed at providing evidence-based guidance on critical aspects of IBD care to all health care professionals who manage patients with IBD. To provide high-quality evidence-based recommendations on medical treatment in CD, ECCO decided to develop these guidelines by adopting the GRADE [Grading of Recommendations Assessment, Development, and Evaluation] approach.9 GRADE is a systematic process for developing guidelines which addresses how to frame the health care questions, summarise the evidence, formulate the recommendations, and grade their strength and the quality of the associated evidence. GRADE increases transparency at all levels of this process and makes explicit the three considerations that lead to a particular recommendation: the quality of the evidence, the balance of benefits and harms, and the patients’ values and preferences. Therefore ECCO reviewed the available high-quality evidence on the medical management of CD and developed evidence-based recommendations on the medical treatment of adult patients with CD. These guidelines do not cover specific situations, such as postoperative management of adult patients with CD, which was already covered in the latest ECCO Guidelines on Crohn’s disease.10 Based on the GRADE workflow, the Guidelines Committee of ECCO [GuiCom] selected a panel of 48 experts supported by a team of methodologists and librarians. Selection was based on IBD expertise, scientific background, and knowledge of the GRADE methodology. All panellists received adequate training in GRADE before starting the process. Additionally, four patients with CD representing the European Federation of Crohn’s and Colitis Associations [EFCCA] were invited to participate in all face-to-face meetings and to provide their experiences and state their preferences. Three domains for medical treatment of CD were identified: 1] induction therapy; 2] maintenance therapy; 3] therapy of fistulising perianal disease. All panellists were assigned to one of three working groups coordinated by one to two working group leaders under the supervision of two Guideline coordinators. The panellists first formulated a series of specific questions using the PICO format [Population, Intervention, Comparator, Outcomes] which were deemed to be clinically important for the medical treatment of CD. The outcomes of all PICO questions were subsequently graded as ‘not important’, ‘important’, or ‘critical’ during a face-to-face kick-off meeting in Vienna, using a Delphi consensus process. A team of professional librarians performed a comprehensive literature search on EMBASE, PubMed/Medline, and Cochrane Central databases using specific search strings for each PICO question [Supplementary Files 1, 2, and 3, available as Supplementary data at ECCO-JCC online]. Two independent working group members [one assigned to the PICO and another one from the same group as a second reviewer] assessed the relevance of each abstract to PICO and included or excluded all the relevant papers for the final data extraction and analysis. Subsequently, the working group members assigned to each PICO question systematically reviewed and summarised the evidence on every outcome, to compile a Summary of Findings [SoF] table for each question. The GRADE method follows a hierarchical approach to synthesise evidence; recent high-quality systematic reviews and meta-analyses of clinical trials were preferentially used to create the recommendations. When these were not available, individual randomised clinical trials [RCTs] followed by observational studies were reviewed; results of individual studies were pooled using random-effects meta-analysis as appropriate and when needed. To define disease activity and severity [mild-to-moderate and moderate-to-severe], we accepted the definitions used by the investigators of the studies selected as an evidence basis for our work. The quality of evidence was classified into the following four categories in accordance with the GRADE approach: ‘high’ [meaning that further research is unlikely to change our in the research may change our in the research to change our in the and [meaning that any of is each PICO the quality of evidence was to the quality of evidence outcomes graded as The strength of each was graded as [meaning the of an the or or as [meaning the balance is the quality of evidence, values or and the outcomes were not in the clinical this was in the To the recommendations, we from the systematic reviews or our group of methodologists performed the All recommendations were to by the panel the ECCO for each with and from a of ECCO members who to the were not selected to be of the The final of all was panel members during a final consensus meeting in and to a final recommendations were at of the panellists with the and associated strength The of the and and the of the were reviewed by two Guideline Committee members and by the ECCO who the final of these The literature search the relevant definitions of and a of the and the the evidence can be in the Supplementary available as Supplementary data at ECCO-JCC As CD is a therapy to in the and in the The that chronic and results in to a recent in medical treatment and disease is that and may patients to their and therapy are to high-quality evidence is not available to this affect the of medical These include disease disease activity and to and of perianal or fistulising the individual for and the individual and the and of each be As is a clinical and is of to disease and therapy at based on and approach will provide the with the to therapy the of of the disease and which is to be to disease to the management of CD a series of health care maintenance be to be and be and appropriate guidance or for and be as in ECCO or the of for induction of of Crohn’s disease performed a meta-analysis of that the of or with in patients with active CD [Supplementary 1, available as Supplementary data at ECCO-JCC online]. The of from to patients with disease with or disease were was significant for induction of clinical [Supplementary 1, available as Supplementary data at ECCO-JCC online]. A recent Cochrane significant and to be in our as was significant in to when with [Supplementary 2, available as Supplementary data at ECCO-JCC online]. the trials of was over for clinical [Supplementary 3, available as Supplementary data at ECCO-JCC online]. significant in to was in trials that [Supplementary available as Supplementary data at ECCO-JCC online]. meta-analysis a significant on clinical the that at of another meta-analysis was to any such A pooled of three trials of a of a in the Crohn’s with the in and was not clinically Two trials with for induction of clinical A pooled a of [Supplementary available as Supplementary data at ECCO-JCC online]. was not by any significant in for [Supplementary available as Supplementary data at ECCO-JCC online]. in trials that the of was to patients with The of or for the treatment of CD not in using for the induction of clinical in patients with active Crohn’s disease to the A Cochrane systematic and included three that at a of with [Supplementary 2, available as Supplementary data at ECCO-JCC online]. Two of these clinical as in or at at was in all three was to for clinical and clinical in patients with active CD in the to the As with steroids which are associated with systemic activity and systemic and and a was to be in the reviewed A Cochrane systematic and meta-analysis from reviewed two that at a of with mesalazine to a mesalazine in patients with active CD [Supplementary 3, available as Supplementary data at ECCO-JCC online]. All trials clinical in or and clinical at was not to mesalazine for clinical in patients with active CD in the [Supplementary available as Supplementary data at ECCO-JCC online]. clinical was in patients in patients mesalazine [Supplementary available as Supplementary data at ECCO-JCC online]. The of was with and in groups [Supplementary and available as Supplementary data at ECCO-JCC online]. studies the of treatment on CD. and to clinical or with the of these the European on the of to or Therefore a was not on to CD, for the treatment of patients with Crohn’s we the of systemic for the induction of clinical and Two on the of systemic or with for the treatment of active available as Supplementary data at ECCO-JCC online]. was at a of 48 and on a basis to and of from to with a of is at over an from these studies in a Cochrane systematic patients on induction of clinical was in patients as with were to be as in clinical in the two studies patients on the of patients from the of systemic was available from one patients with The of was in patients with included of and in patients with and in was for the outcomes to which a quality of evidence the of thiopurines as for the induction of of Crohn’s disease Several studies on the of thiopurines with for induction of and in [Supplementary available as Supplementary data at ECCO-JCC online]. trials the of thiopurines for induction of clinical in with or patients were The active was in four of these and the active was in the The trials were in of of active and of for of the trials for the of The pooled was performed on an basis and for induction of thiopurines and in the active with in the group Three trials on clinical not with of disease these of of disease were of the patients as with of clinical The of clinical was was and to data and the quality of evidence was for this [Supplementary available as Supplementary data at ECCO-JCC online]. one on during The pooled of any was not and thiopurines were in two of of developed The quality of evidence was deemed to a of and on a quality of The groups was at for and for of the trials on at the of the induction data were available that for a pooled trials in of such as or in thiopurines as with a of at and at and for the thiopurines and a of in the group and a significant in in and one relevant was this patients with active CD were randomised to of or for with a of at that was over a [Supplementary available as Supplementary data at ECCO-JCC online]. a of patients with were in clinical The of treatment for and was in with this is by and such as the of studies were that for the induction of of CD. was in the the of for CD and the decided to Three and studies the of and thiopurines for induction of in [Supplementary available as Supplementary data at ECCO-JCC online]. These studies used and of Two studies used at of and and one used at All patients were and received systemic steroids at of the individual studies or the pooled a significant in the to [Supplementary available as Supplementary data at ECCO-JCC online]. the of is with the data are and the quality of evidence is for can be Based on the evidence, on a for the of for clinical in patients with CD not be may be as an for patients with disease when be The to therapy in patients a be the of and to in patients with Crohn’s disease who not to therapy are and therapies for the treatment of CD include and is not in the European for CD, is available in and is a at a of at 2, and during induction and every is a at a of and followed by every is a at a of at 2, and followed by every on agents and from several meta-analyses of their for induction of clinical and clinical [Supplementary available as Supplementary data at ECCO-JCC in patients who not adequate or were to data were available for the induction two studies a the evidence was to on clinical were and data on were by to the of patients included in the meta-analysis on outcomes and and and quality of are was in of The of on and in a that with and were to for induction of The of of biologic agents is a of that patients with fistulising perianal complicated from the of to a of or of agents be the first in disease these results are based on from clinical the of and thiopurines over to clinical and one the of therapy of with as with for the induction of clinical in patients to therapies [Supplementary available as Supplementary data at ECCO-JCC online]. this therapy was not to for clinical therapy was associated with at this was at the of was in to associated with therapy the of used in this was the used in CD patients of therapy with a when starting to in patients with Crohn’s who an to therapy The and Crohn’s the of with over in patients to who to to steroids or [Supplementary available as Supplementary data at ECCO-JCC online]. therapy in of clinical at as with therapy was to result in at this was in for were of in therapy A in clinical is patients who or an to thiopurines and in therapy is in such maintenance in with the benefits in of A of of the of therapy starting therapy in this be in the of evidence, an approach be for induction of in patients with Crohn’s disease with to therapy to therapy high-quality is an that to the by the and CD, induction be using a of systematic and meta-analysis pooled the results from in which was with for induction of in patients with active available as Supplementary data at ECCO-JCC online]. patients with or induction of clinical and induction of clinical at were and a meta-analysis was an of clinical of [Supplementary available as Supplementary data at ECCO-JCC online]. The quality of evidence was The of clinical was [Supplementary available as Supplementary data at ECCO-JCC online]. The quality of evidence was CD patients that of patients at as with of The quality of evidence was on or The pooled of any was not and [Supplementary available as Supplementary data at ECCO-JCC online]. the pooled of any was not and [Supplementary available as Supplementary data at ECCO-JCC the quality of evidence was The of to be for induction of and in patients with Crohn’s disease with to therapy to therapy is a that by the in is at a of at 2, and for and every who do not at can from an at Three randomised trials patients with or on induction of clinical induction of clinical and in adult patients with active available as Supplementary data at ECCO-JCC online]. in these studies were followed for to 10 was in patients with [Supplementary available as Supplementary data at ECCO-JCC online]. clinical was in patients with [Supplementary available as Supplementary data at ECCO-JCC online]. The quality of evidence for these outcomes was of with were not with [Supplementary available as Supplementary data at ECCO-JCC online]. The quality of evidence for this was to from the of or for the treatment of active Crohn’s disease in patients who therapy systematic and meta-analysis performed an of and for induction of in patients with active CD who were or to a of patients with or on induction of clinical and clinical [Supplementary available as Supplementary data at ECCO-JCC online]. The pooled of clinical and clinical were not and the quality of evidence was for a of patients with or on or The pooled of any was not and the pooled of any was not and the quality of evidence was surgery be as an in is for the induction of in patients with CD, as a and of at or a or a Crohn’s of with and is a knowledge on how to CD in of the the and or in patients with disease. Therefore the is to the who the individual and of systemic steroids are in in CD, are by important Additionally, of not disease Therefore we that the of or to steroids the of 10 or within of starting steroids, a within of steroids, or the for a of in all a are not in thiopurines a of and are for in CD patients are with steroids at the of patients with a of steroids and in at and is associated with a of this may be medical and surgery are not or are associated with individual patients with CD as a or with or to therapy we the of These include agents [such as and or All these agents are in and CD The on and and the induction of in the of with thiopurines is for of therapy over was in the performed to The the of or the of and over or in with this be and in The for the of Crohn’s that the of with in patients at of as with a was associated with of and for surgery in patients with A that is associated with to clinical the and of therapy to be a in in the therapy not to be associated with at in the a that therapy is associated with for and as with Therefore the is to the who and to be as specific such as the at for or and at for specific such as patients who or are is evidence on the and in patients with or as a first assessed the and of these agents when used in therapy as with to be in the in was in patients with in patients with CD with disease or to at one surgery be as an the of a for induction of and for using of clinical the or of therapy not on on the disease severity impact of disease in the individual the and for the inflammatory of and disease appropriate studies that the of over a on the of and and that for disease be studies were by this as important research the of for maintenance of in patients with Crohn’s disease for the maintenance of of CD [Supplementary available as Supplementary data at ECCO-JCC online]. significant [Supplementary available as Supplementary data at ECCO-JCC online]. trials that assessed and were from to with trials a of were significant in the of patients an or to or The data were and this [Supplementary available as Supplementary data at ECCO-JCC online]. are for the maintenance of in patients with Crohn’s disease The of maintenance treatment with or to patients with CD who are in one [Supplementary available as Supplementary data at ECCO-JCC online]. meta-analysis included data from trials and A of patients with to were included and followed for to was to in disease activity in was to for the maintenance of in patients outcomes were in four trials and a of patients followed for to The of during maintenance treatment with thiopurines was with The of in patients with thiopurines was and were the the of therapy in patients with Crohn’s disease for that the of thiopurines disease Two studies the of of the for of Crohn’s disease in and the trials [Supplementary available as Supplementary data at ECCO-JCC online]. The excluded from our table was not or the adult patients with a recent of CD were randomised to or to were to active disease in this The results were not significant for any of the critical outcomes of clinical not the two groups patients with and were in The of as and were in patients in the group and in the group methotrexate for the maintenance of in patients with Crohn’s disease on the of are from one patients were of or of for [Supplementary available as Supplementary data at ECCO-JCC online]. with active CD, who to of treatment with were assigned to at a of or for for CD were the of patients who in was in the group in the group 50% of the patients in the group by the of the were in in the group as with the group over the observational [one and the a and patients in the group in the of the was one treatment of these of severity to treatment or from the The of was in patients with Crohn’s disease who with maintenance treatment using the same treatment is Two systematic reviews the of maintenance treatment with and to patients with CD who disease with the same [Supplementary available as Supplementary data at ECCO-JCC online]. trials and were pooled in the meta-analysis from one was on two on and two on A of patients were included and followed for to of the studies included and one included all was as a The of with was The following values were with with and with A significant the three are pooled data available on of all as a performed in the of a Cochrane the for for and were and with is as with for the maintenance of in CD the and of do not the of that may in and observational for clinical in patients with Crohn’s disease who with at every was to in clinical in patients with CD who with [Supplementary available as Supplementary data at ECCO-JCC online]. patients every and patients every were in clinical as with patients and was at clinical and a of with data are to the the of to clinical in patients with Crohn’s disease who with outcomes for the maintenance of with in CD patients [Supplementary available as Supplementary data at ECCO-JCC to in the induction were to every or or a of the patients were in clinical as with of A that at clinical was by of patients every and by of patients every as with in the The treatment every and was and was treatment every and Therefore was every or was in of patients of patients The pooled of any was not patients who were and are data on as this was assessed in a of patients at was significant in patients in the group as with patients in the treatment were during the of were and with significant in the and was an of in the maintenance groups patients in and data are to the are randomised trials or with agents for the maintenance of clinical in patients with CD who or with the same A included trials used the to define clinical with The a time of All were the the the quality of evidence was specific was the in the maintenance Based on is evidence to to or in patients who to induction treatment with any or is a to that and to trials that for the of who from a biologic over the Crohn’s disease patients in clinical under is evidence to for or the of to clinical outcomes as to care from two with a of patients with CD were used to this [Supplementary available as Supplementary data at ECCO-JCC online]. These two of over clinically based for any of our critical clinical [one clinical [one [one [one or [one the a of IBD patients with to maintenance therapy were randomised to or groups were or to a and of the that in patients in clinical a or was in and of in clinical or at were and based the group who received during the patients with CD, with an induction therapy with and were randomised to the following three based on clinical and levels of with of or of or based on clinical The was to a was in clinical with from to in the three in in in studies important in their which the strength of our The outcomes in studies were clinical important such as and to be The in Crohn’s that is on and and that during the induction may outcomes and treatment the that with adequate of patients are Crohn’s disease patients who to an is evidence to for or the of to clinical outcomes to the of in patients on therapy with active to the of of and to clinical was with on clinical in one in a of patients with CD with were randomised to every or based on and levels using the was in clinical the group and the group [Supplementary available as Supplementary data at ECCO-JCC online]. studies a adequate and clinical outcomes from clinical to Based on these observational recent clinical guidelines and a group of experts supported the of the quality of evidence from observational a of patients with active IBD with who and clinical were for and at a of was in of patients in the as with in the clinical was in and in the group another a of the using a of was to a at was this group and a group in which were of was significant in clinical the approach was in the evidence not an a and clinical outcomes a of thiopurines in Crohn’s disease patients in on maintenance as the of is when the treatment is our meta-analysis to the two of in CD patients in on maintenance therapy [Supplementary available as Supplementary data at ECCO-JCC online]. from four trials were included received from to before randomised to or or to or All studies a time of to results that the of clinical is [Supplementary available as Supplementary data at ECCO-JCC online]. meta-analysis for was the data a with of the results were not significant [Supplementary available as Supplementary data at ECCO-JCC online]. for the be performed the data from the To the evidence for the of clinical is in of of as when the treatment was the of was not and from studies that patients treatment for are and this an important research from observational studies and for the of and in patients to treatment with The time and the of patients included in the studies of the meta-analysis are to and that may in the reviewed the literature to the approach of using thiopurines an literature we not evidence the two treatment one was of thiopurines was with thiopurines in the of therapy in patients with IBD. The was as was not to data from and CD specific was patients with Crohn’s disease who with the of and we with A Cochrane based on two the same patients who therapy with or [Supplementary available as Supplementary data at ECCO-JCC online]. The same the of for therapy or These results are to an of in the therapy studies included and studies are to the A of when agents are with the and were as 10 in one meta-analysis of patients included in the patients with Crohn’s disease who with the of and we with the basis of a meta-analysis of studies on by the data included were the and groups to be to the relevant PICO question. The result of this not any in maintenance of clinical therapy and [Supplementary and Supplementary available as Supplementary data at ECCO-JCC online]. this meta-analysis was to of in the studies with a are quality data available for clinical in the which is an that follows the of patients in the on the of were in patients with or at years of The meta-analysis by which was not any in with and therapy [Supplementary available as Supplementary data at ECCO-JCC online]. is evidence to or of therapy in Crohn’s disease patients the to therapy be and and be with the randomised