Patient selection for urgent endoscopic retrograde cholangio-pancreatography by endoscopic ultrasound in predicted severe acute biliary pancreatitis (APEC-2): a multicentre prospective study.

OBJECTIVE: Routine urgent endoscopic retrograde cholangiopancreatography (ERCP) with endoscopic biliary sphincterotomy (ES) does not improve outcome in patients with predicted severe acute biliary pancreatitis. Improved patient selection for ERCP by means of endoscopic ultrasonography (EUS) for stone/sludge detection may challenge these findings. DESIGN: A multicentre, prospective cohort study included patients with predicted severe acute biliary pancreatitis without cholangitis. Patients underwent urgent EUS, followed by ERCP with ES in case of common bile duct stones/sludge, within 24 hours after hospital presentation and within 72 hours after symptom onset. The primary endpoint was a composite of major complications or mortality within 6 months after inclusion. The historical control group was the conservative treatment arm (n=113) of the randomised APEC trial (Acute biliary Pancreatitis: urgent ERCP with sphincterotomy versus conservative treatment, patient inclusion 2013-2017) applying the same study design. RESULTS: Overall, 83 patients underwent urgent EUS at a median of 21 hours (IQR 17-23) after hospital presentation and at a median of 29 hours (IQR 23-41) after start of symptoms. Gallstones/sludge in the bile ducts were detected by EUS in 48/83 patients (58%), all of whom underwent immediate ERCP with ES. The primary endpoint occurred in 34/83 patients (41%) in the urgent EUS-guided ERCP group. This was not different from the 44% rate (50/113 patients) in the historical conservative treatment group (risk ratio (RR) 0.93, 95% CI 0.67 to 1.29; p=0.65). Sensitivity analysis to correct for baseline differences using a logistic regression model also showed no significant beneficial effect of the intervention on the primary outcome (adjusted OR 1.03, 95% CI 0.56 to 1.90, p=0.92). CONCLUSION: In patients with predicted severe acute biliary pancreatitis without cholangitis, urgent EUS-guided ERCP with ES did not reduce the composite endpoint of major complications or mortality, as compared with conservative treatment in a historical control group. TRIAL REGISTRATION NUMBER: ISRCTN15545919.

Rehabilitation to improve outcomes of lumbar fusion surgery: a systematic review with meta-analysis.

PURPOSE: To evaluate the effectiveness of rehabilitation strategies on disability, pain, pain-related fear, and return-to-work in patients undergoing lumbar fusion surgery for degenerative conditions or adult isthmic spondylolisthesis. METHODS: Six electronic databases were systematically searched for randomized controlled trials (RCTs) evaluating the effect of rehabilitation (unimodal or multimodal). The estimated effect size was calculated for interventions with homogeneous content using a random-effects model. Certainty of evidence was assessed by GRADE. RESULTS: In total, 18 RCTs, including 1402 unique patients, compared specific rehabilitation to other rehabilitation strategies or usual care. Most described indications were degenerative disc disease and spondylolisthesis. All rehabilitation interventions were delivered in the postoperative period, and six of them also included a preoperative component. Intervention dose and intensity varied between studies (ranging from one session to daily sessions for one month). Usual care consisted mostly of information and postoperative mobilization. At short term, low quality of evidence shows that exercise therapy was more effective for reducing disability and pain than usual care (standardized mean difference [95% CI]: -0.41 [-0.71; -0.10] and -0.36 [-0.65; -0.08], four and five studies, respectively). Multimodal rehabilitation consisted mostly of exercise therapy combined with cognitive behavioral training, and was more effective in reducing disability and pain-related fear than exercise therapy alone (-0.31 [-0.49; -0.13] and -0.64 [-1.11; -0.17], six and four studies, respectively). Effects disappeared beyond one year. Rehabilitation showed a positive tendency towards a higher return-to-work rate (pooled relative risk [95% CI]: 1.30 [0.99; 1.69], four studies). CONCLUSION: There is low-quality evidence showing that both exercise therapy and multimodal rehabilitation are effective for improving outcomes up to six months after lumbar fusion, with multimodal rehabilitation providing additional benefits over exercise alone in reducing disability and pain-related fear. Additional high-quality studies are needed to demonstrate the effectiveness of rehabilitation strategies in the long term and for work-related outcomes.

Pain patterns in chronic pancreatitis: a nationwide longitudinal cohort study.

OBJECTIVE: Pain in chronic pancreatitis is subdivided in a continuous or intermittent pattern, each thought to represent a different entity, requiring specific treatment. Because evidence is missing, we studied pain patterns in a prospective longitudinal nationwide study. DESIGN: 1131 patients with chronic pancreatitis (fulfilling M-ANNHEIM criteria) were included between 2011 and 2018 in 30 Dutch hospitals. Patients with continuous or intermittent pain were compared for demographics, pain characteristics, quality of life (Short-Form 36), imaging findings, disease duration and treatment. Alternation of pain pattern and associated variables were longitudinally assessed using a multivariable multinomial logistic regression model. RESULTS: At inclusion, 589 patients (52%) had continuous pain, 231 patients (20%) had intermittent pain and 311 patients (28%) had no pain. Patients with continuous pain had more severe pain, used more opioids and neuropathic pain medication, and had a lower quality of life. There were no differences between pain patterns for morphological findings on imaging, disease duration and treatment. During a median follow-up of 47 months, 552 of 905 patients (61%) alternated at least once between pain patterns. All alternations were associated with the Visual Analogue Scale pain intensity score and surgery was only associated with the change from pain to no pain. CONCLUSION: Continuous and intermittent pain patterns in chronic pancreatitis do not seem to be the result of distinctly different pathophysiological entities. The subjectively reported character of pain is not related to imaging findings or disease duration. Pain patterns often change over time and are merely a feature of how severity of pain is experienced.

Health outcomes of 1000 children born to mothers with inflammatory bowel disease in their first 5 years of life.

OBJECTIVE: The aim of this study was to describe the long-term health outcomes of children born to mothers with inflammatory bowel disease (IBD) and to assess the impact of maternal IBD medication use on these outcomes. DESIGN: We performed a multicentre retrospective study in The Netherlands. Women with IBD who gave birth between 1999 and 2018 were enrolled from 20 participating hospitals. Information regarding disease characteristics, medication use, lifestyle, pregnancy outcomes and long-term health outcomes of children was retrieved from mothers and medical charts. After consent of both parents, outcomes until 5 years were also collected from general practitioners. Our primary aim was to assess infection rate and our secondary aims were to assess adverse reactions to vaccinations, growth, autoimmune diseases and malignancies. RESULTS: We included 1000 children born to 626 mothers (381 (61%) Crohn's disease, 225 (36%) ulcerative colitis and 20 (3%) IBD unclassified). In total, 196 (20%) had intrauterine exposure to anti-tumour necrosis factor-α (anti-TNF-α) (60 with concomitant thiopurine) and 240 (24%) were exposed to thiopurine monotherapy. The 564 children (56%) not exposed to anti-TNF-α and/or thiopurine served as control group. There was no association between adverse long-term health outcomes and in utero exposure to IBD treatment. We did find an increased rate of intrahepatic cholestasis of pregnancy (ICP) in case thiopurine was used during the pregnancy without affecting birth outcomes and long-term health outcomes of children. All outcomes correspond with the general age-adjusted population. CONCLUSION: In our study, we found no association between in utero exposure to anti-TNF-α and/or thiopurine and the long-term outcomes antibiotic-treated infections, severe infections needing hospital admission, adverse reactions to vaccinations, growth failure, autoimmune diseases and malignancies.

Urgent endoscopic retrograde cholangiopancreatography with sphincterotomy versus conservative treatment in predicted severe acute gallstone pancreatitis (APEC): a multicentre randomised controlled trial.

BACKGROUND: It remains unclear whether urgent endoscopic retrograde cholangiopancreatography (ERCP) with biliary sphincterotomy improves the outcome of patients with gallstone pancreatitis without concomitant cholangitis. We did a randomised trial to compare urgent ERCP with sphincterotomy versus conservative treatment in patients with predicted severe acute gallstone pancreatitis. METHODS: In this multicentre, parallel-group, assessor-masked, randomised controlled superiority trial, patients with predicted severe (Acute Physiology and Chronic Health Evaluation II score ≥8, Imrie score ≥3, or C-reactive protein concentration >150 mg/L) gallstone pancreatitis without cholangitis were assessed for eligibility in 26 hospitals in the Netherlands. Patients were randomly assigned (1:1) by a web-based randomisation module with randomly varying block sizes to urgent ERCP with sphincterotomy (within 24 h after hospital presentation) or conservative treatment. The primary endpoint was a composite of mortality or major complications (new-onset persistent organ failure, cholangitis, bacteraemia, pneumonia, pancreatic necrosis, or pancreatic insufficiency) within 6 months of randomisation. Analysis was by intention to treat. This trial is registered with the ISRCTN registry, ISRCTN97372133. FINDINGS: Between Feb 28, 2013, and March 1, 2017, 232 patients were randomly assigned to urgent ERCP with sphincterotomy (n=118) or conservative treatment (n=114). One patient from each group was excluded from the final analysis because of cholangitis (urgent ERCP group) and chronic pancreatitis (conservative treatment group) at admission. The primary endpoint occurred in 45 (38%) of 117 patients in the urgent ERCP group and in 50 (44%) of 113 patients in the conservative treatment group (risk ratio [RR] 0·87, 95% CI 0·64-1·18; p=0·37). No relevant differences in the individual components of the primary endpoint were recorded between groups, apart from the occurrence of cholangitis (two [2%] of 117 in the urgent ERCP group vs 11 [10%] of 113 in the conservative treatment group; RR 0·18, 95% CI 0·04-0·78; p=0·010). Adverse events were reported in 87 (74%) of 118 patients in the urgent ERCP group versus 91 (80%) of 114 patients in the conservative treatment group. INTERPRETATION: In patients with predicted severe gallstone pancreatitis but without cholangitis, urgent ERCP with sphincterotomy did not reduce the composite endpoint of major complications or mortality, compared with conservative treatment. Our findings support a conservative strategy in patients with predicted severe acute gallstone pancreatitis with an ERCP indicated only in patients with cholangitis or persistent cholestasis. FUNDING: The Netherlands Organization for Health Research and Development, Fonds NutsOhra, and the Dutch Patient Organization for Pancreatic Diseases.

Effect of Early Surgery vs Endoscopy-First Approach on Pain in Patients With Chronic Pancreatitis: The ESCAPE Randomized Clinical Trial.

Importance: For patients with painful chronic pancreatitis, surgical treatment is postponed until medical and endoscopic treatment have failed. Observational studies have suggested that earlier surgery could mitigate disease progression, providing better pain control and preserving pancreatic function. Objective: To determine whether early surgery is more effective than the endoscopy-first approach in terms of clinical outcomes. Design, Setting, and Participants: The ESCAPE trial was an unblinded, multicenter, randomized clinical superiority trial involving 30 Dutch hospitals participating in the Dutch Pancreatitis Study Group. From April 2011 until September 2016, a total of 88 patients with chronic pancreatitis, a dilated main pancreatic duct, and who only recently started using prescribed opioids for severe pain (strong opioids for ≤2 months or weak opioids for ≤6 months) were included. The 18-month follow-up period ended in March 2018. Interventions: There were 44 patients randomized to the early surgery group who underwent pancreatic drainage surgery within 6 weeks after randomization and 44 patients randomized to the endoscopy-first approach group who underwent medical treatment, endoscopy including lithotripsy if needed, and surgery if needed. Main Outcomes and Measures: The primary outcome was pain, measured on the Izbicki pain score and integrated over 18 months (range, 0-100 [increasing score indicates more pain severity]). Secondary outcomes were pain relief at the end of follow-up; number of interventions, complications, hospital admissions; pancreatic function; quality of life (measured on the 36-Item Short Form Health Survey [SF-36]); and mortality. Results: Among 88 patients who were randomized (mean age, 52 years; 21 (24%) women), 85 (97%) completed the trial. During 18 months of follow-up, patients in the early surgery group had a lower Izbicki pain score than patients in the group randomized to receive the endoscopy-first approach group (37 vs 49; between-group difference, -12 points [95% CI, -22 to -2]; P = .02). Complete or partial pain relief at end of follow-up was achieved in 23 of 40 patients (58%) in the early surgery vs 16 of 41 (39%)in the endoscopy-first approach group (P = .10). The total number of interventions was lower in the early surgery group (median, 1 vs 3; P < .001). Treatment complications (27% vs 25%), mortality (0% vs 0%), hospital admissions, pancreatic function, and quality of life were not significantly different between early surgery and the endoscopy-first approach. Conclusions and Relevance: Among patients with chronic pancreatitis, early surgery compared with an endoscopy-first approach resulted in lower pain scores when integrated over 18 months. However, further research is needed to assess persistence of differences over time and to replicate the study findings. Trial Registration: ISRCTN Identifier: ISRCTN45877994.

Postoperative bracing after lumbar surgery: a survey amongst spinal surgeons in Belgium.

PURPOSE: Bracing is frequently prescribed following lumbar surgery for degenerative conditions. However, previous studies failed to demonstrate the advantage of postoperative lumbar bracing in both short- and long-term outcome in terms of pain, quality of life and fusion rate. The purpose of this study was to assess the prescription patterns and rationale for postoperative bracing amongst spinal surgeons in Belgium. METHODS: A 16-item online survey was distributed by email to spinal surgeons affiliated to the Spine Society of Belgium (N = 252). RESULTS: A total of 105 surgeons (42%) completed the survey. The overall bracing frequency following lumbar surgery was 38%. A brace was more often prescribed following the fusion procedures (52%) than after the non-fusion procedures (21%) (p < 0.0001). The majority of surgeons (59%) considered bracing after at least one type of lumbar surgery. Orthopaedic surgeons (73%) reported a significantly higher rate of prescribing postoperative bracing compared to neurosurgeons (44%) (p = 0.003). Pain alleviation (67%) was the main goal for prescribing a postoperative brace. A total of 42% of the surgeons aimed to improve fusion rate by bracing after lumbar fusion procedures. A quasi-equal level of the scientific literature (29%), personal experience (35%) and teaching from peers (36%) was reported to contribute on the attitudes towards prescribing bracing. CONCLUSIONS: Postoperative bracing was prescribed by Belgian spinal surgeons following more than one-third of lumbar procedures. This was underpinned by beliefs regarding pain alleviation and higher fusion rate. Interestingly, based on the scientific literature these beliefs have been demonstrated to be false. These slides can be retrieved under Electronic Supplementary Material.

2018 EULAR recommendations for physical activity in people with inflammatory arthritis and osteoarthritis.

Regular physical activity (PA) is increasingly promoted for people with rheumatic and musculoskeletal diseases as well as the general population. We evaluated if the public health recommendations for PA are applicable for people with inflammatory arthritis (iA; Rheumatoid Arthritis and Spondyloarthritis) and osteoarthritis (hip/knee OA) in order to develop evidence-based recommendations for advice and guidance on PA in clinical practice. The EULAR standardised operating procedures for the development of recommendations were followed. A task force (TF) (including rheumatologists, other medical specialists and physicians, health professionals, patient-representatives, methodologists) from 16 countries met twice. In the first TF meeting, 13 research questions to support a systematic literature review (SLR) were identified and defined. In the second meeting, the SLR evidence was presented and discussed before the recommendations, research agenda and education agenda were formulated. The TF developed and agreed on four overarching principles and 10 recommendations for PA in people with iA and OA. The mean level of agreement between the TF members ranged between 9.8 and 8.8. Given the evidence for its effectiveness, feasibility and safety, PA is advocated as integral part of standard care throughout the course of these diseases. Finally, the TF agreed on related research and education agendas. Evidence and expert opinion inform these recommendations to provide guidance in the development, conduct and evaluation of PA-interventions and promotion in people with iA and OA. It is advised that these recommendations should be implemented considering individual needs and national health systems.

Accelerometry-Based Activity Recognition and Assessment in Rheumatic and Musculoskeletal Diseases.

One of the important aspects to be considered in rheumatic and musculoskeletal diseases is the patient's activity capacity (or performance), defined as the ability to perform a task. Currently, it is assessed by physicians or health professionals mainly by means of a patient-reported questionnaire, sometimes combined with the therapist's judgment on performance-based tasks. This work introduces an approach to assess the activity capacity at home in a more objective, yet interpretable way. It offers a pilot study on 28 patients suffering from axial spondyloarthritis (axSpA) to demonstrate its efficacy. Firstly, a protocol is introduced to recognize a limited set of six transition activities in the home environment using a single accelerometer. To this end, a hierarchical classifier with the rejection of non-informative activity segments has been developed drawing on both direct pattern recognition and statistical signal features. Secondly, the recognized activities should be assessed, similarly to the scoring performed by patients themselves. This is achieved through the interval coded scoring (ICS) system, a novel method to extract an interpretable scoring system from data. The activity recognition reaches an average accuracy of 93.5%; assessment is currently 64.3% accurate. These results indicate the potential of the approach; a next step should be its validation in a larger patient study.

Qualitative study exploring the views of patients and healthcare providers on current rehabilitation practices after lumbar fusion surgery.

OBJECTIVES: To explore the views of patients and healthcare providers on current rehabilitation after lumbar fusion surgery (LFS) to fuel the development of a novel rehabilitation care pathway. DESIGN: A cross-sectional, qualitative study with an interpretive descriptive design. SETTING: Academic and non-academic hospital setting in Belgium. PARTICIPANTS: 31 caregivers from (non)-academic settings and 5 patients with LFS were purposefully sampled and in-depth interviewed. RESULTS: Out of the data of all interviews, participants reported opinions on 23 thematic clusters that were expressed in a time-contingent manner from the preoperative, perioperative to postoperative phase. Afterwards, themes were mapped to the Consolidated Framework for Implementation Research, with a larger role for concepts related to the innovation, inner and individual domain. As an overarching theme, the importance of an 'individualised, patient-centred rehabilitation built on a strong therapeutic alliance with an accessible interprofessional team' was stressed for patients undergoing LFS. Specifically, participants stated that a biopsychosocial approach to rehabilitation should start in the preoperative phase and immediately be continued postoperatively. No consensus was observed for movement restrictions postoperatively. Uniform communication between the involved caregivers was considered essential for optimal therapeutic alliance and clinical outcome. The precise role and competence of each member of the interprofessional team needs, therefore, to be clearly defined, respected and discussed. An accessible case manager to guide the patient trajectory and tackle problems could further support this. Interestingly, only patients, psychologists and physiotherapists addressed return to work as an important outcome after LFS. CONCLUSIONS: This qualitative study identified key experiences and points to consider in the current and future rehabilitation pathway for LFS. Future research should incorporate these findings to build a novel rehabilitation pathway for LFS and evaluate its feasibility and cost-effectiveness. TRIAL REGISTRATION NUMBER: This study was registered at clinicaltrials.gov (NCT03427294).

Synthesis of guidance available for assessing methodological quality and grading of evidence from qualitative research to inform clinical recommendations: a systematic literature review.

OBJECTIVE: To understand (1) what guidance exists to assess the methodological quality of qualitative research; (2) what methods exist to grade levels of evidence from qualitative research to inform recommendations within European Alliance of Associations for Rheumatology (EULAR). METHODS: A systematic literature review was performed in multiple databases including PubMed/Medline, EMBASE, Web of Science, COCHRANE and PsycINFO, from inception to 23 October 2020. Eligible studies included primary articles and guideline documents available in English, describing the: (1) development; (2) application of validated tools (eg, checklists); (3) guidance on assessing methodological quality of qualitative research and (4) guidance on grading levels of qualitative evidence. A narrative synthesis was conducted to identify key similarities between included studies. RESULTS: Of 9073 records retrieved, 51 went through to full-manuscript review, with 15 selected for inclusion. Six articles described methodological tools to assess the quality of qualitative research. The tools evaluated research design, recruitment, ethical rigour, data collection and analysis. Seven articles described one approach, focusing on four key components to determine how much confidence to place in findings from systematic reviews of qualitative research. Two articles focused on grading levels of clinical recommendations based on qualitative evidence; one described a qualitative evidence hierarchy, and another a research pyramid. CONCLUSION: There is a lack of consensus on the use of tools, checklists and approaches suitable for appraising the methodological quality of qualitative research and the grading of qualitative evidence to inform clinical practice. This work is expected to facilitate the inclusion of qualitative evidence in the process of developing recommendations at EULAR level.

Self-report and device-based physical activity measures and adherence to physical activity recommendations: a cross-sectional survey among people with inflammatory joint disease in four European countries.

OBJECTIVES: Self-monitoring of physical activity (PA) has the potential to contribute to successful behaviour change in PA interventions in different populations, including people with inflammatory joint diseases (IJDs). The objectives of this study were to describe the use and knowledge of self-report-based and device-based PA measures in people with IJDs in four European countries, and to explore if the use of such devices, sociodemographic or disease-related variables were associated with adherence to the recommendations of at least 150 min of moderate to vigorous PA per week. SETTING: Cross-sectional survey, performed in 2015-2016. PARTICIPANTS: People with IJDs in Belgium, Denmark, Ireland and Sweden. PRIMARY AND SECONDARY OUTCOME MEASURES: Use of self-report and device-based PA measures, receipt of instructions how to use PA measures, confidence in using them, adherence to PA recommendations and associated factors for adherence to PA recommendations. RESULTS: Of the 1305 respondents answering questions on PA measures, 600 (46%) reported use of any kind of self-report or device-based measures to self-monitor PA. Between country differences of 34%-58% was observed. Six per cent and four per cent received instructions from health professionals on how to use simple and complex devices, respectively. Independent associated factors of fulfilment of recommendations of PA were living in Ireland (OR=84.89, p<0.001) and Sweden (OR=1.68, p=0.017) compared with living in Denmark, not perceiving activity limitations in moderate activities (OR=1.92, p<0.001) and using a device to measure PA (OR=1.56, p<0.001). Those living in Belgium (OR=0.21, p<0.001) were less likely to fulfil recommendations of PA. CONCLUSIONS: Almost half of the participants with IJDs used self-report-based or deviced-based PA measures, although few used wearable devices regularly. The results indicate that participants meeting public PA health guidelines were engaged in self-monitoring of PA.

Best practice rehabilitation pathway for the management of single and double-level lumbar fusion surgery: a modified Delphi Study.

BACKGROUND: There is limited evidence to guide the rehabilitation of patients following single or double-level lumbar fusion surgery (LFS). This is reflected in extensive variability in current rehabilitation regimes and subsequent low clinical success rates, which urges a call for a consensus rehabilitation pathway. AIM: To establish consensus on the optimal pre-, peri- and postoperative rehabilitation of LFS. DESIGN: A modified Delphi Study. SETTING: Belgium and the Netherlands. POPULATION: A multidisciplinary panel of 31 experts in the field of LFS and rehabilitation participated. Nine patients validated the consensus pathway. METHODS: A three-round online Delphi questionnaire was followed by an in-person consensus meeting. In each round, experts could suggest new statements, and received group summary statistics and feedback for reconsidered statements. Consensus threshold was set at ≥75% agreement. The resulting rehabilitation pathway was validated by patients through an online questionnaire and subsequent in-person focus group. RESULTS: A total of 31 experts participated in the first online round, with 27 (87%) completing all online rounds, and 17 (55%) attending the in-person consensus meeting. Consensus was reached on 122 statements relating to pre-, peri- and postoperative rehabilitation of LFS, and validated by patients. Key components of the rehabilitation pathway included prehabilitation, education, physiotherapy in every phase, early postoperative mobilization, and little movement restrictions. Patients emphasized the need for support during the return-to-work process. CONCLUSIONS: This process resulted in 122 expert-consensus statements on best practice rehabilitation for managing LFS, validated by patients. CLINICAL REHABILITATION IMPACT: The proposed rehabilitation pathway can serve as guidance to support clinicians, reduce practice variability, and subsequently improve clinical outcomes after LFS.

Aggressive fluid hydration plus non-steroidal anti-inflammatory drugs versus non-steroidal anti-inflammatory drugs alone for post-endoscopic retrograde cholangiopancreatography pancreatitis (FLUYT): a multicentre, open-label, randomised, controlled trial.

BACKGROUND: Pancreatitis is the most common complication of endoscopic retrograde cholangiopancreatography (ERCP). Prophylactic rectal administration of non-steroidal anti-inflammatory drugs (NSAIDs) is considered as standard of care to reduce the risk of post-ERCP pancreatitis. It has been suggested that aggressive hydration might further reduce this risk. Guidelines already recommend aggressive hydration in patients who are unable to receive rectal NSAIDs, although it is laborious and time consuming. We aimed to evaluate the added value of aggressive hydration in patients receiving prophylactic rectal NSAIDs. METHODS: FLUYT, a multicentre, open-label, randomised, controlled trial done across 22 Dutch hospitals, included patients aged between 18 and 85 years with moderate to high risk of post-ERCP pancreatitis. Patients were randomly assigned (1:1) by a web-based module with varying block sizes to a combination of aggressive hydration and rectal NSAIDs (100 mg diclofenac or indomethacin; aggressive hydration group) or rectal NSAIDs (100 mg diclofenac or indomethacin) alone (control group). Randomisation was stratified according to treatment centre. Aggressive hydration comprised 20 mL/kg intravenous Ringer's lactate solution within 60 min from the start of ERCP, followed by 3 mL/kg per h for 8 h. The control group received normal intravenous saline with a maximum of 1·5 mL/kg per h and 3 L per 24 h. The primary endpoint was post-ERCP pancreatitis and was analysed on a modified intention-to-treat basis (including all patients who underwent randomisation and an ERCP and for whom data regarding the primary outcome were available). The trial is registered with the ISRCTN registry, ISRCTN13659155. FINDINGS: Between June 5, 2015, and June 6, 2019, 826 patients were randomly assigned, of whom 388 in the aggressive hydration group and 425 in the control group were included in the modified intention-to-treat analysis. Post-ERCP pancreatitis occurred in 30 (8%) patients in the aggressive hydration group and in 39 (9%) patients in the control group (relative risk 0·84, 95% CI 0·53-1·33, p=0·53). There were no differences in serious adverse events, including hydration-related complications (relative risk 0·99, 95% CI 0·59-1·64; p=1·00), ERCP-related complications (0·90, 0·62-1·31; p=0·62), intensive care unit admission (0·37, 0·07-1·80; p=0·22), and 30-day mortality (0·95, 0·50-1·83; p=1·00). INTERPRETATION: Aggressive periprocedural hydration did not reduce the incidence of post-ERCP pancreatitis in patients with moderate to high risk of developing this complication who routinely received prophylactic rectal NSAIDs. Therefore, the burden of laborious and time-consuming aggressive periprocedural hydration to further reduce the risk of post-ERCP pancreatitis is not justified. FUNDING: Netherlands Organisation for Health Research and Development and Radboud University Medical Center.

Position Statement on Exercise Dosage in Rheumatic and Musculoskeletal Diseases: The Role of the IMPACT-RMD Toolkit.

There is convincing evidence to suggest that exercise interventions can significantly improve disease-related outcomes as well as comorbidities in rheumatic and musculoskeletal diseases (RMDs). All exercise interventions should be appropriately defined by their dose, which comprises of two components: a) the FITT (frequency, intensity, time and type) and b) the training (ie, specificity, overload, progression, initial values, reversibility, and diminishing returns) principles. In the published RMD literature, exercise dosage is often misreported, which in "pharmaceutical treatment terms", this would be the equivalent of receiving the wrong medication dosage. Lack of appropriately reporting exercise dosage in RMDs, therefore, results in limited clarity on the effects of exercise interventions on different outcomes while it also hinders reproducibility, generalisability and accuracy of research findings. Based on the collective but limited current knowledge, the main purpose of the present Position Statement is to provide specific guidance for RMD researchers to help improve the reporting of exercise dosage and help advance research into this important field of investigation. We also propose the use of the IMPACT-RMD toolkit, a tool that can be used in the design and reporting phase of every trial.

Implementation of Physical Activity into routine Clinical pracTice in Rheumatic Musculoskeletal Disease: The IMPACT-RMD study protocol and rationale.

BACKGROUND: Physical activity is an important intervention for improving disease-related symptoms and systemic manifestations in rheumatic and musculoskeletal disease (RMDs). However, studies suggest that RMD patients report that the lack of individualized and consistent information about physical activity from managing doctors and healthcare professionals, acts as a barrier for engagement. On the other hand, managing doctors and healthcare professionals report lack of knowledge in this area and thus lack of confidence to educate and advise RMD patients about the beneficial effects of physical activity. The aim of the present study therefore, is to develop two e-Learning courses for RMD doctors and health professionals: a) the first one to provide consistent information about the collective benefits of physical activity in RMDs and b) the second on how to implement physical activity advice in routine clinical practice. METHODS: An international collaboration of seven countries, consisting of one academic institution and one patient organization from each country, will co-develop the two e-Learning courses. The final e-Learning courses will primarily target to improve - through physical activity advice - RMD symptoms which are important for patients. DISCUSSION: The main result of this study will be to co-develop two e-Learning courses that can be used by managing RMD doctors and healthcare professionals to be made aware of the overall benefits of physical activity in RMDs as well as how to implement physical activity advise within their practice.

Widespread pain in axial spondyloarthritis: clinical importance and gender differences.

BACKGROUND: There is a remarkable lack of detailed knowledge on pain areas in axial spondyloarthritis (axSpA), and their clinical relevance is largely unknown. Pain area may reflect local disease processes, but amplification of nervous system signalling may alter this relationship. Also, gender differences in pain area may exist in axSpA, possibly confounding disease activity outcomes. Therefore, we firstly detailed pain locations in axSpA and evaluated gender differences. Secondly, we explored the relationship of regional pain definitions with clinical outcomes. Finally, we explored the role of pain area in the assessment of disease activity. METHODS: Body charts informed on the presence of axial, peripheral articular and non-articular pain in 170 patients (108 men, 62 women) with axSpA. Multivariate Odds Ratios (ORs) were used to compare genders. General linear models were used to explore clinical differences in disease activity (Bath Ankylosing Spondylitis Disease Activity Index [BASDAI]), activity limitations (Bath Ankylosing Spondylitis Functional Index [BASFI]), fear of movement (Tampa Scale for Kinesiophobia 11-item version [TSK-11]), anxiety (Hospital Anxiety and Depression Scale subscale anxiety [HADS-A]) and depression (HADS subscale depression [HADS-D]) between four subgroups classified by widespread non-articular pain (WNAP+/-) and physician global assessment of disease activity (PGDA+/-) (p < .05). Principal Component Analysis (PCA) was performed to explore gender differences in the structure of disease activity. RESULTS: Axial thoracic pain was least prevalent (lumbar, 74.4%; cervical, 47.6%; cervicothoracic, 47.6%; thoracic, 32.4%), but it was about three times more likely in women (OR, 2.92; p = .009). Axial cervicothoracic junction pain spread more diffusely in women (OR, 2.48; p = .018). Women exhibited a two- to threefold increased likelihood of widespread axial (OR, 3.33; p = .007) and peripheral articular (OR, 2.34; p = .023) pain. A subgroup of WNAP+/PGDA- combined with low PGDA (27% of all patients) was associated with worse BASFI, BASDAI, HADS-A and HADS-D in men and worse TSK-11 and HADS-A in women (p < .05). Disease activity outcomes showed a two-factor structure in women but not in men. CONCLUSIONS: In patients with axSpA, the location and spread of pain was different between genders and was related to worse clinical status. On the basis of pain area and PGDA, clinical subgroups exhibiting a remarkably distinct health status were identified. Outcome instruments such as BASDAI should acknowledge gender differences to ensure structural validity.

TGR5 signalling promotes mitochondrial fission and beige remodelling of white adipose tissue.

Remodelling of energy storing white fat into energy expending beige fat could be a promising strategy to reduce adiposity. Here, we show that the bile acid-responsive membrane receptor TGR5 mediates beiging of the subcutaneous white adipose tissue (scWAT) under multiple environmental cues including cold exposure and prolonged high-fat diet feeding. Moreover, administration of TGR5-selective bile acid mimetics to thermoneutral housed mice leads to the appearance of beige adipocyte markers and increases mitochondrial content in the scWAT of Tgr5 +/+ mice but not in their Tgr5 -/- littermates. This phenotype is recapitulated in vitro in differentiated adipocytes, in which TGR5 activation increases free fatty acid availability through lipolysis, hence fuelling ß-oxidation and thermogenic activity. TGR5 signalling also induces mitochondrial fission through the ERK/DRP1 pathway, further improving mitochondrial respiration. Taken together, these data identify TGR5 as a druggable target to promote beiging with potential applications in the management of metabolic disorders.

A survey across four European countries to determine rheumatology health professionals' awareness of physical activity measures in people with inflammatory joint diseases.

OBJECTIVES: The objectives of this study were to determine rheumatology health professionals' (HPs)' awareness of and confidence in using physical activity (PA) measures in people with inflammatory joint diseases (IJDs), their own self-reported PA levels and to identify HP-related educational needs. METHODS: Rheumatology HPs in Denmark, Sweden, Ireland and Belgium participated in an on-line survey. Descriptive statistics and latent class analysis (LCA) were undertaken SPSS (v21and SASv9.4) to describe data aggregates and range and to identify subclasses of groups with respect to use of PA measures. RESULTS: 322 (n=322, 75.5% women) HPs responded from Denmark (n=50, 15.5%), Sweden (n=66, 20.5%), Ireland (n=28, 8.7%) and Belgium (n=178, 55.3%) and the majority of respondents (n=286, 91.7%) reported it was important to measure PA in people with IJDs. Only 28.2% of HPs used simple body worn sensors to measure PA levels in their patients. The majority were interested in on-line education on measuring PA (82.9%). LCA, used to generate classes of PA measures employed by HPs, revealed three distinct classes reflecting differences in self-reported PA levels, awareness of PA measures, further education requirements and professional background. CONCLUSIONS: The majority of respondents reported that they considered measuring PA as important in people with IJDs; however, the majority lacked confidence in how to measure it. There was strong interest in further education around measuring PA. Three distinct respondent classes were identified to inform targeted education on how to measure PA.

Fluid hydration to prevent post-ERCP pancreatitis in average- to high-risk patients receiving prophylactic rectal NSAIDs (FLUYT trial): study protocol for a randomized controlled trial.

BACKGROUND: Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) is the most common complication of ERCP and may run a severe course. Evidence suggests that vigorous periprocedural hydration can prevent PEP, but studies to date have significant methodological drawbacks. Importantly, evidence for its added value in patients already receiving prophylactic rectal non-steroidal anti-inflammatory drugs (NSAIDs) is lacking and the cost-effectiveness of the approach has not been investigated. We hypothesize that combination therapy of rectal NSAIDs and periprocedural hydration would significantly lower the incidence of post-ERCP pancreatitis compared to rectal NSAIDs alone in moderate- to high-risk patients undergoing ERCP. METHODS: The FLUYT trial is a multicenter, parallel group, open label, superiority randomized controlled trial. A total of 826 moderate- to high-risk patients undergoing ERCP that receive prophylactic rectal NSAIDs will be randomized to a control group (no fluids or normal saline with a maximum of 1.5 mL/kg/h and 3 L/24 h) or intervention group (lactated Ringer's solution with 20 mL/kg over 60 min at start of ERCP, followed by 3 mL/kg/h for 8 h thereafter). The primary endpoint is the incidence of post-ERCP pancreatitis. Secondary endpoints include PEP severity, hydration-related complications, and cost-effectiveness. DISCUSSION: The FLUYT trial design, including hydration schedule, fluid type, and sample size, maximize its power of identifying a potential difference in post-ERCP pancreatitis incidence in patients receiving prophylactic rectal NSAIDs. TRIAL REGISTRATION: EudraCT: 2015-000829-37 . Registered on 18 February 2015. ISRCTN: 13659155 . Registered on 18 May 2015.