Jost Langhorst

Noninvasive Markers in the Assessment of Intestinal Inflammation in Inflammatory Bowel Diseases: Performance of Fecal Lactoferrin, Calprotectin, and PMN-Elastase, CRP, and Clinical Indices

OBJECTIVES:The aim of this study was to compare the performance of fecal lactoferrin (Lf), calprotectin (Cal), polymorphonuclear neutrophil elastase (PMN-e), as well as serum C-reactive protein (CRP) in patients with inflammatory bowel diseases (IBD) to address (a) whether these markers can differentiate IBD patients with endoscopically assessed inflammation from IBD patients without inflammation and from irritable bowel syndrome (IBS); (b) whether they correlate with endoscopic severity of inflammation; and (c) whether a combination of fecal markers with the respective disease-specific activity indices may increase the diagnostic accuracy with reference to the endoscopic severity of inflammation.METHODS:Fecal levels of Lf, Cal, and PMN-e and serum CRP were assessed in 139 patients undergoing diagnostic ileocolonoscopy (54 IBS patients, 42 ulcerative colitis [UC], 43 Crohns disease [CD]). Disease activity was determined for CU with the colitis activity index (CAI) and for CD with the Crohns disease activity index (CDAI). The performance of each marker with reference to endoscopic inflammatory activity was assessed by computing correlations, and sensitivity and specificity using published as well as adjusted cutoffs. A comprehensive activity index was computed by combining results from fecal markers, serum CRP, and a clinical activity index.RESULTS:UC or CD patients with active inflammation demonstrated significantly higher levels of Lf, Cal, and PMN-e in feces as well as serum-CRP when compared to patients with inactive inflammation as well as patients with IBS (all P < 0.05). Using adjusted cutoffs enabled a marked improvement of all markers with an overall diagnostic accuracy in IBD of 80.0% for Lf, 80.0% for Cal, 74.1% for PMN-e, 64.0% for CRP, and 79.0% for the respective clinical disease scores. Cal showed the highest diagnostic accuracy in CD (81.4%), whereas Lf was superior to the other markers in UC (83.3%). The comprehensive activity index yielded a further improvement of sensitivity and specificity, with a diagnostic accuracy of 95.3% for UC patients.CONCLUSION:The fecal markers Lf, Cal, and PMN-e are able to differentiate active IBD from inactive IBD as well as from IBS. None of these three stool markers is consistently superior in its ability to reflect endoscopic inflammation, but all three are superior to CRP in their diagnostic accuracy. A combination of the stool markers with the CRP and a disease-specific activity index in a categorical comprehensive activity index can increase the diagnostic accuracy with reference to the endoscopic inflammation in UC.

3rd European Evidence-based Consensus on the Diagnosis and Management of Crohn’s Disease 2016: Part 1: Diagnosis and Medical 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].

Efficacy of different types of aerobic exercise in fibromyalgia syndrome: a systematic review and meta-analysis of randomised controlled trials

IntroductionThe efficacy and the optimal type and volume of aerobic exercise (AE) in fibromyalgia syndrome (FMS) are not established. We therefore assessed the efficacy of different types and volumes of AE in FMS.MethodsThe Cochrane Library, EMBASE, MEDLINE, PsychInfo and SPORTDISCUS (through April 2009) and the reference sections of original studies and systematic reviews on AE in FMS were systematically reviewed. Randomised controlled trials (RCTs) of AE compared with controls (treatment as usual, attention placebo, active therapy) and head-to-head comparisons of different types of AE were included. Two authors independently extracted articles using predefined data fields, including study quality indicators.ResultsTwenty-eight RCTs comparing AE with controls and seven RCTs comparing different types of AE with a total of 2,494 patients were reviewed. Effects were summarised using standardised mean differences (95% confidence intervals) by random effect models. AE reduced pain (-0.31 (-0.46, -0.17); P < 0.001), fatigue (-0.22 (-0.38, -0.05); P = 0.009), depressed mood (-0.32 (-0.53, -0.12); P = 0.002) and limitations of health-related quality of life (HRQOL) (-0.40 (-0.60, -0.20); P < 0.001), and improved physical fitness (0.65 (0.38, 0.95); P < 0.001), post treatment. Pain was significantly reduced post treatment by land-based and water-based AE, exercises with slight to moderate intensity and frequency of two or three times per week. Positive effects on depressed mood, HRQOL and physical fitness could be maintained at follow-up. Continuing exercise was associated with positive outcomes at follow-up. Risks of bias analyses did not change the robustness of the results. Few studies reported a detailed exercise protocol, thus limiting subgroup analyses of different types of exercise.ConclusionsAn aerobic exercise programme for FMS patients should consist of land-based or water-based exercises with slight to moderate intensity two or three times per week for at least 4 weeks. The patient should be motivated to continue exercise after participating in an exercise programme.

Faecal S100A12 as a non-invasive marker distinguishing inflammatory bowel disease from irritable bowel syndrome

Objective: S100A12 is a pro-inflammatory protein that is secreted by granulocytes. S100A12 serum levels increase during inflammatory bowel disease (IBD). We performed the first study analysing faecal S100A12 in adults with signs of intestinal inflammation. Methods: Faecal S100A12 was determined by ELISA in faecal specimens of 171 consecutive patients and 24 healthy controls. Patients either suffered from infectious gastroenteritis confirmed by stool analysis (65 bacterial, 23 viral) or underwent endoscopic and histological investigation (32 with Crohn’s disease, 27 with ulcerative colitis, and 24 with irritable bowel syndrome; IBS). Intestinal S100A12 expression was analysed in biopsies obtained from all patients. Faecal calprotectin was used as an additional non-invasive surrogate marker. Results: Faecal S100A12 was significantly higher in patients with active IBD (2.45 ± 1.15 mg/kg) compared with healthy controls (0.006 ± 0.03 mg/kg; p<0.001) or patients with IBS (0.05 ± 0.11 mg/kg; p<0.001). Faecal S100A12 distinguished active IBD from healthy controls with a sensitivity of 86% and a specificity of 100%. We also found excellent sensitivity of 86% and specificity of 96% for distinguishing IBD from IBS. Faecal S100A12 was also elevated in bacterial enteritis but not in viral gastroenteritis. Faecal S100A12 correlated better with intestinal inflammation than faecal calprotectin or other biomarkers. Conclusions: Faecal S100A12 is a novel non-invasive marker distinguishing IBD from IBS or healthy individuals with a high sensitivity and specificity. Furthermore, S100A12 reflects inflammatory activity of chronic IBD. As a marker for neutrophil activation, faecal S100A12 may significantly improve our arsenal of non-invasive biomarkers of intestinal inflammation.

Elevated human beta-defensin-2 levels indicate an activation of the innate immune system in patients with irritable bowel syndrome.

OBJECTIVES:Irritable bowel syndrome (IBS) is a highly prevalent functional disorder. According to the Rome criteria, macroscopic and histological inflammation is a crucial exclusion criterion for IBS. Human defensins appear to be part of the innate immune system in the gastrointestinal tract. Human β-defensin-2 (HBD-2) was the first inducible human antimicrobial protein discovered. The expression is induced by probiotic microorganisms and proinflammatory cytokines. Recent results imply that HBD-2 is expressed in active intestinal inflammation, especially in ulcerative colitis (UC). Our aim was to evaluate fecal measurements of HBD-2 in patients with active UC and IBS, and in healthy controls (HCs).METHODS:Fecal specimens were collected from a total of 100 participants (30 with active UC, 46 IBS, and 24 HCs). Exclusion criteria were the current use of probiotics and antibiotics. Furthermore, IBS patients with elevated C-reactive protein or leukocytes, a history of bacterial overgrowth or infectious gastrointestinal disease over the last 6 month were excluded. Disease status was addressed in all participating subjects by medical history and current symptoms. In addition, each IBS and UC patient underwent ileocolonoscopy with histopathology. Fecal inflammation markers lactoferrin (Lf) and calprotectin (Cal) were measured by enzyme-linked immunosorbent assay (ELISA) and reported as μg/g. Fecal HBD-2 was measured by ELISA and reported as ng/g feces. In addition, immunoblots were performed for fecal HBD-2. Paraffin-embedded tissue from colonic biopsies was tested for HBD-2 peptides by immunohistochemistry.RESULTS:Lf as well as Cal was elevated in active UC (mean: 152.1±s.d. 374.7 μg/g; 103.5±87.1 μg/g), compared with IBS (8.3±19.4 μg/g; 18.6±23.3 μg/g), and HCs (0.4±0.5 μg/g; 7.1±7.9 μg/g). Scheffe post hoc tests revealed significant differences (P=0.006; P<0.001) between active UC vs. IBS and HC. In contrast, HBD-2 levels were highest in active UC (mean: 106.9±s.d. 91.5 ng/g), almost as high in IBS (pts 76.0±67.9 ng/g), and lowest for HCs (29.9±16.1 ng/g). Scheffe post hoc tests revealed significant differences (P<0.001) between the groups of patients (UC and IBS) vs. HCs. Immunohistochemical investigation was consistent with fecal secretion data and demonstrated the presence of β-defensin 2 peptides in colonic epithelial enterocytes in UC as well as IBS patients with elevated fecal HBD-2.CONCLUSIONS:The results indicate significantly elevated levels of HBD-2 in patients with IBS compared with HCs and similar to those with active UC. The results support an activation of the mucosal innate defense system toward a proinflammatory response in IBS patients in the absence of macroscopic signs of inflammation.

Comparison of 4 neutrophil-derived proteins in feces as indicators of disease activity in ulcerative colitis

Background: To evaluate the diagnostic use of fecal concentrations of lactoferrin (Lf), calprotectin (Cal), polymorphonuclear neutrophil‐elastase (PMN‐e), and lysozyme (Lys) as indicators of disease activity in patients with active and inactive ulcerative colitis (UC). Methods: A total of 76 fecal specimens were collected from 31 patients with UC in times of active and inactive status of disease. Disease activity was determined with the colitis activity index (CAI; Rachmilewitz index), which includes a combination of laboratory parameters and clinical symptoms, with a score of at least 6 indicating active disease. Fecal Lf, Cal, PMN‐e, and Lys were measured and reported as micrograms per milliliter feces. Levels of more than 7.25, more than 6.00, at least 0.062, and at least 0.6 for Lf, Cal, PMN‐e, and Lys, respectively, were considered elevated as specified by the manufacturers. Results: Based on the CAI classification, 25 of the samples were from patients with active disease status and 51 were from patients with inactive status. Lf, PMN‐e, and Cal but not Lys showed increased levels in samples from patients in active disease compared with those in remission (median for Lf: 28.12 ± 110.86 versus 179.54 ± 334.09, P < 0.001; median for Cal: 15.13 ± 30.27 versus 116.23 ± 182.29, P < 0.001; median for PMN‐e: 0.21 ± 0.44 versus 1.02 ± 0.89, P < 0.001; median for Lys: 1.54 ± 2.39 versus 3.75 ± 5.39, P > 0.05). All 4 parameters correlated with the CAI (Lf: r = 0.441, P < 0.001; Cal: r = 0.505, P < 0.001; PMN‐e: r = 0.604, P < 0.001; Lys: r = 0.295, P < 0.05). Introducing a composite index based on Lf, Cal, and PMN‐e, the specificity was 72.5% and the sensitivity 88% compared with the CAI. Conclusions: Among the neutrophil‐derived proteins in feces, PMN‐e, Cal, and Lf represent useful markers of disease activity in patients with UC. Using all 3 markers in a composite index may be an additional noninvasive tool for the management of ambulant patients with UC.

Effects of Mind-Body Therapy on Quality of Life and Neuroendocrine and Cellular Immune Functions in Patients with Ulcerative Colitis

Background: The aim of this study was to investigate the effects of mind-body therapy on neuroendocrine and cellular immune measures, health-related quality of life and disease activity in patients with ulcerative colitis (UC) in remission. Methods: Thirty UC patients in remission or with low disease activity were randomly assigned to an intervention group (n = 15) or a usual-care waiting control group (n = 15). Intervention consisted of a structured 60-hour training program over 10 weeks which included stress management training, moderate exercise, Mediterranean diet, behavioral techniques and self-care strategies. Quality of life, perceived stress and disease activity were assessed with standardized questionnaires (IBDQ, SF-36, PSS, CAI). In addition, the distribution of circulating lymphocytes and lymphocyte subsets as well as the β-adrenergic modulation of TNF-α production in vitro were analyzed. Urine catecholamines and plasma cortisol, prolactin and growth hormone were measured pre- and postinterventionally, and were compared with a healthy control group (n = 10). Results: In response to therapy, patients in the intervention group showed significantly greater improvement in the SF-36 scale Mental Health and the Psychological Health Sum score compared with changes observed in the usual-care waiting control group. Patients in the intervention group showed significantly greater improvement on the IBDQ scale Bowel Symptoms compared with the control group. However, no significant group differences in circulating lymphocyte subsets or endocrine parameters were observed in response to therapy. In addition, no significant effects of intervention on either the basal levels of TNF-α or the suppressive action of the β-adrenergic agonist isoproterenol on TNF-α production were observed. Conclusion: Mind-body therapy may improve quality of life in patients with UC in remission, while no effects of therapy on clinical or physiological parameters were found, which may at least in part be related to selective patient recruitment.

Effects of Traditional Cupping Therapy in Patients With Carpal Tunnel Syndrome: A Randomized Controlled Trial

UNLABELLED We investigated the effectiveness of cupping, a traditional method of treating musculoskeletal pain, in patients with carpal tunnel syndrome (CTS) in an open randomized trial. n = 52 outpatients (58.5 +/- 8.0 years) with neurologically confirmed CTS were randomly assigned to either a verum (n = 26) or a control group (n = 26). Verum patients were treated with a single application of wet cupping, and control patients with a single local application of heat within the region overlying the trapezius muscle. Patients were followed up on day 7 after treatment. The primary outcome, severity of CTS symptoms (VAS), was reduced from 61.5 +/- 20.5 to 24.6 +/- 22.7 mm at day 7 in the cupping group and from 67.1 +/- 20.2 to 51.7 +/- 23.9 mm in the control group [group difference -24.5mm (95%CI -36.1; -2.9, P < .001)]. Significant treatment effects were also found for the Levine CTS-score (-.6 pts: 95%CI -.9; -.2, P = .002), neck pain (-12.6mm; 95%CI -18.8; -6.4, P < .001), functional disability (DASH-Score) (-11.1 pts; 95%CI -17.1; -5.1, P < .001), and physical quality of life (.3; 95%CI .0; .3, P = .048). The treatment was safe and well tolerated. We conclude that cupping therapy may be effective in relieving the pain and other symptoms related to CTS. The efficacy of cupping in the long-term management of CTS and related mechanisms remains to be clarified. PERSPECTIVE The results of a randomized trial on the clinical effects of traditional cupping therapy in patients with carpal tunnel syndrome are presented. Cupping of segmentally related shoulder zones appears to alleviate the symptoms of carpal tunnel syndrome.

A systematic review and meta-analysis of mindfulness-based stress reduction for the fibromyalgia syndrome

OBJECTIVES This paper presents a systematic review and meta-analysis of the effectiveness of mindfulness-based stress reduction (MBSR) for FMS. METHODS The PubMed/MEDLINE, Cochrane Library, EMBASE, PsychINFO and CAMBASE databases were screened in September 2013 to identify randomized and non-randomized controlled trials comparing MBSR to control interventions. Major outcome measures were quality of life and pain; secondary outcomes included sleep quality, fatigue, depression and safety. Standardized mean differences and 95% confidence intervals were calculated. RESULTS Six trials were located with a total of 674 FMS patients. Analyses revealed low quality evidence for short-term improvement of quality of life (SMD=-0.35; 95% CI -0.57 to -0.12; P=0.002) and pain (SMD=-0.23; 95% CI -0.46 to -0.01; P=0.04) after MBSR, when compared to usual care; and for short-term improvement of quality of life (SMD=-0.32; 95% CI -0.59 to -0.04; P=0.02) and pain (SMD=-0.44; 95% CI -0.73 to -0.16; P=0.002) after MBSR, when compared to active control interventions. Effects were not robust against bias. No evidence was further found for secondary outcomes or long-term effects of MBSR. Safety data were not reported in any trial. CONCLUSIONS This systematic review found that MBSR might be a useful approach for FMS patients. According to the quality of evidence only a weak recommendation for MBSR can be made at this point. Further high quality RCTs are required for a conclusive judgment of its effects.

Amount of systemic steroid medication is a strong predictor for the use of complementary and alternative medicine in patients with inflammatory bowel disease: results from a German national survey.

Objectives: Previous studies have suggested that inflammatory bowel disease (IBD) patients rank high among users of complementary and alternative medicine (CAM). To further elucidate this phenomenon, we sent questionnaires to a large sample of IBD patients in Germany to determine the patterns and predictors of their CAM use. Methods: Pretested 73‐item questionnaires were mailed to a randomly selected representative sample of 1000 IBD patients from the approximately 16,000 members and associates of the German Crohns and Colitis Association. Predictors of CAM use were evaluated by logistic regression models. Results: Completed questionnaires were returned by 684 patients (female patients, 61.4%; Crohns disease patients, 58.3%; ulcerative colitis patients, 38.2%). Of the 671 adult respondents, 344 (51.3%) had experience with CAM, and significantly more of the ulcerative colitis patients (59.8%) than the Crohns disease patients (48.3%) had experience with CAM. There was no difference by gender. Homeopathy (52.9%) and herbal medicine (43.6%) were the most commonly used types of CAM. The most frequent personal reasons for CAM use were the search for an “optimum treatment” (78.9%) and the wish to stop taking steroids (63.8%). Using logistic regression, we found that total cortisone intake (P = 0.0077), but not duration of disease, was a strong predictor of CAM use. Other predictors were experience with psychosomatic and psychotherapeutic support (P = 0.0029), relaxation techniques (P = 0.0284), an academic education (P = 0.0173), a diet utilizing whole grains (P = 0.0123), and a normal body weight (P = 0.0215). Although 80% of patients indicated that they were interested in using CAM in the future, only 24.7% felt sufficiently informed about it. Conclusions: More than 50% of a large group of German IBD patients had used CAM. Prolonged or intensive steroid treatment, an academic education, active ways of coping, and a health‐conscious life‐style are associated with CAM use. Given the potential side effects and interactions, the treating physician should focus on thorough information about the benefits and limitations of conventional and complementary treatment options, especially for IBD patients who have received prolonged or intensive steroid treatment.