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The pathogenesis of inflammatory bowel disease (IBD) implicates several interconnecting factors. Immunity and external factors interact, and most aspects are still under investigation. Autophagy and apoptosis are two critical pathways that decide the fate of the individual cells of the intestinal mucosa. Experimental and clinical data indicate that the two are closely interconnected and usually mutually exclusive. However, despite the abundant information on their role, very limited translation into therapeutic application has been seen during recent years. In this review, research on these two pathways is presented. After a general overview of autophagy and apoptosis, their association with IBD, including the important mitophagy and ferroptosis, is discussed. The influence of autophagy- and apoptosis-related genes is also discussed. Finally, the interplay of autophagy and apoptosis in IBD is presented and the implications for treatment applications are examined. It is shown that dysregulated autophagy leads to increased apoptosis of enterocytes and impairs the tight junction proteins of the protective intestinal barrier. Dysregulated autophagy also induces the downregulation of lysozyme and the other antimicrobial proteins’ production. Mucus production by the goblet cells is also reduced due to defective autophagy and increased apoptosis. [ABSTRACT FROM AUTHOR]

With survival outcomes ever improving for patients with a wide range of lymphoma histologies, the focus on reducing long‐term complications of therapy has increased. Recently published, complimentary population and retrospective series have highlighted the importance of considering bone health in patients treated for lymphoma. Fracture‐related events or the requirement for secondary bone prophylaxis, likely linked to glucocorticoid‐induced osteoporosis (GIO) are substantial and clinically meaningful in a significant minority of patients following routinely employed steroid‐containing immunochemotherapy. In this review, we describe the pathophysiology of GIO, the risk of GIO in observational front‐line lymphoma studies and efficacy of prophylactic measures from several prospective clinical trials are summarized. Finally, areas of importance for future research are discussed and recommendations for GIO risk assessment and management in lymphoma are provided based on the current available literature. [ABSTRACT FROM AUTHOR]

Purpose of the Review: Patients with inflammatory bowel disease (IBD) have increased bone fragility, demonstrated by increased fracture risk, and often have low bone density and altered bone geometry, but the underlying pathophysiology remains poorly understood. Recent Findings: Children and adolescents with IBD appear to have decreased bone formation, at diagnosis, which frequently improves with treatment of their underlying IBD. There is a growing body of evidence regarding how the immune system interacts with bone metabolism. There are likely multi-factorial etiologies that contribute to suboptimal bone accrual and subsequent lack of peak bone mass attainment in growing patients with IBD. There appears to be differential effects dependent upon IBD sub-type and bone compartment. Summary: Pediatric patients with IBD require recognition of several risk factors that may adversely impact their bone accrual. Future studies are necessary to further delineate the effects of IBD on pediatric bone health. [ABSTRACT FROM AUTHOR]

Purpose: Crohn's disease (CD) belongs to chronic disorders with unpredictable disease course. The aim of this study was to identify how genetic testing (NOD2/CARD15) can be used in patients with CD to predict the need for surgical treatment (to define an aggressive type of disease where the patient can profit from early surgery).Methods: The patients who were tested genetically had undergone a surgery due to CD at the Department of Surgery University Hospital Brno Bohunice between 2010 and 2016. The control group consisted of patients with CD who had been diagnosed with CD at least 5 years prior to the testing and had not required any surgical intervention. The second control group was healthy subjects.Results: In total, there were 117 operated patients for CD, 77 patients with CD that had not undergone surgery for CD and 30 healthy subjects. For patients with at least one genetic mutation, the risk of the necessity of surgical treatment of CD is 1.96 times higher than for patients with no mutation. Patients with two or more mutations were generally operated on at a younger age, in a shorter time after being diagnosed and each patient had a partial resection of the ileum.Conclusion: The group of operated patients with CD had a significantly higher distribution of at least one genetic mutation as opposed to the non-operated group. In patients with two or more mutations, the disease course was more aggressive. This group of patients might profit from the conservative top-down or early surgical therapy. [ABSTRACT FROM AUTHOR]

Diagnostic and therapeutic recommendations of the actual guidelines regarding inflammatory bowel disease (IBD)-associated bone loss are based on the experiences from the general osteoporotic population. Moreover, the fracture, as an end point of the bone loss has a different relationship to the bone mineral density in these patients compared to the general population. In this review we aimed to review the literature of the novel therapeutic possibilities regarding IBD-related bone loss. Dual-energy X-ray absorptiometry measurement should be performed in the presence of a risk factor such as age above 50, postmenopausal state, low trauma bone fracture in the history, corticosteroid therapy for more than 3 months or signs of hypogonad-ism. Serum Vitamin D and calcium levels should be measured in all patients. Supplementation is definitely needed in case of low serum calcium or Vitamin D concentrations and in patients under corticosteroid induction therapy. Short-term use of bisphosphonates in case of steroid induction was proved to be efficacious in preventing bone loss, but recent approvals do not include these indications. As fluorides and hormone replacement therapy have considerable side effects, their use in the young generation is also not acceptable. [ABSTRACT FROM AUTHOR]

Background: Influence of genetic variants in the NOD2 gene may play a more important role in disease activity, behaviour and treatment of pediatric- than adult-onset Crohn's disease (CD).Methods: 85 pediatric- and 117 adult-onset CD patients were tested for the three main NOD2 CD-associated variants (p.R702W, p.G908R and p.10007fs) and clinical data of at least two years of follow-up were compared regarding disease behaviour and activity, response to therapy and bone mineral density (BMD).Results: Chronic active and moderate to severe course of CD is associated in patients with pediatric-onset (p=0.0001) and NOD2 variant alleles (p=0.0001). In pediatric-onset CD the average PCDAI-Score was significantly higher in patients carrying NOD2 variants (p=0.0008). In addition, underweight during course of the disease (p=0.012) was associated with NOD2 variants. Interestingly, osteoporosis was found more frequently in patients carrying NOD2 variant alleles (p=0.033), especially in pediatric-onset CD patients with homozygous NOD2 variants (p=0.037). Accordingly, low BMD in pediatric-onset CD is associated with a higher PCDAI (p=0.0092), chronic active disease (p=0.0148), underweight at diagnosis (p=0.0271) and during follow-up (p=0.0109). Furthermore, pediatric-onset CD patients with NOD2 variants are more frequently steroid-dependent or refractory (p=0.048) and need long-term immunosuppressive therapy (p=0.0213).Conclusions: These data suggests that the presence of any of the main NOD2 variants in CD is associated with osteoporosis and an age of onset dependent influence towards underweight, higher disease activity and a more intensive immunosuppressive therapy. This observation supports the idea for an early intensive treatment strategy in children and adolescent CD patients with NOD2 gene variants. [ABSTRACT FROM AUTHOR]

Background: Crohn's disease impacts the bone health of patients and results in a high prevalence of low bone mineral density (BMD) disease such as osteoporosis and osteopenia. Bisphosphonates can reduce bone loss by inhibiting bone resorption. Aim: To assess the effectiveness and safety of bisphosphonates for osteoporosis or osteopenia in Crohn's disease. Methods: A literature search included PubMed, EMBASE, the Science Citation Index, and the Cochrane Library was conducted to identify studies up to March, 2012. Randomized controlled trials (RCTs) comparing bisphosphonates with placebo or no intervention for osteoporosis or osteopenia in adult patients with Crohn's disease were analyzed. Results: Five RCTs involving 423 participants were included. All patients received daily calcium and vitamin D supplementation. Overall, bisphosphonates improved hip BMD at 12 months ( n = 193, MD = 0.99, 95 % CI: 0.14-1.84) compared with placebos or no intervention. No significant differences of spine BMD at both 12 months ( n = 193, MD = 1.78, 95 % CI: −0.99 to 4.55) and 24 months ( n = 231, MD = 0.70 %, 95 % CI: −0.48 to 1.88), hip BMD at 24 months ( n = 231, MD = 0.25 %, 95 % CI: −0.65 to 1.15), new vertebral fractures ( n = 117, RD = −0.01, 95 % CI: −0.08 to 0.05) or adverse events ( n = 422, RR = 1.03, 95 % CI: 0.71-1.49) between bisphosphonates groups and control groups were noted. Subgroup analyses of participants treated with corticosteroid in the preceding year found no difference between two groups. Conclusions: There was no evidence to support the use of bisphosphonates for osteoporosis or osteopenia in Crohn's disease. More randomized controlled clinical trials assessing the effects of bisphosphonates are needed. [ABSTRACT FROM AUTHOR]

OBJECTIVES:To assess the effectiveness and safety of zoledronate (ZOL) in preventing glucocorticoid therapy-associated bone loss in patients with acute flare of Crohn's disease (CD) in a randomized, double-blind, placebo-controlled trial.METHODS:Forty CD patients starting a glucocorticoid therapy (60 mg prednisolone per day) for acute flare (CD activity index (CDAI) >220) were randomized to compare the effect of ZOL (4 mg intravenous, n=20) or placebo (n=20) on change in lumbar bone mineral density (BMD). All patients received calcium citrate (800 mg) and colecalciferol (1,000 IU) daily. Dual energy X-ray absorptiometry (DXA) of the lumbar spine (L1-L4) was performed at baseline and day 90. Follow-up examinations at day 1/7/14/30 and 90 included laboratory tests and adverse event/serious adverse events reports.RESULTS:Thirty-six patients were available for per-protocol analysis. With placebo (n=18), a decrease in BMD was seen (T-score: −0.98±0.8, day 0 and −1.25±0.77, day 90, P=0.06), with ZOL (n=18) BMD increased (−1.15±1.02, day 0 and −0.74±1.09, day 90, P=0.03). The change in BMD under placebo (−0.26±0.21) vs. ZOL (+0.41±0.19) was highly significant (P=0.006). In all, 14 out of 18 patients with ZOL had an increase in BMD (+0.64±0.48), 12 of 18 with placebo a decrease (−0.50±0.39). Changes of clinical findings and laboratory results of inflammation (leukocytes, platelets, and C-reactive protein) were the same in- and between-groups throughout the study. With ZOL, serum bone degradation marker β-Cross-Laps decreased. Study medication was safe and well tolerated.CONCLUSIONS:ZOL is effective in preventing glucocorticoid therapy-induced bone loss in patients with acute flare of CD and should be considered whenever a glucocorticoid therapy is started in CD patients. [ABSTRACT FROM AUTHOR]

Aliment Pharmacol Ther 31, 1286–1295 Background Ulcerative colitis is characterized by leucocyte infiltration into the colonic mucosa. Granulocyte–monocyte apheresis depletes these cells. Aim To assess the non-inferiority of 5–10 apheresis treatments in patients with steroid-dependent or steroid-refractory ulcerative colitis. Methods A total of 196 adults with moderate–severe ulcerative colitis were randomized 1:1 to 5 ( n = 96) or 10 ( n = 90) open label apheresis treatments. The primary endpoint was non-inferiority of clinical activity index score after 12 weeks. Results The intent-to-treat population comprised 82 and 80 patients for the 5- and 10-treatment groups, respectively. The difference between the two groups in mean clinical activity index was 0.24 with an upper 95% confidence interval of 1.17, which was below a predefined non-inferiority threshold of 1.33. Clinical activity index score improved from baseline in both groups (from 8.7 to 5.6 with 5 treatments, and from 8.8 to 5.4 with 10), with no significant difference between the groups ( P = 0.200). Outcomes for the 5- and 10-treatment groups were similar – Clinical remission: 44% and 40%, respectively ( P = 0.636); clinical response: 56% and 59%, respectively ( P = 0.753). The treatment was well tolerated in both groups. Conclusions This prospective study comparing apheresis regimens in ulcerative colitis demonstrates that 5 treatments were not inferior to 10 treatments in steroid-refractory or -dependent ulcerative colitis. [ABSTRACT FROM AUTHOR]

Patients with inflammatory bowel disease (IBD) often undergo several radiologic imaging studies, which – with the exception of magnetic resonance imaging (MRI) and B-scan ultrasound (US) – subject patients to ionizing radiation. With contrast enhanced ultrasound microvascular imaging of the bowel is possible. Hence, the aim of our study was to assess the perfusion pattern of inflamed bowel walls in Crohn's disease compared with healthy volunteers quantitatively using a specific quantification software. We evaluated 4 volunteers and 20 patients with proven Crohn's disease, who went through an active episode based on clinical symptoms and complementary imaging by MRI (19 patients) and computed tomography (1 patient), respectively, with dynamic contrast-enhanced ultrasound (CEUS) using a second generation contrast agent (SonoVue®, Bracco, Germany). Retrospectively, we applied the quantification software Qontrast® (Bracco, Italy) to obtain contrast-enhanced sonographic perfusion maps for each lesion. Patients had significant higher peak values (median 46.86, lower quartile 37.91, upper quartile 53.20) and significant higher regional blood volume (median 2133.65, lower quartile 1202.90, upper quartile 2820.44) than volunteers. Considering the very low peak value of the healthy, it is easy to understand that the time-to-peak was significantly shorter in the volunteers (median 4.45, lower quartile 1.82, upper quartile 6.88) than in the patients (median 12.15, lower quartile 9.18, upper quartile 15.74). Our study showed clear differences between inflamed and normal bowel wall vascularity regarding all perfusion parameters. These results show that a quantitative assessment of the bowel wall vascularisation and inflammation, respectively, is possible. The software used here enables us to collect data, not only in a semi-quantitative but also in a reproducible, quantitative manner which is comparable with the evaluation of CT or MRI generated data. [ABSTRACT FROM AUTHOR]

The article presents papers presented at the Regensburg Conference on topics such as ultrasound contrast agents as markers of vascularity and microcirculation, perfusion imaging of tissue transplants with Contrast Harmonic Ultrasound Imaging (CHI) and Magnetic Resonance Imaging (MRI) as compared to laser-induced Indocyanine Green (ICG) fluorescence angiography, and the use of antithrombotic agents in microvascular surgery.

The purposes of this study was to provide a retrospective comparison of semiquantitatively measured bowel wall vascularity by power Doppler sonography, endoscopic-histopathological biopsy findings, and disease activity in patients with confirmed Crohn's disease. Thirty-two out of 1,332 patients with histologically confirmed Crohn's disease (18 female, 14 male; mean age 38.8 years) met the inclusion criteria: ileocolonoscopy with biopsy and power Doppler sonographic determination of bowel wall vascularity with assessment of disease activity within a period of 5 days. Sonographic determination of bowel wall vascularity was based on a semiquantitative score. Endoscopic bowel wall biopsy specimens were assessed using a self-developed inflammation score and the disease activity was calculated using Crohn's disease activity index (CDAI). A significant association (p < 0.05) was shown for results of histology and bowel wall vascularity in the terminal ileum (kappa = 0.66; sensitivity 95%; specificity 69%). There was no observed association between CDAI and histology, although there was an association between CDAI and bowel wall vascularity (sensitivity 82%). Increased bowel wall vascularity in the terminal ileum measured by power Doppler ultrasound reflects inflammatory activity in histologically examined bowel wall. Power Doppler ultrasound may be able to monitor activity changes of the bowel wall determined by pharmaceutical treatment. [ABSTRACT FROM AUTHOR]

Presents abstracts of several research on neurogastroenterology and motility, featured at a symposium in T ü bingen, Germany from October 2 to 4, 2002. 'Movement and role of individual mitochondria in myenteric nerve processes,' by P. Vanden Berghe, G.W. Hennig and T.K. Smith; 'On the enteric sensory neurone in the mouse,' by W. Kinze, M.H. M ü ller, W. Jiang and D. Grundy; Intestino-intestinal secretomotor reflexes in the rat,' by N. Quinson and J.B. Furness.

Inflammatory bowel diseases (IBD) are chronic conditions that primarily affect the gastrointestinal tract, with a complex pathogenesis; they are characterized by a significant heterogeneity of clinical presentations and of inflammatory pathways that sustain intestinal damage. After the introduction of the first biological therapies, the pipeline of therapies for IBD has been constantly expanding, and a significant number of new molecules is expected in the next few years. Evidence from clinical trials and real-life experiences has taught us that up to 40% of patients do not respond to a specific drug. Unfortunately, to date, clinicians lack a valid tool that can predict each patient's response to therapies and that could help them in choosing what drug to administer. Several candidate biomarkers have been investigated so far, with conflicting results: clinical, genetic, immunological, pharmacokinetic and microbial markers have been tested, but no ideal marker has been identified so far. Based on recent evidence, multiparametric models seemingly hold the greatest potential for predicting response to therapy. In this narrative review, we aim to summarize the current knowledge on predictors and early markers of response to biological therapies in IBD. [ABSTRACT FROM AUTHOR]

The most prominent treatment for the serious cases of Crohn's disease (CD) are biological tumour necrosis factor (TNF) inhibitors. Unfortunately, therapy nonresponse is still a serious issue in ~1/3 of CD patients. Accurate prediction of responsiveness prior to therapy start would therefore be of great value. Clinical predictors have, however, proved insufficient. Here, we integrate genomic and expression data on potential pre-treatment biomarkers of anti-TNF nonresponse. We show that there is almost no overlap between genomic (annotated with tissue-specific expression quantitative trait loci data) and transcription (RNA and protein data) biomarkers. Furthermore, using interaction networks we demonstrate there is little direct interaction between the proposed biomarkers, though a majority do have common interactors connecting them into networks. Our gene ontology analysis shows that these networks have roles in apoptotic signalling, response to oxidative stress and inflammation pathways. We conclude that a more systematic approach with genome-wide search of genomic and expression biomarkers in the same patients is needed in future studies. [ABSTRACT FROM AUTHOR]

Background: Sarcoidosis is a systemic disease characterized by the formation of immune granulomas in various organs, mainly the lungs and the lymphatic system. Exaggerated granulomatous reaction might be triggered in response to unidentified antigens in individuals with genetic susceptibility. The present study aimed to determine the genetic variants implicated in a familial case of sarcoidosis.Methods: Sarcoidosis presentation and history, NOD2 profile, NF-κB and cytokine production in blood monocytes/macrophages were evaluated in individuals from a family with late appearance of sarcoidosis.Results: In the present study, we report a case of familial sarcoidosis with typical thoracic sarcoidosis and carrying the NOD2 2722G > C variant. This variant is associated with the presence of three additional SNPs for the IL17RA, KALRN and EPHA2 genes, which discriminate patients expressing the disease from others. Despite a decrease in NF-κB activity, IL-8 and TNF-A mRNA levels were increased at baseline and in stimulated conditions.Conclusions: Combination of polymorphisms in the NOD2, IL17RA, EPHA2 and KALRN genes could play a significant role in the development of sarcoidosis by maintaining a chronic pro-inflammatory status in macrophages. [ABSTRACT FROM AUTHOR]