Our growing understanding of the immunopathogenesis of inflammatory bowel disease (IBD) has opened new avenues for developing targeted therapies. These advances in treatment options targeting ...different mechanisms of action offer new hope for personalized management. In this review we highlight emerging novel and easily administered therapeutics that may be viable candidates for the management of IBD, such as antibodies against interleukin 6 (IL-6) and IL-12/23, small molecules including Janus kinase inhibitors, antisense oligonucleotide against SMAD7 mRNA, and inhibitors of leukocyte trafficking to intestinal sites of inflammation (e.g., sphingosine 1-phosphate receptor modulators). We also provide an update on the current status in clinical development of these new classes of therapeutics.
PURPOSE: The objective of the study was to examine the effect of dorzolamide–timolol (DT) eye drop used before intravitreal ranibizumab (IVR) injection on intraocular pressure (IOP) change. METHODS: ...50 eyes of 50 patients who received DT eye drops 1 h before IVR injection due to diabetic retinopathy and macular edema were considered Group 1, and 50 eyes of 50 patients who did not receive DT eye drops were considered Group 2. Those patients who had previously undergone intravitreal injection had intraocular surgery, and used any eye drops were not included in the study. Before the injection, IO P values were measured with a Tonopen contact handheld tonometer before the blepharostat was placed (BIOP), after the blepharostat was placed (AIOP), and at the 1 st min after the injection (IIOP). RESULTS: There were 25 males and 25 females in Group 1 and 25 males and 25 females in Group 2; the mean age was 65.66 ± 9.94 years in Group 1 and 65.54 ± 7.43 years in Group 2 ( P = 0.98). In Group 1, BIOP was 18.91 ± 18.91, AIOP was 21.62 ± 6.16 mmHg, and IIOP was 49.21 ± 10.95 mmHg. In Group 2, BIOP was 20.18 ± 4.19 mmHg, AIOP was 24.60 ± 4.90 mmHg, and IIOP was 49.96 ± 9.72 mmHg. IIOP-BIOP difference was 30.30 ± 9.85 mmHg in Group 1 and 29.78 ± 9.33 mmHg in Group 2 and the difference was not statistically significant ( P = 0.78). In Group 1, the IIOP-AIOP difference was 27.58 ± 10.60 mmHg and in Group 2, 25.36 ± 10.46 mmHg. The difference between IIOP and AIOP was not statistically significant ( P = 0.27). CONCLUSION: The use of topical DT eye drops before IVR injection does not affect the intraocular pressure change.
PURPOSE: To examine the relationship between the presence and severity of retinopathy in women with diabetes mellitus and sleep quality assessed using Pittsburgh Sleep Quality Index (PSQI). METHODS: ...Among 90 female patients with type 2 diabetes, 30 patients without retinopathy were classified into Group 1, 30 patients with nonproliferative diabetic retinopathy as Group 2, and 30 patients with proliferative diabetic retinopathy as Group 3. People who had a known sleep problem, had a history of using medication other than sleeping pills that would affect sleep, had lower or upper respiratory tract disease, had history of previous surgery, or were unable to answer the survey questions appropriately were excluded from the study. RESULTS: The mean age was 52.6 ± 6.18 years in Group 1, 55.15 ± 8.15 years in Group 2, and 60.35 ± 5.93 years in Group 3. While no statistical difference was observed between Groups 1 and 2 ( P = 0.27), a statistical difference was observed between both Groups 1 and 3 ( P = 0.01) and Groups 2 and 3 ( P = 0.02). PSQI scores were found to be 5.10 ± 1.07 in Group 1, 7.30 ± 2.34 in Group 2, and 6.70 ± 1.21 in Group 3. In terms of these scores, there was a statistical difference between Group 1 and both Group 2 ( P = 0.01) and Group 3 ( P = 0.01), while no difference was observed between Groups 2 and 3 ( P = 0.31). CONCLUSION: Although the presence of retinopathy significantly impairs sleep quality in diabeticwomen, no relationship was found between the severity of retinopathy and impaired sleep quality.
The intestinal epithelium has a strategic position as a protective physical barrier to luminal microbiota and actively contributes to the mucosal immune system. This barrier is mainly formed by a ...monolayer of specialized intestinal epithelial cells (IECs) that are crucial in maintaining intestinal homeostasis. Therefore, dysregulation within the epithelial layer can increase intestinal permeability, lead to abnormalities in interactions between IECs and immune cells in underlying lamina propria, and disturb the intestinal immune homeostasis, all of which are linked to the clinical disease course of inflammatory bowel disease (IBD). Understanding the role of the intestinal epithelium in IBD pathogenesis might contribute to an improved knowledge of the inflammatory processes and the identification of potential therapeutic targets.
An unmet medical need exists for the development of targeted therapies for the treatment of inflammatory bowel disease (IBD) with easily administered and stable oral drugs, particularly as most ...patients on biologics i.e., tumor necrosis factor (TNF) inhibitors and anti-integrins are either primary non-responders or lose responsiveness during maintenance treatment. A new class of small molecules, sphingosine-1-phosphate (S1P) receptor modulators, has recently shown efficacy in IBD. Here we provide an overview of the mechanism of action of this novel treatment principle in the context of intestinal inflammation. The remarkable impact of therapeutic modulation of the S1P/S1P receptor axis reflects the complexity of the pathogenesis of IBD and the fact that S1P receptor modulation may be a logical therapeutic approach for the future management of IBD.
The pathogenesis of inflammatory bowel disease （IBD） is complex and largely unknown. Until recently, research has focused on the study of protein regulators in inflammation to reveal the cellular and ...molecular networks in the pathogenesis of IBD. However, in the last few years, new and promising insights have been generated from studies describing an association between an altered expression of a specific class of non-coding RNAs, called microRNAs （miRs or miRNAs） and IBD. The short （approximately 22 nucleotides）, endogenous, single-stranded RNAs are evolutionary conserved inanimals and plants, and regulate specific target mRNAs at the post-transcriptional level. MiRNAs are involved in several biological processes, including development, cell differentiation, proliferation and apoptosis. Furthermore, it is estimated that miRNAs may be responsible for regulating the expression of nearly one-third of the genes in the human genome. Thus, miRNA deregulation often results in an impaired cellular function, and a disturbance of downstream gene regulation and signaling cascades, suggesting their implication in disease etiology. Despite the identification of more than 1900 mature human miRNAs, very little is known about their biological functions and functional targets. Recent studies have identified dysregulated miRNAs in tissue samples of IBD patients and have demonstrated similar differences in circulating miRNAs in the serum of IBD patients. Thus, there is great promise that miRNAs will aid in the early diagnosis of IBD, and in the development of personalized therapies. Here, we provide a short review of the current state-of-the-art of miRNAs in IBD pathogenesis, diagnostics and therapeutics.
Biological treatment with tumor necrosis factor (TNF) inhibitors is successful in the management of inflammatory bowel disease (IBD). All TNF inhibitors antagonize the pro-inflammatory cytokine TNF-α ...but with varying efficacies in IBD. The variations in efficacy probably are caused by structural differences between the agents that affect their mechanisms of action and pharmacokinetic properties. Several mechanisms have been proposed, such as modulation of the expression of pro-inflammatory mediators and a reduction in the number of activated immune cells. However, it seems that clinical efficacy is the result of a number of different mechanisms and that binding of transmembrane TNF by TNF inhibitors. Knowledge of the mechanisms of action has been obtained mainly through the use of in vitro assays that may differ significantly from the situation in vivo. This review discusses the available data on TNF inhibitors in order to identify mechanisms of importance for their efficacy in IBD. Thus, a better understanding of the mechanistic basis for clinical efficacy can lead to a more rational use of TNF inhibitors in the management of IBD.
This study employs spectroscopy-based metabolic profiling of fecal extracts from healthy subjects and patients with active or inactive ulcerative colitis (UC) and Crohn’s disease (CD) to substantiate ...the potential use of spectroscopy as a non-invasive diagnostic tool and to characterize the fecal metabolome in inflammatory bowel disease (IBD). Stool samples from 113 individuals (UC 48, CD 44, controls 21) were analyzed by
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H nuclear magnetic resonance (NMR) spectroscopy (Bruker 600 MHz, Bruker BioSpin, Rheinstetten, Germany). Data were analyzed with principal component analysis and orthogonal-projection to latent structure-discriminant analysis using SIMCA-P + 12 and MATLAB. Significant differences were found in the metabolic profiles making it possible to differentiate between active IBD and controls and between UC and CD. The metabolites holding differential power primarily belonged to a range of amino acids, microbiota-related short chain fatty acids, and lactate suggestive of an inflammation-driven malabsorption and dysbiosis of the normal bacterial ecology. However, removal of patients with intestinal surgery and anti-TNF-α antibody treatment eliminated the discriminative power regarding UC versus CD. This study consequently demonstrates that
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H NMR spectroscopy of fecal extracts is a potential non-invasive diagnostic tool and able to characterize the inflammation-driven changes in the metabolic profiles related to malabsorption and dysbiosis. Intestinal surgery and medication are to be accounted for in future studies, as it seems to be factors of importance in the discriminative process.
Inflammatory bowel disease(IBD)is a group of chronic disorders of the gastrointestinal tract comprising Crohn’s disease(CD)and ulcerative colitis(UC).Their etiologies are unknown,but they are ...characterised by an imbalanced production of pro-inflammatory mediators,e.g.,tumor necrosis factor(TNF)-α,as well as increased recruitment of leukocytes to the site of inflammation.Advantages in understanding the role of the inflammatory pathways in IBD and an inadequate response to conventional therapy in a large portion of patients,has over the last two decades lead to new therapies which includes the TNF inhibitors(TNFi),designed to target and neutralise the effect of TNF-α.TNFi have shown to be efficient in treating moderate to severe CD and UC.However,convenient alternative therapeutics targeting other immune pathways are needed for patients with IBD refractory to conventional therapy including TNFi.Indeed,several therapeutics are currently under development,and have shown success in clinical trials.These include antibodies targeting and neutralising interleukin-12/23,small pharmacologic Janus kinase inhibitors designed to block intracellular signaling of several pro-inflammatory cytokines,antibodies targeting integrins,and small anti-adhesion molecules that block adhesion between leukocytes and the intestinal vascular endothelium,reducing their infiltration into the inflamed mucosa.In this review we have elucidated the major signaling pathways of clinical importance for IBD therapy and highlighted the new promising therapies available.As stated in this paper several new treatment options are under development for the treatment of CD and UC,however,no drug fits all patients.Hence,optimisations of treatment regimens are warranted for the benefit of the patients either through biomarker establishment or other rationales to maximise the effect of the broad range of mode-of-actions of the present and future drugs in IBD.
Background
The Prostate Imaging Reporting and Data System version 2 (PI‐RADSv2) has been in use since 2015; while interreader reproducibility has been studied, there has been a paucity of studies ...investigating the intrareader reproducibility of PI‐RADSv2.
Purpose
To evaluate both intra‐ and interreader reproducibility of PI‐RADSv2 in the assessment of intraprostatic lesions using multiparametric magnetic resonance imaging (mpMRI).
Study Type
Retrospective.
Population/Subjects
In all, 102 consecutive biopsy‐naïve patients who underwent prostate MRI and subsequent MR/transrectal ultrasonography (MR/TRUS)‐guided biopsy.
Field Strength/Sequences
Prostate mpMRI at 3T using endorectal with phased array surface coils (TW MRI, DW MRI with ADC maps and b2000 DW MRI, DCE MRI).
Assessment
Previously detected and biopsied lesions were scored by four readers from four different institutions using PI‐RADSv2. Readers scored lesions during two readout rounds with a 4‐week washout period.
Statistical Tests
Kappa (κ) statistics and specific agreement (Po) were calculated to quantify intra‐ and interreader reproducibility of PI‐RADSv2 scoring. Lesion measurement agreement was calculated using the intraclass correlation coefficient (ICC).
Results
Overall intrareader reproducibility was moderate to substantial (κ = 0.43–0.67, Po = 0.60–0.77), while overall interreader reproducibility was poor to moderate (κ = 0.24, Po = 46). Readers with more experience showed greater interreader reproducibility than readers with intermediate experience in the whole prostate (P = 0.026) and peripheral zone (P = 0.002). Sequence‐specific interreader agreement for all readers was similar to the overall PI‐RADSv2 score, with κ = 0.24, 0.24, and 0.23 and Po = 0.47, 0.44, and 0.54 in T2‐weighted, diffusion‐weighted imaging (DWI), and dynamic contrast‐enhanced (DCE), respectively. Overall intrareader and interreader ICC for lesion measurement was 0.82 and 0.71, respectively.
Data Conclusion
PI‐RADSv2 provides moderate intrareader reproducibility, poor interreader reproducibility, and moderate interreader lesion measurement reproducibility. These findings suggest a need for more standardized reader training in prostate MRI.
Level of Evidence: 2
Technical Efficacy: Stage 2
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