Shorter Disease Duration Is Associated With Higher Rates of Response to Vedolizumab in Patients With Crohn's Disease But Not Ulcerative Colitis.

Background & aimsPatients with Crohn's disease (CD), but not ulcerative colitis (UC), of shorter duration have higher rates of response to tumor necrosis factor (TNF) antagonists than patients with longer disease duration. Little is known about the association between disease duration and response to other biologic agents. We aimed to evaluate response of patients with CD or UC to vedolizumab, stratified by disease duration.MethodsWe analyzed data from a retrospective, multicenter, consortium of patients with CD (n = 650) or UC (n = 437) treated with vedolizumab from May 2014 through December 2016. Using time to event analyses, we compared rates of clinical remission, corticosteroid-free remission (CSFR), and endoscopic remission between patients with early-stage (≤2 years duration) and later-stage (>2 years) CD or UC. We used Cox proportional hazards models to identify factors associated with outcomes.ResultsWithin 6 months initiation of treatment with vedolizumab, significantly higher proportions of patients with early-stage CD, vs later-stage CD, achieved clinical remission (38% vs 23%), CSFR (43% vs 14%), and endoscopic remission (29% vs 13%) (P < .05 for all comparisons). After adjusting for disease-related factors including previous exposure to TNF antagonists, patients with early-stage CD were significantly more likely than patients with later-stage CD to achieve clinical remission (adjusted hazard ratio [aHR], 1.59; 95% CI, 1.02-2.49), CSFR (aHR, 3.39; 95% CI, 1.66-6.92), and endoscopic remission (aHR, 1.90; 95% CI, 1.06-3.39). In contrast, disease duration was not a significant predictor of response among patients with UC.ConclusionsPatients with CD for 2 years or less are significantly more likely to achieve a complete response, CSFR, or endoscopic response to vedolizumab than patients with longer disease duration. Disease duration does not associate with response vedolizumab in patients with UC

Skunk River Review Fall 2001, vol 13

https://openspace.dmacc.edu/skunkriver/1022/thumbnail.jp

Ulcerative colitis and irritable bowel patients exhibit distinct abnormalities of the gut microbiota

<p>Abstract</p> <p>Background</p> <p>Previous studies suggest a link between gut microbiota and the development of ulcerative colitis (UC) and irritable bowel syndrome (IBS). Our aim was to investigate any quantitative differences in faecal bacterial compositions in UC and IBS patients compared to healthy controls, and to identify individual bacterial species that contribute to these differences.</p> <p>Methods</p> <p>Faecal microbiota of 13 UC patients, 11 IBS patients and 22 healthy volunteers were analysed by PCR-Denaturing Gradient Gel Electrophoresis (DGGE) using universal and Bacteroides specific primers. The data obtained were normalized using in-house developed statistical method and interrogated by multivariate approaches. The differentiated bands were excised and identified by sequencing the V3 region of the 16S rRNA genes.</p> <p>Results</p> <p>Band profiles revealed that number of predominant faecal bacteria were significantly different between UC, IBS and control group (p < 10^-4). By assessing the mean band numbers in UC (37 ± 5) and IBS (39 ± 6), compared to the controls (45 ± 3), a significant decrease in bacterial species is suggested (p = 0.01). There were no significant differences between IBS and UC. Biodiversity of the bacterial species was significantly lower in UC (μ = 2.94, σ = 0.29) and IBS patients (μ = 2.90, σ = 0.38) than controls (μ = 3.25, σ = 0.16; p = 0.01). Moreover, similarity indices revealed greater biological variability of predominant bacteria in UC and IBS compared to the controls (median Dice coefficients 76.1% (IQR 70.9 - 83.1), 73.8% (IQR 67.0 - 77.5) and 82.9% (IQR 79.1 - 86.7) respectively). DNA sequencing of discriminating bands suggest that the presence of <it>Bacteroides vulgatus, B. ovatus, B. uniformis</it>, and <it>Parabacteroides sp</it>. in healthy volunteers distinguishes them from IBS and UC patients. DGGE profiles of Bacteroides species revealed a decrease of Bacteroides community in UC relative to IBS and controls.</p> <p>Conclusion</p> <p>Molecular profiling of faecal bacteria revealed abnormalities of intestinal microbiota in UC and IBS patients, while different patterns of Bacteroides species loss in particular, were associated with UC and IBS.</p

African-American inflammatory bowel disease in a Southern U.S. health center

<p>Abstract</p> <p>Background</p> <p>Inflammatory Bowel Diseases (IBD) remain significant health problems in the US and worldwide. IBD is most often associated with eastern European ancestry, and is less frequently reported in other populations of African origin e.g. African Americans ('AAs'). Whether AAs represent an important population with IBD in the US remains unclear since few studies have investigated IBD in communities with a majority representation of AA patients. The Louisiana State University Health Sciences Center in Shreveport (LSUHSC-S) is a tertiary care medical center, with a patient base composed of 58% AA and 39% Caucasian (W), ideal for evaluating racial (AA vs. W) as well and gender (M vs. F) influences on IBD.</p> <p>Methods</p> <p>In this retrospective study, we evaluated 951 visits to LSUHSC-S for IBD (between 2000 to 2008) using non-identified patient information based on ICD-9 medical record coding (Crohn's disease 'CD'-555.0- 555.9 and ulcerative colitis 'UC'-556.0-556.9).</p> <p>Results</p> <p>Overall, there were more cases of CD seen than UC. UC and CD affected similar ratios of AA and Caucasian males (M) and females (F) with a rank order of WF > WM > AAF > AAM. Interestingly, in CD, we found that annual visits per person was the highest in AA M (10.7 ± 1.7); significantly higher (* -p < 0.05) than in WM (6.3 ± 1.0). Further, in CD, the female to male (F: M) ratio in AA was significantly higher (*- p < 0.05) (1.9 ± 0.2) than in Caucasians (F:M = 1.3 ± 0.1) suggesting a female dominance in AACD; no differences were seen in UC F: M ratios.</p> <p>Conclusion</p> <p>Although Caucasians still represent the greatest fraction of IBD (~64%), AAs with IBD made up >1/3 (36.4%) of annual IBD cases from 2000-2008 at LSUHSC-S. Further studies on genetic and environments risks for IBD risk in AAs are needed to understand differences in presentation and progression in AAs and other 'non-traditional' populations.</p

Innate Immune Mechanisms That Regulate Disease Flare in Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a heterogenous autoimmune disease characterized by dysfunction within the innate and adaptive immune systems. The breakdown in immune tolerance that accompanies this promotes aberrant B cell activation, production of autoantibodies targeting self-nucleic acids, overproduction of pro-inflammatory cytokines, and widespread tissue damage. While some patients experience persistently active disease, most SLE patients follow a relapsing-remitting course with periods of clinical quiescence interspersed with unpredictable disease flares. Delineating the underlying mechanisms that contribute to pathogenesis of SLE as well as those that trigger flares will aid in development of novel therapeutics to improve patient outcomes. Several cytokines have been implicated in SLE including type I interferons (IFNs) and the IL (interleukin)-1 superfamily. Type I IFNs are overexpressed in both the circulation and non-lesional skin of SLE patients compared to controls. Levels of type I IFNs correlate with disease activity and severity and promote increased death of SLE keratinocytes after exposure to ultraviolet (UV) light. This likely contributes to photosensitivity, or enhanced sensitivity to UV light, which is experienced by up to 90% of patients. The IL-1 family of cytokines includes IL-1beta (IL-1β) which is activated by the inflammasome, a component of the innate immune system that detects infectious or endogenous danger signals. Inflammasome inhibition in lupus-prone mice improves several disease manifestations including nephritis. The specific mechanisms by which cutaneous type I IFNs contribute to photosensitivity and IL-1β influences lupus pathogenesis are currently unknown. The primary focus of this dissertation is to examine the role of type I IFNs in the skin and IL-1β in the kidney. The first objective of this study was to explore the activation and regulation of cell death pathways in keratinocytes exposed to type I IFNs and UV irradiation. Immortalized human keratinocytes were treated with IFN-α and UVB light in combination with apoptosis, necroptosis, and pyroptosis inhibitors or neutralizing antibodies. Cell death was measured by Annexin V and propidium iodide or cleaved caspase-3 staining. We identified enhanced activation of caspase-8-dependent apoptosis in IFN-primed keratinocytes after UVB exposure. This apoptosis occurred independently of known caspase-8-activating death ligands but was dependent on interferon regulatory factor 1 (IRF1). Lastly, we observed increased UVB-induced keratinocyte apoptosis in mice that overexpressed epidermal IFN-к compared to wild-type mice. Together, these data suggest that photosensitivity exhibited by SLE patients may result from IFN priming of keratinocytes that drives IRF1 expression and sensitizes cells to undergo increased apoptosis after minimal exposures to UVB. Continued investigation into mechanisms by which this occurs will provide prophylactic options to prevent SLE flares. The second part of our study involved investigating how loss of IL-1β affects disease severity in the lupus-prone NZM2328 mouse model. We generated a knockout strain (NZM-Il1b-/-) and examined common manifestations of disease. Surprisingly, loss of IL-1β did not affect overall survival, autoantibody generation, or renal immune cell infiltration; however, it did worsen renal immune complex deposition and proteinuria, specifically in female mice. IL-17 and TNF signaling pathways were enriched in the kidneys of female NZM-Il1b-/- mice, suggesting a potential mechanism by which nephritis is aggravated. Female patients with lupus nephritis also demonstrate upregulation of these signaling pathways, suggesting they may be of clinical relevance. Together, these data suggest that blocking IL-1β may need to be approached with caution in SLE patients, especially those with nephritis, to prevent potential exacerbation of disease.PhDImmunologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/178017/1/snloftus_1.pd

Sex differences revealed in a mouse CFA inflammation model with macrophage targeted nanotheranostics

Monocyte derived macrophages (MDMs) infiltrate sites of infection or injury and upregulate cyclooxygenase-2 (COX-2), an enzyme that stimulates prostaglandin-E2 (PgE2). Nanotheranostics combine therapeutic and diagnostic agents into a single nanosystem. In previous studies, we demonstrated that a nanotheranostic strategy, based on theranostic nanoemulsions (NE) loaded with a COX-2 inhibitor (celecoxib, CXB) and equipped with near-infrared fluorescent (NIRF) reporters, can specifically target circulating monocytes and MDMs. The anti-inflammatory and anti-nociceptive effects of such cell-specific COX-2 inhibition lasted several days following Complete Freund’s Adjuvant (CFA) or nerve injury in male mice. The overall goal of this study was to investigate the extended (up to 40 days) impact of MDM-targeted COX-2 inhibition and any sex-based differences in treatment response; both of which remain unknown. Our study also evaluates the feasibility and efficacy of a preclinical nanotheranostic strategy for mechanistic investigation of the impact of such sex differences on clinical outcomes. Methods: CFA was administered into the right hind paws of male and female mice. All mice received a single intravenous dose of NIRF labeled CXB loaded NE twelve hours prior to CFA injection. In vivo whole body NIRF imaging and mechanical hypersensitivity assays were performed sequentially and ex vivo NIRF imaging and immunohistopathology of foot pad tissues were performed at the end point of 40 days. Results: Targeted COX-2 inhibition of MDMs in male and female mice successfully improved mechanical hypersensitivity after CFA injury. However, we observed distinct sex-specific differences in the intensity or longevity of the nociceptive responses. In males, a single dose of CXB-NE administered via tail vein injection produced significant improved mechanical hypersensitivity for 32 days as compared to the drug free NE (DF-NE) (untreated) control group. In females, CXB-NE produced similar, though less prominent and shorter-lived effects, lasting up to 11 days. NIRF imaging confirmed that CXB-NE can be detected up to day 40 in the CFA injected foot pad tissues of both sexes. There were distinct signal distribution trends between males and females, suggesting differences in macrophage infiltration dynamics between the sexes. This may also relate to differences in macrophage turnover rate between the sexes, a possibility that requires further investigation in this model. Conclusions: For the first time, this study provides unique insight into MDM dynamics and the early as well as longer-term targeted effects and efficacy of a clinically translatable nanotheranostic agent on MDM mediated inflammation. Our data supports the potential of nanotheranostics as presented in elucidating the kinetics, dynamics and sex-based differences in the adaptive or innate immune responses to inflammatory triggers. Taken together, our study findings lead us closer to true personalized, sex-specific pain nanomedicine for a wide range of inflammatory diseases

Characterizing the High Disease Burden of Transthyretin Amyloidosis for Patients and Caregivers

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