Inflammatory Bowel Disease-Associated Colorectal Cancer Epidemiology and Outcomes: An English Population-Based Study.

INTRODUCTION: Patients with inflammatory bowel diseases (IBDs) of the colon are at an increased risk of colorectal cancer (CRC). This study investigates the epidemiology of IBD-CRC and its outcomes. METHODS: Using population data from the English National Health Service held in the CRC data repository, all CRCs with and without prior diagnosis of IBD (Crohn's, ulcerative colitis, IBD unclassified, and IBD with cholangitis) between 2005 and 2018 were identified. Descriptive analyses and logistic regression models were used to compare the characteristics of the 2 groups and their outcomes up to 2 years. RESULTS: Three hundred ninety thousand six hundred fourteen patients diagnosed with CRC were included, of whom 5,141 (1.3%) also had a previous diagnosis of IBD. IBD-CRC cases were younger (median age at CRC diagnosis [interquartile range] 66 [54-76] vs 72 [63-79] years [ P < 0.01]), more likely to be diagnosed with CRC as an emergency (25.1% vs 16.7% [ P < 0.01]), and more likely to have a right-sided colonic tumor (37.4% vs 31.5% [ P < 0.01]). Total colectomy was performed in 36.3% of those with IBD (15.4% of Crohn's, 44.1% of ulcerative colitis, 44.5% of IBD unclassified, and 67.7% of IBD with cholangitis). Synchronous (3.2% vs 1.6% P < 0.01) and metachronous tumors (1.7% vs 0.9% P < 0.01) occurred twice as frequently in patients with IBD compared with those without IBD. Stage-specific survival up to 2 years was worse for IBD-associated cancers. DISCUSSION: IBD-associated CRCs occur in younger patients and have worse outcomes than sporadic CRCs. There is an urgent need to find reasons for these differences to inform screening, surveillance, and treatment strategies for CRC and its precursors in this high-risk group.

Decreasing Risk of First and Subsequent Surgeries in Patients With Crohn's Disease in England From 1994 through 2013.

BACKGROUND & AIMS: Gastrointestinal (GI) surgery is an important part of the treatment algorithm for patients with Crohn's disease (CD) that is complicated or does not respond to medical therapy. Cohort studies from Denmark and Canada have shown that the risk of primary surgery is decreasing but there is a lack of contemporary data on subsequent resections. We examined trends in first and second GI resections in patients with CD. METHODS: We performed a retrospective cohort study using the United Kingdom primary care database ResearchOne, collecting data from patients with Crohn's disease from 1994 through 2013. We compared rates of first and second GI resections with etiological factors. RESULTS: Among 3059 incident cases of CD, 13%, 21%, and 26% of the patients underwent surgical resections after 1, 5, and 10 years, respectively. Of patients with an initial resection, 20% required an additional operation when followed for 10 years after the initial resection. We found a significant reduction in first surgery, from 44% to 21% after 10 years of disease, from 1994 to 2003 (χ2 for trend, P < .05). There was a significant reduction in second resections, in a 10-year follow-up period, from 40% in 1994 to 17% in 2003 (χ2 for trend, P < .05). Duration of disease, younger age at diagnosis, smoking, and immunomodulator use were positively associated with first surgeries. Duration of disease was significantly associated with the risk of undergoing a second resection. CONCLUSION: In a retrospective analysis of a United Kingdom primary care database, we observed a significant reduction in first and subsequent GI surgeries among patients with CD over the past 20 years in England.

A multimodal (FACILE) classification for optical diagnosis of inflammatory bowel disease associated neoplasia.

BACKGROUND: Characterization of colonic lesions in inflammatory bowel disease (IBD) remains challenging. We developed an endoscopic classification of visual characteristics to identify colitis-associated neoplasia using multimodal advanced endoscopic imaging (Frankfurt Advanced Chromoendoscopic IBD LEsions [FACILE] classification). METHODS: The study was conducted in three phases: 1) development - an expert panel defined endoscopic signs and predictors of dysplasia in IBD and, using multivariable logistic regression created the FACILE classification; 2) validation - using 60 IBD lesions from an image library, two assessments of diagnostic accuracy for neoplasia were performed and interobserver agreement between experts using FACILE was determined; 3) reproducibility - the reproducibility of the FACILE classification was tested in gastroenterologists, trainees, and junior doctors after completion of a training module. RESULTS: The experts initially selected criteria such as morphology, color, surface, vessel architecture, signs of inflammation, and lesion border. Multivariable logistic regression confirmed that nonpolypoid lesion, irregular vessel architecture, irregular surface pattern, and signs of inflammation within the lesion were predictors of dysplasia. Area under the curve of this logistic model using a bootstrapped estimate was 0.76 (0.73 - 0.78). The training module resulted in improved accuracy and kappa agreement in all nonexperts, though in trainees and junior doctors the kappa agreement was still moderate and poor, respectively. CONCLUSION: We developed, validated, and demonstrated reproducibility of a new endoscopic classification (FACILE) for the diagnosis of dysplasia in IBD using all imaging modalities. Flat shape, irregular surface and vascular patterns, and signs of inflammation predicted dysplasia. The diagnostic performance of all nonexpert participants improved after a training module.

Increasing Prescription of Opiates and Mortality in Patients With Inflammatory Bowel Diseases in England.

BACKGROUND & AIMS: The prescription of opiate medications is increasing. Individuals with inflammatory bowel diseases (IBD) can develop serious complications from opiate use, but few data are available on the prescription of these drugs to patients with IBD. We examined trends in prescriptions of opiates and their association with all-cause mortality in individuals with IBD. METHODS: We performed a retrospective cohort study of 3517 individuals with Crohn's disease (CD) and 5349 with ulcerative colitis (UC) using the primary care database ResearchOne, which holds de-identified clinical and administrative information from the health records of approximately 6 million persons (more than 10% of the total population) in England. We explored trends in prescriptions of all opiates, codeine, tramadol, or strong opiates, separately from 1990 through September 14, 2014. Associations between opiates and all-cause mortality were examined using propensity score-matched analysis. RESULTS: There was a statistically significant increase in the prescription of opiate medications, with 10% of subjects receiving an opiate prescription from 1990 through 1993 compared to 30% from 2010 through 2013 (chi-square for trend, P < .005). Prescription of strong opiates was significantly associated with increased premature mortality of patients with CD (heavy use) or UC (moderate or heavy use). There was a significant association between heavy use of any opiate or codeine alone and premature mortality of patients with UC. Use of tramadol alone, or in combination with codeine, was not associated with premature mortality in patients with CD or UC. CONCLUSIONS: In an analysis of primary care patients with IBD in England, we found prescriptions for opiate drugs to have increased significantly from 1990 through 2013. Heavy use of strong opiates among patients with IBD associates with increased all-cause premature mortality.

Folic Acid Supplementation May Reduce Colorectal Cancer Risk in Patients With Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis.

GOALS: To evaluate the role of folic acid supplementation in colorectal cancer (CRC) chemoprevention in patients with inflammatory bowel disease (IBD). BACKGROUND: CRC is a serious complication of IBD. Folic acid supplementation has been shown to be chemopreventative in sporadic CRC. Patients with IBD are at risk of folate deficiency though intestinal malabsorption and also competitive inhibition by concurrent sulfasalazine use. To date, there have been several studies reporting on folic acid supplementation in patients with IBD and CRC. STUDY: We searched electronic databases for studies reporting folic acid use and CRC incidence in patients with IBD. We produced a pooled hazard ratio with 95% confidence intervals using a random-effects model. Preplanned subgroup analyses were performed to explore for any potential sources of heterogeneity. RESULTS: Ten studies reporting on 4517 patients were included. We found an overall protective effect for folic acid supplementation on the development of CRC, pooled hazard ratio=0.58 (95% confidence interval, 0.37-0.80). There was low to moderate heterogeneity among studies, I=29.7%. Subgroup analyses suggested that folic acid use was protective in hospital-based studies, studies from North America and those that were performed before folate fortification of foods in 1998. CONCLUSIONS: CRC remains an important complication of IBD. Chemoprevention is an attractive strategy and folic acid as a cheap, safe, and well-tolerated supplement may have a role. Focused prospective studies are required to precisely define any potential effect.

Peptidylarginine deiminase inhibition reduces vascular damage and modulates innate immune responses in murine models of atherosclerosis.

RATIONALE: Neutrophil extracellular trap (NET) formation promotes vascular damage, thrombosis, and activation of interferon-α-producing plasmacytoid dendritic cells in diseased arteries. Peptidylarginine deiminase inhibition is a strategy that can decrease in vivo NET formation. OBJECTIVE: To test whether peptidylarginine deiminase inhibition, a novel approach to targeting arterial disease, can reduce vascular damage and inhibit innate immune responses in murine models of atherosclerosis. METHODS AND RESULTS: Apolipoprotein-E (Apoe)(-/-) mice demonstrated enhanced NET formation, developed autoantibodies to NETs, and expressed high levels of interferon-α in diseased arteries. Apoe(-/-) mice were treated for 11 weeks with daily injections of Cl-amidine, a peptidylarginine deiminase inhibitor. Peptidylarginine deiminase inhibition blocked NET formation, reduced atherosclerotic lesion area, and delayed time to carotid artery thrombosis in a photochemical injury model. Decreases in atherosclerosis burden were accompanied by reduced recruitment of netting neutrophils and macrophages to arteries, as well as by reduced arterial interferon-α expression. CONCLUSIONS: Pharmacological interventions that block NET formation can reduce atherosclerosis burden and arterial thrombosis in murine systems. These results support a role for aberrant NET formation in the pathogenesis of atherosclerosis through modulation of innate immune responses.

Patients with Endoscopically Visible Polypoid Adenomatous Lesions Within the Extent of Ulcerative Colitis Have an Increased Risk of Colorectal Cancer Despite Endoscopic Resection.

OBJECTIVES: Ulcerative colitis (UC) is associated with an increased risk of colorectal cancer (CRC). Few studies have looked at long-term outcomes of endoscopically visible adenomatous lesions removed by endoscopic resection in these patients. We aimed to assess the risk of developing CRC in UC patients with adenomatous lesions that develop within the segment of colitis compared to the remainder of an ulcerative colitis cohort. METHODS: We identified patients with a confirmed histological diagnosis of UC from 1991 to 2004 and noted outcomes till June 2011. The Kaplan-Meier method was used to estimate cumulative probability of subsequent CRC. Factors associated with risk of CRC were assessed in a Cox proportional hazards model. RESULTS: Twenty-nine of 301 patients with UC had adenomatous lesions noted within the segment of colitis. The crude incidence rate of developing colon cancer in patients with UC was 2.45 (95 % CI 1.06-4.83) per 1000 PYD and in those with UC and polypoid adenomas within the extent of inflammation was 11.07 (95 % CI 3.59-25.83) per 1000 PYD. Adjusted hazards ratio of developing CRC on follow-up in UC patients with polypoid dysplastic adenomatous lesions within the extent of inflammation was 4.0 (95 % CI 1.3-12.4). CONCLUSIONS: The risk of developing CRC is significantly higher in UC patients with polypoid adenomatous lesions, within the extent of inflammation, despite endoscopic resection. Patients and physicians should take the increased risk into consideration during follow-up of these patients.

Paradigm Shift in the Surveillance and Management of Dysplasia in Inflammatory Bowel Disease (West).

Patients with long-standing inflammatory bowel disease (IBD) colitis have a 2.4-fold higher risk of developing colorectal cancer (CRC) than the general population, for both ulcerative colitis (UC) and Crohn's disease (CD) colitis. Surveillance colonoscopy is recommended to detect early CRC and dysplasia. Most dysplasia discovered in patients with IBD is actually visible. Recently published SCENIC (Surveillance for Colorectal Endoscopic Neoplasia Detection and Management in Inflammatory Bowel Disease Patients: International Consensus Recommendations) consensus statements provide unifying recommendations for the optimal surveillance and management of dysplasia in IBD. SCENIC followed the prescribed processes for guideline development from the Institute of Medicine (USA), including systematic reviews, full synthesis of evidence and deliberations by panelists, and incorporation of the GRADE methodology. The new surveillance paradigm involves high-quality visual inspection of the mucosa, using chromoendoscopy and high-definition colonoscopy, with endoscopic recognition of colorectal dysplasia. Lesions are described according to a new classification, which replaces the term 'dysplasia associated lesion or mass (DALM)' and its derivatives. Targeted biopsies are subsequently done on areas suspicious for dysplasia, and resections are carried out for discrete, resectable lesions.

Modulation of calcium-induced cell death in human neural stem cells by the novel peptidylarginine deiminase-AIF pathway.

PADs (peptidylarginine deiminases) are calcium-dependent enzymes that change protein-bound arginine to citrulline (citrullination/deimination) affecting protein conformation and function. PAD up-regulation following chick spinal cord injury has been linked to extensive tissue damage and loss of regenerative capability. Having found that human neural stem cells (hNSCs) expressed PAD2 and PAD3, we studied PAD function in these cells and investigated PAD3 as a potential target for neuroprotection by mimicking calcium-induced secondary injury responses. We show that PAD3, rather than PAD2 is a modulator of cell growth/death and that PAD activity is not associated with caspase-3-dependent cell death, but is required for AIF (apoptosis inducing factor)-mediated apoptosis. PAD inhibition prevents association of PAD3 with AIF and AIF cleavage required for its translocation to the nucleus. Finally, PAD inhibition also hinders calcium-induced cytoskeleton disassembly and association of PAD3 with vimentin, that we show to be associated also with AIF; together this suggests that PAD-dependent cytoskeleton disassembly may play a role in AIF translocation to the nucleus. This is the first study highlighting a role of PAD activity in balancing hNSC survival/death, identifying PAD3 as an important upstream regulator of calcium-induced apoptosis, which could be targeted to reduce neural loss, and shedding light on the mechanisms involved.

Inhibiting protein arginine deiminases has antioxidant consequences.

Ulcerative colitis is a dynamic, idiopathic, chronic inflammatory condition that carries a high colon cancer risk. We previously showed that Cl-amidine, a small-molecule inhibitor of the protein arginine deiminases, suppresses colitis in mice. Because colitis is defined as inflammation of the colon associated with infiltration of white blood cells that release free radicals and citrullination is an inflammation-dependent process, we asked whether Cl-amidine has antioxidant properties. Here we show that colitis induced with azoxymethane via intraperitoneal injection + 2% dextran sulfate sodium in the drinking water is suppressed by Cl-amidine (also given in the drinking water). Inducible nitric oxide synthase, an inflammatory marker, was also downregulated in macrophages by Cl-amidine. Because epithelial cell DNA damage associated with colitis is at least in part a result of an oxidative burst from overactive leukocytes, we tested the hypothesis that Cl-amidine can inhibit leukocyte activation, as well as subsequent target epithelial cell DNA damage in vitro and in vivo. Results are consistent with this hypothesis, and because DNA damage is a procancerous mechanism, our data predict that Cl-amidine will not only suppress colitis, but we hypothesize that it may prevent colon cancer associated with colitis.

Peptidylarginine deiminase inhibition disrupts NET formation and protects against kidney, skin and vascular disease in lupus-prone MRL/lpr mice.

OBJECTIVES: An imbalance between neutrophil extracellular trap (NET) formation and degradation has been described in systemic lupus erythematosus (SLE), potentially contributing to autoantigen externalisation, type I interferon synthesis and endothelial damage. We have demonstrated that peptidylarginine deiminase (PAD) inhibition reduces NET formation and protects against lupus-related vascular damage in the New Zealand Mixed model of lupus. However, another strategy for inhibiting NETs--knockout of NOX2--accelerates lupus in a different murine model, MRL/lpr. Here, we test the effects of PAD inhibition on MRL/lpr mice in order to clarify whether some NET inhibitory pathways may be consistently therapeutic across models of SLE. METHODS: NET formation and autoantibodies to NETs were characterised in lupus-prone MRL/lpr mice. MRL/lpr mice were also treated with two different PAD inhibitors, Cl-amidine and the newly described BB-Cl-amidine. NET formation, endothelial function, interferon signature, nephritis and skin disease were examined in treated mice. RESULTS: Neutrophils from MRL/lpr mice demonstrate accelerated NET formation compared with controls. MRL/lpr mice also form autoantibodies to NETs and have evidence of endothelial dysfunction. PAD inhibition markedly improves endothelial function, while downregulating the expression of type I interferon-regulated genes. PAD inhibition also reduces proteinuria and immune complex deposition in the kidneys, while protecting against skin disease. CONCLUSIONS: PAD inhibition reduces NET formation, while protecting against lupus-related damage to the vasculature, kidneys and skin in various lupus models. The strategy by which NETs are inhibited will have to be carefully considered if human studies are to be undertaken.

Performance characteristics of unsedated ultrathin video endoscopy in the assessment of the upper GI tract: systematic review and meta-analysis.

BACKGROUND AND AIMS: Reports on the performance of unsedated ultrathin endoscopy via the transnasal (uTNE) and transoral (uTOE) routes are conflicting. We aimed to estimate the technical success rate, patient preference, and acceptability of uTNE and uTOE alone and in comparison with conventional EGD (cEGD; with or without sedation). METHODS: A systematic review and meta-analysis was performed on all primary studies reporting the outcomes of interest. Electronic databases (Cochrane library, MEDLINE, EMBASE) were searched on February 1, 2014. RESULTS: Thirty-four studies met the inclusion criteria with 6659 patients in total. The pooled technical success rate was 94.0% for uTNE (95% confidence interval [CI], 91.6-95.8; 30 studies) and 97.8% for uTOE (95% CI, 95.6-98.9; 16 studies). The difference in proportion of success for uTNE compared with cEGD was -2.0% (95% CI, -4.0 to -1.0; 18 studies), but that difference was not significant when uTNE < 5.9 mm in diameter was used (-1.0%; 95% CI, -3.0 to .0; 9 studies). There was no significant difference in success rate between uTOE and cEGD (.0%; 95% CI, -1.0 to 2.0; 10 studies). The pooled difference in proportion of patients who preferred uTNE over cEGD was 63.0% (95% CI, 49.0-76.0; 10 studies), whereas preference for uTOE versus cEGD was not significantly different (38.0%; 95% CI, -4.0 to 80.0; 2 studies). Acceptability was high for both uTNE (85.2%; 95% CI, 79.1-89.9; 16 studies) and uTOE (88.7%; 95% CI, 82.4-92.9; 10 studies). CONCLUSIONS: Technical success rate for uTNE < 5.9 mm is equivalent to cEGD. uTNE has high patient acceptability, with better patient preference, and therefore could be a useful alternative to cEGD for screening purposes. uTOE had a similar technical success rate but an equivocal preference to cEGD.

Peptidylarginine deiminase 2-catalyzed histone H3 arginine 26 citrullination facilitates estrogen receptor α target gene activation.

Cofactors for estrogen receptor α (ERα) can modulate gene activity by posttranslationally modifying histone tails at target promoters. Here, we found that stimulation of ERα-positive cells with 17ß-estradiol (E2) promotes global citrullination of histone H3 arginine 26 (H3R26) on chromatin. Additionally, we found that the H3 citrulline 26 (H3Cit26) modification colocalizes with ERα at decondensed chromatin loci surrounding the estrogen-response elements of target promoters. Surprisingly, we also found that citrullination of H3R26 is catalyzed by peptidylarginine deiminase (PAD) 2 and not by PAD4 (which citrullinates H4R3). Further, we showed that PAD2 interacts with ERα after E2 stimulation and that inhibition of either PAD2 or ERα strongly suppresses E2-induced H3R26 citrullination and ERα recruitment at target gene promoters. Collectively, our data suggest that E2 stimulation induces the recruitment of PAD2 to target promoters by ERα, whereby PAD2 then citrullinates H3R26, which leads to local chromatin decondensation and transcriptional activation.

Synthesis and Use of a Phosphonate Amidine to Generate an Anti-Phosphoarginine-Specific Antibody.

Protein arginine phosphorylation is a post-translational modification (PTM) that is important for bacterial growth and virulence. Despite its biological relevance, the intrinsic acid lability of phosphoarginine (pArg) has impaired studies of this novel PTM. Herein, we report for the first time the development of phosphonate amidines and sulfonate amidines as isosteres of pArg and then use these mimics as haptens to develop the first high-affinity sequence independent anti-pArg specific antibody. Employing this anti-pArg antibody, we further showed that arginine phosphorylation is induced in Bacillus subtilis during oxidative stress. Overall, we expect this antibody to see widespread use in analyzing the biological significance of arginine phosphorylation. Additionally, the chemistry reported here will facilitate the generation of pArg mimetics as highly potent inhibitors of the enzymes that catalyze arginine phosphorylation/dephosphorylation.

Peptidylarginine deiminases: novel drug targets for prevention of neuronal damage following hypoxic ischemic insult (HI) in neonates.

Neonatal hypoxic ischaemic (HI) injury frequently causes neural impairment in surviving infants. Our knowledge of the underlying molecular mechanisms is still limited. Protein deimination is a post-translational modification caused by Ca(+2) -regulated peptidylarginine deiminases (PADs), a group of five isozymes that display tissue-specific expression and different preference for target proteins. Protein deimination results in altered protein conformation and function of target proteins, and is associated with neurodegenerative diseases, gene regulation and autoimmunity. In this study, we used the neonatal HI and HI/infection [lipopolysaccharide (LPS) stimulation] murine models to investigate changes in protein deimination. Brains showed increases in deiminated proteins, cell death, activated microglia and neuronal loss in affected brain areas at 48 h after hypoxic ischaemic insult. Upon treatment with the pan-PAD inhibitor Cl-amidine, a significant reduction was seen in microglial activation, cell death and infarct size compared with control saline or LPS-treated animals. Deimination of histone 3, a target protein of the PAD4 isozyme, was increased in hippocampus and cortex specifically upon LPS stimulation and markedly reduced following Cl-amidine treatment. Here, we demonstrate a novel role for PAD enzymes in neural impairment in neonatal HI Encephalopathy, highlighting their role as promising new candidates for drug-directed intervention in neurotrauma. Hypoxic Ischaemic Insult (HI) results in activation of peptidylarginine deiminases (PADs) because of calcium dysregulation. Target proteins undergo irreversible changes of protein bound arginine to citrulline, resulting in protein misfolding. Infection in synergy with HI causes up-regulation of TNFα, nuclear translocation of PAD4 and change in gene regulation as a result of histone deimination. Pharmacological PAD inhibition significantly reduced HI brain damage.

Advanced endoscopic imaging: a review of commercially available technologies.

The rapid strides made in innovative endoscopic technology to improve mucosal visualization have revolutionized endoscopy. Improved lesion detection has allowed the modern endoscopist to provide real-time optical diagnosis. Improvements in image resolution, software processing, and optical filter technology have resulted in the commercial availability of high-definition endoscopy as well as optical contrast techniques such as narrow-band imaging, flexible spectral imaging color enhancement, and i-scan. Along with autofluorescence imaging and confocal laser endomicroscopy, these techniques have complemented and enhanced traditional white light endoscopy. They have the potential to serve as red-flag techniques to improve detection of mucosal abnormalities as well as allow optical diagnosis and virtual histology of detected lesions. This review will focus on these emerging commercially available technologies and aims to provide an overview of the technologies, their clinical applicability, and current status.

Association between thiopurine use and nonmelanoma skin cancers in patients with inflammatory bowel disease: a meta-analysis.

OBJECTIVES: Thiopurines are the mainstay of treatment for patients with inflammatory bowel disease (IBD). Thiopurine therapy increases the risk of nonmelanoma skin cancers (NMSCs) in organ transplant patients. The data on NMSC in patients with IBD on thiopurines is conflicting. METHODS: We searched electronic databases for full journal articles reporting on the risk of developing NMSC in patients with IBD on thiopurine and hand searched the reference lists of all retrieved articles. Pooled adjusted hazard ratios and 95% confidence intervals (CIs) were determined using a random-effects model. Publication bias was assessed using Funnel plots and Egger's test. Heterogeneity was assessed using Cochran's Q and the I(2) statistic. RESULTS: Eight studies involving 60,351 patients provided data on the risk of developing NMSC in patients with IBD on thiopurines. The pooled adjusted hazards ratio of developing NMSC after exposure to thiopurines in patients with IBD was 2.28 (95% CI: 1.50 to 3.45). There was significant heterogeneity (I(2)=76%) between the studies but no evidence of publication bias. Meta regression analysis suggested that the population studied (hospital-based vs. population-based) and duration of follow-up contributed significantly to heterogeneity. Grouping studies based on population studied and duration showed higher hazard rations in hospital-based and shorter duration studies. CONCLUSIONS: The risk of developing NMSC in patients with IBD on thiopurines is only modestly elevated. The difference in pooled risk between population-based and hospital-based studies suggests the possibility that ascertainment bias could have contributed to this increased risk.

The role of thiopurines in reducing the need for surgical resection in Crohn's disease: a systematic review and meta-analysis.

OBJECTIVES: The thiopurine (TP) analogs azathioprine and mercaptopurine have proven efficacy in inducing and maintaining clinical remission in Crohn's disease (CD). Their impact on the long-term need for surgery is uncertain since studies have reported conflicting results. The aim of this systematic review was to summarize and evaluate evidence of the published literature regarding those studies assessing the impact of TPs on the risk of first surgical resection in CD. METHODS: We searched Medline, EMBASE, CINAHL, and hand searched reference lists of identified articles, without language restrictions in August 2013. RESULTS: Seventeen retrospective observational studies (eight population based, three multicenter, and six referral center) representing 21,632 participants met our inclusion criteria. Of these 10 studies involving 12,586 participants provided data on the hazard ratio (HR) and 95% confidence intervals (CIs) evaluating use of TPs and surgical risk. The combined pooled HR of first intestinal resection with TP use was 0.59 (95% CI 0.48-0.73). CONCLUSIONS: TP use is associated with a 40% lowered risk of surgical resection in patients with CD. Despite significant reductions in rates of surgical resection in patients with CD over the last 5 decades and increasing use of TPs, a large proportion of patients with CD still require resectional surgery.

The impact of timing and duration of thiopurine treatment on first intestinal resection in Crohn's disease: national UK population-based study 1989-2010.

OBJECTIVES: The efficacy of thiopurines (TPs) in altering the risk of surgery in Crohn's disease (CD) remains controversial. We evaluated the impact of TP therapy, optimal timing, and duration of TP therapy on first intestinal resection rates using a population-based cohort. METHODS: We constructed a population-based cohort of incident cases of CD between 1989 and 2005. We used the Kaplan-Meier analysis to calculate time trends in TP use and first intestinal resection in three groups defined by time period of diagnosis: 1989-1993, 1994-1999, and 2000-2005 groups A, B, and C, respectively. We quantified impact of duration and timing of TP treatment on likelihood of surgery using Cox regression and propensity score matching. RESULTS: We identified 5,640 eligible patients with CD. The 5-year cumulative probability of TP use increased from 12, 18, to 25% ( P<0.0001) while probability of first intestinal resection decreased from 15, 12 to 9% (P<0.001) in groups A, B, and C, respectively. Patients treated with at least 6 months of TP therapy had a 44% reduction in the risk of surgery (hazards ratio (HR): 0.56; 95% confidence interval (CI): 0.37-0.85) and those receiving at least 12 months of TP therapy had a 69% reduction in the risk of surgery (HR: 0.31; 95% CI: 0.22-0.44). Early treatment (<12 months from diagnosis) vs. late treatment with TP showed no additional benefit in reducing risk of surgery (HR: 0.41; 95% CI: 0.27-0.61 vs. 0.21; 95% CI: 0.13-0.34). CONCLUSIONS: Over the past 20 years, TP use has doubled, whereas intestinal surgery has fallen by one-third among the UK population of Crohn's patients. Prolonged exposure is associated with a reduced likelihood of surgery whereby more than 12 months TP therapy reduces the risk of first intestinal surgery two-fold; however, early initiation of TP treatment offered no apparent additional benefit.

Chemical and biological methods to detect post-translational modifications of arginine.

Post-translational modifications (PTMs) of protein embedded arginines are increasingly being recognized as playing an important role in both prokaryotic and eukaryotic biology, and it is now clear that these PTMs modulate a number of cellular processes including DNA binding, gene transcription, protein-protein interactions, immune system activation, and proteolysis. There are currently four known enzymatic PTMs of arginine (i.e., citrullination, methylation, phosphorylation, and ADP-ribosylation), and two non-enzymatic PTMs [i.e., carbonylation, advanced glycation end-products (AGEs)]. Enzymatic modification of arginine is tightly controlled during normal cellular function, and can be drastically altered in response to various second messengers and in different disease states. Non-enzymatic arginine modifications are associated with a loss of metabolite regulation during normal human aging. This abnormally large number of modifications to a single amino acid creates a diverse set of structural perturbations that can lead to altered biological responses. While the biological role of methylation has been the most extensively characterized of the arginine PTMs, recent advances have shown that the once obscure modification known as citrullination is involved in the onset and progression of inflammatory diseases and cancer. This review will highlight the reported arginine PTMs and their methods of detection, with a focus on new chemical methods to detect protein citrullination.